10.5061/DRYAD.RJDFN2ZCR
Elliott, Jonathan
0000-0002-6992-6851
Oregon Health & Science University
McBride, Alisha
Oregon Health & Science University
Balba, Nadir
Oregon Health & Science University
Thomas, Stanley
Creighton University
Pattinson, Cassandra
University of Queensland
Morasco, Benjamin
VA Portland Health Care System
Wilkerson, Andrea
Pacific Northwest National Laboratory
Gill, Jessica
National Institutes of Health
Lim, Miranda
0000-0003-3876-3196
Oregon Health & Science University
Feasibility and preliminary efficacy for morning bright light therapy to
improve sleep and plasma biomarkers in US Veterans with TBI. A
prospective, open-label, single-arm trial
Dryad
dataset
2022
FOS: Health sciences
Oregon Health & Science University
2022-03-10T00:00:00Z
2022-03-10T00:00:00Z
en
https://doi.org/10.1371/journal.pone.0262955
257601 bytes
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CC0 1.0 Universal (CC0 1.0) Public Domain Dedication
Mild traumatic brain injury (TBI) is associated with persistent sleep-wake
dysfunction, including insomnia and circadian rhythm disruption, which can
exacerbate functional outcomes including mood, pain, and quality of life.
Present therapies to treat sleep-wake disturbances in those with TBI
(e.g., cognitive behavioral therapy for insomnia) are limited by marginal
efficacy, poor patient acceptability, and/or high patient/provider burden.
Thus, this study aimed to assess the feasibility and preliminary efficacy
of morning bright light therapy, to improve sleep in Veterans with TBI
(NCT03578003). Thirty-three Veterans with history of TBI were
prospectively enrolled in a single-arm, open-label intervention using a
lightbox (~10,000 lux at the eye) for 60-minutes every morning for
4-weeks. Pre- and post-intervention outcomes included questionnaires
related to sleep, mood, TBI, post-traumatic stress disorder (PTSD), and
pain; wrist actigraphy as a proxy for objective sleep; and blood-based
biomarkers related to TBI/sleep. The protocol was rated favorably by ~75%
of participants, with adherence to the lightbox and actigraphy being ~87%
and 97%, respectively. Post-intervention improvements were observed in
self-reported symptoms related to insomnia, mood, and pain;
actigraphy-derived measures of sleep; and blood-based biomarkers related
to peripheral inflammatory balance. The severity of comorbid PTSD was a
significant positive predictor of response to treatment. Morning bright
light therapy is a feasible and acceptable intervention that shows
preliminary efficacy to treat disrupted sleep in Veterans with TBI. A
full-scale randomized, placebo-controlled study with longitudinal
follow-up is warranted to assess the efficacy of morning bright light
therapy to improve sleep, biomarkers, and other TBI related symptoms.
The VA Portland Health Care System approved this study, and each subject
gave written and verbal informed consent prior to participation
(IRB#4085). In this prospective study, Veterans (n=54) were identified
from the VA Portland Health Care System Sleep Clinic between 08/2017 and
08/2018. Subjects were excluded if they were not Veterans, currently
diagnosed with bipolar disorder, dementia, depression, or macular
degeneration, and were either currently using a lightbox or a shift-worker
(n=8). No subjects reported using melatonin, and the use of other sleep
medications were not excluded for. Eligible subjects (n=46) were consented
and further evaluated for TBI by a licensed physician using the Head
Trauma Events Characteristics (HTEC; recommended by the Department of
Defense and the Department of Veteran Affairs [47]), consisting of a
~20-minute diagnostic interview. In total, n=13 were excluded for not
meeting HTEC-defined criteria for sustaining mild TBI. The remaining n=33
subjects, unless otherwise noted, were included in subsequent analyses
(Fig 1). This single-arm open-label trial was registered on
clinicaltrials.gov as NCT03578003 and presented in accordance with the
CONSORT extension for pilot and feasibility trials guidelines [48–50].
Overview All subjects followed an identical protocol in this single-arm,
open-label study. The baseline period was 7-days, where subjects were
instructed to not alter their normal daily routine, including their
sleep-wake schedule. Following this, subjects were instructed to receive
60-minutes of bright light therapy (LightPad Mini, Aurora Light Solutions
Inc., Reno, NV, USA) every day for 28 consecutive days. Self-report
questionnaires were administered pre- and post-intervention, and wrist
actigraphy (Actiwatch-2, Philips Respironics, Bend, OR, USA) was collected
continuously (35-days). Daily study diaries noting bedtime, wake time,
daytime naps, prolonged nocturnal awakenings (>15-30 minutes), and
the timing/duration of light therapy were recorded. Light therapy Study
personnel provided verbal and visual explanation of how to set-up and turn
on/off the lightbox, including correctly positioning the distance (no
further than 25-inches), angle (~45°) and pitch (variable) relative to the
subject’s face, increasing the intensity to its maximum level, and
personalizing use of the device based on subjects’ home configurations.
Subjects were permitted to engage in specific activities that did not
require them to move away from the lightbox or otherwise avert their eyes
or substantially change the direction of their gaze. These activities
principally included using a computer or reading. The Aurora LightPad
Mini, per the manufacturer and confirmed by our own independent photometer
assessments (Dr.meter LX1010B, London, England), produced up to 10,000 lux
at the eye, at a distance of 25-inches. Thus, subjects were instructed to
keep the lightbox no less than 25-inches from their face. A printed
infographic illustrating the above points was attached to each lightbox
for constant reinforcement. Light validation and reporting In line with
guidance on reporting light exposure in human chronobiology and sleep
research studies,[51] we characterized the spectral power distributions
(SPD) and illuminance reaching the eye of the participants when using the
Aurora LightPad Mini (Table 1). SPDs were recorded using a calibrated
spectrophotometer (Konica Minolta, CL-500A Spectrophotometer, NJ, USA;
calibrated on 09/09/2019), after allowing the lightbox 10-minutes for
warm-up. Spectral radiance measurements were at a distance of 6-inches
from the light source, an appropriate distance given the size of the LED
light source (5.25” H x 7.5” L; 10x18 LED array), to minimize the
influence of reflected light on the SPD measurement. Spectral irradiance
estimates were made in an idealized set-up representing how subjects were
instructed to position the lightbox, e.g., keeping it at an ~45° angle
relative to their field of vision, and angled toward their eyes (generally
upward). Ambient light was minimized during these measurements to
characterize the output/stimulus provided by the lightbox. Illuminance was
recorded using a calibrated illuminance meter (Konica Minolta, T-10A
Illuminance Meter, NJ, USA; calibrated 12/17/2018) at a distance of
25-inches reflecting the maximum distance communicated to subjects in dark
ambient conditions. The lightbox was positioned at the edge of a table to
minimize any reflections off other surfaces before the light reached the
detecting source. This series of SPD and illuminance measurements was made
on three different lightboxes, with data presented as a group average
(Supporting information Table S1). Actigraphy Wrist actigraphy was
continuously collected in 2-min epochs for all 35-days. Subjects wore the
actiwatch on their non-dominant wrist. Ensuring the photometer was exposed
to the light source during treatment (e.g., not under long sleeves, not
underneath a table, in a pocket, or otherwise obstructed) was a particular
priority. While light detection at the wrist is not the same as light
detection at the retina, it provides a crude estimate of adherence, as
well as the timing and dose of subject’s light exposure. Actigraphy data
were analyzed using the Actiware version 6.0.9 proprietary algorithm
(Philips Respironics, Bend, OR, USA) with the activity threshold set to
“medium”. Actigraphy based outcomes have been validated against in-lab
polysomnography [52]. Each study day, from 12:00 PM to 11:58 AM was
analyzed individually for bedtime, sleep onset, wake time, mid-sleep time,
total sleep time (TST), time in bed (TIB), sleep onset latency (SOL),
sleep efficiency (SE), wake after sleep onset (WASO), total activity,
average activity/epoch, and number of nocturnal awakenings. Actigraphy
metrics came from data averaged across 3-5 consecutive final days before
the pre- and post-intervention assessments. To minimize heterogeneity
within subjects, sleep diaries were examined for days where subjects
reported not working, working aberrant schedules, or when ill or
traveling; these periods were excluded from analyses. On average, the
aforementioned sleep diary assessment resulted in excluding 1-2 days over
the 35-day study period per subject. Questionnaires Sleep Sleep quality
outcomes consisted of the Insomnia Severity Index (ISI) and the Sleep
Hygiene Index (SHI). Together these assessments probe difficulty
initiating and maintaining sleep, and common behavioral habits
contributing to sleep disruption. The ISI is a 7-item measure, each item a
5-point Likert scale [53,54]. The SHI is a 13-item measure, each item a
5-point Likert [55]. TBI and PTSD TBI-relevant outcomes were the
Neurobehavioral Symptom Inventory (NSI) and the PTSD checklist for DSM-5
(PCL-5). The NSI assesses TBI relevant symptom severity over the past
2-weeks, and is composed of 22-items, each a 5-point Likert scale [56–58].
The PCL-5 is used for screening/provisional diagnosis of PTSD, and
assessing symptom severity over the 30-days using 20-items, each a 5-point
Likert [59]. The total score can be subdivided into four subscales or
“clusters”: Cluster B (intrusion), cluster C (avoidance), cluster D
(mood/cognition), and cluster E (arousal). PTSD was determined by a total
score ≥33 and meeting “cluster criteria”, as before,[6–8] requiring
subjects to rate one B item, one C item, two D items, and two E items as 2
(“moderately”) or higher [59]. Mood Metrics related to mood were derived
from the Patient Health Questionnaire (PHQ-9) and NIH PROMIS
Emotional-Distress and Anxiety (EDA) short-form 4a. The PHQ-9 assesses
mood and depression severity over the previous 2-weeks. It is 9-items,
each a 4-point Likert scale. The EDA comes from the NIH PROMIS catalog and
assesses anxiety severity over the past 7-days. It is composed of 4-items,
each a 5-point Likert scale. Pain Metrics of pain come from the NIH PROMIS
Pain Interference short-form 4a and the Pain Intensity short-form 3a,
assessing perceived pain over the past 7-days. Pain Interference is
composed of 4-items, each a 5-point Likert scale. Pain intensity is
composed of 3-items, each a 5-point Likert scale. Quality of life The
World Health Organization Disability Assessment Schedule (WHO-DAS 2.0)
assesses general health and disability in major life domains following the
conceptual framework for the International Classification of Functioning,
Disability, and Health over the past 30-days. It is composed of 12-items,
each a 5-point Likert scale. Blood-based biomarkers Whole blood was
collected pre- and post-intervention (i.e., generally day 1 and 35 of the
protocol, corresponding to the beginning of baseline and end of
intervention), immediately inverted 10x and stored at 4℃ until processing
for plasma and serum (~1-3 hours). Aliquots were stored at -80℃ until a
sufficient number was obtained for batch assays. Plasma samples were sent
to the NIH NINR Biomarker Core Laboratory (PI: J.M.G.) for 4-plex and
3-plex immunoassays (exploratory outcomes) using an ultrasensitive
single-molecule enzyme-linked immunosorbent assay via SimoaTM technology
(Quanterix, Lexington, MA, USA) [60–62]. The 4-plex measured
concentrations of glial fibrillary acidic protein (GFAP), neurofilament
light chain (NfL), tau, and ubiquitin C-terminal hydrolase-L1 (UCHL1)
[63]. The 3-plex measured concentrations of interleukin-6 (IL-6),
interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-ɑ). Of the
n=33 subjects, pre- and post-blood samples were obtained in n=25 subjects.
For the 4-plex assay, a final n=13 was used (12-subjects excluded due to
either unreadable results (n=3 to 5 per assay), data not being obtained in
duplicate (n=7 to 8 per assay), or having a coefficient of variance
>15% (n=2 to 3 per assay) (Fig 1). UCHL1 was detectable for only 4
subjects (2 of which were not obtained in duplicate), as such these UCLH1
data were excluded. No outliers were detected using the extreme
studentized deviate analysis. For the 3-plex assay, a final sample size of
n=23 was used (2 subjects excluded due to meeting outlier criteria). The
average coefficients of variance for the 4-plex and 3-plex assays were,
4.5±3.0% and 3.2±2.5%, respectively. Statistical analysis Analyses were
performed using GraphPad Prism v8.4.2. Alpha of 0.05, defined a priori,
was used for all tests unless otherwise noted. Mean differences between
pre- and post-intervention outcomes were assessed via paired, two-tailed
t-tests. Pearson r correlation coefficient, and corresponding confidence
intervals, were analyzed comparing the percent improvement in ISI score
(primary outcome) to ancillary outcome measures (Questionnaires: SHI,
PCL-5, NSI, PHQ-9, EDA, Pain intensity, Pain interference, WHO-DAS 2.0. 2.
Actigraphy: TST, TIB, SE, WASO, SOL. Blood-based biomarkers: GFAP, NfL,
tau, IL-6, IL-10, TNF- ɑ). Subsequently, exploratory multiple linear
regression analyses were performed to parse out the most impactful
contributing variables to subjects percent improvement in ISI score.
Models included 1) all questionnaires with a significant post-intervention
change, 2) significant actigraphy derived metrics, and 3) significant
blood-based biomarker changes (including additional combinations of models
encompassing all variables, and models with hierarchal inclusion). As a
final measure of association, the odds ratio was used. These models were
strictly exploratory and should be interpreted as such.