In the U.S., traumatic brain injury (TBI) afflicts more than 1.4 million persons per year, according to the National Institutes of Health. The causes of TBI, or head injury, and its manifestation vary just as much as a patient’s response to treatment. For researchers striving to identify valid therapies, this complexity only adds salt to the wound.

“The major issue in trauma research is that it’s a complex disease, and the brain is the most complex organ in the body,” said John T. Povlishock, Ph.D., professor and chair of the Department of Anatomy and Neurobiology at the Virginia Commonwealth University School of Medicine.

For decades researchers have focused efforts on quantifying the number of cells and their processes that were either injured or atrophy after TBI, using this information to investigate the biological mechanisms underlying the damage to the brain. In these studies, the VCU investigative team has discovered various neuroprotective approaches while also noting that many diffusely injured neurons and their axonal processes can mount various reparative responses.

Povlishock and his department’s team of faculty — including professor Linda Phillips, Ph.D., and associate professor Tom Reeves, Ph.D. — were intrigued by these novel observations, and have shifted their focus to studying these restorative processes.

Confocal image of a brain region showing synaptic reorganization after injury. Matrix proteins (green) are visible throughout the area. Reactive non-neuronal cells (red) can produce these matrix proteins as indicated by yellow co-localization within their cell bodies.

“Many neurons may die following a brain injury,” Reeves said. “Therefore, we study the properties of surviving neurons, to see whether we can intervene and help them to recover.”

It’s this theory of plasticity that has led the team to investigate the diffuse neuronal, axonal, synaptic and vascular responses to TBI, and what has set their work apart from others in the TBI arena.

“We’ve been really fortunate to have NIH support for these projects,” Phillips said.

The team recently received multiple five-year renewal grants from NIH to examine ways of intervening with the natural restorative power of the brain — demonstrating that their studies are gaining national attention among peers.

“We really have a leadership role worldwide in understanding diffuse rather than localized brain damage,” Povlishock said. “We understand how cells and their processes are diffusely injured by trauma and how they reorganize postinjury, which is particularly relevant to human head injury.”

The team takes a multidisciplinary approach to their investigations. In particular, Povlishock and Phillips look at the neuron’s structural and molecular makeup while Reeves studies the function of the cells by recording action potentials and conduction in nerve fibers.

“Our research is very much a team effort,” Phillips said. “We have taken the time to develop models of injury that demonstrate good repair and others that show poor repair. Our approach in general has been to compare these models in order to see where and how each model responds. We hope that will help us to identify which mechanism and which therapy is worth following up on.”

The collaboration also facilitates the group’s ability to use multifaceted experimental approaches. With multiple end-point measures, they can manipulate the brain’s environment, explore therapies, and assess the likelihood that the brain will recover better structurally and functionally, ultimately in the hope of making the person behave in a more normal fashion.

In the coming years, Povlishock will further his research in axonal and neuronal somatic responses to TBI and explore various therapeutic approaches to repair damaged axons and restore synaptic input.

Electron micrograph of axons, neuronal processes particularly vulnerable to brain injury. The VCU team studies postinjury recovery of axons with dark myelin ‘coats’, as well as those which are smaller and unmyelinated.

Phillips will build on her studies in plasticity, focusing on the role of extracellular matrix proteins and the influence their regulatory metalloproteinases have on extent of recovery achieved after TBI. She compared the importance of understanding a cell’s environment to that of a seed’s growing through the earth: “It is important that the neurons grow in a nourished environment.

“We have some clues that there are compounds that are applicable in the human brain to regulate, or control, how the environment changes after brain injury,” Phillips added, but indicated that they faced a long road before these therapies would be ready for clinical trials.

Reeves will continue his investigation into the role of unmyelinated — or uncoated — axons in TBI.

“I’ve become the cheerleader of the unmyelinated axons,” Reeves said. Through microscopy, he and his colleagues have determined the prevalence of these injured axons and he believes they are part of the problem in recovery.

“We’re not only descriptive, but we also are actively exploring where we can intervene,” he added. “Certain drugs that are very common, such as immunosuppressants, are very complex and have other effects relevant to brain injury. Some of them are neuroprotective. If they are in the system before or shortly thereafter injury, the severity of the damage is greatly diminished.”

Renewing interest

Phillips said that TBI research in the U.S. has evolved since she joined the department in the late ‘80s. Nationally speaking, major research sites have cropped up — many due to the influence of investigators who have ties to the VCU Department of Anatomy and Neurobiology.

“The models are better. The techniques — imaging in particular — are better,” she said. “The number of people involved is greater. The interest in plasticity is growing, and the idea of reconnecting is becoming an interest of more and more investigators.”

Phillips said that this renewed interest encourages her.

“A lot of clues are also coming from other diseases that affect the nervous system,” she said. “For example, my lab is working with an antibiotic used in therapy models for multiple sclerosis. Others are using this approach and are seeing that this antibiotic alters matrix enzymes and actually helps the patients with the disease. Perhaps in the trauma models we use, we will see a similar benefit.”

The team foresees promising therapies on the horizon — either applied acutely after the injury or later during the rehabilitation of the patient.

“Our goal is to come up with these therapies,” Phillips said.