Neurophysiology Markers of PTSD's Presence, Severity and Therapy Outcome
Conditions: PTSD
Sponsor: VA Office of Research and Development

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NCT04209387  
Project Title: Neurophysiology Markers of PTSD's Presence, Severity and Therapy 
 
 
 
 
 
HUMAN SUBJECTS RESEARCH PROTOCOL 
 
 
Protocol Version and Date: Version 9,  2/23/2023 
 
Principal Investigator: Mo Modarres, PhD 
 
Co-Investigators: 
Institution(s): Bedford ENRM VA Hospital 
 
1.0 
Objective and Specific Aims: 
This project evaluates novel PTSD biomarkers which are based on measures of coherent activity 
among the regions of cerebral cortex during sleep. In preliminary studies on EEG acquired during 
sleep from Veterans with PTSD alone as well as other co-morbidities, we have shown that the 
neuromarkers were highly sensitive/specific to the presence of PTSD, and highly sensitive to the 
severity of symptoms in PTSD group. 
The overall goal of this project is to further validate these novel neurophysiology markers 
in retrospective and prospective studies. The Overall hypothesis to be studied is as follows: 
 
Specific Aim 1: Formally establish the sensitivity/specificity of the novel PTSD neuromarkers by 
analyzing a large existing dataset 
Hypothesis 1.1: Neuromarkers can distinguish PTSD from non-PTSD groups with clinically 
acceptable sensitivity and specificity. 
Hypothesis 1.2: In PTSD group, Neuromarkers will strongly correlate with PTSD symptom 
severity and measures of functional outcome. 
 
Specific Aim 2: Evaluate improvement on the performance of the neuromarkers using a dense array 
EEG montage [Prospective Study 1] 
 
Specific Aim 3: Evaluate the sensitivity of Neuromarker to the improvements in PTSD symptoms 
Hypothesis 2: Neuromarkers will strongly correlate with the improvement of PTSD symptoms 
 
2.0 
Background and Significance 
2.1 Background 
Post-traumatic stress disorder (PTSD) is a chronic and disabling neuropsychiatric disorder that is 
characterized by severe sleep disturbances, avoidance behaviors, physiological hyper-arousal, and 
re-experiencing symptoms following exposure to a traumatic event [1]. Epidemiologic studies 
have shown that nearly 56% of people will experience a psychologically traumatic event and 
between 7-12% of individuals will meet criteria for PTSD during their lifetimes [2-5]. In the 
United States military, Veterans have an even higher risk of developing PTSD compared to the 

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civilian population, with the lifetime prevalence of PTSD estimated at 19% for Vietnam-era 
Veterans [6]. Similar patterns are observed among OIF/EIF Veterans: Approximately 17% of 
active duty soldiers and 25% of OIF met criteria for PTSD 3-6 months post-deployment [7]. 

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The current practice for diagnosing of PTSD primarily relies on subjective clinical assessments by 
the clinicians and patients’ self-reports. Subjective evaluation of PTSD symptom severity is also 
an integral part of the current treatment approaches for PTSD, which includes pharmacotherapy 
[8,9], prolonged exposure (PE) therapy [10-12], cognitive processing therapy (CPT) [10, 13,14], 
eye movement desensitization and reprocessing (EMDR) [12,15,16], and stress inoculation 
training [17,18]. An objective and neurophysiologically-based method for directly assessing brain 
function is desperately needed to improve diagnosis of PTSD and corresponding assessment of 
treatment response. 
This need is highlighted by the recommendations from the Institute of Medicine, National 
Academy of Science (IOM-NAS), which conducted a comprehensive assessment of the current 
PTSD diagnosis and treatment methods and identified potential shortcomings of the current 
diagnostic and treatment techniques [19]. A major recommendation by the IOM-NAS was to fill 
the urgent need for development of methods for the more precise and objective diagnosis of PTSD 
and its severity level, for the objective and faster evaluation of treatment efficacy, and for the 
ability to predict who might be at risk of relapse. 
Rationale and Novel Approach for Developing Neurophysiology Markers for PTSD 
A number of neuro-imaging studies using magnetic resonance imaging (MRI and fMRI) and 
positron emission tomography (PET) have reported altered brain activity in PTSD in the 
ventromedial prefrontal cortex (vmPFC), insula, amygdala, and hippocampus [20-23]. More recent 
evidence, however, suggest that abnormal network connectivity and communication is the 
underlying cause of PTSD. Bluhm et al. [24] reported diminished levels of connectivity between 
the posterior cingulate cortex and the right frontal cortex as well as the left thalamus in their PTSD 
group. Sripada et al. [25] reported a decrease in the rostral anterior cingulate cortex/vmPFC, and 
an increase in the salience network including the amygdala, during resting state MRI study. 
Our Approach: Based on the above findings, and supported by strong association between PTSD 
and sleep disturbances (reviewed in next paragraph), we hypothesized that a neuro-physiologically 
based marker, derived from dynamic measures of impaired synchronous activity among the 
regions of cerebral cortex during awake period prior to sleep onset and various stages of sleep, 
could be utilized for the objective assessment of PTSD presence and severity, as well as a potential 
predictor of treatment response. We tested this hypothesis by developing markers based on the 
relative level of coherent electroencephalograph (EEG) between various cortical regions in 
specific frequency bands and during sleep. 
The selection of sleep as the test condition was motivated by the extraordinarily high prevalence of 
sleep disturbances in individuals with PTSD, to the point that some have proposed that sleep 
disturbances are a hallmark feature of the disorder [31-42]. Over 70% of civilians and Veterans 
with PTSD have reported persistent and severe nightmares and disturbed sleep [33]. 
2.2 Preliminary Studies 
In preliminary studies on EEG acquired during sleep from Veterans with PTSD alone (n=38), TBI 
alone (n=30), PTSD and TBI (n=25), and an aged matched no PTSD or TBI control group (n=38), 
we have shown that a set of neuromarkers were highly sensitive/specific to the presence of PTSD, 
and highly sensitive to the severity of symptoms in PTSD group. 
The PTSD neuromarkers of this project are built from combination of regional brain coherence 
markers (BCM). BCM computation is based on the levels of coherence and synchronicity between 
pairs of scalp EEG activity. These coherence values were computed for the entire sleep study using 

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5-second sliding windows that were overlapped by 1 second. The frequency band spanned from 
0.2 Hz to 50 Hz with a resolution of 0.2 Hz. Vectors of BCM were constructed over each of the 
five stages of sleep study (Awake [W], Rapid Eye Movement [REM], non-REM [NREM] stages 
N1, N2, and N3). Our analysis showed that the markers computed in awake and stage N2 sleep 
were significantly different in PTSD than the control group and also produced the highest level of 
correlation with the PTSD symptom. 
The following figure shows the excellent capability of the PTSD diagnostic Neuromarker 
(PTSDdx) and PTSD severity marker (PTSDsev) in differentiating Controls from PTSD, and in 
correlation with symptoms, respectively. 
 

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2.3 Significance 
The goal of this project is to develop a much-needed objective biomarker in PTSD that will allow 
more accurate treatment choices and faster evaluation of treatment response for Veterans with 
PTSD. However, current clinical practice is based on subjective assessments and it lacks 
“objective” PTSD diagnostic and assessment methods based on underlying brain mechanisms of 
dysfunction. We propose to use quantitative EEG, a non-invasive, cost-effective, totally portable 
procedure, to precisely measure activity and connectivity between different parts of the brain 
during awake and sleep states in Veterans with and without PTSD. If successful, these objective 
neuromarkers can be used not only for more accurate detection of the presence and severity of 
PTSD, but also for a faster and more accurate evaluation of response to current therapy, informing 
the potential need to switch interventions, and identifying those at high risk for relapse. 
 
3.0 
Research Design and Methods 
3.1 Drug/Device Information 
For EEG sleep studies of the project, LiveAmp EEG hardware 
attached to electrode cap (Fig. 1-HS) from Brain Products 
GmbH, Germany will be used. Such devices are battery- 
operated and routinely used at the sleep laboratories and 
patient’s home for the clinical/research assessment of sleep and 
neurological disorders. 
3.2 Type of Study 
This project consists of three type of studies: 
 
Study 1. This is a retrospective study. At ENRM VA, the 
Neuromarker analyses will be applied to a large existing database (n=656) containing sleep EEG 
recordings along with health and functional outcome measures, from Veterans with PTSD only 
(n=107), TBI only (n=126), both PTSD and TBI (n=87), depression only (n=80), and controls (no 
PTSD/TBI/Depression; n=256). 
 
Study 2. This is a prospective pilot study at ENRM VA that will be conducted to evaluate 
potential improvement on the performance of the Neuromarkers using a dense array (up to 64 
channels) EEG montage that covers all areas of the brain and with greater resolution, as 
compared to the original 6-channel EEG protocol. The sample will include up to 25 PTSD and 
control subjects. 
 
Study 3. This is a prospective study conducted at ENRM VA on a single cohort of up to 55 
Veterans with PTSD at multiple times during their ongoing clinical treatment for PTSD at the 
ENRM VA. Night time sleep EEG measures will be collected at pre-treatment, after first session 
of therapy, immediately after completion of therapy, and at 3-month post therapy. Measures of 
PTSD symptom severity, as well as measures of health and functional outcomes will be collected 
at the beginning and completion of therapy. 
 
3.3 Study Procedures 
 
Retrospective Study. At ENRM VA, we will perform secondary analysis on a database of 
Veterans who have previously consented and enrolled in the VA Portland Health Care System 
Sleep Laboratory Data Repository (IRB #3636, “Sleep Disorders Data Repository”). The director 
 
 
 
 
 
 
 
 
 
 
 
Figure 1-HS.Wearable 64 channel 
EEG sleep device from BrainProducts 
corp. 

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of this data repository, Dr. Miranda Lim, is a co-Investigator on this proposal. Study 
inclusion/exclusion criteria are as follows: Referral to the VA Portland Sleep Lab for a sleep 
evaluation; Able to understand the purpose of the data repository and provide verbal and written 
consent. 
The data repository contains sleep polysomnography (PSG) recordings from a multitude of 
electrophysiological (including EEG) and cardio-respiratory sensors/electrodes that are monitored 
during the overnight clinical sleep study. Other types of information residing in the database 
include demographic information, medical history (including diagnosis and treatment history of 
PTSD, TBI, substance use). All subjects in the data repository have undergone baseline clinical 
intake evaluation consisting of 7 validated symptom surveys scored that use Likert scales: (1) 
Epworth Sleepiness Scale (ESS, 8 item): Assesses degree of excessive daytime sleepiness; (2) NIH 
PROMIS Global Health (NIH-PGH, 9 item): Assesses general physical, emotional, social health, 
activities of daily living, fatigue; (3) Insomnia Severity Index (ISI, 7 item): Quantifies difficulty in 
falling asleep, staying asleep, and impact upon daily functioning; (4) Functional Outcomes of 
Sleep (FOSQ-10, 10 item): Assesses degree of difficulty carrying out certain activities due to 
sleepiness; (5) Patient Health Questionnaire (PHQ-9, 9 item): Used in screening, diagnosis, 
monitoring and measuring of severity of depression; (6) PTS symptoms checklist (PCL-5, 20 
items: Assesses the 20 items in the DSM-V criteria for PTSD; (7) Rivermead Post-concussive 
Symptoms Questionnaire. 
Polysomnography (PSG). Participants underwent in-lab overnight sleep study, which was followed 
by performing standard sleep staging by a registered PSG technician and interpreted by a Board- 
certified sleep physician. The database contains sleep EEG recordings from Veterans with PTSD 
only (n=107), TBI only (n=126), PTSD and TBI (n=87), depression only (n=80), and controls (no 
PTSD/TBI/Depression; n=256). 
De-identification and Data Transfer to ENRM VA: The PSG recordings in the data repository, 
comprised of electrophysiological measures (such as EEG, EOG, EMG) will be exported to a 
binary format and will be completely stripped of any identification marks and will be saved with 
coded filenames. A separate text file containing epoch by epoch (30 second duration) sleep stages 
will be also generated for each sleep study with no patient’s identification inside the file nor as part 
of the filename. Other de-identified data includes a spreadsheet with demographic information and 
survey data from Table 1. The de-identified data will be transferred from Portland VA to ENRM 
VA via a shared network folder with limited access permission. 
 
Prospective Study I. The retrospective study of the existing database is from clinical sleep studies 
where 6 EEG electrodes, covering the occipital, central, and frontal lobes of the two hemispheres, 
were used. This is because all sleep states can be scored by these limited number of electrodes. 
However, using these 6 EEGs limits the coherence analysis to general areas of the frontal, central, 
and occipital lobes and with no direct representation for other areas of the brain. The aim of this 
prospective study is to evaluate potential improvement on the performance of the Neuromarkers 
using a dense array (up to 64 channels) EEG montage that covers all areas of the scalp. In the 
control and PTSD subjects, we will perform sleep studies using a dense array EEG montage and 
will compare the performance of the Neuromarkers in distinguishing PTSD from non-PTSD 
groups. 
This entails starting with the coherence analysis based on the six electrodes used in the preliminary 
study followed by evaluating the nominal improvement in discrimination ability (PTSD vs. 
absence of PTSD) with the use of extra channels. The control subjects will be recruited by 

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advertising in the Bedford VA common areas, and by distributing informational flyers via VA 
providers, Veteran organizations, and other Veteran networks (including Veteran Services 
Offices, Veteran Centers, CBOC’s, and other programs). We may also place an advertisement 
on Craigslist. Eligible Veterans will be able to self-refer to be screened for the study. The PTSD 
group will be recruited from Veterans undergoing treatment of PTSD at ENRM VA before the 
start of their treatment (Veterans with PTSD recruitment described in Section 4.2.3). 
Depending on the outcome of this study and the amount of potential improvements that might be 
achieved using a denser EEG arrays, we will identify the exact montage to be used in the follow- 
up prospective study with PTSD patients undergoing psychotherapy. We will thus start with the 6- 
channel EEG of the standard clinical sleep study, and potentially expand it by including more EEG 
locations to presumably produce results that are superior (more precise) to those obtained in 
preliminary studies 
 
Prospective Study II. Up to sixty (60) Veterans with PTSD symptoms undergoing treatment at 
the ENRM VA will be recruited by the Research Coordinator. The study protocol will be 
explained to potential subjects which will be given ample time to consider their participation in 
the study and ask any questions they may have. They may take it home with them if they need 
more time and then return to the PTSD clinic. If the Veteran agrees to participate, they will sign 
all informed consent documents and be given a copy to retain. All protocols and informed 
consents related to this project will be approved by the ENRM VA Institutional Review Board 
(IRB). 
 
3.4 Data Collection 
Sleep Study: EEG data acquisition: Study protocol with respect to overnight sleep study will 
consist of patients wearing an ambulatory home sleep monitoring device, LiveAmp from 
BrainProductsCorp. LiveAmp has a small footprint and can record up to 64 unipolar channels where 
On the days of the sleep studies and supported by the biomedical engineer, the research health 
specialist of the project will attach the EEG electrodes to the scalp and will demonstrate to the patient 
as how to attach/detach the EEG electrodes to/from the device as well as how to turn the device on 
and off when in bed at night, and after waking up in the morning, respectively. 
Patients will be instructed on how to wear the cap and attach it to the device while sleeping in their 
own bed. Furthermore, Over-night live support will be available where the patient will be 
reminded via phone call to start the study. The patients can also call the technician during the night 
in case of any difficulty with the continuation of the study. The device will be retrieved the next 
day after the study when we will examine the quality of the quality of the acquired signals. 
These sleep studies will be performed at 4 points of time during their course of the treatment 
Study Visit 1. Within one week before initiation of their treatment protocol, to capture sleep EEG 
data representing pre-treatment phase 
Study Visit 2 Within one week after their first therapy session to capture the data and BCM that 
could be used for the development of early predictor of response to treatment. 
Study Visit 3 Immediately a at the conclusion of their treatment phase, to capture the data 
representing recovery from PTSD symptoms. 
Study Visit 4 About three months after their last therapy sessions, to capture the data associated 
with possible remission or relapse. 

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Screening Questionnaires:  
(S-1): Montreal Cognitive Assessment (MoCA) [79]: the MoCA is a brief neuropsychological 
screening measure that will be used to assess participants’ general cognitive status. In order to better 
account for possible neurodegenerative disorders, we will be using the MoCA to assess cognitive 
functioning in Veterans older than 65. Veterans who score 26 or higher on the MOCA will be 
considered eligible to participate in the study.  
Demographic, PTSD Questionnaires and Quality of Life Surveys : Data collection protocol will 
consist of administrating the following: 
(D-1): Demographic, Medical History, and Use of Medications forms: Demographic data to be 
collected will include self-reported age, gender, race, ethnicity, and employment status. Other 
baseline variables will include time from most recent prior event to screening contact, other 
traumatic life events and timing, prior history of mental health treatment, and current medications. 
(D-2): The Beck Depression Inventory (BDI-II) [56]: BDI_II 21-item self-report multiple-choice 
inventory and is composed of items relating to symptoms of depression such as hopelessness and 
irritability, cognitions such as guilt or feelings of being punished, as well as physical symptoms 
such as fatigue, weight loss, and lack of interest in sex [67]. The test takes about 10 minutes to 
complete. 
(D-3): Pittsburgh Sleep Quality Index (PSQI) [57]: The 15-item PSQI measures quality and 
patterns of sleep in adults. It takes an estimated 3 to 6 minutes to complete. A global PSQI score 
greater than 5 has yielded a diagnostic sensitivity of 89.6% and specificity of 86.5% (kappa = 0.75, 
p<0.001) in distinguishing good and poor sleepers. Internal consistency reliability has been 
estimated to range from .77 to .81. 
(D-4): Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) 
[58] The Q-LES-Q-SF is a self-reported questionnaire that is among the most frequently used 
outcome measures in psychiatry research (e.g., in clinical trial of PTSD treatment with psycho- 
therapy methods, [59]). The 16-item Q-LES-Q-SF evaluates overall enjoyment and satisfaction 
with physical health, mood, work, household and leisure activities, social and family relationships, 
daily functioning, sexual life, and economic status. 
(D-5): Patient-Reported Outcomes Measurement Information System® (PROMIS)-29:The 
publicly available PROMIS instruments contain a fixed number of items from seven PROMIS 
domains: depression; anxiety; physical function; pain interference; fatigue; sleep disturbance; and 
ability to participate in social roles and activities. The PROMIS-29, a generic health-related quality 
of life survey, assesses each of the 7 PROMIS domains with 4 questions. The questions are ranked 
on a 5-point Likert Scale. 
(D-6): PTSD Patient Checklist (PCL-5) [52]: PCL-5 is the revised version of PCL-M used in the 
preliminary studies, where a 20-item self-report assesses the 20 DSM-5 symptoms of PTSD 
(corresponding to criteria B-E in the above; total symptom severity score ranging from 0 to 80). 
According to PCL-5 [52], the current estimate for PCL-5 diagnostic cut-point for PTSD is 33 
(compared with a value of 50 used for PCL-M of the preliminary studies). Also, similar to PCL-M, 
it is expected that a change of 10 points in PCL-5 is to be considered as a minimum threshold for 
clinically meaningful improvement [52]. 
(D-7): Clinician-Administered PTSD Scale (CAPS-5) [55]: CAPS-5 is a 30-item structured 
interview and is considered the gold standard in PTSD diagnostics and evaluations. It consists of 
20 questions to assess the four DSM-5 [53] PTSD symptom clusters: Criterion B: Presence of one 

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(or more) of intrusion symptoms associated with the traumatic event (Items 1-5); Criterion C: 
Persistent avoidance of stimuli associated with the traumatic event (Items 6-7); Criterion D: 
Negative alterations in cognitions and mood associated with the traumatic event (Items 8-14); 
Criterion E: Marked alterations in arousal and reactivity associated with the traumatic event (Items 
15-20). CAPS-5 uses a five-point symptom severity rating scale for all symptoms: (0) Absent; (1) 
Mild/Subthreshold, (2) Moderate/threshold, (3) Severe, and (4) Extreme/incapacitating. 
 
 
(D-8): Patient Health Questionnaire-9 (PHQ-9) [70]: The PHQ-9 is the depression segment of the full 
 
PHQ, which scores each of the DSM05 criteria for Major Depressive Disorder (MDD). Items ask about 
 
depressive symptoms experienced over the last two weeks and each of the nine items are scored as “0” 
 
(not at all), “1” (several days), “2” (more than half the days), or “3” (nearly every day). A total severity 
 
score ranges between 0 and 27 points and indicates none to minimal depression (0-4), mild 
 
depression (5-9), moderate depression (10-14), moderately severe depression (15-19), and severe 
 
depression (20+).  
 
 
 
(D-9): Columbia Suicide Severity Rating Scale (CSSRS) [71]: The CSSRS is a state-of-the-art suicide 
 
measure that assesses the severity of suicidal ideation for both lifetime and current (i.e., the last 30 days) 
 
time frames. Severity of suicidal ideation is rated on a 6-point scale ranging from no suicidal ideation (0) 
 
to active suicidal ideation with specific plan and intent (5). Additionally, the measure assesses lifetime 
 
and current suicide attempts. The CSSRS demonstrates good internal consistency [72].  
 
 
(D-10): Brief Addiction Monitor (BAM) [73]: The Brief Addiction Monitor is a 17-item measure of 
 
addiction severity.  
 
 
(D-11): Brief Pornography Screener (BPS): Brief Addiction Monitor (BAM) [74]: The BPS is a 5-
 
item measure developed to detect problematic use of pornography among clinical and non-clinical 
 
samples. Only those endorsing use will complete the screener.  
 
 
(D-12): NORC Diagnostic Screen for Gambling Disorders (NODS) Control, Lying, and 
 
Preoccupation (CLiP) [75]: This is a 3-item diagnostic interview instrument for adult problem gambling 
 
and gambling disorder. Only those endorsing use will complete the screener.  
 
(D-13): Adult ADHD Self-Report Scale (ASRS-v1.1) [76, 77]: This is an 18-item self-report measure 
that evaluates adult ADHD. The ASRS is a highly reliable and valid scale that has also been shown to 
have high concurrent validity with the rater-administered version. Each item on the checklist is rated 
either “never”, “rarely”. “sometimes”, “often”, or “very often” (76, 77, 78). This screening measure will 
be used at baseline only.  
 
 
 
 

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Table 1 depicts the data collection 
instruments and the study times. 
D1-D13 will be administered 
on the same days of the EEG 
sleep studies. 
Data Collection  
Instrument and 
Measures 
PTSD Subjects  
Study 
Visit 1 
Study 
Visit 2 
Study 
Visit 3 
Study 
Visit 4 
Demographics 
D-1 
X 
BDI-II 
D-2 
X 
X 
X 
PSQI 
D-3 
X 
X 
X 
Q-LES-Q-SF 
D-4 
X 
X 
X 
PROMIS-29 
D-5 
X 
X 
X 
PCL-5 
D-6 
X 
X 
X 
CAPS-5 
D-7 
X 
X 
PHQ-9 
D-8 
X 
X 
X 
CSSRS 
D-9 
X 
X 
X 
BAM 
D-10 
X 
X 
 
BPS 
D-11 
X 
 
 
NODS-CliP  
D-12 
X 
 
 
ASRS 
D-13 
X 
 
X 
X 
EEG Sleep Study 
X 
X 
X 
X 

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3.5 Analysis Plan 
Hypothesis 1.1 PTSDdx will discriminate PTSD patients from control subjects without PTSD; 
The primary evaluations will be based on computation of PTSDdx and PTSDsev markers similar to 
the approach used in preliminary studies. This will occur in multiple phases, all of which will 
randomly divide and analyze the full sample of 656 veterans into 3 groups of 219, 219, and 218 
subjects, and in proportion to the presenting symptom/condition status of veterans, as follows: 
Condition 
(Group) 
Total N 
Subsample 
Sample 1 
Sample 2 
Sample 3 
PTSD only 
(group A) 
107 
36 
36 
35 
TBI only 
(group B) 
126 
42 
42 
42 
PTSD & TBI 
(group C) 
87 
29 
29 
29 
Depression only (group D) 
80 
26 
27 
27 
Controls (no PTSD, TBI, depression) 
(group E) 
256 
86 
85 
85 
 
To test our first hypothesis and in the first phase of analysis, we will use the specific PTSDdx 
neuromarker previously identified in our preliminary study of 76 veterans, and evaluate it 
separately in all 3 subsamples. Analysis of covariance (ANCOVA) will be used to compare 
adjusted mean PTSDdx scores between the PTSD only group (Group A) vs. planned contrasts with 
the remaining 4 groups. The a-priori-defined contrasts will consist of the following 5 comparisons: 
A vs. E, A vs. B/C/D combined, A vs. B, A vs. C, and A vs. D. Thus, for each subsample, there 
will be 5 planned comparisons, and hence a total of 15 comparisons. We expect the largest 
differences in mean PTSDdx scores between PTSD only (group A) and controls (Group E), but 
nonetheless, also expect the PTSD only group to have higher mean PTSDdx scores than Groups B, 
C, and D. 
In these analyses, models will be adjusted for potential confounding variables (e.g. current use of 
sleep medications) identified by use of student t-tests (or Wilcoxon tests) for continuous variables 
and chi-square tests for categorical variables. Given the 5 planned comparisons for each 
subsample, a modified p-value of 0.01 will be used to define statistical significance. While 
arbitrary, “validation” of the previously identified PTSDdx neuromarker will be based on statistical 
significance as follows: (i) all 3 comparisons of Group A vs. Group B at p<0.01, AND at least 9 of 
the 12 remaining comparisons at p<0.01. 
In the second phase of this hypothesis, the approach used to identify the most promising PTSDdx 
neuromarker described in Preliminary Studies will be applied to the much larger dataset of 656 
veterans. For this analysis, Subsamples 1 and 2 will serve as training (development) samples, and 
Subsample 3 will serve as the validation sample. For subsample 1, ANCOVA will again be used to 
identify the 5 most promising PTSDdx neuromarkers (based on corresponding F and p-values) rank 
ordered across the 5 planned comparisons described above. This process will be repeated for 
Subsample 2. From these results, the most promising PTSDdx neuromarker will be selected based 
on the lowest aggregate rank scores across both subsamples and across all 5 planned comparisons. 
Once this this PTSDdx neuromarker is identified, it will be formally tested using the 5 defined 
planned comparisons within Subsample 3, and again using a p-value of <0.01 to define statistical 
significance. In aggregate, these analyses will determine whether the originally identified PTSDdx 
neuromarker can discriminate between veterans with and without PTSD, and whether a potentially 

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more promising PTSDdx neuromarker is identified. 
Hypothesis 1.2: PTSDsev will strongly correlate with PTSD symptom severity level 
Using the same database as in retrospective study and focusing only on PTSD subjects, an 
analogous approach to that described for hypothesis 1.1 will be used. The principal difference will 
be that the independent variable, PTSDsev, is a continuous variable rather than a categorical 
variable. Therefore, multiple linear regression will be used with PTSDsev as the independent 
variable, and the PCL-5 symptom severity scale as the dependent variable acquired on the day of 
the sleep study. We will also examine the correlation of PTSDsev with the other measures of quality 
of health and life in the database, particularly RQP (Rivermead Post-Concussive Symptom 
Questionnaire), PHQ-9 (Patient Health Questionnaire), FOSQ (Functional Outcome of Sleep 
Quality), ISI (Insomnia Severity Index), and Promis-29. The results of these analyses will provide 
a comprehensive examination of this hypothesis with respect to how accurately PTSDsev can 
determine the severity of PTSD, and how well it is correlated with quality of life measures. 
Hypothesis 2: Use of a dense array (up to 64 channel) EEG montage, as compared to 6-
channel EEG, will improve discrimination of PTSD patients from control subjects 
without PTSD. 
For this analysis, the most promising PTSDdx neuromarker identified in Hypothesis 1.1 (phase 2 
development and validation analysis) will be prospectively evaluated in up to 25 PTSD and 
control subjects. First, a standardized effect size (mean difference / standard deviation) and 
corresponding 95% confidence interval will be calculated for the PTSDdx neuromarker using the 
conventional 6- channel EEG approach. Then, using forward stepwise linear regression, extra 
EEG electrodes whose addition increases the model coefficient of determination (R2) by at least 
1% will be included as candidate extra EEG channels. Once a final model is fit (with >6 
electrodes), the corresponding standardized effect size and 95% confidence interval will be 
calculated. Given the pilot nature and sample size for this analysis (n=25), interpretation will not 
be based on formal statistical testing, but rather on the difference in the two effects sizes generated 
from the 6-channel EEG analysis vs. the >6-channel EEG analysis. Given that effect sizes can be 
interpreted as “small” (0.2), “medium” (0.5), or “large” (>0.8), we will use half of the width of 
adjacent categories (i.e. 0.15) to interpret meaningful improvement with the use of more than 6 
EEG channels. For example, if the standardized effect size for the 6-channel EEG was 0.70, the 
>6- 
channel EEG effect size would need to be >0.85 to indicate meaningful improvement and potential 
indication for a more complex EEG testing approach. 
Hypothesis 3: PTSDsev will strongly correlate with the changes of PTSD symptoms and other 
measures of Quality of Health and Life as a result of psychotherapy. 
For this analysis, change in PTSDsev identified from Aim 1 is the primary independent variable of 
interest and change in CAPS-5, PCL-5, BDI-II, Q-LES-Q-SF, and PSQI serve as dependent 
variables. Since the CAPS-5 will be administered at only 2 time-intervals, multiple linear 
regression analysis will be used adjusting for baseline CAPS-5 score and CAPS-5 score after 
treatment as the dependent variable. For the PCL-5, BDI-II, Q-LES-Q-SF, and PSQI there will be 
4 outcome measurements corresponding to pre-treatment, within one week after the initiation of 
therapy, at the completion of treatment, and at three-months post therapy. For these measures, 
linear mixed models will be used to examine the strength of association between the slope 
(change) for PTSDsev and the slope for the dependent variables (evaluated in separate models). To 
assess if the rate of change is curvilinear, a quadratic parameter will be tested. Due to multiple 

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observations per subject, an autoregressive correlation structure will be specified to account for 
within-subject correlation. Also, given 5 outcome variables of interest, a “corrected” p-value of 
<0.01 will be used to define statistical significance. 
 
4.0 
Human Subjects 
 
4.1 General Characteristics 
The project has three groups of human subjects’ involvement: 
1. A retrospective study, where the analyses will be applied to a large existing database of 
health-related and functional outcome measures, as well as sleep EEG recordings. Database 
contains sleep EEG recordings from Veterans with PTSD only (n=107), with TBI only 
(n=126), with both PTSD and TBI (n=87), with depression only (n=80), and controls (no 
PTSD/TBI/Depression; n=256. The inclusion of records from TBI and depression only 
groups is to provide training data for the neuromarker to become maximally sensitive and 
specific to PTSD in the presence of co-morbidities such as depression and TBI. 
2. Prospective study 1 with up tp 25 PTSD and control PTSD (n=10) and control (n=10) where 
we will evaluate potential improvement on the performance of the neuromarkers using a 
dense array (up to 64 channel) EEG montage. For each participant, we will perform 2 sets of 
sleep studies that will be at least one week apart. 
3. Prospective study 2 in a cohort (n=60) of Veterans undergoing psychotherapy, where we 
will evaluate the sensitivity of neuromarkers to the improvements in PTSD symptoms, and 
other functional and HRQoL measures, in response to psychotherapy. These participants 
will undergo sleep studies at four times of time (a) Within one week before initiation of their 
treatment protocol; (b) Within one week after their first therapy session; (c) at the 
conclusion of their treatment phase; and (d) About three months after their last therapy 
sessions 
 
4.2 Inclusion of Vulnerable Subjects 
Vulnerable subjects will be enrolled in this study. These subjects are part of VA population 
and will not be specifically recruited. 
 
4.3 Inclusion of Pregnant Women 
Pregnant women will not be included in this study 
 
4.3 Inclusion of Incompetent Subjects 
We will not enroll incompetent subjects in this study 
 
4.4 Inclusion/Exclusion Criteria 
Inclusion Criteria. Veterans who meet diagnostic criteria for PTSD. Prior traumatic experience(s) 
does not have to be direct combat (e.g. may include search and rescue of combat operations). 
Persons previously treated for PTSD will be eligible so long as current diagnostic criteria are 
present. Specific inclusion criteria are as follows: 
1. Adults aged 18 and older:  In order to better account for possible neurodegenerative 
disorders, we will be using the MoCA to assess cognitive functioning in Veterans older 
than 65. Veterans who score a 26 or higher on the MoCA will be considered eligible to 
participate in the study. 

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2. Current (past 3 months) diagnosis of PTSD as indicated by medical record review. 
3. Ability to read and speak English to complete surveys and participate in therapy. 
4. Explicit denial of suicidal or homicidal ideation or intent, which will be corroborated by 
reviewing the patient chart 
 
Exclusion Criteria: 
1. Brain injury prohibiting speech, writing, and purposeful actions. 
2. Identified to have current suicidal or homicidal ideation (immediate referral to a crisis 
center/hospital). 
3. Major confounding psychiatric disorder; i.e. assessment indicates presence of: 
(i) Major mental health disorder that involves psychosis; or 
(ii) Otherwise in the state of psychological crisis (appropriate referral to occur). 
4. Current or recent (within 1 month of study entry) DSM-5 substance use disorder.  
5. Individuals who are taking either illicit or prescribed Rx that could interfere with EEG, 
including benzodiazepines and certain mood stabilizers. This will be done by (a) asking what 
medications they are taking  and (b) checking their medical records while screening for 
possible participants. 
 
4.5 Recruitment Procedures 
To reach the larger population of Veterans, one recruitment strategy will consist of the distribution 
of informational flyers via VA providers, Veteran organizations, and other Veteran networks. 
Research study staff will also give recruitment presentations to primary care providers, mental 
health clinicians, and other providers at the Bedford VA to enhance recruitment. This will only 
take place with the proper approvals from local VA- and non-VA programs that support Veterans 
(including Veteran Services Offices, Veteran Centers, CBOC’s, and other programs). Additionally, 
at Crossroads events in the ENRM VA Hospital, too, information (e.g., flyers) about the present 
study and other investigators’ studies will be distributed at a table in a highly frequented area of 
the hospital. Eligible Veterans will be able to self-refer to be screened for the study. 
 
In addition, the recruitment process will include the following: 
The names of Veterans coming to the following clinics at ENRM VA for appointments: Tobacco 
Cessation Program, Veterans Community Care Center (VCCC), Mental Health Clinic (MHC), the 
Community Stabilization Program (CSP), Primary Care Behavioral Health (PCBH), the 
Community Residential Center (CRC), and the VASH program. 
 
These names will be obtained by searching CPRS for entry/provider codes associated with these 
programs. Research Study Staff will access these Veterans’ medical records only to determine 
whether they meet the study eligibility criteria for psychiatric diagnosis/ suicidal intent. 
 
We will then send a letter to the Veteran to invite him/her to learn more about the study (attached 
to this application) and will also include the recruitment flyer (will be presented to the IRB 
committee before the start of recruitment of the first subject). The letter will contain contact 
information for the research team, so the veteran can contact the research team for more 
information. It will state that if we don’t hear from the Veteran within two weeks, that we will call 

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and contact them about the study. It will also state that if Veterans do not want to be called, they 
can call our research staff and let us know. The identifiable information will be used only by 
members of the research team. This information will not be disclosed to anyone outside the VA. 
 
4.5.1 Subject Identification and Pre-Enrollment Screening: 
Callers will first be provided information about the study purpose and procedures and given 
time to ask all questions they may have. If the Veteran is interested in the study, a screening 
will take place using a brief screening assessment. Eligible participants will be scheduled to 
meet with the PI or study staff, who will obtain informed consent from the interested 
participants. 
 
4.5.1a  Use of PHI for Recruitment and/or Screening before consent is 
obtained: 
Our protocol will request a waiver of HIPAA authorization for recruitment and 
screening purposes. 
 
4.5.1 b Consent for Recruitment and/or Screening: 
Our protocol will request a waiver for informed consent for recruitment and 
screening purposes. 
 
4.5.2 
Enrollment: 
At initial assessment (Study Visit 1) research study staff will discuss the study and consent 
with the potential participant and allow the subject unlimited time to decide to participate. 
Confidential spaces will be acquired for an initial in-person interview and consenting 
procedure, to be conducted at the Bedford VA. 
 
4.5.2a HIPAA Authorization: 
Potential subjects will sign a freestanding authorization form. 
 
4.5.2b Informed Consent: 
Participants will sign a consent form. Research Coordinator. The study protocol 
will be explained to potential subjects which will be given ample time to 
consider their participation in the study and ask any questions they may have. 
They may take it home with them if they need more time and then return to the 
PTSD clinic. If the Veteran agrees to participate, they will sign all informed 
consent documents and be given a copy to retain. All protocols and informed 
consents related to this project will be approved by the ENRM VA Institutional 
Review Board (IRB). 
4.5.2c Master List 
The subject’s name will be added to the master list immediately after consent. 
Master list will be maintained in a double lock procedure: locked in a cabinet 
located within a locked office. 
 
4.5.2d 
VHA health record will not be created 
 

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4.5.2e Certificate of Confidentiality 
A certificate of confidentiality is not needed for this research. 
 
4.6 Risk/Benefit Ratio 
4.6.1 Potential Risks and Methods to be Used to Minimize Risks: 
Potential Risks: PTSD is a disabling anxiety disorder with high rates of comorbid disabling 
symptoms including sleep disturbance, depressive disorders, panic disorder, substance misuse 
or dependence, high somatic symptom severity, decreased role functioning, and an increased 
risk of suicidal behavior. Left untreated, PTSD can persist for decades if not over an entire life 
span. Thus, any therapy that can be delivered safety and effectively in the treatment of PTSD 
offers substantial potential benefit to the affected individual. 
Participation in the study carries the risk of unanticipated breach of confidentiality. With 
regards to EEG sleep studies, the proposed method of acquiring Neuromarkers in the PTSD 
subjects involve LiveAmp hardware from Brain Products GmbH, Germany during an 
overnight home sleep study. Such devices are battery-operated and routinely used at the sleep 
laboratories and patient’s home for the clinical/research assessment of sleep and neurological 
disorders. Potential risk could possibly be minor skin irritation associated with wearing the 
electrode cap the attachment/detachment of EEG electrodes which will be minimized by 
following routine clinical sleep study procedures. 
 
Risk of COVID-19 exposure: Coming into the hospital/lab for a research EEG test may 
increase the risk of COVID-19 exposure. The exposure risk would be the same with clinical 
EEG appointments and we are taking the necessary precautions to minimize this risk (see 
below).  
 
Protection Against Risks 
(1) 
Retrospective studies, confidentiality is protected by storage of all study PSG records and 
questionnaires behind a VA firewall and accessed by permission and password. The PSG 
recordings in the data repository, comprised of electrophysiological measures (such as EEG, 
EOG, EMG) will be exported to a binary format and will be completely stripped of any 
identification marks and will be saved with coded filenames. These de-identified PSG records 
will thus be converted to a series of numbered binary files containing a matrix of the raw data 
(EEG/EOG/EMG in microvolts) with no patient identification associated with the file. A 
separate text file containing epoch by epoch (30 second duration) sleep stages will be also 
generated for each sleep study with no patient’s identification inside the file nor as part of the 
filename. Other de-identified data includes a spreadsheet with demographic information, 
survey data from Table 1, and information about PTSD therapy. The de-identified data will be 
transferred from Portland VA to ENRM VA via a shared network folder between the two VAs 
and limited access permission. 
(2) 
Prospective Studies: Risk, confidentiality, and data security will be minimized via use of 
good clinical practices including recording, storage, transfer, and analysis on de-identified data 
files extracted from sleep records and D1-D6 surveys, locking all data files, use of a subject 
identification code system, maintenance of data only on a secure system, and recording data 
without HIPPA identifiers. Subjects will be able to terminate the testing at their request at any 
time without prejudice. Study information will be entered into the password protected 
database accessible via secured-internet connection. The database sits behind VA firewall on a 
secure VA server and will utilize whole database encryption technology. Only registered users 

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will be assigned a password to access the database for online data entry or data transfer. When 
study personnel leave the study, their access to the study materials and database will be 
terminated. Instruments D1-D13 will be recorded on laminated paper data collection forms 
with a permanent marker and responses will be directly entered into the REDCap site for the 
project. Laminated forms will be erased and sanitized with an alcohol wipe after data has been 
entered. Informed consent forms will be kept in locked file cabinets at ENRM VA. 
(3) 
Protection against risk of COVID-19: Lab staff will be tested for COVID-19 on a bi-
weekly basis and will be in full appropriate PPE (including mask, face shield or goggles, 
gown, and gloves) during all in-person interactions. Before arriving on campus, participants 
will be given updated hospital policies, the link to the hospital screening questions, and a map 
with the most direct route to the lab. Upon arrival in the lab, Veterans will be given a surgical 
mask and hand sanitizer. Lab staff will ask the Veteran the screening questions again and take 
their temperature to ensure safety before entering the lab for the research assessment. The lab 
space and all surfaces and equipment will be thoroughly cleaned and sanitized before and after 
each visit. This plan was developed following the guidelines of labs currently conducting 
clinical EEG assessments at VA hospitals.  
 
4.6.2 Data and Safety Management Plan: 
 
The sleep studies protocol of this project coincides with the duration of PTSD treatment which 
can last as long as 12 sessions over several weeks/months. Subjects would therefore be 
monitored by the clinicians before and after the patients undergo their home sleep study (as 
part of their routine therapy). Patients will be advised to contact the PTSD clinic-clinical 
coordinator immediately in the event of any unforeseen difficulties with wearing the device 
during sleep including excessive interference with their comfort. In case of such occurrence, 
patients will be advised to detach the electrodes from their scalp and face, and wash the site of 
electrode attachment with soap and warm water. 
 
The database sits behind VA firewall on a secure VA server and will utilize whole database 
encryption technology. Only registered users will be assigned a password to access the 
database for online data entry or data transfer. When study personnel leave the study, their 
access to the study materials and database will be terminated. Instruments D1-D13 will be 
recorded on laminated paper data collection forms with a permanent marker and responses 
will be directly entered into the REDCap site for the project. Laminated forms will be 
erased and sanitized with an alcohol wipe after data has been entered.   Informed consent 
forms will be kept in locked file cabinets at the ENRM VA Hospital. 
To ensure data quality and minimize missing data, several levels of data checks will be 
implemented. First, when data collectors enter data into the data entry program, they will be 
notified which fields have been skipped. In general, all fields with the exception of some text 
fields will have valid codes associated with them, so that no true blank variables should exist in 
the database. Furthermore, when appropriate, skip patterns will exist for some variables, which 
can automatically populate variables that would then be considered "not applicable". Second, 
the data entry program will also not allow an entry that isn't considered valid mostly through 
the use of drop down controls in which only valid answers are presented. 
All efforts will be made to minimize missing data from these key variables. Any reasons for 
missing data will be recorded for each patient for a global sensitivity analyses to examine the 
effect of missing-ness on the conclusions of the study hypotheses. Also, the linear mixed 
effects modeling approach described for aim 3 can accommodate missing outcome data with 

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confirmation that they missing data appear to be missing at random. Moreover, multiple 
imputation will be used to fill in missing values. 
 
Data will be kept in keeping with VA regulations, which are 7 years post-closing of the study. 
Data access will be limited to study personnel. If a study team member were to be removed 
from the protocol, access to the data would likewise be terminated. In the unlikely event of 
data being lost, the IRB will be informed immediately. 
 
4.6.2.2 Data Safety Monitoring 
Retrospective Studies. Confidentiality is protected by storage of all study PSG 
records and questionnaires behind a VA firewall and accessed by permission and 
password. 
De-identification and Data Transfer to ENRM VA. The PSG recordings in the 
data repository, comprised of electrophysiological measures (such as EEG, EOG, 
EMG) will be exported to a binary format and will be completely stripped of any 
identification marks and will be saved with coded filenames. These de-identified 
PSG records will thus be converted to a series of numbered binary files 
containing a matrix of the raw data (EEG/EOG/EMG in microvolts) with no 
patient identification associated with the file. A separate text file containing 
epoch by epoch (30 second duration) sleep stages will be also generated for each 
sleep study with no patient’s identification inside the file nor as part of the 
filename. Other de-identified data includes a spreadsheet with demographic 
information, survey data from Table 1, and information about PTSD therapy. 
The de-identified data will be transferred from Portland VA to ENRM VA via a 
shared network folder between the two VAs and limited access permission. 
Prospective Studies. 
Risk, confidentiality, and data security will be minimized via use of good clinical 
practices including recording, storage, transfer, and analysis on de-identified data 
files extracted from sleep records and D1-D13 surveys, locking all data files, use 
of a subject identification code system, maintenance of data only on a secure 
system, and recording data without HIPPA identifiers. Subjects will be able to 
terminate the testing at their request at any time without prejudice. 
Study information will be entered into the password protected database 
accessible via secured-internet connection. The database sits behind VA firewall 
on a secure VA server and will utilize whole database encryption technology. 
Only registered users will be assigned a password to access the database for online 
data entry or data transfer. When study personnel leave the study, their access to 
the study materials and database will be terminated. Instruments D1-D13 
will be recorded on laminated paper data collection forms with a permanent 
marker and responses will be directly entered into the REDCap site for the 
project. All data will be entered before COB on the collection date and 
laminated forms will be erased and sanitized with an alcohol wipe after 
data has been entered.). Informed consent forms will be kept in locked file 
cabinets at ENRM VA. 
 
4.6.3 Potential Benefits 
It is unlikely that participation in this study will benefit participants. It is hoped that data 
collected in this study will enable development of objective means of assessing PTSD that will 

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greatly enhance PTSD diagnosis and management. Diagnosis for PTSD is currently established 
on the basis of a patient’s clinical history, mental status examination, duration of symptoms, 
and clinician administered symptom checklists or patient self-reports. The novel PTSD 
biomarker developed in this study could contribute to a more precise and objective diagnosis of 
PTSD and its severity level, selection of specific evidence-based treatments, objective 
evaluation of treatment efficacy, and also for predicting who might be at the risk of relapse. 
 
4.7 Costs and Payments 
Participants in the study will receive either a voucher or a gift card for the amount of $100.00 for 
each test day, which amounts to a total of $400.00 for their participation in Tests 1-4. If they 
withdraw from the study, they will be compensated for all of the study parts that they have 
completed by the time of their withdrawal. 
 
4.8 Providing for Reuse of Data 
  
 Participants will be given the option to have their data be added to the “EEG” data Repository, a 
new data repository being set up here at the ENRM VA Hospital, for future research studies 
pertaining to EEG data collection and approved to be data banked. All data will be stored and 
maintained according to VA regulations and only investigators approved through the EEG data 
repository committee will have access to this data. Any future use of the data will be reviewed 
and approved by this committee. The creation and management of this data repository will be 
approved by the hospital IRB and Research and Development committee before any data from 
this study will be stored in it for future use. Once the Data Repository has been approved, an 
amendment to this project will be submitted to store the data in the data repository.  
 
 
5.0 
Resources 
• Research Lab 
• Equipment and personnel time will be covered by the grant 
 
6.0 Collaborations 
All of the retrospective and prospective studies will be performed at Bedford ENRM VA. Outside 
collaborators include Dr. Miranda Lim at Portland VA, and Dr Kevin Kip at Tampa VA. Dr. Lim 
is the director of a Portland VA project for developing a data repository that contains EEG sleep 
records and clinical outcome measures from Veterans with PTSD, TBI, and depression. She will 
supervise the efforts of the research assistant at Portland VA with regards to transferring the data 
from this data repository to Dr. Modarres for utilization in the development of algorithms and 
predictors for human PTSD subjects. 
Dr. Kip is a Biostatistician and will provide guidance to the PI for the statistical analysis of the 
data, which will be all performed by the PI Dr. Kip will not have access to the data. 
 
7.0 
Qualifications of the Investigators 
Dr. Modarres is a biomedical engineer/scientist with experience and expertise in brain 
monitoring and novel analysis techniques and clinical assessment of this technology. His R&D 
effort in the past 25 years has centered around developing state-of-the art monitoring devices and 
analytical methods that have been applied to quantify sleep and brain function abnormalities and 
disorders. His experience includes having been the Principal Investigator on a number of multi- 
year NHLBI, NIMH, NINDS, DOD, and VA supported grants on the development and clinical 

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testing of novel, neuro-physiologically based techniques for objective assessment of brain 
function. He is also the first author on a manuscript that describes the preliminary findings, and 
sole inventor on A VA sponsored patent application, on the novel neuro-physiological based 
markers of PTSD to be further validated in the current VA merit grant supported by this IRB. 
 
 
 
 
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