Fletcher White, PhD, once called himself an "aficionado of all things mice."
As the Vergil K. Stoelting Professor of Anesthesia at the Indiana University School of Medicine, White has dedicated his more than three-decade career to understanding chronic pain. And while his studies often use animal models, his approach to research has evolved to blend what he’s investigating in the laboratory to the experiences of patients in the hospital.
"I like being able to look at clinically relevant information and modeling those attributes back at the bench with an eye on potentially bringing solutions back to the bedside," White said.
March is National Brain Injury Awareness Month, and approximately 2.5 million people sustain a traumatic brain injury each year in the United States, according to the U.S. Centers for Disease Control and Prevention. Nearly three-quarters of these injuries are classified as mild.
Post-traumatic headaches are one of the most common and persistent symptoms that occur within a week after a traumatic brain injury. Symptoms may include throbbing pain, fatigue, dizziness and memory issues. Between 30% and 90% of people with mild traumatic brain injuries develop post-traumatic headaches, and these headaches can result in chronic pain.
White, a primary member of Stark Neurosciences Research Institute, led a longitudinal clinical study investigating how non-migraine headaches develop in patients who have a history of mild traumatic brain injuries. The study, funded through the U.S. Department of Defense, followed nearly 50 patients who came to emergency departments of level 1 trauma centers in Indianapolis with a mild traumatic brain injury.
Patients who met the criteria for the study were followed for three visits over the course of four to six months at the IU Health Neuroscience Center. During each visit, individuals filled out questionnaires, were tested for pain level responses and donated small amounts of blood.
Most subjects felt some level of head pain during their first visit, about one or two weeks after their stay in the emergency department. But for some patients, White said, the head pain continued to linger over the next two visits and eventually developed into chronic pain.
The research team, also comprised of Tyler Nguyen, PhD, assistant research professor of anesthesia, and Kelly Naugle, PhD, associate professor of kinesiology at the IU Indianapolis School of Health & Human Sciences, worked with Takashi Hato, MD, the Gilman-Brater Scholar in Nephrology, to better understand the context of pain associated with mild traumatic brain injury. Hato used RNA sequencing to analyze patient blood samples and show changes in gene expression over time.
Using this data, White said the research team could look back at the blood analysis and see what genetic changes may have occurred between visits.
"Having collected blood across all three visits," White said, "we were able to start to ask, if at six months a subject has chronic head pain, what biomarkers were evident at the first or second visit, which might be predictive of the subject’s condition."
The team identified several genes, but one promising target, a gene called NOD2, saw an increase in gene expression for study patients with post-traumatic head pain at both visit one and visit three. The gene is associated with an inflammasome complex, White said, which is integral for a cascade of immune system responses, including chronic inflammation.
"It turns out that this sort of chronic inflammation in our patients appears to be an important linchpin," he said.
White said his team has modeled the injury and immune system response in an animal model that's genetically engineered to use a bioluminescent signal to monitor enzymes and behavior.
"If we interrupt this bioluminescent signal at early time points post injury, do we improve otherwise poor outcomes? I think from the standpoint of what we see clinically, but also in the animals, that's a pretty useful thing to go after, especially with brain injuries," White said, adding that early detection and treatment for neurotrauma conditions is key to potentially reducing chronic pain.
White also leads preclinical and clinical studies investigating bone fracture-induced chronic pain, drugs that produce opioid-sparing strategies in chronic pain conditions and post-traumatic epilepsy after traumatic brain injury. In addition to the Department of Defense, White’s research is funded by the National Institutes of Health, the U.S. Department of Veterans Affairs and the Indiana State Department of Health.
Looking back on his academic career to date, White said it was his arrival at the IU School of Medicine in 2009 that allowed him to launch his translational clinical research of traumatic brain injury studies to model at the bench.
"My clinical inroads into this branch of neuroscience was based, in large part, on my past experiences at other medical centers in the Midwest and East Coast," White said. "But coming here to IU opened a number of vistas that are clearly unique to this institution based in large part on the enormous expertise and patient population present in the Indianapolis medical environment."
