According to the CDC, every year approximately 1.7 million Americans suffer a traumatic brain injury, or TBI. TBI can be caused by a blunt bump or jolt to the head, or by a penetrating injury. The severity of a TBI may range from “mild,” i.e., a brief change in mental status or consciousness to “severe,” i.e., an extended period of unconsciousness or amnesia after the injury. The majority of TBIs that occur each year are concussions or other forms of mild TBI. Traumatic brain injury remains a mystery both in terms of diagnosis and treatment. In 2006, Joseph Giacino, director of rehabilitation neuropsychology at Spaulding Rehabilitation Hospital, said on PBS’s Charlie Rose program that “There’s not a single proven treatment for traumatic brain injury at present.” This fact may stem from the rapid time course of TBI sequelae and the need to intervene quickly to prevent irreversible injury or death. Now, as mechanisms for TBI become elucidated, some researchers are translating those to ideas for novel treatments.
Dr. Michael Whalen, HMS associate professor of pediatrics at Massachusetts General Hospital, is one of those researchers. Whalen has drawn upon previous research on therapeutic effects of infrared light to devise neuroprotective “helmets” in animal models. We had a chance to speak with Dr. Whalen about his research.
Ravi Parikh, Medgadget: Can you give us a bit of your background? Why motivated you to study TBI?
Dr. Michael Whalen: I am a pediatric intensivist who trained at Childrens Hospital Pittsburgh under the mentorship of Dr. Patrick Kochanek. I joined his laboratory knowing nothing about TBI, but his enthusiasm for the subject was infectious and I developed a long standing interest in experimental TBI and in clinical management of TBI.
Medgadget: Can you give us some background into how we treat and prevent traumatic brain injury currently? What are the challenges with management of TBI?
Whalen: TBI is prevented by wearing safety belts and avoiding texting while driving… and perhaps to some degree by wearing football helmets, however these do not protect against concussion very well.
Management of TBI is supportive, meaning we use a number of therapies and devices (mechanical ventilators, intravenous infusion pumps, intracranial pressure monitors, etc.) to maintain physiological homeostasis. Therapy is directed towards reducing intracranial pressure that comes from brain swelling, and prevention of secondary brain injury that can occur in the setting of hypoxemia, hypotension, fever, seizures, etc.
Medgadget: Tell us more about your development of membrane “resealing agents” to restore the blood brain barrier after injury.
Whalen: We serendipidously discovered that Kollidon VA64, a polymer commonly used as a binding agent in pills and medicinal products, reseals injured cell membranes when injected intravenously in mice following an experimental TBI. When VA64 is mixed with Evans blue dye (a marker for BBB damage), very little Evans blue traverses the BBB in the injured brain- for up to 24 h. These findings suggest that VA64 may have protective properties that involve blood brain barrier repair, but more work is needed to confirm these findings using alternative methods to assess BBB damage. Interestingly, VA64 reduces brain edema (swelling) independent of effects on BBB and cell resealing in another brain injury model, suggesting that VA64 acts via a number of different mechanisms that may or may not require membrane resealing.
Medgadget: Another area of interest for you is the role of infrared light in treatment of TBI. Do you have an idea of the mechanism for this? What stage are you in investigating and applying this potential therapy?
Whalen: It is actually near-infrared therapy that we are testing. There are many mechanisms by which near infrared light therapy may improve cognitive function as has been shown by us in TBI models and others in Alzheimers disease models- these mechanisms include modulation of the brain’s inflammatory response, ATP generation, oxygen radical signaling, and others including possibly neurogenesis. We are in preclinical testing stages in mouse TBI models trying to determine optimal dose parameters to best inform clinical trials that are ongoing in Boston.
Medgadget: You are unique in, as both a clinician and researcher, you often witness the very illness you try to treat. Where are we in developing reasonable interventions in the field for treating TBI?
Whalen: Clinical trials aimed at improving outcomes after TBI have failed for a number of reasons, including heterogeneity of TBI as a disease process and lack of rigorous preclinical drug testing prior to inclusion in human trials. Nonetheless, laboratories around the world make potentially translatable discoveries every month, and I am confident that some will translate in the field.
Medgadget: Any last thoughts about the future of TBI management?
Whalen: I believe that it will take a combined effort across multiple disciplines to provide a better understanding of the pathophysiological mechanisms of TBI before we start to realize significant treatment advances. Moreover, TBI is a heteroenous disease- blast injury differs from concussion which differs from contusion injury- the mechansims differ and treatments that work for one subtype may not work, or may actually worsen outcome, in another. Also, funding is very tight right now, so many good ideas remain untested. Hopefully this will change over time and investigators will have more resources to find treatments for TBI.
This is the first of a series of interviews with TBI researchers and specialists. We hope that these interviews give insight into how medical technology can be used to solve one of medicine’s most intractable issues.
Check out a press release featuring Dr. Whalen’s and others work into TBI: Looking into the Matter