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 Simoa^TM 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.