Head Injury Treatment With Healthy and Advanced Dietary Supplements: A Pilot Randomized Controlled Trial of the Tolerability, Safety, and Efficacy of Branched Chain Amino Acids in the Treatment of Concussion in Adolescents and Young Adults.

Concussion is a common injury in the adolescent and young adult populations. Although branched chain amino acid (BCAA) supplementation has shown improvements in neurocognitive and sleep function in pre-clinical animal models of mild-to-moderate traumatic brain injury (TBI), to date, no studies have been performed evaluating the efficacy of BCAAs in concussed adolescents and young adults. The goal of this pilot trial was to determine the efficacy, tolerability, and safety of varied doses of oral BCAA supplementation in a group of concussed adolescents and young adults. The study was conducted as a pilot, double-blind, randomized controlled trial of participants ages 11-34 presenting with concussion to outpatient clinics (sports medicine and primary care), urgent care, and emergency departments of a tertiary care pediatric children's hospital and an urban tertiary care adult hospital, between June 24, 2014 and December 5, 2020. Participants were randomized to one of five study arms (placebo and 15 g, 30 g, 45 g, and 54 g BCAA treatment daily) and followed for 21 days after enrollment. Outcome measures included daily computerized neurocognitive tests (processing speed, the a priori primary outcome; and attention, visual learning, and working memory), symptom score, physical and cognitive activity, sleep/wake alterations, treatment compliance, and adverse events. In total, 42 participants were randomized, 38 of whom provided analyzable data. We found no difference in our primary outcome of processing speed between the arms; however, there was a significant reduction in total symptom score (decrease of 4.4 points on a 0-54 scale for every 500 g of study drug consumed, p value for trend = 0.0036, [uncorrected]) and return to physical activity (increase of 0.503 points on a 0-5 scale for every 500 g of study drug consumed, p value for trend = 0.005 [uncorrected]). There were no serious adverse events. Eight of 38 participants reported a mild (not interfering with daily activity) or moderate (limitation of daily activity) adverse event; there were no differences in adverse events by arm, with only two reported mild adverse events (both gastrointestinal) in the highest (45 g and 54 g) BCAA arms. Although limited by slow enrollment, small sample size, and missing data, this study provides the first demonstration of efficacy, as well as safety and tolerability, of BCAAs in concussed adolescents and young adults; specifically, a dose-response effect in reducing concussion symptoms and a return to baseline physical activity in those treated with higher total doses of BCAAs. These findings provide important preliminary data to inform a larger trial of BCAA therapy to expedite concussion recovery.

Tunable White Light for Elders (TWLITE): A Protocol Demonstrating Feasibility and Acceptability for Deployment, Remote Data Collection, and Analysis of a Home-Based Lighting Intervention in Older Adults.

Sleep disturbances are common in older adults and may contribute to disease progression in certain populations (e.g., Alzheimer's disease). Light therapy is a simple and cost-effective intervention to improve sleep. Primary barriers to light therapy are: (1) poor acceptability of the use of devices, and (2) inflexibility of current devices to deliver beyond a fixed light spectrum and throughout the entirety of the day. However, dynamic, tunable lighting integrated into the native home lighting system can potentially overcome these limitations. Herein, we describe our protocol to implement a whole-home tunable lighting system installed throughout the homes of healthy older adults already enrolled in an existing study with embedded home assessment platforms (Oregon Center for Aging & Technology-ORCATECH). Within ORCATECH, continuous data on room location, activity, sleep, and general health parameters are collected at a minute-to-minute resolution over years of participation. This single-arm longitudinal protocol collected participants' light usage in addition to ORCATECH outcome measures over a several month period before and after light installation. The protocol was implemented with four subjects living in three ORCATECH homes. Technical/usability challenges and feasibility/acceptability outcomes were explored. The successful implementation of our protocol supports the feasibility of implementing and integrating tunable whole-home lighting systems into an automated home-based assessment platform for continuous data collection of outcome variables, including long-term sleep measures. Challenges and iterative approaches are discussed. This protocol will inform the implementation of future clinical intervention trials using light therapy in patients at risk for developing Alzheimer's disease and related conditions.

Dietary Supplementation With Branched Chain Amino Acids to Improve Sleep in Veterans With Traumatic Brain Injury: A Randomized Double-Blind Placebo-Controlled Pilot and Feasibility Trial.

Study Objectives: Traumatic brain injury (TBI) is associated with chronic sleep disturbances and cognitive impairment. Our prior preclinical work demonstrated dietary supplementation with branched chain amino acids (BCAA: leucine, isoleucine, and valine), precursors to de novo glutamate production, restored impairments in glutamate, orexin/hypocretin neurons, sleep, and memory in rodent models of TBI. This pilot study assessed the feasibility and preliminary efficacy of dietary supplementation with BCAA on sleep and cognition in Veterans with TBI. Methods: Thirty-two Veterans with TBI were prospectively enrolled in a randomized, double-blinded, placebo-controlled trial comparing BCAA (30 g, b.i.d. for 21-days) with one of two placebo arms (microcrystalline cellulose or rice protein, both 30 g, b.i.d. for 21-days). Pre- and post-intervention outcomes included sleep measures (questionnaires, daily sleep/study diaries, and wrist actigraphy), neuropsychological testing, and blood-based biomarkers related to BCAA consumption. Results: Six subjects withdrew from the study (2/group), leaving 26 remaining subjects who were highly adherent to the protocol (BCAA, 93%; rice protein, 96%; microcrystalline, 95%; actigraphy 87%). BCAA were well-tolerated with few side effects and no adverse events. BCAA significantly improved subjective insomnia symptoms and objective sleep latency and wake after sleep onset on actigraphy. Conclusion: Dietary supplementation with BCAA is a mechanism-based, promising intervention that shows feasibility, acceptability, and preliminary efficacy to treat insomnia and objective sleep disruption in Veterans with TBI. A larger scale randomized clinical trial is warranted to further evaluate the efficacy, dosing, and duration of BCAA effects on sleep and other related outcome measures in individuals with TBI. Clinical Trial Registration: [http://clinicaltrials.gov/], identifier [NCT03990909].

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.

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.

Dietary therapy restores glutamatergic input to orexin/hypocretin neurons after traumatic brain injury in mice.

Study Objectives: In previous work, dietary branched-chain amino acid (BCAA) supplementation, precursors to de novo glutamate and γ-aminobutyric acid (GABA) synthesis, restored impaired sleep-wake regulation and orexin neuronal activity following traumatic brain injury (TBI) in mice. TBI was speculated to reduce orexin neuronal activity through decreased regional excitatory (glutamate) and/or increased inhibitory (GABA) input. Therefore, we hypothesized that TBI would decrease synaptic glutamate and/or increase synaptic GABA in nerve terminals contacting orexin neurons, and BCAA supplementation would restore TBI-induced changes in synaptic glutamate and/or GABA. Methods: Brain tissue was processed for orexin pre-embed diaminobenzidine labeling and glutamate or GABA postembed immunogold labeling. The density of glutamate and GABA immunogold within presynaptic nerve terminals contacting orexin-positive lateral hypothalamic neurons was quantified using electron microscopy in three groups of mice (n = 8 per group): Sham/noninjured controls, TBI without BCAA supplementation, and TBI with BCAA supplementation (given for 5 days, 48 hr post-TBI). Glutamate and GABA were also quantified within the cortical penumbral region (layer VIb) adjacent to the TBI lesion. Results: In the hypothalamus and cortex, TBI decreased relative glutamate density in presynaptic terminals making axodendritic contacts. However, BCAA supplementation only restored relative glutamate density within presynaptic terminals contacting orexin-positive hypothalamic neurons. BCAA supplementation did not change relative glutamate density in presynaptic terminals making axosomatic contacts, or relative GABA density in presynaptic terminals making axosomatic or axodendritic contacts, within either the hypothalamus or cortex. Conclusions: These results suggest TBI compromises orexin neuron function via decreased glutamate density and highlight BCAA supplementation as a potential therapy to restore glutamate density to orexin neurons.