THE two men in the hospital ward had both hit their heads in car accidents, but that was where the similarities ended. One would spend weeks unconscious in critical care, near to death. The other had only a mild concussion; he never lost consciousness, but somehow didn’t feel quite right.
Yet months later their roles were reversed. “The one with the severe injury is almost back to normal function,” says Douglas Smith, director of the Center for Brain Injury Repair at the University of Pennsylvania in Philadelphia, “and the one with concussion can’t go back to work, probably ever.”
Smith’s two patients illustrate one of the frustrating paradoxes of head injuries: even seemingly mild impacts can have devastating long-term consequences. And we have no way of predicting who will fully recover and who will have lingering problems.
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Concussion, or mild traumatic brain injury as doctors call it, has long been seen as a benign and temporary affliction. But over the past decade there has been growing realisation that longer-term symptoms can affect between 10 and 15 per cent of those diagnosed with it. These range from fuzzy thinking and memory lapses to, for the most unfortunate, serious neurological conditions such as premature Alzheimer’s disease.
In fact, concussion is thought to be the single biggest environmental cause of Alzheimer’s. Even a mild impact can double the risk of developing early dementia, according to a massive study of older military veterans in the US, which was presented at the Alzheimer’s Association International Conference in July (). In that, the risk jumped from 7 to 15 per cent.
“Concussion is thought to be the single biggest environmental cause of Alzheimer’s disease”
It now appears that concussion is not a single, discrete event, but can be the beginning of a degenerative disease lasting weeks, months or longer. “It is an injury that can keep on taking,” Smith says. As details of that process emerge, researchers are beginning to identify where its progression might be blocked. And the advent of new brain scanning techniques may some day let us identify people in the emergency room who are most at risk of long-term problems.
If the research lives up to its promise, that would be good news for us all. The most common causes of concussion are falls and car or bike accidents, and we face an estimated 1 in 4 chance of sustaining a concussion in our lifetime.
That’s not the only reason research into concussion is getting record levels of funding. On the battlefield, mild traumatic brain injury has been dubbed the signature injury of service in Iraq and Afghanistan, affecting up to 40 per cent of soldiers who see combat duty. One of the biggest threats to soldiers stationed in these countries is from roadside bombs, often improvised from cast-off artillery shells or other weapons. The introduction of better body and vehicle armour means more soldiers than ever are surviving such blasts, but are left with concussion and other serious injuries.
Then there are the hundreds of thousands of people with sports-related concussions each year, most of whom never go to hospital. This group is especially worrying, since many players of contact sports like rugby, American football or ice hockey experience repeated concussions, and evidence is growing that these serial injuries can heighten the risk of severe brain degeneration years or even decades later.
The risk for athletes is getting increasing attention, particularly in the US, where 75 retired American footballers recently sued the National Football League for doing too little to protect players from the effects of repeated concussions. And the media has jumped on cases such as that of former American footballer David Duerson, who committed suicide last year fearing dementia was setting in. Duerson was careful to shoot himself in the chest, not the head, so that scientists at the Boston-based Center for the Study of Traumatic Encephalopathy could examine his brain. Sure enough, Duerson’s autopsy revealed telltale signs of brain deterioration, though it has not yet been proven that these changes caused his symptoms.
One reason it has taken so long to understand concussion is that a blow to the head can cause many bad things to happen to the brain, including bleeding, swelling and the death of nerve cells. With all this chaos going on, it has been difficult to unpick which problems are the most important.
Nor is there a standard way to image the brain to gauge the severity of concussion. “If you fall on your leg and it hurts, we can take an X-ray, and it really helps us decide what to do,” says Jeffrey Bazarian, a neuroscientist at the University of Rochester Medical Center in New York state. “We don’t have something like that for concussion.”
Leaky neurons
For a long time we have suspected that the fibres, or axons, of nerve cells may be particularly vulnerable to concussive blows. “A neuron is like a big, long spaghetti strand with the cell body at one end. This makes it very susceptible to stretch,” says Bazarian. “When the head gets struck, the head rotates on the neck, and the brain rotates inside the skull. All those spaghetti strands get stretched.”
“A nerve cell is like a big long spaghetti strand, making it very susceptible to stretch damage”
Back in the 1980s, researchers thought that axon damage occurred only after the most severe impacts, because it was seen in the brains of people who had died from their injuries. Gradually animal studies began to point to damage occurring from milder blows too, although direct evidence about what happens in humans was still lacking.
That is now changing thanks to more sensitive forms of brain scanning. One in particular, known as diffusion tensor imaging (DTI), is especially valuable. Developed only within the past few years, this technique tracks the movements of water molecules in the brain. Normally they move predominantly along the length of the axons. After a blow to the head, however, water also moves laterally, a sign that stretching has made the axons leakier.
The worst of this stretch damage occurs to axons in the brain’s frontal lobes, furthest from the axis of rotation at the neck, according to unpublished DTI studies led by Jamshid Ghajar, a neurosurgeon and president of the Brain Trauma Foundation in New York City. This could explain why people with concussion experience problems concentrating and planning actions – key functions of the frontal lobes – rather than, say, loss of vision or movement control, which are handled in other parts of the brain.
This idea also explains why animals are less susceptible to concussion than people: animal brains are too small to experience the same forces. “If you’re in the front seat of your car with your dog next to you, and you’re in an accident, you might lose consciousness for 5 minutes,” says Smith. “When you wake up, your dog is licking you. That’s because his 60-gram brain doesn’t experience the deformation that your 1500-gram brain does.”
The immediate effects of axon stretching are fairly well understood. The axon surface is studded with molecular channels designed to transport sodium or calcium ions into the axon when the neuron fires an electrical signal. When the axon is stretched, these ion channels are pulled open and the ions flow in, sparking a storm of electrical activity.
In response, nerve cells frantically pump the ions back out again. This rapidly depletes the brain’s store of energy – especially since the calcium influx chokes off the mitochondria, the cells’ energy source. The result is that the brain suddenly flips from overactivity to a state of exhaustion that can last for several days.
This exhaustion may help to explain why athletes are prone to repeat concussions shortly after returning to play. Indeed, more than three-quarters of athletes who experience repeat concussions in a single season incur the second within 10 days of the first, according to a study by Michael McCrea, director of brain injury research at the Medical College of Wisconsin in Milwaukee (). And the second injury is often worse, McCrea adds. “If you pile a second injury on top of the first one, before the brain has fully recovered, that’s not good.”
If this short-lived leakiness and exhaustion were all that happened after a concussion, people should recover completely once its effects had passed – and that is what happens in most cases. But for some it is the beginning of a longer, more serious disease process in which nerve cells continue to degenerate. In unpublished work, Ghajar used DTI to track the health of people who had experienced mild brain injuries. He found that axon damage was initially confined to the frontal lobe. But in those who still had symptoms one year later, the damage had spread to other regions of the brain that were not affected initially. “I think it’s a domino effect,” says Ghajar. “The question is: why?”
Answers are now beginning to emerge. For one thing, the initial influx of calcium ions leads to local inflammation. Also, even mild injuries can cause long-term problems with the sodium channels.
Using isolated rat axons stretched by a puff of air, Smith’s team has shown that the cells respond to a single gentle stretch by adding more sodium channels within hours of the injury. “What we suspect is that although the stretch injury was mild, it still disrupted the sodium channels enough that more were needed,” says Smith. The extra channels may make it easier to restore normal ion flow after the injury, but they also make the cells leakier after a second injury ().
Stretching can also damage an axon’s internal structure, especially the microtubules that transport molecules around the cell. The microtubules behave like Silly Putty, says Smith – when pulled gradually they stretch smoothly, but when jerked suddenly they become brittle and can snap. If that happens, it’s like breaking a train track: all the microtubules’ cargo derails at the break. When this happens in an axon, which it seems to after a blow to the head, the long-term consequences can be dire.
That’s because one of the main cargoes within axons is a molecule called amyloid precursor protein, which helps to regulate connections betwen nerve cells. When APP piles up at the site of a microtubule break, it is broken down into a smaller protein, amyloid beta. This can accumulate within the axons and has also been found aggregated into fibrous plaques within the brain, presumably after being released from dying cells.
These amyloid plaques are all too well known – they are a hallmark of Alzheimer’s and other degenerative brain diseases. In Alzheimer’s, amyloid beta causes changes to another protein known as tau, which also forms tangled plaques. Tau tangles also turn up in people who have had repeated concussions, notes Mark Burns, a neuroscientist at Georgetown University in Washington, DC.
The usual suspects
The sequence of events in Alzheimer’s is not exactly the same as what happens after head injury. In particular, the amyloid plaques appear to be temporary, not permanent, after head injury, and the tau plaques tend to occur deeper within the brain in Alzheimer’s than after a head injury, says Burns. But the fact that the same two proteins are suspects in both sorts of brain disease suggests a new lead to follow.
Indeed, Burns has more direct evidence linking amyloid beta to brain injury. His team delivered mild-to-moderate brain injuries to mice, then tested their ability to walk along a 6-millimetre-wide beam. Uninjured mice can do it relatively easily, but injured ones can no longer muster the necessary coordination. “They’ll go from about five mistakes per 50 steps to 50 mistakes,” says Burns. Three weeks after injury, the mice have regained a little of their coordination, but still average 40 to 45 mistakes per 50 steps.
But when Burns gave mice a drug that blocks the production of amyloid beta, they recovered far more quickly, making just 25 mistakes per 50 steps after three weeks (). A different drug – one that helps the body clear away unwanted amyloid beta instead of preventing its formation – also speeded up the mice’s recovery, Burns’s team reported earlier this year ().
All this suggests that amyloid beta and perhaps tau are involved in the dementia that sometimes follows concussion. If so, then drugs to block the amyloid beta cascade may speed up recovery from concussion and ward off at least some of its long-term effects in people too. Much testing remains before this could happen, of course, but if they prove safe enough, such drugs could be given routinely after a concussion as a preventative measure.
Burns is not the only researcher with promising potential therapies to treat axon injury. Earlier this year Ramona Hicks, who directs the brain injury repair programme at the US National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, convened a workshop to review axonal injury and its treatment.
Though no therapies are yet ready for clinical use, Hicks is optimistic that our growing understanding of brain injury, and our increasing ability to peer into the injured brain with advanced imaging technologies like DTI, should yield much progress in the next few years. If so, the day may come when physicians will know in the emergency room which concussed patients are at greatest risk of complications and begin treatment to prevent them. That way athletes, blast-shocked soldiers and those who are simply unlucky enough to fall in the street will have a greater chance of complete recovery.
