The Sports and Health Research Program (SHRP) is a public-private partnership of the National Institutes of Health (NIH), the Foundation for the NIH (FNIH) and the National Football League (NFL), aimed at addressing major public health issues related to sports participation and other activities involving repetitive head injuries. Launched in 2012, SHRP was made possible by a $30 million commitment from the NFL with an initial focus on traumatic brain injury (TBI) and plans to investigate other areas of research on serious medical conditions prominent in athletes and relevant to the general population. To date, SHRP has supported three Requests for Applications (RFAs), and in December 2013, announced the selection of eight projects to receive support to answer some of the most fundamental problems on TBI, including understanding the long-term effects of repeated head injuries and improving diagnosis for concussions.

On March 31, 2015, 39 scientists and clinicians attended a meeting at the Marriot Marquis in Washington, DC to review current SHRP projects, receive an update on a longitudinal clinical study, and discuss pilot projects on sports-related brain injury. Organized by Patrick Bellgowan, PhD from the National Institute of Neurological Disorders and Stroke (NINDS), and Stephanie James, Ph.D., Director of Science for the FNIH, the meeting brought together experts in concussion, TBI and chronic traumatic encephalopathy as well as stakeholders from sports and military interests. The March 31^st SHRP meeting marked the first time SHRP stakeholders have been able to meet with grantees and hear about their research first-hand. In attendance were representatives from the NFL, National Hockey League, Fédération Internationale de Football Association (FIFA), United States Olympic Committee, National Intrepid Center of Excellence, Companions in Courage Foundation, and Abbott Diagnostics, as well as representatives from several NIH Institutes and FNIH.

NIH Investment in TBI Research

TBI research at NIH encompasses the full range of TBI severity, from mild (concussion) through severe TBI (car crash or serious fall). NIH funded $87 million of research on TBI in FY 2014, with NINDS contributing approximately 60 percent of these funds. The National Institute on Child Health and Human Development (NICHD) supports research on pediatric TBI and coordinates NIH rehabilitation research through the National Center for Medical Rehabilitation Research. As part of an international initiative for TBI research (InTBIR) aimed at lessen the global burden of TBI by 2020, NIH is currently funding two large TBI clinical research programs in the United States to collect data to determine what treatments work best for which patients with TBI. One of these, Approaches and Decisions in Acute Pediatric TBI (ADAPT) focuses on treatment effectiveness in 1000 children with severe TBI, while the other, Transforming Research and Clinical Knowledge in TBI (TRACK-TBI ) focuses on effective treatments in 3000 adults with TBI across the spectrum of injury severity. NINDS also supports the Federal Interagency Traumatic Brain Injury Research (FITBIR) Informatics System, a $10 million project funded by the Department of Defense (DOD) to build a central inter-agency repository for sharing data to promote collaboration, accelerate research, and advance knowledge on the characterization, prevention, diagnosis and treatment of TBI. Together with DOD and the Uniformed Services University of the Health Sciences (USUHS), NINDS found the Center for Neuroscience and Regenerative Medicine (CNRM ), a collaborative federal intramural research program that brings together clinicians and scientists across disciplines to catalyze innovative approaches to TBI research.

Concussion: The Scope of the Issue

Although concussions are the most common type of TBI, little is known about what happens in the brain at the time of concussion. A concussion can be defined as a sudden change in neurologic function that occurs immediately after the brain encounters a mechanical force. A variety of symptoms accompany concussion including loss or alteration in consciousness, headache, cognitive impairment, behavioral changes, dizziness, and sleep disturbances. When these symptoms persist for more than three weeks, patients are said to suffer from post-concussive syndrome.

Another mystery surrounding the pathophysiology of concussion includes why repetitive concussions increase one’s chances of having worsened and longer duration symptoms upon subsequent concussive episodes. Repeated concussion has also been associated with a degenerative disorder, known as chronic traumatic encephalopathy (CTE).  Diagnosis of CTE can only be done post-mortem and is characterized by cerebral atrophy and multi-focal aggregation of the tau protein in neurons and astrocytes around blood vessels near the basin of cortical sulci. While there appears to be an intermediate stage leading up to CTE where tau deposition begins to become confluent in multiple brain regions, it is not clear whether this is associated with a clinical syndrome and what causes these sequelae to progress.

The pathophysiology of concussion is a dynamic process, and key questions remain to be solved, including:

1. What are the key pathophysiological targets for acute diagnosis and treatment?
2. How does concussion affect brain development in pediatric and adolescent populations?
3. What are the underlying mechanisms of post-concussive syndrome (PCS)?
4. What are the underlying mechanisms of increased vulnerability to prolonged PCS with repeated concussion?
5. What dose of TBI (e.g., number, intensity, temporal pattern, regional factors) is associated with foci of tau deposits?
6. How does tau deposition evolve to affect widespread brain regions? (e.g., spread vs. different regional rates of neurodegeneration)
7. Given similar exposures, how can we predict an individual’s risk for CTE? (e.g., genetics, lifestyle, environmental influences, etc.)

Collaborative Agreements (U01 grants) on CTE and Delayed Effects of TBI:
Neuropathology and Neuroimaging Correlation

Most attention in TBI research has focused on acute care and short-term outcomes for people hospitalized for moderate-severe TBI. Much less is known about the late effects of moderate-severe TBI, and even less about the late effects of mild TBI. In March 2013, NIH released a Request for Applications and selected two four-year projects, each funded at $6 million, aimed at studying the neuropathology associated with CTE and the delayed effects of TBI in order to identify neuroimaging signatures of the neuropathology as a foundation for the development of in vivo diagnostic tools.

Wayne Gordon, Ph.D., Professor and Vice Chair of the Brain Injury Research Center of Mount Sinai , is the principal investigator of the late effects of traumatic brain injury project at the Icahn School of Medicine at Mount Sinai. This study aims to examine TBI as a neurodegenerative condition in non-athletes, and the extent to which the neuropathology overlaps with other degenerative diseases such as CTE and Alzheimer’s disease. By collecting data from two large cohorts, Dr. Gordon and his co-investigators hope to identify uniform behavioral and cognitive information that is linked with pre- and post-mortem imaging and neuropathology. Their study involves:

• Using an ex vivo MRI specimen processing protocol, whole brain and individual cortical hemispheres undergo connectome & 7T imaging at Massachusetts General Hospital (MGH), followed by whole mount histopathological analysis at USUHS, Brigham Women's Hospital and the University of Washington. Additionally, this project takes advantage of a new procedure using Histelide to visualize and quantify amyloid beta and tau within tissue slices.
• Conduct of various genomic analyses as well as the collection of plasma and serum specimens for banking and biomarker analysis. This study will provide a tremendous amount of data from non-athletes who have suffered TBI and may identify neuroimaging signatures associated with the neuropathology of CTE and the late effects of TBI to pave the way for earlier detection and better treatment.

Ann McKee, M.D., Professor of Neurology and Pathology at the Boston University School of Medicine , leads the Understanding Neurological Injury and Traumatic Encephalopathy (UNITE) study. The UNITE study is a retrospective analysis of professional and amateur athletes, veterans, and other individuals who sustained repetitive TBI before passing away. It aims to establish consensus criteria for the pathological diagnosis of CTE, to validate a pathological staging scheme of CTE severity, to differentiate CTE from other neurodegenerative conditions, and to determine the neuropathology of posttraumatic neurodegeneration after a single TBI. The UNITE study also aims to establish a nationwide brain donation program for TBI to serve as a national resource for TBI biospecimen and data sharing. Progress to date includes:

• In February 2015, NINDS convened nine expert neuropathologists in Boston for the first consensus meeting to evaluate preliminary pathological consensus criteria for CTE. A summary of this workshop describes that in CTE, the tau lesion considered pathognomonic was an abnormal perivascular accumulation of tau in neurons, astrocytes, and cell processes in an irregular pattern at the depths of the cortical sulci. In addition to delineating required criteria for diagnosis of CTE, the group also defined five supportive pathological features that were frequent in CTE brains, as well as findings considered exclusions to the diagnosis of primary CTE.
• As of March 2015, the UNITE BrainBank hosts over 250 brain specimens from a variety of athletes and military veterans. Of the 186 athlete brains that have been evaluated, neuropathological diagnosis indicated that 77% were positive for CTE. UNITE seeks to integrate this specimen collection with a clinicopathological correlation, through retrospective clinical histories and comprehensive neuropathological examination. To date, 67 cases have come through consensus, and a paper describing the methods of this analysis is being prepared for submission.

Pilot Projects on Sports-related Brain Injury

SHRP is currently funding six pilot projects focused on developing new ways to diagnose and treat athletes who suffer concussions. These are up to 2-year projects, collectively funded at approximately $2 million. A brief description of each pilot project and their preliminary findings follow:

1. Cortical GABA in pediatric sports concussion
   Deficits in memory, attention, cognitive and executive functions are the most common disabilities following TBI. The brain contains numerous chemicals, like gamma-amino butyric acid (GABA), that are important for many brain functions including cognition and movement, and may be altered by TBI. Led by Jeffrey Ojemann, M.D., at Seattle Children’s Hospital, the goal of this study is to monitor brain GABA levels related to working memory using functional MRI in adolescents who have sports-related concussions and compare those levels to uninjured controls. It will evaluate 20 children, aged 14-18 years old, who are split into concussed and control groups. This study targets the frontal, occipital and motor areas of the brain, with the assumption that cognitive regions are more vulnerable to concussion injury. Ultimately, this research may identify diagnostic tools to reliably detect when the brain is injured and when it has recovered following a concussion, to determine when it is safe to resume normal activities for concussed athletes.

2. Evaluation of spot light: a concussion injury management app for youth sports
   Clinicians have varying approaches to the diagnosis and management of sports-related concussion and these guidelines need the support of a firm evidence base. SpotLight is a concussion injury management application (app) that coordinates diagnosis, management, and return to play (RTP) procedures from any injury to safe return to sport. The evaluation of SpotLight clinical trial designed to test whether youth football teams that use SpotLight will report increased rates of concussion, increased referrals to physicians for care, and increased athlete compliance with RTP guidelines compared to teams that do not use SpotLight. Lara McKenzie, Ph.D., pediatric expert at Nationwide Children’s Hospital and Principle Investigator for this study, reports that 80 youth football teams were enrolled in the SpotLight study during the 2014 season. If successful, SpotLight will provide an easy-to-use app that effectively helps parents, coaches, and others involved in youth sports to better recognize, respond to, and ensure that athletes are fully recovered from sports-related concussion before returning to play.

3. Eye movement dynamics: a rapid objective involuntary measure of concussion/mild-TBI
   Research indicates that oculomotor performance (e.g., eye movements such as saccades and smooth pursuit) may represent a sensitive biomarker of mild TBI. Nicholas Port, Ph.D., Steven Hitzeman, O.D. and their team at Indiana University have developed a portable eye-tracking instrument that can be used to diagnose concussions on the sidelines and monitor injury progression in high school and college athletes. This sideline tracker is portable, low cost, and usable in direct sunlight. Over three years, their team collected post-injury eye movement exams on 34 concussed football and soccer players. They have also collected data to compare these eye-tracking data to results from commonly used cognitive tests to determine if changes in eye movement can serve as a biomarker for sports-related mild TBI. In addition to conducting a longitudinal comparison of oculomotor performance in concussed athletes, non-concussed athletes and non-athlete controls, this study will also examine mild TBI diagnostic neuropsychological measures. Their preliminary results indicate that post-concussion smooth pursuit eye tracking shows a large effect, and that smooth eye pursuit is impaired following concussion.

4. Imaging and biomarkers in adolescents cleared for return to play after concussion
   Emerging evidence suggests that concussions may cause persistent, long-term effects in young athletes, even after they have been allowed to return to play. This study, led by Harvey Levin, Ph.D. at the Baylor College of Medicine, seeks to investigate the effects of sports concussion on brain function and structure in adolescent athletes who meet clinical guidelines for return to play. Using several neuroimaging techniques, it will also evaluate the validity and prognostic usefulness of specific microRNA (miRNA) biomarker levels in the plasma of acutely concussed and non-concussed adolescent athletes. miRNAs are sensitive to tissue and disease specific pathologies, and this project will evaluate their use as potential biomarkers for concussions and recovery. This study will also determine if these biomarkers correspond with cognitive test results and neuroimaging data. Preliminary neuroimaging of concussed athletes indicates that some brain regions show reduced function while others show increased function, despite recovery of cognitive performance and return to play.

5. Somatosensory processing: assessing youth sport-related concussion and recovery
   Research suggests that the somatosensory system may be affected by brain injury. Stacy Suskauer, M.D., from Kennedy Krieger Institute, and her team are investigating whether somatosensory system information processing (SSIP) can be used as a biomarker for concussion and recovery in youth 13-17 years old. By using a portable device that delivers vibrations to the fingertips, the investigators will test their perception of vibrations and associated activity of sensory neurons in the brain. The study also aims to assess the neurological basis of SSIP in youth with sports-related concussion through evaluation of concentration of GABA and glutamate in primary sensorimotor cortex.

6. Characterization of the brain and serum metabolome in mouse models of concussion
   Studies have suggested that head injury may change levels of various brain byproducts - known as the brain metabolome - but this has not been investigated systematically. Michael Whalen, M.D., at Massachusetts General Hospital and his team have developed a mouse model of TBI to conduct a detailed analysis of changes in the brain metabolome following concussion. They aim to study the relationship between cerebral blood flow derangements and functional outcome, and compare those differences with serum byproducts. This study may determine whether there is a difference between concussion and contusion, if there is a safe rest interval between concussions that mitigates the development of cognitive deficits. Preliminary results indicate that the safe rest interval depends on injury severity, and results of this project may uncover metabolites that contribute to serious effects of TBI and may help identify potential targets for detecting and treating concussions.

Future Directions for SHRP

The stakeholders meeting stimulated a great deal of discussion about the high quality science being done by the SHRP program and what remains missing from the portfolio.

• How common is the CTE pathology?
• What are the relationships between TBI and CTE?  
• Could non-specialists be trained to screen autopsy brain banks with subsequent confirmation by neuropathologists to better understand prevalence of CTE?  
• Should a next step include enlisting medical examiners to collect brain tissue from individuals who die with a history suggestive of exposure to repeated concussion?
• Can the techniques now in use to follow outcomes in college athletes with concussion be modified for use in children?
• What kinds of questions apply when evaluating school aged children for consequences of concussion (e.g., performance in school, behavioral issues, etc.)?
• Does concussion adversely affect neurodevelopment in children?
• What neural substrates underlie adverse late outcomes in TBI?
• What is the validity of these multiple measurements to assess concussion, and how do these translate into clinical significance? Do they have predictive value?
• How can clinicians effectively intervene acutely post-concussion to attenuate longer-term consequences?
• Can educational models be designed to inform the broad spectrum of caregivers- from trainers to parents to physicians?