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Ohio State study: Post-concussion therapies may improve long-term outcomes

KEITH ARNOLD
Special to the Legal News

Published: May 23, 2022

The Chronic Brain Injury Program at The Ohio State University has advanced research in post-concussion treatment with a recent study of immune cells and their contribution to chronic inflammation, according to a university announcement.
The new research in mice has suggested that certain post-concussion therapies may ward off cognitive decline and depression, two common conditions among people who have suffered a moderate traumatic brain injury.
“In a moderate brain injury, if the CT scan doesn’t show damage, patients go home with a concussion protocol,” said program faculty advisor and senior author of the study Jonathan Godbout. “Sometimes people come back weeks, months later with neuropsychiatric issues. It’s a huge problem affecting millions of people.”
The study in mice clarified the role of specific immune cells, called microglia, that contribute to chronic inflammation in the brain.
Researchers were successful in eliminating the cells for a week-long period, using a technique called forced cell turnover. They, then, allowed the cells to repopulate for a two-week period, the study reported.
Godbout explained that turning over the microglia in the mice’s brains resulted in a positive effect on behavior, cognitive status and level of inflammation in the brain.
“It’s almost like hitting the reset button,” he said.
Compared to brain-injured mice recovering naturally, mice that were given the intervention showed less inflammation in the brain and fewer signs of thinking problems 30 days after the injury, a press release detailed.
Researchers noted that clearing microglia in humans isn’t feasible. The findings of the study, however, highlight pathways to target that could lower the brain’s overall inflammatory profile after a concussion, potentially reducing the risk for behavioral and cognitive problems long after the injury.
Approximately 85 percent of traumatic brain injuries are similar to the type of concussion examined in this study, which involves dispersed impact to the head that causes brain tissue to bump against the skull, the release continued.
Previous research has suggested that at least 75 percent of people who experience a moderate brain injury have long-term mental health and cognitive complications.
Godbout’s lab previously linked depressive symptoms in mice to microglia’s sustained high-alert status after a head injury, causing the cells to overreact to later challenges to the immune system and become excessively inflammatory.
In a more recent study in mice, the researcher’s team showed that forced turnover of microglia before a head injury could reduce later neuropsychiatric complications.
“That was a proof of principle to show that a lot of the inflammation, especially in the long term, is mediated by microglia,” he said. “But there is an acute phase of inflammation––you want to initiate that repair process. There’s a positive to that early inflammatory response in the brain or spinal cord. If it lasts a long time and doesn’t fully resolve, that’s when it’s dangerous.”
In the new study––the results of which are published online in the Journal of Neuroscience––researchers waited for seven days after the brain injury to force the turnover of microglia, giving the cells time to carry out their work promoting initial healing.
An experimental drug that inhibits a protein that microglia in mice need for survival was added to their food for a week, resulting in depletion of over 95 percent of microglia in their brains.
After a 16-day waiting period, researchers compared the so-called “intervention mice” to injured mice that recovered without the cell turnover treatment, the study noted.
The treated mice performed better than the control mice on tasks testing their memory and depressive symptoms.
Further analyses of injured brain tissue suggested the cell turnover reversed some injury-related damage to neurons, lowered overall inflammation and improved the brain’s ability to adapt to change, researchers said.
Additionally, researchers examined how the mice would respond to infection and found that that sickness behavior was lower in the intervention mice.
The combined findings suggest that the repopulating microglia returned in a less “primed” state of readiness, lowering chances for a lifetime of exaggerated inflammatory responses in the brain to any challenge to the immune system––that brain inflammation being the likely culprit behind the neuropsychiatric complications that follow a head injury, Godbout said.
“If microglia in the human brain don’t return to normal and chronic inflammation persists after a head injury, it’s not just a secondary brain injury that causes problems. Even getting a viral infection after concussion recovery can progress into a cognitive or behavioral issue or amplify some other part of behavior, like depression,” he said. “There is a real connection between a head injury and mental health, and the risk doesn’t go away.
“Now we’re looking more closely at the pathways that cause changes in microglia, and targeting something specific in that pathway. That is a way forward.”
This work was supported by the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the National Institute of Dental and Craniofacial Research, an Ohio State University Presidential Fellowship and the Thailand Research Fund-Royal Golden Jubilee Program, the press release listed.
Ohio State co-authors of the study, including Chelsea Bray, Kristina Witcher, Dunni Adekunle-Adegbite, Michelle Ouvina, Mollie Witzel, Emma Hans, Zoe Tapp, Jonathan Packer, Ethan Goodman, Fangli Zhao, Shane O’Neil, John Sheridan, Olga Kokiko-Cochran and Candice Askwith, joined Godbout, who also serves as assistant director of basic science in the Institute for Behavioral Medicine Research and professor of neuroscience in The Ohio State University College of Medicine.
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