In 1999, when the Department of Veterans Affairs (VA) established its Brain Rehabilitation Research Center (BRRC) at the Malcom Randall VA Medical Center in Gainesville, Florida, it was in part a response to exciting new discoveries in neuroplasticity (the brain’s ability to form new connections and pathways after injury); neurogenesis (the ability of the brain to grow new neural cells and the dendrites that connect them); and angiogenesis (the generation of new blood vessels that oxygenate tissue and restore function).

These advances helped to establish a core mission for the new BRRC: to identify the mechanisms involved in each of these areas – how, exactly, the brain might be induced to generate new pathways and neural tissues – and use that knowledge to develop interventions for people who suffer central nervous system damage.

Veterans who’ve suffered injuries to the central nervous system also suffer impairments in cognitive, motor, or emotional functioning – often in combination. Even a single functional impairment can significantly affect a person’s health and quality of life, and can impose significant emotional and financial burdens. In the BRRC’s two decades of existence, its investigators have focused their efforts primarily on recovery and neuro-rehabilitation from two of the most prevalent causes of these impairments: traumatic brain injury (TBI) and stroke.

Creative and Innovative Collaborations

Supported by the VA’s Office of Rehabilitation Research and Development (RR&D), the BRRC is adjacent to the University of Florida (UF) campus, and each of the Center’s investigators is dually appointed to the University’s College of Medicine. The two facilities share resources, including the BRRC’s 11,000 square feet of laboratories and workstations and sophisticated tools for measuring and analyzing both brain function and motor control performance.

The BRRC is also part of a research consortium that includes colleagues in the UF College of Medicine and the Brooks Rehabilitation Hospital in Jacksonville, Florida, whose Clinical Research Center shares the BRRC’s mission of advancing neural rehabilitation. Nationwide, BRRC investigators collaborate with other VHA institutions including the health care centers in Portland, Oregon, and Tampa, Florida, as well as two other RR&D centers in Cleveland, Ohio: The Functional Electrical Stimulation (FES) Center, which evaluates neurostimulation methods, and the Advanced Platform Technology (APT) Center, where investigators explore engineering solutions to create new rehabilitation interventions.

By design, BRRC’s investigative leadership is composed of twelve scientists, each with his or her own research program in basic or clinical science. The fields studied by each, while varied, are also interrelated, including neuroscience, biomedical engineering, electrical engineering, neuropsychology, experimental psychology, neurology, physical therapy, biomechanics, and muscle physiology.

According to Janis Daly, Ph.D., the BRRC’s director, the interdisciplinary nature of the center’s work “gives us the capability to consider a problem from multiple vantage points.” These different perspectives often generate creative and innovative explorations that hold promise for new treatments. 

For example, BRRC investigators are working to discover neuropathologies underlying the cognitive problems often associated with TBI. Neuroscientists Prodip Bose, M.D., Ph.D., and Floyd Thompson, Ph.D., have identified structural and functional damage to a structure called the locus coeruleus (LC) during brain injury. Located in the pons of the brainstem, the LC is a hub of neural activity which, under normal circumstances, relays critical brain signals to parts of the brain that serve other functions – the spinal cord, cerebellum, cerebrum, hypothalamus, amygdala, and others. Damage to the LC causes a complex of dysfunctions, and now that Drs. Bose and Thompson have identified it as a consequence of brain injury, several new clinical studies have been launched to address these dysfunctions.

William Perlstein, Ph.D., a BRRC investigator who also directs the Clinical-Cognitive Neuroscience Laboratory at UF, has identified two different types of cognitive dysfunction that often occur among chronic sever TBI patients: Deficits in “regulative” function, which supports cognitive control of thoughts and behaviors, and “evaluative” function, which monitors the need for regulative control. Working forward from this distinction, Perlstein is in the process of assessing different treatments he’s designed to restore metacognition – the awareness and understanding of one’s own thought processes – in patients with regulative and evaluative dysfunction. Perlstein’s treatments will target executive function (the set of mental skills that enable people to coordinate thoughts and behaviors and get things done) and attention.

BRRC investigators also have made important advances in rehabilitating the brain after stroke. David Clark, Sc.D., has developed ground-breaking methods for measuring brain function during walking, and discovered that as people develop problems with gait due to aging, disease or a stroke event, they are increasingly likely to experience a corresponding loss of cognitive resources in the brain’s frontal lobe. “In other words,” Daly said, “he found that stroke survivors attempting challenging walking tasks require a great deal more brain resources in the pre-frontal cortex than those who have not had a stroke.”

Clark and other investigators are building on this finding to target specific interventions for gait training after stroke. The experimental treatments are of two types: first, interventions involving “activity-dependent plasticity,” or treatments that draw on a patient’s own intrinsic brain activity and ability to learn and form new processes. Using Clark’s methods of measuring brain activity, these treatments may be adjusted and refined over time, so that therapy is more individualized and, ultimately, the patient’s gait becomes more coordinated. A second type of gait treatment under investigation involves brain stimulation – either transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) – to facilitate brain signal activity in the pre-frontal cortex while a patient is undergoing gait training.

The BRRC’s sophisticated technologies and processes for measuring brain activity have also helped a research team led by Daly to develop treatments for stroke patients with upper-limb dysfunction. One of the team’s most important findings was that while undergoing treatment and regaining motor function, patients demonstrate changes in brain activity – but these changes are highly variable and individualized. Daly’s findings suggest neurorehabilitation interventions need to be customized to match the brain activity patterns of individual patients. So far, Daly’s precision-treatment protocol is producing greater improvement in upper-limb function, compared to other interventions in use, and can be integrated into treatment plans for stroke survivors with chronic limb dysfunction.

The technologies used by BRRC investigators to measure brain and motor performance aren’t simply diagnostic tools; they can also be useful in treatment. For the past two years, Daly and her colleagues have been developing a neural feedback system for improving upper limb coordination in stroke survivors: While viewing functional magnetic resonance imaging or functional near infrared spectroscopy images of their own brains, stroke survivors practice difficult wrist and hand movements. Receiving feedback in real time, while practicing challenging motor tasks, has encouraged these patients to modify their own brain signals during movement.

“We’re providing them a signal that’s showing them how their brain is working and how strong the signal is,” said Daly, “and we’re asking them to enhance that signal. These are folks who, for example, can’t extend their wrist in preparation for grasping something. While they’re practicing extending their wrist, we’re showing them their brain signal, and we’re asking them to enhance the signal in that spot in the brain while they’re attempting to move. It’s biofeedback, based on brain signaling.”

Translation into Practice

Because the mechanisms of neuroplasticity are incompletely understood, most studies of its processes haven’t yielded clinically significant improvements yet – there are no “cures” for the complex of cognitive, motor and emotional dysfunctions caused by TBI and stroke. BRRC investigators are focused on the difficult task of discovering the neural mechanisms that prevent recovery and rehabilitation, a challenging endeavor that will be built on valid diagnostic and measurement tools. Several such tools have been translated into practice while the Center’s investigators continue to research neuroplasticity and complete studies aimed at providing treatments that can be easily deployed into practice. Examples of the diagnostic and clinical tools developed by BRRC researchers and in use today include:

•The Gait Assessment and Intervention Tool (GAIT), developed by Daly and initially designed for stroke survivors, was recently translated into Spanish and is undergoing reliability testing for patients with multiple sclerosis. A comprehensive scoring system for assessing incremental improvements in the components of gait, the tool is currently being used for stroke survivors in Thailand, Colombia, and Spain.

•The first FDA-approved blood test to evaluate for mild TBI (mTBI), which was developed with significant contributions from Kevin Wang, Ph.D., and colleagues at the BRRC. The test, which measures levels of two proteins associated with brain injury, allows for TBI diagnosis in the field, which will make it a critical tool, for example, in evaluating whether injured service members should be returned to combat.

•A diagnostic tool for the early detection of brain disease risks, developed by Keith White, Ph.D., and colleagues. White’s patented method, which uses commercially available MRI systems, detects elevated iron oxide nanoparticles in the brain. White’s tool builds on research indicating that abnormal iron oxides may be formed early in the disease process, possibly due to a malfunction in the brain’s iron-storage protein.

To improve the accuracy of MRI data, White has also developed a patented method to correct for a patient’s head motion in the scanner, which can result in inaccurate measurement. White’s method is available for use in research and clinical applications.

• A new intervention for restoring non-verbal communication skills to patients who have suffered TBI. The treatment, developed by Susan Leon, Ph.D., targets a condition known as aprodosia – a deficit in understanding or expressing the variations in vocal tone, pitch, or rhythm used to convey emotional cues – that is often cause by damage to the areas of the brain involved in language production. The intervention is currently being evaluated by Leon and another BRRC investigator, Kay Waid-Ebbs, Ph.D.
• A smartphone application, developed by Waid-Ebbs, to help veterans with TBI apply the principles involved in Goal Management Training™ (GMT, a validated metacognitive intervention for treating TBI) to everyday tasks. The application, VA Task Manager, is available for download from the Google Play Store.
• An objective, quantitative tool for diagnosing post-traumatic stress disorder (PTSD), developed by Mo Modarres, Ph.D., the bioengineer who coordinates the BRRC’s brain function measurement. Building on his encephalographic (EEG) measurements of brain activity among veterans with and without PTSD, Modarres has identified EEG signal markers and produced a diagnostic index for both the presence of PTSD and its severity. Modarres has also developed and patented a portable EEG system that can be used in veterans’ homes to diagnose PTSD and sleep disorders associated with TBI and PTSD.

“EEG is a non-invasive method to collect brain signals from surface electrodes on the scalp,” Daly said, “and the EEG signal for those with PTSD exhibits significantly different characteristics compared to those who don’t have PTSD. In both clinical practice and in research, it’s important that we apply an accurate, objective measure in identifying those with PTSD, in order to provide proper care.”

A Future Paradigm for Brain Rehabilitation Research

Because brain injuries are often sustained in traumatic experiences, there is a strong correlation or “dual diagnosis” of PTSD and TBI. The Defense and Veterans Brain Injury Center (DVBIC) reports nearly 350,000 diagnoses of TBI in the military since 2000, and studies suggest up to half of all service members with combat-related TBI meet the diagnostic criteria for PTSD.

As more has become known about the relation between TBI and PTSD, some BRRC investigators have turned their attention toward the problem of how to diagnose and treat the neural dysfunctions associated with PTSD – a chronic condition that affects the brain’s limbic structures and can lead to hyperarousal, a persistent perception of threat, flashbacks, and nightmares. In recent years, BRRC investigators, led by John Williamson, Ph.D., and Damon Lamb, Ph.D., have begun to examine new methods for mitigating the emotional dysregulation that often accompanies PTSD.

With novel treatments such as these being explored by BRRC researchers, Dr. Daly is optimistic that the Center will, over the next five years, lay the foundation for a paradigm shift in precision neurorehabilitation for veterans with TBI and stroke who suffer persistent cognitive, motor and emotional dysfunction. This foundational work, Daly said, will include the discovery of new neuroplastic targets for treatment; new sensitive measures and biomarkers; and new treatments based on neuroplastic mechanisms, developed and tested for feasibility.

In the near future, said Daly, “We’ll be testing 17 new interventions for restoring these signature problems of TBI and stroke: cognitive and motor dysfunction, and the devastating emotion dysregulation that accompanies PTSD and TBI. As a Center, we respond to the needs of veterans and we, under the auspices of the VA RR&D, are mandated to be within their mission – so as their mission changes, and as veterans’ needs evolve and change, we’ll respond.”

This article originally appears in Veterans Affairs & Military Medicine Outlook 2019 Spring Edition: