A Non-Pharmacological Method for Enhancing Sleep in PTSD
Phase: NA
Conditions: PTSD, Sleep Problems
Sponsor: University of Arizona

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DoP version: 18Mar2020 
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1 
UACCESS EDOC NUMBER (FOR PROJECTS REQUIRING AN IRB
FEE) 
PROJECT TITLE: 
A Non-Pharmacologic Method For Enhancing Sleep in PTSD 
INVESTIGATOR 
Principal Investigator Name, 
Degree(s): 
William D. “Scott” Killgore, Ph.D. 
Principal Investigator UA netID 
killgore 
Status/Rank: 
Professor 
Center: 
Section: 
Department: 
Psychiatry 
College: 
College of Medicine 
Contact phone:  
(520) 626-6336
Official University Email: 
Killgore@psychiatry.arizona.edu 
ADVISOR CONTACT INFORMATION (REQUIRED FOR ALL STUDENTS AND RESIDENTS) 
Name, Degree(s), UA NetID: 
N/A 
Contact phone:  
Official University Email: 
ALTERNATE/COORDINATOR CONTACT INFORMATION 
Name, UA NetID: 
Bryan Clines, bclines 
Contact phone:  
(520) 621-3454
Official University 
Email: 
bclines@psychiatry.arizona.edu 
2 

 
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SECTION 1: REQUIRED SIGNATURES 
1. PRINCIPAL INVESTIGATOR 
3 
I will conduct my research according to the University of Arizona HSPP Investigator Manual. 
4 
 
 
06/30/14 
 
William D. “Scott” Killgore, 
Ph.D. 
 
 
Signature 
 
Date 
 
Print Name 
 
5 
2. ADVISOR (FOR ALL STUDENTS AND RESIDENTS ACTING AS THE PI) 
6 
I will oversee the student researcher according to the University of Arizona HSPP Investigator Manual. 
7 
N/A 
 
 
 
 
 
 
Signature 
 
Date 
 
Department 
 
8 
3. SCIENTIFIC/SCHOLARLY REVIEW (CANNOT BE ASSOCIATED WITH THE PROJECT) 
9 
I have examined the proposal cited above, and find that the information contained therein is complete and that the scientific or 
10 
scholarly validity of the project appears appropriate.   
11 
 
 
06/17/14 
 Nicholas Breitborde, Ph.D. 
 
 
Signature 
 
Date 
 
Print Name 
breitbor@email.arizona.edu 
 (520)626-7534 
Official University Email 
 
Phone number 
 
 
 
12 
4. DEPARTMENT/CENTER/SECTION REVIEW 
13 
I have reviewed this application and determined that all departmental requirements are met and that the investigator has 
14 
adequate resources to conduct the Human Research. 
15 
 
 
06/10/14 
 Karen Weihs, M.D. 
 
 
Signature 
 
Date 
 
Print Name 
weihs@email.arizona.edu 
 (520)626-8940 
Official University Email 
 
Phone number 
 
 
 
16 
5. RESPONSIBLE PHYSICIAN (PROJECTS INVOLVING MEDICAL PROCEDURES WHICH THE PI IS NOT 
17 
AUTHORIZED TO CONDUCT) 
18 
I am a physician licensed by the State of Arizona (or US license for the SAVAHCS). I will be responsible for ensuring that all 
19 
procedures that are part of this project and that require the attendance of a licensed physician will have a suitable physician 
20 
present during the procedures. If at any time this is not possible, I will inform the IRB before any procedures are conducted. 
21 
N/A 
 
 
 
 
 
 
Signature 
 
Date 
 
Print Name 
 
22 
 
23 
 
24 
 
25 

 
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26 
 
27 
6. NATIVE AMERICAN OR INTERNATIONAL INDIGENOUS POPULATIONS REVIEW 
28 
Signature needed only if research takes place in Indian Country or among international Indigenous populations, actively 
29 
recruits Native Americans or international Indigenous populations for enrollment, and/or requires stratification of Native 
30 
Americans or international Indigenous populations as one of the statistical analyses or study aims.  
31 
 32 
 
Social and Behavioral Projects:  American Indian Studies, (520)621-7108 
33 
 
Biomedical Procedures:  Office of Outreach and Multicultural Affairs, (602)827-2327 
34 
 
35 
I have examined the proposal cited above and advise that further appropriate tribal/Indigenous approval [  ]is [  ]is not 
36 
necessary. 
37 
N/A 
 
 
 
 
 
 
Signature 
 
Date 
 
Print Name 
 
 
38 

 
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39 
SECTION 2: GENERAL INFORMATION 
1. Not including this project submission, how many: 
a. Human Research studies is the PI involved in as key personnel? 
4 to be IRB 
approved for 
opening, key 
personnel on 
6 studies 
b. Active subjects are there in the PI's open Human Research study/ies? 
15 active 
subjects at 
Harvard of 
155 enrolled 
or 
completed; 
studies to be 
transferred to 
a site PI 
upon Dr. 
Killgore’s 
transfer 
c. Investigators are involved on the PI's open Human Research studies? 
3 
d. Research coordinators are involved on the PI's open Human Research studies? 5 
2. What is the expected length of this project? 
4 years 
3. Retention of study materials before, during, and after completion of the project:  
 
a. Where will the original signed consent and PHI 
Authorization documents be stored (building name and 
room)? 
UAHS 7309 or 7310A 
b. How long will the data/consents be kept after conclusion of the 
project? 
 6 years 
 Other:  
4. If the Human Research project is funded, identify all 
sponsoring entity/ies): 
Department of Defense  
5. If funding support is from a federal agency (such as a training 
grant, infrastructure grant, salary support, project grant, etc.), list 
federal agency and grant number 
Department of Defense  
PT130770 
6. Total funding amount OR per subject amount: 
$3,823,700 

 
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7. The Principal Investigator hereby affirms that ALL individuals who meet the definition of 
"investigator" for this project in the current "Policy on Investigator Conflict of Interest in 
Research" have completed the mandatory Conflict of Interest training 
(http://orcr.arizona.edu/coi/training) and Disclosure of Significant Financial Interests 
(https://uavpr.arizona.edu/COI/).  
 Yes 
8. Will this project be registered on ClinicalTrials.gov because …? 
 Yes 
 No 
a. the local PI is the sponsor of the clinical trial (including NIH-funded clinical trials 
where the local PI is the funding recipient OR IND holder);  
OR 
b. The PI has been designated by a sponsor, contractor, grantee, or awardee to register 
the clinical trial to ClinicalTrials.gov, as the Responsible Party (responsible for 
conducting the trial, and has sufficient data rights) 
 
If yes, please check the appropriate box: 
 ClincialTrials.gov "NCT" number for this trial (define): NCT02370173 
 Registration pending 
 Clinical trial does not require registration (click above to see what studies 
qualify) 
 
 
 
 
40 
SECTION 3.  PROJECT NARRATIVE 
 
41 
1) Background 
42 
During the past decade, over 2 million U.S. military personnel have deployed on potentially dangerous 
43 
missions in support of the wars in Iraq and Afghanistan [1].  Combat duty is inherently hazardous and 
44 
many deployed Soldiers have experienced intense and personally life-threatening situations or witnessed 
45 
horrific and traumatic events.  The neuroendocrine stress response that is associated with these types of 
46 
potentially life-threatening experiences prepares the brain and body for survival.  As part of this survival 
47 
response, several brain systems become hyper-responsive and sensitized to potential threat.  In particular, 
48 
exaggerated amygdala responses during stressful experiences enhance the encoding of vivid and indelible 
49 
emotional memories [2, 3].  For some combat veterans, the intensity and horrific nature of these 
50 
experiences is perceived as so overwhelming that they continue to have sustained physiological arousal, 
51 
heightened startle reflexes, and uncontrollable intrusive memories and nightmares that persist for years or 
52 
even decades after the traumatic experience.  If these symptoms are sustained and lead to impairments in 
53 
daily functioning, the service member may be diagnosed with post-traumatic stress disorder (PTSD).  
54 
Initial rates of PTSD in Soldiers returning from combat duty in Iraq and Afghanistan were reported to be 
55 
as high as 17% [4], and subsequent reports have confirmed rates as high as 20% [5], depending on the 
56 
method of assessment.  Furthermore, PTSD often presents as a comorbid disorder with a range of other 
57 

 
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psychiatric and/or somatic problems [6-8].  Treatment for PTSD usually involves some combination of 
58 
cognitive therapy, exposure therapy, and pharmacotherapy.  Unfortunately, current therapeutic 
59 
interventions show variable efficacy and frequent treatment failures [9, 10].  Consequently, alternative 
60 
approaches or augmentations to existing treatments are needed.   
61 
 
62 
Sleep disruption in PTSD 
63 
Sleep disruption has been labeled the “hallmark of PTSD.”  In fact, sleep problems appear to be the most 
64 
prevalent complaint of individuals with PTSD [11], and may contribute significantly to the persistence 
65 
and severity of the disorder [12-14].  A recent meta-analysis confirmed the presence of sleep 
66 
abnormalities in patients with PTSD, including excessive stage 1 sleep, reduced slow wave sleep, and 
67 
elevated rapid-eye-movement density, when compared to unaffected individuals [15].  Over two-thirds of 
68 
combat veterans with PTSD endorse problems with sleep, particularly insomnia and nightmares [13, 16, 
69 
17], with rates of self-reported sleep complaints exceeding 90% in some studies [18].  Neylan and 
70 
colleagues (1998) found that initial insomnia (difficulty falling asleep) occurred in 44% of combat 
71 
veterans with PTSD, 6% of veterans without PTSD and 5% of healthy comparison subjects.  Moreover, 
72 
91% of veterans with PTSD reported difficulties maintaining sleep (i.e., staying asleep after initial sleep 
73 
onset) [19].  In another study, early morning awakening was reported by 43% of individuals with PTSD 
74 
compared to 13% of individuals without PTSD [20].  Nightmares leading to awakening have been 
75 
reported to occur frequently in about 50% of combat veterans with PTSD, compared to only 5% of 
76 
veterans without PTSD and 3% of healthy controls [19].  Moreover, the severity of sleep disturbance 
77 
correlates with overall PTSD symptom severity [21, 22], even when accounting for the effects of 
78 
potentially confounding variables such as alcohol use and psychiatric comorbidity [23].  Recent findings 
79 
suggest that insomnia and sleep problems may actually play a mediating role between combat stressors 
80 
and the eventual development of psychological symptoms among veterans of the war in Iraq [24].  
81 
Soldiers who develop insomnia in the months following a combat deployment are more likely to show 
82 
symptoms of PTSD and depression when re-assessed at one year post-deployment [25], and sleep 
83 
problems are better predictors of suicide among military personnel than measures of either depression or 
84 
hopelessness [26].  Thus, sleep may be a leverage point for affecting recovery from PTSD. 
85 
Research on conditioned fear points to a critical role for sleep in the treatment of PTSD.  Indeed, 
86 
PTSD has been conceptualized as a disorder of fear conditioning, involving hyper-responsive fear 
87 
reactions via sustained and exaggerated amygdala activation [27].  There is a large animal literature 
88 
showing that quality sleep facilitates the extinction of conditioned fear [28-31].  Moreover, Pace-Schott 
89 
and colleagues, recently demonstrated the same effect in humans [32], showing that after a person has 
90 
been conditioned to fear a particular stimulus and then provided with multiple extinction trials, the 
91 
extinction response only generalizes to other similar stimuli following a night of undisturbed sleep, but 
92 
fails to generalize to other similar stimuli if post-learning sleep is prevented.  These results suggest that 
93 
extinction of conditioned fear is facilitated by sleep.  Other research shows that sleep disruption amplifies 
94 
the effects of anxiety on anticipatory brain functioning in the amygdala [33].  By extension, the potential 
95 
for rapid recovery from PTSD may be hampered by the inability to obtain normal restorative sleep.  In 
96 
other words, the PTSD patient may be locked in a vicious circle whereby one of the major symptoms of 
97 
the disorder may itself be preventing full recovery and leading to continuation or even exacerbation of 
98 
symptoms.  Therefore, effective treatment and recovery from PTSD may be crucially dependent upon, or 
99 

 
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at the very least facilitated by, direct interventions aimed at improving the quality and duration of the 
100 
individual’s sleep. 
101 
 
102 
Light Therapy for Sleep Disruption & Implications for PTSD 
103 
The most common approaches to sleep disturbance involve short-term prescription hypnotic 
104 
medications, but these can have negative or even dangerous side effects [34].  Therefore, alternative, non-
105 
pharmacologic approaches are needed.  While psychological or behavioral treatments may be helpful, 
106 
many service members perceive stigma associated with traditional talk-therapy approaches.  An 
107 
alternative non-pharmacologic approach that shows promise for treating sleep disruption is bright light 
108 
therapy (BLT), particularly within the short-wavelength (i.e., blue) spectrum [35-40].  Exposure to bright 
109 
light at certain times of the day has been shown to reset the timing of the sleep and wake cycle [41], 
110 
enhance subjective and objective measures of alertness [42, 43], increase prefrontal brain activation [44], 
111 
and to improve overall sleep quality [43].  The effectiveness of BLT is potentially mediated by the 
112 
entrainment of circadian cycles that regulate sleep and other homeostatic bodily functions [45-48].  Light 
113 
exposure during the early morning phase-advances the timing of the circadian clock, while exposure 
114 
during the late evening delays it [49].   
115 
Sleep-wake cycles and other endogenous circadian rhythms are regulated predominantly by the 
116 
suprachiasmatic nucleus (SCN) of the hypothalamus.  The SCN generates an endogenous rhythm of 
117 
slightly over 24 hours [50].  This rhythm is entrained or synchronized by environmental cues, most 
118 
prominently by light exposure cycles that correspond to transitions from night to day.  This process is 
119 
mediated by photoreceptive ganglion cells in the retina (i.e., melanopsin receptors), which appear to be 
120 
specialized for relaying light/dark information, particularly within the blue wavelengths, to the SCN via 
121 
the optic nerve [51].  This information is then sent from the SCN to the pineal gland, resulting in the 
122 
synthesis and release of the hormone melatonin which signals the biological night and prepares the 
123 
organism to sleep [40, 52, 53].   
124 
Initial studies on circadian effects of light showed that bright white light effectively suppresses 
125 
melatonin and shifts both melatonin secretion and circadian rhythms [40, 54-56], resulting in shifts in 
126 
sleep and wakefulness periods [57, 58].  More recently, it has been found that shorter wavelength light in 
127 
the blue spectrum (446-477nm) is particularly effective at suppressing melatonin [59], and outperforms 
128 
longer wavelength red light in terms of melatonin-suppression, circadian phase shifting, antidepressant 
129 
effects, and increasing alertness [38, 39, 60-65].  Given that the melanopsin receptors appear to be 
130 
primarily responsive to blue wavelength light [40], and that similar melatonin suppressing effects can be 
131 
produced with significantly lower light intensities in the blue-wave spectrum, numerous studies have now 
132 
begun to focus on using this wavelength for improving daytime alertness, subjective sleep quality [43], 
133 
and phase advancing individuals with delayed sleep phase disorders [39, 48]. BLT is particularly effective 
134 
for circadian rhythm sleep disorders [66-68], which involve a shift between the individual’s sleep pattern 
135 
and the pattern desired by social norms [69].  BLT also appears to improve the irregular sleep-wake 
136 
patterns seen in Alzheimers’ dementia, which involve periodic sleep disruption and nightly restlessness 
137 
[69].  
138 
Bright light therapy has long been recognized as an extremely effective treatment for Seasonal 
139 
Affective Disorder (SAD)[70].  Evidence for the efficacy BLT in SAD has accumulated over nearly three 
140 
decades of research investigations, including a number of placebo-controlled trials.  Some studies have 
141 

 
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shown that either morning or evening BLT is superior to placebo, while others find greater evidence of 
142 
morning light superiority [41].  More recently, BLT has also shown efficacy in nonseasonal Major 
143 
Depression, producing net reductions in depression and anxiety symptoms in the range of 12-35% 
144 
compared with dim light placebo conditions [71-73], and having potent synergistic effects when used as 
145 
an adjunct to medication.  BLT also appears to have a mild anxiolytic effect [74], and has recently been 
146 
shown to be effective in reducing anxiety and depression in patients with seizure disorders [75].  In 
147 
several studies, significant effects on mood were found within 1 week or less of BLT treatment initiation 
148 
[73], with increasing benefits seen over several weeks.  Recent evidence also suggests blue light 
149 
wavelengths may be particularly effective for reducing depressive symptoms and features [61, 76, 77].  
150 
Importantly, the effectiveness of BLT in SAD and nonseasonal depression appears comparable to that of 
151 
antidepressant medication [78], with the additional advantages of a low side effect profile [79] and 
152 
quicker onset of action [73, 80].  Moreover, BLT provides a viable option for patients who resist, refuse, 
153 
or do not respond to pharmacological treatment. 
154 
In summary, there is convincing evidence that BLT has therapeutic 
155 
effects on anxiety and depression, and has strong effects on the normal circadian 
156 
rhythm of alertness and sleep-wake cycles.  These features are all central to the 
157 
symptomatology of PTSD, yet no published studies have examined the effects 
158 
of BLT on PTSD outcome.  One unpublished pilot study at the University of 
159 
South Carolina and Dorn VA Medical Center using 10000 Lux BLT (broad 
160 
spectrum white light) for 45 minutes per day for two weeks in 9 PTSD patients.  
161 
Compared with placebo, BLT was associated with greater percent improvement 
162 
in scores on the Clinical Global Impression Scale and the Clinician 
163 
Administered PTSD Scale (CAPS-5), with more than 20% improvement found 
164 
for BLT, while less than 4% of placebo participants showed improvement 
165 
(Youngstedt, Ginsberg, Kline, & Zielinski, unpublished data).  These pilot 
166 
results suggest that BLT may be an effective treatment for PTSD, though larger 
167 
controlled studies are needed to provide confirmation and to examine the effects 
168 
of BLT on particular PTSD symptoms.  Based on the evidence summarized above, we propose that BLT 
169 
in the blue wavelength spectrum will lead to significantly improved sleep, less depression, and less 
170 
anxiety among combat veterans and other individuals with PTSD, and that these improvements will lead 
171 
to a global improvement in overall PTSD severity relative to control groups with and without combat 
172 
exposure.  Based on recent evidence suggesting that the effect of light therapy on melatonin, sleep, and 
173 
mood is mediated primarily via short wavelength blue light melanopsin receptors in the eye, we propose 
174 
to compare an active treatment device with wavelengths peaking at 469 nm (blue) versus an identical 
175 
placebo device fitted with amber colored diodes (see Figure 1).  Thus, this study will be the first, large 
176 
placebo controlled study examining the effectiveness and neuroimaging correlates of BLT in PTSD.   
177 
! "#$%&' () %&
*(+"%, - &! . , %/&
Figure1.BlueLight(BL)and
amberplacebolight(PL)devices

 
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178 
A. 3. Preliminary Data 
179 
Our group has a long history of using functional 
180 
neuroimaging techniques to study PTSD.  Using a 
181 
paradigm known as the Masked Affect Task (MAT), 
182 
our lab reported that combat exposed veterans with 
183 
PTSD showed exaggerated amygdala responses to 
184 
fear-related facial stimuli perceived below the 
185 
threshold of conscious awareness when compared to 
186 
combat exposed veterans without PTSD [27].  We 
187 
have now collected pilot data on 65 participants, 
188 
including 14 individuals with PTSD, 14 individuals 
189 
with panic disorder, and 15 participants with simple 
190 
phobias using this same paradigm. As evident in the 
191 
figure, compared to healthy controls or other anxiety 
192 
groups viewing masked fearful faces, patients with 
193 
PTSD showed greater activation within the 
194 
amygdala, one of the primary brain structures 
195 
involved in the assessment of threat.  PTSD subjects 
196 
also showed reduced activation within the ventromedial prefrontal 
197 
cortex relative to healthy controls.  This suggests that the 
198 
hyperarousal and exaggerated startle reflexes associated with PTSD 
199 
may be partly the result of abnormal responses in the amygdala.  At 
200 
present, no neuroimaging studies have yet examined the role of 
201 
sleep in this process.  However, recent data from Yoo and 
202 
colleagues suggests that loss of normal sleep is associated with 
203 
reduced functional connectivity between the VMPFC and the 
204 
amygdala, suggesting that sleep loss may reduce the ability of the 
205 
prefrontal cortex to regulate the emotional responses of the 
206 
amygdala [81].  We have also conducted an fMRI study showing that reduced sleep is associated with 
207 
altered functional connectivity between the VMPFC and amygdala, and the strength of such connectivity 
208 
is directly related to the severity of symptoms of anxiety, depression, and reduced emotional functioning 
209 
[82].  Our preliminary studies of cognitive functioning during sleep deprivation support the prefrontal-
210 
emotional dysregulation model [83-92]. Notably, the anterior cingulate cortex (ACC) and hippocampus 
211 
demonstrate abnormalities in neurometabolites such as n-acetylaspartate (NAA), a putative marker of 
212 
neuronal integrity, in patients with PTSD (Karl and Werner, 2010).[83-92] Because sleep disruption is 
213 
one of the most common symptoms of PTSD, the associated reduction in sleep quantity and quality may 
214 
serve to exacerbate the difficulties these patients have regulating emotions, serving to develop a vicious 
215 
circle of hyperarousal, decreased sleep, and emotional dysregulation.  
216 
- 0.6 
- 0.4 
- 0.2 
0.0 
0.2 
0.4 
0.6 
0.8 
HC 
SAP 
PTSD 
PD 
Parameter Estimate 
- 1.2 
- 1.0 
- 0.8 
- 0.6 
- 0.4 
- 0.2 
0.0 
0.2 
0.4 
0.6 
0.8 
HC 
SAP 
PTSD 
PD 
Parameter Estimate 
**
***
*
Amygdala
VMPFC
***
**
*
*
*
Figure2.MaskedAffectTask:PreliminaryfMRIdatafromvarious
anxietydisorders(n=65)showsgreateramygdalaac va onand
reducedVMPFCac va on.Notethatamygdalaac va onis
greatestamongPTSDsubjects(n=14)rela vetosmallanimal
phobics(n=15),panicpa ents(n=14),andhealthycontrols(n=
22).*p<.05,**p<.005,***p<.001.
-1.20 
-1.00 
-0.80 
-0.60 
-0.40 
-0.20 
0.00 
!
" # $%&!' () *%$+!
!
!, (- %!" *. /%!
Reduction in Sleep Problems 
Figure3.ScoresonthePi sburghSleepQualityIndex
(PSQI)showedgreaterreduc oninsleepproblems
following6-weeksoftreatmentwiththeac vebluelight
(n=7)treatmentversusamberlight(n=5)placebo.

 
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The proposed investigation will examine changes in sleepiness, neuropsychological functioning, 
217 
symptom severity, as well as brain functioning and neurochemistry before and after a 6-week treatment 
218 
period with BLT.  To this end, we have collected pilot data showing that 6-weeks of daily morning 
219 
exposure to BL improves sleep, cognitive performance, brain functioning, and underlying axonal integrity 
220 
in concussion patients compared to equivalent exposure to amber placebo light (PL).  Our preliminary 
221 
findings in a small pilot sample of 12 participants (BL n = 7; PL n = 5) suggest that BL treatment may be 
222 
effective at improving sleep and accelerating recovery.  While fully cognizant of the fact that these data 
223 
are preliminary, we present the following findings to provide support for the feasibility of the study 
224 
design and demonstrate our capacity to collect, process, and analyze relevant data.   
225 
Subjective Symptom Improvement.  Figure 3 depicts subjective sleep quality, as measured with 
226 
the Pittsburgh Sleep Quality Index (PSQI) pre- and post-
227 
intervention by group.  While there was no change in the Amber 
228 
Light Placebo group between pre- and post-treatment assessment, 
229 
by trend, PSQI scores were reduced in the Blue Light group (p = 
230 
.07), suggesting improvement. Of note, in contrast to the Amber 
231 
Light group, for which sleep quality remained clinically abnormal 
232 
(i.e., PSQI ≥ 5), the post-treatment PSQI mean reflected good sleep 
233 
quality for the Blue Light group (i.e., PSQI < 5).  These findings 
234 
suggest that BL was more effective in improving subjective sleep 
235 
quality than the PL treatment. 
236 
Actigraphic Sleep:  Participants were monitored using wrist 
237 
actigraphy for the duration of the study (1-week before treatment and throughout the treatment period).  
238 
We compared actigraphic sleep between the baseline week and the final week of the study.  After removal 
239 
of one outlier (z > 2.5), participants in the BL group (n = 6) showed an increase in the minutes of sleep 
240 
objectively measured by wrist actigraphy compared to the PL group (n = 5) (see Figure 4).  On the whole, 
241 
those in the amber placebo group improved by only 8.1 minutes of additional sleep per night, whereas 
242 
those in the active BL group gained nearly twice as many minutes of sleep per night on average (i.e., 15.0 
243 
minutes).  Findings suggest that BL was associated with greater 
244 
improvement in objective sleep quantity than PL.  
245 
Objective Sleepiness/Alertness. On an objective measure of 
246 
sleepiness, participants were monitored with 
247 
electroencephalography (EEG) while 
248 
attempting to sleep for 20 minutes in a 
249 
quiet, darkened room. Figure 5 shows 
250 
daytime sleepiness, as measured with the 
251 
Multiple Sleep Latency Test (MSLT) at 
252 
11:50am, 1:50pm and 3:50pm pre- and 
253 
post-intervention by group.  There was a 
254 
significant change in sleep onset latency 
255 
between pre- and post-treatment by 
256 
group (p=.02), with the BL group taking 
257 
longer to fall asleep in sleep-conducive 
258 
0 
5 
10 
15 
20 
25 
30 
35 
40 
45 
Amber Light 
Blue Light 
Mean Change in Response time (ms) on PVT 
-1.5 
-1.0 
-0.5 
0.0 
0.5 
1.0 
1.5 
2.0 
2.5 
3.0 
3.5 
Amber Light 
Blue Light 
Mean Change in PVT Lapses 
Figure6.Comparedtotheplacebolight(n=5),6-weeksofac vebluelight(n=7)treatmentwasassociatedwithsignificantly
fasterresponse meandfewera en onallapsesonthepsychomotorvigilancetest(PVT).
! "
#"
$"
%&"
%' "
 ( )*+, - . "
 "/ +01, "
2 , *3"45*36, "73"8), , 9"2 73: ;, <"
Figure4.Comparedtotheplacebolight(n=5),theac vebluelight
(n=7)treatmentresultedinagreaterimprovementinthenumber
ofminutesofsleep(viaac graphy)a er6-weeks.
Figure5.Comparedtotheplacebolight(n=5),theac vebluelight
(n=7)treatmentresultedinagreaterlatencytofallasleepduring
theday meMSLTa er6-weeks.

 
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conditions than the PL group.  This indicates greater enhancement of alertness in the BL group following 
259 
treatment compared to the PL condition. 
260 
Psychomotor Vigilance Test (PVT):  The PVT is a 10-minute computerized measure of sustained 
261 
attention and psychomotor vigilance that has been shown to be exquisitely sensitive to sleep deprivation.  
262 
The PVT currently serves as the “gold standard” for assessing degradation in alertness and vigilance 
263 
following sleep loss.  Figure 6 depicts mean 
264 
change in response time for correct trials for 
265 
one of three PVT administrations.  There was 
266 
a significant group difference, with the PL 
267 
group showing slower mean response times 
268 
between pre- and post-treatment assessment.  
269 
In addition, there was a significant group 
270 
difference on PVT attentional lapses (i.e., 
271 
response time > 500ms) between pre- and 
272 
post-treatment assessment, with more 
273 
attentional lapses in the PL than the BL 
274 
group. This preliminary finding is presented 
275 
in Figure 6.  Together, these findings suggest 
276 
that BL was associated with greater post-
277 
treatment alertness and vigilance compared to PL treatment.  
278 
d)  Neuropsychological Performance Changes:  Figure 7 depicts the change in cognitive 
279 
functioning, as measured with the Repeatable Battery for the Assessment of Neuropsychological Status 
280 
(RBANS) between pre- and post-intervention assessment by group.  Of note, the BL group showed not 
281 
only a marked increase in Total test performance, but also a significant improvement on the Attention and 
282 
Delayed Memory subscales.  In contrast, in the PL group, cognitive performance declined in three of five 
283 
subscales (i.e., Visuo-constructional, Language, and Attention) and Total test performance, but not for the 
284 
BL group.  Importantly, the difference in change between pre- and post-treatment group proved 
285 
significant or marginally significant for the Visuo-constructional subscale (p = .06), Language subscale (p 
286 
= .03) and Total test performance (p = .04) between PL and BL groups.  This suggests that sleep 
287 
improvement in the BL group was paralleled by improvements in cognitive functioning, while such 
288 
findings were not observed for the PL group.  
289 
-10 
-8 
-6 
-4 
-2 
0 
2 
4 
6 
Immed Mem Visuo-const 
Language 
Attention 
Del Mem 
Total 
Mean Change in RBANS 
Figure7.Six-weeksofac vebluelight(n=7)treatmentresultedinimprovementsacrossanumberofneurocogni vedomainson
theRepeatableBa eryforNeuropsychologicalStatusrela vetotheamberlightplacebogroup(n=5).

 
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e)  Task-Related Functional MRI:  Figure 8 
290 
shows functional brain activation for 14 subjects (7 
291 
BL, 7 PL) during the n-back working memory task 
292 
and the multi-source interference task (MSIT) that 
293 
subjects performed in the MRI scanner pre-and 
294 
post-treatment (blue = BL > PL; amber = PL > BL).  
295 
Specifically, the figure shows increases in medial 
296 
prefrontal cortex activation between pre- and post-
297 
assessment for the most difficult task condition (i.e., 
298 
2-back) in the blue light condition.  Blue light also 
299 
resulted in increased activation within the thalamus 
300 
and dorsolateral prefrontal cortex (DLPFC) on the 
301 
MSIT following six weeks of BL compared to PL 
302 
treatment.  
303 
f)  Resting State Functional Connectivity:  
304 
Participants also completed a 6-minute resting state 
305 
functional connectivity (rsFC) MRI scan which 
306 
allows the identification of intrinsic patterns of 
307 
temporal correlation among various regions within 
308 
the brain.  Based on our prior published work in 
309 
healthy controls showing that minor fluctuations in nocturnal sleep, even as little as an hour or two, can 
310 
have significant effects on rsFC [93], we hypothesized that improvement in sleep in subjects with mTBI 
311 
would also be associated with improved functional connectivity within behavioral control and memory 
312 
regions of the brain. As shown in Figure 9, we found that six weeks of BL treatment was associated with 
313 
significantly (p< .05) greater inter-regional functional connectivity for the prefrontal cortex and 
314 
hippocampus with other cortical regions in this very preliminary sample (7 BL, 5 PL).  In contrast, those 
315 
receiving PL showed greater functional connectivity of the insula with other posterior cortical regions, 
316 
suggesting greater emotional/visceral sensory processing in the PL group.  Overall, BL treatment was 
317 
associated with increased functional connectivity between memory and attention processing regions. 
318 
Medial Prefrontal 
Cortex 
DLPFC 
Thalamus 
N-Back Task 
MSIT Task 
Figure8.Func onalMRIFindings:Thebluelight(n=7)condi onshowedsignificantly
greaterincreasesinfunc onalac va onduringtheN-BacktaskandMSITtaskcompared
totheamberlightplacebogroup(n=7)withinthemedialprefrontalcortex,dorsolateral
prefrontalcortex(DLPFC)andthalamus.P<.005,k≥10.

 
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g)  Diffusion Tensor Imaging:  
319 
Participants also completed a diffusion 
320 
tensor imaging (DTI) scan.  These data 
321 
were preprocessed in FSL (i.e., eddy current 
322 
correction, reconstruction of diffusion 
323 
tensors, estimation of diffusion parameters, 
324 
registration to anatomical image and 
325 
standard space).  For demonstration of 
326 
feasibility, preliminary data (8 BL, 8 PL) 
327 
have been analyzed in FSL, although the 
328 
sample is currently too small to conduct 
329 
statistical parametric analyses.  Pre- to post-
330 
treatment increases in fractional anisotropy 
331 
(FA) were seen in key regions implicated in 
332 
PTSD, including the rostral and subgenual 
333 
anterior cingulate regions for those 
334 
receiving BL but not for the amber PL 
335 
group.  Greater FA is generally considered 
336 
to signify better white matter health.  These 
337 
preliminary data raise the intriguing possibility that improvement in sleep during the six-week treatment 
338 
period with BL may lead to an accelerated re-myelination process relative to those in the PL group.  We 
339 
believe further research into this intriguing and potentially important possibility and its relation to PTSD 
340 
symptom change is warranted. 
341 
Summary.  Our preliminary findings clearly demonstrate that the methods proposed herein are 
342 
feasible and that our team can effectively collect, process, and analyze the data, thereby accomplishing the 
343 
aims of the study.  We have now implemented this paradigm with over 30 brain injured participants, and 
344 
all were able to complete the study procedures without difficulty.  Furthermore, the case findings we 
345 
highlight also provide limited but compelling evidence that the BLT program was associated with 
346 
improvement in symptoms, neuropsychological status, and neurocircuitry changes in the hypothesized 
347 
direction.  Thus, the preliminary data suggest that the protocol we propose is feasible and shows 
348 
significant promise for improving sleep and brain functioning. 
349 
 
350 
B. SPECIFIC AIMS/HYPOTHESES 
351 
Project Overview.  Combat veterans and other individuals with PTSD will complete two comprehensive 
352 
sessions including neurobehavioral assessments, repeated polysomnographic sleep studies, and 
353 
neuroimaging sessions (functional MRI, structural MRI, and proton spectroscopy) separated by 6 weeks 
354 
of actigraphically monitored at-home treatment.  During the intervening 6 weeks, participants will be 
355 
randomly assigned to receive 30 minutes of daily morning blue light therapy (BL) or an amber light 
356 
placebo treatment (PL).  Sleep quality and quantity will be measured using subjective reports, objective 
357 
actigraph readings, and polysomnography.  Globally, we hypothesize BL will improve sleep quality and 
358 
quantity relative to PL, and these improvements will be associated with improvements in neurocognitive 
359 

 
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function, alterations in proton metabolites in the limbic system and medial prefrontal cortex, and reduced 
360 
PTSD symptom severity at follow-up assessment.  The following are the Specific Aims and Hypotheses: 
361 
AIM 1:  Evidence suggests that morning bright light therapy suppresses daytime melatonin and 
362 
leads to an entrainment of the circadian rhythm that modulates daytime alertness and nighttime sleep.  
363 
The first objective will be to assess the validity of this effect in PTSD patients. 
364 
Hypothesis 1:  Six weeks of BLT will improve sleep relative to PL among PTSD subjects. 
365 
1a:  Six weeks of morning blue light therapy (BLT) will improve objective and subjective 
366 
measures of sleep duration and quality as measured by actigraphy, sleep logs, sleep scales, and 
367 
polysomnography relative to an amber light placebo therapy (PL) condition. 
368 
AIM 2:  If light therapy is successful in entraining the circadian rhythm and improving nighttime 
369 
sleep in patients with PTSD, this should be associated with improvement in symptoms and cognitive 
370 
functioning, as sleep has been shown to be critical in the process of extinguishing conditioned fears.  
371 
Therefore, the second Aim is to evaluate the association between changes in sleep patterns and 
372 
improvement in symptom expression, emotional wellbeing, and cognitive functioning in patients with 
373 
PTSD. However, even if Aim 1 is not successful, the present study will provide important cross-sectional 
374 
data regarding the relationship between measured sleep, cognitive functioning, and fear extinction in 
375 
individuals with PTSD. 
376 
Hypothesis 2:  BL will improve cognitive functioning, symptoms of PTSD, and generalization of 
377 
fear extinction relative to PL. 
378 
2a:  Six weeks of BL will improve measures of neurocognitive (i.e., memory and executive 
379 
functions) and mood functioning relative to PL. 
380 
2b: The PTSD group receiving six weeks of BL will show significant reduction in self-
381 
reported symptom scores on the PTSD symptom checklist and CAPS, lower emotional distress on clinical 
382 
measures, and greater generalization of conditioned fear extinction relative to the PTSD group receiving 
383 
PL. 
384 
AIM 3:  At present, there are no known studies that have examined the neurobiological correlates 
385 
of symptom improvement in patients with PTSD following light exposure therapy.  The present study 
386 
aims to provide clear evidence of functional and neurochemical changes that are associated with changes 
387 
in sleep, cognition, and PTSD symptoms from pre- to post-treatment. Even if Aim 1 is not supported, the 
388 
obtained cross sectional data will provide critical insights regarding the association between sleep, 
389 
neurometabolites, and brain function within patients with PTSD.  This correlational information is 
390 
currently lacking for PTSD and will fill an important knowledge gap regardless of whether the light 
391 
therapy is successful. 
392 
Hypothesis 3:  Six weeks of BL will produce reliable changes in brain activation and 
393 
neurochemistry relative to PL, particularly for PTSD subjects. 
394 
3a:  Relative to PL, six weeks of BL will lead to significantly increased ventromedial 
395 
prefrontal activation and reduced amygdala activation during the backward masked affect fMRI task. 
396 
3b:  Relative to PL, six weeks of BL will lead to significantly greater negative functional 
397 
connectivity between the ventromedial prefrontal cortex and amygdala during resting state fMRI. 
398 
3c: Relative to PL, six weeks of BL will be associated with increased activation of the 
399 
VMPFC, and reduced activation within the amygdala and dorso-medial prefrontal cortex during the 
400 
extinction recall scan. 
401 

 
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3d: Relative to PL, six weeks of BL will be associated with increased levels of GABA and 
402 
reduced glutamate in the amygdala-hippocampal complex and anterior cingulate gyrus as measured by 
403 
proton magnetic resonance spectroscopy (1H MRS). 
404 
3e: Relative to PL, six weeks of BL will produce increased levels of N-acetyl-aspartate 
405 
(NAA), choline (Cho), and reduced phosphocreatine (Cr) within the amygdala-hippocampal complex and 
406 
anterior cingulate gyrus. 
407 
AIM 4:  The fourth Aim is to demonstrate whether changes in subjective and objective measures 
408 
of sleep are associated with changes in symptom severity, cognitive functioning, brain activation, and 
409 
neurochemistry. Regardless of the success of the light therapy approach outcome in Aim 1, the available 
410 
data will provide some of the first longitudinal data examining changes in sleep patterns over time in 
411 
individuals with PTSD and their correlation with these other metrics.  Thus, useful data will be acquired 
412 
even if the primary hypothesis of Aim 1 is not supported. 
413 
Hypothesis 4:  Improvements in sleep noted in Hypothesis 1, will be linearly correlated with 
414 
improvements in cognitive and symptom functioning in Hypothesis 2 and structural and functional 
415 
brain changes in Hypothesis 3. 
416 
4a:  Changes in sleep parameters identified in Hypothesis 1 will correlate with 
417 
improvements in memory, executive functioning, and neuropsychological performance on neurocognitive 
418 
measures described in Hypothesis 2. 
419 
4b: Changes in sleep parameters identified in Hypothesis 1 will correlate with changes in 
420 
neurochemistry as outlined in Hypothesis 3d and 3e above. 
421 
 
422 
2) Lay Summary (approximately 400 words) 
423 
Sleep disturbance is nearly ubiquitous among individuals suffering from PTSD and is a major problem 
424 
among service members returning from combat deployments.  Recent evidence suggests that adequate 
425 
restorative sleep may a crucial component in the ability to generalize fear extinction learning, and 
426 
ultimately may be a key feature in the process of recovery from PTSD.  The proposed study aims to test a 
427 
novel, inexpensive, and easy to use non-pharmacologic approach to improving sleep among service 
428 
members and other individuals with PTSD.  Our approach is based on recent scientific discoveries 
429 
regarding the role of the photosensitive retinal ganglion cell system in regulating sleep-wake patterns.  
430 
Moreover, our protocol employs a novel, non-pharmacologic intervention for influencing this system to 
431 
regulate sleep and cognition.  Primary outcome measures will include not only PTSD symptom 
432 
improvement but also include cutting-edge neuroimaging of brain structure, function, connectivity, and 
433 
neurochemistry changes.  The proposal is firmly grounded in the emerging scientific literature 
434 
regarding sleep, light exposure, brain function, anxiety, and resilience.  Prior evidence suggests that blue 
435 
light therapy is effective for improving mood and fatigue, and our pilot data further suggest that this 
436 
treatment may be effective for improving daytime sleepiness and brain functioning in brain injured 
437 
individuals.  Thus, this intervention, in our own research and in the work of others, has been shown to 
438 
affect critical sleep regulatory systems.    Improving sleep may be a vital component of recovery in these 
439 
service members.  Our approach would directly address this issue.  Our preliminary data have shown that 
440 
this approach is extremely well tolerated and is effective for improving sleep, mood, cognitive 
441 
performance, and brain function among individuals with brain injuries.  The protocol is actually less 
442 

 
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burdensome than it appears, as over 30 participants have already successfully completed this same 
443 
protocol in our pilot study of mild traumatic brain injury without any complaints or discontinuations due 
444 
to excessive burden.  Finally, the potential impact of this study is high because of the capability of 
445 
transitioning the research to direct clinical application almost immediately.  If the BL treatment is 
446 
demonstrated as effective, this approach would be readily available for nearly immediate large-scale 
447 
implementation, as the devices have been widely used for years in other contexts, are already safety 
448 
tested, and commercially available from several manufacturers for a very low cost.  Thus, the impact of 
449 
this research on treating PTSD would be high and immediate. 
450 
 
451 
3) Setting of the Human Research 
452 
 
This study requires three visits including an initial assessment and two testing/scanning sessions 
453 
separated by six-weeks of daily light exposure treatment at home. 
454 
 For the initial assessment and the baseline testing session, subjects will be seen at the Lab of Dr. 
455 
Killgore in the University of Arizona Department of Psychiatry. There, subjects will complete personality 
456 
assessments, a comprehensive cognitive assessment battery, and several tests of motor functioning.  
457 
  
458 
 
Magnetic Resonance Imaging (MRI) Procedures:  The data collection will occur at the research-
459 
dedicated University of Arizona scanner facility that houses a new 3 Tesla magnet (see Equipment for 
460 
description). For functional neuroimaging, audio and visual stimulus presentation equipment is available 
461 
through the Resonance Technologies headphone/goggle system or high-definition MRI-compatible LCD-
462 
display (viewed through a mirror in the head cage).  An fMRI compatible EEG system including caps, 
463 
cabling, and pre-amplifier is integrated with this space (see Equipment for description).  Scanner data are 
464 
transferred securely to a RAID storage system for subsequent transfer to PI laboratories. Offline analysis 
465 
will take place in the Laboratory of PI Dr. Killgore. 
466 
 
In January 2013, the University of Arizona purchased a Siemens Magnetom TIM Skyra 3T that is 
467 
capable of high-resolution imaging capabilities. This whole-body 3.0T device will be configured with 48 
468 
receiver channels and up to 204 integrated coil elements. It is capable of integrated parallel acquisition 
469 
techniques and provides higher signal to noise in the parallel imaging mode than its predecessor, the Trio. 
470 
The maximum acceleration factor using parallel imaging is 16 using either mSENSE or GRAPPA, and 
471 
3D scanning can be accelerated in two directions (maximum acceleration factor of 4 in second direction). 
472 
The gradients of the Skyra have a maximum amplitude of 45 mT/m and a maximum slew rate of 200 T 
473 
Tm-1s-1, yielding a minimum rise time of 225μs. The vector gradient performance (vector summation of 
474 
all three gradient axes) results in a maximum effective amplitude of 78 mT/m and a maximal effective 
475 
slew rate of 346 Tm-1s-1. All three gradient coils are force-compensated to reduce vibration and deliver 
476 
superior eddy current performance. The water cooled gradient amplifier has a maximum amplitude 
477 
potential of 2,250 volts and a maximum current output of 750 amps. The instrument has a minimum slice 
478 
thickness (in two dimensions) of 0.1 mm and a minimum partition thickness (in three dimensions) of 0.05 
479 
mm. The instrument produces high sensitivity, with main field, or B0, homogeneity of 1.4 ppm VRMS for 
480 
a 40 cm diameter spherical volume. Single shot EPI sequences for measuring diffusion-weighted data sets 
481 
with up to 256 directions of diffusion weighting are also a part of this instrument’s capability. It provides 
482 

 
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diffusion tensor imaging and parametric maps derived from fractional anisotropy calculated in real time, 
483 
automatically. Additional sequence options include Arterial Spin Labeling, and susceptibility weighted 
484 
imaging (SWI) with both fully supported with parametric and phase map reconstructions.  
485 
 
All structural and functional MRI studies will be conducted in concert with the University of 
486 
Arizona Translational Bioimaing Resource. Subjects in this study will be studied in a scanner that has a 
487 
field strength of 3 Tesla. This field strength has been approved by the FDA for routine clinical use. The 
488 
three instruments are maintained by GE service engineers and currently meet or exceed manufacturer's 
489 
specifications on performance. For functional neuroimaging, audio and visual stimulus presentation 
490 
equipment is available through the Resonance Technologies headphone/goggle system. 
491 
 
A research area, Room 1564 (400 square feet), located immediately adjacent to the 3.0 Tesla 
492 
scanner, is equipped with 3 PC/Linux workstations and sgi O2 for data transfer and storage, image 
493 
processing, and data manipulation. All workstations are networked through a central hub and are 
494 
protected against external tampering using firewalls within the UAMC computer network. 
495 
 
Functional MRI is mostly done in MR3, a General Electric 3.0T HD Signa Excite scanner. It is 
496 
equipped with Optimized ACGD Gradients (40mT/m, 150 mT/m/ms slew rate running 12x software). It is 
497 
a 55cm diameter long bore magnet. This instrument is equipped with a head coil, 8 channel HR brain 
498 
array, a phased array neurovascular coil, 8 channel phased array spine coil, extremity coils (knee and 
499 
wrist) and a torso coil. MR3 has multinuclear spectroscopy capability and high order shims. 
500 
 
501 
4) Resources available to conduct the Human Research  
502 
 
Dr. Killgore’s effort is 100% devoted to research; he does not have clinical or teaching time 
503 
mandated as part of his FTE. He funds several Research Technicians and Research Assistants and one lab 
504 
manager.  
505 
 
The Department of Psychiatry has staff devoted to research administration, including an upper 
506 
level administrator and a regulatory coordinator. All have experience with IRB/regulatory matters and 
507 
grants administration. Business office staff is knowledgeable in grants finance and accounting, and federal 
508 
work-study students devoted to research are available for data entry and other administrative support. 
509 
 
Dr. Killgore’s Lab includes computing equipment such as backup drives and external hard drives, 
510 
backup surge protectors, intercom system, neuroimaging workstations with 6 TB minimum storage each; 
511 
Actiwatch sleep monitors watches, docks, and software analysis programs; Coulbourne Fear Conditioning 
512 
Suite, FaceRead + Observer XT System, sleep profiler ambulatory EEG monitoring systems, and other 
513 
software including EPrime, MatLab, SPSS, and Adobe Captivate. 
514 
 
The Department of Psychiatry provides personal computer resources for word processing, email 
515 
transmission, internet access, and simple statistical analysis for staff, in addition to laser printers, fax 
516 
machines, scanners and photocopy machines. In addition to these resources, the University of Arizona 
517 
maintains full computer and data analytic processing components available to all university faculty on a 
518 
fiber-optic network system, with automatic daily backup available on a secure server. There is full time 
519 
computer support in the Department of Psychiatry for these resources. 
520 
 
This project may use non-FDA-approved devices that are approved for use on the Translational 
521 
Bioimaging Resource (TBIR) MRI scanner through IRB protocol 1911166043, “Translational 
522 

 
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Bioimaging Resource Umbrella MRI Protocol.” TBIR, a UA Core Facility 
523 
(https://ua.ilab.agilent.com/landing/3645#/about), is housed within the UA Biosciences Research 
524 
Laboratory (BSRL) building. 
525 
All study personnel will have up to date CITI training and study protocol training from the PI or PI 
526 
designee. 
527 
 
528 
5) Study Population 
529 
 
The target population is combat-exposed military personnel and other non-military individuals 
530 
who meet diagnostic criteria for PTSD. Participants in the study will include active duty or recently 
531 
discharged combat-exposed military personnel from Operation Enduring Freedom/Operation Iraqi 
532 
Freedom (OEF/OIF) meeting DSM-V diagnostic criteria for PTSD, in addition to some individuals from 
533 
the general population who meet DSM-V diagnostic criteria for PTSD to achieve a total sample size of 90 
534 
participants, which we anticipate will require enrolling up to 108 individuals to account for attrition. An 
535 
 
age range of 18-50 years has been selected to minimize possible developmental and degenerative 
536 
effects that could be expected in younger and older subjects and to encompass the age range of the 
537 
majority of military personnel. Participants will be recruited from several sources. Active duty 
538 
participants will be recruited according to the guidelines specified by the CDMRP upon award receipt. 
539 
The PI, a U.S. Army Reserve Research Psychologist (Lieutenant Colonel), already has a number of 
540 
established relationships and collaborations with leaders in the Army Medical Department (AMEDD), the 
541 
Pentagon, several major medical treatment facilities (MTFs), and all three of the Army’s primary research 
542 
laboratories, including the Walter Reed Army Institute of Research (WRAIR), the U.S. Army Institute of 
543 
Environmental Medicine (USARIEM), and the U.S. Army Aeromedical Research Laboratory 
544 
(USAARL). It is anticipated that potential recruitment of active duty, Reserve, and National Guard 
545 
participants will be effectively facilitated according to the guidelines specified by the CDMRP. 
546 
Participants will be recruited primarily from the Tucson area via IRB approved internet, newspaper, and 
547 
radio advertisements, and contact with individual units. Facebook advertisements and flyers will also be 
548 
utilized to recruit subjects, as described in greater detail below.  
549 
 
550 
Inclusion Criteria: 
551 
1) age 18-50 years; 
552 
2) right handedness or right-hand dominance as assessed by the Edinburgh Handedness Inventory (EHS) 
553 
(necessary to avoid mixed lateralization on brain imaging); 
554 
3) SCID diagnosis consistent with PTSD 
555 
 
556 
Exclusion Criteria: 
557 
1) History of head injury with loss of consciousness for greater than 30 minutes, or post-traumatic 
558 
amnesia for >24 hours, or major neurological illness (e.g. epilepsy, multiple sclerosis/MS); 
559 
2) Chronic medical (e.g. heart conditions, cystic fibrosis, diabetes, cancer, HIV/AIDS, HEP C, thyroid 
560 
problems, high blood sugar) or psychiatric (e.g. bipolar disorder/manic or hypomanic episodes, 
561 
personality disorders, schizophrenia/other psychotic disorders, severe OCD or ADHD) conditions that 
562 
would confound interpretation of results; 
563 

 
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3) Left-handedness or left-hand dominance if ambidextrous (could affect brain lateralization and add error 
564 
variance to scanning); 
565 
4) Abnormal visual acuity that cannot be corrected by contact lenses (necessary to see stimuli in the 
566 
magnetic environment of the scanner); 
567 
5) IQ estimate less than 70; 
568 
6) Metal within the body, pregnancy, or other contraindication for MRI procedures; 
569 
7) Ongoing trauma (e.g. currently being in an abusive relationship) or non-qualifying trauma (e.g. index 
570 
trauma emotional/verbal abuse, children being taken away by the CPS, divorce, natural deaths by age 
571 
or illness); 
572 
8) Previous formal treatment with light therapy; 
573 
9) History of light-induced migraine or epilepsy; medical complications that could elevate the risk of 
574 
discomfort associated with light-therapy; 
575 
10) Use of medications that could affect functional neuroimaging results (e.g., beta-blockers, mood 
576 
stabilizers, atypical antipsychotics, benzodiazepines, hypertension medication, chemotherapy, 
577 
photosensitive medications etc.). Patients currently taking other psychotropic medications (i.e., 
578 
“treatment as usual”) must be stabilized for at least 4-weeks prior to participation. Although 
579 
participants will not be excluded from participation, detailed history and dosages will be documented 
580 
and examined as appropriate in statistical analyses. 
581 
11) Current suicidal intent based on an assessment conducted by a licensed clinical psychologist; 
582 
12) Currently taking or anticipating the need to take sleep-inducing medications (e.g., zolpidem) or 
583 
supplements that have known effects on sleep (e.g., melatonin) during the course of the study.  
584 
a. Patients currently taking other psychotropic medications (i.e., “treatment as usual”) must be 
585 
stabilized for at least 4-weeks prior to participation.  Although participants will not be 
586 
excluded from participation, detailed history and dosages will be documented and examined as 
587 
appropriate in statistical analyses. Due to the broad range of sleeping disturbances that are 
588 
observed with PTSD and the likely difficulty in recruiting sufficient numbers of participants, 
589 
we will not be excluding any particular sleep disorder, but will collect data regarding these 
590 
sleep related problems so that it may be possible to statistically control for the effect of the 
591 
BLT treatment on different forms of sleep problems; 
592 
13) Index trauma occurring before the participant is 18 years of age; 
593 
14) Index trauma occurring 10 years or longer prior to participation in the study; 
594 
15) WRAT4 reading test score indicative of less than a 6th grade level of reading comprehension; 
595 
16) Drug use: Marijuana use not exclusionary. Past drug dependence (other than marijuana) not 
596 
exclusionary if individuals have sustained remission (no drug use in the past 12 months).  
597 
6) Recruitment Methods and Consenting Process 
598 
Please note: The Human Research Protection Office (HRPO) with US Army Medical Research and 
599 
Materiel Command must approve any major amendment to this study prior to its implementation. 
600 
Therefore, implementation of any amendment which requires HRPO approval, including use of revised 
601 
consents, will not begin until HRPO approval is received. 
602 
 
603 

 
FORM: Application for Human Research 
NUMBER 
FORM DATE 
PAGE 
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02/2014 
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hrppsops@huronconsultinggroup.com 
 
Participants will be recruited from several sources. Active duty participants will be recruited 
604 
according to the guidelines specified by the Department of Defense's (DoD's) Congressionally Directed 
605 
Medical Research Programs (CDMRP) upon award receipt. The PI, a U.S. Army Reserve Research 
606 
Psychologist (Lieutenant Colonel), already has a number of established relationships and collaborations 
607 
with leaders in the Army Medical Department (AMEDD), the Pentagon, several major medical treatment 
608 
facilities (MTFs), and all three of the Army’s primary research laboratories, including the Walter Reed 
609 
Army Institute of Research (WRAIR), the U.S. Army Institute of Environmental Medicine (USARIEM), 
610 
and the U.S. Army Aeromedical Research Laboratory (USAARL). It is anticipated that recruitment of 
611 
active duty, Reserve, and National Guard participants will be effectively facilitated and will proceed 
612 
according to the guidelines specified by the CDMRP.  Civilian veterans, Reserve Soldiers, National 
613 
Guard Soldiers, and nonmilitary combat-exposed civilians will also be recruited primarily from the local 
614 
Tucson and surrounding area, from clinical programs within the Department of Psychiatry, and local 
615 
events and advertisements on the web (including our own websites, appropriate sections of community 
616 
websites and forums [e.g. Craigslist], Facebook or other social media, and reputable clinical trial referral 
617 
websites [e.g. StudyKik], and similar websites). Our lab will post IRB approved advertising text on 
618 
similarly themed Facebook groups, which allow for outside posts of this nature. We will adhere to any 
619 
page specific posting requirements as well as Facebook Terms of Service for appropriate behavior. We 
620 
may also utilize print, radio advertisements, TV, and UAHS and College of Medicine hallway and lobby 
621 
monitors and flyers on campus, as well as UA list serves such as 3D memos etc. (ad text will be IRB 
622 
approved), Residence Halls, and other UA buildings (with the appropriate recruitment site authorization 
623 
obtained prior).   
624 
 
We will make approved screening surveys (e.g., Recruitment Survey.pdf) available on UA 
625 
departmental (e.g., Department of Psychiatry, Department of Psychology) or other UA-affiliated websites 
626 
(e.g., UAHS Clinical Research Studies website), as well as other online media appropriate for research 
627 
advertising such as clinical trial referral websites, survey websites (e.g., Qualtrics, Survey Monkey), 
628 
research data management (e.g., REDCap), and crowdsourcing websites (e.g., Amazon Mechanical Turk 
629 
[MTurk]). Crowd-sourcing platforms facilitate recruitment of and payment to individuals for their 
630 
participation in online surveys. When disseminated via this method, our surveys will be restricted to 
631 
participants who live in Arizona and will be securely hosted in Qualtrics, REDCap, or other such 
632 
reputable survey-host.  
633 
 
In addition, UA Clinics (i.e. CAPS, Campus Health, etc.), and outside clinics/businesses in the 
634 
greater Tucson area will be utilized to refer patients to the study. Treating physicians at clinics may be 
635 
informed of the study and the inclusion/exclusion criteria, if they feel they have a patient who qualifies 
636 
they will provide the patient with a study recruitment flyer and the patient will contact our office if they 
637 
are interested. Recruitment site authorization will be obtained prior to recruitment occurring at any site; 
638 
this documentation will be kept within our research files. A trained research assistant will initially screen 
639 
individuals who respond to these advertisements via telephone interview. Individuals meeting basic 
640 
eligibility requirements will be scheduled for an intake visit. Participants whose intake visits are 
641 
scheduled more than six weeks after the date of the initial phone screen will be given a shortened follow-
642 
up phone screen prior to the intake visit, in order to ensure that no changes have taken place which may 
643 
affect their eligibility. Recruitment and advertisement materials will include brief descriptions of the 
644 

 
FORM: Application for Human Research 
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hrppsops@huronconsultinggroup.com 
purpose of the study, the general procedures of the study, important inclusion and exclusion criteria, the 
645 
amount of compensation, and the phone number or email address to contact if interested.  
646 
 
To encourage full participation and minimal subject discontinuation, subject compensation will 
647 
follow the prorated schedule as seen in Section 12. 
648 
 
649 
 
Subjects will be made aware via the Informed Consent Form that if they are active duty military 
650 
personnel, they are not eligible to receive compensation for time spent completing assessments unless 
651 
they are on official military leave status in accordance with Title 24 United States Code 30. Therefore, 
652 
any active duty military personnel not on leave status will not receive compensation for time spent 
653 
completing assessments as attested to by all subjects as part of the informed consent process.  
654 
We will request that subjects attest to their understanding of this by initialing the following: 
655 
 
656 
Participants who are active duty cannot be compensated for any of the research activities while they 
657 
are “on-duty”.  It will be the volunteer’s responsibility to ensure they have taken leave and obtained 
658 
the right permissions, if required, in order to receive compensation for this study.  
659 
______    Please initial to indicate you acknowledge this requirement. 
660 
 
661 
If you are active duty military personnel, you are not eligible to receive compensation for time 
662 
spent completing assessments while you are “on duty.”  In accordance with Title 24 United States 
663 
Code 30, active duty military personnel must be on leave status during each of the three assessment 
664 
sessions in order to be compensated.  If you are on active duty, it is your responsibility to ensure that 
665 
you have completed the appropriate paperwork for leave and obtained the necessary permissions to 
666 
allow you to participate in this study.  If you are on leave status, you will be compensated for the 3 
667 
assessment sessions according to the schedule listed above. 
668 
Screening Procedures: 
669 
 
Potential subjects will be screened over the phone by a clinically trained research assistant to 
670 
verify that subjects meet all inclusion criteria and do not meet any of the exclusionary criteria. 
671 
Information collected during screening will not be used as a part of the research data. Subjects who meet 
672 
basic eligibility requirements will be scheduled for an intake visit. Informed consent will be obtained prior 
673 
to initiating any further screening procedures. After informed consent has been determined, a supervised 
674 
Research Technician who has been trained and meets predetermined qualifications to administer a 
675 
Structured Clinical Interview by doctoral level clinical psychologists with training and experience 
676 
administering these instruments will conduct a structured clinical interview to screen for any psychiatric 
677 
diagnoses. Once eligibility for the study has been confirmed or rejected, the subject will be placed into the 
678 
appropriate experimental group, or excluded from the study if any information yielded from this visit is 
679 
consistent with the exclusionary criteria. 
680 
 
681 
Informed Consent Process: 
682 
• Either the PI or a trained research assistant will be responsible for explaining the study, answering 
683 
questions, and obtaining written informed consent from participants. 
684 

 
FORM: Application for Human Research 
NUMBER 
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PAGE 
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22 of 44 
 
 
 
 
 
 
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hrppsops@huronconsultinggroup.com 
• Initial description of the study will be provided during the telephone screening process. The actual 
685 
consent process will occur during the in-person intake visit. The consent process is the first part of 
686 
the visit, and will take place in a private office. The participant will have the opportunity to read 
687 
the consent form, and each section will be explained in detail by the research assistant. The 
688 
participant will have a chance to ask questions and have them answered fully before making a 
689 
decision to participate. All volunteers will receive a copy of the signed consent form once they and 
690 
the study staff member obtaining consent have signed the form. 
691 
• Only adult participants with normal intellectual capacity (IQ≥70) will be included in the study. 
692 
Any evidence of altered mental status or capacity, due to substances, medications, cognitive status, 
693 
or injury will result in discontinuation of the consent process. 
694 
• Participants will be consented in a private office, but may be accompanied by anyone of their 
695 
choosing. There will be no time pressure and potential volunteers may discuss possible 
696 
participation with anyone and may choose to suspend the consent process and return on another 
697 
occasion, as long as they have not been disqualified or the study has terminated. 
698 
• Participants will be monitored closely by study staff and queried about continued participation 
699 
after completion of each major component of the study (i.e., neurocognitive testing, functional 
700 
imaging, sleep study, etc.) and if there are visible signs that the participant may be having 
701 
difficulty tolerating the procedures. 
702 
• We will not enroll subjects who cannot provide written informed consent; therefore plans to 
703 
consent the subject’s Legally Authorized Representative are not applicable. 
704 
• Because the study requires the ability to read many self-report instruments and complete several 
705 
written tasks, we will not be enrolling anyone that cannot read with at least 6th grade proficiency, 
706 
as indicated by the WRAT 4 Reading test. Because the study requires the ability to comprehend a 
707 
variety of self-report instruments that are only available in English, we will not be enrolling 
708 
participants whose primary language is not English. No waiver of consent is being sought for this 
709 
study. 
710 
• All participants will be adults (age 18 to 50), thus issues regarding assent from minors are not 
711 
relevant. 
712 
 
713 
7) Procedures involved in the Human Research 
714 
General Procedure: Over a 4-year period, 108 participants between the ages of 18 and 50 will be 
715 
recruited to participate (to reach a final n of 90 subjects, assuming 20% attrition).  Participants will 
716 
comprise active duty, Reserve, National Guard, or recently discharged combat-exposed military personnel 
717 
or DoD contractors from Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) meeting 
718 
DSM-V diagnostic criteria for PTSD, in addition to some non-military individuals who meet the DSM-V 
719 
diagnostic criteria for PTSD.  Combat-exposed individuals within 10 years of return from OIF/OEF will 
720 
be eligible.  An age range of 18-50 years has been selected to minimize possible developmental and 
721 
degenerative effects that could be expected in younger and older subjects and to encompass the age range 
722 
of the majority of military personnel.  
723 

 
FORM: Application for Human Research 
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hrppsops@huronconsultinggroup.com 
Prior to data analysis, subjects who consent will have a follow-up phone call where they will be 
724 
administered the PCL-5, PHQ-9, and be asked about general sleep problems using the ESS and ISI.  
725 
The procedures will essentially be identical to those used successfully in our pilot study of patients 
726 
with mTBI.  Participants will attend three laboratory sessions (see Figure 10 below).  Visit 1 involves 
727 
informed consent, demographic data collection, and basic psychiatric assessment.  Participants will be 
728 
provided with a wrist actigraph sleep monitor.  After a week of at home monitoring, each participant will 
729 
return for Visit 2, which is involves comprehensive neurocognitive assessment, neuroimaging, fear 
730 
conditioning testing, objective sleepiness monitoring and heart rate monitoring.  Then participants will be 
731 
randomly assigned to one of two light therapy conditions (n = 45 per group) differing only in the 
732 
wavelength emitted by each light therapy device. Participants will be randomly assigned to either the BL 
733 
condition or the PL condition, using computerized permuted block randomization to match groups by 
734 
gender. Participants assigned to the active treatment condition will undergo 6-weeks of at-home treatment 
735 
with a light device fitted with blue light (BL) diodes, while those assigned to the Placebo (PL) condition 
736 
will undergo 6-weeks of identical treatment with a device fitted with amber light diodes.  To objectively 
737 
monitor sleep, participants will wear a wrist actigraph for the duration of the study.  During the 6 weeks 
738 
of treatment, participants will use the light device for 30-minutes each morning, within 2-hours of 
739 
awakening (verified via light sensor built into the wrist actigraph, daily time stamped electronic sleep 
740 
diary, and compliance as measured by wattage usage/time meter).  After 6-weeks, participants return for 
741 
Visit 3 and undergo a follow-up neurocognitive assessment, neuroimaging, fear conditioning, objective 
742 
sleepiness monitoring, and heart rate monitoring.  These procedures have been extremely successful and 
743 
well tolerated in our pilot study. 
744 
 
745 
Subject Screening: Participants whose intake visits are scheduled more than six weeks after the date of 
746 
the initial phone screen will be given a shortened follow-up phone screen prior to the intake visit, in order 
747 
to ensure that no changes have taken place which may affect their eligibility. 
748 
Intake Visit (Visit 1):  Participants will be given a full description of the study, have the opportunity to 
749 
ask questions, and will provide written informed consent, and will be evaluated for PTSD severity using 
750 
the Structured Clinical Interview for DSM-V (SCID). The Morningness Eveningness Questionnaire 
751 
(MEQ) will be administered to assess circadian rhythm disturbances prior to light treatment. The combat 
752 
exposure scale (CES) will also be administered to participants with combat-related PTSD to inform us of 
753 
the extent and nature of combat exposure in military participants. The Weschler Abbreviated Scale of 
754 
Intelligence (WASI-II) will be administered to control for variation in intelligence levels amongst 
755 
participants. The AUDIT and MUSE questionnaires will also be given to determine the degree and extent 
756 
of alcohol and marijuana use, though neither of these scales will be utilized as a means to determine 
757 

 
FORM: Application for Human Research 
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hrppsops@huronconsultinggroup.com 
exclusion from the study. The Rivermead Post-Concussive Symptoms Questionnaire (RPCSQ) will be 
758 
administered to confirm that any participants who may have experienced concussion during their 
759 
traumatic event did not lose consciousness or experience post-traumatic amnesia. Research Technicians 
760 
who have been trained and meet predetermined qualifications to administer a Structured Clinical 
761 
Interview by doctoral level clinical psychologists with training and experience with these instruments will 
762 
administer the SCID. All SCID administrations will be reviewed via supervision by a qualified doctoral 
763 
level clinical psychologist immediately following the participant’s interview.  Female participants will 
764 
also provide information about their menstrual cycle (length of cycle and time since last menses) because 
765 
this is critical in the interpretation of brain metabolite levels during magnetic resonance spectroscopic 
766 
imaging.  We do not know if MRI scanning presents a risk to unborn fetuses, so we will ask all female 
767 
participants of childbearing potential to complete a urine pregnancy test immediately prior to the scan. 
768 
Female participants must have a negative pregnancy test before the MRI scan can be initiated. This 
769 
pregnancy test will be performed in the Department of Psychiatry. All subjects will wear a heart rate 
770 
monitor for the duration of this visit. Selection criteria for all subjects are as follows: 
771 
During Visit 1, participants will be fitted with a wrist-worn actigraph to monitor sleep/wake 
772 
patterns.  This device will also log exposure to light in three wavelengths (red, green, blue) to measure 
773 
compliance with the protocol.  Participants will also be introduced to the online sleep diary collection 
774 
system and will be given an automated email each morning reminding them to log in and complete the 
775 
sleep diary. 
776 
Visits 2 and 3: Assessment/Scanning Visits:  One week after Visit 1, participants will return for 
777 
Visit 2. Participants will complete a detailed demographic (Day of Scan Questionnaire (DSIQ)) and health 
778 
questionnaire and will be fitted for a heart rate monitor to be worn for the duration of the visit, save for 
779 
the MRI scan where heart rate will be measured by MRI safe leads as part of the MRI scanner. Subjects 
780 
will complete a comprehensive baseline assessment of neurocognitive and emotional functioning, coping 
781 
capacity, and resilience.  Participants will also undergo a validated de novo fear conditioning and 
782 
extinction procedure [98-101], and a series of functional neuroimaging and neurochemistry scans.  
783 
Additionally, participants will complete subjective and objective measures of sleepiness and alertness 
784 
throughout the day.  The following specific tasks and procedures will be administered during the 
785 
assessment session: 
786 
Emotional Functioning/Coping/Symptom Severity:  PTSD severity will be assessed using the 
787 
20-item National Center for PTSD Checklist, Military Version (PCL-5), Patient Health Questionnaire 
788 
(PHQ-9), and Clinician Administered PTSD Scale-5 (CAPS-5). Further assessment of psychopathology 
789 
will be made via administration of the Beck Depression Inventory (BDI-II); Beck Anxiety Inventory 
790 
(BAI); and Spielberger State-Trait Anxiety Inventory (STAI).  Participants will also complete measures 
791 
resilience (Connor-Davidson Resilience Scale (CD-RISC)), Evaluation of Risks (EVAR), the Satisfaction 
792 
with Life Scale (SWLS) and the Gratitude Questionnaire (GQ6).  The Balloon Analogue Risk Test 
793 
(BART) will be done to measure risk taking. 
794 
Subjective Sleep Measures:  To assess general sleep quality, daytime sleepiness, and 
795 
parasomnias, participants will complete the Pittsburgh Sleep Quality Index (PSQI)[102], the Epworth 
796 
Sleepiness Scale (ESS) [103], the Insomnia Severity Index (ISI)[104], and the Disturbing Dream and 
797 
Nightmare Severity Index (DDNSI) [22].  The Stanford Sleepiness Scale (SSS) [105] will be completed at 
798 

 
FORM: Application for Human Research 
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three times during the assessment day. The Functional Outcome of Sleep Questionnaire (FOSQ) and 
799 
Sleep Diaries A & B will also be done.  
800 
Neurocognitive Assessment:  All participants will complete a comprehensive neurocognitive 
801 
assessment battery to include: 
802 
1. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).  The 
803 
RBANS is a brief battery of well-normed neuropsychological tests with two alternate forms (RBANS A 
804 
and RBANS B) to permit repeated testing. The test provides several index scores, including: Total Score, 
805 
Immediate Memory, Visuospatial/Constructional, Language, Attention, and Delayed Memory.  This brief 
806 
battery will be administered to assess change in cognitive performance in each group following treatment. 
807 
Subject responses will be recorded via recording device for the Semantic Fluency portion of the RBANS 
808 
assessment in order to ensure that their complete responses are captured given that they may respond 
809 
faster than the study team may otherwise be able to record. No identifiers will be used and these recording 
810 
will be assigned to the subject ID number only. Recordings will be listened to the same day they are 
811 
created and compared to the initial response collection to ensure the study team captured the subject’s 
812 
complete response, anything missed will be transcribed onto the RBANS form. The recording will then be 
813 
deleted. 
814 
2. Fear Conditioning Paradigm. Our group has developed a fear-conditioning/fear extinction 
815 
paradigm that is highly effective at discriminating individuals with PTSD from healthy controls [98-101].  
816 
The protocol consists of 4 experimental phases: Habituation, Conditioning, Extinction and Extinction 
817 
Recall.  Subjects first choose a level of mild 
818 
electric shock that is “highly annoying but not 
819 
painful” while being administered shocks of 
820 
increasing intensities through electrodes 
821 
connected to two fingers.  For this paradigm, the 
822 
conditioned stimuli (CSs) consist of digital 
823 
photographs of three differently colored vehicles 
824 
(blue, red or yellow) displayed on a computer 
825 
screen within the image of two different 
826 
photographic environments (contexts), a 
827 
“conditioning context” in which the 
828 
unconditioned (shock) stimulus (US) 
829 
accompanies certain CSs (CS+s) during 
830 
Conditioning and an “extinction context” in 
831 
which CS+s occur without USs during the Extinction and Extinction Recall phases.  Before each 
832 
experimental phase except Habituation, subjects are told they "may or may not be shocked." During 
833 
Conditioning, 16 CS+’s (8 each of 2 different colors) are presented in the conditioning context and a 0.5-
834 
sec US (shock) immediately follows the offset of 10 of 16 CS+ presentations (5 of the 8 of each CS+ 
835 
color).  Sixteen randomly interspersed presentations of the third vehicle color (CS-s) are never paired with 
836 
the US. During the Extinction phase, one CS+ color (CS+E) appears 16 times in the extinction context, 
837 
along with 16 interspersed CS-s and no USs. The other CS+ color (CS+U) does not appear and therefore 
838 
remains un-extinguished. During the Extinction Recall phase, the 8 CS+Es and 8 CS+Us are presented in 
839 
the extinction context with 16 interspersed CS-s and no USs. The measurement of conditioned fear is 
840 

 
FORM: Application for Human Research 
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hrppsops@huronconsultinggroup.com 
palm-recorded skin conductance response (SCR), a reliable index of sympathetic activation. Participants 
841 
will be conditioned and undergo extinction prior to entry into the scanner.  During scanning, participants 
842 
will again be confronted with the previously extinguished stimuli to evaluate extinction recall, a hallmark 
843 
deficit of PTSD.  It is expected that improved sleep due to the BL condition will lead to improved 
844 
generalization of the extinction response and extinction recall. 
845 
Modified Sleep Latency Test (MSLT):  Participants will undergo 3 MSLT procedures with 
846 
polysomnographic (PSG) recording over the course of the assessment day.  A trained technician will fit 
847 
each participant with a standard electrode montage for PSG recording.  Standard PSG will be recorded 
848 
using the Polysmith 11.0 system that is installed in our sleep laboratory facilities.  During each MSLT, the 
849 
participant will be given up to 20 minutes to fall asleep in a private, darkened, sound-attenuated bedroom.  
850 
PSG recordings will be scored by a trained technician to determine the latency to fall sleep.  The mean 
851 
latency to sleep is taken as an indication of objective sleepiness. 
852 
                  Psychomotor Vigilance Test (PVT):  The PVT is a 10-minute computerized measure of 
853 
sustained attention and psychomotor vigilance that has been shown to be exquisitely sensitive to sleep 
854 
deprivation.  The PVT currently serves as the “gold standard” for assessing degradation in alertness and 
855 
vigilance following sleep loss.   
856 
Functional Neuroimaging:   Subjects will be screened for any contraindications to MRI and magnetic 
857 
materials. The investigator or MRI Technologist will explain the MRI system and the scan that they are 
858 
about to take part in. The subject will be asked to lie down on the scanner bed. Some part of the subject’s 
859 
body may be covered or enclosed within an FDA or UA HSPP approved MRI coil. The subject may be 
860 
asked to interact with a peripheral system such as a button, joystick, or TV system before, during, or after 
861 
the scan.  
862 
Blood Oxygen Level Dependent (BOLD) functional magnetic resonance imaging (fMRI) will 
863 
be collected at the University of Arizona Translational Bioimaing Resource. The MRI hardware and 
864 
procedures immediately to follow are approved by the FDA. A Siemens Skyra 3T whole body high-speed 
865 
imaging device equipped for echo planar imaging (EPI) (Siemens Medical Systems, Iselin, NJ) will be 
866 
used.  Head movement will be restricted using expandable foam cushions. After an automated scout 
867 
image is acquired and shimming procedures performed to optimize field homogeneity, high-resolution 3D 
868 
MPRAGE sequences (TR/TE/flip angle=7.25ms/3ms/7°) with an in-plane resolution of 1.3 mm, and 1 
869 
mm slice thickness, will be collected for spatial normalization, positioning the slice prescription, and for 
870 
subsequent morphometric analysis. Then a T1-weighted (TR/TE/flip angle=8sec/39msec/90°) and a T2-
871 
weighted (TR/TE/flip angle=10sec/48ms/120°) sequence will be used to gather sets of images to assist in 
872 
registration of the functional data to the high-resolution anatomical scan. Functional MRI images (blood 
873 
oxygenation level dependent or BOLD; Kwong et al 1992) will be acquired using a gradient echo T2*-
874 
weighted sequence (TR/TE/flip angle=2 sec/40msec/90°).  Prior to each scan, four images are acquired 
875 
and discarded to allow longitudinal magnetization to reach equilibrium. The T1, T2, and gradient-echo 
876 
functional images will be collected in the same plane (whole brain acquisition; axonal slices angled 
877 
perpendicular to the AC-PC line) with the same slice thickness (3.125 mm, skip 1mm; voxel size 3.125 x 
878 
3.125 x 3.125 mm), excitation order (descending) and phase encoding (head-to-foot).  During fMRI, 
879 
participants will complete four functional tasks: 
880 

 
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1. Masked Affect Task (MAT):  This task, first developed by our group back in the mid-1990’s 
881 
[110], presents a series of facial expressions displaying happiness or fear, each for only 16 msec and 
882 
masked immediately by a neutral image from a different poser for 184 msec (Figure 14).  At this rate of 
883 
presentation, the “masked” affective expression is not consciously perceived, yet is still processed via an 
884 
extrastriate pathway to the amygdala that bypasses normal cortical processing.  This task has been shown 
885 
to selectively activate the amygdala in healthy participants.  Moreover, in our laboratory, exaggerated 
886 
amygdala response has been found on this task in patients with PTSD [27].  Our laboratory has extensive 
887 
experience using this task with patients with PTSD and anxiety disorders [27, 111-115], and healthy 
888 
adults and children [116-118]. 
889 
2. Extinction Recall (ER):  This task measures the 
890 
retention of the extinction memory established during the 
891 
previous fear conditioning session.  While undergoing fMRI, 
892 
participants will view the previously conditioned images from 
893 
the Fear Conditioning and Extinction Task.  Here, 8 CS+E, 8 
894 
CS+U, and 16 CS- trials will be presented (without any 
895 
shocks).  Skin conductance responses will also be collected 
896 
while participants are undergoing the scan.  During this task, 
897 
the contrast of interest will be CS+E vs. CS+U, permitting the 
898 
isolation of psychophysiological and brain responses that are 
899 
specific to extinction recall. 
900 
3. Resting State Scan (RS):  Emerging evidence suggests 
901 
that the brain shows stable patterns of functional connectivity 
902 
during the resting state and that these patterns may be 
903 
particularly useful in elucidating specific networks [119-122].  
904 
Therefore, in addition to the probe tasks described above subjects will also be scanned for 10 minutes 
905 
with eyes closed and instructed to let their “mind wander.”  Functional connectivity will be evaluated 
906 
from pre- to post-treatment for the two conditions.   
907 
4. Anticipation Task: The Emotional Anticipation Task was adapted on the basis of Aupperle et al.’s 
908 
(2013) study design and lasts a total of 7 min and 8 seconds. Two version of the anticipation tasks will be 
909 
used, in order to have two different versions of the tasks for the baseline and follow up visit. Participants 
910 
are presented with a grey background with a black arrow alternating randomly in its direction from left to 
911 
right (Baseline). Participants are instructed to indicate via button press which direction the arrow was 
912 
pointing in. Participants are told that when the screen turns yellow, a negative picture will soon appear 
913 
(Negative Anticipation (NA)). If the screen turns blue, a positive picture will soon appear (Positive 
914 
Anticipation (PA)), and if the screen turns green a positive or a negative picture will soon appear 
915 
(Uncertain Anticipation (UA)).  The picture stimuli consist of positive and negative pictures from the 
916 
International Affective Picture System (IAPS). The most unpleasant (e.g., mutilated bodies) as well as the 
917 
most pleasant (e.g., animals) pictures were chosen from the picture set.  The aim of this task is to 
918 
investigate whether the intervention changes neural responses during anticipation of negative stimuli.  
919 
200 ms 
0 ms 
Target (16 ms) 
16 ms 
Mask (184 ms) 
Trial = 200 ms 
MaskedAffectTask
Figure14.MaskedAffectTask:Atargetemo onalfacial
expressionispresentedfor16msandmaskedimmediatelyby
aneutralfaceforalongerdura on(184ms).Thiseffec vely
preventsawarenessofthetargetemo onalexpression,
althoughitisperceivedatanon-consciouslevel.

 
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Spectroscopic Neuroimaging:   While all MRI 
920 
hardware used during this study is FDA-approved, as part of the 
921 
MRI session, one MRI sequence will be conducted that uses 
922 
investigational software that enables collection of unique 
923 
spectroscopic data. This scan, referred to as the MEGA-PRESS 
924 
sequence, uses Proton Magnetic Resonance Spectroscopy (MRS) 
925 
to measure chemicals in the brain, specifically, cerebral 
926 
metabolites and neurotransmitter concentrations.  It is very 
927 
similar to other FDA-approved MRS sequences, but it does a 
928 
better job at quantifying certain metabolites, namely, GABA.  
929 
Per the Master Research Agreement (MRA) between Siemens 
930 
and the University of Arizona, as a Works in Progress (WIP), the 
931 
MEGA-PRESS sequence complies with all FDA guidelines for 
932 
magnetic resonance imaging (https://www.fda.gov/regulatory-
933 
information/search-fda-guidance-documents/criteria-significant-
934 
risk-investigations-magnetic-resonance-diagnostic-devices-
935 
guidance-industry-and) and is suitable for testing in a clinical 
936 
environment. Because of this, the MEGA-PRESS sequences does not increase the risk to subjects. 
937 
A key element of the proposed project involves assessment of changes in brain neurochemistry 
938 
as a function of 6-weeks of light therapy treatment and associated changes in sleep quality.  Growing 
939 
evidence suggests that some of the deficits in memory and emotional regulation that occur for patients 
940 
with PTSD are related to alterations in neurochemistry within key regions of the hippocampus and ACC 
941 
(Karl & Werner, 2010).  In particular, patients with PTSD show decreased NAA in the hippocampus and 
942 
ACC, as well as reduced concentrations of choline in the hippocampus and increased levels in the ACC.  
943 
These are often compared directly as ratios relative to creatine (Cr).  Assuming that improved sleep leads 
944 
to improvement in emotional functioning, this will permit us to identify a potential mechanism for this 
945 
improvement.  Presently, for 1H MRS imaging, two voxels will be placed, one encompassing the dorsal 
946 
anterior cingulate cortex just anterior to the genu of the corpus collosum and another placed at the 
947 
amygdala-hippocampal complex within the mesial temporal lobe (see figure 15).  All 1H MRS 
948 
measurements will be performed using a Siemens TIM Trio 3T whole body high-speed imaging device 
949 
(Siemens Medical Systems, Iselin, NJ) and a 32-channel single-tuned (170.3 MHz) “birdcage” coil for 
950 
radiofrequency (RF) transmission and signal reception, both of which are approved by the FDA.  The 
951 
following brain metabolites will be collected and analyzed: alanine (Ala), aspartate (Asp), choline (Cho), 
952 
Gamma Amino Butyric Acid (GABA), Glutamate (Glu), Glutamine (Gln), glutathione (GSH), glycine 
953 
(Gly), myo-I, N-acetylaspartate (NAA), N-acetylaspatylglutamate (NAAG), creatine (Cr), 
954 
phosphocreatine (PCr), scyllo-inositol (Scy), taurine (Tau) and lactate (Lac).  
955 
Figure15.MRSSpectroscopy:Placementof
voxelswithinthedorsalACCandle 
hippocampus.

 
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At Home Six-Week Light Exposure Treatment:    At the 
956 
conclusion of Visit 2, participants will be randomly assigned to either the BL 
957 
condition or the PL condition, using computerized permuted block 
958 
randomization to match groups by gender.  All participants will be given a 
959 
goLITE® unit to take home and provided with detailed training and 
960 
instruction on its use.  Depending on the light condition assigned, the 
961 
goLITE will include either blue or amber LEDs.  The goLITE BLU is 
962 
commercially available and has a narrow bandwidth, peaking at  = 469 nm, 
963 
at 214 Lux, and panel irradiance mW/cm2) = 1.23 at 20 cm.  A similar 
964 
appearing amber LED system (goLITE AMBER) will be employed for the 
965 
PL devices, but will peak at  = 578 nm, at 188 Lux, and total irradiance 
966 
(mW/cm2) = 0.35.  Both of these devices have undergone extensive ocular 
967 
safety testing (Sliney, 2009) and have been used successfully without incident in our prior study.  Each 
968 
participant will be instructed to use the unit each morning (within 2 hours of awakening and prior to 10:30 
969 
am) for 30 minutes per day over the next 6 weeks.  Participants are permitted to engage in sedentary 
970 
activities (e.g., read, watch TV, surf the internet, eat, engage in daily hygiene) while the unit is activated, 
971 
as long as the light is within arm’s reach and projecting to the eyes from within a 45-degree angle to either 
972 
side (see Figure 14). A wattage use meter will be connected to the goLITE device to measure participant 
973 
compliance in terms of duration, timing, and intensity of light exposure. They will be asked to record this 
974 
via the Sleep Diaries A & B. This same procedure 
975 
has been used in our prior work and has been well 
976 
tolerated by participants, allowing them 
977 
considerable flexibility to choose whether to use the 
978 
light immediately upon arising, or after morning 
979 
hygiene, meals, drive, etc., but while still ensuring 
980 
that all treatment occur in the morning hours.  
981 
Safety and efficacy of the device itself is not 
982 
being tested, rather, the effects of specific 
983 
wavelengths of light on human performance; the 
984 
device is simply used as a convenient method to 
985 
deliver the light in a controlled and reliable way in 
986 
order to assure the scientific validity of the results.  
987 
Actigraphic Sleep Measurement:  Daily sleep, activity, and light exposure will be collected 
988 
via the Respironics Actiwatch Spectrum®.  This actigraphic wrist-watch device uses a built-in 
989 
accelerometer to unobtrusively measure and record ambulatory activity levels and sleep 24 hours a day.  
990 
This data can then be analyzed via sleep analysis software (Actiware 5®) that includes algorithms that 
991 
transform activity data into probable sleep periods.  The Actiwatch Spectrum also includes three-color 
992 
light sensors that provide irradiance and luminous lux recordings in three-color bands of the visible 
993 
spectrum, including red, green, and blue (Figure 17).  The light sensor will be used to verify that subjects 
994 
are in fact undergoing the daily light treatment and will permit covariation of other daily light sources in 
995 
the statistical analyses.  The device also records periods of off-wrist time to determine compliance.  Data 
996 
Figure17.Ac watchSpectrumandAc gram:Thedevicecollects
wristac vitydata(blackbars)thataretranslatedintosleep/wake
periods(white/redbarsatbo omofgraph),aswellasminuteby
minutelightexposure(yellow=totallight;blue=bluelight;green
=greenlight;red=redlight).
Figure16.Par cipants
willmaintainthedeviceat
armslengthwithinthe
peripheralvisionfor30
minuteseachmorning.

 
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will be scored by the Actiware 5® program, checked for validity, and summary indices of total sleep time, 
997 
sleep efficiency, sleep onset latency, wake after sleep onset (WASO), and fragmentation index will be 
998 
calculated for each day and averaged across the study period.   
999 
Compliance Monitoring:  Compliance with the study requirements will be monitored in 
1000 
several ways.  First, participants are required to log into the internet each day to complete the sleep diary 
1001 
and report timing of light usage.  This is an effective means for monitoring general compliance.  On-line 
1002 
compliance will be monitored, and participants will be contacted by phone and/or email if they have not 
1003 
logged in for more than 48 hours.  Second, use of the lights will be monitored by a recording device built 
1004 
into the light device that records a time stamp each time the light is engaged.  Third, participants are 
1005 
required to wear the wrist acticgraph at all times.  This device includes a light monitor that is sensitive to 
1006 
various wavelengths of light.  This light data will be evaluated at the conclusion of the study to identify 
1007 
whether there is a detectible change in blue/red light during the period of reported light exposure. 
1008 
Post-Treatment Assessment and Scan:   At the completion of 6-weeks of BL or PL, participants 
1009 
will return to the imaging center for Visit 3 to complete an 
1010 
identical series of assessment and neuroimaging tasks as in 
1011 
Visit 2, as well as a repeated administration of the CAPS.  
1012 
Participants will return wrist actigraphs and the goLITE 
1013 
device.  
1014 
Please note that subjects will be offered and required 
1015 
to wear earplugs and/or earphones to minimize the scanner 
1016 
noise. Subjects will be able to converse with a staff member 
1017 
via a microphone and speaker system at all times during the 
1018 
scanning session. Subjects will be provided with an 
1019 
emergency button to indicate an immediate concern. 
1020 
Subjects may ask to have a scan stopped and discontinue 
1021 
participation in the study at any time. 
1022 
Follow-Up. After subjects complete the study, prior 
1023 
to data analysis, subjects will be sent an email (Follow-up 
1024 
Script.doc) with a link to an online ICF Addendum 
1025 
(PTSD_ICF_addendum.doc) and, if they agree, subjects 
1026 
will complete a 10- to 15-minute follow-up online survey, 
1027 
where they will be administered the PCL-5, PHQ-9, and be 
1028 
asked about general sleep problems using the ESS and ISI. 
1029 
If subjects cannot complete this follow-up online, follow-up 
1030 
assessments will be administered over the phone.  
1031 
 
1032 
D.  DATA ANALYSIS 
1033 
Global Statistical Analysis Approach:  Behavioral 
1034 
data from the neurocognitive, sleep, and symptom measures 
1035 
will be evaluated for clinical severity and transformed into change metrics from baseline to post-treatment 
1036 
sessions.  Baseline characteristics between subject groups will be examined using analysis of variance 
1037 
(ANOVA) and chi-square tests, as appropriate, and randomization will be stratified by severity of PTSD 
1038 
10
20
30
40
50
60
70
80
90
100
0
0.2
0.4
0.6
0.8
1
Power (1-β err prob)
t tests - M
eans: D
iference betw
een tw
o dependent m
eans (m
atched pairs)
Tail(s) = Tw
o. E
fect size dz = 0.5. α err prob = 0.05
Total sam
ple size
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
0
0.2
0.4
0.6
0.8
1
Power (1-β err prob)
F tests - AN
O
VA: R
epeated m
easures. w
ithin-betw
een interaction
N
um
ber of groups = 2. R
epetitions = 2. C
orr am
ong rep m
easures = 0.5. N
onsphericity 
correction ε = 1. E
fect size f = 0.25. α err prob = 0.05
Total sam
ple size
A)
B)
Interac onPower
TotalSample
n=90
WithinGroup
Pre-PostComparison
n=45
MedEffectSize(d=.50)
Figure18.Poweranalysesshowthattheproposedsample
sizeshouldbeadequatetoaddresstheprimary
hypotheses.
10
20
30
40
50
60
70
80
90
100
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Power (1-β err prob)
t tests - C
orrelation: P
oint biserial m
odel
Tail(s) = Tw
o. E
fect size |r| = 0.3. α err prob = 0.05
Total sam
ple size
C)
Correla onPower
TotalSample
n=90

 
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and gender.  Randomization will consist of permuted blocks to achieve balance over time.  Repeated 
1039 
measures analysis of variance (ANOVA) and linear mixed-model approaches will be used for the primary 
1040 
analyses examining the efficacy of light treatment condition on measures of mood and sleep.  Between 
1041 
group factors will correspond to the two light conditions (BL vs PL) and will control for any baseline 
1042 
differences in demographic variables and severity scores as appropriate.  Based on specific hypotheses, 
1043 
separate ANOVAs will be performed for each type of dependent variable (e.g., subjective sleep scores, 
1044 
CAPS-2 symptom scores, mood scores, MRS metabolites).  The relationship between these change 
1045 
indices and sleep variables will be analyzed using correlation and linear regression models in SPSS.  Tests 
1046 
for normality will be conducted for all variables.  In the case on non-normality, appropriate data 
1047 
transformation or non-parametric techniques will be employed (e.g., Kruskal-Wallis or Friedman tests for 
1048 
ANOVA; Mann-Whitney U or Wilcoxon for 2-group comparisons).  Inflation of Type I error will be 
1049 
controlled first through the use of planned comparisons based on the hypotheses and the use of protected 
1050 
omnibus F-tests.  Post-hoc analyses will be undertaken with protected comparisons (e.g., Tukey) or 
1051 
Bonferroni adjustment.  Functional MRI data will be analyzed using statistical parametric mapping 
1052 
(SPM8) software, implementing the general linear model to compare pre- to post-therapy changes in 
1053 
functional responses between the active and placebo groups and across diagnostic groups, and sleep 
1054 
variables will be tested as covariates in the models.  Finally, proton spectroscopy data for each of the 
1055 
metabolites will be quantified and compared for pre- to post-therapy changes in metabolite concentrations 
1056 
between the active and placebo treatment groups and across diagnostic groups.  Type I error during 
1057 
neuroimaging will be controlled via whole brain False Discovery Rate (FDR) correction or small volume 
1058 
corrections using Family Wise Error (FWE) rate within a priori specified regions of interest. To handle 
1059 
missing data, we will first determine the potential cause of the data loss.  Statistically, missing data can be 
1060 
considered as falling into three types:  1) missing completely at random, 2) missing at random, or 3) 
1061 
missing not at random.  The type of missing data will dictate the approach.  Assuming type 1, and that the 
1062 
number of missing values is low, we will use a standard listwise deletion procedure.  However, assuming 
1063 
that a larger number of values is missing, and data are not missing completely at random, we will be able 
1064 
to apply missing data imputation methods. 
1065 
Power Analysis:  A power analysis based on a proposed sample size of 90 subjects suggested that 
1066 
with an omnibus 2 between-groups (BL vs. PL) x 2 within-subjects (pre- vs post-treatment) mixed design, 
1067 
assuming a moderate effect size (f = .25), and  = .05, there should provide be adequate power to detect 
1068 
most effects.  First, the primary hypotheses of the study focus on interaction effects across groups (i.e., 
1069 
treatment x session interactions), which will have exceptional power (1-) = 0.99 to detect a moderate 
1070 
effect size at  = .05 (see Figure 18A).  Paired comparisons within each group of will also have excellent 
1071 
power of .91 to detect moderate effect size changes (d = .50), with 2-tailed tests (see Figure 18B).  
1072 
Without regard to group differences, a sample size of 90 would yield power = 0.84 to detect a moderate 
1073 
linear association (i.e., r  .30) between a predictor variable (e.g., average sleep; change in sleep 
1074 
parameters, PTSD symptom severity; neurocognitive performance; etc.) and an outcome variable (e.g., 
1075 
fMRI signal intensity changes; spectroscopic metabolite changes; etc.), with a two-tailed test at  = .05 
1076 
(see Figure 16).  Thus, the proposed sample size of n = 45 per group appears to provide adequate power 
1077 
for testing the major hypotheses of the proposed study.   
1078 

 
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Functional Image Pre-Processing:  Functional neuroimaging data will be preprocessed in SPM8 
1079 
[123].  Following standard algorithms, functional images will be slice-time corrected, co-registered to 
1080 
their anatomical T1-weighted images, realigned, unwarped to correct for field inhomogeneity, normalized 
1081 
to the standard three-dimensional space of the Montreal Neurological Institute (MNI), spatially smoothed 
1082 
using an isotropic Gaussian kernel (full width half maximum [FWHM] = 6 mm), and resliced to 2x2x2 
1083 
mm isotropic voxels using sinc interpolation.  Depending on the specific task, functional data will be 
1084 
convolved to an event-related or boxcar waveform based on the experimental design and the canonical 
1085 
hemodynamic response function.  Artifact detection will be conducted with the Artifact Detection Tool 
1086 
(ART) program.  Images with global intensities exceeding 3 standard deviations or scan-to-scan 
1087 
movement exceeding 1mm will be statistically regressed out of the design matrix.  For event related 
1088 
analyses, individual subject motion parameters will also be included as nuisance regressors in the design 
1089 
matrix. 
1090 
FMRI Statistical Analysis:  At the first stage, activation during the conditions of interest will be 
1091 
fitted using the general linear model in SPM8 for each subject individually.  This procedure yields a 
1092 
statistical parametric map that isolates the activity unique to the condition of interest (e.g., masked affect) 
1093 
relative to the activity associated with the control condition (e.g., simple perception of neutral facial 
1094 
expressions).  Thus, for each subject, a “contrast image” will be produced that reflects the pattern of 
1095 
BOLD signal change due to the independent variable for each task.  At the second stage, subject specific 
1096 
contrast images will be entered as the dependent variables in a series of random effects analyses in SPM8 
1097 
[124].  Functional data will be analyzed from two approaches, including region of interest (ROI) analyses 
1098 
and whole brain exploratory analyses. 
1099 
1. ROI Analyses.  First, a series of region of interest (ROI) analyses will be performed.  The 
1100 
primary hypotheses for the MAT involve changes in the amygdala, anterior cingulate gyrus, and 
1101 
ventromedial prefrontal cortex for the MAT, whereas the ACC and dorsolateral prefrontal cortex are 
1102 
hypothesized to differ across groups for the MSIT. Consequently, ROIs will be placed in these regions, 
1103 
defined according to the boundaries of the published anatomical atlas of Tzourio-Mazoyer and colleagues 
1104 
[125] and PickAtlas Utility [126].  These ROI analyses will be carried out at an FDR small volume 
1105 
corrected threshold of p = .05, k (extent) = 10.  Each of the probe tasks has been selected because of its 
1106 
prior involvement in the neurocircuitry of PTSD.  
1107 
2. Whole Brain Exploratory Analyses.  Furthermore, whole brain analyses will be undertaken to 
1108 
examine global patterns of activation for each of the previously described analyses.  Because these 
1109 
analyses will be exploratory in nature, they will be evaluated at a stringent correction for multiple 
1110 
comparisons using a whole brain family-wise error (FWE) correction of p < .05, k = 10.  
1111 
3. Resting State Functional Connectivity Analysis:  Preprocessed resting state data will be 
1112 
analyzed using the fMRI Functional Connectivity Toolbox (CONN).  Physiological and other noise 
1113 
sources are reduced through the implementation of a CompCor strategy implemented within the toolbox.  
1114 
For each subject, gray and white matter masks will be created from the previously segmented images in 
1115 
SPM8 and entered as nuisance covariates in the analyses, as will subject specific motion parameters.  
1116 
Regions of Interest (ROIs) will be created from the Automated Anatomical Labeling Atlas [125].  ROI to 
1117 
ROI and seed-to-voxel analyses will be run individually at the first level and then imported into a second 
1118 
level random effects group analysis.  Primary seed regions for connectivity analyses will include the 
1119 

 
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subgenual and rostral ACC, VMPFC, and amygdala.  Data will be analyzed at an FDR corrected 
1120 
significance level of p < 05. 
1121 
MRS Analyses: The goal will be to determine whether BL treatment is more effective than PL at 
1122 
altering bran metabolites that are associated with alertness, cognitive processing, and inhibitory capacity.  
1123 
All MRS processing will be carried-out in a fully automated fashion using methods previously published 
1124 
by our group [127].  Metabolite ratios will be derived as a ratio of each raw metabolite integral to the total 
1125 
sum of the creatine and phosphocreatine integrals, and will be T1-corrected using values previously 
1126 
reported in the literature.  Our primary endpoints of interest are Glu (excitatory neurotransmitter), GABA 
1127 
(inhibitory neurotransmitter), and NAA (marker of neuronal energy production).  Standard linear and 
1128 
mixed model approached will be employed for comparing metabolite ratios between the active BL and 
1129 
placebo light conditions within the dorsal ACC and amygdala-hippocampal complex.  As described 
1130 
above, all analyses will be undertaken with α = .05, employing corrections for multiple comparisons (e.g., 
1131 
Tukey post-hoc corrections; Bonferroni corrections) as appropriate. We expect that the active BL 
1132 
condition will lead to increased levels of GABA, N-acetyl-aspartate (NAA), and choline (Cho), and 
1133 
reduced glutamate and phosphocreatine (Cr) in the amygdala-hippocampal complex and anterior cingulate 
1134 
gyrus compared to the PL condition.  Furthermore, it is expected that these changes will be linearly 
1135 
related to changes in sleep parameters and cognitive/symptom score changes from pre- to post-
1136 
assessment. 
1137 
8) Risks to subjects 
1138 
 
Participation in this study may involve some risks or discomforts, which are described below. 
1139 
 
1140 
 
During the study visits, subjects may be asked some questions during the brief clinical interview 
1141 
and on the questionnaires that deal with personal or emotional matters. These questions might cause 
1142 
psychological discomfort. Subjects may refuse to answer any questions that make them uncomfortable. If 
1143 
they reveal during these sessions that they are currently or have recently had thoughts of self-harm or 
1144 
suicide, appropriate follow-up evaluation and referral for care will be ensured. Results of the clinical 
1145 
evaluation will be kept in a locked cabinet and identified using only subject unique study identification 
1146 
number. 
1147 
 
Subjects may find the sensation of the electric shock used in the picture-viewing task to be 
1148 
uncomfortable. However, they will be able to choose their own level of shock, which should be strong 
1149 
enough to annoying or uncomfortable, but not painful. The apparatus that provides the shock is powered 
1150 
by a 9-volt electric battery, identical to those used in toy electronics. These mild shocks are not dangerous 
1151 
or harmful, but may be annoying. 
1152 
Unlike X-rays or CAT scans, magnetic resonance (MR) technology does not use ionizing 
1153 
radiation. Instead, it uses strong magnetic fields and radio waves to collect the images and data. With the 
1154 
exception of one sequence (MEGA-PRESS spectroscopy work-in-progress (WIP) pulse sequence), all 
1155 
MRI procedures involved are standard. The radio frequency exposure, magnetic fields and gradients, and 
1156 
noise levels produced by the MRI sequences used in this study are no greater than or fall below the FDA's 
1157 
limits, so subjects are exposed to no greater risk than those of routine MRI scans (see MEGA-PRESS 
1158 
Sequence Manual.pdf and Request allowance for running MEGA-PRESS WIP (Rouse, Trouard, et al, 
1159 

 
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2019). During the scan, subjects will wear a birdcage coil around their heads; this is an FDA-cleared 
1160 
device and its use in this study will be as approved by FDA. 
1161 
 
1162 
The four risks the FDA associates with MRI scanning are: 1) tissue heating due to RF fields, 2) 
1163 
peripheral nerve stimulation due to quick changes in magnetic field, 3) hearing damage due to acoustic 
1164 
noise, and 4) force and torque on magnetic materials in or on a participant. That said, the FDA lists “MRI 
1165 
Devices within FDA specified parameters” as non-significant risk devices. The research scanner in the 
1166 
TBIR fits within this description. With regard to tissue heating and peripheral nerve stimulation, the 
1167 
Siemens scanner is not capable of running a sequence that is outside the FDA safety guidelines. With 
1168 
regard to hearing damage, volunteers wear ear protection when in the scanner. In addition, any non-FDA 
1169 
approved sequence conducted is within FDA parameters for tissue heating, peripheral nerve stimulation, 
1170 
and hearing damage. 
1171 
 
1172 
With regard to force and torque on magnetic materials, anyone entering the magnet room must remove 
1173 
all metal objects from their body. In addition, significant risks may exist for people with: 
1174 
 
1175 
• Cardiac pacemakers 
1176 
• Metal clips on blood vessels (also called stents) 
1177 
• Artificial heart valves 
1178 
• Artificial arms, hands, legs, etc. 
1179 
• Brain stimulator devices 
1180 
• Implanted drug pumps 
1181 
• Ear implants 
1182 
• Eye implants or known metal fragments in eyes 
1183 
• Exposure to shrapnel or metal filings (wounded in military combat, sheet metal workers, welders, and 
1184 
others) 
1185 
• Other metallic surgical hardware in vital areas 
1186 
• Certain tattoos with metallic ink 
1187 
• Certain transdermal (skin) patches such as NicoDerm (nicotine for tobacco dependence), Transderm 
1188 
Scop (scopolamine for motion sickness), or Ortho Evra (birth control) 
1189 
 
1190 
Volunteers are screened before entering the magnet to be sure they do not have any of these items. If 
1191 
subjects are unsure whether they have any of these items in their body, they will be informed that most 
1192 
would have been implanted as part of a surgical procedure, and that trying to remember past operations 
1193 
may help them remember if they have any implanted devices or history of exposure to shrapnel or metal 
1194 
filings, and, if so, they will not be able to participate in this study. 
1195 
 
1196 
Significant risks also can arise if certain materials (many types of metal objects) are brought into the 
1197 
scanning area, as they can be pulled into the magnet at great speed, which might cause serious injury. 
1198 
Therefore, these types of items are not permitted in the scanning area. Subjects will not be allowed to 
1199 
bring anything with them into the scanning room. 
1200 
 
1201 

 
FORM: Application for Human Research 
NUMBER 
FORM DATE 
PAGE 
F200 
02/2014 
35 of 44 
 
 
 
 
 
 
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hrppsops@huronconsultinggroup.com 
The MR exams are painless, and except for pulsating sounds or vibrations, subjects will not be aware that 
1202 
scanning is taking place. 
1203 
 
1204 
The scans will take place on a 3T scanner, which are approved by the FDA for routine clinical studies in 
1205 
children and adults. However, as part of the MRI session, subjects will receive an MRI scan that measures 
1206 
chemicals in the brain, the MEGA-PRESS sequence, that is not FDA approved, though it does comply 
1207 
with the same FDA guidelines used for routine FDA approved MRI scans. Therefore, all MRI scans used 
1208 
in this study do not expose subjects to any more risk that a routine MRI exam. 
1209 
 
1210 
Although there are no known risks from these scans, there could be adverse effects that are delayed or 
1211 
very mild, such that they have not yet been recognized. Most people experience no ill effects from these 
1212 
scans, but some people do report claustrophobia (fear of being in enclosed small spaces), dizziness, mild 
1213 
nausea, headaches, and a metallic taste in their mouth, double vision, or the sensation of flashing lights. 
1214 
Some subjects also experience feelings of panic and/or anxiety. These symptoms are rare, and if present, 
1215 
disappear shortly after leaving the scanner. In addition to these physical risks, the MRI system can be 
1216 
psychologically unsettling to some volunteers that are bothered by loud noises or small spaces. 
1217 
 
1218 
Volunteers can ask to be removed from the scanner at any point during the procedure without any 
1219 
repercussions. 
1220 
 
1221 
Steps taken to minimize risk: 
1222 
 
1223 
For the first three MRI risks described above, all sequences operate within the FDA limits of non-
1224 
significant risk. For the fourth risk, force/torque on magnetic materials, all volunteers are checked 
1225 
multiple times for these materials before entering the magnetic field. In addition, volunteers can ask to be 
1226 
removed from the scanner at any point during the procedure without any repercussions. 
1227 
Subjects will be screened for any contraindications to MRI and magnetic materials. The investigator or 
1228 
MRI Technologist will explain the MRI system and the scan that they are about to take part in. The 
1229 
volunteer will be asked to lie down on the scanner bed. Some part of the volunteer’s body may be covered 
1230 
or enclosed within an FDA or UofA HSPP approved MRI coil. The volunteer may be asked to interact 
1231 
with a peripheral system such as a button, joystick, or TV system before, during, or after the scan. 
1232 
 
1233 
Although both light devices (placebo [PL] and blue light [BLT]) are safe to use (Sliney, 2009, 
1234 
2006; Apollo Health, 2009), we will minimize unnecessary direct exposure to the bright lights to reduce 
1235 
the possibility of discomfort or persistent visual symptoms. Although looking directly at the LEDs for 
1236 
brief periods is not known to be harmful, it is unnecessary and may lead to glare, eyestrain, or other 
1237 
irritating visual sensations that can be easily avoided by keeping the panel at an angle in the peripheral 
1238 
vision. It is sufficient that the light reaches the eyes indirectly from the side. Looking directly at the LEDs 
1239 
does not provide any additional benefit. Prolonged staring at the LEDs could lead to significant eye 
1240 
irritation, lingering afterimages, or other symptoms such as headaches. Although the light emissions of 
1241 
the device are well within safe limits and no problems have ever been reported, we want to minimize any 
1242 
risks or discomforts. While extremely unlikely, it is possible that prolonged continuous staring at the 
1243 

 
FORM: Application for Human Research 
NUMBER 
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PAGE 
F200 
02/2014 
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LEDs could lead to more severe changes in vision such as photoretinitis, a condition that is most 
1244 
commonly associated with looking for too long at very bright light sources such as snow on a bright 
1245 
sunny day or looking at the sun during an eclipse. Such a condition could lead to temporary or long-term 
1246 
vision problems. As individuals may differ in sensitivity to light, some subjects may experience eye 
1247 
fatigue or irritation during the use of the light exposure device. If subjects notice any unusual sensations 
1248 
or discomforts, they are advised to discontinue use and to contact the Principal Investigator immediately. 
1249 
 
1250 
 
Thus, to minimize risk, subjects will be instructed via the following for the goLITE Blu: 
1251 
 
1252 
NOTE: DO NOT STARE DIRECTLY AT THE LIGHTS ON THE LED PANEL. 
1253 
IT IS SUFFICIENT THAT THE LIGHT REACHES YOUR EYES DIRECTLY FROM THE 
1254 
SIDE. 
1255 
 
1256 
 
There is the potential for skin irritation due to the heart rate monitor leads or wearing the 
1257 
actiwatch. This can be alleviated with use of lotions and/or creams. 
1258 
 
1259 
9) Potential benefits to subjects and/or society 
1260 
 
It is not anticipated that subjects will derive direct benefit from participation in the proposed 
1261 
study. However, it is anticipated that findings from this study will help to advance scientific and medical 
1262 
understanding of treatment of PTSD and sleep disorders. The study will provide basic scientific 
1263 
information about the effects of short wavelength light on sleep patterns and potential treatment of PTSD. 
1264 
Such information may improve the ability to treat sleep disorders and cognitive performance among 
1265 
patients with PTSD. 
1266 
 
1267 
Incidental MRI findings: 
1268 
Study assessments (labs, MRI scans, psychological assessments, etc.) are not intended to provide medical 
1269 
benefit. Personnel involved conducting this study may not be trained or licensed to clinically review lab 
1270 
findings, MRI images, etc. If study personnel notice something irregular in subjects’ study information, 
1271 
the investigator may provide de-identified reports or images to a licensed physician, radiologists, or other 
1272 
qualified practitioner for further review. In the unlikely case that such a qualified clinician determines a 
1273 
finding to be an irregularity, subjects will be advised to consult their primary care physician. Subjects 
1274 
may be provided copies of their study information or MRI images for this purpose, but this medical 
1275 
consultation will be on subjects’ own time and at their cost. If subjects are provided a copy of their study 
1276 
information, we make no promises as to the clinical value of the data. The University of Arizona and its 
1277 
employees have no funds set aside for the payment of treatment expenses that may arise from subjects 
1278 
volunteering for an MRI scan. 
1279 
 
There may be instances in which an abnormality exists but is not identified in our analyses. Our 
1280 
team is not trained in clinically diagnosing issues pertaining to abnormalities found in the collected data. 
1281 
Further, our data analyses are not intended to treat, diagnose, or replace the expertise of a medical doctor 
1282 
or a medical diagnosis. As such, the University of Arizona and its employees are not responsible for 
1283 

 
FORM: Application for Human Research 
NUMBER 
FORM DATE 
PAGE 
F200 
02/2014 
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hrppsops@huronconsultinggroup.com 
abnormalities that go undetected through participation in these research activities and subjects will be told 
1284 
that they should not rely on our data or analyses to reveal abnormalities. 
1285 
 
1286 
10) 
Provisions to protect the privacy of subjects and the confidentiality of data 
1287 
 
Collected data are computerized. A unique study-specific ID number is assigned to each subject 
1288 
and used for identification purposes. A separate password-protected data file, stored on a stand-alone PC, 
1289 
maintains the ID number and identifying information for each participant.  Only the PI and Project 
1290 
Coordinator have access to that file.   
1291 
Data collected will be entered into REDCap in de-identified format. Subjects’ identities will be linked 
1292 
via a coded/subject ID. REDCap requires authorized users to enter a username and password unique to 
1293 
each study staff member.  
1294 
Study data will be maintained on secure servers maintained by University of Arizona College of 
1295 
Medicine IT, accessible only through secure UA networks by UA-affiliated computers. Only authorized 
1296 
researchers associated with this project will be given access via a unique medadmin username and 
1297 
password. 
1298 
 
All information regarding experimental subjects are kept in a locked file cabinet in the University 
1299 
of Arizona Department of Psychiatry. The signed consent forms are stored separately from the research 
1300 
data in a locked file cabinet in the Department of Psychiatry. Any study forms that contain personally 
1301 
identifying information for our participants (e.g., signed consent forms, payment information) are kept 
1302 
separately from research records and data in separate locked filing cabinets in the Department of 
1303 
Psychiatry. All subject voice recordings will be used to verify that the study team collected complete 
1304 
responses and will be verified and deleted the same day they are collected. These recordings will only be 
1305 
linked to subject IDs during that period. 
1306 
 
The Imaging Center will be provided with Subject ID numbers only. MRI Records are kept in a 
1307 
locked office. Subject identifiable information is not used for research data. HIPAA requirements will be 
1308 
followed to protect subject confidentiality. 
1309 
For subjects who agree, their information will be saved for future use to allow possible contact for 
1310 
other studies conducted by the PI. 
1311 
A final study report will be made available to the sponsor, the Department of Defense (DoD). Only 
1312 
non-identifiable data will be shared. DoD maintains a secure file transfer system, "DoD SAFE," which 
1313 
can be used to securely transfer study information to the sponsor. 
1314 
 
Research data will be stored in a secure area for a period of 6 years following the conclusion of the 
1315 
study. All data and links will be destroyed as soon as possible. 
1316 
11) 
Cost to subjects  
1317 
 
There are no costs to subjects, except for their time. 
1318 
 
1319 
12) 
Subject compensation 
1320 
 
Potential subjects who complete pre-screening surveys (Recruitment Survey.pdf) through 
1321 
crowdsourcing websites will be compensated in line with the specific site’s payment policy (e.g., Amazon 
1322 

 
FORM: Application for Human Research 
NUMBER 
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PAGE 
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hrppsops@huronconsultinggroup.com 
Mechanical Turk will pay $0.60 after the survey is completed, a rate of $0.12 per min in compliance with 
1323 
research guidelines for fair wages within the MTurk community, with a predetermined 5-minute effort 
1324 
allotted).  
1325 
 
Subjects will receive $1200 for completion of all three study sessions, successful adherence to 
1326 
daily light exposure treatment, and compliance with all study procedures and proper use of all study 
1327 
equipment. This payment is also intended to cover all transportation expenses to and from the study site. 
1328 
 
If subjects choose to withdraw from the study prematurely or are disqualified for any reason, 
1329 
subjects will be compensated according to the following schedule for the time subjects were undergoing 
1330 
scanning and testing: 
1331 
 
1332 
• Discontinuation during or following the initial intake visit: $75 ($25/hour, 3 hours max for day), 
1333 
following return and adherence of all study-related tasks and equipment.  
1334 
• Discontinuation before the end of second visit: $17.05/hour, up to a maximum of 8.5 hours and 
1335 
$145 for the day (i.e., max = $220 total for both days), following return and adherence of all 
1336 
study-related tasks and equipment. 
1337 
• Discontinuation any time during the 6-week light exposure period: $220 maximum total payment, 
1338 
following return and adherence to all study-related tasks and equipment. 
1339 
• Fully compliant participants will receive $980 for completion of all light exposure sessions, proper 
1340 
use of light meter, and completion of all research activities during the final visit. Payment to 
1341 
participants who discontinue their participation between the second visit and the final visit is 
1342 
variable depending on days of light exposure missed: 
1343 
o 1 day missed: Maximum total payment $1200 
1344 
o 2 days missed: Maximum total payment of $1195 
1345 
o 3 days missed: Maximum total payment of $1190 
1346 
o 4 days missed: Maximum total payment of $1180 
1347 
o 5 days missed: Maximum total payment of $1160 
1348 
o 6 days missed: Maximum total payment of $1120 
1349 
o 7 days missed: Maximum total payment of $1040 
1350 
o 8 days missed: Maximum total payment of $880 
1351 
o 9 days missed: Maximum total payment of $560 
1352 
o More than 9 days missed: $220 maximum from completion of first 2 visits 
1353 
 
1354 
 
Payment cannot be rendered until all study-related equipment has been returned. In order to be 
1355 
compensated for participation in this study, subjects must be a U.S. citizen or other person legally entitled 
1356 
to earn money in the U.S.  By law, payments to subjects may be considered taxable income. 
1357 
 
1358 
 
If the participant is an active duty military personnel, the participant is not eligible to receive 
1359 
compensation for time spent completing assessments while they are “on duty”.  In accordance with Title 
1360 
24 United States Code 30, active duty military personnel must be on leave status during each of the three 
1361 
assessment sessions in order to be compensated.  If the participant is on active duty, it is their 
1362 
responsibility to ensure that they have completed the appropriate paperwork for leave and obtained the 
1363 

 
FORM: Application for Human Research 
NUMBER 
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PAGE 
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hrppsops@huronconsultinggroup.com 
necessary permissions to allow them to participate in this study.  If the participant is on leave status, they 
1364 
will be compensated for the 3 assessment sessions according to the schedule listed above. 
1365 
 
1366 
 
The necessary information to capture receipt of subject payment will be collected via the Subject 
1367 
Payment Form.  
1368 
Method of payment:  Participants will be paid in cash or check. Patients may need to complete a W-9 
1369 
(IRS Request for Taxpayer Identification Number and Certification) in the Psychiatry business office 
1370 
depending on the amount of compensation being provided for this study and their extent of involvement.    
1371 
 
1372 
 
1373 
13) 
Medical care and compensation for injury  
1374 
 
Subjects will be offered the care needed to treat any injury that directly results from taking part in 
1375 
this research study.  We reserve the right to bill their insurance company or other third parties, if 
1376 
appropriate, for the care they get for the injury.  We will try to have these costs paid for, but subjects may 
1377 
be responsible for some of them.   
1378 
 
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay 
1379 
subjects or give them other compensation for an injury, should one occur.  However, they are not giving 
1380 
up any of their legal rights by signing this form. 
1381 
 
If subjects think they have been injured or have experienced a medical problem as a result of 
1382 
taking part in this research study, they are to tell the person in charge of this study as soon as possible. 
1383 
Siemens will pay for the actual cost of reasonable and necessary medical treatment if a study subject 
1384 
is injured during the Trial, to the extent the injury is a direct result of the proper performance of study 
1385 
procedures that: 
1386 
• are pursuant to the study plan, 
1387 
• are not standard of care, unless included in the study plan, 
1388 
• would not otherwise have been performed but for a subject's participation in the study, 
1389 
• are not a result of the negligence or willful misconduct of UA personnel, and 
1390 
• are not the result of normal progression of a study subject's underlying disease. 
1391 
 
1392 
14) 
Monitoring the data for subject safety  
1393 
 
The principal investigator will oversee the collection, maintenance, and analysis of all data.  The 
1394 
UA HSPP will be contacted immediately in the case of unexpected adverse events. This is not a treatment 
1395 
trial. Sai Parthasarathy, MD, is director of the sleep laboratory and oversees collection of sleep PSG and 
1396 
actigraphy data. Patricia Haynes, PhD, is an expert in PTSD and contributes to the design, development, 
1397 
analysis and interpretation of data. In addition to Dr. Haynes, in the event a subject should report suicidal 
1398 
ideation and she is not available for consultation/assessment, Michael Grandner PhD, or another qualified 
1399 
clinician, will provide assessment to promote the well-being of the subject. Ted Trouard, PhD, is an 
1400 
expert in the development and application of novel MRI technologies and will assist with collection of 
1401 

 
FORM: Application for Human Research 
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F200 
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magnetic resonance spectroscopy imaging, analysis strategies, and statistical analysis of MRS and DTI 
1402 
data.  
1403 
 
Subjects may refuse to answer any questions that make them uncomfortable. In addition, subjects 
1404 
may terminate their participation in the study at any time.  If significant psychopathology (e.g., threat of 
1405 
harm to self or others) is discovered at any time during or after a subject’s visit, we will contact one of the 
1406 
psychiatrists on staff to determine the level of risk and establish a contract for safety.  If the subject does 
1407 
not already have an established relationship with a psychiatrist, we will provide the appropriate referrals 
1408 
for psychiatric evaluation.  
1409 
 
Assessment of MRI scanning-related safety issues will occur at every scanning session by the 
1410 
study staff.  Risks to subjects will be minimized by following standard MRI procedures. Individual scans 
1411 
will be aborted if any safety parameters are breached.  If the safety issue involves the patient that cannot 
1412 
be eliminated within the time course of the study, their involvement in the study will be terminated. If the 
1413 
safety issue involves the scanner or the scanning environment, no further scans will be conducted from 
1414 
that point, until assurances are made that all safety parameters have returned to allowable limits. 
1415 
 
Female participants must have a negative pregnancy test before the MRI scan can be initiated. If 
1416 
the results of the pregnancy test are positive, one of the clinically trained study investigators will explain 
1417 
why the scan cannot be completed.  
1418 
 
No long-lasting physical or economic harm is anticipated during scanning. Every effort will be 
1419 
made to reassure the patient and minimize any such discomforts while scanning. Subjects will be offered 
1420 
and required to wear earplugs and/or earphones to minimize the scanner noise. Subjects will be able to 
1421 
converse with a staff member via a microphone and speaker system at all times during the scanning 
1422 
session. Subjects will be provided with an emergency button to indicate an immediate concern. Subjects 
1423 
may ask to have a scan stopped and discontinue participation in the study at any time. 
1424 
 
In case of an adverse event, the principal investigator will evaluate and report such events to the 
1425 
UA HSPP per UA HSPP guidelines as well as report to HRPO per federal guidelines. 
1426 
The diagnostic assessment, MRI, and heart rate measures may reveal previously unidentified 
1427 
psychiatric disorders and/or brain or heart abnormalities the subject didn’t know they had. If any 
1428 
abnormalities are identified, they will be provided with information about the finding and encouraged to 
1429 
follow up with their primary care physician.  Subjects will be made aware that we are not providing 
1430 
psychiatric, neuroradiological, or other clinical services; only that we will let them know in the event that 
1431 
anything abnormal is noticed by the study team. We are unable to assume responsibility or offer 
1432 
compensation for related medical costs that they make as a result of being informed of an abnormal 
1433 
finding. 
1434 
There may be instances in which an abnormality exists but is not identified in our analyses. Our team 
1435 
is not trained in clinically diagnosing issues pertaining to abnormalities found in the collected data. 
1436 
Further, our data analyses are not intended to treat, diagnose, or replace the expertise of a medical doctor 
1437 
or a medical diagnosis. Thus, subjects will be aware that they should not rely on our analyses to reveal 
1438 
abnormalities in their data, and our lab claims no responsibility for abnormalities that go undetected 
1439 
during participation in any research related activities. 
1440 
 
1441 
 
1442 

 
FORM: Application for Human Research 
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PAGE 
F200 
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hrppsops@huronconsultinggroup.com 
15) 
Withdrawal of subjects 
1443 
 
If any disqualifying condition is discovered during the study or if it becomes evident that the 
1444 
participant is unable or unwilling to comply with study procedures, research study staff may withdraw 
1445 
that individual from the study. 
1446 
 
Subjects can voluntarily withdraw from the study at any time by speaking with the PI or study 
1447 
team. The study will then ensure the subject withdraws from the study safely and will provide any 
1448 
necessary follow-up care.  
1449 
In order to protect subjects, study resources and the integrity of study data, the Principal 
1450 
Investigator reserves the right to remove any subject at his discretion from the study. This will be 
1451 
communicated to prospective subjects during the consent process.  
1452 
If a subject chooses to withdraw from the study or his/her participation is ended prematurely, any 
1453 
information collected up to that point will be kept. 
1454 
 
1455 
16) 
Sharing of results with subjects  
1456 
 
Subjects will be informed of any new information that pertains to their rights or safety 
1457 
immediately. 
1458 
 
Subjects have the right to see and get a copy of their health information that is used or shared for 
1459 
treatment or for payment. To ask for this information, subjects will contact the person in charge of this 
1460 
research study.  Subjects may only get such information after the research is finished. 
1461 
SECTION 4: LIST OF ATTACHMENTS FOR THIS SUBMISSION 
Document Name 
Version Date 
1. F107 
2. Informed Consent Form 
3. UAMC SRA Approval Letter 
4. Grant Award/Notice of Funding 
5. PI CV 
6. goLITE Blu Pamphlet  
7. Edinburgh Handedness Inventory 
8. PHQ-9 
9. CAPS-5 
10. BDI -II 
11. BAI 
12. STAI  
13. CD-RISC 
14. PSQI 
15. ESS 
16. DDNSI 
17. SSS 
1. 06/10/14 
2. 07/14/14 
3. 06/05/14 
4. 04/25/14 
5. N/A 
6. 2013 
7. N/A 
8. 1999 
9. N/A 
10. N/A 
11. N/A 
12. N/A 
13. 09/21/11 
14. 1989 
15. N/A 
16. Unk 
17. N/A 

 
FORM: Application for Human Research 
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FORM DATE 
PAGE 
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hrppsops@huronconsultinggroup.com 
18. RBANS 
19. Polysmith 11.0 
20. Watch & Light Subject Guide, v.2 
21. Subject Payment Form (BL PTSD) 
22. Training Face Image Pairs Set A 
23. Training Face Image Pairs Set A 
24. ISI 
25. Light Device/Watts up Pro instructions 
26. Note to File 
27. Shock Expectation Questionnaire 
28. DSIQ-Baseline visit 
29. DSIQ-Post treatment visit 
30. PCL 5-Criterion A 
31. SCID-V 
32. Watt’s up PRO/Light Device agreement 
33. Compensation schedule handout 
34. Actiwatch Spectrum Pro instruction guide 
35. Sleep Diary A 
36. Sleep Diary B 
37. Phone Screen—BL PTSD 
38. Phone Script 
39. Combat Exposure Scale (CES) 
40. WRAT4 Reading Comprehension Test 
41. Rivermead Post Concussion Symptoms Questionnaire (RPCSQ) 
42. Alcohol Use Disorders Identification Test (AUDIT) 
43. Marijuana Use Questionnaire (MUSE)  
44.  BL PTSD Recruitment flyer 
45. BL PTSD Recruitment flyer version B (for non-military) 
46. BL PTSD recruitment handout 
47. Satisfaction With Life Scale (SWLS) 
 
18. 1998 
19. N/A 
20. N/A 
21. 07/14/14 
22. N/A 
23. N/A 
24. N/A 
25. N/A 
26. N/A 
27. N/A 
28. N/A 
29. N/A 
30. N/A 
31. Unk 
32. Unk 
33. N/A 
34. N/A 
35. N/A 
36. N/A 
37. N/A 
38. 06.15.15 
39. 06.15.15 
40. N/A 
41. N/A 
42. N/A 
43. N/A 
44. 06.02.15 
45. 06.02.15 
46. 06.02.15 
47.  
 
1462 
 
1463 
Submission List for F200: Application for Human Research 
1464 
 
1465 
Required items for all F200 submissions: 
1466 
• F107: Verification of Training Form 
1467 
• Current PI/Co-PI CVs or biosketch, if not included with copy of grant application 
1468 
 
1469 
Other Items as applicable: 
1470 

 
FORM: Application for Human Research 
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Experience. Redefined.™  
http://www.huronconsultinggroup.com/SOP 
hrppsops@huronconsultinggroup.com 
• Biosafety Review letter (for UA - Institutional Biosafety Committee) 
1471 
• Certificate of Confidentiality 
1472 
• Compressed Gases Review letter (for UA – Research Instrumentation) 
1473 
• Contract – complete or draft copy of contract including budget 
1474 
• Data Collection Tools – surveys, questionnaires, diaries not included in the protocol, data 
1475 
abstraction form for records review 
1476 
• Data Monitoring Charter and Plan  
1477 
• Drug/Device information – Investigator's Brochure, drug product sheet, device manual, user's 
1478 
manual, instructions for use, package insert, IND/IDE documentation, FDA 1572 form, 510k 
1479 
indication, FDA exemption, sponsor determination of device risk, etc. 
1480 
• Export Control Review 
1481 
• Grant Application(s) – complete copy of grant, regardless of home institution or funding agency, 
1482 
and a copy of the Notice of Grant Award 
1483 
• Informed Consent/Permission/Assent Form(s) – including study specific release of information 
1484 
documents, DHHS approved sample consent forms.  If consent will not be documented in writing, 
1485 
a script of information to be provided orally to subjects 
1486 
• Other Approval letters (e.g., school districts, Tribal, other IRB approvals) 
1487 
• Participant Materials – All written materials to be provided to or meant to be seen or heard by 
1488 
subjects (e.g. study newsletter, physician to participant letter, wallet cards, incentive items, 
1489 
holiday/birthday cards, certificates, instructional videos/written guides, calendars, certification of 
1490 
achievement, etc.) 
1491 
• PHI Authorization Form(s) 
1492 
• Protocol – including all amendments/revisions, sub- or extension-studies 
1493 
• Radiation Safety Review letter 
1494 
• Recruitment Materials – telephone scripts, flyers, brochures, websites, email texts, 
1495 
radio/television spots, newspaper advertisements, press releases, etc. 
1496 
• Scientific Review Committee letter (for cancer related projects – AZCC SRC; other units as 
1497 
applicable if the unit has a scientific review committee) 
1498 
• Site Authorizations for research purposes and/or access to administrative records/samples 
1499 
o External sites (such as schools, other hospitals or campuses, etc.) 
1500 
o UAHN University Campus, South Campus and clinics Site Review Authority (SRA) approval 
1501 
• Supplemental site information (for sites engaged in research where the UA is the IRB of record)  
1502 
o Copy of any approvals granted from that site (including determinations if this site has an IRB 
1503 
of its own) 
1504 
o Site-specific F107 
1505 
o Copy of the site's human subjects training policy 
1506 
o CV and medical license (if applicable) of site PI 
1507 
• Travel Authorization documentation (for UA – Office of Global Initiatives) 
1508 
• Use of retrospective research samples and/or data – IRB approval letter, original consent under 
1509 
which samples/data were collected, letter allowing access to samples 
1510 

 
FORM: Application for Human Research 
NUMBER 
FORM DATE 
PAGE 
F200 
02/2014 
44 of 44 
 
 
 
 
 
 
©2009 Huron Consulting Services, LLC.  
Huron Consulting Group 
Use and distribution subject to End User License Agreement at  
Experience. Redefined.™  
http://www.huronconsultinggroup.com/SOP 
hrppsops@huronconsultinggroup.com 
 
1511 
Submitting documents to the IRB 
1512 
All materials must be typed and submitted electronically.  Maintain electronic copies of all information 
1513 
submitted to the HSPP office in case revisions are required. It is recommended that version dates be used 
1514 
while naming documents.  
1515 
1. Documents must be submitted to the VPR-IRB@email.arizona.edu account and not to individual 
1516 
staff email accounts.  After contact by a staff member future correspondence may be 
1517 
communicated directly to the staff member concerning the submission. 
1518 
2. If acknowledgement of receipt is needed, please request a "Read Receipt" through your 
1519 
email server.   If you use Microsoft Outlook 2007, this is accomplished by clicking "Options" and 
1520 
choosing the "Request a Read Receipt" checkbox in a new email. 
1521 
3. One submission request per email (e.g. one new project submission, one continuing review plus 
1522 
attachments, or one modification request).  
1523 
4. All submissions must have signatures. An email acknowledgement in place of a signature will not 
1524 
be acceptable. If electronic signatures are not available for use, the signature pages may be signed 
1525 
and scanned as a separate Adobe PDF document and attached to the submission email. 
1526 
5. Microsoft Word documents are REQUIRED for (applications, consents, recruitment materials, 
1527 
and data collection instruments (if available).  PDFs may be submitted for documents that 
1528 
typically are not revised by the IRB (e.g. Investigator Brochures, sponsor protocols). 
1529 
6. The email subject line must include: IRB # (if assigned one), PI Last Name, and type of 
1530 
submission (Modification, New Project, Continuing Review, Reportable Item, etc.). 
1531 
7. The email must provide a list of the documents submitted for review.  While the documents 
1532 
attached do not have to adhere to a specific naming scheme, it is requested that each document be 
1533 
named to clearly reflect what is inside.  
1534 
Submissions not following these guidelines will be returned without review 
1535