Improving symptom burden in adults with persistent post-concussive symptoms: a randomized aerobic exercise trial protocol

Leah J Mercier, Tak S Fung, Ashley D Harris, Sean P Dukelow, Chantel T Debert, Leah J Mercier, Tak S Fung, Ashley D Harris, Sean P Dukelow, Chantel T Debert

Abstract

Background: Persistent post-concussive symptoms (PPCS) affect up to 30% of individuals following mild traumatic brain injury. PPCS frequently includes exercise intolerance. Sub-symptom threshold aerobic exercise has been proposed as a treatment option for symptom burden and exercise intolerance in this population. The primary aim of this study is to evaluate whether a progressive, sub-symptom threshold aerobic exercise program can alleviate symptom burden in adults with PPCS.

Methods: Fifty-six adults (18-65) with PPCS (>3mos-5 yrs) will be randomized into two groups: an immediate start 12-week aerobic exercise protocol (AEP) or delayed start 6-week placebo-like stretching protocol (SP), followed by AEP. Aerobic or stretching activities will be completed 5x/week for 30 mins during the intervention. Online daily activity logs will be submitted. Exercise prescriptions for the AEP will be 70-80% of heart rate at the point of symptom exacerbation achieved on a treadmill test with heart rate monitoring. Exercise prescription will be updated every 3-weeks with a repeat treadmill test. The Rivermead Post-concussion Symptom Questionnaire will be the primary outcome measure at 6 and 12-weeks of intervention. Secondary outcomes include assessments of specific symptoms (headache, quality of life, mood, anxiety, fatigue, dizziness, sleep parameters, daytime sleepiness) in addition to blood biomarkers and magnetic resonance imaging and spectroscopy data for quantification of brain metabolites including γ-aminobutyric acid (GABA), glutathione, glutamate and N-acetyl aspartate (NAA) all measured at 6 and 12-weeks of intervention.

Discussion: This trial will evaluate the use of aerobic exercise as an intervention for adults with PPCS, thus expanding our knowledge of this treatment option previously studied predominantly for adolescent sport-related concussion.

Trial registration: ClinicalTrials.gov - NCT03895450 (registered 2019-Feb-11).

Keywords: Aerobic exercise; Concussion; Exercise intolerance; Mild traumatic brain injury; Persistent post-concussive symptoms; Post-concussion syndrome; Quality of life; Randomized controlled trial.

Conflict of interest statement

The authors declare they have no competing interests.

Figures

Fig. 1
Fig. 1
Study Design Protocol

References

    1. Giza CC, Hovda DA. The new neurometabolic cascade of concussion. Neurosurgery. 2014;75(Suppl 4):S24–S33. doi: 10.1227/NEU.0000000000000505.
    1. Korley FK, Kelen GD, Jones CM, Diaz-Arrastia R. Emergency department evaluation of traumatic brain injury in the United States, 2009-2010. J Head Trauma Rehabil. 2016;31(6):379–387. doi: 10.1097/HTR.0000000000000187.
    1. McCrory P, Meeuwisse W, Dvorak J, Aubry M, Bailes J, Broglio S, et al. Consensus statement on concussion in sport-the 5(th) international conference on concussion in sport held in Berlin, October 2016. Br J Sports Med. 2017;51(11):838–847.
    1. Ahman S, Saveman BI, Styrke J, Bjornstig U, Stalnacke BM. Long-term follow-up of patients with mild traumatic brain injury: a mixed-method study. J Rehabil Med. 2013;45(8):758–764. doi: 10.2340/16501977-1182.
    1. Theadom A, Parag V, Dowell T, McPherson K, Starkey N, Barker-Collo S, et al. Persistent problems 1 year after mild traumatic brain injury: a longitudinal population study in New Zealand. Br J Gen Pract. 2016;66(642):e16–e23. doi: 10.3399/bjgp16X683161.
    1. Lannsjo M, af Geijerstam JL, Johansson U, Bring J, Borg J. Prevalence and structure of symptoms at 3 months after mild traumatic brain injury in a national cohort. Brain Inj. 2009;23(3):213–219. doi: 10.1080/02699050902748356.
    1. Kraus J, Hsu J, Schaffer K, Vaca F, Ayers K, Kennedy F, et al. Preinjury factors and 3-month outcomes following emergency department diagnosis of mild traumatic brain injury. J Head Trauma Rehabil. 2009;24(5):344–354. doi: 10.1097/HTR.0b013e3181ae35fd.
    1. Theadom A, Starkey N, Barker-Collo S, Jones K, Ameratunga S, Feigin V, et al. Population-based cohort study of the impacts of mild traumatic brain injury in adults four years post-injury. PLoS One. 2018;13(1):e0191655. doi: 10.1371/journal.pone.0191655.
    1. Hiploylee C, Dufort PA, Davis HS, Wennberg RA, Tartaglia MC, Mikulis D, et al. Longitudinal study of Postconcussion syndrome: not everyone recovers. J Neurotrauma. 2017;34(8):1511–1523. doi: 10.1089/neu.2016.4677.
    1. Sigurdardottir S, Andelic N, Roe C, Jerstad T, Schanke AK. Post-concussion symptoms after traumatic brain injury at 3 and 12 months post-injury: a prospective study. Brain Inj. 2009;23(6):489–497. doi: 10.1080/02699050902926309.
    1. Hou R, Moss-Morris R, Peveler R, Mogg K, Bradley BP, Belli A. When a minor head injury results in enduring symptoms: a prospective investigation of risk factors for postconcussional syndrome after mild traumatic brain injury. J Neurol Neurosurg Psychiatry. 2012;83(2):217–223. doi: 10.1136/jnnp-2011-300767.
    1. McMahon P, Hricik A, Yue JK, Puccio AM, Inoue T, Lingsma HF, et al. Symptomatology and functional outcome in mild traumatic brain injury: results from the prospective TRACK-TBI study. J Neurotrauma. 2014;31(1):26–33. doi: 10.1089/neu.2013.2984.
    1. Aubry M, Cantu R, Dvorak J, Graf-Baumann T, Johnston KM, Kelly J, et al. Summary and agreement statement of the 1st international symposium on concussion in sport, Vienna 2001. Clin J Sport Med. 2002;12:6–11. doi: 10.1097/00042752-200201000-00005.
    1. McCrory P, Johnston K, Meeuwisse W, Aubry M, Cantu R, Dvorak J, et al. Summary and agreement statement of the 2nd international conference on concussion in sport, Prague 2004. Br J Sports Med. 2005;39(4):196–204.
    1. Chrisman SP, Schiff M, Rivara FP. Physician concussion knowledge and the effect of mailing the CDC’s “heads up” toolkit. Clin Pediatr. 2011;50:1031–1039. doi: 10.1177/0009922811410970.
    1. Moser RS, Schatz P. A case for mental and physical rest in youth sports concussion: It's never too late. Front Neurol. 2012;3:171. doi: 10.3389/fneur.2012.00171.
    1. Schneider KJ, Leddy JJ, Guskiewicz KM, Seifert T, McCrea M, Silverberg ND, et al. Rest and treatment/rehabilitation following sport-related concussion: a systematic review. Br J Sports Med. 2017;51(12):930–934. doi: 10.1136/bjsports-2016-097475.
    1. Grool AM, Aglipay M, Momoli F, Meehan WP, 3rd, Freedman SB, Yeates KO, et al. Association between early participation in physical activity following acute concussion and persistent Postconcussive symptoms in children and adolescents. JAMA. 2016;316(23):2504–2514. doi: 10.1001/jama.2016.17396.
    1. Leddy JJ, Haider MN, Ellis M, Willer BS. Exercise is medicine for concussion. Curr Sports Med Rep. 2018;17(8):262–270. doi: 10.1249/JSR.0000000000000505.
    1. Lemmens J, De Pauw J, Van Soom T, Michiels S, Versijpt J, van Breda E, et al. The effect of aerobic exercise on the number of migraine days, duration and pain intensity in migraine: a systematic literature review and meta-analysis. J Headache Pain. 2019;20(1):16. doi: 10.1186/s10194-019-0961-8.
    1. Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2017;4:CD003200.
    1. Chekroud SR, Gueorguieva R, Zheutlin AB, Paulus M, Krumholz HM, Krystal JH, Chekroud AM. Association between physical exercise and mental health in 1.2 million individuals in the USA between 2011 and 2015- a cross-sectional study. Lancet Psychiatry. 2018;5:739–746. doi: 10.1016/S2215-0366(18)30227-X.
    1. Stern Y, MacKay-Brandt A, Lee S, McKinley P, McIntyre K, Razlighi Q, et al. Effects of aerobic exercise on cognition in younger adults: A randomized clinical trial. Neurology. 2019;92:e1-e12.
    1. Dolezal BA, Neufeld EV, Boland DM, Martin JL, Cooper CB. Interrelationship between sleep and exercise: A systematic review. Adv Prev Med. 2017;2017:1–14.
    1. McIntyre M, Kempenaar A, Amiri M, Alavinia SM, Kumbhare D. The role of sub-symptom threshold aerobic exercise for persistent concussion symptoms in patients with post-concussion syndrome: A systematic review. Am J Phys Med Rehabil. 2019. 10.1097/PHM.0000000000001340. Epub ahead of print.
    1. Leddy John J., Haider Mohammad N., Ellis Michael J., Mannix Rebekah, Darling Scott R., Freitas Michael S., Suffoletto Heidi N., Leiter Jeff, Cordingley Dean M., Willer Barry. Early Subthreshold Aerobic Exercise for Sport-Related Concussion. JAMA Pediatrics. 2019;173(4):319. doi: 10.1001/jamapediatrics.2018.4397.
    1. Kurowski BG, Hugentobler J, Quatman-Yates C, Taylor J, Gubanich PJ, Altaye M, et al. Aerobic exercise for adolescents with prolonged symptoms after mild traumatic brain injury: an exploratory randomized clinical trial. J Head Trauma Rehabil. 2017;32(2):79–89. doi: 10.1097/HTR.0000000000000238.
    1. Definition of mild traumatic brain injury J Head Trauma Rehabil. 1993;8:86–87. doi: 10.1097/00001199-199309000-00010.
    1. The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research. World Health Organization: Geneva. 1993.
    1. Leddy JJ, Willer B. Use of graded exercise testing in concussion and return-to-activity management. Competitive Sports. 2013;12(6):370–376.
    1. Borg G. A category scale with ratio properties for intermodal and interindividual comparisons. In: Geissler HG, Petzold P, editors. Berlin: VEB Deutscher Verlag der Wissenschaften; 1982. p. 25-34.
    1. Borg G. Psychophysical basis of perceived exertion. Med Sci Sports Exerc. 1982;14:377–381.
    1. King NS, Crawford S, Wenden FJ, Moss NE, Wade DT. The Rivermead post concussion symptoms questionnaire: a measure of symptoms commonly experienced after head injury and its reliability. J Neurol. 1995;242(9):587–592. doi: 10.1007/BF00868811.
    1. Silverberg ND, Otamendi T. Advice to rest for more than 2 days after mild traumatic brain injury is associated with delayed return to productivity: A case-control study. Front Neurol. 2019;10:362. doi: 10.3389/fneur.2019.00362.
    1. von Steinbuchel N, Wilson L, Gibbons H, Hawthorne G, Hofer S, Schmidt S, et al. Quality of life after brain injury (QOLIBRI): scale development and metric properties. J Neurotrauma. 2010;27(7):1167–1185. doi: 10.1089/neu.2009.1076.
    1. von Steinbuchel N, Wilson L, Gibbons H, Hawthorne G, Hofer S, Schmidt S, et al. Quality of life after brain injury (QOLIBRI): scale validity and correlates of quality of life. J Neurotrauma. 2010;27(7):1157–1165. doi: 10.1089/neu.2009.1077.
    1. Kosinski M, Bayliss MS, Bjorner JB, Ware JE, Jr, Garber WH, Batenhorst A, et al. A six-item short-form survey for measuring headache impact: the HIT-6. Qual Life Res. 2003;12(8):963–974. doi: 10.1023/A:1026119331193.
    1. Castien RF, Blankenstein AH, Windt DA, Dekker J. Minimal clinically important change on the headache impact Test-6 questionnaire in patients with chronic tension-type headache. Cephalalgia. 2012;32(9):710–714. doi: 10.1177/0333102412449933.
    1. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606–613. doi: 10.1046/j.1525-1497.2001.016009606.x.
    1. Fann JR, Bombardier CH, Dikmen S, Esselman P, Warms CA, Pelzer E, et al. Validity of the patient health Questionnaire-9 in assessing depression following traumatic brain injury. J Head Trauma Rehabil. 2005;20(6):501–511. doi: 10.1097/00001199-200511000-00003.
    1. Cook KF, Bombardier CH, Bamer AM, Choi SW, Kroenke K, Fann JR. Do somatic and cognitive symptoms of traumatic brain injury confound depression screening? Arch Phys Med Rehabil. 2011;92(5):818–823. doi: 10.1016/j.apmr.2010.12.008.
    1. Löwe B, Schenkel I, Carney-Doebbeling C, Göbel C. Responsiveness of the PHQ-9 to psychopharmacological depression treatment. Psychosomativs. 2006;47:62–67. doi: 10.1176/appi.psy.47.1.62.
    1. Spitzer RL, Kroenke K, Williams JBW, Löwe B. A brief measure for assessing generalized anxiety disorder: the gad-7. Arch Intern Med. 2006;166(10):1092–1097. doi: 10.1001/archinte.166.10.1092.
    1. Krupp LB, LaRocca NG, Muir-Nash J. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus Erythematosus. Arch Neurol. 1989;46(10):1121–1123. doi: 10.1001/archneur.1989.00520460115022.
    1. Jacobson G. P., Newman C. W. The Development of the Dizziness Handicap Inventory. Archives of Otolaryngology - Head and Neck Surgery. 1990;116(4):424–427. doi: 10.1001/archotol.1990.01870040046011.
    1. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14(6):540–545. doi: 10.1093/sleep/14.6.540.
    1. Parcell DL, Ponsford JL, Rajaratnam SM, Redman JR. Self-reported changes to nighttime sleep after traumatic brain injury. Arch Phys Med Rehabil. 2006;87(2):278–285. doi: 10.1016/j.apmr.2005.10.024.
    1. Kempf J, Werth E, Kaiser PR, Bassetti CL, Baumann CR. Sleep-wake disturbances 3 years after traumatic brain injury. J Neurol Neurosurg Psychiatry. 2010;81(12):1402–1405. doi: 10.1136/jnnp.2009.201913.
    1. Masel BE, Scheibel RS, Kimbark T, Kuna ST. Excessive daytime sleepiness in adults with brain injuries. Arch Phys Med Rehabil. 2001;82(11):1526–1532. doi: 10.1053/apmr.2001.26093.
    1. Gosselin N, Lassonde M, Petit D, Leclerc S, Mongrain V, Collie A, et al. Sleep following sport-related concussions. Sleep Med. 2009;10(1):35–46. doi: 10.1016/j.sleep.2007.11.023.
    1. Sinclair KL, Ponsford J, Rajaratnam SM. Actigraphic assessment of sleep disturbances following traumatic brain injury. Behav Sleep Med. 2014;12(1):13–27. doi: 10.1080/15402002.2012.726203.
    1. Sebela Antonin, Kolenic Marian, Farkova Eva, Novak Tomas, Goetz Michal. Decreased need for sleep as an endophenotype of bipolar disorder: an actigraphy study. Chronobiology International. 2019;36(9):1227–1239. doi: 10.1080/07420528.2019.1630631.
    1. Falck RS, Best JR, David JC, Eng JJ, Middleton LE, Hall PA, et al. Sleep and cognitive function in chronic stroke: a comparative cross-sectional study. Sleep. 2019;42(5):1-11.
    1. Landry GJ, Best JR, Liu-Ambrose T. Measuring sleep quality in older adults: a comparison using subjective and objective methods. Front Aging Neurosci. 2015;7:166.
    1. Hehar H, Mychasiuk R. The use of telomere length as a predictive biomarker for injury prognosis in juvenile rats following a concussion/mild traumatic brain injury. Neurobiol Dis. 2016;87:11–18. doi: 10.1016/j.nbd.2015.12.007.
    1. Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res. 2002;30(10):e47. doi: 10.1093/nar/30.10.e47.
    1. Saleh MG, Oeltzschner G, Chan KL, Puts NAJ, Mikkelsen M, Schar M, et al. Simultaneous edited MRS of GABA and glutathione. Neuroimage. 2016;142:576–582. doi: 10.1016/j.neuroimage.2016.07.056.
    1. Friedman Seth D., Poliakov Andrew V., Budech Christopher, Shaw Dennis W.W., Breiger David, Jinguji Thomas, Krabak Brian, Coppel David, Lewis Tressa Mattioli, Browd Samuel, Ojemann Jeffrey G. GABA alterations in pediatric sport concussion. Neurology. 2017;89(21):2151–2156. doi: 10.1212/WNL.0000000000004666.
    1. Rytter HM, Westenbaek K, Henriksen H, Christiansen P, Humle F. Specialized interdisciplinary rehabilitation reduces persistent post-concussive symptoms: a randomized clinical trial. Brain Inj. 2019;33(3):266–281. doi: 10.1080/02699052.2018.1552022.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir