'Mini-brain' shines light on concussions

A biomedical engineering professor at the University of Cincinnati is doggedly pursuing answers to one of medicine’s black boxes: concussions.

Concussions are a common injury, responsible for as many as 3 million emergency room visits every year. Children playing sports or other recreation activities sustain nearly 4 million concussions every year, according to estimates by the Centers for Disease Control and Prevention.

UC College of Engineering and Applied Science Assistant Professor Volha “Olga” Liaudanskaya wants to know more about the milder, repetitive blows children in youth sports can sustain that can also lead to injury. In her lab at UC's Bioscience Center, she is studying how cells in the brain are affected by concussive forces — and how this trauma can lead to neurodegenerative diseases.

"We still know very little about what’s going on in the brain. And the injury can depend on the severity and location,” she said. “Brain trauma is so different from patient to patient, both the intensity of the injury and the patients themselves.”

Liaudanskaya and her team of student researchers are studying traumatic brain injury, or TBI, at the cellular level using novel models she created.

She calls them “mini-brains” and in her lab studies three brain cell types that regulate brain activity, including neurons. To that, she added two vascular cells, creating a complex “pentaculture” of five cell types that she can track simultaneously using living tissue.

“There was a big part missing, which was a vascular unit. For neurodegenerative diseases, the vascular system is a critical driver of inflammation, degeneration and proteinopathies like Alzheimer’s, Parkinson’s and chronic traumatic encephalopathy or CTE,” she said.

For people with a history of concussions or repeated blunt-force head trauma, understanding this vascular contribution is especially important.

As most middle-schoolers learn, the mitochondria is “the powerhouse of the cell,” generating energy and regulating cellular processes.

“But it does so much more,” Liaudanskaya said. “Sex hormones, metabolism, epigenetic signatures — all are regulated by mitochondria. That’s why we wanted to look at them.”

Liaudanskaya is examining how mitochondria are affected and react to these concussive forces.

“The mitochondria plays a big role in neurodegeneration,” she said.

To study her mini-brains, she uses a specialized imaging tool called a confocal microscope that uses a laser and a pinhole aperture resulting in detailed — and extraordinary — 3D images that map the cells.

“We tagged mitochondria in neurons with a red fluorescent protein. You can see that here,” she said, pointing to a rotating 3D image on her computer screen. “We added green tags to the astrocytic mitochondria. You can see these large green cells. And white are the microglial mitochondria.”

Combined they create a detailed and colorful tapestry of the cellular function of the brain.

“We can track the mitochondria as it migrates in the cell. We can fluorescently tag mitochondria to see where it goes and what it does and what’s going on,” she said.

But first researchers have to subject the cells to concussive-like forces. They use mechanical devices that allow for consistent, measurable and replicable forces across samples, simulating blunt-force trauma that can cause concussions and traumatic brain injury.

Liaudanskaya’s most recent paper, published in the journal Frontiers in Cellular Neuroscience, examines the benefits of this computer modeling to study neurodevelopment and neurological disease. It’s one of the important ways her lab is tracking the cause and effect of blunt-force trauma through to the rise of neurodegenerative diseases. This concussion research helps explain how a single impact — or repeated mild head injuries — can create a cascade of cellular damage over time.

And she is not just looking at the traumatic brain injuries from car accidents or extreme collisions but the smaller, repetitive concussive forces that athletes, particularly children in youth sports, endure every season across sports.

“That was my dream because it’s not understood at all. There are no diagnostic markers out there of any kind,” she said.

Liaudanskaya said children are potentially exposed to mild brain injuries more often than we know.

“So we wanted to understand what mild injuries do to the brain. Is there a threshold? Is it an accumulation? Can we heal it? What causes long-term neurodegeneration that is common in boxers and American football players,” she said, noting that these are key questions in TBI research.

Liaudanskaya found that in injured brain cells, certain proteins that normally stabilize neurons fail to return to their normal function. Fibers between nerve cells break down. There is chronic inflammation and metabolic dysfunction. And these are hallmarks of neurodegenerative disease.

Still, most people with concussions fully recover given enough time and the absence of any additional traumatic blows, she said.

“If you protect your brain for six months, you can recover. We see a pattern develop in the third month. Everything is stabilizing at the structural level, but you still have inflammation. If you extend it to six months and have another concussion, you start over,” she said.