Research Seeks to Change Outcomes of Traumatic Brain Injuries

Researchers have advanced evidence for a treatment option that could prevent memory deficits and emotional problems in patients suffering from axonal injury caused by traumatic brain injuries (TBIs).

Axons are processes that connect a neuron to other neurons. These connections are crucial for every thought and feeling that we experience. When an axon is damaged, it cannot relay these messages to important processing centers in the brain.

Using a novel combination of high-resolution imaging and a GRIN lens implanted in the brain of mice, researchers documented axonal injury and the recovery process after a blunt injury to the brain. GRIN lenses are microscopic glass lenses that allows scientists to focus closely on the cells for good image quality. These lenses are smaller than Lincoln’s nose on a U.S. penny and were adopted by a handful of biologists to better study the brain.

Tracking the time in which axons become affected, they employed a clinically approved drug, minocycline, to reduce inflammation, which slowed axon injury, recovered axons from injury, and preserved function. They tested the drug’s effectiveness for immediate use within 45 minutes of the incident, compared to delayed use at three days post-injury – both time points showed positive effects. These findings were published on May 8 in Scientific Reports.

Jonathan Lifshitz, PhD, and Rachel Rowe, PhD, from the Translational Neurotrauma Research Program at the University of Arizona College of Medicine – Phoenix, collaborated with Chelsea Pernici, PhD, and Teresa Murray, PhD, from the Center for Biomedical Engineering and Rehabilitation Sciences at Louisiana Tech University. The study was led by Drs. Pernici and Murray who used a new imaging technology to show how diseases and injuries affect the brain over time and how medicines could reduce brain damage. This novel imaging was created in Murray's lab. Through this technology, the group of researchers were able to repeatedly image the same axons in the brain before and after brain injury, providing proof of TBI-related axonal pathology. Secondly, minocycline drug treatment promoted the recovery of injured axons.

“The fine communication elements of neurons — axons — are torn, ruptured and damaged, which contributes to a multitude of clinical symptoms,” said Dr. Lifshitz, director of the Translational Neurotrauma Research Program at the U of A College of Medicine – Phoenix. “To date, these processes have been inferred from fixed histological sections, clinical imaging and cells in culture. No one has observed an axon prior to injury, the consequence of injury and the outcome. Here, we show that axons do sustain injury and can either recover or become truncated.”

Their research showed that some damaged axons continue to degrade and some even break apart after days or weeks, which is a permanent lost connection to other neurons. Furthermore, they saw that some previously healthy axons became damaged over time because of the inflammation caused by the TBI.

With treatment, a much larger percentage of the damaged axons healed, compared to those without treatment. As predicted, the immediate treatment resulted in the fewest number of damaged axons. Surprisingly, the delayed treatment resulted in the highest percentage of axons that healed from their injury. For both treatments (immediate and delayed), the damage did not spread as much to undamaged axons.

“Most brain injuries cause damage to just a few axons,” said Dr. Murray, an associate professor of Biomedical Engineering at Louisiana Tech University. “These few axons can’t be seen on MRIs and CT scans. So, most TBI patients are sent home with the hope that they will get better over time. However, even a few damaged axons can disrupt communication in the brain and affect neurological function.”

Dr. Murray developed an improved GRIN lens system to see more details of brain cells. Her team also designed 3D-printed hardware to help them find the exact same cells for each imaging session. Her improved GRIN lenses allowed the team to find and evaluate the same injured axons over several weeks post-injury.

“The novel fluorescence imaging method using GRIN lenses allows researchers to study brain cells in both time and space, offering a unique opportunity to better understand the effect of drugs on brain structure over time,” Dr. Pernici said. “It’s exciting to see that although axons become damaged after TBI, the injury can resolve and with this method, we have the opportunity to better understand that timescale.”

No drug currently is on the market that is clinically used to prevent axon injury. The current results add evidence to support continued investigation of minocycline for TBI treatment.

“This study provides hope that we can use minocycline effectively if the drug can be taken early in the process and not given long-term. This could help reduce the inflammation, and thus some of the permanent damage caused by brain injury,” Dr. Murray said.

The team plans to continue their research by pairing minocycline with another drug to see if this early damage can be reduced further. If successful, this could greatly lessen the chances of memory loss and emotional problems for people suffering a TBI.