Autonomic and Fronto-cortical Correlates of Script-driven Imagery of Trauma-related Nightmares Compared With Such Imagery of Index Trauma in PTSD Using Ambulatory Physiological and fNIRS Recordings
Phase: NA
Conditions: Posttraumatic Stress Disorder
Sponsor: Massachusetts General Hospital

 
1. 
Detailed Protocol 
“Autonomic and fronto-cortical correlates of script-driven imagery of trauma-related 
nightmares compared with such imagery of index trauma in PTSD using 
ambulatory physiological and fNIRS recordings.” 
PI: Edward F. Pace-Schott, Ph.D. 
05/21/2020 
 
BACKGROUND AND SIGNIFICANCE 
 
Overview: 
In those with posttraumatic stress disorder (PTSD), trauma-related nightmares are a hallmark 
re-experiencing symptom1, 2 and a common and severe source of distress3-8 often resulting in 
re-traumatization due to the lack of insight afforded by wakefulness. Proposed research will 
examine whether such nightmares might serve as targets for imaginal exposure during 
prolonged exposure therapy (PE), a first line treatment for PTSD. PE produces significant PTSD 
symptom reduction.9 However, approximately 30% of patients prematurely drop out from PE 
treatment10-16 and most still meet diagnostic criteria for PTSD at end of treatment.12 Thus, 
means for increasing the efficacy of PE are important areas of investigation.17-19 Fear extinction 
learning and memory are the neurocognitive underpinnings of PE.17, 20 Because increased 
physiological arousal during PE can aid in extinction learning,17, 21 recall of trauma-related 
nightmares might serve as an effective target for PE because of their greater immediacy and 
salience relative to the more temporally distant traumatic event. Our research group has 
developed standardized script-driven imagery (SDI) procedures whereby the degree of 
psychophysiological arousal induced by recollection of the traumatic event that precipitated 
posttraumatic symptoms (index trauma) can be assessed in those with PTSD.22-25 A canonical 
variable for physiological reactivity to SDI (SDI-PR) is derived from skin conductance (SC), 
facial electromyography (EMG) and electrocardiography (ECG) and has served as a unitary, 
objective measure capable of distinguishing those with versus without clinician-diagnosed 
PTSD.22, 26-29 Members of our team have also developed a novel ambulatory device, the 
NINscan, that can record SC, EMG and ECG along with simultaneous functional near-infrared 
spectroscopic (fNIRS) imaging of the lateral prefrontal cortex (LPFC).30-32 fNIRS yields 
concentrations of oxygenated (O2Hb) and deoxygenated (HHb) hemoglobin that can be used to 
assess cortical activation. Specific areas of the LPFC have been shown to activate and/or 
deactivate during SDI of an index trauma in persons with PTSD.33 Notably, the LPFC includes 
the right inferior frontal gyrus (rIFG), a region shown to play a prominent role in inhibiting 
unwanted behavior and cognition,34-37 in which reduced activation accompanies reduced 
inhibitory performance in persons with PTSD, compared to controls.38, 39 In participants with 
PTSD and trauma-related nightmares, proposed research will compare psychophysiological 
responses and LPFC activation between SDI of a recent trauma-related nightmare versus SDI 
of the index trauma. During nights over a 2-week period, participants will audio-record time-
stamped nightmare reports following all nightmare-induced awakenings. During two to four such 
nights, ambulatory polysomnography (PSG) will allow analysis of sleep physiology immediately 
preceding nightmare awakenings. A trauma-related nightmare report having sufficient length, 
clarity and resemblance to the index trauma will be selected and recorded as a script for SDI. 
The overarching goal of the proposed research will be to compare within-subject similarities and 
differences in brain and autonomic activation between imaginal replay of a trauma-related 
nightmare versus imaginal replay of the index trauma to determine the relative degree to which 
each evokes autonomic and frontocortical activations. 
 

 
2. 
Significance:  
Posttraumatic stress disorder (PTSD) is a major public health issue with lifetime prevalence 
estimates as high as 7.8%40 and 12-month prevalence as high as 3.6%.41, 42 Repetitive 
nightmares with content resembling an experienced trauma have been characterized as a highly 
specific “hallmark” symptom of PTSD.2, 4, 5 Trauma-related nightmares (TRNs) are endorsed 
by as many as 50-70%43,44 of individuals with PTSD, even when the traumatic event(s) occurred 
as long as 40 years previously.45, 46 TRNs are highly correlated with more severe and persistent 
PTSD47 and poorer overall sleep quality.48, 49 TRNs disrupt sleep in at least two ways. First, they 
may produce anticipatory anxiety surrounding sleep and result in difficulty initiating sleep or 
sleep avoidance.50 Second, they cause awakenings from sleep and acute physiological arousal 
that may make returning to sleep difficult.48, 50 TRNs, insomnia, nocturnal panic attacks, night 
sweats, and simple and complex motor behaviors during sleep are especially common in 
combat veterans with PTSD.51-54 These sleep disturbances, including TRNs, are often treatment 
resistant and contribute to poor treatment outcomes.55 TRNs are linked to PTSD maintenance. 
For example, veterans who reported having nightmares had higher PTSD severity at both post-
deployment baseline and at 6-month follow-up, at which time 41% of nightmare suffers 
continued to meet criteria for PTSD compared to less than 10% in those who did not experience 
nightmares.47  
Increased physiological arousal during prolonged exposure therapy (PE) can facilitate 
extinction learning.17, 21 Hence recall of TRNs might serve as an effective target for PE because 
of their greater immediacy and salience relative to the more temporally distant traumatic event. 
Enhancement of extinction learning by increased arousal is a documented phenomenon in 
experimental and clinical paradigms.17, 21, 56-58 For example, sustained self-reported arousal 
during exposure therapy for Social Anxiety Disorder (SAD) predicted superior treatment 
outcome.59 Similarly, enhanced exposure treatment for SAD has been reported with 
administration of Yohimbine, an alpha-2 agonist that increases noradrenergic neurotransmission 
and arousal.60 In PE, the focus on “hot spots” is a naturalistic example of increasing arousal 
during exposure. Therapists typically direct patients to focus on “hot spots” after the initial 
recounting of the trauma from start to finish. Hence, we hypothesize that if trauma-nightmare 
SDI elevates responding above that produced by the index-trauma SDI, imaginal trauma-
nightmare exposure could improve PE treatment outcome. 
TRNs rarely occur in the sleep laboratory. Consequently, information on their physiological 
associates during sleep is limited and knowledge of their brain substrates is entirely lacking.2, 3, 
48, 54, 61-64 Although there have been laboratory and ambulatory studies in which TRNs were 
recorded using standard polysomnography (PSG),44, 48, 54, 62, 63, 65 none have achieved a large 
sample or imaged brain activity. This motivates our proposed exploratory use of simultaneous 
PSG and functional near-infrared spectroscopic (fNIRS) imaging techniques. Although REM 
may be more conducive to the occurrence of TRNs,2, 5, 62 a significant percentage can arise from 
NREM, especially N2.44, 62, 63, 65-70 The two most successful attempts to record the physiology of 
TRNs used ambulatory PSG,62, 63 one of which reported 57% of nightmares from REM and 37% 
from NREM sleep.62 Arousals resulting in nightmare reports are often accompanied by sleep-
disruptive events such as apneas, leg movements, startle-like arousals,67 excessive body 
movements68-71 and phasic sympathetic activation.6, 52, 68  
 
Near-Infrared Neuromonitoring: 
Human tissue is sufficiently transparent to near-infrared (NIR) wavelengths (650-950 nm) to 
enable non-invasive monitoring of brain oxygenation, perfusion, and neural activity.30-32 By 
shining 2+ colors of NIR light on the scalp and placing a detector some distance away, the 
recorded signals can be used to measure concentrations of oxy-hemoglobin (O2Hb), deoxy-
hemoglobin (HHb), and total-hemoglobin (HbT, generally proportional to cerebral blood volume, 
CBV). We have validated NIRS sensitivity to functional changes in brain oxygenation against 

 
3. 
simultaneous fMRI72, 73 and others have since validated it against cerebral blood flow and 
volume.74 Given multiple overlapping NIRS measurements, diffuse optical tomography (DOT) 
reconstruction techniques30, 75-78 can be used to generate 2D or 3D images79, 80 of the same 
cerebral variables, with spatial resolutions down to ~5 mm.81 Temporal resolution can be 
upwards of 20 Hz.82 The ability of fNIRS to image the brain is limited to the cortical mantle to a 
depth of ~10 mm.83, 84 Consequently, the midline limbic structures such as the amygdala and 
ventromedial prefrontal cortex (vmPFC), hypothesized to be important to the generation of 
REM-sleep dreams, and especially their affective content,7, 85, 86 cannot be imaged using fNIRS. 
However, dorsomedial PFC areas lying within ~10 mm of the surface of the cortical mantle, that 
have been inversely correlated with amygdala activity in PTSD patients,87 could possibly be 
imaged using NINscan technology.  Positron emission tomography (PET) studies have 
suggested that, during REM sleep, the lateral PFC (LPFC) remains in a deactivated state 
relative to wakefulness.88-90 The relative deactivation of frontal areas may contribute to TRNs by 
withdrawal of top-down control of limbic structures.6, 91, 92 Nevertheless, the lateral PFC is 
intimately involved in the regulation of emotion in the waking state.93 To engage higher level 
emotion regulatory processes such as cognitive reappraisal, the lateral PFC may recruit more 
primitive paralimbic regions along with their associated functions such as fear extinction.94 
Specifically, the right inferior frontal gyrus (rIFG), a lateral region accessible to fNIRS imaging, 
has been uniquely implicated in domain-general inhibition (e.g., of action, cognition, emotion)34-
37 and impairment of its inhibitory function has been linked to PTSD.38, 39 Activations and 
deactivations of the left and right IFG have been reported during script driven imagery (SDI) and 
PTSD symptom provocation paradigms.33 The phenomenology of TRNs suggests a hyper-
aroused state during which the dreamer may attempt to access resources to counter perceived 
fearful circumstances, which may provoke partial awakenings and hybrid sleep-wake states. 
Under such circumstances, frontal activity may increase. Alternatively, decreased lateral PFC 
activity may allow the intense midline and subcortical limbic activity presumably taking place 
during nightmares. In either case, the ability to visualize changes in blood flow across a broad 
region of the lateral PFC may yield important clues as to the neural mechanisms underlying this 
previously inaccessible phenomenon.  
 
SPECIFIC AIMS 
 
Specific Aim 1: Optimize standard operating procedures for using the NINscan device in 
our established SDI protocol as a flexible and portable alternative to previously 
employed laboratory-based hardware that lacked simultaneous fNIRS capacity.”  
Hypothesis 1: “NINscan will be easily optimized for SDI assessment in the MGH 
psychophysiology laboratory including event marking and systems for viewing incoming data in 
real time.”  
Specific Aim 2: Compare autonomic reactivity (SDI-PR) and fNIRS activation of the LPFC 
during SDI of the index trauma script and a trauma-related nightmare script. 
Hypothesis 2: SDI-PR and LPFC activations during SDI of the trauma-nightmare script will 
exceed activations during SDI of the index-trauma. 
Exploratory Aim 1: Determine whether the sleep stage immediately prior to trauma-
nightmare awakenings and the trauma-nightmare content determine which individuals 
respond more to trauma-nightmare SDI or show a greater response to index-trauma SDI. 
Exploratory hypothesis 1A: Individuals for whom the nightmare used to create their trauma-
nightmare script was preceded, before awakening, by REM versus NREM sleep, will show 
greater SDI-PR and rIFG HbD responses to the trauma-nightmare script than to the index-
trauma script.  
Exploratory hypothesis 1B: Individuals for whom the trauma-nightmare script is judged most 
similar to the index trauma and/or the most severely stressful by 3 independent judges will show 

 
4. 
greater SDI-PR and rIFG HbD responses to the nightmare script, compared to the index-trauma 
script. 
 
 
INCLUSION/EXCLUSION CRITERIA 
 
 
Phase 1 
1. Age 18-60 years 
2. Normal or corrected to normal visual acuity, normal hearing  
3. Index event that meets DSM-5 PTSD stressor criterion A, viz. “The person was exposed 
to death, threatened death, actual or threatened serious injury, or actual or threatened 
sexual violence” by direct exposure, witnessing in person, or having a close relative or 
friend exposed to violent or accidental actual or threatened death. 
4. Self-report of at least 2 nightmares per week related to the index trauma. The trauma 
nightmares must contain veridical (vs., symbolic, interpreted, etc.) content that is 
reminiscent of the index trauma.  
5. Individuals who meet criteria for at least three of the four DSM-5 criterion categories. 
 
 
Phases 2 & 3 
During the 2-week monitoring period (Phase 1), at least 4 recorded nightmares related to 
the index trauma with at least one suitable for creating a script for SDI. 
 
Exclusion Criteria: 
1. 
Lifetime history of psychosis, bipolar disorder, autism spectrum or other 
neurodevelopmental disorder, active risk to self or others 
2. 
History of sleep apnea or an apnea/hypopnea index of >15 on the diagnostic night of 
ambulatory PSG (i.e., 15 or more sleep apnea-hypopneas per hour of sleep)  
3. 
Neurologic conditions that could confound outcome variables, including past 
neurosurgical procedures, seizure, neurodegenerative disease, stroke, known 
structural brain lesion, significant head trauma with extended loss of consciousness 
and/or persistent neurological sequela (mild TBI allowed)  
4. 
Medical conditions that could confound outcome variables such as severe 
cardiovascular or other systemic disease 
5. 
Use of benzodiazepines, beta blockers, prazosin or antipsychotics (antidepressants 
or mood stabilizers with stable dose for ≥ 3 months allowed) 
6. 
Current Alcohol and Substance Use Disorder or positive urine toxicology screen for 
drugs of abuse  
7. 
MRI contraindications (e.g., metal in body or eyes, pacemaker, pump, stimulator, 
shunt, claustrophobia, weight >250 lbs.) 
8. 
Pregnancy, breastfeeding or nursing: A pregnancy test (urine ß-HCG) will be 
conducted prior to the structural MRI for all women of child-bearing capacity 
9. 
Supervisees of study investigators 
 
 
SUBJECT ENROLLMENT AND SCREENING 
 
Sampling Plan, recruitment, and retention strategies: 
There are highly specific requirements for participants to begin Phase 1 and then to progress to 
Phases 2 and 3. Therefore, sampling will focus on identifying and retaining individuals with the 

 
5. 
highest probability of generating usable nightmares. However, as noted above, in our sample 
we will aim for an equal proportion of men and women and an ethnic and racial composition 
reflecting the most recent Massachusetts census.  
 
Recruitment 
The recruitment target is for 50 participants (25 male and 25 female) to complete Phases 1-3 of 
the study. Withdrawals from the study will be replaced such that the targets for study completers 
are achieved. We will enroll 2-3 participants/month. Participants will be recruited through: the 
Boston Medical Center, the VA Boston Healthcare System specialty mental health clinics, the 
National Center for PTSD participant re-contact database, the Red Sox Foundation and 
Massachusetts General Hospital Home Base Program, outreach to military or first-responder 
organizations including our ongoing collaboration with the Boston Fire Department, and 
outreach to the general public (see below). Key personnel in this study provide access to PTSD 
patient populations at the above facilities. Specifically, our Consultant, Suzanne Pineles, Ph.D. 
is an investigator and Clinical Psychologist in the National Center for PTSD and is Assistant 
Professor in the Department of Psychiatry at Boston University School of Medicine (for which 
the Boston Medical Center serves as a teaching hospital) and Co-Investigator Kaloyan Tanev, 
MD is Medical Director of the Home Base Outpatient Clinic. Outreach to the general public will 
occur via internet bulletin boards, social media, MGH research participation websites (e.g., 
“Rally,” “RSVP for health”), e-posting and physical postings at universities, re-contacting 
participants in past PTSD studies who have signed an agreement to be re-contacted (this is 
included in our consent forms). Notably, at the VA Boston Healthcare System alone, 6,448 male 
and 685 female Veterans with a documented PTSD diagnosis attended at least one 
appointment in FY2017. Based on our consultant Dr. Pineles’ previous experiences recruiting 
participants with PTSD at the VA Boston Healthcare System, we anticipate no difficulty meeting 
our recruitment goal of 2-3 participants/month.  
  
Retention 
Any withdrawals from the study will be replaced such that a total of 50 study completers will be 
achieved. During the 14-day Phase 1 sleep-recording period, research staff will be in frequent 
contact with each participant. Participants will come to the Sleep and Anxiety Disorders lab to 
be instrumented for recordings on each evening prior to recording nights and they will also 
arrange with staff to return the equipment (usually on the following day). At each evening visit, 
participants will also meet with the PI or other clinical staff to complete the Columbia-Suicide 
Severity Rating Scale (C-SSRS)95 via Zoom at which time they will be asked of any difficulties 
they have encountered with the study procedures and will be able to solve such problems with 
staff assistance. As in all of our studies, participants are encouraged to call the PI 24/7 with any 
concerns. For additional incentive to complete all study assessments, we offer a $100 bonus for 
completing the entire protocol.   
 
When a candidate subject responds to an advertisement, they will be instructed to leave a 
phone number but remain anonymous until accepted into the first phase of the study. They will 
then be called and given a detailed description of the study. If they continue to be interested in 
participation, a phone screening will be conducted by one of the study investigators by a trained 
research assistant. Those not meeting inclusion/exclusion criteria or who choose not to 
participate will, therefore, remain anonymous. In the phone screening, major inclusion criteria 
will be confirmed and exclusion criteria ruled out based upon the candidate participant’s self-
report. Candidate participants’ names, addresses and email addresses will be obtained if (and 
only if) they are determined to meet these initial inclusion/exclusion criteria and wish to 
participate.  
 

 
6. 
 
STUDY PROCEDURES 
 
Overview of protocol: The protocol consists of screenings followed by 3 experimental Phases. 
Individuals diagnosed with PTSD who report frequent TRNs will be recruited from the MGH-Red 
Sox Foundation’s Home Base program, the Boston VA Medical Center, local hospital trauma 
clinics, and from the community. Interested individuals will first complete a telephone screening 
followed by a series of structured clinical interviews using a Zoom Healthcare Secure Room to 
diagnose PTSD and comorbid psychiatric disorders, confirm initial inclusion criteria, rule out 
exclusion criteria and create an audio-recorded account of their index trauma. Participants 
passing screenings will then proceed to Phase 1 and complete 2 weeks of at-home sleep and 
nightmare diaries and time-stamped audio-recorded reports of dream content upon awakening 
from any nightmare. They will also wear a wrist actigraph throughout this period, complete two 
to four nights of ambulatory PSG, and complete on-line questionnaires. Nightmare data will be 
examined for frequency and thematic similarity of nightmares to a participant’s reported index 
trauma. Those reporting at least 4 such nightmares with at least one that is clearly related to the 
index trauma and sufficiently detailed for script creation will be invited to participate in Phase 2. 
Phase 2 participants will undergo a structural MRI scan and will then be scheduled to undergo 
MRI-guided positioning of fNIRS sources and optodes using the BrainSight2 System. Phase 3. 
Participants’ nightmare and index trauma reports will be audio-recorded for use as scripts during 
SDI. The participant will then undergo two SDI sessions on a single day, one with a nightmare 
script and one with an index-trauma script, during which they will wear the NINscan. Sessions 
will be separated by 1 hour and counterbalanced across participants for script order.  
 
Informed Consent: 
When a candidate subject responds to an advertisement, they will be instructed to leave a 
phone number but remain anonymous until accepted into the first phase of the study. They will 
then be called and given a detailed description of the study. If they continue to be interested in 
participation, a phone screening will be conducted by a trained post-doctoral fellow or research 
assistant. Those not meeting inclusion/exclusion criteria or who choose not to participate will, 
therefore, remain anonymous.  
 
During the phone screening, major inclusion criteria will be confirmed and exclusion criteria 
ruled out based upon the candidate participant’s self-report. Candidate participants’ names, 
addresses and email addresses will be obtained only when they are determined to meet these 
initial inclusion/exclusion criteria. They will then be scheduled for a visit to MGH to sign a 
consent form, complete questionnaires, be given the C-SSRS, and provide a hand-written 
account of their trauma as well as a urine toxicology sample. The day before the subject comes 
to MGH to sign consent they will be sent a copy of the consent form via email so that they may 
read it ahead of signing.  
 
They will then come to MGH to provide written informed consent, complete a urine toxicology 
screen, fill out the Life Events Checklist (LEC-5), fill out the PCL-5, provide a hand-written 
account of their trauma, and will be paid an additional $30. No minors or other individuals 
unable to provide informed consent will be recruited. All individuals invited to the interview will 
undergo the entire interview. Those excluded or placed on a waiting list will be paid $50 for their 
time. 
 
Screening: Participant candidates will first complete a telephone screening for the inclusion and 
exclusion criteria detailed in “Protection of Human Subjects” and summarized below. Those 
passing telephone screening will undergo psychiatric and sleep disorders interviews using the 

 
7. 
Structured Clinical Interview for DSM-5, Research Version (SCID-5-RV)96 and the Clinical 
Interview for DSM-5 Sleep Disorders Module (SCISD),97 and screened for suicidality using the 
Columbia-Suicide Severity Rating Scale (C-SSRS).95 They will then be screened for PTSD 
symptomatology with the CAPS-5, PCL-5, Childhood Trauma Questionnaire (CTQ),98 Trauma 
History Questionnaire (THQ),99 Life Events Checklist for DSM-5 (LEC-5)100 and Peri-traumatic  
Distress Inventory (PDI).101 Phase 1 inclusion criteria will be a SCID-5-RV-based diagnosis of 
PTSD and self-report of at least 2 nightmares per week related to a specific “index trauma” that 
contains veridical content reminiscent of the index trauma. Phase 2 and 3 criteria will be at least 
4 audio-recorded, time-stamped nightmares related to the index trauma during the 14 nights of 
Phase 1 with at least one that is suitable for SDI.  
 
Phase 1: Participants accepted to Phase 1 will give an audio-recorded narrative of the index 
trauma for later SDI. They will then receive an actiwatch, a voice-activated, time-stamping digital 
audio-recorder, a list of bodily sensations that they might experience during nightmares, and 
copies of the Evening/Morning Sleep Questionnaire (EMSQ) diary.102, 103 All nightmares 
resulting in awakenings will be recorded at the time of awakening. Participants will be instructed 
to depress the actiwatch event marker when they awaken and when they complete recording 
and to estimate the subjective duration of the nightmare. Audio-recorded nightmare reports will 
be compared, by study staff, with the audio-recorded narrative account of the index trauma. 
Participants will also complete a battery of questionnaires, remotely, and two to four nights of 
ambulatory PSG using the Somte-PSG ambulatory recorder (Compumedics USA, Inc., 
Charlotte, NC). The first night will screen for sleep disorders and acclimate participants to PSG. 
Participants who do not record 4+ TRNs one of which is suitable for SDI during Phase 1 will be 
debriefed, paid for portions of the study completed and discharged. 
 
Phase 2: Participants will undergo a structural T1 MPRAGE MRI scan. This will be used along 
with the BrainSight Frameless Stereotactic System (Rogue Research, Inc., Montreal, CN) to 
localize fNIRS optodes at 8 bilateral regions of interest (ROIs) (4 per hemisphere) including the 
frontopolar cortex (BA 10), as well as superior (BA 9), middle (BA 46) and inferior (BA 47) 
frontal gyri.  
 
Phase 3: When we capture a suitable nightmare from a participant, the recorded nightmare 
report will be transcribed and audio-recorded by an investigator as a TRN script following our 
standard procedures.28 Participants will then come to the laboratory and complete 2 SDI 
sessions with NINscan monitoring, one of which will use the script derived from the TRN and the 
other the script derived from the index trauma. Presentation order of the scripts derived from the 
TRN and from the index trauma will be counterbalanced across participants. Because PTSD 
symptomatology and extinction memory may vary with the menstrual cycle,104-106 female 
participants not on oral contraceptives will undergo SDI during the early follicular phase of their 
cycle. 
  
Script Driven Imagery: Adapting standardized SDI protocols,22, 26-28 scripts will be created from 
audio-recorded accounts of the index trauma about which a participant’s TRNs represent a re-
experiencing. The audio-recorded report and list of bodily sensations experienced from an 
awakening during Phase 1 will provide material for the nightmare script. Account of a second 
personalized stressful event unrelated to the index traumatic event will be similarly recorded as 
well as one recording each of a recalled positive and emotionally neutral experience. These 
accounts will be transcribed and the subject will clarify and expand on details as necessary. 
Scripts approximately 30 sec in duration will then be composed and recorded by experienced 
staff, portraying each experience in the second person, present tense. Six 30-sec standard 
generic scripts of both neutral and emotional situations (2 each of neutral, fearful and positive 

 
8. 
experiences) will also be recorded. Script recordings will be played to participants through 
headphones as they vividly imagine each event and physiological data are continuously 
sampled. 
 
Processing of fNIRS signal: Accelerometry data will be used to identify any head motions 
during the measurement periods. The 25-Hz optical data (raw-background) will be digitally low 
pass filtered at 5Hz followed by application of the modified Beer-Lambert Law107 per channel, 
following our previous work.108 This will provide continuous measures of O2Hb, HHb, and HbT 
concentrations relative to resting baseline. 
 
PSG measures: Sleep measures obtained from ambulatory PSG will include amounts of each 
sleep-stage (N1, N2, N3, REM) as a percent of total sleep time (TST) and spectral power in 7 
frequency bands within each sleep stage. REM-specific measures include REM latency, REM 
fragmentation,109 REM rapid eye movement density (REMD),110 REM power in the theta (4-7Hz) 
frequency (REMtheta),111 and heart rate variability during REM.112, 113 On the diagnostic night, 
pulse-oximeter, respiration transducers, nasal cannula and tibialis channels will be added to 
screen for OSA and periodic limb movement disorder. Any participant showing 10+ apneas or 
hypopneas/h or >15 leg movements with arousals/h, will be withdrawn and referred to a sleep 
clinic. An experienced research PSG technician will score sleep using AASM criteria.114, 115 
NINscan-based PSG measures will be scored as in our previous work108, 116, 117 using the same 
criteria.114, 115 
 
Structural MRI: images will be acquired with a 32-channel head coil in a 3T Siemens Prisma 
scanner using automated scout and shimming and high-resolution 3D T1 MPRAGE sequences 
(TR/TE 1,2,3,4/flip angle = 2530ms/1.69, 3.55, 5.41, 7.27ms/7°) with an in-plane resolution and 
slice thickness of 1.0 mm. 
  
Targeting ROIs using BrainSight Frameless Stereotactic System: The BrainSight system 
enables real-time visualization of probe locations relative to a subject’s previously acquired 
structural MRI image allowing precise, unobtrusive placement of optical probes with respect to 
underlying anatomy. The device can be used to non-invasively and accurately locate fNIRS 
optodes on a subject’s scalp over specific cortical areas. We will visualize 100 mm2 circular 
ROIs (approximately 8, 10mm-diameter fNIRS voxels) centered on specific MNI coordinates in 
each subject in order to ensure imaging approximately the same LPFC areas across subjects. 
  
Actigraphy and sleep diary: The waterproof Actiwatch 2 (Philips Respironics, Bend, OR) is 
worn on the non-dominant wrist 24h/day118, 119 and counts arm movements in 1-min epochs. 
Participants press an event marker when beginning to attempt sleep and when waking for the 
day. Epochs are scored as sleep or wake using a standardized algorithm. The EMSQ102, 103 
queries daytime activities and the time one begins attempting sleep (evening), and wake time, 
subjective sleep latency, total sleep time, and number of awakenings (morning). 
 
Self-report assessments: A secure online MGH system will obtain the: 1.) Pittsburgh Sleep 
Quality Index 120 with PTSD addendum;121 2.) Insomnia Severity Index;122 3.) Morningness-
Eveningness questionnaire;123 4.) Spielberger State-Trait Anxiety Inventory;124 and 5.) Inventory 
of Depressive Symptomatology.125  
 
Outcome and predictor variables: For Hypothesis 2, outcomes will be “difference scores” 
between biosignals from the 30-s trauma-related epoch of the nightmare and index-trauma SDI 
and their baseline epochs (30 s of silence preceding the respective script).22, 26-28 For fNIRS, the 
quantities used to compute difference scores will be O2Hb minus HHb concentrations (HbD)30, 72 

 
9. 
at each ROI. Peripheral outcome will be SDI-PR22, 26-28 computed from HR, SC and EMG 
responses to the index trauma and nightmare scripts. Primary outcome of Exploratory 
Hypotheses 1A and 1B will be whether or not SDI-PR and HbD are larger in response to 
trauma-nightmare SDI than to index trauma SDI. Predictor variables for Exploratory Hypothesis 
1A will be sleep stage prior to awakening from trauma nightmare. Predictor variables for 
Exploratory Hypothesis 1B will be ratings by 3 judges, blind to all other participant data, on two 
7-point Likert-type scales of 1) the degree of similarity between each individual’s index-trauma 
and trauma-nightmare scripts, and 2) the emotional severity of the recorded trauma-nightmare 
experience. 
 
Statistical analyses: As feasibility assessments of NINscan methodology, Hypothesis 1 The 
qualitative optimization of NINscan’s biosensor configuration, biosignal acquisition, event 
marking, and interface with software delivering SDI stimuli, rather than quantitative hypothesis 
testing, is the focus of Aim 1. To test Hypothesis 2, the two primary outcome variables (rIFG 
fNIRS HbD and SDI-PR) will be compared between trauma-nightmare and index-trauma SDI 
using multiple regression adjusting for age, sex and duration since trauma. Secondary 
outcome variables (HbD from the 7 remaining fNIRS ROIs) will be compared between groups 
using the same regression model as for the primary fNIRS outcomes adjusting for multiple 
comparisons using the false discovery rate.126 Analysis of Exploratory Hypothesis 1A: We will 
investigate whether a stronger response to the trauma-nightmare as compared to the index-
trauma script is associated with REM sleep using logistic regression, with REM sleep (0/1), sex 
(M/F) and duration since trauma as predictors. Analysis of Exploratory Hypothesis 1B: The 
similarity between the trauma-nightmare and index-trauma scripts and the severity of the 
trauma-nightmare script will be evaluated for each subject by 3 judges using 7-point Likert 
scales. The relationship between these evaluations and a greater SDI-PR or rIFG HbD 
response to trauma-nightmare than index-trauma SDI will be assessed using ordinal regression, 
with sex, judge ID, and duration since trauma as additional covariates.  
 
Power analysis: For the primary outcome in Aim 2, we will compare physiological response 
and fNIRS in the rLIFC between scripts for the index trauma and the associated nightmare in 
each of 40 subjects completing the study (i.e., dropouts will be replaced). Based on a paired t-
test at the 0.05/2 two-tailed significance level (adjusting for the two outcome measures), we will 
have 80% power to detect an effect size of d=0.50. In order to power the hypothesis in 
Exploratory Aim 1, we first assume that each of 50 subjects have one nightmare and that 60% 
of these nightmares will occur during REM sleep.62 For this situation, we will have 80% power to 
detect whether the probability of having greater SDI-PR or rIFG HbD response to the trauma-
nightmare, compared to the index-trauma script is 0.70 or greater for patients who had 
nightmares during REM sleep, and 0.30 or less for those whose nightmares were not during 
REM sleep, based on Fisher's exact test, at the 0.05 two-tailed significance level. 
 
 
 
POTENTIAL RISKS AND PROTECTION FROM RISKS 
 
Risks of self-report during clinical screening, completing questionnaires and recording 
nightmares:   
Participants may feel uncomfortable or embarrassed revealing psychological information during 
clinical interviews and when completing questionnaires. Interviews and questionnaires may also 
induce negative emotional reactions due to the reactivation of trauma-related memories. For the 
same reason, dictating dream reports following awakenings from nightmares may induce or 

 
10. 
exacerbate trauma-related negative emotional reactions. The protections from these risks that 
we implement are detailed below.    
  
Risks from script-driven imagery (SDI) procedures: 
Risks from the SDI procedure primarily include negative emotional reactions to the reactivation 
of trauma-related memories. There is a chance that recalling one’s traumatic memories could 
worsen PTSD symptoms. However, we regard this as unlikely for two reasons. First, subjects 
with PTSD repeatedly experience traumatic memory reactivations as a feature of the disorder. 
Second, we have reactivated traumatic memories in hundreds of PTSD subjects during more 
than 30 years’ experience with the script preparation procedure and have found few instances 
of symptomatic exacerbation. The protections from these risks that we implement are detailed 
below.     
 
Risks from NIRS and NINscan monitoring: 
NIRS is an investigational tool in regular use for over 40 years. Although no adverse effects 
have been reported, it is possible that effects not yet reported may occur. If lasers like those in 
the device are shone directly into the eye, eye injury could potentially occur. NIRS monitoring 
requires coupling sensors to the skin on the scalp. This is achieved by fastening the sensors to 
a pad or cap, placing it over the head, and holding it in place with a head or chin strap. 
Positioning the sensors may require parting the hair and will require making secure contact with 
the skin. It is possible that skin irritation could occur beneath sensors. The study team has 
received extensive training on the psychophysiological procedures and this will minimize 
discomfort from the application of the electrodes.  
 
Risks from ambulatory polysomnography:  
The removal of some of the sleep recording electrodes and sensors placed with tape may pull 
slightly on exposed skin and feel like a band-aid being removed. Participants may feel this 
sensation despite our use of tapes and materials specially designed for people’s skin. 
Participants may not sleep as well as usual when wearing ambulatory PSG equipment. As a 
result they may be sleep deprived and feel tired in the morning.  
 
Risks from structural MRI:  
Although MRI is thought to be hazard free, some subjects may find the enclosed space of the 
scanner to be physically uncomfortable or anxiety-producing. Every effort will be made to 
reassure the patient and minimize any discomforts while in the fMRI scanner. Subjects will be 
able to converse with a staff member via a microphone and speaker system. Every effort will be 
made to reassure the patient and minimize any such discomforts. Noise from the scanner can 
also cause discomfort. To reduce the discomfort caused by loud noises, subjects will wear 
earplugs that minimize ambient scanner noise while still allowing communication with staff. 
Subjects may ask to have a scan stopped and discontinue participation in the study at any time.  
 
Unexpected Findings: 
As NIRS is not a clinical measurement, it is possible, but unlikely, that we could find a clinical 
abnormality in healthy participants. Unexpected findings may also occur during the structural 
MRI.  
 
Accidental data release: 
There is a small possibility of an inadvertent release of a subject’s data with identifiable 
information, as with any electronic data. 
 
 

 
11. 
Protection Against Risks  
 
Written informed consent will be obtained from each subject. Subjects can request that a study 
be stopped at any time during their participation.  
 
Repeated safety assessments: 
We will conduct careful screening to identify individuals at higher risk for developing suicidal 
ideation, for example those with a history of active suicidal ideation or attempt and those with 
current suicidal ideation. Such individuals will not be enrolled in the study and appropriate 
clinical care and referrals will be provided. Either Dr. Lasko or Dr. Pace-Schott (a 
Massachusetts Licensed Mental Health Counselor) will use Zoom to administer the C-SSRS95 at 
every visit to MGH which include the initial psychiatric and sleep interviews, the two to four visits 
for PSG instrumentation, and the day of SDI testing. At every visit, there will be a licensed 
clinician present to provide assistance as well as a licensed clinical psychologist or psychiatrist 
on call. If a participant endorses any of the C-SSRS queries concerning suicidal ideation, intent 
or plan, they will be assessed by the licensed clinician investigator present who will then consult 
with one of the two psychiatrist co-investigators on our protocol (Kaloyan Tanev, MD and John 
W. Winkelman, MD, PhD). Minimally, the participant will be instructed on how to contact MGH's 
Acute Psychiatry Service (APS), which provides emergent psychiatric care on a 24-hour/day 
basis for individuals in the Massachusetts area. We also provide a complete listing of 
emergency mental health services in Boston. However, if acute suicidality or other psychiatric 
distress is detected while a participant is enrolled in the protocol, we will accompany them to the 
MGH Emergency Department and remain with them until they are evaluated by health care 
providers or emergency services. If a participant develops suicidal ideation outside of study 
visits they will have the PI’s number that can be called 24/7 and he will advise them to 
immediately go to the nearest emergency room and facilitate their doing so by identifying local 
resources. If the participant is homicidal, MGH hospital security will be called and standard 
procedures for addressing such issues at MGH will be followed.  
 
Clinical screening:  
Because trauma history is being evaluated, we expect a degree of emotional distress during the 
screening sessions. The risk of an increase in symptoms during screening will be discussed 
during the informed consent process. If an adverse emotional reaction occurs during screening, 
a psychologist (Drs. Lasko or Pineles), psychiatrist (Drs. Tanev or Winkelman) or a Licensed 
Mental Health Counselor (Dr. Pace-Schott, the PI) will be available for guidance and 
intervention, including making referrals to initiate or supplement treatment, carrying out the 
emergency procedures detailed above and/or withdrawing the participant from the study. 
 
Home-based nightmare reporting: 
Should a severe emotional reaction occur during nightmare reporting, participants will be 
instructed first to go to the nearest emergency room. They can also contact the PI, Dr. Pace-
Schott, a Licensed Mental Health Counselor (LMHC), 24h/day, 7 days per week and he can 
also provide guidance. If nightmare recording elicits persisting distress during the following 
day(s), the above noted clinicians will be available for guidance and intervention, including 
making referrals to initiate or supplement treatment, carrying out the emergency procedures 
detailed above and/or withdrawing the participant from the study. We will further protect 
participants by reminding them that they are free to withdraw from the study at any point. 
 
Script-driven imagery: 
We will seek to protect participants from the emotional distress that might be aroused by the 
SDI procedure in the following ways. Only investigators and highly trained research assistants 

 
12. 
will conduct the SDI procedure. If an adverse emotional reaction occurs during SDI, a 
psychologist (Drs. Lasko or Pineles), psychiatrist (Drs. Tanev or Winkelman) or a Licensed 
Mental Health Counselor (Dr. Pace-Schott, the PI) will be available for guidance and 
intervention, including making referrals to initiate or supplement treatment, carrying out the 
emergency procedures detailed above and/or withdrawing the participant from the study. 
Participants will be reminded at each study visit that they are free to withdraw from the study at 
any point. There is also a chance that recalling one’s traumatic memories could worsen PTSD 
symptoms. However, we regard this as unlikely for two reasons. First, subjects with PTSD 
repeatedly experience traumatic memory reactivations as a feature of the disorder. Using SDI, 
we have reactivated traumatic memories in hundreds of PTSD subjects during more than 30 
years’ experience with the script preparation procedure and have found few instances of 
symptomatic exacerbation. As noted above, all participants will be assessed for suicidal ideation 
at every study visit including the SDI sessions.  
 
Ambulatory polysomnography: 
All subjects will be told that sleeping when wearing ambulatory PSG equipment, especially after 
the first night, can result in some sleep loss and resultant daytime sleepiness. They will be 
cautioned not to drive or operate dangerous machinery until they determine that they are fully 
alert. After being instrumented for ambulatory Somte-PSG recording during Phase 1, 
participants who have come by public transportation will be given taxi vouchers to return home. 
Free parking will be provided for those who drive. The PI is on call 24 hours a day, 7 days per 
week, to address any participant concerns throughout the study. 
 
Near-Infrared Spectroscopy: 
NIR light delivery by our NINscan system will be well below the Maximum Permissible Exposure 
(MPE) level for long-duration (8 h) exposures, which is the ANSI limit for light delivery at these 
wavelengths. Moreover, the CW-NIRS light sources are diffused and diverge in a wide angle 
(>50 deg) at the probe end because of a diffusing filter affixed over the light source. This results 
in a Nominal Ocular Hazard Distance (NOHD) of less than 5 cm, which is lower than the 10 cm 
focusing distance of the retina. Hence, the NIRS measurements do not necessitate eye 
protection. 
 
MRI: 
A pregnancy test (urine ß-HCG) will be conducted prior to the structural MRI for all women of 
child-bearing capacity; a positive test will preclude scanning. Three levels of screening for 
metallic objects on or inside the body are completed prior to MRI scanning session. First, 
participants are queried during the initial telephone screening and anyone with a pacemaker, 
medication pump, vagal stimulator, deep brain stimulator, TENS unit, ventriculo-peritoneal shunt 
or any other introduced metal such as shrapnel are disqualified. Second, before the anatomical 
scanning session, each participant must complete the Martinos Center Patient/Volunteer 
Screening Form. An affirmative answer to most items on this form disqualifies the participant. A 
few items (e.g., tattoos), however, may be brought to the attention of the Martinos Center MRI 
managers who alone can determine whether or not this participant can be scanned. Third, 
participants must pass through a ferrous metal detector before entering the MRI environment. 
The Martinos Center for Biomedical Imaging has clearly written and posted safety protocols 
designed for all contingencies associated with MRI scanning and the MRI environment. This 
includes a protocol for rapidly contacting emergency first responders. All research staff who 
participate in MRI scanning at the Martinos Center must have completed MRI safety training. In 
addition, a Martinos Center Certified MRI Scanner must be present at all scanning sessions and 
2 such individuals must be present on evenings, weekends and holidays. A certified scanner 
must have participated in regular Martinos Center scanning sessions as a trainee for at least 4 

 
13. 
months and must pass an examination administered by one of the MRI center managers. The 
PI and all current research assistants are Certified MRI Scanners.  
 
Unexpected Findings:  
Although MRI and fNIRS scans associated with this protocol are for research purposes only, an 
MGH radiologist is available for consultation whenever a brain anomaly is noted. If necessary, 
the radiologist will inform the participant of the finding and offer to communicate that information 
to their physician of choice (e.g., primary care or specialist) for follow-up. 
 
Data Protection:  
All study staff will be trained on the importance of confidentiality. All research staff must have 
successfully completed the Collaborative Institutional Training Initiative (CITI) basic training for 
biomedical researchers as well as periodic refresher trainings. All data will be coded with a 
random alphanumeric subject code, unrelated to the participant’s name, initials, or dates related 
to their participation. All research data will be labeled with this code only, and the mapping 
between patient and code will be kept in an encrypted and password-protected location 
accessible only by the study investigators and the research coordinator. Only the PI and 
requisite co-investigators will have access to the subject’s personal data. 
 
POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO HUMAN SUBJECTS AND 
OTHERS 
 
Benefit to subject: 
 
It is anticipated that most subjects will not derive direct benefit from participation in the study. 
However, participants will be referred, if desired, to appropriate clinical services should any 
serious psychopathology be noted during clinical psychiatric screenings, any sleep disorder 
noted during the clinical sleep interview or the acclimation/sleep disorder screening night or if 
any anomaly is noted on their structural MRI. In addition, if desired by the participant, referrals 
can be made for treatment of PTSD at any point before, during or after the study. The 
investigators are well positioned to make such referrals given their extensive network of clinician 
colleagues at MGH and other Boston area hospitals. There will be no costs incurred by the 
subject as a participant in planned procedures. 
 
Importance of the knowledge to be gained: 
 
During PE for PTSD, trauma-related nightmares might offer targets for exposure treatments that 
are of greater immediacy and salience than the more temporally distant index trauma that 
originally precipitated an individual’s PTSD. As such, use of trauma-related nightmares might 
strengthen arousal during PE and thereby enhance therapeutic extinction leading to greater 
reductions in PTSD symptoms. The proposed research will provide preliminary evidence as to 
whether or not this is the case by comparing both autonomic and brain responses to script-
driven imagery of the original traumatic experience to script-driven imagery of a recent trauma-
related nightmare. Additionally, the ability to assess activity in the LPFC during SDI might 
provide crucial information relating to individual differences in treatment response. For example, 
greater engagement of the LPFC following transcranial magnetic stimulation has been shown to 
predict treatment outcome from PE in PTSD.127 Moreover, the Phase-4 participants will provide 
the first glimpse into LPFC activity during nightmares, and could generate hypotheses on 
potential methods to assess treatments of nightmares (pharmacological or behavioral) in 
naturalistic settings.    
 

 
14. 
Compensation: 
 
Participants will be paid up to a maximum of $475 for completion of Phases 1-3 of the study. 
This amount is in line with our standard practice. Partial completion of the study will be 
compensated on the following schedule.  
 
$30 for in-person visit to MGH to sign consent and perform urine toxicology screen. 
$70 for completing on-line clinical interviews 
$150 for completing Phase 1 of the study (14 days of audio-recording of experienced 
nightmares, nightmare and sleep diaries, actigraphy, 2-4 ambulatory PSG nights, online 
questionnaires) 
$125 for completing the 2 script-driven imagery procedures and positioning of fNIRS optodes  
$100 bonus for completing entire protocol 
 
Participants will be informed that they will be discontinued in the study if: (a) if at the clinical 
interviews they do not meet study criteria, (b) if they produce a positive urine toxicology screen 
after signing consent, (c) if they produce a positive pregnancy test at the structural MRI, (d) if a 
sleep disorder is detected on the diagnostic night of ambulatory PSG, (e) if an insufficient 
number TRNs are obtained during Phase 1. However, they will be compensated in full for the 
activities they have completed based upon the schedule above.  
 
 
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Questionnaires 
 
Psychiatric Interview:  
- 
Structured Clinical Interview for DSM-5, Research Version (SCID-5-RV) 
- 
Clinician Administered PTSD Scale for DSM-5 (CAPS-5; past month version)  
- 
Life Events Checklist (LEC-5; standard self-report)  
- 
PTSD Checklist for DSM-5 (PCL-5)  
 
Sleep Interview:  

 
21. 
- 
Clinical Interview for DSM-5 Sleep Disorders Module (SCISD) 
- 
Cover pages for SCISD 
 
REDCap Questionnaires 
- 
Pittsburg Sleep Quality Index (PSQI) 
- 
Pittsburg Sleep Quality Index addendum for PTSD (PSQI – PTSD addendum) 
- 
Epworth Sleepiness Scale (ESS) 
- 
Morningness-Eveningness Questionnaire (MEQ) 
- 
Insomnia Severity Scale (ISI)  
- 
Spielberger Trait Anxiety Inventory (STAI – Trait)  
- 
Revised NEO Personality Inventory (NEO-PI-R)  
- 
Peritraumatic Distress Inventory (PDI)  
- 
Quick Inventory of Depressive Symptomatology – Self-report (QIDS-SR) 
- 
Childhood Trauma Questionnaire (CTQ) 
 
Questionnaires given before and after script-driven imagery 
- 
Stanford Sleepiness Scale (SSS)  
- 
Spielberger State Anxiety Inventory (STAI- State)  
- 
The Positive And Negative Affect Schedule – Mood Scale (PANAS)