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Healing the injured brain: How can research help?

Neurologist Michael E. Selzer, MD, PhD, is the director of Rehabilitation Research and Development for VA. (Photo by Mitchell Mirkin)

"Your skull gets pounded against your Kevlar [helmet]. Your brain gets tossed around like an egg in a bucket of water," is how Retired Army Pfc. Chris Lynch, who suffered a brain injury during training in 2000, explained his injury in a recent interview with the American Forces Press Service. Through intensive therapy, Lynch has recovered much of his ability to do everyday tasks, and now reaches out to newly brain-injured troops to offer support.

Traumatic brain injury (TBI) has been called the "signature injury" of the current U.S. military deployment. More than 26,000 troops have been wounded in Iraq alone, the majority of them from blasts. It is estimated that more than 60 percent of these blast injuries—such as from roadside bombs, mortars, or rocket-propelled grenades—result in TBI.

VA now routinely screens OIF/OEF veterans for TBI (as well as for posttraumatic stress disorder). Using a standardized one-page form, clinicians ask questions such as: "During your deployment, did you experience a blast or explosion? A fall? A vehicle crash? A wound above the shoulders?" The form, based on a screening tool developed by the Defense and Veterans Brain Injury Center (http://www.dvbic.org), goes on to cover symptoms such as headaches, memory or sleep problems, irritability, and sensitivity to light. Veterans who screen positive are referred for an exam and possibly tests such as brain scans.

Some patients with TBI receive care through regional polytrauma teams. Those with more complex injuries are treated at one of VA's four main polytrauma centers, in Minneapolis, Tampa, Richmond or Palo Alto (http://www.polytrauma.va.gov). Initially established as TBI clinics in the early 1990s, these sites were tasked in 2003 with providing comprehensive care for polytrauma, which typically includes TBI along with a web of other serious injuries: amputations, fractures, burns, hearing and vision loss, organ damage.

How can research help meet the challenge of caring for veterans with TBI, and what clinical issues are driving VA research in this area? Research Currents discussed these issues with Michael Selzer, MD, PhD, VA's director of Rehabilitation Research and Development and a neurologist who studies regeneration of the central nervous system.

RESEARCH CURRENTS: VA and DoD already have screening tools in use. Can research yield improvements in this area?

There is lots of room to make these assessments better. One of the areas we're working on with the Defense and Veterans Brain Injury Center is the evaluation of mild TBI. We want to be able to better detect the subtle neurological problems that people might have—either soon after their injury, or at a later stage of care.

Right now, when we give someone a full battery of neuropsychological tests, it can take up to eight hours. We look at a variety of thinking abilities and skills—for example, the ability to recall events in the past, or to remember something when you're distracted and have to come back to it. What we don't know is the minimum testing you need to accurately assess each skill. Once we learn more in this area, we can use that knowledge to develop screening tools that are as reliable and accurate as possible, and that are quick and practical-especially for evaluating troops on the battlefield or in field hospitals.

RC: Is TBI difficult to diagnose?

Yes, because it's a complex and varied phenomenon—not only in severity, but in terms of where in the brain the injuries occur. Symptoms vary greatly depending on what nerve pathways are interrupted. When we evaluate people with TBI, we need to find out not only about the obvious deficits—like weakness on one side, which often happens with more severe injuries—but even subtle things, like loss of attention. A good example would be a secretary who had been functioning at a high level and could take notes at meetings where six people were talking back and forth to each other. Now, after even a relatively mild brain injury, she finds she can't take in all this information anymore, because it's coming from too many directions at one time.

It's important to remember that even mild TBI can have a very serious impact on a person's life. For example, if you lose those subtle intellectual capacities that made you an effective worker in the modern workforce, that can be very disabling.

Neuron image courtesy of Vanderbilt University

RC: Are brain scans helpful in diagnosing TBI?

In TBI, the structural damage is not as easy to see as it with stroke, because the damage is not all in once place—it's scattered. But as imaging technology continues to evolve, we're able to do more. Conventional magnetic resonance imaging (MRI) is useful to a large extent because it can show damage to many—but not all—of the brain's structures. Diffusion tensor imaging (DTI), a newer type of MRI, is particularly valuable because it shows damage to nerve fibers, which is an important factor in TBI.

Still, the only way an MRI can tell you about an injury's effect on brain function is if you've done studies to correlate certain parts of the brain and certain nerve fiber pathways with certain functions. More research is needed to determine all those correlations, especially when the damage is more subtle or scattered.

Conventional MRI, which can show the structure of the brain in high detail, is generally combined with functional MRI (fMRI), which measures blood flow or oxygen use—indicators of activity—in different parts of the brain as the person performs a task. If you correlate fMRI with structural MRI—that is, actually superimpose one scan on the other—you can tell what parts of the brain are not functioning during the performance of a task that is impaired because of the brain injury. By determining with high resolution what parts of the brain show fMRI abnormalities, eventually we may be able to use fMRI and high resolution structural MRI to predict the deficits in mental ability that are easily missed in the field. This type of correlation is done routinely in research nowadays, but we haven't yet employed it on a large scale for clinical diagnosis.

There are other types of scans, such as positron emission tomography, that may be useful as well.

RC: What is considered state-of-the-art treatment for TBI?

It's basically a mix of therapies—cognitive, speech, occupational—plus medication to control specific symptoms, such as anxiety or pain. The therapies are based on practicing and finding strategies to compensate for lost skills. They can be very helpful in improving the quality of life of those with TBI, but the amount of improvement you can get is limited. We don't yet have a real way of reversing the deficits.

We had hoped a lot of this therapy would be generalizable, but it isn't. Take, for example, the case of someone who is aphasic—they have lost language ability—and can't think of the right word for a ball. You can train them to get better at naming the ball. Unfortunately, teaching them to name the ball doesn't make them better at naming something else. Each thing needs to be practiced on its own. It's very time-consuming and painstaking, and there's a limit to how far you can go.

RC: So these therapies demand not only skilled and dedicated therapists, but diligence and perseverance on the part of patients.

That's correct. And not everyone has the same stick-to-it-iveness. In some people, the injury itself causes a loss of initiative, which can affect the course of therapy. Because these injuries are so different from one another, and because people are so different from one another, it's often difficult to predict how much recovery to expect. One area where research might help is in developing models to help predict the path of recovery.

RC: Do current therapies take advantage of brain "plasticity"—the innate ability of the brain to "rewire" itself to compensate for damaged nerve cells and lost function?

Yes. As patients go through therapy and relearn and practice skills, nerve cells in their brain may change their shape to a limited extent. For example, a nerve cell has a fiber—axon—that it uses to talk with other nerve cells. These axons can sprout new branches, and these branches can travel for very short distances—generally, less than one millimeter. As long as the nerve cells haven't been killed, the brain can rewire its connections, to some degree, over short distances.

Along with this, synapses-the junctions where nerve cells talk with each other—become stronger with use. So through a combination of increased strength of the synapses plus local sprouting, we can regain some of the local connections. That means a nerve can now activate not just the neighboring nerve it used to activate, but also other nerves that had lost their inputs because of the injury. So the function in a finger could be regained, for example, if the nerves that activate the neighboring finger were spared and could assume the extra function. But those same intact nerves would not be able to activate a leg that had lost its nerve supply—the distance in the brain between where the hand is represented and the leg is represented is too great.

So the brain's intrinsic plasticity can allow for some improvements, but we can't get huge changes.

RC: How critical is the timing of treatment for TBI? Is there a limited window of opportunity for improvement?

We don't know as much about timing and plasticity in TBI as we do in stroke, in part because the animal models are not as well-developed, and in part due to the great variability of TBI and the difficulty until now of being able to image the injury. We're encouraged by what we've seen in stroke—even patients who have what appear to be fixed deficits are able to recover more function with additional therapy, even two or three years after the stroke. The same may be true in TBI. An interesting question is whether doing therapy during the stage when the brain is undergoing its natural repair mechanisms and is most plastic—soon after an injury—is better than doing it later.

RC: How can research contribute to better treatments?

To go beyond the limits of the current therapies, you have to repair the nervous system. VA scientists and others are exploring various ways to do this.

There are brain chemicals that appear to block the re-growth of nerve cells. Some of the research involves neutralizing these chemicals. Along similar lines, it may be possible to provide drugs that enhance the natural ability of nerve cells to grow. Researchers are looking at proteins called trophic factors, which are present in the brain in very small amounts and are needed for nerve cells to be healthy and re-grow their fibers.

Another way to repair brain damage is to replace brain cells that have been killed or damaged. This could involve adult stem cells or other "nerve progenitors" that would be transplanted and develop into nerve cells to replace the lost ones.

Electrical stimulation of the brain has not been tried in relation to TBI but has found application in the treatment of other neurological disorders, such as Parkinson's disease and epilepsy.

RC: How heavily should VA invest in these avenues of research?

The Office of Research and Development has to be sure that it invests in research both to provide near-term benefits to our soldiers returning from OEF/OIF with TBI, and to give them hope for more profound improvements in the long term. TBI research should be balanced between these two essential goals.

At one end of the research spectrum, we have to do clinical studies that will find the optimal parameters—such as dose, frequency of treatment, duration of treatment—for therapies whose effectiveness is already partially established, based on preliminary studies in patients. At the other end of the spectrum, research on the cellular and molecular mechanisms by which the brain can be repaired through regeneration or replacement of nerve cells and nerve fibers may in the long run provide the potential for more profound functional improvement. But the chances of failure are greater, and the time it takes to develop a clinical treatment based on the findings is much longer. Lying somewhere between these two extremes is "translational research," in which studies on experimental animals have already produced strong reason to expect that a proposed therapy will prove safe and effective, and is therefore ready for preliminary studies in human patients. All three types of research are important.

Because of the enormous impact of TBI on our soldiers in OEF/OIF, the VA research community is accelerating its efforts at all three levels of investigation: fundamental science, translational research and clinical research. We cannot afford to be confined by our current techniques. Fine-tuning them is part of what we need to do, but that alone will not lead to the kind of big recovery we are seeking for our veterans with TBI. We must think outside the box, so that they can have the best available treatments as quickly as possible, and have hope for even greater improvements in the future.

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