Finding Cures for Chronic Brain Injury

By Lauren Moore, Marketing and Communications Manager, Brain Injury Association of America

For many people who sustain a brain injury, they are able to fully recover. They return to the lives they lived before their injury – their relationships, their careers, their hobbies. But many others cannot return to business as usual. They may have to leave the workforce, abandon beloved hobbies, and in some cases, change the trajectory of their lives entirely. Some individuals continue to live with the effects of their injuries – physical, cognitive, psychological, and emotional – for the rest of their lives.

But what if they didn’t have to?

Imagine a world where people no longer have to live with the lifelong effects of brain injury. Where rather than accelerating a disease, doctors were able to slow its progression – or stop it in its tracks outright.

That’s the vision of the Brain Injury Research Fund, the Brain Injury Association of America’s grant program. Established in 2019, the Brain Injury Research Fund’s theme and overall goal is finding cures for chronic brain injury. While little is known about the nature, extent, and mechanisms that allow a brain injury to affect a person’s health and functioning later in life, we do know that brain injuries can evolve into lifelong health conditions that impair not just the brain, but other organ systems as well, and may persist or progress over a person’s lifespan. And every year, through the Brain Injury Research Fund, the Brain Injury Association of America is able to provide funding for researchers who are working towards the shared goal of finding cures for chronic brain injury.

University of Michigan Alumni Brain Health Study Adds Biomarkers

There have been many studies about the effects of sports on brain health, but much of that research has been focused on professional athletes, or other people who have extreme lifetime exposures to head injury. But an ongoing study at the University of Michigan is taking a different approach.

Seed grant recipient James Eckner, MD, is part of a team exploring the effects of early-life contact sport participation – former high school athletes – on long-term brain health. The research funding he received from the Brain Injury Association of America is allowing his team to include the use of blood biomarkers i n their study.

“In this context, blood biomarkers hold a great deal of promise and may be able to help identify former athletes at elevated risk for future cognitive decline before any overt changes appear,” Dr. Eckner explained. “If successful, this may facilitate earlier intervention and improved outcomes.”

Understanding the effects of early-life contact sport participation on long-term brain health is of critical societal importance, Dr. Eckner added. “We know there are a ton of physical, cognitive, psychological, and social benefits associated with sport, but there is growing evidence that for at least some former athletes repetitive head impacts sustained during contact sport play can have negative long-term consequences on brain health as well. Unfortunately, these complex relationships are still poorly understood.”

The new knowledge that Dr. Eckner’s research generates has the potential to help young athletes and their families make better decisions to maximize the benefits of playing sports, while minimizing the potential risks.

Exploring Treatment Options for Newborns with Hypoxic Brain Injuries

Hypoxic-ischemic encephalopathy (HIE), a person’s brain doesn’t get enough blood and oxygen, is a leading cause of lifelong neurological disabilities such as cerebral palsy and cognitive impairment. While HIE can affect people of all ages, it typically occurs in newborns, and is one of the most serious birth complications affecting full-term infants.

Though advances have been made, many children with HIE still face significant challenges as they grow, and effective pharmacological treatments remain limited, explained grant recipient Xiaodi Chen, MD, PhD, who received a seed grant for his research project “Syn3 Effects on Chronic Inflammation and Neurodevelopment in Neonatal HIE.”

Syn3, Dr. Chen explained, is a novel compound that enhances brain-derived neurotrophic factor signaling and reduces inflammation — two processes central to brain recovery after injury. “Preliminary studies in our lab have shown that Syn3 can reduce acute brain injury in neonatal models,” he explained. This inspired Dr. Chen to investigate whether early intervention with Syn3 could also alter chronic inflammation and support better neurodevelopmental outcomes long-term. “Ultimately, I hope this research will pave the way for more effective treatments and improved quality of life for children and families affected by neonatal brain injury,” he said.

Examining the Effects of TBI Across Generations

Survivors of domestic violence (DV) and intimate partner violence (IPV) are at a high risk for brain injury, yet they are frequently overlooked. However, DV and IPV often include head and facial trauma, with about 90 percent of survivors experiencing persistent concussion symptoms. Being pregnant can amplify both the severity and frequency of such assaults.

“As someone from a historically marginalized background, I have always been drawn to research that center on underrepresented and overlooked populations,” said grant recipient Brenda Lujan, who hopes to close the gap in literature surrounding how TBI affects fetal brain development, an area she said has been largely overlooked in both clinical and preclinical research, with her project “The Pathophysiology of TBI Crosses Generations in Pregnancy.”

So far, Lujan has conducted a range of behavioral assays on offspring at key developmental timepoints to assess the effects of TBI compared to controls. Currently, she is analyzing data related to her second and third aims, which focus on behavioral and structural outcomes in the offspring. Lujan is also preparing to move forward with the first aim, which will examine gene expression changes in fetal brain tissue collected after injury.

“Although my role is on the preclinical side, I am motivated by the real-world impact this research could have, especially for vulnerable groups often left out of medical research,” Lujan said. “By identifying the molecular, structural, and behavioral consequences of in-utero exposure to TBI, this project aims to build a foundational understanding of how early-life injury may contribute to long-term neurodevelopmental outcomes. Ultimately, I hope this work serves as a call to action for increased research and awareness around TBI during pregnancy and its implications for offspring health.”

Studying Comorbid Contributors to Alzheimer’s Disease

“If you’ve seen one brain injury, you’ve seen one brain injury.” It’s an often repeated phrase in the brain injury community, and one that resonated with dissertation grant recipient Elise Webber.

“There are a lot of different factors that contribute to outcomes, but we don’t necessarily know on a molecular basis what alters the course of brain injury,” Webber said. Understanding the real world modifiers that affect a brain injury patient’s outcome – their age, health, prior brain injuries, drug or alcohol use, or mental health issues, to name a few – may be a key component in determining a patient’s prognosis.

“Something I was curious about was how chronic stress can change the outcome of brain injury, particularly when derived from social isolation,” Webber said. “That was the driving force in developing this project, with the end goal of being able to better treat people down the line.”

In her research project “Traumatic Brain Injury and Chronic Stress, Comorbid Contributors to Alzheimer’s Disease,” Webber aims to understand the drivers of neurodegeneration after TBI, potentiated by environmental or lifestyle factors such as chronic stress. In understanding how those drivers work, she hopes to look at real world applications and explore what can be done after TBI to reduce the risk of poor outcomes.

“It’s important to understand the driving factors after TBI, and I hope to contribute to that understanding with my work,” Webber said.

Exploring New Uses for Existing Drugs

Naltrexone is an FDA-approved drug that treats opioid use disorder and alcohol use disorder, and is currently in clinical trials testing its effectiveness at treating neurological and autoimmune diseases.

Through her project “Low Dose Naltrexone as a Rehabilitation-Relevant Therapeutic to Promote Recovery after Severe TBI,” grant recipient Ashley Russell, PhD., at the University of Pittsburgh, is exploring the possibility that low dose naltrexone could also be effective in treating severe TBI.

TBI causes chronic neuroinflammation and accelerated brain aging, which is linked to cognitive and psychological health disorders with few effective treatment options for the post-acute setting.

This proposed project will test the efficacy of low-dose naltrexone on reducing microglia-specific inflammasome induction to promote neurobehavioral recovery after severe TBI.

When selecting research projects to fund, the Brain Injury Research Fund’s research committee considered applications that focused on one of five established research priorities:

• Progressive Degenerative Processes: Chronic brain injury can cause neurodegenerative diseases, such as Parkinson’s Disease, Lewy Body Dementia, Chronic Traumatic Encephalopathy, and possibly Multiple Sclerosis and Alzheimer’s Disease. Typically, there is a marked delay from injury to disease onset. What neurological processes are triggered by brain injury that cause these chronic, progressive diseases and how can the progression from injury to neurological disease be halted?
• Late Consequences of Childhood TBI: Childhood traumatic brain injury (TBI), even when mild, is associated with adult problems of behavioral regulation, (i.e., addiction, criminal behavior, socially inappropriate behavior). Is this relationship causal or does TBI mediate other bio/psycho/social processes? What factors create the risk of adult consequences from childhood TBI and how can that risk be diminished?
• Excess Mortality: Moderate and severe TBI reduces life expectancy by nine years. Even after living to one year post-injury, persons with this severity of injury are 50 percent more likely to die than age-, sex- and race/ethnicity-matched members of the general population. Causes of death involve all organ systems, not just those associated with behavioral or neurological pathology. What biological processes are responsible for this excess mortality and how can these relationships be ameliorated?
• Chronic Health Condition Management: Brain injury is recognized as a chronic health condition that, for some, requires proactive medical management. More research is required to inform evidence-based disease management protocols, including studies addressing these questions:
  • Which brain injuries increase risk for negative outcomes?
  • What pre-existing conditions require management?
  • What conditions develop post injury that could be prevented or detected early?
  • How can the individual participate in their self-management?
  • How can access to medical and rehabilitation care be used to reduce negative outcomes?
  • How can community-based resources be accessed to improve function and reduce institutionalization?
• Social Determinants of Health: Disability is a product of both impairments in brain function and environmental factors that create barriers to health and independence. What community characteristics exacerbate or minimize the manifestation of impairments due to brain injury? How do social determinants of health affect brain injury outcomes? What community interventions are effective in ameliorating the influence of environmental factors on brain injury outcomes?

Interested in being a champion for brain injury research? There are several ways for you to support the Brain Injury Research Fund. Learn more here.

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