Appendix A
Highlights of Selected Recent TBI Research Efforts
The landscape of recent of traumatic brain injury (TBI) research is dynamic and diverse. Over the past decade, various government agencies, academic institutions, nonprofit organizations, and other stakeholders have sought to study, diagnose, treat, classify, measure, and track TBI. This appendix provides selected highlights of some of these recent efforts.
Efforts to study TBI can be broadly categorized in terms of purpose, funding source (e.g., government, academic, private, public–private partnership), target populations (e.g., civilian, military, pediatric, athletes), or type of effort (e.g., consortia, research networks, guideline creation, studies). However, the landscape of TBI research may be best understood as a constellation of efforts working within their respective settings and scopes to meet specific—and often overlapping—research aims to better understand TBI.
RESEARCH PRIORITY-SETTING EFFORTS
The diversity of the TBI research landscape mirrors the diversity of populations impacted by TBI, from military personnel (Veterans, active duty military personnel, cadets and military trainees), to athletes (professional, collegiate, student, youth), to patients across the entire lifespan. The Department of Defense (DoD) and the Department of Veterans Affairs (VA) are heavily involved in the TBI research and care landscape across the gamut from funding to implementation. From enlistment, to active duty, to Veteran status, many military personnel are impacted by TBI throughout their career and beyond. Military personnel and Veterans also make up a large and unique population that can be studied to better understand long-term impacts of TBI. Athletes face a heightened risk of TBI, and their lives and livelihoods are impacted by TBI in unique ways. The National Football League (NFL), the National Collegiate Athletic Association (NCAA), and other athletic institutions have supported athlete-focused research to explore the effects of TBI on athletes during and after their athletic careers.
Because of the complexity and breadth of TBI, the research needed to diagnose, treat, and improve outcomes can vary according to the setting in which TBI occurs, the individual,
the setting where TBI is being diagnosed or treated, and numerous other factors. Thus, funders and organizing bodies that support and advocate for TBI research often have needs that are connected to specific populations and settings. Other TBI initiatives address crosscutting issues and include all or more than one of these population groups. For instance, the needs of athletes and their coaches to assess potential TBI in high-pressure scenarios share some similarities with the needs of military medical staff assessing potential TBI in combat; the challenges of mild TBI are of similar significance in civilian and military settings; the study of TBI among aging Veterans may offer insights into the impacts of TBI among aging civilians; and novel advances in classification and measurement could improve the sensitivity of all TBI research, while efforts to promote data interoperability similarly affect all research settings.
National Research Action Plan
The current TBI landscape has been fundamentally shaped by the National Research Action Plan (NRAP) (DoD et al., 2013; White House, 2012). Mandated by Executive Order 13625 (August 31, 2012), NRAP was created to promote
strategies to establish surrogate and clinically actionable biomarkers for early diagnosis and treatment effectiveness; develop improved diagnostic criteria for TBI; enhance our understanding of the mechanisms responsible for PTSD [posttraumatic stress disorder], related injuries, and neurological disorders following TBI; foster development of new treatments for these conditions based on a better understanding of the underlying mechanisms; improve data sharing between agencies and academic and industry researchers to accelerate progress and reduce redundant efforts without compromising privacy; and make better use of electronic health records to gain insight into the risk and mitigation of PTSD, TBI, and related injuries. (sec. 5b)
NRAP called for interagency collaboration to promote new research and innovations in PTSD, TBI, and related conditions. The major funders of TBI research under the current iteration of NRAP have been the National Institutes of Health (NIH), DoD, the VA, and the Centers for Disease Control and Prevention (CDC). NRAP’s original 10-year mandate is now coming to a close. During this period, it has served as a launching pad for a host of research efforts of various sizes and scopes. Since its launch in 2012, the landscape of TBI research has advanced, and new challenges, research needs, and questions have emerged in the field.
Brain Trauma Blueprint
The Brain Trauma Blueprint, launched by the nonprofit Cohen Veterans Bioscience, aims to provide a coordinated framework to “identify unmet patient needs, associated research priorities, landscape state of the science, identify research gaps and barriers and provide recommendations for progress” (Brain Trauma Blueprint, 2021). A 2-day State of the Science Summit was held in 2019 on “Pathways to Effective Treatments for Traumatic Brain Injuries,” focusing on chronic effects of TBI and the need to develop precision therapeutics (Cohen Veterans Bioscience, 2019). Building on the summit discussions, a six-part series is currently in development and is being published in the Journal of Neurotrauma1:
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1 See https://www.braintraumablueprint.org/soss2019 (accessed January 10, 2022) for “outcomes currently under development from the summit.”
- “Roadmap for Advancing Preclinical Science in Traumatic Brain Injury” (Smith et al. 2021b)
- “Epidemiology of Chronic Effects of Mild Traumatic Brain Injury” (Haarbauer-Krupa et al., 2021)
- “Phenotyping the Spectrum of Traumatic Brain Injury: A Review and Pathway to Standardization” (Pugh et al., 2021)
- “Biomarker Development to Advance Diagnosis and Treatment of Traumatic Brain Injury”
- “Designing Successful Clinical Trials for Traumatic Brain Injury”
- “A Review of Implementation Concepts and Strategies Surrounding Traumatic Brain Injury Clinical Care Guidelines” (Lumba-Brown et al., 2021).
Congressionally Directed Medical Research Program on TBI and Psychological Health
The Congressionally Directed Medical Research Program (CDMRP) on TBI and Psychological Health2 was established in fiscal year 2007. Funds provided by Congress through the Defense Appropriations Act support research addressing key medical issues affecting military service members, Veterans, and other military health system beneficiaries. In April 2021, the CDMRP office held a stakeholders meeting to identify potential areas of impact for its program of peer-reviewed TBI awards. The 2021 funding priorities were subsequently announced, with the following core program areas:
Understand: Research will address knowledge gaps in foundational science, epidemiology, and etiology of TBI and psychological health.
Prevent: Research will address the prevention or progression of TBI or psychological health conditions through population, selective, and indicated prevention approaches. Efforts that focus on primary prevention (including protection), screening, diagnosis, and prognosis are within scope.
Treat: Research will address immediate and long-term treatments and improvements in systems of care, including access to and delivery of healthcare services. Treatment topics may include novel treatments and interventions, personalized medicine approaches, length and durability of treatment, rehabilitation, relapse, and relapse prevention. (FY21 TBIPHRP Focus Areas, https://cdmrp.army.mil/tbiphrp/pdfs/FY21-TBIPHRP-FOCUS-AREAS.pdf [accessed December 14, 2021])
ENABLING RESEARCH INFRASTRUCTURE
Several efforts have focused on developing standards for research data and establishing systems for collecting TBI-related data to inform future research (see Table A-1).
Common Data Elements (CDE)3 standards were first published in 2010 through efforts funded by NIH and the Department of Health and Human Services (HHS). CDE Version 2
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2 See https://cdmrp.army.mil/tbiphrp (accessed January 10, 2022) and https://cdmrp.army.mil/tbiphrp/pdfs/FY21-TBIPHRP-FOCUS-AREAS.pdf (accessed January 10, 2022).
3 More information about CDE is available at https://www.commondataelements.ninds.nih.gov/Traumatic%20Brain%20Injury (accessed July 2, 2021).
was published in 2012, and the guidelines have been continually updated since. CDE established data standards for TBI clinical research that are relevant to patients of all ages in all populations, along with common definitions and metadata protocols to ensure that data are captured and recorded consistently in studies throughout the TBI landscape. Pediatric Common Data Elements (PED-CDE)4 was first established in 2013, with the goal of enhancing the ability to conduct multicenter research and provide evidence-based care across Canada to assist in the diagnosis and treatment of pediatric mild TBI.
In 2011, the Federal Interagency TBI Research (FITBIR) informatics system5 was created through joint funding from DoD, the VA, and NIH. FITBIR offers a secure, centralized database for TBI clinical research and serves as a data repository, allowing for comparison of new and existing data. FITBIR includes data collected from more than 80,000 individuals from both military and civilian populations. Federal grants for TBI research typically stipulate that research data be shared via FITBIR.
In 2018, the National Concussion Surveillance System (NCSS)6 was created by CDC, with the aim of measuring the number and causes of concussions, the prevalence of brain injury, and the impacts of prevention measures. NCSS deals with civilian population data, with a focus on youth sports.
RESEARCH NETWORKS, CONSORTIA, AND STUDIES
As a diverse and interdisciplinary field, TBI research is often conducted through collaboration. The establishment of TBI research networks has aided collaboration and connected experts throughout the field (see Table A-2). A number of TBI networks have been formed, with an emphasis on improving patient outcomes; consolidating data and biological samples;
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4 More information about PED-CDE is available at https://www.ctrc-ccrt.ca/projects/ped-cde-pediatric-common-data-elements-mtbi-concussion (accessed July 2, 2021) and https://www.thechildren.com/canada-pediatric-mild-traumatic-brain-injury-common-data-elements-study-mtbi-cde (accessed July 2, 2021).
5 More information about FITBIR is available at https://fitbir.nih.gov (accessed July 2, 2021).
6 More information about NCSS is available at https://www.cdc.gov/traumaticbraininjury/research-programs/ncss/index.html (accessed July 2, 2021).
TABLE A-1 TBI Research Infrastructure
| Effort | Key Funders | Year(s) | Target Population(s) | Description |
|---|---|---|---|---|
| Common Data Elements (CDE) | NIH, HHS | 2010–present | Effort to create data standards for TBI clinical research | |
| Pediatric Common Data Elements (PED-CDE) | CIHR | 2013–2018 | Pediatric TBI patients | Effort to create an assessment battery to advance clinical TBI |
| Federal Interagency TBI Research (FITBIR) informatics system | DoD, VA, NIH | 2011–Present | Military personnel and civilians | Centralized TBI research database for clinical research |
| National Concussion Surveillance System (NCSS) | CDC | 2018 | Civilians and youth athletes | Database created to investigate the incidence of TBI and the efficacy of prevention efforts |
NOTE: CDC = Centers for Disease Control and Prevention; CIHR = Canadian Institutes of Health Research; DoD = Department of Defense; HHS = Department of Health and Human Services; NIH = National Institutes of Health; TBI = traumatic brain injury; VA = Department of Veterans Affairs.
accelerating research in specific areas, such as concussions research; and connecting clinicians to improve clinical standards of care.
COllaborative Neuropathology NEtwork Characterizing OuTcomes of TBI (CONNECT-TBI)7 was established in 2020 among more than 10 universities in the United States, the United Kingdom, and Canada (Smith et al., 2021a). CONNECT-TBI is a network of brain banks and research institutions that share tissues and clinical datasets to support TBI research, investigate the pathologies of TBI, and explore the connections between TBI and neurodegenerative disease. CONNECT-TBI includes datasets from military, civilian, and athlete populations.
The Strategies to Innovate Emergency Clinical Care Trials Network (SIREN)8 was established in 2016 by NIH in collaboration with clinical centers at U.S. academic institutions. SIREN supports clinical trials with the aim of improving the outcomes of patients with neurologic, cardiac, respiratory, and hematologic emergencies by identifying effective treatments that can be provided in the earlier stages of TBI care. SIREN is associated with three noteworthy clinical studies:
- ProTECT (Progesterone for the Treatment of TBI III)9—failed clinical progesterone trial for moderate to severe TBI
- BOOST3 (Brain Oxygen Optimization in Severe TBI, Phase 3)10—study for severely injured intensive care unit (ICU) patients over the age of 14
- HOBIT (Hyberbaric Oxygen Brain Injury Treatment Trial)11—study for adults aged 16–65 years with severe TBI
The Big Ten-Ivy League Concussion Taskforce12 is a network and database established in 2012 to improve understanding of sport-related concussion and TBI. Studies conducted within the network are aimed at informing biomedical and behavioral sciences, enhancing clinical practice, and benefiting civilian and military populations through innovative TBI research (Putukian et al., 2019). The network’s efforts are focused on student athlete TBI cases.
The Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI)13 project arose from a workshop held to promote international TBI research. The CENTER-TBI prospective longitudinal observational study included 4,500 patients with 6-month patient follow-up, and the CENTER-TBI registry includes observational data from more than 15,000 patients. CENTER-TBI’s aims are to better characterize TBI as a disease; to identify effective interventions; to develop an open-source database that is compatible with FITBIR; to validate CDE for international settings; and to translate research outputs into practical information and guidelines for patients, clinicians, and policy makers.
Linking Investigations in Trauma and Emergency Services (LITES)14 was established in 2018 through collaboration between DoD and the University of Pittsburgh. The project
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7 More information about CONNECT-TBI is available at http://connect-tbi.med.upenn.edu/team (accessed July 2, 2021) and https://gbirg.inp.gla.ac.uk/connect-tbi (accessed July 2, 2021).
8 More information about SIREN is available at https://siren.network/about-siren (accessed July 2, 2021).
9 More information about ProTECT is available at https://clinicaltrials.gov/ct2/show/NCT00822900?term=ProTECT&cond=TBI+%28Traumatic+Brain+Injury%29&draw=2&rank=2 (accessed July 2, 2021).
10 More information about BOOST3 is available at https://clinicaltrials.gov/ct2/show/NCT03754114?term=BOOST3&cond=TBI+%28Traumatic+Brain+Injury%29&draw=2&rank=2 (accessed July 2, 2021).
11 More information about HOBIT is available at https://clinicaltrials.gov/ct2/show/NCT02407028?term=HOBIT&cond=TBI+%28Traumatic+Brain+Injury%29&draw=2&rank=1 (accessed July 2, 2021).
12 More information about Big Ten-Ivy League Concussion Taskforce is available at https://www.btaa.org/research/traumatic-brain-injury-research-collaboration (accessed July 2, 2021).
13 More information about CENTER-TBI is available at https://www.center-tbi.eu (accessed July 2, 2021).
14 More information about LITES is available at https://www.litesnetwork.org (accessed July 2, 2021).
created a network of medical professionals, prehospital providers, and emergency medical services providers to provide injury care and conduct outcomes research. The project’s goal is to inform clinical practice guidelines and update existing standards of care for traumatic injuries. The network is focused on adults with TBI who have hemorrhagic shock (SWAT [Shock, Whole Blood and Assessment of TBI] Trial)15 or need platelet transfusion (CriSP [Cold Stored Platelet Early Intervention in TBI] Trial).16
The DoD TBI Center of Excellence (TBICoE)17 (originally called the Defense and Veterans Brain Injury Center) was established in 1992 to support a network of military treatment facilities and VA medical centers with TBI education and research initiatives (Jaffee and Martin, 2010).
The International Initiative for Traumatic Brain Injury Research (InTBIR)18 coalition, supported by the European Commission, NIH’s National Institute of Neurological Disorders and Stroke, the Canadian Institutes of Health Research, One Mind, DoD, and the Ontario Brain Institute, coordinates and leverages clinical research activities on TBI research to improve care and lessen the global burden of TBI. InTBIR is focused on investigating the causal relationship between TBI treatments and clinical outcomes. InTBIR investigates TBI among civilian, military, athlete, and pediatric populations.
TBI Model Systems (TBIMS)19 was first established in 1987 as a demonstration project and expanded by HHS through the Administration for Community Living (Dijkers et al., 2010). A network of 16 TBIMS sites distributed throughout the United States focus on rehabilitation research and knowledge translation. The TBIMS National Database is currently the largest multisite longitudinal TBI study with information from preinjury through acute care and long-term outcomes among patients who received inpatient rehabilitation (Tso et al., 2021). In 2008, the VA and the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR) collaborated to establish a VA TBIMS among the five Polytrauma Rehabilitation Centers that address TBI rehabilitation in Veterans.
TBI research is also driven by individual studies and the efforts of dedicated clinicians and researchers working day by day to generate evidence and improve TBI patient outcomes. Many studies have been conducted and consortia created, efforts that often are conducted in parallel with other initiatives, such as the creation of guidelines or the development of a new database.
The Injury and Traumatic Stress Clinical Consortium (INTRuST)20 was established in 2016 through DoD funding. The consortium aims to combine research efforts by PTSD and TBI experts to develop innovative treatments. INTRuST maintains an imaging data repository, which includes only data from military patients with TBI severe enough to have required inpatient rehabilitation.
Operation Brain Trauma Therapy (OBTT) is a multicenter, preclinical drug and biomarker screening consortium that began in 2010 (Kochanek et al., 2018). Its aim is to define therapies that show efficacy and have promise for randomized controlled trials (RCTs), including
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15 More information about SWAT Trial is available at https://clinicaltrials.gov/ct2/show/NCT03402035?term=SWAT&cond=TBI+%28Traumatic+Brain+Injury%29&draw=2&rank=1 (accessed July 2, 2021).
16 More information about CriSP Trial is available at https://clinicaltrials.gov/ct2/show/NCT04726410?term=CRiSP&cond=TBI+%28Traumatic+Brain+Injury%29&draw=2&rank=1 (accessed July 2, 2021).
17 More information about TBICoE is available at https://health.mil/About-MHS/OASDHA/Defense-Health-Agency/Research-and-Development/Traumatic-Brain-Injury-Center-of-Excellence (accessed July 2, 2021).
18 More information about InTBIR is available at https://intbir.nih.gov (accessed July 2, 2021).
19 More information about TBIMS is available at https://msktc.org/tbi/model-system-centers (accessed July 2, 2021).
20 More information about INTRuST is available at https://cdmrp.army.mil/phtbi/research_highlights/16_Dec_intrust_highlight (accessed July 2, 2021).
TBI protein biomarker responses. OBTT has evaluated 10 therapeutics and assessed several blood biomarkers.
Warfighter Brain Health (WBH)21 was chartered in 2011 by the U.S. Army Medical Research and Development Command to lead the development and acquisition of material products to warfighters suffering from brain injuries and psychological health issues. The project aims to advance knowledge, technology prototypes, training, tools, and practice guidelines for TBI assessment. Notably, the project has resulted in the development of a blood test to detect brain injury.
Approaches and Decisions in Acute Pediatric TBI Trial (ADAPT)22 was conducted between 2014 and 2018 (final results not yet published). This international trial, supported by NIH and the University of Pittsburgh, was designed to evaluate the impact of interventions on severe TBI in children.
Army Study to Assess Risk and Resilience in Service members (ARMY STARRS) was a “multicomponent epidemiological and neurobiological study designed to generate actionable evidence-based recommendations to reduce army suicides and increase knowledge about risk and resilience factors for suicidality and its psychopathological correlates” (Ursano et al., 2014, p. 107). The study included a pre/post deployment component and a longitudinal study component.
Chronic Effects of Neurotrauma Consortium (CENC)23 was conducted between 2013 and 2019. The largest study of TBI among Veterans, it aimed to address the long-term effects of mild TBI (mTBI) among military service personnel and Veterans. In 2019, CENC was succeeded by Long-term Impact of Military-relevant Brain Injury Consortium (LIMBIC),24 which extended the research and has often been called LIMBIC-CENC to acknowledge those connections. LIMBIC aims to fill the gaps in basic science knowledge about mTBI and determine the effects on late-life outcomes and neurodegeneration. It also aims to identify service members most susceptible to the effects of mTBI and the most effective treatment strategies for these individuals. LIMBIC is funded by DoD and the VA in partnership with universities, research institutes, and health care organizations.
The Concussion Assessment, Research and Education Consortium (CARE)25 began in 2014 with support from the NCAA and DoD. The largest mTBI study to date, it focuses on understanding the neurobiopsychosocial nature of concussive injury and recovery among student athletes and cadets in order to enhance the safety and health of youth athletes, service members, and civilian populations. Phase I is complete, and Phase II is ongoing.
Evaluation of Biomarkers of Traumatic Brain Injury (ALERT-TBI)26 was conducted between 2012 and 2017 with funding from Banyan Biomarkers and DoD. It aimed to evaluate the utility of the Banyan UCH-L1/GFAP (ubiquitin carboxy-terminal hydrolase-L1/glial fibrillary acidic protein) Detection Assay as an aid in the evaluation of suspected TBI.
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21 More information about WBH is available at https://www.usammda.army.mil/index.cfm/project_management/neuro_psychological (accessed July 2, 2021).
22 More information about ADAPT is available at https://www.adapttrial.org (accessed July 2, 2021) and https://clinicaltrials.gov/ct2/show/NCT04077411?term=ADAPT&cond=TBI+%28Traumatic+Brain+Injury%29&draw=2&rank=1 (accessed July 2, 2021).
23 More information about CENC is available at https://vcurrtc.org/projects/viewPartner.cfm/13 (accessed July 2, 2021).
24 More information about LIMBIC is available at https://www.limbic-cenc.org/index.php/about (accessed July 2, 2021).
25 More information about CARE is available at http://careconsortium.net (accessed July 2, 2021).
26 More information about ALERT-TBI is available at https://clinicaltrials.gov/ct2/show/NCT01426919 (accessed July 2, 2021).
TABLE A-2 TBI Consortia and Networks
| Effort | Key Funders | Year(s) |
|---|---|---|
| COllaborative Neuropathology NEtwork Characterizing OuTcomes of TBI (CONNECT-TBI) | NINDS, University of Pennsylvania | 2020–present |
| Strategies to Innovate Emergency Clinical Care Trials Network (SIREN) | NIH, academic institutions | 2016–present |
| Big Ten-Ivy League Concussion Taskforce | Academic institutions | 2012–present |
| Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) | 20 European universities | 2013–present |
| Linking Investigations in Trauma and Emergency Services (LITES) | DoD, University of Pittsburgh | 2018–present |
| TBI Center of Excellence (TBICoE), formerly Defense and Veterans Brain Injury Center (DVBIC) | DoD | 1992–present |
| International Initiative for Traumatic Brain Injury Research (InTBIR) | NIH, European Commission, Canadian Institutes of Health Research | 2011–2019 |
| TBI Model Systems (TBIMS) | NIDILRR, Administration for Community Living, HHS | 1987–present |
| VA TBMIS Research Program | VA, NIDILRR (HHS) | 2008–present |
| Operation Brain Trauma Therapy (OBTT) | DoD and academic institutions | 2010–present |
| Warfighter Brain Health (WBH) | DoD, USAMMDA | 2011–present |
| Approaches and Decisions in Acute Pediatric TBI Trial (ADAPT) | NIH, University of Pittsburgh | 2014–2019 |
| Army Study to Assess Risk and Resilience in Servicemembers (ARMY STARRS) and STARRS Longitudinal Study (STARRS-LS) | DoD, NIMH, Uniformed Services University, UCSD, Harvard, Univ. of Michigan | 2009–present |
| Chronic Effects of Neurotrauma Consortium (CENC) | DoD, VA | 2013–2019 |
| Long-term Impact of Military-relevant Brain Injury Consortium (LIMBIC) | DoD, VA, universities, private research institutions | 2019–present |
| Concussion Assessment, Research and Education Consortium (CARE) | NCAA, DoD | 2014–present |
| Evaluation of Biomarkers of Traumatic Brain Injury (ALERT-TBI) | Banyan Biomarkers, DoD | 2012–2017 |
| NCAA concussion study | NCAA | 1999–2001 |
| Predicting and Preventing Post-concussive Problems in Pediatrics (5P) | CHEO research institute | 2013–2015 |
| Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) | NIH, DoD, OneMind, NeuroTruama Sciences LLC, Abbott Laboratories | 2009–present |
| TBI Endpoint Development Initiative (TED) | DoD, FDA, PPPs | 2014–present |
NOTE: CENC = Chronic Effects of Neurotrauma Consortium; CHEO = Children’s Hospital of Eastern Ontario; DoD = Department of Defense; FDA = Food and Drug Administration; GFAP = glial fibrillary acidic protein; HHS = Department of Health and Human Services; NCAA = National Collegiate Athletic Association; NIDILRR = National Institute on Disability, Independent Living, and Rehabilitation Research; NIH = National Institutes of Health; NIMH = National Institute of Mental Health; NINDS = National Institute of Neurological Disorders and Stroke; PPP = public–private partnership; TBI = traumatic brain injury; UCH-L1 = ubiquitin carboxy-terminal hydrolase-L1; UCSD = University of California, San Diego; USAMMDA = U.S. Army Medical Materiel Development Activity; VA = Department of Veterans Affairs.
| Target Population(s) | Description |
|---|---|
| Athletes, military personnel, and civilians | Network to promote the sharing of tissue and datasets |
| Civilians | Network created to improve patient outcomes by identifying emergency treatments |
| Student athletes | Efforts to understand the causes and effects of sports-related concussion |
| European civilians | Various efforts to study TBI, develop TBI databases, and translate research to policy |
| Adults with TBI | Investigation of TBI care to inform guidelines for clinical practice |
| Military personnel | Effort to support a multicenter network of military TBI treatment facilities |
| Civilians, military personnel, athletes, and pediatric populations | International effort to reduce TBI burden by leveraging and coordinating TBI research |
| Civilians | Longitudinal study of long-term outcomes of individuals with moderate to severe TBI who received inpatient rehabilitation. |
| Military service members and Veterans | Longitudinal study of outcomes after inpatient rehabilitation at 5 VA Polytrauma Rehabilitation Centers |
| Preclinical | Studies to explore TBI drugs and biomarker screening |
| Military personnel | Studies and database to support development of comprehensive TBI strategies |
| Pediatric populations | International efforts to study the impact of server mild TBI (mTBI) interventions |
| Military personnel | Multicomponent studies to generate evidence-based recommendations |
| Military Veterans | Study to investigate the long-term effects of mTBI among military service personnel and Veterans |
| Military Veterans | Further research for TBI military personnel and Veterans; newest iteration of CENC |
| Student athletes and cadets | Study to explore concussive injury and recovery |
| Adults with moderate to mild TBI | Study to evaluate the utility of Banyan UCH-L1/GFAP detection assay |
| College football players | Prospective cohort study to evaluate concussions among college football players |
| Pediatric populations | Study to develop indicators for pediatric persistent postconcussive symptoms |
| Civilians | Largest-scale initiative to analyze clinical TBI data and TBI outcomes |
| Civilians, athletes, military personnel | Efforts to identify/validate measures of TBI and recovery |
The NCAA concussion study was conducted between 1999 and 2001 (Guskiewicz et al., 2003). The seminal prospective cohort study evaluated 2,905 college football players to explore how common concussions are among college football players, average recovery time, and whether concussions occur more frequently among players who have previously experienced concussion.
Predicting and Preventing Post-concussive Problems in Pediatrics (5P)27 was conducted between 2013 and 2015 by the Children’s Hospital of Eastern Ontario (CHEO) research institute in Canada (Zemek et al., 2013). This prospective, multicenter cohort study aimed to derive and validate easy-to-use prognosticators that would enable clinicians to identify children and youth at risk of persistent postconcussive symptoms. The study focused on pediatric patients aged 5–18 years who were evaluated within the first 48 hours after a TBI.
Transforming Research and Clinical Knowledge in TBI (TRACK-TBI),28 which began in 2009, is the largest, most comprehensive civilian TBI initiative. The study is funded by NIH, DoD, and industry and philanthropic partners. Its aim is to collect and analyze detailed clinical data on subjects across the TBI spectrum, including computed tomography (CT) and magnetic resonance imaging (MRI) data, blood biospecimens, and detailed clinical outcomes. The study also aims to identify TBI subgroups based on imaging and blood biomarkers in order to develop precision medicine for TBI.
The TBI Endpoint Development (TED) Initiative29 began in 2014 with the aim of identifying and validating measures of brain injury and recovery for use in clinical trials to enable the development of precision TBI treatment. TED is supported by DoD; the Food and Drug Administration (FDA); and various public–private partnerships involving academia, industry, philanthropy, and patient advocacy organizations. One impetus for TED was to develop an improved classification system for TBI.
EDUCATION AND AWARENESS-RAISING INITIATIVES
CDC’s HEADS UP initiative (see Table A-3) provides information and resources for parents, health care and school professionals, coaches, and athletes aimed at “raising awareness and informing action to improve prevention, recognition, and response to concussion and other serious brain injuries.”30 The program has reportedly “distributed more than 6 million copies of [the] HEADS UP materials and trained over 3 million coaches” (Baldwin et al., 2016).
Since 1986, the nonprofit ThinkFirst National Injury Prevention Foundation has focused on reducing youth and geriatric neurotrauma by developing and providing educational programs on injury prevention education and awareness for children, young adults, parents, and older adults (Youngers et al., 2017).
An effort by DoD’s TBICoE (formerly the Defense and Veterans Brain Injury Center [DVBIC]), “A Head for the Future” provides fact sheets on TBI and stories and videos from service members and Veterans.31
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27 More information about 5P is available at http://www.5pconcussion.com (accessed July 2, 2021) and https://clinicaltrials.gov/ct2/show/NCT01873287 (accessed July 2, 2021).
28 More information about TRACK-TBI is available at https://tracktbi.ucsf.edu (accessed July 2, 2021).
29 More information about TED is available at https://tbiendpoints.ucsf.edu (accessed July 2, 2021). See also Manley et al., 2017.
30 More information about HEADS UP is available at https://www.cdc.gov/headsup/about/index.html (accessed July 2, 2021).
31 See https://www.health.mil/About-MHS/OASDHA/Defense-Health-Agency/Research-and-Development/Traumatic-Brain-Injury-Center-of-Excellence/A-Head-for-the-Future (accessed August 25, 2021).
TABLE A-3 Selected TBI Educational Efforts
| Effort | Key Funders | Year(s) | Target Population(s) | Description |
|---|---|---|---|---|
| HEADS UP | CDC | 2003–present | Youth and elderly | Educational initiative to improve TBI awareness and prevention among youth and elderly |
| A Head for the Future | DoD | 2019 | Military personnel | Effort to improve TBI awareness and prevention among service members and Veterans |
Note: CDC = Centers for Disease Control and Prevention; DoD = Department of Defense; TBI = traumatic brain injury.
A number of awareness-raising and educational programs are undertaken each March for Brain Injury Awareness Month, led by the Brain Injury Association of America.
In addition, trauma-focused educational efforts may have relevance to TBI. For example, “Stop the Bleed,” founded by the American College of Surgeons, is a call-to-action awareness campaign that trains and empowers individuals to respond aptly in a bleeding emergency before professional help arrives. The course is taught by qualified instructors who focus on identification and treatment, as well as the basics of bleeding control through wound packing and pressure dressings.32
CARE GUIDELINES
To achieve the best possible outcomes and reduce TBI-related morbidity and mortality, up-to-date, evidence-based guidelines, clinical best practices, and care recommendations are essential (see Table A-4). Much of the current TBI research is focused on addressing the need for such guidelines, and as TBI research advances, guidelines must be continually assessed and revised. Brain Trauma Foundation TBI Guidelines committees33 have been creating TBI guidelines since 1995. The committees include representatives of various professional societies and academic institutions, including the American Association of Neurological Surgeons (AANS), Congress of Neurological Surgeons (CNS), Army Contracting Command, Aberdeen Proving Ground, Natick Contracting Division, Stanford University, and the Brain Trauma Foundation. The committees create evidence-based guidelines for treating TBI that aim to advance high-quality care and lower TBI-related morbidity and mortality. Since the initial guideline publication in 1995, updated guidelines have been published in 2000, 2007, and 2016.
DoD has established protocols for TBI assessment and return to duty34 and continues to explore metrics for assessing readiness to return (Scherer et al., 2013). These guidelines are used primarily in military settings to manage mTBI among military personnel.
The International Forum on Consensus in Sport Concussion35 first established guidelines
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32 See https://www.stopthebleed.org (accessed August 25, 2021).
33 More information about Brain Trauma Foundation TBI Guidelines committees is available at https://www.braintrauma.org/coma/guidelines (accessed July 2, 2021) and https://www.braintrauma.org/uploads/13/06/Guidelines_for_Management_of_Severe_TBI_4th_Edition.pdf (accessed July 2, 2021).
34 More information about DoD protocols for TBI assessment is available at DoD Clinical Recommendation January 2021, Progressive Return to Activity Following Acute Concussion/Mild Traumatic Brain Injury. https://jts.amedd.army.mil/assets/docs/cpgs/Progressive_Return_to_Activity_Following_Acute_Concussion_mTBI_Clinical_Recommendation_2021.pdf (accessed March 2, 2022).
35 More information about International Forum on Consensus in Sport Concussion is available at https://waset.org/sports-concussion-prevention-diagnosis-and-treatment-conference-in-august-2021-in-paris (accessed July 2, 2021).
TABLE A-4 Selected TBI Clinical Guidance Development Efforts
| Effort | Key Funders | Year(s) | Target Population | Description |
|---|---|---|---|---|
| Brain Trauma Foundation TBI Guidelines committees | AANS, CNS, Army Contracting Command, Stanford University, Brain Trauma Foundation | 1995–present | Specified subpopulations (ex., severe TBI) | Committees formed to support the creation of evidence-based guidelines for TBI care |
| DoD protocols for TBI assessment and return to duty | Military personnel | Guidelines for military personnel who experience mTBI | ||
| International consensus conferences and statements on concussion in sport | 2001–present | Sports participants | Forum developed to conduct systematic TBI evidence review every 4 years | |
| Guidelines for disorders of consciousness | ANN, ACRM, NIDILRR | 2018 | Persons with prolonged disorders of consciousness | Recommendations for patients with prolonged disorders of consciousness |
| Pediatric mTBI CDC Resources | CDC | 2018 | Children with mTBI | Guidelines for pediatric mTBI |
Note: AANS = American Association of Neurological Surgeons; ACRM = American Congress of Rehabilitation Medicine; ANN = American Academy of Neurology; CDC = Centers for Disease Control and Prevention; CNS = Congress of Neurological Surgeons; DoD = Department of Defense; mTBI = mild traumatic brain injury; NIDILRR = National Institute on Disability, Independent Living, and Rehabilitation Research; TBI = traumatic brain injury.
in 2001, and its sixth conference is scheduled for 2022. Every 4 years, the forum conducts a systematic review of concussion evidence to inform a series of evidence-based statements. The most recent consensus statement was released in 2017 following the fifth international conference (McCrory et al., 2017).
In 2018, the American Academy of Neurology (ANN), American Congress of Rehabilitation Medicine (ACRM), and NIDILRR created new guidelines for disorders of consciousness (Giacino et al., 2018). These guidelines provided updated care recommendations for patients with prolonged disorders of consciousness, such as vegetative states, unresponsive wakefulness syndrome, and minimally conscious states.
CDC’s pediatric mTBI guidelines were first published in 2018 (Lumba-Brown et al., 2018).36 They address diagnosis, prognosis, management, and treatment for pediatric mTBI.
As part of its HEADS UP initiative, a toolkit for healthcare professionals was first developed by CDC in 2003 and rereleased in 2007 (CDC, 2013). The website now includes online training courses for health care providers and youth sports coaches, among other resources.37
FEDERAL INVESTMENTS IN TBI RESEARCH
Significant resources have been devoted to TBI over the past decade, including through federal and philanthropic research investments that have supported long-term clinical stud-
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36 More information about CDC’s pediatric mTBI guidelines is available at https://www.cdc.gov/traumaticbraininjury/PediatricmTBIGuideline.html (accessed July 2, 2021).
37 See https://www.cdc.gov/headsup/resources/index.html (accessed September 24, 2021).
ies. According to available information, federal agencies invested approximately $330 million in fiscal year 2019 and approximately $2 billion over the 5-year period 2014 to 2019.
Information on support for TBI in the Federal RePORTER database for 2014 to 2019 shows 5,041 projects with $2,111,385,035 funding involving NIH; the CDMRP; the National Science Foundation; the NIDILRR; the Center for Neuroscience and Regenerative Medicine (based at the Uniformed Services University of the Health Sciences), CDC, the Combat Casualty Care Research Program, the Agency for Healthcare Research and Quality, and the National Institute of Food and Agriculture. TBI projects were also supported at the VA and DVBIC, although this funding was not reported in the available total.38 NIH estimates of funding for TBI has increased from $87 million in 2014 to $134 million in 2019.39 Recent annual funding among participating agencies of the NRAP has included funding from DoD ($141 million); VA Office of Research and Development ($41.9 million); NIH ($134 million); NIDILRR ($16 million); and CDC ($3 million), totaling approximately $335.9 million. The most recent request for proposals issued by the CDMRP in Traumatic Brain Injury and Psychological Health, released in August 2021, indicated that $175 million had been allocated to the program.40
REFERENCES
Baldwin, G., M. Breiding, and D. Sleet. 2016. Using the public health model to address unintentional injuries and TBI: A perspective from the Centers for Disease Control and Prevention (CDC). NeuroRehabilitation 39(3):345-349.
Brain Trauma Blueprint. 2021. Traumatic brain injury: A new roadmap outlining opportunities, barriers, and recommendations for advancing treatment solutions. Press release. https://www.braintraumablueprint.org/tbi-new-roadmap-advancing-treatment (accessed July 31, 2021).
CDC (Centers for Disease Control and Prevention). 2013. HEADS UP in 10 years: The anniversary viewbook of CDC’s HEADS UP. https://www.cdc.gov/headsup/pdfs/HeadsUp_10YrViewBook-a.pdf (accessed September 24, 2021).
Cohen Veterans Bioscience. 2019. Pathways to effective treatments for traumatic brain injuries. Proceedings of the Second Annual Brain Trauma Blueprint State of the Science Summit. June 5–6, 2019. https://www.braintraumablueprint.org/wp-content/uploads/2020/11/braintraumablueprint-tbisummit2019-proceedings.pdf (accessed July 31, 2021).
Dijkers, M., C. Harrison-Felix, and J. Marwitz. 2010. The Traumatic Brain Injury Model Systems history and contributions to clinical service and research. Journal of Head Trauma Rehabilitation 25(2):81-91.
DoD (Department of Defense), VA (Department of Veterans Affairs), HHS (Department of Health and Human Services), and ED (Department of Education). 2013. National research action plan: Responding to the Executive Order Improving Access to Mental Health Services for Veterans, Service Members, and Military Families (August 31, 2012).https://obamawhitehouse.archives.gov/sites/default/files/uploads/nrap_for_eo_on_mental_health_august_2013.pdf (accessed July 31, 2021).
Giacino, J. T., D. I. Katz, N. D. Schiff, J. Whyte, E. J. Ashman, S. Ashwal, R. Barbano, F. M. Hammond, S. Laureys, G. S. F. Ling, R. Nakase-Richardson, R. T. Seel, S. Yablon, T. S. D. Getchius, G. S. Gronseth, and M. J. Armstrong. 2018. Practice guideline update recommendations summary: Disorders of consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research. Neurology 91(10):450-460.
Guskiewicz, K. M., M. McCrea, S. W. Marshall, R. C. Cantu, C. Randolph, W. Barr, J. A. Onate, and J. P. Kelly. 2003. Cumulative effects associated with recurrent concussion in collegiate football players: The NCAA Concussion Study. Journal of the American Medical Association 290(19):2549-2555.
___________________
38 See https://federalreporter.nih.gov, using a search for “Traumatic Brain Injury” or TBI (accessed May 13, 2021).
39 Based on NIH Resources—Estimates of Funding for Various Research, Condition, and Disease Categories (RCDC) available at https://report.nih.gov/funding/categorical-spending# (accessed May 13, 2021). Searching “Injury - Traumatic Brain Injury” provided results of 2014 ($87 million); 2015 ($93 million); 2016 ($105 million); 2017 ($116 million); 2018 ($133 million); 2019 ($134 million); 2020 estimated ($143 million); and 2021 estimated ($130 million).
40 See https://cdmrp.army.mil/funding/tbiphrp (accessed August 25, 2021).
Haarbauer-Krupa, J., M. J. Pugh, E. M. Prager, N. Harmon, J. Wolfe, and K. C. Yaffe. 2021. Epidemiology of chronic effects of traumatic brain injury. Journal of Neurotrauma 38(23):3235-3247.https://doi.org/10.1089/neu.2021.0062.
Jaffee, M., and E. M. Martin. 2010. Defense and Veterans Brain Injury Center: Program overview and research initiatives. Military Medicine 175(7 Suppl):37-41.
Kochanek, P. M., C. E. Dixon, S. Mondello, K. Wang, A. Lafrenaye, H. M. Bramlett, W. Dietrich, R. L. Hayes, D. A. Shear, J. S. Gilsdorf, M. Catania, S. M. Poloyac, P. E. Empey, T. C. Jackson, and J. T. Povlishock. 2018. MultiCenter pre-clinical consortia to enhance translation of therapies and biomarkers for traumatic brain injury: Operation brain trauma therapy and beyond. Frontiers in Neurology 9:640.
Lumba-Brown, A., K. O. Yeates, K. Sarmiento, M. Breiding, T. Haegerich, G. Gioia, M. Turner, et al. 2018. Centers for Disease Control and Prevention guideline on the diagnosis and management of mild traumatic brain injury among children. JAMA Pediatrics 172(11):e182853.
Lumba-Brown, A., E. Prager, N. Harmon, M. McCrea, M. Bell, J., Ghajar, S. Pyne, and D. Cifu. 2021. A review of implementation concepts and strategies surrounding traumatic brain injury clinical care guidelines. Journal of Neurotrauma 38(23). https://doi.org/10.1089/neu.2021.0067.
Manley, G. T., C. Mac Donald, A. Markowitz, D. Stephenson, A. Robbins, R. Gardner, E. Winkler, Y. Bodien, S. Taylor, J. Yue, L. Kannan, A. Kumar, M. McCrea, K. Wang, and TED Investigators. 2017. The Traumatic Brain Injury Endpoints Development (TED) Initiative: Progress on a public-private regulatory collaboration to accelerate diagnosis and treatment of traumatic brain injury. Journal of Neurotrauma 34(19):2721-2730.
McCrory, P., W. Meeuwisse, J. Dvořák, M. Aubry, J. Bailes, S. Broglio, R. Cantu, et al. 2017. Consensus statement on concussion in sport-the 5th international conference on concussion in sport held in Berlin, October 2016. British Journal of Sports Medicine 51(11):838-847.
Pugh, M. J., E. Kennedy, E. Prager, J. Humpherys, K. Dams-O’Connor, D. Hack, M. K. McCafferty, J. Wolfe, K. Yaffe, M. McCrea, A. Ferguson, L. Lancashire, J. Ghajar, and A. Lumba-Brown. 2021. Phenotyping the spectrum of traumatic brain injury: A review and pathway to standardization. Journal of Neurotrauma 38(23).https://doi.org/10.1089/neu.2021.0059.
Putukian, M., B. D’Alonzo, C. Campbell-McGovern, and D. Wiebe. 2019. The Ivy League-Big Ten Epidemiology of Concussion Study: A report on methods and first findings. American Journal of Sports Medicine 47(5):1236-1247.
Scherer, M., M. Weightman, M. Radomski, L. Davidson, and K. McCulloch. 2013. Returning service members to duty following mild traumatic brain injury: exploring the use of dual-task and multitask assessment methods. Physical Therapy 93(9):1254-1267
Smith, D., J-P. Dollé, K. E. Ameen-Ali, A. Bretzin, E. Cortes, J. Crary, K. Dams-O’Connor, R. Diaz-Arrastia, B. Edlow, R. Folkerth, L-N. Hazrati, S. Hinds, D. Iacono, V. Johnson, C. D. Keene, J. Kofler, G. Kovacs, E. Lee, G. Manley, D. Meaney, T. Montine, D. Okonkwo, D. Perl, J. Trjanowski, D. Wiebe, K. Yaffe, T. McCabe, and W. Stewart. 2021a. Collaborative Neuropatholoy Network Characterizing ouTcomes of TBI (CONNECT-TBI). Acta Neuropathologica Communications 9:32. https://doi.org/10.1186/s40478-021-01122-9.
Smith, D. H., P. Kochanek, S. Rosi, R. Meyer, C. Ferland-Beckham, E. Prager, S. Ahlers, and F. Crawford. 2021b. Roadmap for advancing pre-clinical science in traumatic brain injury. Journal of Neurotrauma.https://doi.org/10.1089/neu.2021.0094.
Tso, S., A. Saha, and M. D. Cusimano. 2021. The Traumatic Brain Injury Model Systems National Database: A review of published research. Neurotrauma Reports 2(1):149-164.
Ursano, R. J., L. J. Colpe, S. G. Heeringa, R. C. Kessler, M. Schoenbaum, M. B. Stein, and A. S. Collaborators. 2014. The Army study to assess risk and resilience in servicemembers (Army STARRS). Psychiatry: Interpersonal and Biological Processes 77(2):107-119.
White House. 2012. Improving access to mental health services for Veterans, service members, and military families. Executive Order 13625 of August 31, 2012. https://obamawhitehouse.archives.gov/the-press-office/2012/08/31/executive-order-improving-access-mental-health-services-veterans-service (accessed July 31, 2021).
Youngers, E. H., K. Zundel, D. Gerhardstein, M. Martínez, C. Bertrán, M. Proctor, M. Spatola, and E. Neuwelt. 2017. Comprehensive review of the ThinkFirst injury prevention programs: A 30-year success story for organized neurosurgery. Neurosurgery 81(3):416-421.
Zemek, R., M. Osmond, N. Barrowan, and on behalf of the Pediatric Emergency Research Canada (PERC) Concussion Team. 2013. Predicting and Preventing Postconcussive Problems in Paediatrics (5P) study: Protocol for a prospective multientre clinical prediction rule derivation study in children with concussion. BMJ Open 3(8):e003550. https://doi.org/10.1136/bmjopen-2013-003550.
