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Clocked!

UCLA researchers are redefining the science of concussion, just as traumatic brain injury is reaching epidemic proportions.

Dr. Patricia A. Ganz

In the fall of 2005, I fell off my horse and ended up with a concussion. It was a frightening experience, replete with all the requisite drama — sirens, an ambulance, a lumpy ER gurney and a brain scan — but I was lucky. After various tests at my local hospital, I was reassured there was no bleeding, no swelling in my head, and that I should rest, take it easy and let myself heal. It was a mild-tomoderate concussion. I would be fine. My wife and I hoped they were right.

Things did not exactly work out the way we hoped.

The following weeks instead brought depression, intense bursts of anger, crying jags and, eventually, noticeable loss of strength and muscle tone. I startled easily at any sharp sound. My short-term memory was shot. This went on for months. For a second opinion, I went to UCLA. There I saw Paul Vespa, MD (FEL ’96), a neurologist and director of the UCLA Brain Injury Program. Dr. Vespa is a quiet fellow, with a calm visage and cerebral demeanor. After chatting with me for a few moments in an examination room, he turned his gaze to a computer screen, poking at the keyboard.

“Why are you looking at the &^%#$ computer?” I said, crossly. “I mean, you haven’t even felt my head where I fell, or … .” “That’s because I’m looking for something else,” he responded. “What?” “Hmm. How can I put it? I’m basically looking at how your brain is using energy, and if the trauma disrupted that.”

Dr. Vespa had just given me Lesson One in UCLA’s new world of concussion research.

THAT WE NEED SOMETHING NEW IN THAT WORLD has grown increasingly clear in recent years. Beginning with the startling news in 2010 that the baseball great Lou Gehrig may have died from repeated concussions and not from what’s come to be called Lou Gehrig’s disease, report after report on the subject has exploded onto the front pages of the nation’s most influential journals, newspapers and magazines. Traumatic brain injury (TBI) became a top priority in sports and sports medicine. It’s also come under the lens of pediatricians, family doctors and emergency-room physicians who see the neural consequences of TBI streaming in every day from the nation’s soccer pitches and football fields.

“When we looked at the film, we saw that the jolt to the head caused a massive flow of ions (needed for key brain functions) That in turn created a huge demand in the brain for glucose, for energy. And this massive burning of glucose was followed by a huge energy depression throughout the brain.”  

And then there is the media frenzy. Concussion being a high-static subject, it is fodder for ESPN and Fox Sports and other talking-head outlets — coverage that rarely leads to reasoned discourse. The result: calls for everything from new protective gear and new field regulations to an outright ban on contact sports. But where is the science?

David A. Hovda, PhD (FEL ’87), director of UCLA’s Brain Injury Research Center, has been trying to answer that question for nearly three decades. As he tells it, a pivotal insight in his quest came not long after arriving in Los Angeles from New Mexico in the mid-1980s. “I’d always been interested in concussion, yet in many ways it seemed at the time that the main questions were all answered: concussion — a trauma to the head resulting from some biomechanical force — sometimes presented with such things as an open wound, loss of consciousness, cerebral swelling, bleeding and the like. Yet we also knew something else: The vast majority of brain traumas did not present with any of those!” Most were closed-head traumas involving little or no loss of consciousness, the kind of thing usually dismissed as having one’s “bell rung” or “getting clocked.” “Yet we knew these patients were still not right,” Dr. Hovda says. “Something was wrong.” Around 1990, the then-chief of UCLA’s Division of Neurosurgery, Donald P. Becker, MD, put the issue directly to Dr. Hovda: “Dave, what happens to the cells that survive a concussion? What happens to them, and how long does it last?”

  Dr. David A. Hovda
  When Dr. David A. Hovda and colleagues at UCLA examined images of concussed brains in rats, they were shocked to see that the injuries caused a neurochemically induced energy crisis that dramatically altered surviving nerve cells.
Photo: Ann Johansson

It was a vexing question, and it wasn’t until Dr. Hovda met a fellow UCLA scientist, Yoichi Katayama, MD, PhD, that the veil began to lift. At the time, Dr. Katayama, who is now a professor of neurosurgery at Nihon University School of Medicine, in Tokyo, Japan, and president of the Japan Neurosurgical Society, was examining the neurochemistry of concussed animal models. “The results were amazing — and problematic,” Dr. Hovda recalls. “When we looked at the film, we saw that the jolt to the head caused a massive flow of ions (needed for key brain functions). That in turn created a huge demand in the brain for glucose, for energy. And this massive burning of glucose was followed by a huge energy depression throughout the brain. There was no bleeding, swelling or wound. But these brains were in a huge energy crisis.”

All of this wrought disturbing changes in the nerve cells that survived the concussion, exactly what originally concerned Dr. Hovda’s mentor. Cells became dysfunctional, and the effect lasted for long periods after the original trauma. Spikes in calcium flows caused breakdowns in the mitochondria, the energy-producing subunit of all cells. The same buildup of calcium also triggered pathways leading to cell death. The jagged flow of other brain chemicals warped the internal structure of neurons, impeding the connectivity between cells — the connectivity required for healthy cognition. How, exactly, did this energy crisis unfold?

Fortunately, there were new neurological-research tools to help answer the question. The scanning technique known as positron emission tomography (PET) allowed researchers like Dr. Hovda to observe a wide array of bodily processes, in particular the way the brain — or any other organ — uses fuel. Another innovation came from the world of animal-disease models. Previously, these modeled only open-wound traumatic brain injury — helpful in assessing major trauma but of little help for the bulk of TBI cases. So researchers invented ways to model the less-dramatic but more-prevalent profile of concussive injury.

Slowly, scientists at other institutions began reporting Dr. Katayama and Dr. Hovda’s findings in human brains. Yet it was not until Dr. Hovda received a call, in the late 1990s, from UCLA’s Gerald A.M. Finerman, MD, an orthopaedic surgeon and renowned sports-medicine expert, that he came to understand how ubiquitous the energy crisis was in all kinds of concussion. Dr. Finerman invited Dr. Hovda to do a PET scan on a football player who had a concussion during practice; he then compared that scan with those of a severe TBI patient. “They looked the same,” Dr. Hovda recalls. “I showed both scans to a friend, and he said, ‘Wow, they’re the same! That can’t happen!’” But it did happen, over and over again.

WHAT DOES IT MEAN TO HAVE A BRAIN that’s in an energy crisis? Could this new understanding of concussion explain some of my own ongoing cognitive issues — my jumpiness, my difficulties in learning and a slowdown in my reasonably decent analytical abilities? I wanted to know, and so I visited neurologist Christopher C. Giza, MD (RES ’94, FEL ’96, ’00), also on the faculty of the UCLA Brain Injury Research Center.

  Dr. Christopher C. Giza
 

Dr. Christopher C. Giza’s research found that someone who suffers a traumatic brain injury may, as a result, become predisposed to developing post-traumatic stress-like responses such as anxiety and hypervigilance.
Photo: Ann Johansson

In the first years of the ’00s, Dr. Giza worked with Dr. Hovda to address a clinical question: How does a traumatic brain injury, especially so-called mild concussion, affect different age groups? One key question was how did mild-tomoderate TBI affect a child’s learning abilities? To find out, Dr. Giza turned to the growing field of enrichment research.

Enrichment is, in essence, all the environmental aspects of cognitive development. Think of it as a sort of beneficial challenge to the brain — things like education, physical play, everyday problem-solving. Such challenges have been shown to improve learning both in lab animals and humans. So what would happen to such benefits after a concussion?

As Dr. Giza recounts his experiments with rats, mild TBI did not cause an obvious neurological impairment. “They walked, ate, groomed and played like regular young rats. But, when we raised them in an enriched environment, which should have made them smarter and is loosely akin to sending them to school, different things happened,” he says. For one, the uninjured (control) pups got smarter and stayed smarter as adults. “But the TBI pups that were raised in an enriched environment showed no benefits of that education. In fact, as adults, the enriched TBI rats acted like rats that never went to school.” The key finding — and something every soccer mom might want to know — was that TBI didn’t cause an obvious problem up front but interfered with the young rats reaching their full cognitive potential.

“In lay terms,” Dr. Giza says, “they went to school but didn’t learn anything.” To find out how mild TBIs affect other cognitive mechanisms, Dr. Giza used a number of tried-andtrue tests in the field of what might loosely be called cognitive relearning. The tests model situations and cues not unlike what might be encountered on the battlefield, the athletic field or even in an accident like mine. In humans, that usually means the sounds and surroundings associated with the original trauma — bombs exploding, the screeching brakes of an oncoming car, a horn blast, the roar of a crowd or even the smell of a horse. (To this day, I get nauseous whenever I encounter barnyard smells.) In neuro-cog terms, these sights and sounds act as mental cues that never get completely erased or “extinguished,” prompting the patient to overreact, startle and panic to sounds long after the real danger is gone. You can see it in combat veterans, football players, untalented equestrians and kids coming home from the soccer field.

“There is a vulnerable period of about seven-to-10 days after a concussion in which the risk of having a second concussion is much higher, even if the athlete’s symptoms have resolved.”  

Dr. Giza’s experiment sounds simple, but it has raised lots of complex questions. “We train the animals to recognize a certain cage and a certain sound as a signal for danger,” Dr. Giza says. “Most TBI rats are slow learners when trained in other ways — memory testing, recognizing objects, etc. — but in fear-based learning, they paradoxically learned faster.” Of course, he goes on, “in some ways that is beneficial. As long as they are in a potentially dangerous environment, like soldiers who serve in combat, being more anxious and more cautious is a good adaptation.”

But the “good” adaptation comes at a big price. The same TBI rats, after training in the fearconditioning chamber, continued to freeze when put in a different “safe” chamber. “When we tried to train them that the danger sound was no longer dangerous, they couldn’t unlearn this,” he says. The enhanced fear-based learning turned out to be maladaptive in real life. “Once we made these observations, we noted that they might compare to the human condition of post-traumatic stress (PTS), where soldiers who become hyper-vigilant and anxious and react quickly can’t seem to turn this off when they come back from war,” Dr. Giza says. “Even in a civilian environment, they are anxious. When they hear certain sounds, it triggers the fear reaction, but since they are no longer on the battlefield, this reaction is not helpful. From our study, it appeared that physical TBI made it easier for the rats to develop this PTS-like state, suggesting that TBI biologically makes the brain more vulnerable to anxiety problems. “They carry this into daily life, like a vet coming back from war,” Dr. Giza says. Or, less dramatically, like a child who just got clocked during her Saturday soccer game. The ramifications of this work rippled through the neuroscience community. “The aftermath of concussion, best described by Drs. Hovda and Giza in the findings from their animal model, has forced the rest of us to re-think how we manage the injury clinically,” says Kevin Guskiewicz, PhD, co-director of the Matthew Gfeller Sport- Related Traumatic Brain Injury Research Center at the University of North Carolina at Chapel Hill. “UCLA is the leader in helping the neuroscience community to understand the neurometabolic cascade of concussion.”

Dr. Christopher C. Giza’s research found that someone who suffers a traumatic brain injury may, as a result, become predisposed to developing post-traumatic stress-like responses such as anxiety and hypervigilance. Photo: Ann Johansson 20 U MAGAZINE

  Dr. Christopher C. Giza
 

Top: Positron emission tomography (PET) scan shows normal distribution and intensity of glucose utilization in an uninjured brain. Red is high and blue-black is low.
Bottom:
PET scan of a patient with mild concussion shows significant disruption of glucose distribution and utilization throughout the brain.
Images: Courtesy of Dr. David A. Hovda

THERE IS HOPE, BUT IT’S A LONG WAY OFF. To this day, there are few proven therapies for the long-term effects of concussion. There are drugs, but they fail as frequently, or perhaps even more frequently, as they work.

When it comes to treatment of sports-related concussion, “We are just scratching the surface,” says John DiFiori, MD (FEL ’94), chief of UCLA’s Division of Sports Medicine and Non-Operative Orthopaedics and head team physician for the UCLA Department of Intercollegiate Athletics. Dr. DiFiori is a realist, but he is that rare realist who has not succumbed to cynicism; he is hopeful. This, despite a lot of unhopeful finds in the latest scientific literature. He notes that helmets are primarily designed to reduce the risk of skull fractures and that other forms of headgear (e.g., rugby) do not appear to reduce the risk of concussion. In fact, such headgear may actually encourage more aggressive play, what is known as “risk compensation.” And mouth guards, while extremely effective in reducing dental trauma, do not decrease the risk or severity of concussions. But recent research has identified several important characteristics of concussion. For example, Dr. DiFiori says, “There is a vulnerable period of about seven-to-10 days after a concussion in which the risk of having a second concussion is much higher, even if the athlete’s symptoms have resolved.” That, he says, is why determining appropriate “return-to-play” protocols is so important — and still so controversial.

Dr. Di Fiori says there’s now growing evidence to help guide safe-to-return-toplay decisions after a concussion. For example, he says, “Children with concussion should be managed more conservatively than adults,” with an emphasis on return to learn before return to sport. One way to help determine when a concussion has occurred and when it is appropriate to return to play involves what Dr. DiFiori calls “baseline testing.” The idea is simple: Use a combination of measures — memory and cognition and balance testing — to establish what is normal for an individual player, perhaps before the season starts. “Then, if the player suffers a concussion, we have an idea of what has changed for that individual,” Dr. DiFiori says. “Our research indicates that these measures can vary based upon gender and sport, so they should be individualized, not compared to general population norms.” And clinical diagnostics are undergoing a promising sea change. A new kind of imaging process, diffusion tensor imaging (DTI), models tiny flows of water into the axon, the “connecting” end of a neuron. DTI may lead to the construction of a kind of concussion “map” that has been correlated to clinical symptoms. Another type of advanced scanning, magnetic resonance spectroscopy (MRS), can show changes in specific chemical markers in different regions of the brain, which may correlate with vulnerability to a second injury.

HERE WAS MY WAY OF PREVENTING ANOTHER CONCUSSION: I sold the horse. Unfortunately, the world does not usually work in such simple, direct ways. We can’t simply ban contact sports, as some have suggested, not as long as humans crave competition, fans crave spectacle and vast economic interests crave profit. And, sure, we’d like to ban war, but doing so seems highly unlikely. Which brings us to PTS. PTS has often been called “the invisible wound,” but to its victims, there is little that is invisible about their suffering. PTS now afflicts hundreds of thousands of returning vets, with devastating consequences; suicide among returning troops is at an all-time high. Many in the medical establishment believe the crisis is so profound and widespread that it may be too late to do anything for those already injured.

But Drs. Hovda, Giza, DiFiori and others who study brain injury say they are making progress in one area: finding ways to intervene to limit the damage of mild traumatic brain injury (MTBI) in the battlefield. One of their prescriptions is already being used — ever since a series of meetings among Dr. Hovda and various top defense leaders, from Admiral Mike Mullen, former chair of the Joint Chiefs of Staff, to Gen. Eric Shinseki, now the head of Veterans Affairs. Their prescription, proposed after visits to Afghanistan, resembles one they’ve long advocated for athletes with mild concussions: immediate removal from the field of battle. “Understanding this didn’t come easily,” Dr. Hovda says. There was resistance from officers trained to send soldiers into combat, not to pull them out. But after much discussion, the military came around; they saw the evidence, and they saw the suffering. “All of it resulted in a directive requiring removal of soldiers with mild TBI from the front lines,” Dr. Hovda says. For Dr. Hovda’s efforts, President Obama nominated him to serve on the Defense Health Board, advising the secretary of defense, and Dr. Hovda received the U.S. Army’s Strength of the Nation Award — the highest civilian award given by the Army — in 2011. In the quest to get UCLA’s new vision of the brain and brain injury on the radar, it was a huge victory. “We made the invisible wound visible,” Dr. Hovda says.

Greg Critser writes frequently about medicine and science. His most recent book is Eternity Soup: Inside the Quest to End Aging (Random House, 2010).

 





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