Concussion and CNS Injuries
Translational Research for Concussion and Other CNS Injuries
Novel pre-clinical research at the University of Maryland is revolutionizing the medical community’s understanding of mechanisms involved in brain and spinal cord injuries, and is leading to more meaningful clinical trials and the development of promising treatments in traumatic brain injury. The source of these advancements is a facility unique in the United States — the Shock, Trauma and Anesthesiology Research (STAR) Organized Research Center (ORC), directed by Alan I. Faden, M.D., the David S. Brown Professor in Trauma and professor of anesthesiology at the University of Maryland School of Medicine. STAR-ORC also comprises the R Adams Cowley Shock Trauma Center (where clinical research is conducted); the Charles “McC.” Mathias, Jr., National Study Center for Trauma and Emergency Medical Systems, established by Congress in 1986; and the basic science and clinical research activities in the Department of Anesthesiology.
Use of diffusion tensor imaging, experimental concussion models
Concussion is now known to occur more often than once thought. This new awareness is due in part to a revised definition in which loss of consciousness is not required; such symptoms as impaired balance, confusion or headache following head injury are sufficient to consider the diagnosis. Also contributing to increased awareness are highly publicized accounts of concussive injuries in both professional and scholastic sports venues and blast injuries suffered by military personnel in the Iraq and Afghan wars.
Concussion is a complex condition that traditional clinical and cognitive measures cannot fully illuminate. Concussive injury can induce inflammatory processes and functional changes in the brain that persist even after a patient’s symptoms have resolved. Dr. Faden’s lab, which has been studying traumatic brain injury since 1985 with continuous federal funding, is using both in vivo and in vitro modeling to elucidate the pathophysiologic processes underlying concussion/brain trauma and potential treatments to improve patient outcomes.
Why clinical evaluation is not enough. Most patients with concussion become symptom-free within a few weeks, though neurocognitive deficits can linger. And even when cognitive function is normal by customary standards, sophisticated imaging technology can reveal abnormal changes in the brain. In athletes, abnormal patterns discovered on functional magnetic resonance imaging (fMRI) have proven predictive of delayed recovery from concussion. Resting fMRI sometimes shows abnormalities in the most vulnerable section of the brain —the limbic system, which includes the frontal and temporal lobes and hippocampus. Even if a resting fMRI shows no anomalies, repeating the scan after the patient has exercised may uncover aberrations.
Diffusion tensor imaging may show abnormalities in brain connections. Measuring subtle changes in magnetic activity of the brain using magnetoencephalography can also map brain connection changes that indicate brain dysfunction. Revealingly, positron emission tomography has shown that patients with clinically severe injury and those with mild injury can have very similar imaging abnormalities, suggesting that so-called “mild” traumatic brain injury may be a misnomer.
The clinical implications of thorough evaluation are profound. “When the brain has not recovered sufficiently,” advises Dr. Faden, “the brain is more susceptible to a second injury if a patient returns to sports activity; such second-impact in the injured brain can be especially devastating for the very young, with some reported deaths from severe brain swelling. We are modeling single and repeated concussive injuries in the lab — using imaging, other physiological variables and measurements of brain chemistry — in order to identify mechanisms that make the brain more susceptible to repeated injury and to suggest future directions for management and treatment.”
Realizing the proper role of exercise in recovery of function. The Veterans Administration has provided a grant to STAR-ORC for basic research that promises to change the approach to brain trauma. In animal models, delayed exercise initiation beginning five weeks after brain trauma markedly reduced chronic inflammation in the brain and strongly improved cognitive recovery; in contrast, early exercise initiation beginning at one week after injury actually increased inflammation and failed to improve outcomes. This is an intervention that can be performed months following the initial trauma to improve recovery — a tactic not part of current conventional practice. Exercise can stimulate the brain’s most potent growth factors and inhibits factors that contribute to inflammation and brain cell loss, but such effects are clearly “time linked.” With more severe experimental injury in particular, early exercise may interfere with behavioral recovery, whereas delayed intervention can boost neurogenesis.
There are other avenues of inquiry as well. Many patients with concussion will experience a change in their sleep pattern. Such sleep abnormalities may contribute to cognitive difficulties in these patients. Is it possible that patients whose sleep patterns are controlled with medication from day one will recover more rapidly than those left untreated? Faden’s group is actively investigating this question in experimental concussion models. Vascular migraine-like headache is also a frequent consequence of concussion. Another important clinical research question is whether early aggressive preventative headache management following concussion accelerates recovery.
Expanding our reach among undertreated patient populations. Most clinical studies of concussion in young adults have involved athletes between 18 and 25 years of age. In 2011, Shock Trauma treated 1,650 patients with “mild” traumatic brain injury. As previously reported by Pat Dischinger and colleagues, this population is older than that for studies of athletes, with an average age of 35 years. Brain response to injury worsens dramatically with aging, with 40 being considered “older” in this context. More than 40% of these patients exhibited a full post-concussion syndrome at three months. Among women in this group, the proportion was greater than 50%. Symptoms can be subtle, and in most environments, these patients are not treated. The STAR-ORC is developing a multidisciplinary clinical and research team that can comprehensively evaluate and treat such patients, as well as high school and college athletes.
In 2011, Maryland’s Governor O’Malley signed into law legislation designed to protect youths 19 years and younger who have suspected concussion. In part, the law requires that a patient be withheld from further sports activity until a clinician licensed in the evaluation and care of concussion clears the youth to return to play. The Center expects to receive a large number of referrals from across the state through local programs, and hopes to redefine what constitutes a thorough evaluation.
The University’s Emergency Medicine Department is another large potential referral source for patients with mild traumatic brain injury. They direct 16 emergency departments around the state, which may include an estimated 9,000 concussions during the year.
Additional brain trauma research efforts at STAR-ORC
Addressing concussion in the elderly. The incidence of concussion among the elderly is increasing faster than in any other age segment, and these patients have worse outcomes. Supported by NIH grants, Dr. David Loane and others at the STAR-ORC have been examining the mechanisms that contribute to impaired recovery in aged animals. STAR is also co-developing with the Department of Epidemiology and Public Health and other groups a joint Program in Aging, Trauma and Emergency Care (PATEC) — with more than 40 participating faculty members from every school on the University of Maryland, Baltimore campus, as well as from the UMCP and UMBC campuses. These include those in trauma care, geriatrics, epidemiology and public health.
Making airlift evacuation safer. There is anecdotal evidence that trauma patients can suffer further injury hours or days later due to inadequate pressure control during airlift, thereby reducing oxygen tension. The U.S. Air Force has provided a grant to Dr. Gary Fiskum, a professor of anesthesiology, for animal model investigation of this issue. In true translational research going from clinical question to animal model, STAR-ORC uses a modified
hyperbaric chamber to simulate air flight and examine its effect on outcome and brain injury mechanisms using both classical and novel blast injury models.
Reducing pain in spinal cord injury. Intractable pain is experienced by 67% to 80% of patients with spinal cord injury. The Center, including Drs. Faden and Junfang Wu, has initiated two collaborative programs — with the School of Nursing (Drs. Susan Dorsey and Cynthia Renn), using transgenic mouse models; and with Dr. Asaf Keller from the Department of Anatomy and Neurobiology in the School of Medicine, using a rat model — to study mechanisms of spinal cord injury induced pain and its treatment.
Real-time outcomes prediction. The Center has been developing advanced analytical methods to predict outcomes in real time in critical care settings. Drs. Thomas Scalea, Deborah Stein and Colin Mackenzie have worked with Peter Hu, as well as colleagues at UMBC, to improve analytic predictions in the critical care setting. Separately, STAR-ORC faculty have been working with the applied mathematician Dr. Larry Goldstein, in collaboration with Microsoft® Research, to devise and apply a new methodology for analyzing streaming data in real time for application to critical care.
The Sports Medicine Program through the Department of Family Medicine offers sports-related concussion diagnosis and post-concussion “back to play” assessments. To refer a patient for a concussion assessment, please call 410-328-5751.
This page was last updated: November 4, 2013