DOI: 10.5061/dryad.rjdfn2zcr
title: 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

description: 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.
description: 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].
 <strong>Overview</strong> 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 (&gt;15-30 minutes), and
 the timing/duration of light therapy were recorded.
 <strong>Light therapy</strong>
 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.
 <strong>Light validation and
 reporting</strong> 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).
 <strong>Actigraphy</strong> 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.
 <strong>Questionnaires</strong>
 <strong>Sleep </strong> 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].  
 <strong>TBI and PTSD</strong>
 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].  
 <strong>Mood</strong> 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.<strong>
 </strong>
 <strong>Pain</strong> 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. <strong>Quality of
 life</strong> 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. <strong>Blood-based
 biomarkers</strong> 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 Simoa<sup>TM</sup>
 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 <em>n</em>=33 subjects, pre- and post-blood
 samples were obtained in <em>n</em>=25 subjects. For the
 4-plex assay, a final <em>n</em>=13 was used (12-subjects
 excluded due to either unreadable results (<em>n</em>=3 to 5
 per assay), data not being obtained in duplicate (<em>n</em>=7
 to 8 per assay), or having a coefficient of variance &gt;15%
 (<em>n</em>=2 to 3 per assay) (<strong>Fig
 1</strong>). 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 <em>n</em>=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. <strong>Statistical
 analysis</strong> Analyses were performed using
 GraphPad Prism v8.4.2. Alpha of 0.05, defined <em>a
 priori</em>, 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 <em>r</em> correlation
 coefficient, and corresponding confidence intervals, were analyzed
 comparing the percent improvement in ISI score (primary outcome) to
 ancillary outcome measures (<em>Questionnaires</em>: SHI,
 PCL-5, NSI, PHQ-9, EDA, Pain intensity, Pain interference, WHO-DAS 2.0. 2.
 <em>Actigraphy</em>: TST, TIB, SE, WASO, SOL.
 <em>Blood-based biomarkers</em>: 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.