Morning Light Treatment for Traumatic Stress: The Role of Amygdala Reactivity
Phase: NA
Conditions: Stress
Sponsor: University of Michigan

 
 
Date of IRB Approval: April 28, 2022 
 
 

 
 
Morning Light Treatment for Traumatic Stress: 
The Role of Amygdala Reactivity 
 
 
Protocol Number:  HUM00161267 
National Clinical Trials (NCT) Number: NCT04117347 
Principal Investigator: Helen Burgess, PhD 
Co-Principal Investigator: Alyson Zalta, PhD 
 
Initial Version: 09 April 2019 
 
Current Version: v13.0 
April 21, 2022 
 
 

 
 
STATEMENT OF COMPLIANCE 
This trial will be carried out in accordance with the United States (US) Code of Federal Regulations (CFR) 
applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 
CFR Part 812) and research best practices.  The PIs and all study team members who are responsible for 
the conduct, management, or oversight of NIH-funded clinical trials will complete Human Subjects 
Protection and best practices training. 
The protocol, informed consent document, recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent documents 
will be obtained before any participant is consented. Any amendment to the protocol will be submitted 
for review and approval by IRBMED before the changes are implemented to the study. All changes to 
the consent form(s) will be IRB approved; a determination will be made regarding whether a new 
consent needs to be obtained from participants who provided consent, using a previously approved 
consent form. 

 
 
AMENDMENTS 
Date 
Version 
Section(s) 
Changes 
Oct. 8, 
2019 
2.0 
1.3 
Updated schedule of activities to clarify timing of self-
report surveys and safety assessments 
3.1.3.3 
Added info on Emotional Regulation Task for fMRI 
5.1 
Changed overall design from “double” to “single” blinded 
to correct a mistake 
6.1 
Changed trauma criterion to remove within 5-year time 
frame 
6.2 
Clarified “significant disease” criterion to mention 
uncontrolled CVD; added beta blockers and opioids and 
SNRIs to contraindicated meds; expanded “acute suicidal 
ideation” criterion to include suicidal behaviors within 
last 6 months 
6.3 
Clarified alcohol and drug use as they relate to 
withdrawals 
6.4 
Indicated that community-based recruitment would 
include Ann Arbor/Ypsi and greater Detroit regions 
6.4.5 
Added section on Pre-screening via REDCap & telephone 
surveys, and the emailing of materials to prospective 
participants 
6.5 
Clarified that travel stipends are only available for visits 
to the research clinic/Rachel Upjohn building 
7.5/7.6 
Added beta blockers and opioids and SNRIs to the list of 
contraindicated meds 
9.5/9.6 
Added Beck Scale for Suicidal Ideation 
Added Demographics form, Work & Social Adjustment 
Form, fMRI screening form, and Treatment Expectation 
and Satisfaction forms; Insomnia Severity Index; 
Morningness/Eveningness Questionnaire 
9.71 
Added section on fMRI practice 
9.7.4 
Added section on Emotional Regulation Task 
9.9.1 
Clarified screening process for fMRI as relates to 
pregnancy and drug screening 
12.2.2/12.3.3.1 Indicated that video files will be stored on MBox 
12.3.2 
Added section naming the Independent Safety Monitor 
12.4 
Added ERT and WSAS to abbreviations list 
13 
Added references for BSSI and WSAS questionnaire 
Jan. 13, 
2020 
3.0 
1.3; 5.1 
Added footnote to SOA and language to section 5.1 that 
allows for Visit 2 activities to occur on two separate days. 
6.5 
Updated incentive schedule to reflect possibility of 
receiving an additional travel stipend related to visit 2 
schedule 
Feb. 4, 
2020 
4.0 
6.2 
Updated Exclusion Criteria to specify excluding for 
significant light treatment use and/or use in the past year  

 
 
Feb. 25, 
2020 
5.0 
6.4.3; 6.4.4  
Updated recruitment strategies to specify flyering at the 
VA and removed flyering at the VA as a future 
recruitment strategy. 
March 5, 
2020 
6.0 
1.3 
Updated SOA to indicate that the PCL-5 and DASS will 
also be collected at lab visits 4 and 6; updated Table of 
Contents 
March 30, 
2020 
7.0 
3.1.5.1 
Removed language that indicated only the clinician would 
be filmed.  
6.5 
Outlined additional travel stipend amount depending on 
distance which participant will be traveling to the lab.  
September 
10, 2020 
8.0 
6.4.3 
Updated to reflect that IRB approved study fliers will be 
posted on Wayne State University campus. 
October 
13, 2020 
9.0 
1.3, 9.9.1 
Added drug test to lab visit 2 
July 1, 
2021 
10.0 
6.4.4 
Added Data Direct/EMERSE as recruitment tools 
12.2.1.1 
Specified data retention plan for data obtained from the 
EMR (used for recruitment) 
 
 
12.4 
Updated Abbreviations List with PHI 
July 16, 
2021 
11.0 
6.2 
Updated and modified Exclusion Criteria to specify 
excluding for significant light treatment use and/or use in 
the past 6 months 
March 3, 
2022 
12.0 
6.4.7 
Added option of free cabs rides for participants with no 
access to timely public transportation or a car/ride with 
family or friends. 
April 21, 
2022 
13.0 
 
Removed Visit 5 fMRI Scan, modified payment scheme to 
remove compensation for Visit 5 fMRI Scan, adding PCL 
to Phone Screening 
 
 

 
 
TABLE OF CONTENTS 
1 
Protocol Summary ................................................................................................................................ 1 
1.1 
Synopsis......................................................................................................................................... 1 
1.2 
Schema .......................................................................................................................................... 2 
1.3 
Schedule of Activities .................................................................................................................... 3 
2 
Introduction .......................................................................................................................................... 5 
2.1 
Study Rationale & Background ..................................................................................................... 5 
2.2 
Innovation ..................................................................................................................................... 6 
3 
Risk/Benefit Assessment ....................................................................................................................... 6 
3.1 
Known Potential Risks ................................................................................................................... 7 
3.2 
Known Potential Benefits .............................................................................................................. 9 
3.3 
Assessment of Potential Risks & Benefits ..................................................................................... 9 
4 
Objectives & Endpoints ....................................................................................................................... 10 
5 
Study Design........................................................................................................................................ 10 
5.1 
Overall Design ............................................................................................................................. 10 
6 
Study Population ................................................................................................................................. 11 
6.1 
Inclusion Criteria ......................................................................................................................... 11 
6.2 
Exclusion Criteria ......................................................................................................................... 11 
6.3 
Lifestyle Considerations .............................................................................................................. 12 
6.4 
Strategies for Recruitment & Retention ..................................................................................... 12 
6.5 
Participant Incentives ................................................................................................................. 14 
6.6 
Screen Failures ............................................................................................................................ 15 
7 
Study Intervention .............................................................................................................................. 15 
7.1 
Description .................................................................................................................................. 15 
7.2 
Administration & Dosing ............................................................................................................. 15 
7.3 
Fidelity ......................................................................................................................................... 15 
7.4 
Measures to Minimize Bias ......................................................................................................... 16 
7.5 
Concomitant Therapy ................................................................................................................. 16 
7.6 
Contraindicated Therapy ............................................................................................................ 16 
8 
End-of-Intervention/End-of-Study ...................................................................................................... 16 
8.1 
Discontinuation of Intervention .................................................................................................. 16 
8.2 
Participant Discontinuation or Withdrawal from Study ............................................................. 17 

 
 
9 
Study Assessments & Procedures ....................................................................................................... 17 
9.1 
Eligibility Confirmation ................................................................................................................ 17 
9.2 
Vision Testing .............................................................................................................................. 17 
9.3 
Psychological Assessment ........................................................................................................... 17 
9.4 
Sleep Assessment ........................................................................................................................ 18 
9.5 
Clinician-administered* & Self-reported Assessments ............................................................... 18 
9.6 
Other Self-reported Assessments ............................................................................................... 18 
9.7 
fMRI ............................................................................................................................................. 18 
9.8 
Treatment expectation & Treatment Satisfaction ...................................................................... 19 
9.9 
Other Research Procedures ........................................................................................................ 19 
9.10 
Safety Assessments ..................................................................................................................... 20 
10 
Adverse Events ................................................................................................................................ 21 
10.1 
Definitions ................................................................................................................................... 21 
10.2 
Classification ............................................................................................................................... 21 
10.3 
Reporting..................................................................................................................................... 22 
10.4 
Unanticipated Problems ............................................................................................................. 22 
11 
Statistical Considerations ................................................................................................................ 23 
11.1 
General Approach ....................................................................................................................... 23 
11.2 
Analysis of Primary Outcome ...................................................................................................... 23 
11.3 
Exploratory Analyses ................................................................................................................... 24 
12 
Supporting Documentation & Oversight Considerations ............................................................... 24 
12.1 
Regulatory, Ethical & Study Oversight ........................................................................................ 24 
12.2 
Data Retention ............................................................................................................................ 25 
12.3 
Safety Oversight .......................................................................................................................... 26 
12.4 
Abbreviations .............................................................................................................................. 27 
13 
References ...................................................................................................................................... 28 
 
 

 
 
1 
 
1 PROTOCOL SUMMARY 
1.1 SYNOPSIS 
Title: 
Morning Light Treatment for Traumatic Stress: The Role of Amygdala 
Reactivity 
Study Description: 
Participants will be enrolled in a 3-arm randomized controlled trial of a 4-
week self-administered wearable morning light treatment to evaluate the 
dose-response association between amount of light therapy (15, 30 or 60 
minutes per day) and the degree of brain reactivity in the amygdala in 
response to an emotional faces fMRI task. 
Primary Objective 
Average blood-oxygen-level-dependent (BOLD) percent signal change in 
the bilateral amygdala from baseline to week 2 and/or baseline to week 4 
of treatment. 
Study Population: 
Individuals with traumatic stress and significant distressing symptoms 
Phase: 
n/a 
Description of 
Sites/Facilities Enrolling 
Participants: 
University of Michigan Sleep and Circadian Research Lab & North Campus 
fMRI suite 
Description of Study 
Intervention: 
Daily self-administered morning light therapy delivered using a 
commercially available device, the Re-Timer. 
Study Duration: 
3 years 
Participant Duration: 
5 weeks 
 
 
 

 
 
2 
 
1.2 SCHEMA 
The figure below shows a sample protocol for an individual whose average sleep schedule is 12-8am: 
 
 
1
2-7
8  Qs, fMRI
9-14
15
16-21
22  Qs
23-28
29
30-35
36  Qs, fMRI
S
T
U
D
Y
 
D
A
Y
Figure 5. Sample protocol for average 12 to 8am sleeper. Study visits are represented by brackets. Qs = REDCap questionnaires, 
clinician administered measures. All study visits will be scheduled for same time of day. Participants will sleep at home with wrist 
actigraphy, sleep and event logs. Participants will be randomized to 1 of 3 durations of morning bright light. The morning light will start 
at average wake time, possibly up to 1 h earlier if required to fit into subject's daily schedule [7, 8].
10
12
11
13
14
15
16
17
18
19
20
21
22
0
23
1
2
3
4
5
6
7
8
9
10
bright light
(15 min, 30 min or 1 h/day)
[
[
[
]
]
[
]
[ 
]
[
]
]
Sleep at Home
with wrist actigraphy,
sleep and event logs

 
 
3 
 
1.3 SCHEDULE OF ACTIVITIES 
Study Phase 
Screening & Baseline 5 
Intervention 
Day Number 1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
Visit Number 
v1 
v26 
 
 
 
 
 
 
v3 
 
 
 
 
 
 
v4 
 
 
 
 
 
 
v5 
 
 
 
 
 
 
v6 
 
 
 
 
 
 
v7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Confirmation 
X 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vision Testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Psychological 
assessment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Accelerometry 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PSQI 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Daily log 2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine screen 3 
X 
x 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Breathalyzer 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Clinician-administered 
assessments  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Self-report 
questionnaires 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X7 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X7 
 
 
 
 
 
 
X 
fMRI 4 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment expectation 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Light therapy 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment fidelity – 
daily contact 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment fidelity – 
data download & 
feedback 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
AE Assessment 
(SAFTEE/CSSRS) 
x 
x 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Treatment satisfaction 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1 – Exact day number can vary by up to one week; 2 – Daily log will capture information about sleep time, treatment time, medication use, etc.; 3 – Urine drug screen administered via dipstick by study team at baseline and 
urine pregnancy screen to ensure drug free participants; 4 – fMRI must occur within 7 days of clinician-administered assessments; 5 – Final screening and eligibility confirmation occur on day 0/v1 and the start of the week-
long baseline period begins at v2; 6 – Visit 2 activities may be split across 2 days separated by no more than 1 month; 7 – Only the PCL-5 and DASS will be administered at these visits 

 
 
4 
 
 
 
 

 
 
5 
 
2 INTRODUCTION 
2.1 STUDY RATIONALE & BACKGROUND 
2.1.1 
Traumatic Stress and the Need for Additional Treatment Strategies That Target Brain Mechanisms 
The mental health burden of trauma is costly for individuals and society [37]. Evidence from a national 
sample of U.S. adults using the DSM-5 criteria, showed that 89.7% of individuals had been exposed to a 
traumatic event, including 53.1% of individuals exposed to direct interpersonal violence victimization 
[38]. Trauma leads to a wide variety of mental health problems including posttraumatic stress disorder 
(PTSD), depression, anxiety, substance use, and suicidality [23, 24]. Although front-line psychotherapies 
and pharmacotherapies exist for traumatic stress, evidence suggests that many individuals fail to receive 
treatment, let alone a therapeutic dose [25-28]. Uptake of these treatments is poor for several reasons 
including stigma, avoidance, unpleasant side effects, and poor accessibility [29]. Moreover, a substantial 
proportion of affected individuals remain symptomatic despite treatment [30-32]. New treatments are 
needed for traumatic stress that can overcome these critical barriers to care while targeting the 
underlying biological mechanisms of the pathology. 
One of the central brain regions implicated in traumatic stress is the amygdala [39, 40]. The amygdala 
plays a critical role in emotional memory and the acquisition of fear responses [41], which are intimately 
related to the clinical manifestation of traumatic stress symptoms. Research has shown increased 
amygdala function during exposure to traumatic reminders [42, 43], and amygdala hyperactivity to 
salient cues has been linked to traumatic stress symptoms including posttraumatic stress symptoms [11, 
12], depressive symptoms [13], and anxiety symptoms [14]. In a rodent model of PTSD, deep brain 
stimulation of the amygdala (inhibits amygdala function) reduced PTSD-like behaviors, demonstrating a 
causal link between changes in amygdala function and PTSD-like behavior [19, 20]. There is currently an 
ongoing trial of deep brain stimulation of the amygdala in humans (NCT02091843) and a published case 
report from the first patient (treatment resistant to psychotherapy and pharmacotherapy) showed 
substantial clinical improvements [21]. These studies suggest that changes in amygdala function are 
causally linked to changes in PTSD-like / PTSD symptoms. Moreover, several studies have demonstrated 
decreased amygdala activation as a result of successful treatment of PTSD [15, 16], depression [41], and 
anxiety disorders [44]. Thus, decreasing amygdala reactivity appears to be a critical treatment target for 
traumatic stress. 
2.1.2 
The Potential of Morning Bright Light as A Novel Treatment for Traumatic Stress 
Morning bright light treatment has good potential as a novel, non-invasive, low risk treatment for 
trauma-related disturbances in mood and arousal. With depression, the most recent meta-analyses 
reveal that morning bright light yields medium treatment effect sizes in seasonal depression (d=0.54, 
[17]) and nonseasonal depression (d=0.62, [18]). Antidepressant effects became statistically significant 
as early as 2 weeks after the initiation of a daily morning bright light treatment [17, 18]. Few studies 
have examined morning bright light treatment for anxiety, but there are some indications of anxiolytic 
effects [34-36]. In terms of post-traumatic stress disorder (PTSD), a recently completed morning bright 
light treatment trial has reported positive effects versus placebo (clinical trial NCT00701064). We have 
also shown in a placebo-controlled pilot trial (n=13) that a 4-week wearable morning bright light 

 
 
6 
 
treatment (Re-Timer) for people with probable PTSD led to clinical improvements in PTSD symptoms. 
While bright light is associated with some side effects (headache, eyestrain, nausea, agitation [45]), 
these often spontaneously remit [45, 46], and patients rarely discontinue due to side effects [46]. Bright 
light devices (with UV filter) are considered safe with no changes in ophthalmologic exams observed 
after 6 years of daily use (in fall and winter months) [47]. 
2.1.3 
Light Reaches the Amygdala via Direct and Indirect Pathways, Can Reduce Amygdala Reactivity 
The primary circadian photoreceptors in the eye are specialized cells known as intrinsically 
photosensitive retinal ganglion cells (ipRGCs) [48]. IpRGCs express melanopsin, a photopigment that can 
respond to light directly [49]. IpRGCs also receive inputs from the rods and cones through conventional 
retinal circuitries [50].  The combination of intrinsic (melanopsin) and extrinsic (rod and cone) inputs 
enable ipRGCs to signal a large dynamic range of light levels in the environment (by a factor of 10 billion; 
from dim starlight to bright sunlight) [51]. IpRGCs transmit the light signal to various brain targets, 
including the amygdala [2]. The light signal reaches the amygdala directly via the ipRGCs [2], and also 
indirectly via other brain targets such as the suprachiasmatic nuclei, which is the central circadian clock 
in the brain [2, 33]. During fMRI scans with cognitive tasks, the application of a light signal immediately 
led to greater amygdala activation [9]. This effect was considered independent from the ongoing 
cognitive brain activity [9]. There is only one study that has examined amygdala activity before and after 
a bright light treatment. In this study, 30 healthy male participants received a 3-week morning bright 
white light treatment (30 min/day) of varying intensity, from 100-11,000 lux.  The brighter the white 
light, the greater the pre- to post-treatment reduction in amygdala reactivity observed during an 
emotional faces fMRI task [10]. Thus, there is compelling evidence to suggest morning bright light 
treatment may reduce traumatic stress by inducing a reduction in amygdala reactivity. Although the 
amygdala is just one part of a larger neural network involved in the pathophysiology of traumatic stress, 
current evidence supports the hypothesis that light treatment can reduce traumatic stress symptoms via 
direct effects on amygdala function. If so, potential synergies with treatments targeting other nodes in 
this network may amplify the impact of this work and the importance of this potentially novel, non-
invasive and scalable treatment. 
2.2 INNOVATION 
This project will be the first to establish if the anatomical links between ipRGCs and the amygdala 
translate into clinically meaningful changes in amygdala reactivity using morning light treatment. 
Amygdala hyperactivity has been associated with many different types of pathology that result from 
trauma exposure (i.e., PTSD, depression, anxiety) [23]; thus, we expect that if morning light treatment 
has a meaningful therapeutic effect on amygdala reactivity, it will have a broad impact on traumatic 
stress symptoms, potentially leading to a shift in clinical practice. The use of a wearable light device, the 
Re-Timer, which is user-friendly and enables the optimization of the therapeutic light wavelength, adds 
to the innovation by facilitating successful translation into future studies and practice.  
3 RISK/BENEFIT ASSESSMENT 
Overall, this study poses no more than minimal risk to the participant.  The known risks fall into the 
following categories: risks associated with the research assessments, risk associated with the 

 
 
7 
 
intervention, risks associated with worsening mental or emotional state, and risk associated with 
breaches of privacy and confidentiality.   
3.1 KNOWN POTENTIAL RISKS 
3.1.1 
Clinical assessments 
The diagnostic and clinical interviews (SCID, HAM-D, etc.) and questionnaires are time consuming, and 
probe potentially sensitive topics like trauma history and suicidal ideation, etc.  Some individuals might 
feel temporary distress at having to answer questions about their personal history.  The instruments 
used in this study are well-tested and not known to cause persistent problems or distress; however, 
individuals are instructed that they can refuse to answer any question with which they are 
uncomfortable.   
3.1.2 
Worsening mental or emotional state 
Some participants may show a worsening of psychological symptoms or suicidality during the course of 
the study period, regardless of assigned treatment arm. Among traumatized individuals, it is common 
for symptoms of emotional distress, including depression, hopelessness, and suicidal ideation to wax 
and wane.  Thus, this risk is inherent in the population. We do not believe these risks are increased as a 
function of being enrolled in this study; if anything, we expect these symptoms to decrease as a function 
of being in the study.  Participants will complete measures of anxiety, depression and suicidal ideation 
throughout the study, and be monitored by study staff and investigators for clinically significant 
changes. 
3.1.3 
fMRI 
The potential risks such of undergoing a functional MRI are typically rare, and generally not considered 
dangerous or life threatening. They include: 
• 
Discomfort or anxiety from being in the confined space of the MRI scanner 
• 
The experience of peripheral nerve stimulation secondary (PNS) to fast imaging sequences, such 
as those employed in this study.  PNS is often described as a light touching sensation on the skin 
surface and may cause mild discomfort, but is not harmful to the participant 
• 
Hearing damage due to loud noises produced by the scanner 
• 
Discovery of a previously unknown minor or significant lesion in the brain (e.g. a tumor) that 
might require additional follow-up 
• 
Injury from objects accelerated by the strong magnetic field of the magnet, striking the 
participant; or metallic substances on the skin or foreign bodies implanted deliberately or 
accidentally in the participant that acquire kinetic or thermal energy from the magnetic or 
radiofrequency emissions of the MRI, causing tissue injury to the participant 
• 
Temporary, slight dizziness or light-headedness when they come out of the scanner 
The University of Michigan’s fMRI Lab has well-established protocols for assessing and reducing risk, and 
addressing any arising complications.  Participants in this study are screened multiple times for 
contraindications to MRI by the study staff and the fMRI Lab technicians.  Women of childbearing 
potential are asked to complete a urine pregnancy test as part of standard fMRI Lab operating 
procedures.  Once in the scanner, participants are provided with custom pads and pillows and ear plugs 

 
 
8 
 
to make the scanning process more comfortable.  The machine is operated in accordance with FDA 
guidelines so the risk of PNS is low.  Participants can communicate with study and fMRI lab staff via an 
intercom, and they can stop the testing at any time.   
3.1.3.1 
fMRI and pregnancy 
According to the NIMH Council Workgroup on MRI Research and Practices (September, 2005), “there is 
no known risk of MR brain scanning of a pregnant woman to the developing fetus for scanning at 4T or 
less, and no known mechanism of potential risks under normal operating procedures.” Nevertheless, 
participants should be warned about potential risks not yet discovered.  
3.1.3.2 
fMRI and incidental findings 
During the formal consent process, all participants will be informed about the potential risks of 
discovering an incidental finding or abnormality on their MRI scan. If an abnormality is found in a 
participant’s MRI scan, Dr. Duval (Co-I) will contact the participant and refer the participant for medical 
follow-up for the problem if the participant requests, including a referral to a primary care physician. If 
the participant has a primary care physician, Dr. Duval will contact the participant’s doctor, at the 
request and with permission from the participant, to inform him/her of the finding on the MRI scan and 
to help him/her get the participant appropriate follow-up. The decision as to whether to proceed with 
further examination and/or treatment lies solely with the participant and his/her primary care physician. 
3.1.3.3 
Emotional Face Assessment Task (EFAT) & Emotional Regulation Task (ERT) 
There is little risk associated with completing either the EFAT or ERT.  Though unlikely, some individuals 
might report mild subjective anxiety.  Co-investigator, Dr. Duval (licensed clinical psychologist) will be 
available during the task and MRI in the event of a more severe response such as anxiety/panic attack or 
distressing levels of anxiety.  Participants will have an opportunity to preview examples of the images 
prior to getting into the scanner. If the study team has any doubts about relief of anxiety/distress, Dr. 
Duval will conduct follow-up telephone calls 1-3 days after the fMRI session to confirm the transient 
nature of the participant’s reaction. 
3.1.4 
Morning Light Treatment 
Reported side effects of morning light treatment are typically mild and short-lived [45, 46], and are 
rarely cause for discontinuation of treatment.  Most commonly reported are headache, eyestrain, 
nausea and agitation. [45] 
Some participants might experience jet lag type symptoms (e.g. transient sleepiness, fatigue and 
headache) like those seen when crossing 1 or 2 time zones because of circadian phase shifts secondary 
to morning light treatment.  These symptoms are short-lived and are akin to what one might feel on a 
Monday morning after a late weekend.   
A rare but serious side effect is mania in bipolar patients who overexpose themselves to the light [45, 
46], but bipolar depressives are excluded from this study and all participants will be provided with strict 
instructions to limit their light treatment to 15 minutes, 30 minutes or 1 hour/day. Note that mania in 
response to morning light treatment is so rare that light treatment has even been clinically tested in 
bipolar patients and found to be safe [96]. 
The light treatment device used in this study, the Re-Timer is commercially-available, and meets all 
international ultraviolet and blue light hazard safety standards.  The emitted light, while brighter than 

 
 
9 
 
most indoor light, is much dimmer than sunlight on a bright day; and the device has an auto-off feature 
after 1 hour of use. 
3.1.5 
Break of privacy or confidentiality 
The collection of study data poses a potential risk of loss of confidentiality around sensitive information 
such as psychiatric status, history of substance abuse, etc. Participants will be informed in the consent 
document that confidentiality will be limited in cases where the participant reveals intentions to harm 
themselves or others, and the investigator feels that the proper authorities may need to be notified in 
order to prevent the occurrence of harm to the participant, or others. Interviews will be conducted by 
experienced mental health workers who will maintain confidentiality, and all data from interviews and 
questionnaires will be coded so as to conceal the identity of the participant. 
Likewise, research data will be labeled with study codes rather than personal identifiers (e.g name, date 
of birth, MRN, etc.).  Identifiers and PHI are maintained in a HIPAA-compliant database, and documents 
are stored in a locked file cabinet.  Access to both electronic and physical data is restricted based on job 
responsibility. 
3.1.5.1 
Video Recording 
The clinician-administered assessments will be videotaped.  The recording equipment will be trained on 
both the clinician and the participant, so participants may be identified by their face and voice.  
Recordings are considered part of the research record and will be afforded the same level 
confidentiality.  The recordings are not transcribed, but rather reviewed for training purposes and to 
assess clinician compliance with the administration guidelines.  The video files will be stored in the study 
database on Michigan Medicine servers and will be available only to authorized study staff.    
3.1.6 
Unknown Risks 
As with any research study, there might be risks that are unknown to the study team.  The research and 
safety assessments, including both systematic and ad hoc monitoring, should contribute to capture of 
most adverse events and allow for the documentation of any heretofore unknown risks. 
3.2 KNOWN POTENTIAL BENEFITS 
Participants may experience an improvement in their traumatic stress symptoms during the study either 
through the act of sharing information about their trauma or through the treatment itself, or even by 
their mere involvement with the study.  
The potential benefit to others is that the study may advance our understanding of how morning light 
therapy may lead to therapeutic benefit for individuals affected by traumatic stress.   
3.3 ASSESSMENT OF POTENTIAL RISKS & BENEFITS 
Given that the potential risks associated with participating are minor and the potential benefits are 
considerable, it is believed that the risks are greatly outweighed by the benefits. 

 
 
10 
 
4 OBJECTIVES & ENDPOINTS 
This study is a part of a larger proposal under the NIH R61/R33 mechanism which requires specific Go-
No Go Criteria to transition between the two phases of the proposal.  This protocol is specific to the R61 
Phase.  The specific aim and objective for this phase (i.e. study) is to establish a significant dose 
response relationship between duration of morning light pulse and reduction in amygdala reactivity 
from baseline to week 2 and/or week 4. 
The endpoint is whole-brain oxygen-level-dependent (BOLD) fMRI signal using a priori regions of 
interest specific to the bilateral amygdala.   
5 STUDY DESIGN 
5.1 OVERALL DESIGN 
• 
Single-blinded randomized controlled mechanistic trial 
• 
Parallel groups 
• 
3 study arms based on light treatment duration: 15-minutes, 30-minutes or 60-minutes/day 
• 
4-weeks of morning bright light treatment delivered via Re-Timer device 
This is a 5-week study (1-week of baseline and 4-weeks of intervention) that includes a screening visit 
plus 6 additional study visits to evaluate outcomes and monitor progress.  Potential participants are pre-
screened for major exclusion criteria using a combination of online and telephone surveys.  On Day 0 
(Visit 1) individuals are consented and eligibility confirmed using several self-report questionnaires.  
Final eligibility is confirmed after the clinician interviews on visit 2 do not reveal any exclusionary 
psychiatric conditions (see below). 
Participants return to the lab for study visit 2 for a battery of psychological assessments to characterize 
the sample, and to begin the week-long baseline period (see Section 1.3 - Schedule of Activities).  At this 
visit, participants are provided with their study materials (Actiwatch Spectrum, daily log, instructions to 
sleep according to a normal schedule, etc.).  To minimize burden participant burden and to 
accommodate calendar challenges (e.g. time change), the activities for this visit may be split across 2 
days such that the psychological assessments are done on one day and the distribution and training of 
study materials occur on a second day within 1 months’ time.    
On Day 8 (Visit 3) participants return to the lab for randomization and baseline outcome assessments.  
Morning light treatment begins on the morning of Day 9.  Thereafter, participants come to the research 
lab weekly to assess adherence to the study procedures and intervention, and monitor for side effects.  
Outcome assessments occur on Day 8, Day 22 (week 2 of intervention) and Day 36 (week 4 of 
intervention).  The exact day number of study visits and activities can vary by up to a week; and we will 
try to schedule study visits for the same time of day.  While the plan is to schedule the fMRI for the 
same day as the psychological assessments, we do allow for a 7-day window in cases where same-day 
scheduling is not possible. 

 
 
11 
 
Data collection is expected to last approximately 19 months with plans to enroll approximately 3 
participants a month with possible exceptions for lower enrollment in November and March when offset 
and onset of daylight savings time can confound circadian rhythms and normal sleep habits. 
6 STUDY POPULATION 
We plan to enroll 66 individuals with a recent history of DSM-5 Criterion A trauma and reported co-
morbid mood and arousal symptoms (as measured by the DASS questionnaire).  These criteria are 
designed to include a wide variety of people with traumatic stress to maximize generalizability while 
ensuring that treatment and outcomes measures are not significantly affected by potential confounding 
variables.  Additionally, we believe that this approach will lead to a transdiagnostic sample that shares 
the common feature of amygdala reactivity [11-14].  Diagnostic information will be collected via the 
Structured Clinician Interview for DSM Disorders (SCID-5-RV) [57] during Visit 2.   
6.1 INCLUSION CRITERIA 
• 
Age 18-60 years old 
• 
Experienced a DSM-5 Criterion A trauma 
• 
Depression Anxiety Stress Scale score (DASS) > 22 
• 
Two or more hyperarousal symptoms  
• 
Normal or corrected to normal vision 
• 
Right-handed 
• 
Fluency in English 
• 
Physically able to travel for study visit attendance 
• 
Stable psychotropic and other medication use for at least 30 days prior to enrollment, and 
throughout the study period 
6.2 EXCLUSION CRITERIA 
• 
Significant chronic disease (e.g. uncontrolled diabetes or cardiovascular disease, advanced liver 
disease, cancer, etc.) 
• 
Retinal pathology or eye disease like current cataracts or glaucoma, or history of eye surgery 
• 
Currently taking photosensitizing medications 
• 
Currently taking benzodiazepines, selective serotonin re-uptake inhibitors (SSRIs), SNRIs, beta 
blockers or opioids for their dampening effects on amygdala reactivity 
• 
History of significant light treatment use OR history of light treatment within the past 6 months 
• 
Lifetime psychotic or bipolar disorder 
• 
Current other significant psychological disorder (e.g. OCD) 
• 
Acute suicidal ideation or suicidal behaviors within the last 6 months 
• 
Substance use disorder within last 3 months 
• 
Diagnosed with obstructive sleep apnea, restless leg syndrome, and/or narcolepsy OR at high 
risk for any of these disorders 
• 
Severe hearing problem 
• 
Intellectual disability or serious cognitive impairment 

 
 
12 
 
• 
History of traumatic brain injury, e.g. any loss of consciousness; any loss of memory for events 
immediately before or after injury; any alteration in mental status at time of the incident; or 
focal neurological deficits that may or may not be transient 
• 
Inability to tolerate enclosed spaces (e.g. the MRI machine) 
• 
Ferrous-containing metals within the body 
• 
Pregnant, trying to get pregnant, or breastfeeding 
• 
Current or recent disruptions to normal sleep schedule: e.g. night work or travel outside the 
Eastern time zone within the past month 
• 
Current psychotherapy 
• 
Epilepsy 
6.3 LIFESTYLE CONSIDERATIONS 
6.3.1 
Alcohol and Drug Use 
Participants are asked to refrain from alcohol consumption for 24 hours prior to their study visits.  Any 
participant breathalyzing positive may be: 
• 
Rescheduled to start the study anew if positive test occurs at Visit 2 or 3, prior to start of light 
treatment 
• 
Withdrawn from the study if positive test occurs at Visits 4-7, after light treatment has started. 
Additionally, participants are asked to refrain from taking illicit drugs for the duration of their study 
enrollment.  Any participant testing positive for drug use may be withdrawn from the study as described 
above. 
Test results will remain confidential.   
6.3.2 
Sleep-wake patterns 
Additionally, participants are asked to maintain their usual sleep-wake patterns as documented during 
the initial week of activity monitoring, and to refrain from napping in the 4 hours immediately after light 
therapy.  Participants might be asked to wake up an hour earlier than usual to accommodate the light 
treatment in context of their life schedule (e.g. work or childcare obligations). 
6.3.3 
Medication and Concomitant therapies 
Participants are asked to maintain their current (from time of enrollment) treatments including all 
medications and non-pharmacological strategies throughout their participation in the study. 
6.3.4 
Naps 
Participants are asked not nap within 4 hours of completing their treatment. 
6.4 STRATEGIES FOR RECRUITMENT & RETENTION 
We will use a multi-pronged recruitment approach to target both community members and clinical 
populations with traumatic stress living in Southeastern Michigan.  

 
 
13 
 
6.4.1 
Online Recruitment 
Our online recruitment strategies will include craigslist.com, Facebook, and umhealthresearch.org, the 
University of Michigan Research Registry.  We will work with MICHR’s Recruitment Core to design 
targeted ads to specific geographical areas (including, but not limited to the surrounding Ann 
Arbor/Ypsilanti and greater Detroit regions), age groups, and multiple races and ethnicities.   
6.4.2 
Dr. Duval 
Dr. Duval has an ongoing non-treatment study for individuals with PTSD.  Individuals who do not meet 
the diagnostic criteria for PTSD yet still report traumatic stress and those individuals who have 
completed the study will be offered the opportunity to participant in the current protocol and/or speak 
with the study team. 
6.4.3 
Flyers 
We will distribute flyers to local clinics and local support groups, including but not limited to those in the 
surrounding Ann Arbor/Ypsilanti and greater Detroit regions. We will also distribute flyers to the Ann 
Arbor VA (where Dr. Duval has a Without Compensation [WOC] appointment). We will post fliers on the 
Wayne State University campus. 
6.4.4 
Data Direct/EMERSE 
We will use two of the online self-serve tools provided by the University of Michigan Data Office for 
Clinical and Translational Research to access clinical data as a means of identifying potential participants 
with a history of trauma or PTSD.  Once identified, these individuals will be approached initially via an 
introductory letter, email, or text inviting them to contact the study team for information. 
6.4.5 
Possible future strategies 
If our initial strategies fail to generate sufficient enrollment numbers to achieve our accrual goals, we 
will consider alternatives, with no specific plan as of yet. We will submit an amendment before 
embarking on any additional strategies.   
6.4.6 
Pre-screening 
Prospective participants will participate in a series of pre-screening surveys: first they complete an 
online survey to determine basic eligibility followed by a telephone interview during screening questions 
for trauma history, psychiatric disorders, and other potentially sensitive criteria are discussed.  Once 
deemed eligible at this stage, individuals are scheduled for an in-person screening visit at which 
additional screening procedures will occur.  In advance of this visit they are sent an example study 
protocol (i.e. schedule) and a pre-study sleep log. 
6.4.7 
Retention 
We use a number of approaches to promote retention of participants throughout the study: 
• 
Schedule all study visits on Day 1 
• 
Daily outgoing communication (e.g. text, phone call, etc.) to support intervention adherence 
• 
Weekly visits to review Re-Timer use and daily logs with participants  
• 
Provide monetary incentive and travel stipend per visit plus a bonus for completing the entire 
study. 

 
 
14 
 
• 
Offer free cab rides to participants with no access to timely public transportation or a car/rides 
with friends and family. 
During weekly lab meetings, the team will review overall participant statuses, as well as enrollment 
numbers and recruitment sources, and the number of withdrawals and lost-to-follow ups to allow for 
adjustments in the recruitment strategy as needed.   
In aggregate, these strategies have proven successful in our other studies of morning light treatment.  If, 
despite our efforts, enrollment is lacking, we will work with Co-I Dr. Abelson who has a relationship with 
Wayne State University Stress, Trauma & Anxiety Research Clinic to expand our reach into the Detroit 
area.  And, we will work with the Michigan Community Outreach Program and the NIMH Outreach 
Partnership Program to help disseminate educational and study information to the public as a means of 
promoting research participation.   
6.5 PARTICIPANT INCENTIVES 
Participants are eligible for up to $1210.00 in incentive payments.  The payment plan was designed to 
partially compensate individuals for the burden of the study visits and associated travel costs, as well as 
promote study completion by including a bonus for finishing the protocol.  Participants will be paid as 
the study progresses for those parts of the study completed. 
• 
Visit 1 - $20 for screening visit – eligibility confirmation and consent 
• 
Visit 2 – Receive study materials, no incentive 
• 
Visit 3 - $225 
o $75 for completing the baseline week of actigraphy and activity/sleep logs 
o $150 for completing the clinical assessments and fMRI 
• 
Visit 4 - $75 for completing previous week of actigraphy and activity/sleep logs 
• 
Visit 5 - $175 
o $75 for completing previous week of actigraphy and activity/sleep logs 
o $100 for completing clinical assessments 
• 
Visit 6 - $75 for completing previous week of actigraphy and activity/sleep logs 
• 
Visit 7 - $400 
o $75 for completing previous week of actigraphy and activity/sleep logs 
o $150 for completing clinical assessments and fMRI 
o $175 bonus for completing the study 
• 
Travel stipend - $80 - $240 for Visit 1-7 (e.g. up to 8 visits to the research clinic including coming 
to the clinic twice for activities associated with Visit 2) 
o The travel stipend will be $10 - $30 per study visit to account for the varying distance 
which different participants must travel to the lab. The travel stipend will always be at 
least $10, increasing by approximately $1 per mile traveled, up to a maximum of $30 for 
30 miles or more. Mileage will be rounded up to the nearest whole number to 
determine the dollar amount given, e.g., 10.4 miles would amount to a travel allowance 
of $11. 
o Participants will be asked to verify from which location they will be traveling to lab visits 
during their phone screen and reconfirm this at Lab Visit 1, which will determine their 
stipend for Visits 1-7. 

 
 
15 
 
o If the fMRI occurs on a different day from the research clinic visit, the travel stipend is 
only provided for the visit to the clinic (e.g. Rachel Upjohn Building). 
6.6 SCREEN FAILURES 
Criteria for screen failures include: 
• 
Positive urine drug screen at baseline  
• 
Study team learns of study exclusion criteria that arises during the baseline week 
7 STUDY INTERVENTION 
7.1 DESCRIPTION 
Morning light treatment is a non-invasive and low-risk therapeutic option for trauma-related stress and 
disturbed mood and arousal.  The light is transmitted directly from retinal photoreceptors to the 
amygdala, a key brain region in the manifestation of traumatic stress symptoms.  The light is delivered 
using a pair of Re-Timer glasses that have been adjusted for each participant to optimize the light 
delivery. 
7.2 ADMINISTRATION & DOSING 
• 
Self-administered in own home 
• 
First thing upon waking (or up to 1 hour earlier to accommodate morning commitments like 
work or childcare) 
• 
Light intensity is about 500 lux 
• 
Duration is pre-set for either 15, 30 or 60 minutes/day depending on study arm 
• 
Daily administration for 4 consecutive weeks (starting the morning after Visit 3) 
7.3 FIDELITY 
• 
Participants are provided with a pre-set alarm clock to the prescribed wake up time (based on 
the baseline week of actigraphy); they are instructed to use their own alarm clock as a backup. 
• 
The Re-Timer glasses are configured with a pre-set timer based on prescribed duration.  
Participants are to activate the timer at the start of each treatment session. 
• 
Participants will record times of use and any interruptions or alterations to the treatment 
session in the daily sleep/activities log. 
• 
Participants will receive a daily communication asking a Yes/No question completion of light 
therapy.  
• 
Participants will meet with the study team weekly to review light treatment data (downloaded 
from the Re-Timer glasses). 

 
 
16 
 
7.4 MEASURES TO MINIMIZE BIAS 
7.4.1 
Randomization 
Participants will be randomized at Visit 3, after the week-long baseline period, to one of 3 daily light 
durations (15, 30 or 60 minutes/day) using a secure web-based treatment assignment system 
implemented by CSCAR (cascar-randomization.appspot.com).  This system uses a minimization approach 
to reduce imbalances in covariates following each round of treatment assignment by using non-uniform 
assignment probabilities for the different treatment groups.  The following minimization variables will 
be used: combat vs. non-combat index trauma; DASS; use of psychoactive medication; ages, sex and 
race. 
7.4.2 
Blinding 
The outcomes assessor will be blinded to study arm, along with rest of the study team except for the PI, 
study coordinator and designated research assistants.  These individuals need to remain unblinded to 
perform safety assessments and provide feedback on intervention compliance.  Blinded staff will wear 
buttons as an upfront visual cue to remind participants not to talk about their treatment. 
7.5 CONCOMITANT THERAPY 
Patients are allowed to continue their usual care throughout the study.  All concomitant treatments 
must be stable for at least 30 days prior to enrollment, and be maintained throughout the study period.  
Allowable therapies include, but are not limited to: 
• 
Prescribed psychotropic medications (except for benzodiazepines, SSRIs, SNRIs, beta blockers, 
and opioids) 
7.6 CONTRAINDICATED THERAPY 
Current participation in psychotherapy or other non-pharmacological treatments for trauma stress is an 
exclusion criterion because of potentially confounding effects on study outcomes. 
Likewise, current or new use of benzodiazepines, SSRIs, SNRIs, beta blockers, or opioids is 
contraindicated because of their potential effects on amygdala reactivity.   
8 END-OF-INTERVENTION/END-OF-STUDY 
8.1 DISCONTINUATION OF INTERVENTION 
Use of the Re-Timer will be stopped in the event of: 
• 
Significant clinical deterioration or expressed suicidal ideation at the determination of the study 
team 
• 
Severe treatment side effects at the determination of the study team 
• 
Significant decline in physical health making compliance with the intervention either ill-advised 
or challenging to complete 
• 
Participant request to discontinue therapy 

 
 
17 
 
Reasons for discontinuation will be documented, and all outcome assessments will proceed as 
scheduled, if possible. 
8.2 PARTICIPANT DISCONTINUATION OR WITHDRAWAL FROM STUDY 
Reasons why a participant might be withdrawn from the study: 
• 
Participant request 
• 
Any new diagnosis that would be considered part of the original exclusion criteria for this study 
• 
Positive breathalyzer or drug test at the study at Visits 3, 4, 5 or 6 
• 
Start of new treatment or therapy during study period 
• 
Significant study intervention non-compliance, i.e. inability or unwillingness to complete study 
intervention or outcome assessments  
• 
Any clinical event or other medical condition or situation such that continued participation in 
the study would not be in the best interest of the subject 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) any time 
• 
Lost-to-follow up 
 
If possible, reasons for withdrawal will be documented.  Data from dropouts or withdraws will be 
retained to minimize data loss.  
9 STUDY ASSESSMENTS & PROCEDURES 
9.1 ELIGIBILITY CONFIRMATION 
At the screening (initial) visit to the lab, Day 0, participants will complete a number of self-report 
questionnaires to confirm eligibility including self-report health questionnaires and basic demographics.   
9.2 VISION TESTING 
Participants will undergo a brief vision test that involves standing a set distance from a standard Snellen-
type eye chart as well as a screening for color-blindness using a common color vision test that involves 
looking at a circular pattern comprised of many dots of various colors, brightness and sizes.   
9.3 PSYCHOLOGICAL ASSESSMENT 
Participants will undergo a clinical-administered assessment to identify lifetime and current psychiatric 
diagnoses, and complete self-report instruments to assess lifetime occurrence and severity of trauma. 
• 
Structured Clinical Interview for DSM-5 (SCID-5-RV) [57] 
• 
Brief Trauma Questionnaire [76] 
• 
Childhood Trauma Questionnaire [77] 

 
 
18 
 
9.4 SLEEP ASSESSMENT 
We will assess sleep using both objective (actigraphy) and subjective (PSQI) measures to use as 
compliance indices and covariates.  Daily logbooks will supplement these assessments, and are designed 
to capture wake/bed times, treatment times, etc. 
• 
Wrist actigraphy using the Actigraph Spectrum every day for duration of study 
• 
Daily Logs 
• 
Pittsburgh Sleep Quality Index (PSQI) [95] 
• 
Morning-ness & Eveningness (Owl-Lark) Questionnaire [135] 
• 
Insomnia Severity Index (ISI) [136] 
9.5 CLINICIAN-ADMINISTERED* & SELF-REPORTED ASSESSMENTS  
We will use validated clinician-rated and self-reported measures of current traumatic stress symptoms.  
Clinician-administered instruments will be video-recorded and used for fidelity checks by MPI, Dr. Zalta.  
We expect to review approximately 20% (random sample) of the recordings. 
• 
*Posttraumatic Stress Disorder Symptom Scale for DSM-5 (PSSI-5) [79] 
• 
PTSD Checklist for DSM-5 (PCL-5) [80] 
• 
*Hamilton Depression Rating Scale (HAM-D) [81] 
• 
*Hamilton Anxiety Rating Scale (HAM-A) [82] 
• 
Depression Anxiety Stress Scale (DASS) [58] 
• 
Beck Scale for Suicidal Ideation (BSSI) [133] 
• 
Work and Social Adjustment Scale (WSAS) [134] 
9.6 OTHER SELF-REPORTED ASSESSMENTS 
• 
Demographics/health Information/Student Status forms 
• 
fMRI screening form 
• 
Treatment Expectation & Treatment Satisfaction Questionnaires 
• 
Follow up Questionnaire completed at study completion 
9.7 FMRI 
Amygdala reactivity will be measured using fMRI and change in BOLD signal measures across the study 
period.  Images will be acquired using an Echo-Planar Imaging sequence (TR=800 ms, FOV=23, 
slice=2.4mm, 96x96 matrix) to measure brain function at rest and during the EFAT task, optimized to 
reduce susceptibility artifact.  fMRIs (initially at visits 3, 5 and 7 but later changed to only visits 3 and 7) 
will be scheduled at the North Campus facility and must occur within 7 days of the clinician-
administered and self-reported assessments of trauma stress and mood (see Section 9.3) 
9.7.1 
fMRI Practice  
As part of the screening process, individuals will be able to lie in the mock scanner located at the Rachel 
Upjohn Building.  This scanner is built to size, and includes simulating scanner noise from speakers so 
people can hear the noises associated with scanning.   

 
 
19 
 
9.7.2 
Resting brain function 
Participants are asked to “remain still, keep your eyes open and the fixation mark, let your mind wander 
freely, but do not fall asleep.”   
9.7.3 
Emotional Face Assessment Task (EFAT) 
The EFAT is an effective probe of amygdala reactivity [72] that has been validated in (1) anxious patients 
[73, 74]; (2) in anxious and healthy participants with pharmacological challenges [73, 75]; and (3) in 
anxious patients undergoing psychotherapy [74]. Participants will view a trio of faces, and are instructed 
to match one of the two faces across the top of the screen that expresses the same emotion as the 
target face shown at the bottom. The target and congruent probe face display one of five expressions 
(angry, happy, fearful, sad, neutral) and the other (incongruent) probe face always displays a neutral (or 
happy if the target is neutral) expression. This design isolates amygdala reactivity specifically to different 
types of cues conveyed by each expression which have similar perceptual characteristics except for the 
emotional signal. The paradigm consists of 20 face trials per expression and 20 shape trials (each 3 
seconds in duration), presented in pseudorandomized order, separated by a 3-7 sec inter-trial ‘jitter” 
(blank screen, fixation cross). During all sessions, our primary measure will be brain response to signals 
of threat (e.g. fear > happy). Besides fMRI signal, we will also obtain behavioral measures of accuracy 
and response time to verify participants are following the instructions. To ensure participants 
understand task instructions, participants will complete practice trials with faces not used in the 
experiment before undergoing fMRI. 
9.7.4 
Emotional Regulation Task 
The ERT assesses an individual’s ability to regulate emotions.  The task is designed to elicit positive and 
negative emotional states; individuals view positive (e.g., flowers), negative (e.g., crying person), and 
neutral (e.g. fire hydrant) images from a curated repository, the International Affective Picture System. 
Participants are instructed to regulate their emotional response by either increasing the amount of their 
emotional response, decreasing it, or simply view the image without any purposeful regulation.  The 
testing paradigm consists of nine iterations of 5 conditions: decrease negative, watch negative, increase 
positive, watch positive, and watch neutral.   The participant’s view alternates between a white fixation 
cross and a picture with the prompt (increase, decrease, or watch) superimposed.  During this time the 
participant tries to regulate their emotion as instructed. Between each trial participants are asked to 
rate the intensity of the emotion they experienced. 
9.8 TREATMENT EXPECTATION & TREATMENT SATISFACTION 
Prior to the start of their morning light treatment, participants will rate their expectations for treatment 
on a 0-10 numerical rating scale (0 “do not expect to benefit” to 10 “expect to benefit a lot”).  
Participants will then rate their level of satisfaction with their treatment at the final study visit. 
9.9 OTHER RESEARCH PROCEDURES 
9.9.1 
Urine drug/pregnancy screen 
All female participants of childbearing age take a urine pregnancy test at visit 1, visit 5, and every visit 
with an fMRI; additionally, we will also do a dip stick drug screen to assess for illicit drug use on all 
participants during lab Visits 1, 2, 5, and at every visit with an fMRI. 

 
 
20 
 
9.9.2 
Breathalyzer 
Participants will be evaluated for recent alcohol use at each study visit by blowing into a breathalyzer. 
9.9.3 
Self-reported medical history 
Participants will fill out a comprehensive medical history and current medications. 
9.10 SAFETY ASSESSMENTS 
9.10.1 SAFTEE for treatment side effects 
An unblinded study team member will administer the SAFTEE (Systematic Assessment for Treatment 
Emergent Events) at weekly study visits.   
If a participant reports a significant worsening of symptoms as indicated by a score of 4 (“bothered quite 
a bit”) or 5 (“bothered extremely”), or endorses any of the following trigger points, the study team will 
contact Dr. Burgess as soon as possible who will then contact the participant for additional information.  
Decisions on subsequent actions (e.g. withdrawal, referral to treatment, etc.) will be made by the MPIs 
who may decide to withdraw the participant from the study, and refer them to appropriate treatment. 
Trigger Point Items from the SAFTEE 
• 
Loss of consciousness (2 or more) 
• 
Seizures (2 or more) 
• 
Difficulty swallowing (3 or more) 
• 
Chest pain (2 or more) 
• 
Shortness of breath (2 or more) 
• 
Rapid heart rate (2 or more) 
• 
Irregular heart beat (2 or more) 
• 
Feeling restless or like you cannot stay still (3 or more) 
• 
Too much energy (3 or more) 
• 
Jumpiness or feeling jittery (3 or more) 
• 
Feeling excited (3 or more) 
• 
Overactive (3 or more) 
• 
Elated (3 or more) 
9.10.2 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is used widely in a variety of clinical and research settings, and is sensitive to change over 
time [97, 132]. All instrument administrators will complete the required online clinical trials training 
module provided by the developers of the measure prior to administering the instrument.  Updated 
training is required every 2 years. Study staff will review the C-SSRS before the participant leaves the 
session. If a participant reports significant suicidality at any point during the study (C-SSRS item 4 or 5 = 
yes), Co-I, Dr. Horwitz (a specialist in suicide), will review the intensity of ideation score (range = 2-25) 
and speak with the participant to discuss the participant’s symptoms and conduct an evaluation before 
the participant leaves the study session. 

 
 
21 
 
10 ADVERSE EVENTS 
The Data and Safety Monitoring Plan is the definitive source for this study’s strategy for upholding data 
integrity and participant safety.  Briefly, this study is considered “minimal risk” because the probability 
and magnitude of harm or discomfort anticipated in the research are not greater than those normally 
encountered in daily life or during the performance of routine medical and psychological care. Safety of 
subjects will be ensured by the continued monitoring of their mental health and medical status.  
Participants will all have access to treatment-as-usual services to address any clinical concerns or study-
induced adverse effects.   
This study will use an independent safety monitor with experience in conducting clinical trials for 
psychiatric disorders, fMRI, biostatistics, and human subjects protections and research ethics.  NIMH will 
approve the safety monitor prior to initial of the study. 
10.1 DEFINITIONS 
An adverse event (AE) is any unfavorable or unintended symptom, sign, or disease associated with a 
medical treatment or procedure that may or may not be related to the treatment or procedure. Adverse 
events can be related to the treatment or to the disorder being treated (e.g. clinical worsening), as well 
as to a concurrent disorder or treatment (e.g. depression or its treatment), or they could be entirely 
unrelated to any of these (e.g., motor vehicle accident).  
10.1.1 Serious adverse event (SAE)  
This study will use the FDA definition of SAE: 
• 
Death 
• 
Hospitalization or prolongation of hospitalization, or emergency room visits 
• 
Persistent or significant disability or incapacity 
• 
Suicide plans or attempts 
10.2 CLASSIFICATION 
All AEs will be classified according to severity and attribution. 
10.2.1 Severity 
• 
(0) No adverse event or within normal limits 
• 
(1) Mild adverse event – did not require treatment 
• 
(2) Moderate adverse event – resolved with treatment 
• 
(3) Severe adverse event – resulted in inability to carry on normal activities and required 
professional medical attention 
• 
(4) Life threatening or disabling adverse event 
• 
(5) Fatal adverse event 
10.2.2 Attribution 
• 
Definite: The AE is clearly related to the investigational agent(s) 
• 
Probable: The AE is likely related to the investigational agent(s) 

 
 
22 
 
• 
Possible: The AE may be related to the investigational agent(s) 
• 
Unlikely: The AE is doubtfully related to investigational agent(s) 
• 
Unrelated: The AE is clearly not related to investigational agents(s) 
10.3 REPORTING 
All SAEs will be reported by the PI to the safety monitor, IRBMED, NIMH, and FDA as appropriate within 
5 days of the study team becoming aware of an event.  Any initial SAE report will be followed by 
submission of a completed resolution report. In addition, the PIs will prepare an annual report on data 
collection and occurrence of any adverse events for review by the above-listed groups. 
In the event that a patient withdraws from the study or the investigators decide to discontinue a patient 
due to SAE, the patient will be monitored by the PIs via ongoing status assessment until: 
• 
A resolution is reached (i.e., the problem has resolved or stabilized with no further 
changes expected) 
• 
The SAE is determined to be clearly unrelated to the study intervention, or  
• 
The SAE results in death 
Should a large number of unexpected SAEs occur, we will modify or terminate the trial if the events are 
severe. We will also monitor safety alerts, defined as events that are relevant to the study populations 
and pose safety risks to study participants. Examples of safety alerts would include a clinically significant 
increase in participant depression or anxiety or certain responses on the SAFTEE. Both SAEs and safety 
alerts will be tracked using a standardized form recording the date of the event, type of event, 
attribution of the event (e.g., judgment regarding whether it was intervention related), whether the 
event was resolved or controlled, and the resolution date.  
10.4 UNANTICIPATED PROBLEMS 
Unanticipated problems, in general, will include any incident, experience, or outcome that meets ALL of 
the following 3 criteria: 
• 
It is unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol, informed consent document, or other research materials; and (b) the characteristics of 
the subject population being studied. 
• 
It is related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research). 
• 
It suggests that the research places subjects or others at a risk of unknown harm or 
addition/increased frequency of harms (including physical, psychological, economic, legal, or 
social harm) than was previously known or recognized. 
The MPIs will have ultimate responsibility for event reporting. Monitoring will occur by the research 
team who will then bring all AEs and UaPs to the attention of the MPIs for evaluation, gradation, and 

 
 
23 
 
appropriate reporting. The MPIs and the study coordinator will be responsible for overseeing data 
integrity, safety monitoring, and reporting of adverse events. 
11 STATISTICAL CONSIDERATIONS 
11.1 GENERAL APPROACH 
The objective of this study is to establish a signification dose response relationship between the 
duration of morning light treatment and reduction in amygdala reactivity from baseline to treatment 
week 2 (study week 3) and/or treatment week 4 (study week 5).   
Statistical analyses will include intent-to-treat and completer analysis. Data will be analyzed using 
responses at all three times (baseline, 2 [when data available] and 4 weeks) as dependent variables 
using a mixed-effects longitudinal model [106, 107] with participants as random intercepts to account 
for between participant variability and time as a predictor.  
11.1.1 Hypothesis 
There will be a significant dose response relationship between light duration and reduction in amygdala 
reactivity. 
11.1.2 Go/No-go Criteria 
A meaningful reduction in amygdala reactivity (Cohen’s d≥0.5) must be observed with one of the three 
daily light durations at treatment week 2 and/or treatment week 4. 
11.2 ANALYSIS OF PRIMARY OUTCOME 
We will first graphically explore the relationship between responses and dose by time and specify how 
dose and time will be parameterized. For example, if a linear dose-dependent relationship is shown at 
each follow-up time (e.g., incremental drop in amygdala reactivity with increasing duration of daily light 
pulse), we will assess it by including dose (in minutes) and will include the interactions of time by dose 
to assess how/if the relationship changes over time (e.g., no difference across groups at baseline and 
dose-dependent relationship at weeks 2 and 4). A test of overall dose response relationship between 
duration of daily light pulse and reduction from baseline in amygdala reactivity will be established based 
on the significance of the interaction term. Time can also be included as categorical indicators to see, for 
example, if 4 weeks, relative to 2 weeks achieve even greater (or no greater) response.  
If a nonlinear dose-dependent relationship is shown in graphs, it will be explored using indicators of 
dose groups. If the relationships at 2 weeks differ from those at 4 weeks, we will analyze them using 
separate models.  
Statistical analysis will be performed using SAS 9.3. Regarding missing data, if “non-ignorable” patterns 
are detected, then “pattern mixture”, “selection models”, or other appropriate strategies will be used to 
examine the impact of the missing data pattern on the key outcomes [108, 109]. All analyses will include 
tests for sex differences, in order to examine sex as a biological variable. 

 
 
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11.3 EXPLORATORY ANALYSES 
11.3.1 fMRI 
In addition to the effect size comparison for the ROI analysis, we will analyze the data with the mixed-
effects longitudinal regression model described above. We will also conduct exploratory whole-brain 
voxel-wise analyses, employing a similar statistical approach across the entire brain in an exploratory 
search to generate hypotheses for subsequent study. Statistical maps for the whole brain analysis will be 
created using a threshold of p<0.001 with a cluster threshold of at least 10 voxels. Brain images will be 
entered into second-level analyses implemented in SPM12 to mirror analyses performed with extracted 
values. We will also conduct exploratory amygdala analyses to evaluate: 1) different sub-regions within 
the amygdala; 2) activation outside of amygdala using whole-brain voxel-wise analyses; and 3) using 
amygdala circuit seeds for functional (psychophysiological interaction analyses) [110], resting state [111, 
112] and effective (dynamic causal modeling) connectivity analyses [113].  
11.3.2 Traumatic stress symptoms 
We will also examine the clinician-administered (PSSI-5, HAM-D, HAM-A) and self-report measures 
(DASS, PCL-5) of traumatic stress symptoms with a mixed-effects longitudinal regression model as 
described above. 
11.3.3 Baseline Analysis and Covariate Adjustment 
With minimization randomization, we do not expect groups differences in the distributions of potentially 
prognostic baseline variables. We will check for imbalances in other baseline variables not used in 
minimization including childhood trauma and objective measures of total sleep time (sleep duration), 
wake after sleep onset (sleep continuity) and sleep quality (PSQI) assessed prior to baseline and include 
them as covariates in the analyses as needed. To explore how much of the change in amygdala reactivity 
and traumatic symptom reductions are associated with an improvement in sleep, we will also include 
separately each potential intermediate outcomes of the weekly average of total sleep time, wake after 
sleep onset and sleep quality assessed prior to each study visit (Days 22, 36) as predictors of outcomes.  
We will also explore if diagnostic status (baseline SCID) moderates the treatment response. 
12 SUPPORTING DOCUMENTATION & OVERSIGHT CONSIDERATIONS 
12.1 REGULATORY, ETHICAL & STUDY OVERSIGHT 
12.1.1 Informed Consent Process 
The recruitment and informed consent process is designed to provide information about study 
participation multiple times and in different formats.  Individuals expressing interest will be provided 
with a verbal explanation of study procedures and the risk-benefit profile and/or be able to read basic 
study information on the umhealthresearch.org website.  From there, individuals are provided with an 
IRB-approved copy of the consent document to review at their leisure.   
The informed consent dialog will take place at the initial study visit (Day 0).  It will consist of a dialog 
between the study team and the potential participant.  The discussion will focus on the voluntary nature 

 
 
25 
 
of research, expectations for participation, a discussion of the risks and benefits associated with being in 
the study, the difference between research and clinical care, and include time for questions. 
The physical location for the consent dialog will be private research space within the Sleep and Circadian 
Research Laboratory. 
12.2 DATA RETENTION 
Research data will be retained for both study record-keeping purposes and for future unspecified 
research use according to IRBMED guidelines for federally-funded projects.  All paper and computer 
records will be identified by the subject ID code rather than name or other identifier.  Consent 
documents and other forms with identifiers will be stored in a separate double-locked setting.   
Data from participants who withdraw from the study will be retained in the study database. 
12.2.1 Study-record keeping 
Hard copies of the data will be maintained for 7 years after which they will be destroyed.  Files will be 
stored in double-locked environment and access-limited under the purview of the MPIs.  All research 
records will be identified by subject ID; pre-screening records will be scrubbed of identifiers and date 
shifted to preserve confidentiality.   
Study database records will be identified by subject ID, and the link between identifiers and subject ID 
will be maintained by the MPI, Dr. Burgess, and lab manager.  The link will be destroyed after 
submission of the NIH final report for Phase 2 (R33) if funded, or publication of the primary manuscript 
for Phase 2, whichever is later.  If Phase 2 is not funded, then the link will be destroyed after submission 
of the final NIH report for this study (Phase 1 – R61). 
12.2.1.1 Protected Health Information (PHI) 
We will abstract basic eligibility and contact information from the Michigan Medicine electronic medical 
records system, MiChart.  These data will be stored separately from study data and will be retained with 
identifiers throughout the duration of the study.  Once the study concludes, the identifiers will be 
destroyed. 
12.2.2 Data Access 
Study data will be stored using the University of Michigan instance of REDCap with access restricted 
based on study roles and responsibilities.  The video files will be stored on UM Dropbox.  The MPI on the 
study, Dr. Zalta of University of California at Irvine, will have access rights to all data elements. 
12.2.3 Data for future unspecified research use 
De-identified study databases will be locked and archived for future unspecified research.  These data 
will be used for analyses related to the main study, new analyses, and in grant proposals for new 
research. 
• 
The data will be stored on Michigan Medicine servers in REDCap and/or statistical datasets that 
are stripped of identifiers  
• 
Access to data will be at the discretion of the MPIs 
• 
Any data shared with collaborators will shared using secure data transfer methods (e.g. 
MiShare) 

 
 
26 
 
12.3 SAFETY OVERSIGHT 
12.3.1 Clinical Monitoring 
The clinical status of participants is monitored throughout the study.  Any >25% worsening from 
baseline measures of depression and anxiety are flagged for review by the MPIs. Any >50% worsening of 
these measures is grounds for discontinuing the participant, with careful follow up (no participant in our 
pilot study worsened to this degree). 
• 
MPI, Dr. Zalta is the study expert in PTSD and traumatic stress.  She will have weekly clinical 
coordinating meetings with Co-Is Dr. Horwitz and Ms. Mooney regarding the clinician-
administered assessments, and review the self-report instruments as needed.  She, and Dr. 
Horwitz and Ms. Mooney, will be available to consult on all noted psychological events.  Any 
indication of clinical worsening or suicidal ideation will be managed in real-time before the 
participant leaves the lab.  In cases where additional treatment is recommended or indicated, 
appropriate referrals or transport to UM Psychiatric Emergency Department will be provided.   
• 
Co-I, Dr. Abelson, will be available to consult on all medical matters and SAFTEE reports.  As with 
instances of worsening psychological status, treatment referrals and communication with 
personal physicians will be provided as needed.   
• 
Co-Is Dr. Duval and Abelson will be available to consult on abnormal fMRI findings.  Any 
incidental findings will be discussed with the participant and their personal physician with 
referrals made as needed. 
• 
Adjudication on whether to withdraw a participant from the study because of change in clinical 
status will be the purview of the MPIs and Co-Is. 
12.3.2 Independent Safety Monitor 
Dr. Adrian Preda (medical doctor) of University of California at Irvine, Professor of Clinical Psychiatry, will 
serve as the independent safety monitor of the study.  He will review adverse events, and offer guidance 
regarding early stopping rules. 
CONTACT INFORMATION FOR DR. PREDA: 
EMAIL: APREDA@UCI.EDU 
OFFICE TELEPHONE: 714-456-8688 
12.3.3 Quality Assurance 
The study will use the Michigan Medicine instance of REDCap, a web-based electronic data capture 
system that is secure and HIPAA-compliant.  Access is restricted by role within the study database, and 
under the purview of the MPI, Dr. Burgess.  Data validation and data quality rules will be implemented 
to minimize errors in data capture, entry and analysis.  
REDCap provides automated export procedures to common statistical packages in which automated 
syntax can be used to score questionnaire responses thereby reducing errors associated with hand 
calculations or Excel formulas.  It is standard procedure in the Burgess Lab that all data manipulations 
are double-checked and initialed by a second study team member. 

 
 
27 
 
Weekly team meetings in which data are reviewed will further serve as a quality assurance measure.  
Data reviewed will include information about mental and physical health symptoms of participants, and 
various psychological characteristics gleaned from the questionnaire battery and participant report.   
12.3.3.1 Video Recordings of Clinician Assessments 
All clinician-administered assessments will be videotaped with a random sample of ~20% reviewed for 
reliability and validity checks.  Recordings will be stored on UM Dropbox, and be accessible only to 
authorized study team members.  Video files will be available to MPI, Dr. Zalta for review via her 
validated UMICH access or MiShare, depending on the storage location. 
12.4 ABBREVIATIONS 
AE – Adverse event 
BOLD – Blood oxygen dependent level 
C-SSRS – Columbia Suicide Severity Rating Scale 
DASS – Depression Anxiety Stress Scales 
DSM-5 – Diagnostic & Statistical Manual of Mental Disorders 
EFAT – Emotional Faces Assessment Task 
ERT – Emotional Regulation Task 
fMRI – Functional magnetic resonance imaging/images 
HAM-A – Hamilton Anxiety Scale 
HAM-D – Hamilton Depression Scale 
HIPAA – Health Insurance Portability & Accountability Act 
ipRGC – Intrinsically photosensitive retinal ganglion cells 
ISI – Insomnia Severity Index 
MEQ – Morningness-Eveningness (Owl-Lark) Questionnaire 
MICHR – Michigan Institute for Clinical Health Research 
MPI – Multiple Principal Investigators 
NIH – National Institutes of Health 
NIMH – National Institute of Mental Health 
PCL-5 – PTSD Checklist for DSM-5 
PHI – Protected Health Information 
PSQI – Pittsburgh Sleep Quality Index 

 
 
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PSSI-5 – Posttraumatic Stress Disorder Symptom Scale 
PTSD – Posttraumatic stress disorder 
ROI – Region of interest 
SAE – Serious adverse event 
SAFTEE – Systematic Assessment for Treatment Emergent Events 
SCID-5-RV – Structured Clinical Interview 
SSRI – Selective serotonin re-uptake inhibitor 
UaP – Unanticipated problem 
WSAS – Work and Social Adjustment Scale 
WOC – Without compensation 
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