Research to Map Brain Imaging Biomarkers

1. Challenge II: The Mechanics of Injury: Innovative Approaches For Preventing And Identifying Brain Injuries Launching in fall 2013, the NFL, Under Armour and GE will invite proposals for new materials and technologies that can protect the brain from traumatic injury and new tools for tracking head impacts in real time. Specific focus areas for this challenge include, but are not limited to: Protection against Injury * Materials or devices that can distribute the force of impact. Smart materials or active polymers that are comfortable but can adapt to sudden impacts are highly desirable * Systems to predict and initiate protective responses to prevent injury activation of adaptive padding at the focus of impact Monitoring and Identifying Injury * Systems that monitor and integrate directional and rotational impact forces. These systems should integrate information with imaging/diagnostic equipment * Sensors to provide biofeedback to modify behaviors that predispose athletes to injury * Systems that monitor biomechanical and physiological responses to detect injury * Systems to efficiently collect, interpret and organize large quantities of real-time data The winners of the challenges will be selected by a panel of external judges that include leading healthcare experts in brain research, imaging technologies, and advocates for advances in brain research. For Challenge I these individuals include: 1. Dr. William J. Heetderks is the Director of Extramural Science Programs at the National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH. 2. Dr. Walter Koroshetz is the Deputy Director of the National Institute of Neurological Disorders and Stroke (NINDS) at the NIH. Before joining NINDS, Dr. Koroshetz served as vice chair of the neurology service and director of stroke and neurointensive care services at Massachusetts General Hospital (MGH). 3. General Peter Chiarelli, USA (Ret.) is the Chief Executive Officer of One Mind for Research. He is a retired four-star General with 40 years of experience designing and implementing American defense policy for the U.S. Army and Department of Defense in peace and during combat operations. 4. Colonel Dallas Hack is the Director of the Combat Casualty Care Research Program and the Chair, Joint Program Committee 6 (Combat Casualty Care), US Army Medical Research and Materiel Command, Ft Detrick, MD, where he coordinates leading edge research focused on new techniques and products to save the lives and reduce morbidity of troops injured in the line of duty. 5. Dr. Geoff Manley is the Chief of Neurosurgery at San Francisco General Hospital and Professor of Neurosurgery at the University of California San Francisco (UCSF).

2. Research to Map Brain Imaging Biomarkers The research will take a whole brain approach to determine the key Magnetic Resonance Imaging (MRI) biomarkers for potential diagnosis, outcome prediction, and therapy management for patients with mild traumatic brain injury. The research study will be guided by an advisory board consisting of a cross-disciplinary team of medical professionals from various institutions. Among those participating: 1. Dr. Thomas McAllister is the Millennium Professor of Psychiatry and Neurology, Director of the Section of Neuropsychiatry and Vice Chair for Neuroscience Research for the Department of Psychiatry at the Geisel School of Medicine at Dartmouth. He has recently been named chair of the Department of Psychiatry and the Albert Eugene Sterne Professor of Clinical Psychiatry at Indiana University School of Medicine. He will begin his duties in the summer of 2013. 2. Dr. Richard Ellenbogen is the Theodore S. Roberts Endowed Professor and Chairman of the Department of Neurological Surgery at The University of Washington. He is Co-Director of the Seattle Concussion Program and is the co-chair of the NFL Head, Neck and Spine Committee. 3. Dr. Russell Lonser is the Chair of The Ohio State University Wexner Medical Center Department of Neurological Surgery, head of the NFL's Research Subcommittee and a member of the NFL's Head, Neck and Spine Medical Committee. 4. Dr. Geoffrey Manley is the Chief of Neurosurgery at San Francisco General Hospital and Professor of Neurosurgery at the University of California San Francisco (UCSF). 5. Dr. PratikMukherjee is an Attending Neuroradiologist and an Associate Professor of Radiology and Biomedical Imaging, Bioengineering and Therapeutic at the University of California San Francisco (UCSF). 6. Lieutenant Colonel Gerald York, is an Active Duty radiologist with a Certificate of Added Qualification (CAQ) in neuroradiology serving at Brooke Army Medical Center in Houston, TX. He has expertise in interpretation of CT and MRI of the brain, spinal cord, and head-neck disorders, including many acute, subacute and chronic traumatic brain injury patients. 7. Colonel Jamie Grimes is the National Director of the Defense and Veterans Brain Injury Center. As national director, COL Grimes oversees all aspects of the organization's mission: to serve active duty military and veterans with traumatic brain injury through state-of-the-art medical care and care coordination and through innovative clinical research and educational programs. 8. Dr. Larry Leverenz is the Clinical Professor in the Department of Health and Kinesiology and Director of Athletic Training Education at Purdue University. He has served professionally as a member of the National Athletic Trainers' Association Education Council and as president of the Commission on Accreditation of Allied Health Education Programs. Currently, he is the President of the World Federation of Athletic Training & Therapy. 9. Dr. TeenaShetty is a Neurologist at Hospital for Special Surgery and is triple board-certified in neurology, neuromuscular medicine, and electrodiagnostic medicine. 10. Dr. Brian Hainline is the Chief Medical Officer at the NCAA. He is a leading sports medicine advocate with more than two decades' experience most recently as the chief medical officer of the United States Tennis Association (USTA).

3. Open Innovation Challenge to Study and Prevent Traumatic Brain Injury In addition to the research program, the NFL is partnering with GE and Under Armour to launch the Head Health Challenge, which has two focus areas that seek new solutions for understanding mild traumatic brain injury. The organizations are pledging to find and fund ideas that accelerate solutions for brain protection. The challenge fund could invest up to $20 million. Sue Siegel, CEO of GE healthymagination, said, "GE is investing in research and development to fast-track advancement in head health. Through our research collaboration and open innovation challenge, we hope to stimulate the broader ecosystem of scientists, engineers, mathematicians, computer scientists, entrepreneurs, and innovators worldwide to bring their talents to this effort and accelerate the current understanding of brain trauma and improve diagnostic tools." Kevin Plank, founder and CEO of Under Armour said, "As longstanding partners of the NFL, we recognize the magnitude of this initiative, and the impact it will have for athletes at all levels. Under Armour was founded upon the pillar of making all athletes better through the relentless pursuit of innovation. We take great pride in supporting this effort to reward new ideas and breakthrough concepts in this space, particularly as it applies to protecting athletes and influencing positive change in sports." Dr. Geoff Manley, professor and vice-chair of the Department of Neurological Surgery at UCSF and Chief of Neurotrauma at San Francisco General Hospital, said, "Traumatic brain injury is one of the greatest unmet medical needs of our time. Every 20 seconds someone in the United States sustains a brain injury. A better understanding of the molecular, physiological, and behavioral/biomechanical changes that occur shortly after a traumatic event is needed to reliably diagnose the types of changes that are difficult to identify using current technologies." Challenge I: Methods for Diagnosis and Prognosis of Mild Traumatic Brain Injuries Starting today, GE and the NFL are inviting proposals for technologies and imaging biomarkers that address identification and management of subclinical and mild traumatic brain injury. Multiple cash awards with a cumulative total value of up to $10 million will be made, along with the possibility of future partnership and collaboration with GE. Entries are being immediately accepted at www.NFLGEBrainChallenge.com. Specific focus areas for this challenge include: * Development and validation of imaging and/or sensor based biomarkers that can aid in the diagnosis and prognosis of mild traumatic brain injury events. These include imaging biomarkers of brain structure, connectivity, function, cognition, neuroinflammation, and molecular markers. * Development of new technologies that are more sensitive to small contusions and injuries that are missed by current technologies; and assessing the long-term chronic impact of these events. * Improved algorithms for the quantification and visualization of markers of brain injury severity and longitudinal change. * Algorithms and tools that link imaging data to clinical, cognitive, and biomechanical data. * Models of individual risk and long-term prognosis and clinical decision support tools using population studies. * Robust methods for triaging acute stage events and developing "Return to Play" guidelines using physiological, molecular, electrical or physical changes in brain or body functions.

4. Proposals for Challenge II should follow these Submission Criteria: • All proposals must be 4 - 6 pages (maximum) and can optionally include 2 additional documents containing supplemental information. The entire submission cannot exceed 10MB (Proposal as well as supplementary documents). • To simplify the submission process, detailed budgets, institutional approval for human or animal studies, or similar information are not required at this time. Optional information will be required only for proposals selected for Awards. • Cover Letters and links to supplemental material such as videos, manuscripts, patents or brochures will not be counted against the 6 page / 10MB limit. • No review of Proposals will begin before the January 30, 2014 submission deadline. • Proposals for Challenge II will be assessed using the following Assessment Criteria: • Potential to improve the Prevention and Identification of Brain Injuries: The proposed technology must demonstrate clear potential to quantify head impact in real time; detect, track or monitor biologic or physiological indicators of traumatic brain injury; protect the brain from traumatic injury; mitigate or prevent short or long-term consequences of brain trauma; and assist in training to prevent traumatic brain injury. • General Criteria to be included in all submitted proposals: • Case studies showing performance data and accuracy results on other applications • High-level description of the benefits, methods, and techniques • Description of ongoing research/development • Proposed program plan on how they will apply the technology to this topic • Relevant background on the team / organization / lab submitting the response • Technologies that can demonstrate commercial viability within 1 - 2 years are preferred. However, game changing technologies will be strongly considered if good progress towards commercial viability and utility can be shown within 1 - 2 years • Monitoring and Identifying Trauma: The proposals must provide clear potential to advance current practices in measuring and detecting injury and head impact exposures, including non-linear impacts. These technologies include but are not limited to: • Monitoring and integration of directional and rotational impact force into data • Monitoring biomechanical, biologic, or physiological responses to detect injury & quantify head impact exposures • Efficiently collecting, interpreting and organizing real-time data • Can be used on the sidelines as first indicators of presence or absence of brain trauma • Can track over time the value of interventions to prevent or mitigate injury • Can identify dangerous play-types to guide sports organizations toward improved playing rules • Protection Against Injury or its Consequences: Technologies that can improve the level of protection offered against head impacts. These proposals may involve materials, protective systems and equipment that include, but are not limited to the following: • Materials or devices that can absorb, distribute and/or dissipate the force of impact. These include smart or active materials • Polymers that are comfortable but can adapt to sudden impacts • Equipment that reduces the force of direct impact transmitted to the brain (e.g. transfer load distribution to torso/lower body) • Equipment to control axial rotation of the head • Novel uniforms and protective padding systems to dissipate excessive force • Improve effective mass by linking the head and neck as a total system to reduce head acceleration and minimize the mechanical effect on the brain • Training: In addition to protection against and monitoring of brain injury, proposals could include training athletes and others to protect themselves from brain injury. Ideas could include: • Sensors that provide biofeedback to modify behaviors that predispose athletes to injury or its consequences • Improved training methods that reduce tissue and brain damage such as: • Novel conditioning regimens • Neck isolation and strengthening protocols • Timeframe: Technologies that can demonstrate commercial viability within 1 - 2 years are preferred. However, high impact or game-changing technologies will be strongly considered if good progress towards commercial viability can be shown within 1 - 2 years. • - See more at: http://www.ninesights.com/community/nfl-ge-grand-challenge/process#/criteria

5. Neck Strength Linked to Concussion Risk A pilot study conducted at the Colorado School of Public Health found that overall neck strength is a statistically significant predictor of concussion risk. The study found that for every one-pound increase in neck strength, concussion risk fell by 5 percent. Researcher Dawn Comstock has submitted this study for peer-review. AAN Concussion Guidelines Updates In March 2013, the American Academy of Neurology (AAN) released an update to their 1997 guidelines for evaluating and managing athletes with concussion. Return-to-play guidelines were specifically cited among the important guidelines issued by AAN, with a recommendation that athletes with suspected concussion be immediately removed from play and not returned until they are evaluated by a licensed health care professional trained in concussions. • Challenges and Key Questions: • Brains studied to date have come from a narrow population of mostly professional athletes, resulting in a lack of data regarding the frequency of CTE. What are the population prevalence and incidence of CTE, and are there genetic susceptibilities to CTE? • A large study of many persons who were exposed to repetitive head injury but have died for other reasons would expand knowledge of CTE. What is the best way to recruit brain donors with histories of repeated head injury while ensuring standard protocols for harvesting and preserving tissue samples are followed? • What is the number of impacts to the head and the related magnitude that cause CTE? • Current imaging technology is a major challenge in understanding CTE as the pathology can only be observed through post-mortem examination and cannot currently be detected through traditional MRI or PET scans. How can CTE be diagnosed in living people? • What neuroimaging tools and biomarkers show promise in diagnosing CTE and providing information about the disease processes and progression? • ICCS Key Findings: • The science of concussion is constantly evolving. • Return-to-play (RTP) decisions remain in the realm of clinical judgment on an individual basis; there is no standard to follow beyond not allowing RTP on the day of the injury. • Physical and cognitive rest is key to recovery. • A progressive RTP protocol is recommended, with athletes advancing once they are asymptomatic at their current level. • Children may take longer to recover than adults, and should not return to sports until they have successfully returned to school; in general, a conservative and cautious approach is recommended with concussion management for children. • Pre-participation physicals allow for the collection of a detailed concussion history, which may help identify athletes who fit into a high-risk category and provide an opportunity to educate all athletes on concussion risk. • A cause-and-effect relationship between CTE and concussions or exposure to contact sports has not yet been demonstrated, and the interpretation of causation in CTE case studies should proceed cautiously. • Current science does not show current protective equipment will prevent concussion. • Athletes, referees, administrators, parents, coaches and health care providers need to be educated about the serious nature of concussions, as well as concussion identification, management and return to play.

6. Collaborative Research on Chronic Traumatic Encephalopathy and Delayed Effects of Traumatic Brain Injury: Neuropathology and Neuroimaging Correlation Grants will be used to fund comprehensive studies of the effects of TBI in individuals exposed to repetitive head injury, as well as individuals who have died after repetitive TBI. One goal of this research will be to develop diagnostic tests that can be used in the general population. This SHRP research initiative will investigate the neuropathology of CTE and the delayed effects of TBI. As part of this effort, grants will be used to support a multi-center team of neuropathologists, neurologists, neuroradiologists and other scientific experts to increase our understanding of CTE and other delayed effects of physical trauma to the brain, as well as the development of improved diagnostic tools that can be used in the general population. Comprehensive studies of the effects of TBI in individuals exposed to repetitive head injury, as well as individuals who have died after repetitive TBI, will be conducted. Its main areas of research include: • Developing a better understanding of how commonly CTE occurs in those exposed to a variety of head injuries. • Development of neuroimaging or other tools that can diagnose the condition in living people, and can inform the relationship between clinical signs, symptoms and risk factors for post-traumatic neurodegeneration and CTE. • Comparisons between repetitive traumatic events and single events. • Characterizing the relationship of CTE with other neurodegenerative disorders such as Amyotrophic Lateral Sclerosis and Alzheimer’s disease. In addition, this research aims to establish a brain-donor program that will link high-quality behavioral information with neuropathology from an unbiased sample and distribute biospecimens and other relevant information to qualified investigators, thereby promoting data and tissue sharing to maximize the value of the brain donation. Pilot Projects on Sports-Related Brain and Spinal Cord Injury The second research initiative includes two funding opportunities – one for exploratory, novel studies and another funding opportunity for pilot or feasibility studies. This initiative will support pilot projects on sportsrelated TBI and spinal cord injury and explore new research directions to address the many gaps in knowledge that exist about these conditions. The program will provide support through small grants and larger exploratory/developmental grants for research on such topics as: Mechanical and biological mechanisms of injury and recovery. • Genetic and environmental risk factors. • Development of age-appropriate diagnostics and equipment for prevention. • Ways that pain medications, psychiatric medications and other substances may interact with the effects of trauma. • Preclinical therapy • development for improving outcomes.