ON IMPACT: Predicting prolonged concussion recovery and the risk of repeated head hits

An estimated 3 million people in the United States are diagnosed with a concussion every year. The majority of those concussions are caused by sports-related injuries. Most people recover quickly, but for a third, it can take three or more months to recuperate. “The question is – can we identify those people early after an injury?” said Jeffrey Bazarian, M.D., professor of Emergency Medicine at the University of Rochester Medical Center (URMC). “If we could know – pretty precisely – which concussed individuals were destined for prolonged recovery, we would be in a much better position to test what medicines or therapies work to shorten the duration of recovery. We want to focus our research on the people who take a long time to get better; then we can start to figure out what medicine works and what therapy works, what works in improving concussion recovery.” Bazarian has been studying concussions for more than a decade and is currently working on a research project to better understand how concussions impact kids.

The study, which is funded by a $10 million grant from the National Institute of Neurological Disorders and Stroke (NINDS), will test ways to predict which kids will have symptoms, such as headache, dizziness, and trouble concentrating, for three or more Jeffrey Bazarian, M.D. months after a concussion. Understanding how the mechanisms of a developing brain are impacted by concussion is critical, and a goal of the multisite study involving the University of Rochester, the University of California, Los Angeles, and four other institutions. The study is focusing on children between the ages of 11 and 18. It will seek to identify a set of biomarkers that could predict which kids will develop persistent symptoms after a concussion.

Ultimately, researchers aim to develop an algorithm to help with the diagnosis and treatment of concussed kids while hoping to also make way for future therapies that could help kids recover from concussions faster. “The biomarkers that are going to be predictive of prolonged recovery are likely to be the ones that best detect disturbed cellular and physiologic function, so that's where the blood tests come in,” Bazarian said.

BLOOD AS A WINDOW TO THE BRAIN

Blood has already proven to be beneficial in diagnosing a concussion. In 2018, the Food and Drug Administration approved a blood test called the Banyan Brain Trauma Indicator ® . URMC was a site for one of the test’s clinical trials and Bazarian was the lead author of a study that appeared in the journal The Lancet Neurology that was used as support for the first blood-based biomarkers of traumatic brain injury in the United States. Kian Merchant-Borna, research faculty in Emergency Medicine, managed the trial that helped lead to this test, which can be used up to 12 hours after a head injury to detect UCH-L1 and GFAP proteins that are present in the blood soon after a hit to the head. Merchant-Borna works with industry partners to bring Kian Merchant-Borna tools – like blood tests – to market, assisting with bridging the gap in concussion diagnosis, brain monitoring, and recovery. Recently, he assisted with getting FDA approval for a disposable set of electrodes used to measure EEG – brainwave activity – that helps clinicians diagnose a brain bleed. He and Bazarian’s relationship has been instrumental in the translation of concussion research into technology that helps with therapeutics and care.

To do this research, Bazarian and Merchant-Borna’s labs work with University of Rochester student-athletes and patients in the Strong Memorial Hospital Emergency Department. “We meet with the subjects and make sure they understand our research and its larger implications,” said Kourtney Korczak, research coordinator for the Bazarian and Merchant-Borna labs. “We then collect blood samples and other neurocognitive data from those who chose to participate.”

They follow these subjects through their recovery, evaluating them along the way. “The subjects are often in their most vulnerable state when we first meet,” said Sarah Dermady, research manager for the Bazarian and Merchant-Borna labs. “But we can make powerful connections while creating a gateway for the enhancement of concussion treatment and diagnoses for the future.”

Beyond the initial diagnosis a person is generally monitored based on what symptoms they have – subjective markers like patient-reported symptoms such as headaches, nausea, or light sensitivity. “Not knowing what is happening in the brain can affect an individual’s quality of life in the long term,” said Merchant-Borna. “Concussion recovery can be difficult to track and symptoms often dissipate before the brain is fully healed.”

RISK OF REPEATED HITS TO THE HEAD

Repeated head hits are a silent danger. Each blow can compound the one before, sometimes without symptoms to warn of a growing injury. In cases where a person’s occupation or activity – like members of the military or athletes – puts them at risk for repeated head hits, the potential to develop chronic traumatic encephalopathy (CTE), a serious neurodegenerative disorder, increases. CTE is a devastating disease that causes debilitating symptoms and, in many cases, premature death. It is also a disease the patient will never know they have because it can only be diagnosed by an autopsy. “We have no way to know who is potentially headed in that direction,” said Bazarian. “Blood-based biomarkers have the potential to be a practical way to monitor brain health in those exposed to clinically silent, repetitive head hits. This might allow early detection of subtle brain injury that is reversible with rest, before it progresses to an irreversible neurodegenerative stage.”

When a brain is injured some of its cellular elements, like neurons and astrocytes, initially release UCH-L1 and GFAP proteins. The injury also causes a perturbation of the blood-brain barrier, allowing those proteins, and others, to enter the bloodstream. Bazarian believes this leak could be key to monitoring brain health in the future. He is currently investigating how these proteins show up in the blood and if these protein levels can be elevated without concussion symptoms and be used to show biochemical evidence of cellular disruption. This could allow clinicians to detect a looming injury before concentration and memory symptoms are present. “Although advanced forms of MRI can also detect subtle brain changes with repeated head hits, they just aren’t practical to perform routinely in a surveillance fashion to monitor brain health. So we are thinking that, for those exposed to repeated head impacts, blood biomarkers are a practical solution to monitoring brain health on a regular basis and for providing an early indication when brain health might be threatened.”

The amount of protein is minimal, but its presence is significant – especially when someone is at risk of repeated hits to the head. In a healthy brain these proteins are cleared out by the glymphatic system – the brain’s unique process of removing waste – but, if head hits happen too close together, the brain’s “drainage system” can become overwhelmed and put the brain on course for permanent damage. “We know that it doesn't take much to disrupt the structure and function of the brain. But we don't have a practical way to monitor people for that,” said Bazarian.

“People who are at risk for repeated head hits – athletes, military service members, victims of repeated domestic assault – are the ones who are most at risk to have undetected permanent damage,” Merchant-Borna said. In May 2020, he and Bazarian were awarded a U.S. patent for an algorithm that can be used to assess the risk of changes and injury to brain white matter following repeated exposure to head impacts. This method was developed as part of their ongoing research to better understand what happens to the brains of athletes, particularly football players, who undergo repeated exposure.

“The partnership we have with the Department of Athletics at the University of Rochester, including the support of both George VanderZwaag, the executive director of athletics, and Eric Rozen, the head athletic trainer, has been invaluable to our research programs,” said Merchant-Borna. Their labs work with the University of Rochester football team, outfitting players with helmets containing accelerometers – sensors that record the number, direction, and force of head blows during each practice and in games. Participating student-athletes also have brain scans and blood draws before and after the season. “This gives us valuable information about exposure and we can look further into the players who have been diagnosed with a concussion as well as those who haven’t but who we can see have had repeated head hits,” said Merchant-Borna. Through this work, researchers have identified a single region of the brain – the midbrain From left: Bazarian and Merchant-Borna – that can be used to examine the impact of a concussion or repeated hits to the head. Changes in the integrity of the neurons in this brain region correlated with the number of times that a player’s head was hit, side to side or back and front.

The amount of research being done in this realm continues to develop. The NFL is expanding its collection of data on head hits by putting sensors in the mouth guards of players at four major universities. The same high-tech mouth guard sensors are currently used by 10 NFL teams. “People aren’t going to stop playing sports, riding bikes, getting into motor vehicles,” said Merchant-Borna. “There is a lot more momentum and awareness that repeated non-concussive head hits can affect someone in the long term and affect an individual's quality of life, productivity, and success.”