U.S. Department of Defense awards UB physicians $4.8 million to launch non-drug, clinical trial on concussion treatment for the military

BUFFALO, N.Y. – The University at Buffalo researchers who have changed the way concussions are treated have been awarded $4.8 million from the U.S. Department of Defense to conduct a clinical trial to evaluate whether incorporating elements from the Buffalo Concussion Protocol to the DOD’s current concussion protocol would improve outcomes for active members of the military who sustain a concussion.

John Leddy, MD, clinical professor of orthopaedics and director of the UB Concussion Management Clinic, and Barry Willer, PhD, professor of psychiatry and research director of the clinic, both of the Jacobs School of Medicine and Biomedical Sciences at UB, are principal investigators on the grant, “Exercise Reset for Concussion—Modifying the Buffalo Concussion Protocol for Application in a Military Environment.” The four-year grant is being awarded from the Traumatic Brain Injury and Psychological Health Research Program as part of the Congressionally Directed Medical Research Programs.

“The CDMRP’s Traumatic Brain Injury and Psychological Health Research Program meets congressional intent by funding research to optimize the understanding, prevention, assessment, and treatment of psychological health conditions and/or traumatic brain injuries for the benefit of our service members, veterans, DOD beneficiaries, and the American public,” said Dwayne Taliaferro, PhD, program manager of the TBIPHRP.  “The research to be performed by Dr. Leddy and his team is timely, highly relevant, and will generate evidence-based knowledge to support implementation by providers within the Military Health System.  We look forward to their progress.”

“Clinical trials are essential to advancing medical breakthroughs,” said Allison Brashear, MD, vice president for health sciences and dean of the Jacobs School. “Our researchers are especially honored and humbled to be conducting this clinical trial because it gives them a rare and meaningful opportunity to improve outcomes for those serving our country. 

“This award is another example of the federal government’s recognition of UB’s groundbreaking research that addresses the most critical issues we face as a country,” she said. “I want to particularly thank Senators Schumer and Gillibrand, and Congressman Brian Higgins, for this important funding and recognition.”

Evidence-based treatment

“Our Buffalo Protocol is the only evidence-based treatment to safely speed concussion recovery with athletes,” said Leddy, who sees patients through UBMD Orthopaedics and Sports Medicine. “This grant will allow us to take our protocol, which we personalize for each individual, and apply it to the military environment. We expect to show that personalized aerobic exercise soon after a concussion safely improves recovery and speeds return to duty in military service members,” he said.

If successful, the assessment and intervention will safely promote sustained functional recovery after a concussion and will be of use in rural or other resource-limited environments.

Leddy and Willer have pioneered individualized, low-level exercise to help concussed athletes recover. Clinical trials they conducted have proven that daily sub-symptom threshold aerobic exercise — meaning exercise that doesn’t exacerbate symptoms -- significantly reduces the risk of prolonged recovery after a concussion.

This non-drug approach has gained wide acceptance nationally and internationally and was responsible for the elimination of the post-concussion recommendation for prolonged periods of rest in the 2017 Concussion in Sport Group statement, which guides the standard of care for concussed athletes. While the researchers note that rest is critical immediately after a concussion, prolonged rest has not proven to be beneficial.

“In our studies of adolescent athletes, we discovered that structured exercise didn’t exacerbate symptoms, it reduced time to recovery by 40% and significantly reduced the rate of delayed recovery after a concussion,” said Willer.

Currently, Progressive Return to Activity (PRA), which Willer and Leddy played a lead role in helping to develop, is the protocol for active service members who sustain a concussion.

“Progressive Return to Activity gets individuals up and about after a concussion with stepwise activity so it’s more structured and standardized than previous return to duty protocols,” said Leddy. “DOD’s current protocol for PRA does not, however, include sub-threshold aerobic exercise.

“For each participant, we will develop their own individualized exercise threshold to work through,” said Leddy, “and we will make it a little more challenging every few days. We are conducting this randomized clinical trial to see if adding our Buffalo Concussion Protocol to the current DOD protocol helps expedite post-concussion recovery.”

The UB study will recruit a total of 160 service members in the U.S. Marines from Camp Lejeune and the U.S. Army stationed at Fort Bragg who have experienced a concussion. Half will receive the standard care consisting of the military’s Progressive Return to Activity protocol and half will receive the standard care plus the modified Buffalo Concussion Protocol.

Promising pilot study

The clinical trial builds on a small UB pilot study that the DoD funded over the past two years. The referenced grant was funded in the amount of $200,000 under the Award No. PT180084 through the Psychological Health and Traumatic Brain Injury Research Program, the legacy program of the Traumatic Brain Injury and Psychological Health Research Program, both managed by the Congressionally Directed Medical Research Programs.

While only 8 participants of the original group of 15 were able to complete the study due to unexpected deployments, the small group demonstrated positive outcomes.

“Those who completed it had a significant reduction in time to recovery,” said Leddy. “Of the 8 who completed it, only one person had delayed recovery of more than a month.”

That’s significant because past research has found that the rate of delayed recovery after concussion, meaning symptoms lasting longer than 28 days, is significantly higher among active service members than in other groups that have been studied.

“We learned that approximately sixty percent of members of the military who have a concussion end up qualifying as having delayed recovery,” said Willer. “That’s a high rate, compared to what we’ve seen with untreated adolescent athletes, where the delayed recovery rate is about 30%. The ill effects of delayed recovery are even more pronounced among service members. A delayed recovery for a service member could prevent or interfere with return to active duty or deployment.  We want to see how much we can reduce that delayed recovery rate with the Buffalo Concussion Protocol.”

Service members, who are naturally concerned with staying in excellent physical shape, saw the use of aerobic exercise in their treatment as extremely advantageous.

Exercise intolerance after concussion

The premise of the Buffalo Concussion Protocol is that people who have had a recent concussion experience exercise intolerance.

“If you put someone who recently had a concussion on a treadmill, they will not be able to reach their target heart rate without significantly exacerbating their concussion symptoms,” said Leddy.

Leddy and Willer have found that prescribing an individualized program of progressive sub-symptom threshold exercise as a treatment within the first week or two after a concussion can expedite full recovery.

In previous studies, the researchers used a treadmill test to evaluate people with concussions; in the current study, realizing that service members on base or in the field may not have access to a treadmill, they developed a “March in Place” test, which evaluates at what point exercise exacerbates symptoms more than mildly.

Leddy and Willer used the pilot grant they received to validate the March in Place test with service members and non-concussed controls.

The goal is to have the individual engage in daily sub-symptom aerobic exercise and to gradually increase intensity as more vigorous activity is tolerated. The March in Place test allows the service members to assess their own progress, at home or in the field.

“We are also trying to answer the question, ‘why does exercise work’ in treating concussion?” said Willer.

Exercise and the autonomic nervous system

Part of the answer may lie in the ability of exercise to improve control of the autonomic nervous system (ANS), which is responsible for involuntary neural processes throughout the body and which can be affected by concussion.

The researchers will recruit a smaller group (84) of healthy controls to study normal physiological measures, such as vision and heart rate as well as baseline data on how the ANS functions.

Valuable information may lie in the presence of concussion biomarkers in the saliva. Participants who have had a concussion will provide saliva samples before and after treatment, which may be an indicator of changes in proteins in the brain.

“We will be looking to see if there are changes in these proteins, some of which are responsible for neuron repair,” said Willer. “It’s possible that the sub-symptom aerobic exercise we are prescribing may help enhance neuroplasticity in the brain and speed recovery.”

Collection and study of these biomarkers will be supervised by Praveen Arany, DDS, PhD, associate professor of oral biology in the UB School of Dental Medicine and Hayley Chizuk, a doctoral candidate in the Department of Rehabilitation Sciences in the UB School of Public Health and Health Professions. Under the supervision of Dr. Willer, Chizuk is doing her dissertation on these proteins and what they reveal about injury and recovery in the brain.

Other researchers involved in the study include Christopher Stavisky, PhD and Jacob McPherson, PhD of the Department of Rehabilitation Sciences in UB’s School of Public Health, and Mohammad Haider, MD, PhD of the Department of Orthopaedics in the Jacobs School of Medicine.  Faculty of the University of North Carolina and the University of Michigan are also collaborating on the research.

This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs and the Defense Health Agency J9, Research and Development Directorate, or the U.S. Army Medical Research Acquisition Activity at the U.S. Army Medical Research and Development Command, in the amount of $4.8 million. The program is the Traumatic Brain Injury and Psychological Health Research Program and the award number is W81XWH-22-1-1115. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.