Michael J. Whalen, MD
Within seconds of impact Ali, age seventeen, is ejected through the car windshield. Her skull is fractured, subdural and epidural bleeding has occurred and her brain has already begun to swell. Her cerebral blood flow is deranged, and rotational and accelerational forces have caused axonal and neuronal damage in her brain. She nearly dies from increased intracranial pressure. Ischemic damage sets in and brain cells begin to die. Ali is comatose. Unbelievably, the detriment is just starting to unfold. The progression of the physiologic and neurologic effects after traumatic brain injury will reveal themselves days, weeks, even months to years after the accident. And the ambulance hasn’t even arrived yet to take Ali to MassGeneral Hospital for Children. Ali’s long-term prognosis is unknown at this point. If she’s lucky, much of her cognitive and motor function will be restored after an amalgamation of therapies—hypothermia to reduce brain swelling, a decompressive craniectomy to relieve the pressure on her brain, drug intervention, rest and time. After months of recovery and strenuous and emotionally draining rehabilitation, she won’t ever be the same person again.
Traumatic brain injury affects the motor, cognitive and mood centers in the brain. What has become clear even in recent years is that genetics plays a significant role in recovery from brain injury and may influence the development of Alzheimer’s and other neuro-degenerative diseases in brain injured patients. For now, clinicians can offer patients supportive care in the Intensive Care Unit. That includes manipulating blood pressure, blood carbon dioxide, and body temperature to optimize brain blood flow and reduce brain swelling, as well as other pharmacologic agents that treat the symptoms of brain injury. Yet families and loved ones must still wait to learn the patient’s outcome. “After four decades of research we still don’t have a treatment protocol to improve neurologic function after traumatic brain injury,” says Dr. Michael Whalen. “We can only tell families that we won’t know the outcome for weeks or even months and that we can only wait and hope for the best. It’s just not good enough.”
It is the goal of Dr. Whalen and his research team in the Neuroscience Center at Massachusetts General Hospital that at a molecular level, they will discover the biochemical picture that unfolds during the acute phase of injury, and over time to ultimately develop a standardized treatment to benefit all patients with traumatic brain injury. “Some patients do well after injury and some don’t,” he says. “We need to understand why so we can help develop an effective therapy and generate a positive long-term outcome for all patients.”
Dr. Whalen is principal investigator of a National Institutes of Health funded research study to understand the mechanisms that initiate cell death and motor and cognitive impairment after traumatic brain injury. Dr. Whalen’s team is targeting a family of transmembrane proteins called tumor necrosis factor receptors (TNFR) in an immature mouse model of traumatic brain injury; the mice are the age-equivalent of two-year-old humans. Dr. Whalen’s group employs recombinant DNA technology to “knock-out” various TNFR genes to determine their function in injury and recovery, particularly with respect to motor and cognitive deficits. TNFR gene products are targeted in the research because they are responsible for cell death, gene expression and secondary signaling. They’re also linked to neurotransmitters that are responsible for cognition and other fundamental brain functions.
“Preliminary research results suggest that TNFR signaling may influence histopathologic damage and motor and cognitive dysfunction after traumatic brain injury,” says Dr. Whalen. “We know that neurological dysfunction occurs over time after an injury. It has become clear that in the experimental realm, with neuroprotective therapies we can limit tissue loss and improve learning and memory as well as motor function.” In short, if the function of targeted genes are modified in injured immature mice models, there are beneficial effects on cognition that last into adulthood. “We hope our work with mouse models will translate into effective therapy for patients that will confer lasting benefits into adulthood,” he says.
Key insights hold promise
Over the years the scientific community has overturned previously accepted theories about what happens during traumatic brain injury. “We know now that the breakage of axons, which serve as cables that connect neurons to muscles in the rest of the body, does not necessarily occur immediately after injury. Instead, traumatic brain injury initiates biochemical cascades that lead to the breakdown of these axon cables over hours, days, and even months.” In addition, initial belief that brain swelling after trauma was a result of the breakage of the blood brain barrier and extracellular fluid accumulation is now understood to be an intra-cellular process, much like what happens during ischemia.
Dr. Whalen is encouraged by recent findings from his group and believes that successful treatment will be a convergence of proven therapies, a finely tuned and appropriately timed intervention system that may begin to be employed in the field by emergency personnel, much like a defibrillator is now for persons experiencing heart attacks. He envisions the discovery of a treatment that serves as a standard practice protocol in brain centers across the country to minimize cell death and motor and cognitive dysfunction in children and adults.
His research is very promising, although Dr. Whalen is mindful of the caveats that exist when applying laboratory research to humans. After all, the human brain is quite complex. What the team does discover may apply to humans, but it may not be the only answer. “In the next five to ten years we hope to have surgical treatments that are aggressive and aimed at the pathophysiology of brain trauma,” he says. “I’d also like to see an emergence of pharmacological therapy that is beneficial. In addition, we also need advances in technology to monitor patients at the bedside. We know we can do more for these patients and our research findings so far are a step forward in determining what that is.”
After five weeks in the ICU, Ali is discharged to an inpatient floor with the involuntary use of one arm. She is transferred to a rehabilitation institute and over time regains use of gross motor skills. One day she could name the president of the United States. Eventually, her fine motor skills resumed and she started playing the piano and writing again. While she still experiences some motor deficits, she has more profound cognitive effects, such as memory loss, headaches and depression. Ali is one of the lucky ones. Today she’s a teacher’s aide in Tiverton, Rhode Island and hopes to continue her education when she feels ready.
Michael J. Whalen, MD, PhD, is assistant professor of Pediatric Critical Care Medicine at Harvard Medical School and MassGeneral Hospital for Children. Dr. Whalen is an established investigator whose studies are focused on the role of inflammation in the pathogenesis of traumatic brain injury. Dr. Whalen is the recipient of a Charles Hood Foundation Research Grant, an NINDS mentored physician scientist grant, and an NIH RO1 grant to study the role of tumor necrosis factor receptors in mouse traumatic brain injury models. Dr. Whalen has authored over fifty abstracts, manuscripts, and book chapters in the field of brain injury, and is the recipient of a number of research awards from the National Neurotrauma Society and Society of Critical Care Medicine.
