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

Jonathan E Elliott, Alisha A McBride, Nadir M Balba, Stanley V Thomas, Cassandra L Pattinson, Benjamin J Morasco, Andrea Wilkerson, Jessica M Gill, Miranda M Lim, Jonathan E Elliott, Alisha A McBride, Nadir M Balba, Stanley V Thomas, Cassandra L Pattinson, Benjamin J Morasco, Andrea Wilkerson, Jessica M Gill, Miranda M Lim

Abstract

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.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. CONSORT diagram.
Fig 1. CONSORT diagram.
The CONSORT diagram outlining the recruitment, flow, data processing and final n’s for select key outcome measures.
Fig 2. Sleep related questionnaire data.
Fig 2. Sleep related questionnaire data.
Pre- and post-morning bright light therapy questionnaire scores for the (A) Sleep Hygiene Index (SHI; range = 0–52; higher = worse sleep hygiene) and (C) Insomnia Severity Index (ISI; range = 0–28; higher = worse insomnia) displayed as truncated violin plots with moderate smoothing (dashed line = median score; dotted lines = 25% and 75% quartiles). Percent change in each Individual for (B) SHI and (D) ISI, normalized to the maximum score of each questionnaire, plotted with the mean and standard deviation overlaid. Shaded symbols are subjects with co-morbid post-traumatic stress disorder (PTSD), open symbols are subjects without co-morbid PTSD. * = p <0.05 vs pre; paired two-tail t-test.
Fig 3. TBI-related symptom severity.
Fig 3. TBI-related symptom severity.
Pre- and post-morning bright light therapy questionnaire scores for the (A) Neurobehavioral Symptom Inventory (NSI; range = 0–88; higher = worse brain injury related symptom severity) and (C) Post-traumatic stress disorder (PTSD) checklist-5 (PCL-5; range = 0–80; higher = worse PTSD symptom severity) displayed as truncated violin plots with moderate smoothing (dashed line = median score; dotted lines = 25% and 75% quartiles). Percent change in each Individual for (B) NSI and (D) PCL-5 normalized to the maximum score of each questionnaire, plotted with the mean and standard deviation overlaid. Shaded symbols are subjects with co-morbid post-traumatic stress disorder (PTSD), open symbols are subjects without co-morbid PTSD. * = p <0.05 vs pre; paired two-tail t-test.
Fig 4. Mood and anxiety.
Fig 4. Mood and anxiety.
Pre- and post-morning bright light therapy questionnaire scores for the (A) Patient Health Questionnaire-9 (PHQ-9; range = 0–27; higher = worse depressive symptom severity) and (C) NIH PROMIS Emotional-Distress and Anxiety (EDA; range 4–20; higher = worse symptom severity) displayed as truncated violin plots with moderate smoothing (dashed line = median score; dotted lines = 25% and 75% quartiles). Percent change in each Individual for (B) PHQ-9 and (D) EDA normalized to the maximum score of each questionnaire, plotted with the mean and standard deviation overlaid. Shaded symbols are subjects with co-morbid post-traumatic stress disorder (PTSD), open symbols are subjects without co-morbid PTSD. * = p <0.05 vs pre; paired two-tail t-test.
Fig 5. Pain interference and intensity.
Fig 5. Pain interference and intensity.
Pre- and post-morning bright light therapy questionnaire scores for the (A) NIH PROMIS Pain Interference (range = 4–20; higher = worse pain interference) and (C) NIH PROMIS Pain Intensity (range = 3–15; higher = pain intensity) displayed as truncated violin plots with moderate smoothing (dashed line = median score; dotted lines = 25% and 75% quartiles). Percent change in each Individual for (B) pain interference and (D) pain intensity, normalized to the maximum score of each questionnaire, plotted with the mean and standard deviation overlaid. Shaded symbols are subjects with co-morbid post-traumatic stress disorder (PTSD), open symbols are subjects without co-morbid PTSD. * = p <0.05 vs pre; paired two-tail t-test.
Fig 6. Quality of life.
Fig 6. Quality of life.
Pre- and post-morning bright light therapy questionnaire scores for the (A) World Health Organization Disability Assessment Schedule 2.0 (WHO-DAS 2.0; range = 0–100%; higher = worse quality of life/greater disability) is displayed as a truncated violin plot with moderate smoothing (dashed line = median score; dotted lines = 25% and 75% quartiles). Percent change in each Individual for (B) WHO-DAS 2.0 is normalized to the maximum score of this questionnaire, plotted with the mean and standard deviation overlaid. Shaded symbols are subjects with co-morbid post-traumatic stress disorder (PTSD), open symbols are subjects without co-morbid PTSD. * = p <0.05 vs pre; paired two-tail t-test.
Fig 7. Neuronal injury and neuroinflammation biomarkers.
Fig 7. Neuronal injury and neuroinflammation biomarkers.
Pre- and post-morning bright light therapy biomarkers for (A) Glial Fibrillary Acidic Protein (GFAP), (C) Neurofilament Light Chain (NfL), and (E) Tau, displayed as truncated violin plots with moderate smoothing (dashed line = median score; dotted lines = 25% and 75% quartiles). Percent change in each Individual for (B) GFAP, (D) NfL, and (F) Tau, plotted with the mean and standard deviation overlaid. Shaded symbols are subjects with co-morbid post-traumatic stress disorder (PTSD), open symbols are subjects without co-morbid PTSD. * = p <0.05 vs pre; paired two-tail t-test.
Fig 8. Peripheral cytokines.
Fig 8. Peripheral cytokines.
Pre- and post-morning bright light therapy biomarkers for (A) Interleukin-6 (IL-6), (C) Tumor Necrosis Factor Alpha (TNF-ɑ), and (E) Interleukin-10 (IL-10) displayed as truncated violin plots with moderate smoothing (dashed line = median score; dotted lines = 25% and 75% quartiles). Percent change in each Individual for (B) IL-6, (D) TNF-ɑ, and (F) IL-10, plotted with the mean and standard deviation overlaid. Shaded symbols are subjects with co-morbid post-traumatic stress disorder (PTSD), open symbols are subjects without co-morbid PTSD. * = p <0.05 vs pre; paired two-tail t-test.

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