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

Jonathan E Elliott, Allison T Keil, Sara Mithani, Jessica M Gill, Maya E O'Neil, Akiva S Cohen, Miranda M Lim, Jonathan E Elliott, Allison T Keil, Sara Mithani, Jessica M Gill, Maya E O'Neil, Akiva S Cohen, Miranda M Lim

Abstract

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: [https://ichgcp.net/clinical-trials-registry/NCT03990909" title="See in ClinicalTrials.gov">NCT03990909].

Keywords: BCAA; blood biomarker; cognition; dietary supplementation; sleep; traumatic brain injury (TBI).

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Elliott, Keil, Mithani, Gill, O’Neil, Cohen and Lim.

Figures

FIGURE 1
FIGURE 1
CONSORT. Participant enrollment, randomization, allocation, and analysis following the CONSORT extension for randomized pilot and feasibility guidelines.
FIGURE 2
FIGURE 2
Serum BCAA concentration. Pre- (open bars) and post-intervention (shaded bars) serum BCAA concentration (μM) for the (A) BCAA, (B) rice protein, and (C) microcrystalline cellulose groups (mean ± standard deviation). Individual data points with connecting lines overlaid. *p < 0.05, paired two-tail t-test.
FIGURE 3
FIGURE 3
Insomnia Severity Index (ISI) and Sleep Hygiene Index (SHI). Pre- (open bars) and post-intervention (shaded bars) ISI scores (range = 0–28; higher = increased impairment) for the (A) BCAA, (B) rice protein, and (C) microcrystalline cellulose groups with SHI scores (range = 0–52; higher = worse sleep hygiene) for the (D) BCAA, (E) rice protein, and (F) microcrystalline cellulose groups (mean ± standard deviation). Individual data points with connecting lines overlaid. *p < 0.05, paired two-tail t-test.
FIGURE 4
FIGURE 4
Actigraphy. (A) Representative pre- and post-intervention 3 consecutive mid-week 24-h periods for the BCAA group produced using Philips Actiware. The yellow line represents ambient light exposure and black columns reflect activity counts in 2-min bins. Sleep and wake is differentiated by the red underline (wake) and the blue shaded period indicates the entire “rest interval” with time in bed resting but not asleep) being the light blue intervals and time in bed asleep being the dark blue intervals. Specific actigraphy metrics are plotted in panels (B) total sleep time, (C) sleep onset latency, (D) sleep efficiency, and (E) wake after sleep onset, in the BCAA group with pre- and post-intervention being open and shaded bars (individual data overlaid). *p < 0.05, paired two-tail t-test.

References

    1. Aquilani R., Boselli M., Boschi F., Viglio S., Iadarola P., Dossena M., et al. (2008). 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. 89 1642–1647. 10.1016/j.apmr.2008.02.023
    1. Aquilani R., Iadarola P., Boschi F., Pistarini C., Arcidiaco P., Contardi A. (2003). Reduced plasma levels of tyrosine, precursor of brain catecholamines, and of essential amino acids in patients with severe traumatic brain injury after rehabilitation. Arch. Phys. Med. Rehabil. 84 1258–1265. 10.1016/s0003-9993(03)00148-5
    1. Aquilani R., Iadarola P., Contardi A., Boselli M., Verri M., Pastoris O., et al. (2005). Branched-chain amino acids enhance the cognitive recovery of patients with severe traumatic brain injury. Arch. Phys. Med. Rehabil. 86 1729–1735. 10.1016/j.apmr.2005.03.022
    1. Balba N. M., Elliott J. E., Weymann K. B., Opel R. A., Duke J. W., Oken B. S., et al. (2018). Increased sleep disturbances and pain in Veterans with co-morbid TBI and PTSD. J. Clin. Sleep Med. 14 1865–1878.
    1. Bastien C. H., Vallières A., Morin C. M. (2001). Validation of the insomnia severity index as an outcome measure for insomnia research. Sleep Med. 2 297–307. 10.1016/S1389-9457(00)00065-4
    1. Belanger H. G., Kretzmer T., Vanderploeg R. D., French L. M. (2009). Symptom complaints following combat-related traumatic brain injury: Relationship to traumatic brain injury severity and posttraumatic stress disorder. J. Int. Neuropsychol. Soc. 16 194–199. 10.1017/S1355617709990841
    1. Blevins C. A., Weather F. W., Davis M. T., Witte T. K., Domino J. L. (2015). The posttraumatic stress disorder checklist for DSM-5 (PCL-5): Development and Initial Psychometric Evaluation. J. Trauma Stress 28 489–498. 10.1002/jts.22059
    1. Blomstrand E. (2001). Amino acids and central fatigue. Amino Acids 20 25–34. 10.1007/s007260170063
    1. Blomstrand E., Hassmen P., Ekblom B., Newsholme E. A. (1991). Administration of branched-chain amino acids during sustained exercise–effects on performance and on plasma concentration of some amino acids. Eur. J. Appl. Physiol. 63 83–88. 10.1007/BF00235174
    1. Boakye P. A., Olechowski C., Rashiq S., Verrier M. J., Kerr B., Witmans M., et al. (2016). Critical review of neurobiological factors involved in the interactions between chronic pain, depression, and sleep disruption. Clin. J. Pain 32 327–336. 10.1097/AJP.0000000000000260
    1. Bombardier C. H., Fann J. R., Temkin N. R., Esselman P. C., Barber J., Dikmen S. S. (2010). Rates of major depressive disorder and clinical outcomes following traumatic brain injury. JAMA 303 1938–1745. 10.1001/jama.2010.599
    1. Borsheim E., Bui Q. U. T., Wolfe R. R. (2007). Plasma amino acid concentrations during late rehabilitation in patients with traumatic brain injury. Arch. Phys. Med. Rehabil. 88 234–238. 10.1016/j.apmr.2006.11.003
    1. Bulson R., Jun W., Hayes J. (2012). Visual symptomatology and referral patterns for Operation Iraqi Freedom and Operation Enduring Freedom veterans with traumatic brain injury. J. Rehabil. Res. Dev. 49 1075–1082. 10.1682/jrrd.2011.02.0017
    1. Cangiano C., Laviano M., Massimo M., Conversano I., Rossi Fanelli F. (1996). Effects of administration of oral branched-chain amino acids on anorexia and caloric intake in cancer patients. J. Natl. Cancer Inst. 88 550–552. 10.1093/jnci/88.8.550
    1. Castriotta R. J., Wilde M. C., Lai J. M., Atanasov S., Masel B. E., Kuna S. T. (2007). Prevalence and consequences of sleep disorders in traumatic brain injury. J. Clin. Sleep Med. 3 349–356. 10.5664/jcsm.26855
    1. Cella D., Yount S., Rothrock N., Gershon R., Cook K., Reeve B., et al. (2007). The Patient-Reported Outcomes Measurement Information System (PROMIS). Med. Care 45 S3–S11. 10.1097/01.mlr.0000258615.42478.55.The
    1. Centers for Disease and Control (2016). Injury Prevention and Control: Traumatic Brain Injury and Concussion. Available online at: (accessed January, 2022).
    1. Cerra F., Mazuski J., Teasley K., Nuwer N., Lysne J., Shronts E., et al. (1983). Nitrogen retention in critically ill patients is proportional to the branched chain amino acid load. Crit. Care Med. 11 775–778. 10.1097/00003246-198310000-00003
    1. Chesterton L. S., Sim J., Wright C. C. B. S., Foster N. E. D. P. (2007). Interrater reliability of algometry in measuring pressure pain thresholds in healthy humans, using multiple raters. Clin. J. Pain 23 760–766. 10.1097/AJP.0b013e318154b6ae
    1. Cifu D., Hurley R., Peterson M., Cornis-Pop M., Rikli P. A., Ruff R. L., et al. (2009). VA/DoD Clinical practice guideline: management of Concussion/Mild Traumatic Brain Injury. J. Rehabil. Res. Dev. 46 C1–C68.
    1. Cole J. T., Mitala C. M., Kundu S., Verma A., Elkind J. A., Nissim I., et al. (2010). Dietary branched chain amino acids ameliorate injury-induced cognitive impairment. Proc. Natl. Acad. Sci. U.S.A. 107 2373–2373. 10.1073/pnas.0910280107
    1. Colten H. R., Altevogt B. M. (eds) (2006). Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. Washington, DC: National Academies Press.
    1. Corrigan J. D., Bogner J. (2007). Initial reliability and validity of the Ohio state university TBI identification method. J. Head Trauma Rehabil. 22 318–329. 10.1097/01.HTR.0000300227.67748.77
    1. Corrigan J. D., Cuthbert J. P., Harrison-Felix C., Whiteneck G. G., Bell J. M., Miller A. C., et al. (2014). US Population Estimates of Health and Social Outcomes 5 Years After Rehabilitation for TBI. J. Head Trauma Rehabil. 29 E1–E9.
    1. De Palo E. F., Gatti R., Cappellin E., Schiraldi C., De Palo C. B., Spinella P. (2001). Plasma lactate, GH and GH-binding protein levels in exercise following BCAA supplementation in athletes. Amino Acids 20 1–11. 10.1007/s007260170061
    1. Dewan M. C., Rattani A., Gupta S., Baticulon R. E., Hung Y. C., Punchak M., et al. (2019). Estimating the global incidence of traumatic brain injury. J. Neurosurg. 130 1080–1097. 10.3171/2017.10.JNS17352
    1. Dijkers M. P. (2004). Quality of life after traumatic brain injury : a review of research approaches and findings. Arch. Phys. Med. Rehabil. 85 S21–S35. 10.1016/j.apmr.2003.08.119
    1. Duclos C., Dumont M., Wiseman-Hakes C., Arbour C., Mongrain V., Gaudreault P.-O., et al. (2014). Sleep and wake disturbances following traumatic brain injury. Pathol. Biol. 62 252–261.
    1. Edwards K. A., Gill J. M., Pattinson C. L., Lai C., Brière M., Rogers N. J., et al. (2020). Interleukin-6 is associated with acute concussion in military combat personnel. BMC Neurol. 20:209. 10.1186/s12883-020-01760-x
    1. Eldridge S. M., Chan C. L., Campbell M. J., Bond C. M., Hopewell S., Thabane L., et al. (2016a). CONSORT 2010 statement: extension to randomised pilot and feasibility trials. Pilot Feasibility Stud. 2:64.
    1. Eldridge S. M., Lancaster G. A., Campbell M. J., Thabane L., Hopewell S., Coleman C. L., et al. (2016b). Defining feasibility and pilot studies in preparation for randomised controlled trials: development of a conceptual framework. PLoS One 11:e0150205. 10.1371/journal.pone.0150205
    1. Elkind J. A., Lim M. M., Johnson B. N., Palmer C. P., Putnam B. J., Kirschen M. P., et al. (2015). Efficacy, dosage, and duration of action of branched chain amino acid therapy for traumatic brain injury. Front. Neurol. 6:73. 10.3389/fneur.2015.00073
    1. Elliott J. E., Balba N. M., McBride A. A., Callahan M. L., Street K. T., Butler M. P., et al. (2021). Different methods for traumatic brain injury diagnosis influence presence and symptoms of post-concussive syndrome in united states veterans. J. Neurotrauma 38 3126–3136. 10.1089/neu.2021.0031
    1. Elliott J. E., Opel R. A., Weymann K. B., Chau A. Q., Papesh M. A., Callahan M. L., et al. (2018b). Sleep disturbances in traumatic brain injury: associations with sensory sensitivity. J. Clin. Sleep Med. 14 1177–1186. 10.5664/jcsm.7220
    1. Elliott J. E., De Luche S. E., Churchill M. J., Moore C., Cohen A. S., Meshul C. K., et al. (2018a). Dietary therapy restores glutamatergic input to orexin/hypocretin neurons after traumatic brain injury in mice. Sleep 41:zsx212. 10.1093/sleep/zsx212
    1. Elliott J. E., Opel R. A., Pleshakov D., Rachakonda T., Chau A. Q., Weymann K. B., et al. (2020). Posttraumatic stress disorder increases the odds of REM sleep behavior disorder and other parasomnias in Veterans with and without comorbid traumatic brain injury. Sleep 43:zsz237.
    1. Fernstrom J. D. (2005). Branched-chain amino acids and brain function. J. Nutr. 135 1539S–1546S. 10.1093/jn/135.6.1539S
    1. Fernstrom J. D. (2013). Large neutral amino acids: dietary effects on brain neurochemistry and function. Amino Acids 45 419–430.
    1. Gijsman H., Scarnà A., Harmer C., McTavish S., Odontiadis J., Cowen P., et al. (2002). A dose-finding study on the effects of branch chain amino acids on surrogate markers of brain dopamine function. Psychopharmacology 160 192–197. 10.1007/s00213-001-0970-5
    1. Guedes V. A., Kenney K., Shahim P., Qu B., Lai C., Devoto C., et al. (2020). Exosomal neurofilament light: A prognostic biomarker for remote symptoms after mild traumatic brain injury? Neurology 94 e2412–e2423.
    1. Hasseman P., Blomstrand E., Ekblom B., Newsholme E. A. (1994). Branched-chain amino acid supplementation during 30-km competitive run: mood and cognitive performance. Nutrition 10 405–410.
    1. Hawkins R. A., Kane R. L. O., Simpson I. A., Vin J. R. (2006). Structure of the blood–brain barrier and its role in the transport of amino acids. J. Nutr. 136 218–226. 10.1093/jn/136.1.218S
    1. Hays R. D., Bjorner J. B., Revicki D. A., Spritzer K. L., Cella D. (2009). Development of physical and mental health summary scores from the patient-reported outcomes measurement information system (PROMIS) global items. Qual. Life Res. 18 873–880. 10.1007/s11136-009-9496-9
    1. Hoge C. W., McGurk D., Thomas J. L., Cox A. L., Engel C. C., Castro C. A. (2008). Mild Traumatic Brain Injury in U.S. Soldiers Returning from Iraq. N. Engl. J. Med. 358 2543–2551.
    1. Horst D., Grance N. D., Conn H. O., Schiff E., Schenker S., Viteri A., et al. (1984). Comparison of dietary protein with an oral, branched chain-enriched amino acid supplement in chronic portal-systemic encephalopathy: a randomized controlled trial. Hepatology 4 279–287. 10.1002/hep.1840040218
    1. James J. H. (2002). Branched chain amino acids in heptatic encephalopathy. Am. J. Surg. 183 424–429. 10.1016/s0002-9610(02)00808-5
    1. Jeter C. B., Hergenroeder G. W., Ward N. H., Moore A. N., Dash P. K. (2013). Human mild traumatic brain injury decreases circulating branched-chain amino acids and their metabolite levels. J. Neurotrauma 30 671–679. 10.1089/neu.2012.2491
    1. Kempf J., Werth E., Kaiser P. R., Bassetti C. L., Baumann C. R. (2010). Sleep-wake disturbances 3 years after traumatic brain injury. J. Neurol. Neurosurg. Psychiatry 81 1402–1405. 10.1136/jnnp.2009.201913
    1. Kirvela O., Jaatinen J., Scheinin H., Kanto J. (1998). The effects of branched chain amino acid infusion on pain perception and plasma concentrations of monoamines. Pharmacol. Biochem. Behav. 60 77–82. 10.1016/s0091-3057(97)00466-8
    1. Knapik J. J., Steelman R. A., Hoedebecke S. S., Austin K. G., Farina E. K., Lieberman H. R. (2016). Prevalence of dietary supplement use by athletes: systematic review and meta-analysis. Sport Med. 46 103–123. 10.1007/s40279-015-0387-7
    1. Korley F. K., Yue J. K., Wilson D. H., Hrusovsky K., Diaz-Arrastia R., Ferguson A. R., et al. (2019). Performance evaluation of a multiplex assay for simultaneous detection of four clinically relevant traumatic brain injury biomarkers. J. Neurotrauma 36 182–187. 10.1089/neu.2017.5623
    1. Lew H. L., Otis J. D., Tun C., Kerns R. D., Clark M. E., Cifu D. (2009). Prevalence of chronic pain, posttraumatic stress disorder, and persistent postconcussive symptoms in OIF/OEF veterans: polytrauma clinical triad. J. Rehabil. Res. Dev. 46 697–702. 10.1682/jrrd.2009.01.0006
    1. Lim M. M., Elkind J. A., Xiong G., Galante R., Zhu J., Zhang L., et al. (2013). Dietary therapy mitigates persistent wake deficits caused by mild traumatic brain injury. Sci. Transl. Med. 5:215ra173. 10.1126/scitranslmed.3007092
    1. Mahmood O., Rapport L. J., Hanks R. A., Fichtenberg N. L. (2004). Neuropsychological performance and sleep disturbance following traumatic brain injury. J. Head Trauma Rehabil. 19 378–390. 10.1097/00001199-200409000-00003
    1. Mahoney C. E., Cogswell A., Koralnik I. J., Scammell T. E. (2019). The neurobiological basis of narcolepsy. Nat. Rev. Neurosci. 20 83–93. 10.1038/s41583-018-0097-x
    1. Manner T., Katz D. P., Askanazi J. (1996). The antinociceptive effects of branched-chain amino acids: Evidence for their ability to potentiate morphine analgesia. Pharmacol. Biochem. Behav. 53 449–454. 10.1016/0091-3057(95)02016-0
    1. Marchesini G., Bianchi G., Merli M., Amodio P., Panella C., Loguercio C., et al. (2003). Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology 124 1792–1801. 10.1016/s0016-5085(03)00323-8
    1. Mastin D. F., Bryson J., Corwyn R. (2006). Assessment of sleep hygiene using the Sleep Hygiene Index. J. Behav. Med. 29 223–227. 10.1007/s10865-006-9047-6
    1. Mathias J. L., Alvaro P. K. (2012). Prevalence of sleep disturbances, disorders, and problems following traumatic brain injury: a meta-analysis. Sleep Med. 13 898–905. 10.1016/j.sleep.2012.04.006
    1. Matthews D. E. (2005). Observations of branched-chain amino acid administration in humans. J. Nutr. 135 1580S–1584S. 10.1093/jn/135.6.1580S
    1. Modarres M. H., Kuzma N. N., Kretzmer T., Pack A. I., Lim M. M. (2017). EEG slow waves in traumatic brain injury: convergent findings in mouse and man. Neurobiol. Sleep Circadian Rhythm 2 59–70. 10.1016/j.nbscr.2016.06.001
    1. Modarres M. H., Opel R. A., Weymann K. B., Lim M. M. (2019). Strong correlation of novel sleep electroencephalography coherence markers with diagnosis and severity of posttraumatic stress disorder. Sci. Rep. 9:4247. 10.1038/s41598-018-38102-4
    1. Moldover J. E., Goldberg K. B., Prout M. F. (2004). Depression after traumatic brain injury: a review of evidence for clinical heterogeneity. Neuropsychol. Rev. 14 143–154. 10.1023/b:nerv.0000048181.46159.61
    1. Mondello S., Buki A., Barzo P., Randall J., Provuncher G., Hanlon D., et al. (2014). CSF and Plasma Amyloid-β Temporal Profiles and Relationships with Neurological Status and Mortality after Severe Traumatic Brain Injury. Sci. Rep. 4:6446. 10.1038/srep06446
    1. Mori M., Adachi Y., Mori N., Kurihara S., Kashiwaya Y., Kusumi M., et al. (2002). Double-blind crossover study of branched-chain amino acid therapy in patients with spinocerebellar degeneration. J. Neurol. Sci. 195 149–152. 10.1016/s0022-510x(02)00009-6
    1. Morin C. M. (1993). Insomnia, Psychological Assessment and Management. New York, NY: Guilford Press.
    1. Neylan T. C., Marmar C. R., Metzler T. J., Weiss D. S., Zatzick D. F., Delucchi K. L., et al. (1998). Sleep disturbances in the Vietnam generation: findings from a nationally representative sample of male Vietnam Veterans. Am. J. Psychiatry 155 929–933. 10.1176/ajp.155.7.929
    1. Nguyen S., Mckay A., Wong D., Rajaratnam S. M. W., Spitz G., Williams G., et al. (2017). Cognitive behavior therapy to treat sleep disturbance and fatigue after traumatic brain injury: a pilot randomized controlled trial. Arch. Phys. Med. Rehabil. 98 1508–1517.e2. 10.1016/j.apmr.2017.02.031
    1. Ohayon M. M., Shapiro C. M. (2000). Sleep disturbances and psychiatric disorders associated with posttraumatic stress disorder in the general population. Compr. Psychiatry 41 469–478. 10.1053/comp.2000.16568
    1. Okie S. (2005). Traumatic brain injury in the war zone. N. Engl. J. Med. 352 2043–2047. 10.1056/nejmp058102
    1. Ott M., Schmidt J., Young B., Ott L., Kryscio R., McClain C. (1994). Nutritional and metabolic variables correlate with amino acid forearm flux in patients with severe head injury. Crit. Care Med. 22 393–398. 10.1097/00003246-199403000-00007
    1. Ouellet M.-C., Savard J., Morin C. M. (2004). Insomnia following traumatic brain injury: a review. Neurorehabil. Neural Repair 18 187–198.
    1. Ozgultekin A., Turan G., Durmus Y., Dincer E., Akgun N. (2008). Comparison of the efficacy of parenteral glutamine and branched-chain amino acid solutions given as extra supplements in parallel to the enteral nutrition in head trauma. e-SPEN 3 211–216.
    1. Paterno R., Metheny H., Cohen A. S. (2018). Memory Deficit in an object location task after mild traumatic brain injury is associated with impaired early object exploration and both are restored by branched chain amino acid dietary therapy. J. Neurotrauma 35 2117–2124. 10.1089/neu.2017.5170
    1. Pattinson C. L., Shahim P., Taylor P., Dunbar K., Guedes V. A., Motamedi V., et al. (2020). Elevated tau in military personnel relates to chronic symptoms following traumatic brain injury. J. Head Trauma Rehabil. 35 66–73. 10.1097/htr.0000000000000485
    1. Peltz C. B., Kenney K., Gill J. M., Diaz-Arrastia R., Gardner R. C., Yaffe K. (2020). Blood biomarkers of traumatic brain injury and cognitive impairment in older veterans. Neurology 95 e1126–e1133. 10.1212/WNL.0000000000010087
    1. Pencharz P. B., Elango R., Ball R. O. (2008). An approach to defining the upper safe limits of amino acid intake. J. Nutr. 138 1996S–2002S. 10.1093/jn/138.10.1996S
    1. Plauth M., Egberts E.-H., Hamster W., Török M., Müller P. H., Brand O., et al. (1993). Long-term treatment of latent portosystemic encephalopathy with branched-chain amino acids: a double-blind placebo-controlled crossover study. J. Hepatol. 17 308–314. 10.1016/s0168-8278(05)80210-7
    1. Rao V., McCann U., Han D., Bergey A., Smith M. T. (2014). Does acute TBI-related sleep disturbance predict subsequent neuropsychiatric disturbances? Brain Inj. 28 20–26. 10.3109/02699052.2013.847210
    1. Richardson M. A., Bevans M. L., Weber J. B., Gonzalez J. J., Flynn C. J., Amira L., et al. (1999). Branched chain amino acids decrease tardive dyskinesia symptoms. Psychopharmacology 143 358–364. 10.1007/s002130050959
    1. Robertson C., Clifton G. L., Grossman R. G., Ou C., Goodman J. C., Borum P., et al. (1988). Alterations in cerabral availability of metabolic substrates after severe head injury. J. Trauma 28 1523–1532. 10.1097/00005373-198811000-00002
    1. Rutherford W. H., Merrett J. D., Mcdonali J. R. (1977). Sequelae of concussion caused by minor head injuries. Lancet 1 1–4. 10.1016/S0140-6736(77)91649-X
    1. Sakai R., Miura M., Amao M., Kodama R., Toue S., Noguchi Y., et al. (2004). Potential approaches to the assessment of amino acid adequacy in rats: a progress report. J. Nutr. 134 1651S–1655S. 10.1093/jn/134.6.1651S
    1. Sandsmark D. K., Elliott J. E., Lim M. M. (2017). Sleep-wake disturbances after traumatic brain injury: synthesis of human and animal studies. Sleep 40:zsx044. 10.1093/sleep/zsx044
    1. Scarna A., Gijsman H., McTavish S. F., Harmer C. J., Cowen P. J., Goodwin G. M. (2003). Effects of a branched-chain amino acid drink in mania. Br. J. Psychiatry 182 210–213. 10.1192/bjp.182.3.210
    1. Scholten J. D., Sayer N. A., Vanderploeg R. D., Bidelspach D. E., Cifu D. (2012). Analysis of US Veterans Health Administration comprehensive evaluations for traumatic brain injury in Operation Enduring Freedom and Operation Iraqi Freedom Veterans. Brain Inj. 26 1177–1184. 10.3109/02699052.2012.661914
    1. Sharma B., Lawrence D. W., Hutchison M. G. (2018). Branched Chain Amino Acids (BCAAs) and traumatic brain injury: a systematic review. J. Head Trauma Rehabil. 33 33–45. 10.1097/HTR.0000000000000280
    1. Skeie B., Kvetan V., Gil K. M., Rothkopf M. M., Newsholme E. A., Askanazi J. (1990). Branched-chain amino acids: their metabolism and clinical utility. Crit. Care Med. 18 549–571.
    1. Skopin M. D., Kabadi S. V., Viechweg S. S., Mong J. A., Faden A. I. (2015). Chronic decrease in wakefulness and disruption of sleep-wake behavior after experimental traumatic brain injury. J. Neurotrauma 32 289–296. 10.1089/neu.2014.3664
    1. Smith C. J., Xiong G., Elkind J. A., Putnam B. J., Cohen A. S. (2015). Brain injury impairs working memory and prefrontal circuit function. Front. Neurol. 6:240. 10.3389/fneur.2015.00240
    1. Smith Q. R., Momma S., Aoyagi M., Rapoport S. I. (1987). Kinetics of neutral amino acid transport across the blood-brain barrier. J. Neurochem. 49 1651–1658. 10.1111/j.1471-4159.1987.tb01039.x
    1. Struder H. K., Hollmann W., Platen P., Donike M., Gotzmann A., Weber K. (1998). Influence of paroxetine, branched-chain amino acids and tyrosine on neuroendocrine system responses and fatigue in humans. Horm. Metab. Res. 30 188–194. 10.1055/s-2007-978864
    1. Tandan R., Bromberg M. B., Forshew D., Fries T. J., Badger G. J., Carpenter J., et al. (1996). A controlled trial of amino acid therapy in amyotrophic lateral sclerosis: I. Clinical, functional, and maximum isometric torque data. Neurology 47 1220–1226. 10.1212/wnl.47.5.1220
    1. Thabane L., Hopewell S., Lancaster G. A., Bond C. M., Coleman C. L., Campbell M. J., et al. (2016). Methods and processes for development of a CONSORT extension for reporting pilot randomized controlled trials. Pilot Feasibility Stud. 2:25.
    1. van Hall G., Raaymakers J. S., Saris W. H., Wagenmakers A. J. (1995). Ingestion of branched-chain amino acids and tryptophan during sustained exercise in man: failure to affect performance. J. Physiol. 486 789–794. 10.1113/jphysiol.1995.sp020854
    1. Vanderploeg R. D., Cooper D. B., Belanger H. G., Donnell A. J., Kennedy J. E., Hopewell C. A., et al. (2014). Screening for postdeployment conditions: development and cross-validation of an embedded validity scale in the neurobehavioral symptom inventory. J. Head Trauma Rehabil. 29 1–10. 10.1097/HTR.0b013e318281966e
    1. Vasterling J. J., Proctor S. P., Amoroso P., Kane R., Heeren T., White R. F. (2006). Neuropsychological outcomes of army personnel following deployment to the Iraq war. JAMA 296 519–529. 10.1001/jama.296.5.519
    1. Vuille-Dit-Bille R. N., Ha-Huy R., Stover J. F. (2012). Changes in plasma phenylalanine, isoleucine, leucine, and valine are associated with significant changes in intracranial pressure and jugular venous O2 saturation in patients with severe traumatic brain injury. Amino Acids 43 1287–1296. 10.1007/s00726-011-1202-x
    1. Wagenmakers A. J. M. (1992). Amino acids metabolism, muscular fatigue and muscle wasting. Speculations on adaptations at high altitude. Int. J. Sports Med. 13 S110–S113. 10.1055/s-2007-1024611
    1. Willie J. T., Lim M. M., Bennett R. E., Azarion A. A., Schwetye K. E., Brody D. L. (2012). Controlled cortical impact traumatic brain injury acutely disrupts wakefulness and extracellular orexin dynamics as determined by intracerebral microdialysis in mice. J. Neurotrauma 29 1908–1921. 10.1089/neu.2012.2404
    1. Wiseman-Hakes C., Murray B., Moineddin R., Rochon E., Cullen N., Gargaro J., et al. (2013). Evaluating the impact of treatment for sleep/wake disorders on recovery of cognition and communication in adults with chronic TBI. Brain Inj. 27 1364–1376. 10.3109/02699052.2013.823663
    1. Worthington A. D., Melia Y. (2006). Rehabilitation is compromised by arousal and sleep disorders: results of a survey of rehabilitation centres. Brain Inj. 20 327–332. 10.1080/02699050500488249
    1. Yudkoff M. (1997). Brain metabolism of branched-chain amino acids. Glia 21 92–98. 10.1002/(sici)1098-1136(199709)21:1<92::aid-glia10>;2-w

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever