The Concussion Crisis

by Linda Carroll

  Over the years, Smith and his colleagues have been able to tease out the details of what leads to the wavy axons with the bulbous lumps. They learned that if the initial stretch had enough force behind it, axons wouldn’t rip but would sustain damage to specific internal structures. Axons get their shape and structure through an assembly of cellular “girders” called microtubules. When the axon was tugged hard and fast enough, the girders were pulled out of alignment, which is what gave the axon a wavy appearance. But the damage wasn’t confined to the axon’s internal scaffolding. Microtubules serve as a sort of conveyor belt to carry supplies and nutrients from one end of the axon to the other. When the axon was tugged hard, the conveyor belt would break, dumping all of its cargo at the site of the break. From the outside of the axon, the expanding pile of protein cargo looked just like the black bulbs seen by Adams and Povlishock. The end of the axon, starting at the bulb, would then wither away and completely detach just like those observed by Povlishock in animals (Figure 8.3). Eventually the axons with the blobs of protein would shrivel and die because they no longer could move supplies up and down their length.

  One thing the Penn researchers didn’t know was the eventual fate of the wavy axons. If you watched the axons long enough, some would eventually straighten out and not develop swellings. But was this because there had been internal repairs to the wrenched girders? Or were they just limping along transmitting garbled signals like a frayed, staticky phone line? The answer is important, Smith says. If an axon can self-repair, then researchers might be able to find treatments to speed up the process. But it’s also possible that some of the axons are beyond repair and are just garbling communications, so it might make sense to find a treatment that would finish them off. Smith compares the damaged axons to phone lines. “I lived in an old house and the previous owner, who worked at the phone company, had jacks installed everywhere,” he says by way of explanation. “Every once in a while, I discovered every phone in the house had a staticky noise problem. That’s because one faulty phone wire was contaminating all the rest. By simply disconnecting the bad wire, I could clear up the signal on all the others. So by analogy, if you get a couple of axons that are not only dysfunctional but also corrupting the whole system, making communication staticky, then you might consider therapies that both rescue axons that can be repaired and at the same time get rid of the guys that are just limping along and mucking everything up.”

  Figure 8.2: Sequence of photos following an axon from right after it’s stretched until two hours later. (Courtesy of Douglas H. Smith, M.D.)

  Figure 8.3: Evolution of an axon bulb and disconnection of the axon following a brain injury. (Courtesy of Douglas H. Smith, M.D.)

  All of Smith’s findings so far were in axons stretched by forces similar to those in a severe TBI. He began to wonder whether the same kinds of damage would be seen in milder brain injuries, like the concussions so prevalent in sports. There was evidence from an autopsy study that this might be the case. Australian researchers had looked at the brains of five people who had suffered a concussion and then died from other causes, such as pneumonia, days to months after their head injures. The study, which was published in 1994 in The Lancet, found the same kinds of axon damage—including bulbs of protein—that Adams had found in the brains of people with severe TBIs.

  Over the years, Smith had seen plenty of cases in which people with concussions—so-called mild traumatic brain injuries—had taken a long time to recover or had never completely recovered. “I like to say that the expression ‘mild traumatic brain injury’ is an oxymoron,” he says. “It’s only mild compared to the train wreck of severe TBI that can leave you in the hospital for years. But for people with concussions that just want to get back to being themselves, it’s not at all mild.”

  Smith figured he had all the tools to answer an intriguing question: Do mild traumatic brain injuries cause permanent changes to the axons? He was very familiar with post-concussion syndrome, so he knew that something serious could occur even in mild head injuries. He started to wonder whether a first concussion might lead to axonal damage so small that it was difficult to detect. Subtle changes in the axons might predispose them to significant damage if they were stretched again soon after the first stretch. Maybe, Smith thought, post-concussion syndrome was due to an accumulation of axonal injuries. The damage from the first jolt might simply make an axon more vulnerable to a second hit.

  He came up with a new experiment. He designed a stretch study that scaled back the intensity of the tug to approximate what an axon would experience in a concussion. When he and his colleagues examined the lightly stretched axons, they found no damage to the microtubules, and the axons outwardly appeared completely normal. The axons were then stretched a second time, twenty-four hours later, in exactly the same way as the first. Smith’s suspicions turned out to be right. When axons were stretched lightly two times in a row, they began to deteriorate. Some took on a wavy appearance. Some developed bulbs of protein. Some eventually died. Smith had proven that the damage from two light stretches could be equivalent to a single strong stretch.

  Now he wanted to know what it was about the first stretch that seemed to make the axons more vulnerable. So he and his colleagues took a closer look at what happened to the axons after an initial light stretch. They found that although the axons appeared to be structurally undamaged, there were subtle changes that might predict increased vulnerability to a second stretch. The researchers noticed there was an increase in the number of the tiny pores that line the outside skin of the axon and allow charged particles, like sodium and calcium, to come inside. When the axon was stretched a second time shortly after the first tug, huge amounts of sodium and calcium rushed in. Other scientists had shown that high levels of calcium in an axon could spark a process that would result in the cell eating away at its own structure. The effect, Smith says, “is like throwing salt water on live circuits.”

  Smith’s results, published in 2009 in The Journal of Neuroscience, added to the rapidly accumulating evidence that even concussions could cause permanent changes in neurons. They also went a long way toward explaining earlier research by University of California–Los Angeles scientists that showed there was a period of time after a concussion in which the brain was extremely vulnerable to a second hit.

  • • •

  UCLA scientists have been looking at the impact of TBIs in both humans and rats for over two decades. Though they have studied a wide range of brain injuries, much of their research has focused on the aftermath of mild TBIs, or concussions. That approach made sense because at the outset all TBIs look like a concussion, explains David Hovda, director of UCLA’s Brain Injury Research Center. The difference between a mild and a severe brain injury, he says, is in the magnitude of the brain’s response and the length of time that response goes on.

  A tall, stout man with a round face that easily breaks into an impish smile, Hovda roams the hallways of the Brain Injury Center perennially clad in a white lab coat that immediately marks him as one of the researchers. Within a short walk from his office are both the ICU, where severe brain injuries are treated, and the brain scanners—normal-sized ones for patients and miniature ones for the rats. In the basement several floors below Hovda’s office is the rat behavioral lab. On the fourth floor is a lab with shelves of bottles containing preserved human brains, and on the fifth floor is the lab housing rat brains. Both labs have a tissue-dissection area where brains can be thin-sliced with a device that is uncomfortably reminiscent of the meat slicer in the deli department of a grocery store.

  Back in the 1990s, when coaches and team doctors were still puzzling over return-to-play issues, Hovda ran an experiment to see if he could determine from brain chemistry how long the effects of a concussion lasted. Earlier studies had shown that glucose metabolism soared right after a jolt to the head. Since glucose is the fuel that powers the brain, this indicated that there was a burst of activity in the brain right after a concussion.
Hovda suspected that changes in glucose metabolism might provide a window into how long it would take for a brain to recover from a jolt to the head. He decided to run an experiment in which glucose metabolism would be carefully monitored in rats for ten days following a concussion. He figured this might give a concrete answer to how long it takes for brain chemistry to return to normal in rats.

  Hovda observed glucose metabolism rise immediately after a concussion, just as earlier studies had shown. But six hours later, glucose metabolism plummeted. This, Hovda realized, could easily explain the slowed mental processing that rats—and humans—experience after a concussion. What surprised Hovda was how long glucose metabolism remained depressed in the rats: an average of five days, but for as long as ten.

  Hovda’s study was quickly picked up by concussion experts seeking scientific evidence upon which to hang return-to-play guidelines. They used his finding that the average recovery time was five days as a justification for sidelining concussed athletes for at least a week. At a scientific meeting, Hovda corralled one of the guideline authors and asked how the one-week rest period had been determined. Dr. Robert Cantu pulled out a reprint of Hovda’s journal article and said, “From your paper.” A mischievous grin spread across Hovda’s face as he responded, “You’re making recommendations from rat data? People aren’t rats. Well, maybe some of them are, but . . .” Turning serious, Hovda asked the neurosurgeon, “Don’t you think we ought to do a study in human beings?” Cantu pointed out that such a study would take time to complete and in the meantime coaches and trainers needed some sort of guidelines so that concussed athletes weren’t sent back to play too soon.

  The episode did get Hovda thinking about the impact of concussions on developing brains. He wondered if there might be any permanent impact from mild-to-moderate TBIs in children. To study this, he tapped into some research from the ’60s showing that stimulating experiences could spark brain growth in the young.

  Researchers from the University of California–Berkeley suspected that a stimulating environment, if it was offered early enough in life, could make kids smarter. To see if this was possible, the researchers had compared rats raised in a standard setting—three to four animals per cage with a dull-colored background and no toys—to those raised in an “enriched environment”—fourteen to twenty rats in a big, colorful, two-level cage with ladders, wheels, tunnels, and a wide assortment of toys. The researchers found that rats raised in the enriched environment not only got smarter, but also grew measurably thicker cerebral cortexes compared to rats reared in a standard setting. That finding prompted the push to get kids into school at an earlier age.

  Hovda wondered whether TBIs might get in the way of this kind of intelligence enhancement. He’d seen studies showing that children often developed behavior problems and learning difficulties after a TBI. Other studies had shown that brain-injured kids were more likely than other children to be put in a special education program. One particularly striking study compared concussed athletes to kids who never hit their heads. All the students were tested at the beginning of the school year to provide a baseline measurement. When they were retested at the end of the school year, the concussed athletes had all returned to baseline. What was disturbing, however, was the realization that the nonconcussed athletes had improved beyond their baseline measurements. That meant that even though the concussed athletes had gotten back to where they started, they’d lost ground compared to their peers. It might also mean that the concussed athletes lost some capacity to expand their brains through life experience, that their brains weren’t as “plastic” anymore. “If you got back to where you were before the brain injury, you might think that is recovery,” Hovda says. “It’s not. I don’t know one person who says, ‘I’m going to stay right here, at this level.’ If you have an injury and as a result you lose plasticity, you haven’t fully recovered even if you’re back to where you were before the injury.”

  Knowing that young brains are especially plastic, Hovda wondered whether you could see something similar in young rats that had experienced a TBI. One way to test this theory would be to see if a TBI blocked the effects of an enriched environment. If the TBI created learning difficulties, then rats raised in an enriched environment would be no smarter than those raised in a standard cage.

  Hovda and his colleagues designed an experiment with three groups of young rats: one group would be put into an enriched environment after a moderate TBI, another group would be put into an enriched environment with no TBI, and the third group would be put in a standard cage, again with no TBI. Before they put any rats into enriched environments, the researchers compared the concussed rats to the uninjured ones. “We tested them all,” Hovda says. “And there were no deficits in the concussed rats. None. Zippo. Nada.” Then the researchers put some of the concussed rats and some of the uninjured rats into an enriched environment. “They all played with each other and did what they were supposed to do,” Hovda says.

  After two and a half weeks, the researchers looked for differences between the rats, using a standard test of rodent intelligence called the Morris Water Maze. At UCLA, researchers have built their maze in a large circular aluminum tub that sits on a table in the corner of a room in the rat behavior research lab. They place a little platform somewhere on the floor of the tub and then add water until the top of the platform is an inch below the surface. The water contains dye so the rats won’t be able to see where the platform is located, and it’s deep enough that the rats will have to swim around until they locate the platform by feel. On the wall to the left of the tub is an abstract ink drawing. On the wall to the right of the tub is a poster of Albert Einstein. The idea is that the rats will be able to use these posters to orient themselves.

  For several days the researchers bring the rats in and put them, one at a time, into the tub and wait about forty-five seconds to see if the rat finds the platform. If the rat doesn’t locate the platform on its own, it is picked up and put on the platform, allowed to stand on it for a full minute, and then put back in the water to locate the platform on its own. When the rats can find the platform within five seconds, it is assumed that they have learned where it is with respect to the posters. The smarter the rat, the fewer tries before it learns where the platform sits.

  The earlier research had shown that rats raised in enriched environments took fewer attempts to learn the location of the platform compared to those reared in standard cages. The UCLA researchers found that this was true with the uninjured rats. But when it came to those rats with a brain injury, the enriched environment didn’t appear to help. Concussed rats that had been raised in an enriched environment took as long to learn the location of the platform as the rats reared in a regular cage. This meant that while the concussion hadn’t affected skills the rats had previously acquired, it did impact their ability to profit from a stimulating environment. “The ones with a concussion couldn’t expand the cortex,” Hovda says. “They couldn’t grow to be smarter. They had lost brain plasticity.”

  The story turned out to be even more complicated than that. Other experiments showed that a concussion didn’t have the same impact everywhere in the brain. While certain areas of the brain became worse at learning, others became better at it. In another experiment, UCLA researchers looked at whether a concussion affected a rat’s ability to link experiences with emotions, like fear. They used a test that is similar in some ways to the Morris Water Maze. Uninjured rats and concussed rats are put in a box that can deliver a mild shock through the floor. During a training period, whenever the shock is sparked, a light is flipped on. The normal rat reaction to shocks is to freeze in place. Eventually, when rats learn to associate light with a shock, they will freeze as soon as a light is turned on, even if there is no accompanying shock.

  When the UCLA researchers ran their experiment, they discovered that concussed rats learned to link light with fear much more quickly than uninjured ones. This meant that the amygdala, the area of the brain t
hat links stimuli with emotional responses, had become more efficient. What’s more, the concussed rats weren’t able to forget the link as quickly as the healthy rats. This meant that rats with mild TBIs were more prone to PTSD. The finding was a surprise, since the researchers had assumed that all learning would be adversely impacted. It meant that certain areas of the brain were slowed down by a TBI and others were tuned up.

  • • •

  At the same time as he was looking at the impact of concussions on brain plasticity, Hovda was trying to tease out the details of the neurochemical changes that occurred after a jolt to the head. The work by UCLA researchers, when coupled with that from several other centers, began to bring the changes in brain chemistry that followed a jolt into focus. The scientists saw a consistent sequence of events that they dubbed the “metabolic cascade.”

  Studies showed that after a jolt to the head, cells and pathways all over the brain are pulled and twisted. That physical movement inevitably leads to a chain of events that always starts with cells sparking and spewing out their neurotransmitters in a kind of mini-seizure.

  Normally the brain uses these chemical messengers frugally. Neurons shoot neurotransmitters back and forth as a way of passing signals to one another. If neuron A has a message to communicate to neuron B, it tosses out a specific chemical. Neuron B grabs the neurotransmitter with a structure called a receptor. What happens next is comparable to what occurs after a key turns in the ignition of a car: once the neurotransmitter locks into its receptor, some very specific machinery in the cell switches on.