Article Text

Download PDFPDF
Role of biomarkers and emerging technologies in defining and assessing neurobiological recovery after sport-related concussion: a systematic review
  1. Jason B Tabor1,
  2. Benjamin L Brett2,
  3. Lindsay Nelson2,
  4. Timothy Meier2,
  5. Linden C Penner1,
  6. Andrew R. Mayer3,
  7. Ruben J Echemendia4,5,
  8. Thomas McAllister6,
  9. William P Meehan III7,8,
  10. Jon Patricios9,
  11. Michael Makdissi10,11,
  12. Silvia Bressan12,
  13. Gavin A Davis13,
  14. Zahra Premji14,
  15. Kathryn J Schneider1,
  16. Henrik Zetterberg15,
  17. Michael McCrea2
  1. 1 Sport Injury Prevention Research Centre, Faculty of Kinesiology; University of Calgary, Calgary, Alberta, Canada
  2. 2 Department of Neurosurgery and Center for Neurotrauma Research, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
  3. 3 The Mind Research Network, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
  4. 4 Psychology, University of Missouri Kansas City, Kansas City, Missouri, USA
  5. 5 Psychological and Neurobehavioral Associates, Inc, State College, PA, USA
  6. 6 Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA
  7. 7 Micheli Center for Sports Injury Prevention, Boston Children's Hospital, Boston, Massachusetts, USA
  8. 8 Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  9. 9 Wits Sport and Health (WiSH), School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand South, Johannesburg, South Africa
  10. 10 Florey Institute of Neuroscience and Mental Health - Austin Campus, Heidelberg, Victoria, Australia
  11. 11 Australian Football League, Melbourne, Victoria, Australia
  12. 12 Department of Women's and Children's Health, University of Padova, Padova, Italy
  13. 13 Murdoch Children's Research Institute, Parkville, Victoria, Australia
  14. 14 Libraries, University of Victoria, Victoria, British Columbia, Canada
  15. 15 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Molndal, Sweden
  1. Correspondence to Dr Michael McCrea, Department of Neurosurgery and Center for Neurotrauma Research, Medical College of Wisconsin, Milwaukee, WI 53226, USA; mmccrea{at}


Objective Determine the role of fluid-based biomarkers, advanced neuroimaging, genetic testing and emerging technologies in defining and assessing neurobiological recovery after sport-related concussion (SRC).

Design Systematic review.

Data sources Searches of seven databases from 1 January 2001 through 24 March 2022 using keywords and index terms relevant to concussion, sports and neurobiological recovery. Separate reviews were conducted for studies involving neuroimaging, fluid biomarkers, genetic testing and emerging technologies. A standardised method and data extraction tool was used to document the study design, population, methodology and results. Reviewers also rated the risk of bias and quality of each study.

Eligibility criteria for selecting studies Studies were included if they: (1) were published in English; (2) represented original research; (3) involved human research; (4) pertained only to SRC; (5) included data involving neuroimaging (including electrophysiological testing), fluid biomarkers or genetic testing or other advanced technologies used to assess neurobiological recovery after SRC; (6) had a minimum of one data collection point within 6 months post-SRC; and (7) contained a minimum sample size of 10 participants.

Results A total of 205 studies met inclusion criteria, including 81 neuroimaging, 50 fluid biomarkers, 5 genetic testing, 73 advanced technologies studies (4 studies overlapped two separate domains). Numerous studies have demonstrated the ability of neuroimaging and fluid-based biomarkers to detect the acute effects of concussion and to track neurobiological recovery after injury. Recent studies have also reported on the diagnostic and prognostic performance of emerging technologies in the assessment of SRC. In sum, the available evidence reinforces the theory that physiological recovery may persist beyond clinical recovery after SRC. The potential role of genetic testing remains unclear based on limited research.

Conclusions Advanced neuroimaging, fluid-based biomarkers, genetic testing and emerging technologies are valuable research tools for the study of SRC, but there is not sufficient evidence to recommend their use in clinical practice.

PROSPERO registration number CRD42020164558.

  • sports medicine
  • physiology
  • neurology

Data availability statement

Data are available upon reasonable request.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Data availability statement

Data are available upon reasonable request.

View Full Text


  • Twitter @BenjaminBrett1, @jonpatricios, @ZapTheLibrarian, @Kat_Schneider7

  • Contributors All authors contributed to article review and interpretation of data, drafting and revision of the manuscript and final approval of the manuscript, and agreed to be accountable for all aspects of the work. JBT and MAM act as guarantor.

  • Funding Education grant from the Concussion in Sport International Consensus Conference Organizing Committee through Publi Creations for partial administrative and operational costs associated with the writing of the systematic review.

  • Competing interests SB, LP and ZP have no competing interests. BB reports grant funding from the National Institute on Aging and National and National Institute of Neurological Disorders and Stroke. He also received speaker honoraria and travel reimbursement for academic conference presentations. GAD is a member of the Scientific Committee of the 6th International Conference on Concussion in Sport; an honorary member of the AFL Concussion Scientific Committee; Section Editor, Sport and Rehabilitation, NEUROSURGERY; and has attended meetings organised by sporting organisations including the NFL, NRL, IIHF, IOC and FIFA; however, has not received any payment, research funding or other monies from these groups other than for travel costs. RJE is a paid consultant for the National Hockey League and co-chair of the National Hockey League /National Hockey League Players Association Concussion Subcommittee, Major League Soccer’s Concussion Committee and the US Soccer Federation. He provides expert testimony in matters related to mTBI and reports a grant from Boston Children’s Hospital (sub-award from the National Football League) and travel support for the CIS conference and other professional conferences, an unpaid board member of CISG and a member of the Scientific Committee of the 6th International Conference on Concussion in Sport. He has served in leadership roles (unpaid) in many professional organisations. MM is a sport and exercise medicine physician working in private consulting practice. He is the Chief Medical Officer for the Australian Football League (AFL) and an Independent Concussion Consultant for World Rugby. He is a shareholder in Olympic Park Sports Medicine Centre in Melbourne. He previously held positions as the senior physician at the Hawthorn Football Club (AFL) and Chief Officer of the AFL Doctors Association. He has received research grants from the Australian Football League, outside the submitted work. He has received travel support from the AFL, FIFA and the International Olympic Committee to attend and present at international conferences. He is a member of the Scientific Committee for the 6th International Conference on Concussion in Sport, an honorary member of the International Concussion in Sport Group and of the Australian Rugby Union Concussion Advisory Group. AM is funded by various NIH and DoD grants but has no financial disclosures. TM reports concussion research grants from NIH; US Dept of Defense; US Department of Energy; & the NCAA; travel expense reimbursement to present findings at various scientific meetings; royalties from American Psychiatric Association Publishing for Textbook of TBI; serving as a member OSMB for NIH sponsored RECOVER study of Long Covid (uncompensated); serving as member, Concussion Scientific Advisory Committee, Australian Football League (uncompensated); Honorarium for TBI lecture at the Harvard Medical School Neuropsychiatry CME course. MAM has received research funding to the Medical College of Wisconsin from the National Institutes of Health, Department of Veterans Affairs, Centers for Disease Control and Prevention, Department of Defense, National Collegiate Athletic Association, National Football League and Abbott Laboratories. He receives book royalties from Oxford University Press. He serves as clinical consultant to Milwaukee Bucks, Milwaukee Brewers, and Green Bay Packers and is Co-Director of the NFL Neuropsychology Consultants without compensation. He serves as consultant for Neurotrauma Sciences, Inc. He receives travel support and speaker honorariums for professional activities. WM reports Dr Meehan receives royalties from ABC-Clio publishing for the sale of his books, Kids, Sports, and Concussion: A guide for coaches and parents, and Concussions; Springer International for the book Head and Neck Injuries in Young Athlete; Wolters Kluwer for working as an author for UpToDate. His research is funded, in part, by philanthropic support from the National Hockey League Alumni Association through the Corey C Griffin Pro-Am Tournament and a grant from the National Football League. TM receives compensation as a member of the Clinical and Scientific Advisory Board for Quadrant Biosciences Inc. LN received funding for unrelated research from the National Institute of Neurological Disorders and Stroke (NINDS), and Centers for Disease Control and Prevention, the Department of Defense, the Medical Technology Enterprise Consortium and the Medical College of Wisconsin Advancing a Healthier Wisconsin Endowment. Dr Nelson has also recently received consulting stipends for grant reviewing (Department of Defense) and research (NINDS). JP is an editor of BJSM for which he receives an honorarium. He is an unpaid consultant to the World Rugby Concussion Advisory Group for which he also serves as an Independent Concussion Advisor (fee per consultation). Other unpaid positions include being medical advisor to South African Rugby, Co-chair of the Scientific Committee, 6th International Conference on Concussion in Sport (travel and accommodation subsidised), Board member of the Concussion in Sport Group and a Scientific Advisory Board member of EyeGuide. KS has received grant funding from the CIHR, NFL Scientific Advisory Board, International Olympic Committee Medical and Scientific Research Fund, World Rugby, Mitacs Accelerate, University of Calgary, with funds paid to her institution and not to her personally. She is an Associate Editor of BJSM (unpaid) and has received travel and accommodation support for meetings where she has presented. She is coordinating the writing of the systematic reviews that will inform the 6th International Consensus on Concussion in Sport, for which she has received an educational grant to assist with the administrative costs associated with the writing of the reviews. She is a member of the AFL Concussion Scientific Committee (unpaid position) and Brain Canada (unpaid positions). She works as a physiotherapy consultant and treats athletes of all levels of sport from grass roots to professional. JT reports doctoral funding through the Canadian Institutes of Health Research (CIHR); Jason also received an honorarium for the administrative parts of the review. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.