FROM MARY ANN LIEBERT, INC., PUBLISHERS
By Dr. Daniel J Corwin, Dr. Sage R Myers, Dr. Kristy B. Arbogast, Dr. Miranda M Lim, Dr. Jonathan E Elliott, Dr. Kristina B Metzger,
Dr. Peter LeRoux, Dr. Jaclynn Elkind, Ms. Hannah Metheny, Dr. Jeffrey Berg, Mr. Kevin Pettijohn, Dr. Christina Master, Dr. Matthew P Kirschen, and Dr. Akiva Cohen
12 Mar 2024
Concussion is a common injury in the adolescent and young adult populations. While 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 branched chain amino acid (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 6/24/2014 and 12/5/2020. Participants were randomized to one of five study arms (placebo and 15g, 30g, 45g, and 54g 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 reporting a mild (not interfering with daily activity) or moderate (limitation with daily activity) adverse event; there were no differences in adverse events by arm, with only 2 reported mild adverse events (both gastrointestinal) in the highest (45g and 54g) BCAA arms. Though 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.
Mild traumatic brain injuries (mTBI), including concussion, are common injuries experienced by adolescents and young adults.1Over the past decade, significant advances in the knowledge and care of concussed adolescents and young adults have occurred. While traditionally, a passive strategy of cognitive and physical rest has been recommended as the sole treatment modality for concussion,2several active rehabilitation strategies have shown efficacy, including aerobic exercise therapy3,4and visio-vestibular rehabilitation.5,6However, these therapeutics are time and labor intensive, and require specialized monitoring and for most prescription from a concussion specialist. In spite of these advances, a pharmacologic intervention to hasten recovery has yet to be identified. Medications commonly prescribed (such as over-the-counter analgesics and anti-emetics7) focus on symptom management without targeting the underlying pathophysiology that leads to concussion symptoms.8Preclinical studies in animal models have demonstrated that the three branched chain amino acids (BCAAs)--valine, leucine, and isoleucine--are reduced following TBI, with their depletion possibly due to their role in both the production of neurotransmitters as well as in cellular metabolism, which is transientlyelevated after injury followed by protracted duration of reduction.9Following BCAA supplementation, injured mice demonstrate improvement in cognitive activity and mitigation of persistent sleep-wake deficits, thought to be mediated through restoration ofexcitatory/inhibitory balance in the hippocampus.10,11In humans, BCAA levels after severe TBI in adults correlate with measures of clinical severity (such as intracranial pressure12). BCAA supplementation in this population led to moderate clinical improvements involving disability and cognitive function.13,14A single study of 18 patients (primarily adults) with mTBI demonstrated decreased concentrations of BCAAs and their metabolites compared to healthy controls.15BCAA supplementation improved actigraphy metrics and self-reported sleep quality in veterans who were recovering from mTBI.16It is unknown whether BCAA supplementation will accelerate the rate of neurocognitive or clinical symptom recovery from concussion in adolescents and young adults.
Therefore, the goal of this pilot, double-blinded, randomized controlled trial was to 1) evaluate whether BCAA supplementation will accelerate the cognitive and symptom recovery of concussed participants in a dose-dependent manner and 2) determine the safety and tolerability of varying concentrations of oral BCAA supplementation. We hypothesized a dose-response improvement in processing speed, symptom burden, physical activity level, and sleep integrity in those receiving BCAA supplementation compared to placebo, with BCAAs being well-tolerated at all doses.17,18METHODSStudy Design and Participant Population Study description is reported in line with the CONSORT statement extension to randomized pilot and feasibility trials (see Supplemental Table 1 for complete checklist).19The trial was registered on ClinicalTrials.gov (identifier NCT01860404) prior to participant enrollment. The study was US Food and Drug Administration (FDA) regulated (FDA IND 117570). Participants were enrolled as a convenience sample, based on availability of research team members. Recruitment occurred in outpatient clinics (sports medicine and primary care), urgent care centers, and emergency departments of a tertiary care pediatric children’s hospital and an urban tertiary care adult hospital, both with a level I trauma designations, from June 25, 2014, through December 5, 2020. Of note, in October 2016, after the enrollment of 12 analyzable subjects, the study was paused due to slow enrollment, and eligibility criteria were modified to broaden age limit, lengthen time from injury to presentation, and include non-sports injury mechanisms. During the pause, we experienced turnover of multiple research staff members; this, in combination with changes in study recruitment policies for acute care locations, extended the enrollment pause while study procedures were being modified. Study enrollment resumed in 2018, however slowed significantly again during the novel coronavirus pandemic inearly 2020. Therefore, in late 2020, after randomizing 42 participants (fewer than our target of 50; see power analysis below), given the ongoing length of the study to date and concurrent advances in concussion care, we decided to halt enrollment to assess efficacy of pilot data.
Page 8of 328Journal of NeurotraumaHead Injury Treatment with HEalthy and Advanced Dietary Supplements (HIT HEADS): A pilot randomized controlled trial of the tolerability, safety, and efficacy of branched chain amino acids (BCAAs) in the treatment of concussion in adolescents and young adults(DOI: 10.1089/neu.2023.0433)This paper has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.Participants were eligible if they were between 11 and 34 years of age (initial lower age limit was 16 years, lowered following initial enrollment phase) and diagnosed with a concussion by the treating provider in alignment with the most recent International Consensus Concussion guidelines at the time.20Additional inclusion criteria included injury within the prior 72 hours (initial criteria was injury within 24 hours, broadened following the initial study phase), weight of at least 40 kg (given dosing considerations21), and a negative pregnancy test and acceptable contraception for study duration for post-menarchal females (due to animal models showing possible harmful effects of BCAA supplementation in utero22). Initial injury mechanism was limited to sport-and recreation-related injuries; however, this was broadened to include all injury mechanisms after the initial enrollment phase. Exclusion criteria included signs of a moderate or severe TBI (including witnessed seizure or admission to an intensive care unit), prior concussion within the preceding 90 days, history of maple syrup urine disease or family history of maple syrup urine disease, active prescription of neurologic or psychoactive medications, and allergy to red dye #40 or sucralose. Following screening, all participants (for those 18 years and older) or parents/guardians (for those younger than 18 years) provided written informed consent; child assent was also obtained for participants younger than 18 years ofage. The study was approved by our institution’s institution review board under IRB#13-010227.Randomization and BlindingFollowing enrollment and completion of informed consent, participants were randomized into one of five groups (placebo and four BCAAdosing groups, as noted below), in a schema of equal allocation, stratified by sex, which was generated a prioriby the study biostatistician. A randomization module was programmed to generate a unique kit number for each participant. The scheme was provided to the Investigational Drug Service (IDS) at the University of Pennsylvania prior to study initiation, where study kits were prepared. Participants and study investigators were blinded to treatment assignment; only the Database Administrator and the University of Pennsylvania Pharmacist had access to the link between kit number and treatment arm. Color and opacity of kits were prepared by
Page 9of 329Journal of NeurotraumaHead Injury Treatment with HEalthy and Advanced Dietary Supplements (HIT HEADS): A pilot randomized controlled trial of the tolerability, safety, and efficacy of branched chain amino acids (BCAAs) in the treatment of concussion in adolescents and young adults(DOI: 10.1089/neu.2023.0433)This paper has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.the IDS as closely matched as possible to ensure adequate blinding between placebo and BCAA dosages. Treatment The three BCAAs, valine, isoleucine, and leucine, were combined together in a 1:1:1 ratio for the four treatment doses. Dose levels were determined both by animal models and prior clinical work in humans in other conditions. In brain-injured mice, the equivalent of 60 grams (g) per day of BCAAs mitigated cognitive impairment, without additional benefit at higher doses.9,10In prior human trials, doses between 15 g/d and 57 g/d were utilized for treatment of neurologic conditions, such as tardive dyskinesia and hepatic encephalopathy.23,24The “no observable adverse effect level” of BCAA intake is likely considerablyhigher than 60g, with no evidence of toxicity in animal models up to 100 g/day and humans of up to 90 g per day.25Given the unknown optimal dose of BCAA supplementation for concussion, we initially chose doses of 15g, 30g, 45g, and 60g divided twice daily as our treatment doses. However, during initial study preparation, precipitation issues were noted at the highest dose due to leucine precipitating at a lower concentration than expected. After further testing, it was determined that the product remained in solution at a concentration of 27g/591milliliter (mL) and therefore, the highest dose level was reduced to 54 g/day.Each treatment dose was divided into twice daily dosing (7.5g, 15g, 22.5g, and 27g, respectively). For each dose, the BCAAs were combined and dissolved in water, with additives (sodium gluconate, Tropical Punch Kool-Aid® powder, and sucralose) to improve palatability. The placebo solution contained sucrose octaacetate and microcrystalline cellulose dissolved in water, with identical additives, to ensure the placebo solution had similar taste, texture, consistency, and appearance as the BCAA solution. The BCAA and placebo solutions were compounded by the University of Pennsylvania IDS laboratory. Stability and durability testing, including bioburden and colony count, were performed by the IDS laboratory in line with organizational and institutional policies prior to any study drug distribution.
Page 10of 3210Journal of NeurotraumaHead Injury Treatment with HEalthy and Advanced Dietary Supplements (HIT HEADS): A pilot randomized controlled trial of the tolerability, safety, and efficacy of branched chain amino acids (BCAAs) in the treatment of concussion in adolescents and young adults(DOI: 10.1089/neu.2023.0433)This paper has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.Monitoring and OutcomesParticipants were monitored for 21 days following enrollment. Participant baseline characteristics, including demographic data, were collected via self-report upon enrollment. Participants were monitored with daily electronic surveys, cognitive testing, as well as continuous actigraphy. Each survey included questions about concussion symptoms, physical activity, cognitive activity, drug compliance, and adverse events. In-person visits were conducted at three time points during study enrollment, between study days 5-9, 12-16, and 22-24, to assess symptom burden and side effects in-person. The primary outcome was to determine if, compared to placebo treatment, BCAAs accelerated neurocognitive recovery. Neurocognitive testing was performed using the CogSport/Axon Sports Computerized Cognitive Assessment Tool (CCAT).26,27The CCAT includes four computerized tests measuring processing speed (via a simple reaction time task), attention (via a choice reaction time task), visual learning (via a one card learning task) and working memory (via a one-back task). In line with prior studies and manufacturer recommendations, average log mean reaction time was compared for the processing speed, attention, and working memory subtests; accuracy was used for the visual memory subtest.26–28Symptoms were assessed via self-report utilizing a9-item symptom instrument, shown to have excellent factorial and construct validity by Piland and colleagues.29Included in the instrument are the following: headache, nausea, balance problems, sleeping more than normal, drowsiness, fatigue, feeling slowed down, feeling mentally foggy, and difficulty concentrating. Each symptom is rated on a 7-point Likert scale (0=no symptom; 6=very severe symptoms), generating a total symptom score ranging from 0 to 54. Physical activity was rated on a 6-point Likert scale of return to baseline physical activity (0=no physical activity; 5=return to full physical activity, including full game play for athletes). Cognitive activity was rated on a 5-point Likert scale of return to baseline cognitive activity at school or work (0=complete cognitive rest; 4=full unrestricted participation in school or work). Participant sleep was assessed using actigraphy (ActiSleep+ Monitor, ActiGraph, Pensacola, FL) worn 24/7 during study participation on the participant’s non-dominant wrist.
Data was collected in 60 sec epochs and analyzed using ActiLife software version 6.13.4 with a 90-min non-wear threshold.30,31Each study day was analyzed individually for bedtime, wake time, total sleep time (TST), sleep efficiency, wake after sleep onset (WASO), number and length of awakenings, activity, and proprietary indices of movement/sleep fragmentation. These respective metrics were averaged across the entire study duration, with daytime sleep periods excluded. Participant compliance withtaking BCAA supplementation was assessed by self-report. Participants reported the number of bottles of study medication (0, 1, or 2, as each daily dose was divided into twice daily increments) consumed. For days in which participants did not answer the survey, it was assumed no drink was consumed. Potential adverse events, in accordance with the CONSORT harm guidelines for pilot randomized trials,19were collected from daily self-report surveys in addition to assessment at scheduled study visits. All adverse events were characterized with descriptions of the event, assessment of severity, indication of whether the event was serious (death, a life-threatening event, hospitalization or prolongation of existing hospitalization, or persistent or significant disability/incapacity), and start and end date. Statistical Considerations and Power AnalysisStandard descriptive statistics were used to summarize demographic data. Our initial analytic plan was to adjust for age and repeated measures among the five treatment arms using a mixed effects model by prescribed dose; given both our inability to reach our enrollment goal, as well as varying response rates (see Table 1), we were unable to fit a model using this approach. Instead, to account for individual characteristics, such as age and varying amounts of follow-up time with unbalanced numbers of repeated measures, in addition to capturing efficacy as opposed to effectiveness (given varying adherence to treatment protocol, see Table 3), we used linear regression to conduct a dose response analysis. The linear regression model included total cumulative study dose received (study dose prescribed multiplied by number of days consuming said dose) as the independent variable and change in outcome (average of each participant’s first 3 measures compared to the participant’s last 3 measures over the course of the study) as the dependent variable among participants with at least 7 reported measurements. This dose response model was fitted separately for each of the four CCAT subtests, total symptom score, physical activity, and cognitive activity; the intercept and slope parameter (with 95% confidence interval and p-value) were obtained from models with each outcome. Though both physical and cognitive activity were assessed on ordinal scales,the outcome measure used in the model was the change in these activity levels, leadingto a continuous variable from which a linear regression model could be fitted. Compliance (average reported drink consumed over study period) and adverse events (average per arm and percent in each arm experiencing adverse events) were compared across arms using Kruskal-Wallis rank test and Fisher’s exact test, where appropriate. Analyses were performed using SAS software, version 9.4 (SAS Institute Inc, Cary, NC), Stata software, release 14.2 (StataCorp LLC, College Station, TX), and GraphPad Prism version 8 (GraphPad Software, San Diego, CA).Prior to study initiation, we estimated an enrollment goal of 50 subjects, or 10 subjects per arm, which would have given us 80% power to detect differences in the processing speed subtest between the BCAA arms and the placebo arm of 0.122 seconds (log mean -0.914), or a 5% difference based on healthy control data (including a standard deviation of 0.08 secondsin healthy individuals, inflated to 0.10 for injured subjects).28As noted above, due to significant slowing of enrollment during the novel coronavirus pandemic in early 2020, in late 2020, after randomizing 42 participants, we decided to halt study enrollment to assess efficacy of pilot data in order to inform a larger, more definitive, full-powered trial.RESULTSIn total, 42 participants were randomized (see Figure 1 for flow diagram). Of those, four participants withdrew prior to providing any follow-up data (all in the 30 g BCAA arm), and therefore were withdrawn from further analysis. Demographics and initial injury characteristics for the 38 analyzed participants are provided in Table 1. Of the 38 participants analyzed, 26 provided at least 7 reported measures in symptoms, physical, and cognitive activity, and 18 provided at least 7 reported measures for neurocognitive testing; 20 provided data through the full 21 days of the study period.
The average number of days for which the survey questions and CCAT battery were completed across the study period by arm is displayed in Table 1. Overall, the median total study dose consumed was 360 g (range 0 to 2052 g; see Table 1 for breakdown by arm). In terms of neurocognitive testing, we did not find a change in outcome with increased total study dose consumed using linear regression analysis (Table 2, Figure 2). Of note, not all patients who completed follow-up completed the neurocognitive testing elements (Table 1). We found a significant reduction in total symptom score by total dose consumed using linear regression analysis (a decrease of 4.4 points [standard error 1.4] for each 500 g of study drug consumed, p-value for trend line = 0.0036; Table 2 and Figure 3a), as well as a significant improvement in return to baseline physical activity by total dose consumed in our adjusted analysis (an increase of 0.503 points [standard error 0.164] for each 500 g of study drug consumed, p-value for trend = 0.0053). We found no change in cognitive score in our linear regression (Table 2, Figure 3c). Actigraphy data is presented in Supplementary Table 2. Because of a limited number of participants with complete actigraphy data, no statistical testing was performed based on this data, however, the raw values for sleep efficiency (93.2% vs. 91.4%) and total sleep time (536.7 minutes vs. 468.1 minutes) were higher in the highest BCAA dose group (54 g/day) vs. the placebo group . In analyzing our compliance, we found lower average reported total drink consumed by arm (81% reported compliance in the placebo arm compared to 49% compliance in the 54g BCAA arm; Table 3, though the trendwas non-significant [p=.581] via Kruskal-Wallis testing). We did not find any difference in adverse events by arm (Table 3) via Kruskal-Wallis testing. Across the study, in total, 13 adverse events were reported among the 38 participants, the majority (10) occurred in either the placebo or lowest BCAA dose groups. No adverse events were severe, and the majority (10 out of 13, including all three adverse events in the 30g, 45g, and 54g BCAA arms) were reported as mild. The majority (12 of the 13) were gastrointestinal side effects (abdominal pain, diarrhea, or bloating).
This pilot, double-blinded, randomized controlled trial is the first evaluation of BCAA supplementation in the treatment of concussion in adolescents and young adults and demonstrated efficacy, high tolerability, and safety of BCAAs. Specifically, we found a significant dose response effect in reduction of concussion symptoms and a return to baseline physical activity in those who consumed higher total doses of BCAAs across the study period, with high tolerability of treatment doses without serious adverse events. This data provides important preliminary work to inform a larger, definitive randomized controlled trial of BCAA therapy for concussed youth and young adults.BCAAs participate directly and indirectly in a variety of important biochemical functions in the brain. In addition to the fundamental use of amino acids for protein synthesis, these specific essential amino acids are pivotal in glutamate synthesis, as they contribute 50% of the nitrogen in glutamate.32Moreover, the decarboxylation of glutamate by glutamic acid decarboxylase (GAD) leads to the synthesis of the primary inhibitory neurotransmitter GABA. Furthermore, de novoglutamate synthesis contributes a significant amount (approximately 40%) of releasable synaptic glutamate.33It has been hypothesized that the increased energy demands of the brain post-injury rapidly deplete BCAA levels.9In addition, it has been noted that BCAAs can enter the Krebs cycle and contribute to increased production of adenosine triphosphate (ATP),14alterations in which have also been implicated as a key component to the pathophysiology of concussion.8Interestingly, animal studies have found that repeated exposure to BCAAs over multiple days is required to observe improvements in cognitive function following TBI.10This suggests that it is not only BCAA supplementation, but repeated exposure to BCAAs, that underlies the clinical improvement noted in our current study (as evidenced by the total dose-response effect in improving concussion symptoms allowing for a return to baseline activity level following injury). Overall, we saw minimal adverse effects with BCAA supplementation, particularly at our higher doses. Multipleprior studies have reported the tolerability of BCAAs, with large reviews reporting either no, or minimal gastrointestinal, side effects,23and the results
herein further support the tolerability of BCAA supplementation. We do note the decrease in treatment compliance as BCAA doses increased; while not related to adverse events experienced by participants, this does suggest, in the setting of concussion, that there may be limited palatability of the highest BCAA doses that might limit compliance. Future work should focus on methods to improve compliance of the highest BCAA doses, particularly given the observed dose-response effect in this study, as well as the importance of repeated BCAA exposure in animal models.10The improvement in concussion-related symptoms and accelerated return to baseline physical activity in a dose-response pattern are key findings of our study. Over the past decade, symptoms have emerged as the principal primary outcome in the largest observational and interventional trialsof concussion.4,34In addition, there has been an effort to incorporate patient-reported outcomes as primary measures of functioning following injury (with return to pre-injury level of activity a key indication of post-injury functioning),35and prior work has demonstrated a strong correlation between symptom burden and quality of life in adolescent concussion.36While our primary outcome, neurocognitive testing, did not show significant differences among our treatment arms, since the inception of our study, multiple limitations to utilizing neurocognitive testing as an objective injury marker have been described.37,38In particular, a “ceiling effect” to neurocognitive testing has been described, reducing its utility as a study endpoint over time.39Since the initial development of the study protocol, however, multiple other objective markers of injury have been developed as key metrics of central nervous system dysfunction, including visio-vestibular testing40,41and evaluation of thepupillary light reflex.42These objective measures, in addition to blood-based biomarkers,43make for key additional objective outcomes to potentially augment subjective symptom scores in future trials. Sleep disturbances have frequently been reported as key elements contributing to dysfunction following concussion,44with sleep alterations in the acute time frame after injury has been identified as a key prognostic factor in the development of persistent post-concussive symptoms.45 Previous work has demonstrated the efficacy of BCAA supplementation to improve sleep disturbances in animal models,11and a recent
randomized trial of Veterans with chronic TBI symptoms showing BCAA efficacy in improving both subjective and objective sleep impairment.16Our data, though limited in sample size and statistical power in this secondary outcome measure, suggest possible improvements in sleep efficiency and total sleep time in those receiving the highest BCAA dose. Since our study inception, several randomized trials of active rehabilitative treatment programs have been conducted showing efficacy in reducing prolonged concussion symptoms.3–5However, these interventions often require either in-person visits or specialized guidance to complete.46The potential reliance on specialist prescription and monitoring has the potential to introduce or exacerbate known disparities in concussion care that exist for underserved communities.47This underlies the importance of developing safe, accessible, and well-tolerated pharmacologic interventions for concussion in adolescents and young adults, such as BCAA supplementation, that could be prescribed from diverse settings without a need for specialist monitoring. The role of BCAAs may also expand beyond treatment into the realm of injury prevention, as a recent animal model study explored the efficacy of administering BCAAs in mice prior to head trauma as a prophylaxis, with improved motor recovery and cognitive function.48There are several key limitations toour study that necessitate a larger, more definitive trial before routine clinical implementation of BCAA therapy for concussion. Firstly, due to a combination of initially more strict inclusion criteria, and the impact of the coronavirus pandemic, our sample size was smaller than anticipated. This, combined with poorer than expected follow-up, led us to have to use alternative statistical analytic methods. However, the improvement in symptoms, physical activity, and sleep, represent strong preliminary data to inform a future larger trial. We were further limited by missing data. This also necessitated the alternative analytic approach described in the methods. Of note, since study inception, multiple investigators have refined remote patient monitoring tools as a means to track participants in observational and interventional studies from multiple settings,49,50making these tools a promising method to maximize follow-up in future trials. In addition, since study inception, several symptom batteries have emerged as a standard of care for assessing concussion symptoms.51As our participants were enrollment in a
convenience sample, our sample may not be representative of the overall population of acutely concussed adolescents and young adults, though our broad enrollment locations (compared to exclusively enrolling from an emergency department or specialty clinic) may assist with generalizability of our results. Finally, as we enrolled subjects over a significantly longer period than initially anticipated, multiple temporal trends in the management of concussion occurred during our study timeframe (specifically a move away from passive treatment recommendations toward a more active therapeutic approach46), which potentially may have impacted our results, results, although one would expect that any active intervention would improve recovery time would have decreased the effect size of the BCAA intervention, making our findings even more promising (and, as noted in Table 1, there was relatively equal distribution of participants across arms in the various study enrollment periods). In conclusion, this preliminary work, while limited by enrollment challenges and small samples sizes, demonstrates the potential efficacy of BCAAs in improving concussions symptoms and allowing for a more rapid return to pre-injury activity levels in concussed adolescents and young adults, representing the first such data in acute mild traumatic brain injury in humans. Importantly, BCAAs were found to be well-tolerated in our participants, with minimal adverse events, even at the highest doses. While a larger, more definitive trial is necessary prior to routine clinical implementation of BCAA therapy for concussed adolescents and young adults, these data demonstrate the promising potential benefit of BCAA supplementation to reduce symptoms and allow for a return to baseline activity following concussion.
TRANSPARENCY, RIGOR, AND REPRODUCIBILITY STATEMENTThe study design and analysis plan were preregistered on May 22, 2013 at ClinicalTrials.gov (NCT01860404); of note, given both our inability to reach our enrollment goal, as well as varying response rates, we were unable to fit a model using our original approach, therefore an alternative statistical plan was implemented by a study biostatistician (KBM) blinded to treatment allocation. Prespecified sample size was 10 subjects per group, yielding statistical power of 80% for detection of a 0.122 seconds (log mean -0.914) difference in the processing speed subtest of the CogSport/Axon Sports Computerized Cognitive Assessment Tool as the primary outcome measure. All participants were assigned to one of four intervention groups (15g, 30g, 45g, and 54g daily of BCAA) or placebo using a random number generator programmed a priori, yielding groups that did not differ statistically in baseline characteristics. In total, 42 participants were randomized; the primary outcome was assessed in 30 participants (after 12 incomplete assessments), and secondary outcomes were assessed in 38 participants (after 4 incomplete assessments), as demonstrated in the study CONSORT diagram. Participants were blinded to group assignment with use of identically appearing placebo treatment. All primary outcomes were assessed by investigators blinded to group assignment. All materials required to perform the interventions may be available upon request from University of Pennsylvania Laboratory service and the corresponding author.The key inclusion criteria, as well as the primary and secondary outcome measures, were standards in the field at time of enrollment. Descriptive statistics of continuous variables utilized non-parametric tests. For the dose-response analysis of primary outcomes, we used linear regression, which assumed normal distribution of total study dose received and of change in outcome measures. Because the sample size was smaller than we modified the planned primary dose-response analyses from a repeated measures mixed effect model to a linear regressions using summarized outcome and dose data. We did not use statistical methods to correct for multiple comparisons, as we interpreted our results holistically by examining the effect of total dose on various outcomes as evidence for overall reduction in concussion-related signs and symptoms, rather than emphasizing a particular relationship with a specific outcome. The findings have not yet been replicated or externally validated, however external validation studies are currently being planned. De-identified data from this study are not available in a public archive. De-identified data from this study will be made available (as allowable according to institutional IRB standards) by emailing the corresponding author as of June 1, 2024. Analytic code used to conduct the analyses presented in this study are not available in a public repository. They may be available by emailing the corresponding author as of June 1, 2024. Intervention protocols are available upon request. The authorsagree to provide the full content of the manuscript on request by contacting the corresponding author.
CONFLICT OF INTEREST
Akiva S. Cohen and the Children’s Hospital of Philadelphia hold a provisional patent, which includes the use of branched chain amino acids as a therapeutic intervention for traumatic brain injury, under the title “Compositions and methods for the treatment of brain injury.” This includes U.S. Provisional Patent Application Nos. 61/883,526 and 61/812,352, U.S. Patent 11/576,88, and European Patent No. 2986113 (regionalized in Germany, Spain, France, UK, and Italy). In addition, Dr. Cohen served as the FDA Investigational New Drug (IND) sponsor.
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13.Aquilani R, Boselli M, Boschi F, et al. Branched-chain amino acids may improve recovery from a vegetative or minimally conscious state in patients with traumatic brain injury: a pilot study.Arch Phys Med Rehabil. 2008;89(9):1642-1647; doi:10.1016/j.apmr.2008.02.023.
14.Aquilani R, Iadarola P, Contardi A, et al. Branched-chain amino acids enhance the cognitive recovery of patients with severe traumatic brain injury.Arch Phys Med Rehabil. 2005;86(9):1729-1735; doi:10.1016/j.apmr.2005.03.022.
15.Jeter CB, Hergenroeder GW, Ward NH 3rd, Moore AN, Dash PK. Human mild traumatic brain injury decreases circulating branched-chain amino acids and their metabolite levels.J Neurotrauma. 2013;30(8):671-679; doi:10.1089/neu.2012.2491.
16.Elliott JE, Keil AT, Mithani S, et al. 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.Front Syst Neurosci. 2022;16:854874; doi:10.3389/fnsys.2022.854874.
17.Evangeliou A, Spilioti M, Doulioglou V, et al. Branched chain amino acids as adjunctive therapy to ketogenic diet in epilepsy: pilot study and hypothesis.J Child Neurol. 2009;24(10):1268-1272; doi:10.1177/0883073809336295.
18.Richardson MA, Small AM, Read LL, Chao HM, Clelland JD. Branched chain amino acid treatment of tardive dyskinesia in children and adolescents.J Clin Psychiatry. 2004;65(1):92-96. doi:10.4088/jcp.v65n0116.
19.Eldridge SM, Chan CL, Campbell MJ, et al. CONSORT 2010 statement: extension to randomised pilot and feasibility trials.BMJ. 2016;355:i5239; doi:10.1136/bmj.i5239.
20.McCrory P, Meeuwisse WH, Aubry M, et al. Consensus statement on concussion in sport: the 4th International Conferenceon Concussion in Sport held in Zurich, November 2012.Br J Sports Med. 2013;47(5):250-258; doi:10.1136/bjsports-2013-092313.
21.Gijsman HJ, Scarnà A, Harmer CJ, et al. A dose-finding study on the effects of branch chain amino acids on surrogate markers of brain dopamine function.Psychopharmacology (Berl). 2002;160(2):192-197; doi:10.1007/s00213-001-0970-5.
22.To CY, Freeman M, Van Winkle LJ. Consumption of a Branched-Chain Amino Acid (BCAA) during Days 2-10 of Pregnancy Causes Abnormal Fetal and Placental Growth: Implications for BCAA Supplementation in Humans.Int J Environ Res Public Health. 2020;17(7):2445; doi:10.3390/ijerph17072445.
23.Als-Nielsen B, Koretz RL, Kjaergard LL, Gluud C. Branched-chain amino acids for hepatic encephalopathy.Cochrane Database Syst Rev. 2003;(2):CD001939; doi:10.1002/14651858.CD001939.
24.Richardson MA, Bevans ML, Read LL, et al. Efficacy of the branched-chain amino acids in the treatment of tardive dyskinesia in men.Am J Psychiatry. 2003;160(6):1117-1124; doi:10.1176/appi.ajp.160.6.1117.
25.Tsubuku S, Hatayama K, Katsumata T, et al. Thirteen-week oral toxicity study of branched-chain amino acids in rats.Int J Toxicol. 2004;23(2):119-126; doi:10.1080/10915810490444424
26.Maruff P, Thomas E, Cysique L, et al. Validity of the CogState brief battery: relationship to standardized tests and sensitivity to cognitive impairment in mild traumatic brain injury, schizophrenia, and AIDS dementia complex.Arch Clin Neuropsychol. 2009;24(2):165-178; doi:10.1093/arclin/acp010.
27.Collie A, Makdissi M, Maruff P, Bennell K, McCrory P. Cognition in the days following concussion: comparison of symptomatic versus asymptomatic athletes.J Neurol Neurosurg Psychiatry. 2006;77(2):241-245; doi:10.1136/jnnp.2005.073155.
28.Louey AG, Cromer JA, Schembri AJ, et al. Detecting cognitive impairment after concussion: sensitivity of change from baseline and normative data methods using the CogSport/Axon cognitive test battery.Arch Clin Neuropsychol. 2014;29(5):432-441; doi:10.1093/arclin/acu020.
29.Piland SG, Motl RW, Guskiewicz KM, McCrea M, Ferrara MS. Structural validity of a self-report concussion-related symptom scale.Med Sci Sports Exerc. 2006;38(1):27-32; doi:10.1249/01.mss.0000183186.98212.d5.
30.Knaier R, Höchsmann C, Infanger D, Hinrichs T, Schmidt-Trucksäss A. Validation of automatic wear-time detection algorithms in a free-living setting of wrist-worn and hip-worn ActiGraph GT3X.BMC Public Health. 2019;19(1):244; doi:10.1186/s12889-019-6568-9.
31.Choi L, Ward SC, Schnelle JF, Buchowski MS. Assessment of wear/nonwear time classification algorithms for triaxial accelerometer.Med Sci Sports Exerc. 2012;44(10):2009-2016; doi:10.1249/MSS.0b013e318258cb36.
32.Sakai R, Cohen DM, Henry JF, Burrin DG, Reeds PJ. Leucine-nitrogen metabolism in the brain of conscious rats: its role as a nitrogen carrier in glutamate synthesis in glial and neuronal metabolic compartments.J Neurochem. 2004;88(3):612-622; doi:10.1111/j.1471-4159.2004.02179.x.
33.Lieth E, LaNoue KF, Berkich DA, et al. Nitrogen shuttling between neurons and glial cells during glutamate synthesis.J Neurochem. 2001;76(6):1712-1723; doi:10.1046/j.1471-4159.2001.00156.x.
34.Zemek R, Barrowman N, Freedman SB, et al. Clinical Risk Score for Persistent Postconcussion Symptoms Among Children With Acute Concussion in the ED.JAMA. 2016;315(10):1014-1025; doi:10.1001/jama.2016.1203.
35.Fineblit S, Selci E, Loewen H, Ellis M Fineblit S, Selci E, Loewen H, Ellis M, Russell K. Health-Related Quality of Life after Pediatric Mild Traumatic Brain Injury/Concussion: A Systematic Review.J Neurotrauma. 2016;33(17):1561-1568; doi:10.1089/neu.2015.4292.
36.Howell DR, Wilson JC, Kirkwood MW, Grubenhoff JA. Quality of Life and Symptom Burden 1 Month After Concussion in Children and Adolescents.Clin Pediatr (Phila). 2019;58(1):42-49; doi:10.1177/0009922818806308.
37.Hang B, Babcock L, Hornung R, Ho M, Pomerantz WJ. Can Computerized Neuropsychological Testing in the Emergency Department Predict Recovery for Young Athletes With Concussions?.Pediatr Emerg Care. 2015;31(10):688-693; doi:10.1097/PEC.0000000000000438.
38.McClure DJ, Zuckerman SL, Kutscher SJ, Gregory AJ, Solomon GS. Baseline neurocognitive testing in sports-related concussions: the importance of a prior night's sleep.Am J Sports Med. 2014;42(2):472-478; doi:10.1177/0363546513510389.
39.Gaudet CE, Konin J, Faust D. Immediate Post-concussion and Cognitive Testing: Ceiling Effects, Reliability, and Implications for Interpretation.Arch Clin Neuropsychol. 2021;36(4):561-569; doi:10.1093/arclin/acaa074.
40.Corwin DJ, McDonald CC, Arbogast KB, et al. Clinical and Device-based Metrics of Gait and Balance in Diagnosing Youth Concussion.Med Sci Sports Exerc. 2020;52(3):542-548; doi:10.1249/MSS.0000000000002163.
41.Corwin DJ, Wiebe DJ, Zonfrillo MR, et al. Vestibular Deficits following Youth Concussion.J Pediatr. 2015;166(5):1221-1225; doi:10.1016/j.jpeds.2015.01.039.
42.Master CL, Podolak OE, Ciuffreda KJ, et al. Utility of Pupillary Light Reflex Metrics as a Physiologic Biomarker for Adolescent Sport-Related Concussion.JAMA Ophthalmol. 2020;138(11):1135-1141; doi:10.1001/jamaophthalmol.2020.3466.
43.Mannix R, Levy R, Zemek R, et al. Fluid Biomarkers of Pediatric Mild Traumatic Brain Injury: A Systematic Review.J Neurotrauma. 2020;37(19):2029-2044; doi:10.1089/neu.2019.6956.
44.Mosti C, Spiers MV, Kloss JD. A practical guide to evaluating sleep disturbance in concussion patients.Neurol Clin Pract. 2016;6(2):129-137; doi:10.1212/CPJ.0000000000000225.
45.Tang S, Sours Rhodes C, Jiang L, et al. Association between Sleep Disturbances at Subacute Stage of Mild Traumatic Brain Injury and Long-Term Outcomes.Neurotrauma Rep. 2022;3(1):276-285; doi:10.1089/neur.2022.0004.
46.Corwin DJ, Grady MF, Master CL, Joffe MD, Zonfrillo MR. Evaluation and Management of Pediatric Concussion in the Acute Setting.Pediatr Emerg Care. 2021;37(7):371-379; doi:10.1097/PEC.0000000000002498.
47.Mohammed FN, Master CL, Arbogast KB, et al. Disparities in Adherence to Concussion Clinical Care Recommendations in a Pediatric Population.J Head Trauma Rehabil. 2023;38(2):147-155; doi:10.1097/HTR.0000000000000823.
48.Dickerman RD, Williamson J, Mathew E, et al. Branched-Chain Amino Acids Are Neuroprotective Against Traumatic Brain Injury and Enhance Rate of Recovery: Prophylactic Role for Contact Sports and Emergent Use.Neurotrauma Rep. 2022;3(1):321-332; doi:10.1089/neur.2022.0031.
49.Corwin DJ, Orchinik J, D'Alonzo B, et al. A Randomized Trial of Incentivization to Maximize Retention for Real-Time Symptom and Activity Monitoring Using Ecological Momentary Assessment in Pediatric Concussion.Pediatr Emerg Care. 2023;39(7):488-494; doi:10.1097/PEC.0000000000002870.
50.Wiebe D, Storey E, Orchinik J, et al. Measuring recovery with ecologic momentary assessment in a randomized trial of exercise after sport-related concussion. Clin J Sport Med. 2022;32(4):345-353; doi:10.1097/JSM.0000000000000946.
51.Sady MD, Vaughan CG, Gioia GA. Psychometric characteristics of the postconcussion symptom inventory in children and adolescents.Arch Clin Neuropsychol. 2014;29(4):348-363; doi:10.1093/arclin/acu014.
See: https://www.liebertpub.com/doi/epdf/10.1089/neu.2023.0433
More than 2 million concussions occur in the youth and adolescent population in the United States each year. The mainstay of treatment remains symptom management with temporary modification of cognitive and physical activity combined with over the counter medication. Although active rehabilitation strategies have shown promise for improving recovery time, these can be time and labor intensive. To date, no targeted pharmacologic intervention to improve clinical outcomes in concussion has been evaluated in humans. In the first clinical trial of a targeted pharmacologic therapeutic for mild traumatic brain injury in pediatric patients, scientists from the Minds Matter Concussion Frontier Program at Children’s Hospital of Philadelphia (CHOP) have found preliminary evidence that adolescents and young adults with concussion who take a specific formulation of branched chain amino acid (BCAA) supplements after injury experience faster symptom reduction and return to physical activity.
Hartmann352
By Dr. Daniel J Corwin, Dr. Sage R Myers, Dr. Kristy B. Arbogast, Dr. Miranda M Lim, Dr. Jonathan E Elliott, Dr. Kristina B Metzger,
Dr. Peter LeRoux, Dr. Jaclynn Elkind, Ms. Hannah Metheny, Dr. Jeffrey Berg, Mr. Kevin Pettijohn, Dr. Christina Master, Dr. Matthew P Kirschen, and Dr. Akiva Cohen
12 Mar 2024
Concussion is a common injury in the adolescent and young adult populations. While 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 branched chain amino acid (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 6/24/2014 and 12/5/2020. Participants were randomized to one of five study arms (placebo and 15g, 30g, 45g, and 54g 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 reporting a mild (not interfering with daily activity) or moderate (limitation with daily activity) adverse event; there were no differences in adverse events by arm, with only 2 reported mild adverse events (both gastrointestinal) in the highest (45g and 54g) BCAA arms. Though 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.
Mild traumatic brain injuries (mTBI), including concussion, are common injuries experienced by adolescents and young adults.1Over the past decade, significant advances in the knowledge and care of concussed adolescents and young adults have occurred. While traditionally, a passive strategy of cognitive and physical rest has been recommended as the sole treatment modality for concussion,2several active rehabilitation strategies have shown efficacy, including aerobic exercise therapy3,4and visio-vestibular rehabilitation.5,6However, these therapeutics are time and labor intensive, and require specialized monitoring and for most prescription from a concussion specialist. In spite of these advances, a pharmacologic intervention to hasten recovery has yet to be identified. Medications commonly prescribed (such as over-the-counter analgesics and anti-emetics7) focus on symptom management without targeting the underlying pathophysiology that leads to concussion symptoms.8Preclinical studies in animal models have demonstrated that the three branched chain amino acids (BCAAs)--valine, leucine, and isoleucine--are reduced following TBI, with their depletion possibly due to their role in both the production of neurotransmitters as well as in cellular metabolism, which is transientlyelevated after injury followed by protracted duration of reduction.9Following BCAA supplementation, injured mice demonstrate improvement in cognitive activity and mitigation of persistent sleep-wake deficits, thought to be mediated through restoration ofexcitatory/inhibitory balance in the hippocampus.10,11In humans, BCAA levels after severe TBI in adults correlate with measures of clinical severity (such as intracranial pressure12). BCAA supplementation in this population led to moderate clinical improvements involving disability and cognitive function.13,14A single study of 18 patients (primarily adults) with mTBI demonstrated decreased concentrations of BCAAs and their metabolites compared to healthy controls.15BCAA supplementation improved actigraphy metrics and self-reported sleep quality in veterans who were recovering from mTBI.16It is unknown whether BCAA supplementation will accelerate the rate of neurocognitive or clinical symptom recovery from concussion in adolescents and young adults.
Therefore, the goal of this pilot, double-blinded, randomized controlled trial was to 1) evaluate whether BCAA supplementation will accelerate the cognitive and symptom recovery of concussed participants in a dose-dependent manner and 2) determine the safety and tolerability of varying concentrations of oral BCAA supplementation. We hypothesized a dose-response improvement in processing speed, symptom burden, physical activity level, and sleep integrity in those receiving BCAA supplementation compared to placebo, with BCAAs being well-tolerated at all doses.17,18METHODSStudy Design and Participant Population Study description is reported in line with the CONSORT statement extension to randomized pilot and feasibility trials (see Supplemental Table 1 for complete checklist).19The trial was registered on ClinicalTrials.gov (identifier NCT01860404) prior to participant enrollment. The study was US Food and Drug Administration (FDA) regulated (FDA IND 117570). Participants were enrolled as a convenience sample, based on availability of research team members. Recruitment occurred in outpatient clinics (sports medicine and primary care), urgent care centers, and emergency departments of a tertiary care pediatric children’s hospital and an urban tertiary care adult hospital, both with a level I trauma designations, from June 25, 2014, through December 5, 2020. Of note, in October 2016, after the enrollment of 12 analyzable subjects, the study was paused due to slow enrollment, and eligibility criteria were modified to broaden age limit, lengthen time from injury to presentation, and include non-sports injury mechanisms. During the pause, we experienced turnover of multiple research staff members; this, in combination with changes in study recruitment policies for acute care locations, extended the enrollment pause while study procedures were being modified. Study enrollment resumed in 2018, however slowed significantly again during the novel coronavirus pandemic inearly 2020. Therefore, in late 2020, after randomizing 42 participants (fewer than our target of 50; see power analysis below), given the ongoing length of the study to date and concurrent advances in concussion care, we decided to halt enrollment to assess efficacy of pilot data.
Page 8of 328Journal of NeurotraumaHead Injury Treatment with HEalthy and Advanced Dietary Supplements (HIT HEADS): A pilot randomized controlled trial of the tolerability, safety, and efficacy of branched chain amino acids (BCAAs) in the treatment of concussion in adolescents and young adults(DOI: 10.1089/neu.2023.0433)This paper has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.Participants were eligible if they were between 11 and 34 years of age (initial lower age limit was 16 years, lowered following initial enrollment phase) and diagnosed with a concussion by the treating provider in alignment with the most recent International Consensus Concussion guidelines at the time.20Additional inclusion criteria included injury within the prior 72 hours (initial criteria was injury within 24 hours, broadened following the initial study phase), weight of at least 40 kg (given dosing considerations21), and a negative pregnancy test and acceptable contraception for study duration for post-menarchal females (due to animal models showing possible harmful effects of BCAA supplementation in utero22). Initial injury mechanism was limited to sport-and recreation-related injuries; however, this was broadened to include all injury mechanisms after the initial enrollment phase. Exclusion criteria included signs of a moderate or severe TBI (including witnessed seizure or admission to an intensive care unit), prior concussion within the preceding 90 days, history of maple syrup urine disease or family history of maple syrup urine disease, active prescription of neurologic or psychoactive medications, and allergy to red dye #40 or sucralose. Following screening, all participants (for those 18 years and older) or parents/guardians (for those younger than 18 years) provided written informed consent; child assent was also obtained for participants younger than 18 years ofage. The study was approved by our institution’s institution review board under IRB#13-010227.Randomization and BlindingFollowing enrollment and completion of informed consent, participants were randomized into one of five groups (placebo and four BCAAdosing groups, as noted below), in a schema of equal allocation, stratified by sex, which was generated a prioriby the study biostatistician. A randomization module was programmed to generate a unique kit number for each participant. The scheme was provided to the Investigational Drug Service (IDS) at the University of Pennsylvania prior to study initiation, where study kits were prepared. Participants and study investigators were blinded to treatment assignment; only the Database Administrator and the University of Pennsylvania Pharmacist had access to the link between kit number and treatment arm. Color and opacity of kits were prepared by
Page 9of 329Journal of NeurotraumaHead Injury Treatment with HEalthy and Advanced Dietary Supplements (HIT HEADS): A pilot randomized controlled trial of the tolerability, safety, and efficacy of branched chain amino acids (BCAAs) in the treatment of concussion in adolescents and young adults(DOI: 10.1089/neu.2023.0433)This paper has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.the IDS as closely matched as possible to ensure adequate blinding between placebo and BCAA dosages. Treatment The three BCAAs, valine, isoleucine, and leucine, were combined together in a 1:1:1 ratio for the four treatment doses. Dose levels were determined both by animal models and prior clinical work in humans in other conditions. In brain-injured mice, the equivalent of 60 grams (g) per day of BCAAs mitigated cognitive impairment, without additional benefit at higher doses.9,10In prior human trials, doses between 15 g/d and 57 g/d were utilized for treatment of neurologic conditions, such as tardive dyskinesia and hepatic encephalopathy.23,24The “no observable adverse effect level” of BCAA intake is likely considerablyhigher than 60g, with no evidence of toxicity in animal models up to 100 g/day and humans of up to 90 g per day.25Given the unknown optimal dose of BCAA supplementation for concussion, we initially chose doses of 15g, 30g, 45g, and 60g divided twice daily as our treatment doses. However, during initial study preparation, precipitation issues were noted at the highest dose due to leucine precipitating at a lower concentration than expected. After further testing, it was determined that the product remained in solution at a concentration of 27g/591milliliter (mL) and therefore, the highest dose level was reduced to 54 g/day.Each treatment dose was divided into twice daily dosing (7.5g, 15g, 22.5g, and 27g, respectively). For each dose, the BCAAs were combined and dissolved in water, with additives (sodium gluconate, Tropical Punch Kool-Aid® powder, and sucralose) to improve palatability. The placebo solution contained sucrose octaacetate and microcrystalline cellulose dissolved in water, with identical additives, to ensure the placebo solution had similar taste, texture, consistency, and appearance as the BCAA solution. The BCAA and placebo solutions were compounded by the University of Pennsylvania IDS laboratory. Stability and durability testing, including bioburden and colony count, were performed by the IDS laboratory in line with organizational and institutional policies prior to any study drug distribution.
Page 10of 3210Journal of NeurotraumaHead Injury Treatment with HEalthy and Advanced Dietary Supplements (HIT HEADS): A pilot randomized controlled trial of the tolerability, safety, and efficacy of branched chain amino acids (BCAAs) in the treatment of concussion in adolescents and young adults(DOI: 10.1089/neu.2023.0433)This paper has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.Monitoring and OutcomesParticipants were monitored for 21 days following enrollment. Participant baseline characteristics, including demographic data, were collected via self-report upon enrollment. Participants were monitored with daily electronic surveys, cognitive testing, as well as continuous actigraphy. Each survey included questions about concussion symptoms, physical activity, cognitive activity, drug compliance, and adverse events. In-person visits were conducted at three time points during study enrollment, between study days 5-9, 12-16, and 22-24, to assess symptom burden and side effects in-person. The primary outcome was to determine if, compared to placebo treatment, BCAAs accelerated neurocognitive recovery. Neurocognitive testing was performed using the CogSport/Axon Sports Computerized Cognitive Assessment Tool (CCAT).26,27The CCAT includes four computerized tests measuring processing speed (via a simple reaction time task), attention (via a choice reaction time task), visual learning (via a one card learning task) and working memory (via a one-back task). In line with prior studies and manufacturer recommendations, average log mean reaction time was compared for the processing speed, attention, and working memory subtests; accuracy was used for the visual memory subtest.26–28Symptoms were assessed via self-report utilizing a9-item symptom instrument, shown to have excellent factorial and construct validity by Piland and colleagues.29Included in the instrument are the following: headache, nausea, balance problems, sleeping more than normal, drowsiness, fatigue, feeling slowed down, feeling mentally foggy, and difficulty concentrating. Each symptom is rated on a 7-point Likert scale (0=no symptom; 6=very severe symptoms), generating a total symptom score ranging from 0 to 54. Physical activity was rated on a 6-point Likert scale of return to baseline physical activity (0=no physical activity; 5=return to full physical activity, including full game play for athletes). Cognitive activity was rated on a 5-point Likert scale of return to baseline cognitive activity at school or work (0=complete cognitive rest; 4=full unrestricted participation in school or work). Participant sleep was assessed using actigraphy (ActiSleep+ Monitor, ActiGraph, Pensacola, FL) worn 24/7 during study participation on the participant’s non-dominant wrist.
Data was collected in 60 sec epochs and analyzed using ActiLife software version 6.13.4 with a 90-min non-wear threshold.30,31Each study day was analyzed individually for bedtime, wake time, total sleep time (TST), sleep efficiency, wake after sleep onset (WASO), number and length of awakenings, activity, and proprietary indices of movement/sleep fragmentation. These respective metrics were averaged across the entire study duration, with daytime sleep periods excluded. Participant compliance withtaking BCAA supplementation was assessed by self-report. Participants reported the number of bottles of study medication (0, 1, or 2, as each daily dose was divided into twice daily increments) consumed. For days in which participants did not answer the survey, it was assumed no drink was consumed. Potential adverse events, in accordance with the CONSORT harm guidelines for pilot randomized trials,19were collected from daily self-report surveys in addition to assessment at scheduled study visits. All adverse events were characterized with descriptions of the event, assessment of severity, indication of whether the event was serious (death, a life-threatening event, hospitalization or prolongation of existing hospitalization, or persistent or significant disability/incapacity), and start and end date. Statistical Considerations and Power AnalysisStandard descriptive statistics were used to summarize demographic data. Our initial analytic plan was to adjust for age and repeated measures among the five treatment arms using a mixed effects model by prescribed dose; given both our inability to reach our enrollment goal, as well as varying response rates (see Table 1), we were unable to fit a model using this approach. Instead, to account for individual characteristics, such as age and varying amounts of follow-up time with unbalanced numbers of repeated measures, in addition to capturing efficacy as opposed to effectiveness (given varying adherence to treatment protocol, see Table 3), we used linear regression to conduct a dose response analysis. The linear regression model included total cumulative study dose received (study dose prescribed multiplied by number of days consuming said dose) as the independent variable and change in outcome (average of each participant’s first 3 measures compared to the participant’s last 3 measures over the course of the study) as the dependent variable among participants with at least 7 reported measurements. This dose response model was fitted separately for each of the four CCAT subtests, total symptom score, physical activity, and cognitive activity; the intercept and slope parameter (with 95% confidence interval and p-value) were obtained from models with each outcome. Though both physical and cognitive activity were assessed on ordinal scales,the outcome measure used in the model was the change in these activity levels, leadingto a continuous variable from which a linear regression model could be fitted. Compliance (average reported drink consumed over study period) and adverse events (average per arm and percent in each arm experiencing adverse events) were compared across arms using Kruskal-Wallis rank test and Fisher’s exact test, where appropriate. Analyses were performed using SAS software, version 9.4 (SAS Institute Inc, Cary, NC), Stata software, release 14.2 (StataCorp LLC, College Station, TX), and GraphPad Prism version 8 (GraphPad Software, San Diego, CA).Prior to study initiation, we estimated an enrollment goal of 50 subjects, or 10 subjects per arm, which would have given us 80% power to detect differences in the processing speed subtest between the BCAA arms and the placebo arm of 0.122 seconds (log mean -0.914), or a 5% difference based on healthy control data (including a standard deviation of 0.08 secondsin healthy individuals, inflated to 0.10 for injured subjects).28As noted above, due to significant slowing of enrollment during the novel coronavirus pandemic in early 2020, in late 2020, after randomizing 42 participants, we decided to halt study enrollment to assess efficacy of pilot data in order to inform a larger, more definitive, full-powered trial.RESULTSIn total, 42 participants were randomized (see Figure 1 for flow diagram). Of those, four participants withdrew prior to providing any follow-up data (all in the 30 g BCAA arm), and therefore were withdrawn from further analysis. Demographics and initial injury characteristics for the 38 analyzed participants are provided in Table 1. Of the 38 participants analyzed, 26 provided at least 7 reported measures in symptoms, physical, and cognitive activity, and 18 provided at least 7 reported measures for neurocognitive testing; 20 provided data through the full 21 days of the study period.
The average number of days for which the survey questions and CCAT battery were completed across the study period by arm is displayed in Table 1. Overall, the median total study dose consumed was 360 g (range 0 to 2052 g; see Table 1 for breakdown by arm). In terms of neurocognitive testing, we did not find a change in outcome with increased total study dose consumed using linear regression analysis (Table 2, Figure 2). Of note, not all patients who completed follow-up completed the neurocognitive testing elements (Table 1). We found a significant reduction in total symptom score by total dose consumed using linear regression analysis (a decrease of 4.4 points [standard error 1.4] for each 500 g of study drug consumed, p-value for trend line = 0.0036; Table 2 and Figure 3a), as well as a significant improvement in return to baseline physical activity by total dose consumed in our adjusted analysis (an increase of 0.503 points [standard error 0.164] for each 500 g of study drug consumed, p-value for trend = 0.0053). We found no change in cognitive score in our linear regression (Table 2, Figure 3c). Actigraphy data is presented in Supplementary Table 2. Because of a limited number of participants with complete actigraphy data, no statistical testing was performed based on this data, however, the raw values for sleep efficiency (93.2% vs. 91.4%) and total sleep time (536.7 minutes vs. 468.1 minutes) were higher in the highest BCAA dose group (54 g/day) vs. the placebo group . In analyzing our compliance, we found lower average reported total drink consumed by arm (81% reported compliance in the placebo arm compared to 49% compliance in the 54g BCAA arm; Table 3, though the trendwas non-significant [p=.581] via Kruskal-Wallis testing). We did not find any difference in adverse events by arm (Table 3) via Kruskal-Wallis testing. Across the study, in total, 13 adverse events were reported among the 38 participants, the majority (10) occurred in either the placebo or lowest BCAA dose groups. No adverse events were severe, and the majority (10 out of 13, including all three adverse events in the 30g, 45g, and 54g BCAA arms) were reported as mild. The majority (12 of the 13) were gastrointestinal side effects (abdominal pain, diarrhea, or bloating).
This pilot, double-blinded, randomized controlled trial is the first evaluation of BCAA supplementation in the treatment of concussion in adolescents and young adults and demonstrated efficacy, high tolerability, and safety of BCAAs. Specifically, we found a significant dose response effect in reduction of concussion symptoms and a return to baseline physical activity in those who consumed higher total doses of BCAAs across the study period, with high tolerability of treatment doses without serious adverse events. This data provides important preliminary work to inform a larger, definitive randomized controlled trial of BCAA therapy for concussed youth and young adults.BCAAs participate directly and indirectly in a variety of important biochemical functions in the brain. In addition to the fundamental use of amino acids for protein synthesis, these specific essential amino acids are pivotal in glutamate synthesis, as they contribute 50% of the nitrogen in glutamate.32Moreover, the decarboxylation of glutamate by glutamic acid decarboxylase (GAD) leads to the synthesis of the primary inhibitory neurotransmitter GABA. Furthermore, de novoglutamate synthesis contributes a significant amount (approximately 40%) of releasable synaptic glutamate.33It has been hypothesized that the increased energy demands of the brain post-injury rapidly deplete BCAA levels.9In addition, it has been noted that BCAAs can enter the Krebs cycle and contribute to increased production of adenosine triphosphate (ATP),14alterations in which have also been implicated as a key component to the pathophysiology of concussion.8Interestingly, animal studies have found that repeated exposure to BCAAs over multiple days is required to observe improvements in cognitive function following TBI.10This suggests that it is not only BCAA supplementation, but repeated exposure to BCAAs, that underlies the clinical improvement noted in our current study (as evidenced by the total dose-response effect in improving concussion symptoms allowing for a return to baseline activity level following injury). Overall, we saw minimal adverse effects with BCAA supplementation, particularly at our higher doses. Multipleprior studies have reported the tolerability of BCAAs, with large reviews reporting either no, or minimal gastrointestinal, side effects,23and the results
herein further support the tolerability of BCAA supplementation. We do note the decrease in treatment compliance as BCAA doses increased; while not related to adverse events experienced by participants, this does suggest, in the setting of concussion, that there may be limited palatability of the highest BCAA doses that might limit compliance. Future work should focus on methods to improve compliance of the highest BCAA doses, particularly given the observed dose-response effect in this study, as well as the importance of repeated BCAA exposure in animal models.10The improvement in concussion-related symptoms and accelerated return to baseline physical activity in a dose-response pattern are key findings of our study. Over the past decade, symptoms have emerged as the principal primary outcome in the largest observational and interventional trialsof concussion.4,34In addition, there has been an effort to incorporate patient-reported outcomes as primary measures of functioning following injury (with return to pre-injury level of activity a key indication of post-injury functioning),35and prior work has demonstrated a strong correlation between symptom burden and quality of life in adolescent concussion.36While our primary outcome, neurocognitive testing, did not show significant differences among our treatment arms, since the inception of our study, multiple limitations to utilizing neurocognitive testing as an objective injury marker have been described.37,38In particular, a “ceiling effect” to neurocognitive testing has been described, reducing its utility as a study endpoint over time.39Since the initial development of the study protocol, however, multiple other objective markers of injury have been developed as key metrics of central nervous system dysfunction, including visio-vestibular testing40,41and evaluation of thepupillary light reflex.42These objective measures, in addition to blood-based biomarkers,43make for key additional objective outcomes to potentially augment subjective symptom scores in future trials. Sleep disturbances have frequently been reported as key elements contributing to dysfunction following concussion,44with sleep alterations in the acute time frame after injury has been identified as a key prognostic factor in the development of persistent post-concussive symptoms.45 Previous work has demonstrated the efficacy of BCAA supplementation to improve sleep disturbances in animal models,11and a recent
randomized trial of Veterans with chronic TBI symptoms showing BCAA efficacy in improving both subjective and objective sleep impairment.16Our data, though limited in sample size and statistical power in this secondary outcome measure, suggest possible improvements in sleep efficiency and total sleep time in those receiving the highest BCAA dose. Since our study inception, several randomized trials of active rehabilitative treatment programs have been conducted showing efficacy in reducing prolonged concussion symptoms.3–5However, these interventions often require either in-person visits or specialized guidance to complete.46The potential reliance on specialist prescription and monitoring has the potential to introduce or exacerbate known disparities in concussion care that exist for underserved communities.47This underlies the importance of developing safe, accessible, and well-tolerated pharmacologic interventions for concussion in adolescents and young adults, such as BCAA supplementation, that could be prescribed from diverse settings without a need for specialist monitoring. The role of BCAAs may also expand beyond treatment into the realm of injury prevention, as a recent animal model study explored the efficacy of administering BCAAs in mice prior to head trauma as a prophylaxis, with improved motor recovery and cognitive function.48There are several key limitations toour study that necessitate a larger, more definitive trial before routine clinical implementation of BCAA therapy for concussion. Firstly, due to a combination of initially more strict inclusion criteria, and the impact of the coronavirus pandemic, our sample size was smaller than anticipated. This, combined with poorer than expected follow-up, led us to have to use alternative statistical analytic methods. However, the improvement in symptoms, physical activity, and sleep, represent strong preliminary data to inform a future larger trial. We were further limited by missing data. This also necessitated the alternative analytic approach described in the methods. Of note, since study inception, multiple investigators have refined remote patient monitoring tools as a means to track participants in observational and interventional studies from multiple settings,49,50making these tools a promising method to maximize follow-up in future trials. In addition, since study inception, several symptom batteries have emerged as a standard of care for assessing concussion symptoms.51As our participants were enrollment in a
convenience sample, our sample may not be representative of the overall population of acutely concussed adolescents and young adults, though our broad enrollment locations (compared to exclusively enrolling from an emergency department or specialty clinic) may assist with generalizability of our results. Finally, as we enrolled subjects over a significantly longer period than initially anticipated, multiple temporal trends in the management of concussion occurred during our study timeframe (specifically a move away from passive treatment recommendations toward a more active therapeutic approach46), which potentially may have impacted our results, results, although one would expect that any active intervention would improve recovery time would have decreased the effect size of the BCAA intervention, making our findings even more promising (and, as noted in Table 1, there was relatively equal distribution of participants across arms in the various study enrollment periods). In conclusion, this preliminary work, while limited by enrollment challenges and small samples sizes, demonstrates the potential efficacy of BCAAs in improving concussions symptoms and allowing for a more rapid return to pre-injury activity levels in concussed adolescents and young adults, representing the first such data in acute mild traumatic brain injury in humans. Importantly, BCAAs were found to be well-tolerated in our participants, with minimal adverse events, even at the highest doses. While a larger, more definitive trial is necessary prior to routine clinical implementation of BCAA therapy for concussed adolescents and young adults, these data demonstrate the promising potential benefit of BCAA supplementation to reduce symptoms and allow for a return to baseline activity following concussion.
TRANSPARENCY, RIGOR, AND REPRODUCIBILITY STATEMENTThe study design and analysis plan were preregistered on May 22, 2013 at ClinicalTrials.gov (NCT01860404); of note, given both our inability to reach our enrollment goal, as well as varying response rates, we were unable to fit a model using our original approach, therefore an alternative statistical plan was implemented by a study biostatistician (KBM) blinded to treatment allocation. Prespecified sample size was 10 subjects per group, yielding statistical power of 80% for detection of a 0.122 seconds (log mean -0.914) difference in the processing speed subtest of the CogSport/Axon Sports Computerized Cognitive Assessment Tool as the primary outcome measure. All participants were assigned to one of four intervention groups (15g, 30g, 45g, and 54g daily of BCAA) or placebo using a random number generator programmed a priori, yielding groups that did not differ statistically in baseline characteristics. In total, 42 participants were randomized; the primary outcome was assessed in 30 participants (after 12 incomplete assessments), and secondary outcomes were assessed in 38 participants (after 4 incomplete assessments), as demonstrated in the study CONSORT diagram. Participants were blinded to group assignment with use of identically appearing placebo treatment. All primary outcomes were assessed by investigators blinded to group assignment. All materials required to perform the interventions may be available upon request from University of Pennsylvania Laboratory service and the corresponding author.The key inclusion criteria, as well as the primary and secondary outcome measures, were standards in the field at time of enrollment. Descriptive statistics of continuous variables utilized non-parametric tests. For the dose-response analysis of primary outcomes, we used linear regression, which assumed normal distribution of total study dose received and of change in outcome measures. Because the sample size was smaller than we modified the planned primary dose-response analyses from a repeated measures mixed effect model to a linear regressions using summarized outcome and dose data. We did not use statistical methods to correct for multiple comparisons, as we interpreted our results holistically by examining the effect of total dose on various outcomes as evidence for overall reduction in concussion-related signs and symptoms, rather than emphasizing a particular relationship with a specific outcome. The findings have not yet been replicated or externally validated, however external validation studies are currently being planned. De-identified data from this study are not available in a public archive. De-identified data from this study will be made available (as allowable according to institutional IRB standards) by emailing the corresponding author as of June 1, 2024. Analytic code used to conduct the analyses presented in this study are not available in a public repository. They may be available by emailing the corresponding author as of June 1, 2024. Intervention protocols are available upon request. The authorsagree to provide the full content of the manuscript on request by contacting the corresponding author.
CONFLICT OF INTEREST
Akiva S. Cohen and the Children’s Hospital of Philadelphia hold a provisional patent, which includes the use of branched chain amino acids as a therapeutic intervention for traumatic brain injury, under the title “Compositions and methods for the treatment of brain injury.” This includes U.S. Provisional Patent Application Nos. 61/883,526 and 61/812,352, U.S. Patent 11/576,88, and European Patent No. 2986113 (regionalized in Germany, Spain, France, UK, and Italy). In addition, Dr. Cohen served as the FDA Investigational New Drug (IND) sponsor.
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See: https://www.liebertpub.com/doi/epdf/10.1089/neu.2023.0433
More than 2 million concussions occur in the youth and adolescent population in the United States each year. The mainstay of treatment remains symptom management with temporary modification of cognitive and physical activity combined with over the counter medication. Although active rehabilitation strategies have shown promise for improving recovery time, these can be time and labor intensive. To date, no targeted pharmacologic intervention to improve clinical outcomes in concussion has been evaluated in humans. In the first clinical trial of a targeted pharmacologic therapeutic for mild traumatic brain injury in pediatric patients, scientists from the Minds Matter Concussion Frontier Program at Children’s Hospital of Philadelphia (CHOP) have found preliminary evidence that adolescents and young adults with concussion who take a specific formulation of branched chain amino acid (BCAA) supplements after injury experience faster symptom reduction and return to physical activity.
Hartmann352
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