The Concussion Crisis

by Linda Carroll

  The sudden release of neurotransmitters that follows a jolt to the head prompts neurons to open the door to two types of charged molecules—calcium and sodium. The sodium electrifies the cells, while the calcium chews away at their internal structures if it stays too long. Making matters worse, the initial mechanical pulling and twisting stretches the tiny pores lining the cell’s outer skin. That results in bigger openings, which allow potassium to rush out of the neurons while even more calcium and sodium flood in. If enough sodium pours in, the results can be catastrophic because sodium brings water with it and that can cause a cell to bloat, just as a person’s hands and feet swell when a large quantity of salt is consumed. Too much bloating can result in a dead neuron.

  In an attempt to get their internal chemistry back to normal, the neurons turn on machinery designed to pump potassium back into the cell and sodium out of it. Potassium serves as a set of brakes to the effects of sodium, by turning off the electricity. But the ion exchange takes a lot of energy, which the cell gets from its internal power plants, the mitochondria. Just as power plants need uranium or coal to produce energy, the mitochondria need glucose to create energy for the cells. It doesn’t take very long for the glucose supply to run low and for the cellular power plant to experience a brownout, which then leaves the brain running at very slow speed. This, Hovda says, explains the slowed processing and fatigue that people experience shortly after a concussion. The situation can worsen if high levels of calcium have entered the cell. Then the brownout can turn into an actual blackout, because calcium will clog the machinery in the mitochondria, disabling them even further. Eventually, if the power plant completely fails, the neuron can die.

  At the same time as the brain needs more and more energy, its blood supply becomes compromised. Blood is what brings glucose to the brain. When the brain needs more energy, the cells fire and send out a message to the body to increase blood flow so that more glucose will be delivered to the mitochondria. But somehow, after a jolt to the head, that message gets garbled, and no matter how many signals the neurons send, there is no increase in blood flow. In severe cases, cells can die because they aren’t getting the fuel they need to run. In response to all of this, the brain releases high quantities of potassium in an attempt to calm things down. The result of that is an even slower and foggier brain.

  One question scientists still haven’t answered is whether there are permanent, though subtle, changes to the brain from mild hits. Some researchers suspect that each hit causes a small amount of permanent damage that is not enough to produce symptoms but might eventually add up to something more severe if the hits keep coming. The theory is that tiny gates positioned at various spots up and down the length of the axon are corroded a little more with each hit. Since the gates play a role in the propagation of an electrical signal up the length of an axon, damage to them can make the axon nonfunctional.

  You can think of the axon as a canal with a series of locks. An electrical impulse, like a ship moving up the canal, starts at one end of the axon when sodium is allowed in. The gate to the next section opens and allows the sodium, and the electrical current, to move into the next segment of the axon. The gate then closes behind it. The process continues until the current has sparked the entire length of the axon.

  One of the consequences from a jolt to the head is the rush of calcium into the axon. This can activate enzymes called proteases, which act like a set of scissors. They will chop away at the gate, leaving it frayed and leaky. Some scientists believe that each mild hit results in a small amount of damage to the gates. They still work, after a fashion, but not as well. As the hits add up, the gates become increasingly more damaged until they’re completely broken. That theory could help explain why people who sustain a concussion are more susceptible to another and why each succeeding concussion seems to result in worsening symptoms. Douglas Smith compares the situation to an airplane losing its engines. “One falls off and the plane might fly fine and the passengers probably wouldn’t even notice,” the Penn scientist says. “But if you lose another one, that’s an entirely different thing.”

  • • •

  For years, scientists had no way to “see” the effects of a concussion in a living TBI survivor. But once researchers recognized that glucose metabolism reflected the brain’s response to a jolt, they realized they already had a tool that might allow them to watch the concussed brain at work. PET (positron emission tomography) scanners, which had been used for years to look at brain function, are designed to detect and interpret emissions from radioactive substances to produce an image. Much of the early work with PET had been done using radioactive glucose, which is injected into the arm of a person shortly before scanning. The glucose eventually wends its way into the brain and then researchers can watch as various regions power up, their activity highlighted by red, orange, and yellow hues on scans. In a typical experiment, researchers might want to see which parts of the brain activate when a person remembers a distressing event. Researchers can ask the person in the PET scanner to concentrate on a traumatic episode and then watch to see which brain regions light up. Colors on the scan range from dark blue to deep red, with blue signaling no activity and red signaling the most.

  Scientists in Hovda’s lab at UCLA had begun using PET to look at a broad spectrum of TBI, from mild to severe. One day Hovda had a fortuitous and stunning insight. He’d ordered up two PET scans: one from a TBI survivor who was in a coma, the other from a concussed football player. When he pulled the scans out and started to examine them, he was sure there had been a mix-up. The two sheets of film he had in front of him looked almost identical. He thought they must both be from the coma patient. Both scans were mostly blue in color with faint smudges of light green scattered here and there. An image from a normal brain would have been marbled with reds, oranges, and yellows. The minor amount of glucose metabolism in both these brains was signaled by the weakly glowing smudges of green. Hovda’s assistant assured him that the scans were the right ones. They were indeed from two separate patients—one in a coma, the other wide awake and recovering from a concussion. Hovda realized that the implications were profound. An athlete recovering from a concussion had the same diminished glucose metabolism as a comatose patient.

  To see if this was a fluke, Hovda and his colleagues scanned forty-two other patients whose TBIs ranged from mild to severe. The researchers found that 86 percent of the patients with severe brain injuries and 67 percent of the patients with mild-to-moderate injuries had the same low levels of glucose metabolism. What was remarkable, the researchers wrote, was that concussed patients who walked up to the scanner on their own power often had the same impaired glucose metabolism as the comatose patient who had been wheeled into the PET-scanning room breathing through a ventilator.

  Other researchers started to examine brain-injured patients with an imaging technology called functional MRI, or fMRI. Like PET, fMRI looks at brain function rather than structure. In the case of fMRI, scans show blood flow, which in turn tells researchers about oxygenation. When a particular region of the brain is working hard, it will need more oxygen and, therefore, higher blood flow. So, if the activity in a particular area of the brain is turned up, it will shine bright on a scan. Researchers at the University of Pittsburgh found that in the days after a concussion, brain activity in an area called the posterior parietal cortex was depressed in some patients. The patients with slowed brain activity turned out to be the ones who had been experiencing the most symptoms. After a concussion, they had reported a host of both cognitive and physical symptoms, such as drowsiness, fatigue, difficulty concentrating, memory problems, blurred vision, headache, and light sensitivity.

  While PET and fMRI can give a clear picture of the brain’s biochemistry, they don’t provide any information about small-scale structural changes, such as diffuse axonal injury. For that, scientists turned to a developing scanning technology known as DTI (diffusion tensor imaging). The technique uses an MRI machine but a dif
ferent method of analysis that exploits the fact that water tends to flow in the same direction as the structures in the brain. So, if you can follow the water with a brain scanner, you should be able to see structures like the bundles of axons that run through the brain. And if these structures are disrupted in some way, that should show up, too.

  The method didn’t always turn up axon damage in symptomatic patients, but some of the scans were stunning in what they revealed. You could see whole groups of axons that appeared to be sheared off. Most of the initial work with DTI was done with severely injured patients, but in 2010 researchers at the Albert Einstein College of Medicine ran an experiment to see if symptoms from mild TBIs could be correlated with actual damage to axons. The researchers focused on executive function, which is known to be seated in the frontal lobes. Before scanning anyone, the researchers tested the executive functions of a group of uninjured volunteers and a group of concussed patients. The test, which was run on a computer, looked at how well people learned from trial and error. “It’s admittedly not a real-world situation,” says Dr. Michael Lipton, associate director of the Gruss Magnetic Resonance Research Center at Albert Einstein. “But it does pick up people who have problems with multitasking and following multistep directions. A secretary, for example, has to manage several things at the same time. She has to plan new activities while keeping in her mind a list of things to do that day; she has to keep track of what she’s finished and what she hasn’t finished. These are the kinds of things we rely on our brains to do, without thinking about it.”

  Lipton’s scans from patients who had problems with the computer test showed damage to axons in an area known to be involved in executive function, the dorsolateral prefrontal cortex. Before there was DTI, he explains, you couldn’t see any of these changes; on traditional scanners, their brains would have looked completely normal. “This shows that there is clearly something wrong with the brains of these people,” he says.

  So far, no one has used DTI to follow concussed patients over a long period of time to see if the missing connections are repaired. No one knows how much rewiring actually takes place. One thing that is becoming increasingly clear, though, is the possibility that a TBI in some patients kicks off a degenerative process that continues for the rest of that person’s life.

  • • •

  Douglas Smith’s axon-stretching experiments, coupled with autopsy results from his lab and others examining patients with severe brain injuries, would eventually yield insights into TBI consequences that could show up decades after a head injury. His research showed how a head injury might spark a lifelong process of neuron degeneration. It also provided a possible explanation for the well-established link between TBI and a heightened risk of Alzheimer’s disease: the researchers found that a single stretch could lead to the accumulation of amyloid beta, the sticky protein that clogs the spaces between neurons in the brains of Alzheimer’s patients. The new discoveries came after Smith and his colleagues decided to watch axons for a longer period of time following the initial stretch.

  Chief among the proteins shuttled up and down the length of an axon is one called amyloid precursor protein (APP), the stuff from which amyloid beta is made. In a healthy axon, proteins moving along the microtubules are kept separate from one another, like boxed products moving on a conveyor belt. When axons are damaged by stretching and the microtubule conveyor belt is broken, all the boxes dump over the end, smash together, and rip apart, allowing their contents to intermingle. In the jumble with APP are enzymes that can slice it up and convert it into the sticky amyloid beta. As the axon bulb swells, increasing amounts of amyloid beta are created.

  Eventually the bulbs burst and disgorge their contents, including heaps of amyloid beta, into the area surrounding the axon. This observation helped explain something that the Scottish researchers had discovered years earlier: the brains of 30 percent of TBI patients who died shortly after a head injury were riddled with the same kinds of plaques found in the brains of people with Alzheimer’s disease. Alarmingly, many of the TBI patients had been fairly young. “It was clear that the plaques were forming within hours of the injury,” Smith says. “In many of the cases, there weren’t as many plaques as you’d see in a case of full-blown Alzheimer’s, but the pathology was startling, especially in relatively young patients.”

  When the Penn researchers first discovered the amyloid beta plaques in the brains of TBI patients, they suspected they’d found a direct connection to Alzheimer’s disease. But the story got more complicated as they took a closer look. When they had the opportunity to examine the brains of patients who survived six months to a few years after a TBI, the researchers found continuing axon deterioration—complete with newly formed protein bulbs—but no plaques. Smith and his colleagues were perplexed. Study after study had established a link between TBI and Alzheimer’s disease. Plaques seemed to sprout prodigiously in the hours after a brain injury, but then mysteriously disappear in the months and years following the TBI.

  A few years earlier, Japanese researchers had discovered that an enzyme called neprilysin was able to slice up amyloid beta and dispose of it. In fact, certain forms of the gene that produced the enzyme seemed to be protective against Alzheimer’s disease. Smith had a new hypothesis. Perhaps TBIs kicked off a degenerative process in the brain that was kept in check by neprilysin. As dying neurons spewed out heaps of amyloid beta, neprilysin would come in and sweep up the gunky protein and recycle it into nontoxic substances. You wouldn’t see plaques as long as the neprilysin was able to keep pace with amyloid beta production. When they checked for differences in the neprilysin gene in the patients who died shortly after a brain injury, the researchers found that all of the patients who developed plaques also had one specific form of the neprilysin gene.

  Smith suspected that this was a less efficient form of the gene, one that allowed the rapid formation of amyloid plaques shortly after a brain injury. Although the plaques seemed to disappear over months, it was possible that the balancing act between amyloid beta production and destruction could eventually be thrown out of whack. The trash heap would grow faster than the street-sweeper enzyme could clean it up, and the result would be a brain clogged with amyloid beta plaques.

  There was a way to test the hypothesis: examine the brains of TBI patients who had survived for many years after their injuries. Smith and his colleagues located the brains of seventy-four patients who died from three hours to forty-seven years after a TBI. The researchers autopsied these brains and then compared them to brains from forty-seven people with no history of brain injury. This time the researchers looked not only for amyloid beta, but also for tau, the protein that makes up the stringy tangles found inside the neurons of people with Alzheimer’s disease. The earlier studies had shown no tangles in the brains of patients who died within weeks of a brain injury.

  Once again, the researchers found clumps of amyloid beta in the brains of about 30 percent of the people who died shortly after a TBI, while very few plaques were seen in the brains of patients who survived a few months to a few years after an injury. But plaques seemed to reemerge with time. The researchers found far more of them in people who died at least four years after a brain injury. And this was true even in people who were in their thirties, forties, and fifties when they died. Even more startling, the researchers also found extensive tau tangles in the brains of many patients who survived multiple years after a TBI. When they examined the brains of people with no history of a TBI, the results were very different: Alzheimer’s pathology was evident only in the brains of people who died when elderly.

  “This is clear evidence that with a single brain injury, you can get both pathologies,” says Smith. “It’s provocative and frightening. These patients have the hallmark pathologies of Alzheimer’s disease even though they are young.”

  Smith’s findings were profound. One moderate-to-severe head injury could kick off a neurodegenerative disease that could come back to haunt people many y
ears after they’d “recovered” from a major jolt to the brain. What Smith’s work couldn’t answer was whether lesser hits could have a similar effect. But there were suggestions from studies of boxers that had been done over the previous several decades. In boxers, at least, it looked like repetitive jolts to the head might set in motion a process that would eventually culminate in dementia and changes in the brain that looked very much like Alzheimer’s disease.

  Chapter 9

  A Pocketful of Mumbles

  Jerry Quarry always had too much heart for his brain’s own good. That’s how it had been ever since he laced on boxing gloves at the age of three and began living by his father’s family motto: “There’s no quit in a Quarry.” Raised to be a fighter by his hardened father in the migrant labor camps of California, Quarry used boxing to escape a hardscrabble heritage he described as right out of The Grapes of Wrath. By the time he’d grown to a powerful six feet and 195 pounds, he had the tools to be a top heavyweight contender: a mean left hook, a crafty counterpunching ability, a granite chin that could take any punch, and, above all, a gritty tenacity.

  What Irish Jerry Quarry lacked was the luck connoted by the green shamrock on the robe he wore into the ring. It was his bad luck to be merely good in a golden age of heavyweight greats defined by Muhammad Ali and Joe Frazier. Twice Quarry fought for the heavyweight championship of the world only to end up broken and heartbroken. He fought Ali and Frazier two times apiece, bravely battling through bloody beatings even after defeat had become as inevitable as it was predictable. Quarry took everything they had without flinching, but his most dangerous and destructive foe wasn’t Ali or Frazier—it was Jerry Quarry.