Total Impact

Game-changing research

Developing therapies to treat and prevent the acute and long-term consequences of concussion

“It’s one thing to study concussion and to want to know what’s going on, but what makes our team unique is our bent to understand the disease and make it better at the same time.” 

This from Arthur Brown, PhD, a Western professor and Robarts Research Institute scientist at the Schulich School of Medicine & Dentistry.

“To the public, it probably sounds intuitive–why wouldn’t you want to try to find a way to treat it? But for scientists, it’s sometimes very daunting to think that way,” Brown laughed, “because the path is long and difficult.”

Brown said the effort of simultaneously advancing the understanding of concussion and developing therapeutic strategies is like “moving all your checkers up the board at the same time.”

It’s a complex game, filled with unknowns. But the promise of a big win for those who suffer from short- and long-term impacts of concussion is what drives him and fellow Robarts scientists, Greg Dekaban, PhD, and Schulich dean Mike Strong, MD, to develop therapies that could radically change its treatment and ease its devastating effects.

Collaborating within the context of the larger concussion research group at Western, the trio is developing therapeutics intended to:

Reduce the body’s inflammatory response to an assault on the brain, stopping the damage when the concussion occurs;
Harness neuroplasticity – the nervous system’s natural ability to rewire circuits—to enhance nerve sprouting that might underpin recovery; and
Prevent the development of chronic traumatic encephalopathy (CTE), a concussion-related dementia.

The team’s desire “to not only understand, but actually fix what happens in concussion” inspired former NHL star and Hockey Hall of Fame inductee Eric Lindros to galvanize the NHL Players Association to issue a fundraising challenge in support of their work.

That endorsement has helped validate the importance of their quest in their three core areas.

(L to R) Arthur Brown, Mike Strong, and Greg Dekaban in the lab at Robarts Research Institute at Western University.

Reducing inflammation – the body’s response to assault on the brain

The damage caused by a concussion is the result of two assaults to the brain—the initial injury, caused by the brain moving inside the skull or shock moving across the tissue, and the body’s natural immune response to the initial impact.

Building on ground-breaking work by Dekaban and Professor Emeritus Lynne Weaver, DVM, PhD, “our data suggests that in both the injured spinal cord and injured brain, the inflammatory response is perhaps a little more robust than it could be,” Brown said, “which may be because it’s been evolved to look after a wound that’s open to the environment and needs to be sealed up to fight infection.”

“But concussion is a closed-head injury,” Brown continued. “There’s no real invaders, no bacteria, or need for sterilization at the site of injury.”

Unable to discriminate that difference, and as part of the very early inflammatory response to injury, our bodies send white blood cells into action, to sterilize bacteria by sticking to the blood vessel walls near the injury, squeezing into the tissue, which causes swelling.

Over a period of time, the nerves repair, but too much scarring can result in persistent headaches, dizziness, irritability, and difficulty with memory and attention.

In an effort to dial-back the body’s inflammatory response, Dekaban and Brown have created an antibody, which when delivered by IV within four hours of the injury, coats the white blood cells so that they can’t bind to the blood vessel wall and cause damage. 

“We find that this acute intervention can reduce the infiltration of white blood cells into the injury area by about 50 per cent and reduce the inflammation. And we’re able to show in models of traumatic brain and spinal cord injury that the reduced inflammation improves outcomes,” Brown said.

Enhancing neuroplasticity

The nervous system’s ability to rewire itself—through the process of neuroplasticity—is well-documented in instances of hemorrhagic stroke and spinal injury, in which undamaged areas of the brain can take over for the damaged ones.

The Brown and Dekaban labs are working to encourage similar growth in the nervous system in their novel approach to concussion.

“When the nervous system develops, there is a lot of growth signal present,” Brown said, “and the nerves talk to each other as they grow out. Once wired, the body responds by cementing these connections with a glue-like substance to prevent new ones from forming.

“Now imagine that you have an injury, and you’ve lost those inputs and connections. With that glue-like substance still present, your nervous system is limited in its ability to rewire. Our teams have identified at least one way for reducing that ‘glue’ in order to facilitate nerve sprouting. We’ve demonstrated this genetically through a mouse model, and now we are developing drugs to mimic what we can do genetically, in hopes of applying it to brain injury.”

Prevention of concussion-related dementia

Considered to be the end result of repeated, mild concussion injuries, chronic traumatic encephalopathy (CTE) presents as a cognitive disorder similar to frontal temporal dementia.

The key pathological feature of CTE is the abnormal deposition of a protein called ‘tau’, which is also involved in the pathology of Alzheimer’s disease.

“It’s believed that the aggregation of tau in the nerve processes makes them sick and impairs their ability to function. That’s basically what’s happening with dementia,” Brown explained.

“Mike (Strong) is pursuing the idea that the aggregation of tau is due to a chemical modification called phosphorylation and is interested in seeing if we modify that phosphorylation – by knowing the enzymes, and the specific proteins involved – if we could reduce their activity, and then maybe reduce the aggregation of tau and avoid dementia. That’s sort of the dream.”

For now, “the best treatment for concussion is absolute rest,” Brown says, “and then a gentle return to play or return to normal activities up until symptoms reappear, and then you back off, and wait a little while. You can keep pushing the envelope towards a normal life without symptoms.”

Crucial to future clinical applications of the group’s findings will be identifying which concussed patients are part of the 85 per cent who recover fully on their own after the prescribed rest period, and those who are among the 15 per cent who struggle and would benefit most from therapeutic interventions.

“Meanwhile, we have to move up our therapies, so that we are ready to take advantage of the information when it comes, ”said Brown.

“We need to know who to treat. We’re not there yet, but I’m sure we’re going to get there, because we would like to do better. (We must) be able to treat concussion and post-concussion syndrome and avoid CTE. In order to do all these things, we still need to more fully understand the basic science of concussion.”

Conquering concussion’s complexity calls for basic science

Concussion. It’s just not as simple as a hit on the head.

“In fact, you don’t even have to be hit on the head to have a concussion, you can have a body hit,” said Arthur Brown. “And the same hit on two different people, brings different results. One person will have a concussion and one person won’t. We don’t understand why that is.”

But as a member of Western University’s concussion research team, and as a Robarts Research Institute scientist, Brown’s keen to find out, as the group works to unravel the complexities surrounding the condition.

Concussion is considered to be a disease of the tracts, or the connections between the nerve cells in the brain, known as “diffuse axonal injury,” Brown said.

“Axons are the bridges that allow the nerve cells to talk to each other,” he continued. “A nerve cell located in one part of your brain will send a very long ‘process’ to communicate to another nerve cell in another part of your brain, or all the way down to your spinal cord. The brain thinks, and the body moves and senses, based on these connections.

“When you’ve had a concussion, our best understanding of it to date, is that it is not a problem with the nerve cell, it’s a problem with the processes.”

How that manifests symptomatically varies amongst the 160,000 Canadians who experience a concussion annually.

“Some people have headaches, some have lack of clarity of thought, many will have difficulty paying attention, and focusing,” Brown said. “And these symptoms, in 85 per cent of the cases, will resolve within a few weeks, with proper rest. It’s the 15 per cent that go on to have persistent problems, and experience post-concussion syndrome where it could be weeks, months, or years of difficulty.”

“We need to be better able to diagnose it, and do a prognosis, and determine ‘who’s in that 15 per cent?’ When you consider that we’re talking about hundreds of thousands of people, 15 per cent becomes a huge number, and it’s terribly debilitating, so it’s important.”

One of the greatest challenges to understanding concussion in human studies, Brown said, is our heterogeneous nature.

“Everyone’s different, not only genetically, but in what we eat, how we sleep, how we manage stress. All that makes for a really mixed patient population. And with this highly variable injury, on a highly variable population, it becomes really tough to sift through all the data and find commonality.”

Animal (mice) studies, help break that complexity down.

“Every model in your study can be a genetically identical individual that’s kept in the same housing, and given the same food, the same handler and the same light/dark cycle,” Brown said.

Mild experimental (anesthetized) concussions can be delivered in the same way, and at the same time of day, and the mice can be followed, comparatively through ‘before and after’ studies.

“Animal models allow us to understand what is going on, and more importantly,” Brown said, “we can look for commonalities between the human and mouse studies. What we want to do at the end of the day is ask, ‘how does this correlate in humans?’”

He’s seen great progress in this regard, collaborating with other members of the concussion research team, and by accessing Western’s world-class imaging facilities to mirror their human studies.

For example, Brown’s lab saw very similar reductions in one particular metabolite – glutamine – in animal models that also happened to be changed after injury for participants in a study done on women rugby players at Western.

“That becomes something we can study in a basic science way,” Brown said, by scanning and following the mice at different time intervals to see if the glutamine is up or down, and in which mouse, and consider if any changes are a sign of a normal healing process or an indication that things are getting worse.

Brown’s team also mimicked Western’s metabolomics blood test study done on Bantam boy hockey players where through machine learning, a group of metabolites distinguished concussed players from non-concussed.

“I actually sent blood samples from these mice to the same lab, because I want it to be the same, to reduce that complexity,” Brown said.

“Then (Western researcher) Mark Daley can run machine learning, and tell the machine, based on metabolomics, whether the mouse is a mouse at 48 hours after a hit, or a non-hit mouse, or whether it is a mouse at 4 weeks or at 48 hours after a hit. Hopefully, we’ll be able to define a set of molecules that will be the same between humans and mice, and ask, ‘why are these molecules different?’ It’s one thing to say they indicate something, but, implicit in the analysis is that there must be something about these molecules that reflect the underlying pathology, or the underlying repair process. We don’t know which, but this is the way to get at it."

Cognitive studies are also possible, with the old ‘mouse in a maze’ model now replaced with sophisticated computerized tests, that correspond with those given to humans. Through a behaviour phenotyping facility run by a core of behavioural neuroscientists associated with Western’s Brain and Mind Institute, mice are trained to nose-poke computer screens as a way to test their performance of cognitive tasks.

“What we are trying to do in all of these studies is do all the same things that we do in humans, in mice,” Brown said. “We’re able to do the same imaging because Robarts has an unbelievable imaging core, we’re able to do the same behaviours, because we have the behaviour phenotyping facility, and we’re able to do the same metabolomics because it’s just a blood analysis, and the machine doesn’t know if it is a mouse or human, and we can apply the same mathematical treatment of the data.”

“This is something very powerful that we can do at Western, that I think others are hard-pressed to do.”

Keri FergusonWritten by Keri Ferguson
Writer (Alumni & Development Communications)