For years we've been told that concussion is sport's bete noire, but what if the problem is something less obvious, yet more insidious? Dylan Cleaver reports in part two of a three-part series on the science behind head injuries in contact sports.

Roll up to Central Casting and ask for a scientist - the chances are you're going to get a man that looks a lot like Dr Lee Goldstein.

Bespectacled, thin and sporting a grey beard that is not quite neat, yet not unruly, Goldstein looks like a man who is at his happiest in a white coat in
the controlled environment of a laboratory. Which, as it happens, is true.

Dr Lee Goldstein has found what he says are the mechanisms that cause CTE. Photo / supplied
Dr Lee Goldstein has found what he says are the mechanisms that cause CTE. Photo / supplied

Unlike the more front-facing members of Boston University's high-profile Alzheimer's Disease Center team - most notably Dr Ann McKee, a recent addition to Time magazine's most influential people list - Goldstein isn't as sought after for photo shoots and current affairs programmes.

He probably should be, because Goldstein has found that when it comes to chronic traumatic encephalopathy (CTE), the disease behind most of these serious contact sport head injuries, concussion is not the biggest enemy.

If anything, "it's irrelevant", Goldstein says.

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This marks a dramatic shift in position in a short period of time. Most of Boston's groups early work was premised on the fact it was concussions doing the damage. Dr Chris Nowinski, perhaps the most vocal booster of BU's work, wrote a book called Head Games, where concussion, and post-concussion syndrome, were the star characters.

According to Goldstein however, they are just bit players. The real enemy is far less obvious, far less dramatic, but in many ways worse.

C

oncussion has dominated discourse when it comes to trying to determine the cause behind several former NFL players dying of CTE.

The film starring Will Smith as Dr Bennet Omalu, the doctor credited with discovering CTE in the brain of deceased Pittsburgh Steelers legend 'Iron Mike' Webster, was simply titled

Concussion

, leaving little doubt what the movie's dark cloud was.

Concussion is unhealthy. Leave no room for doubt there. The effects of concussions can be long-lasting; the effects of multiple concussions in a short space of time catastrophic.

https://zen.nzherald.co.nz/administration/gallery/gallery.cfm?gallery_id=206622

Contact sports, particularly rugby, have made huge strides in recent years to not only discourage contact with the head, but to remove players from the game who are showing signs of having suffered a head injury.

It is to be encouraged and applauded.

There is a feeling among some in the scientific community, however, that the reasons organisations such as the NFL and World Rugby are taking concussion more seriously are less than altruistic.

Will Smith starred in the 2015 movie Concussion based on a forensic pathologist and neuropathologist, Dr Bennet Omalu, who discovered CTE. Photo / supplied
Will Smith starred in the 2015 movie Concussion based on a forensic pathologist and neuropathologist, Dr Bennet Omalu, who discovered CTE. Photo / supplied

"The NFL is made up of 32 owners who make bazillions of dollars and if the very nature of the way the game is played leads to this neurodegenerative disease, then there's a big problem," says Dr Robert Stern, professor of neurology at Boston University. "If they can make the discussion, the dialogue, the narrative, focus on concussions then they may protect themselves."

Stern is suggesting that the causes of CTE might be more fundamental than big, obviously symptomatic concussive blows. And that is a scarier prospect for contact sports to contemplate.

"Subconcussive blows repetitively in close proximity put in effect the cascade that we think is leading to CTE," says neurosurgeon Dr Bob Cantu, the author of Concussion and our Kids. "Goldstein has shown that in his rodent animal model… he's shown that in animals [that] didn't ever show signs of concussion."

Cantu, a spritely 70-something who runs an eponymous concussion centre near Emerson Hospital in Boston's satellite suburbs, has been a thorn in the NFL's bloated side for years. He is sometimes referred to as the godfather of concussion, was there at the start of the CTE age and remains an active salesman for safety in football.

Goldstein is responsible for the biggest breakthroughs in understanding the mechanisms behind CTE. It turns out they are relatively mundane, and that ordinariness is ultimately what makes them so frightening: How do you stop something that is barely perceptible?

"What we set out to do was to find out whether concussion was related to CTE because our evidence from the neuropathology suggested no connection," Goldstein tells the Herald. "In fact, we had cases of young adults, even teenagers, who'd never had a concussion in their lives, who'd never had a documented, reported or witnessed concussion, who had CTE. So that just didn't add up."

This ran counter to the popular narrative, which seemed so obvious: big, strong athletes were succumbing to a disease similar to pugilistic dementia. Like boxers, they were frequently subjected to concussive injuries.

It made sense.

But as any scientist will tell you, correlation does not equal causation. So Goldstein set out to discover what CTE was, and what relationship it had, if any, with concussion.

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"The mechanism that leads to concussion is completely different to the mechanism that triggers CTE," he says.

"It's a little bit like thinking about the relationship of a hacking cough and lung cancer in a cigarette smoker. Yes, they can both occur in smokers, but the hacking cough has nothing to do whatsoever with the lung cancer. You're certainly not going to diagnose lung cancer by lining up people with a hacking cough. You can say you're doing something by focusing on the hacking cough because it's easier to see or hear but it's not doing a goddamn thing for your problem, which is lung cancer."

This is Goldstein's not-so-subtle point. Sports administrators and team owners know they have a problem if it's determined that their players succumb to CTE at greater rates than the general population. If they focus on the concussion that, when symptomatic, people can see, they look like they're doing something about it.

He acknowledges that concussion has become the Holy Grail of sport. Goldstein also admits that is interesting from a neurological perspective. Yet, he asks, what progress has actually been made?

"Every three to five years there's another consensus meeting where all the bigwigs get together and it's really no different to how the Egyptians described concussion in the 17th century BC. It's just a collection of signs and symptoms. It's a syndrome, not a disease and it's arbitrary what we call concussion. It's interesting but it doesn't have anything to do with CTE.

"So in [American] football or rugby we're focusing on the concussion but what we're missing is everything else. You're focusing on the one percenter, when the other 99 are equally at risk and they're going back for the next hit.

Pittsburgh Steelers center Mike Webster, whose brain Dr Bennet Omalu first discovered CTE in. Photo / AP
Pittsburgh Steelers center Mike Webster, whose brain Dr Bennet Omalu first discovered CTE in. Photo / AP

"Who cares about the concussion? What we really care about is the progressive neurodegenerative disease that will ultimately lead to the loss of your mind and death. In my opinion, concussion is the hacking cough," he says.

It is persuasive testimony, certainly, but not universally accepted. Research in 2012 and 2013 by doctors, including prominent neuropathologist and social media presence Dr Willie Stewart suggests CTE-like pathology has been discovered in individuals who have experienced a "single moderate or severe traumatic brain injury".

Dean Lonergan was knocked out and twitching during a league test against the Kangaroos, before returning to play.
Dean Lonergan was knocked out and twitching during a league test against the Kangaroos, before returning to play.

His point is not to deny the existence of CTE or the likelihood that repetitive head trauma plays a part, but that the mechanism behind it is not established fact.

Others point to the idea that beyond the BU group, there appears to be no consensus about whether CTE pathology is related to the "progressive neurodegenerative disease" it is claimed to be.

This is a variant on the "media has got ahead of the science" argument, in that it is a criticism that the "pathology has got ahead of the epidemiology". Applied to Goldstein's work, critics would argue - and some do - that there has been an oversimplification of the cause-and-effect relationships at play between exposure to contact sport and development of CTE pathology, and premature linking of clinical outcomes to the observed pathology.

Goldstein hears all the critics and has an answer for them that can be summed up in three words: "Prove me wrong."

If it's not concussion that is contact sport's primary danger, what should we be focusing on? It's all very well pointing out the flaws in the search for a concussion antidote, but it doesn't alter the fact that former NFL and, possibly, rugby players (more than one former rugby star's brain has been examined by Boston University) appear to be susceptible to CTE, a disease that remains diagnosable only in post-mortem.

If it is not concussion, what is the cause of the "cascade" that Cantu mentioned? What causes tau protein (see sidebar) to collect in the crevices of the brain?

Recent brain scans of a recent NFL player who was diagnosed with CTE in post mortem. Photo / supplied
Recent brain scans of a recent NFL player who was diagnosed with CTE in post mortem. Photo / supplied

That's what Goldstein spends hours upon hours in his lab doing. His translational research, mostly on rodents, looks for the mechanisms that cause CTE. Only when you know the mechanisms can you go after the diagnostics and, ultimately, the treatments.

It was the military that led Goldstein and his Boston University colleagues away from the idea that there was a cause-and-effect relationship between concussion and CTE. Many veterans who presented with CTE symptoms (and were eventually diagnosed) had no recorded history of concussion. They had all been subject to blast trauma, though.

"We worked out the mechanisms for blast neurotrauma, which didn't make us any friends," he says. "Once we figured that out it gave us insights into what was happening in the impact side of the equation. What we were able to do was show was that it's completely independent of concussion.

"We've been able to show [a] causal linkage between blast exposure and the development of CTE in an animal model. It's virtually a perfect replica of what we see in people.

"It has to do with the motion of the head. It drives people crazy but it's actually a simple mechanism."

In a room at the back of the hospital they have a device that generates a shockwave equivalent to that given off when 8kg of TNT is ignited. This is bigger than your average double-happy. Get close enough to it, Goldstein says, and it'll ruin your day.

"We put our mice in there and they all survive and they look fine, but they're not," Goldstein says. "They all get CTE, just like we see in people. But if we hold the head, wrap their heads and keep them still while that same blast goes over them, nothing happens, they're perfectly fine. We call it the bobble-head model."

Goldstein fires up his laptop and you're suddenly confronted by the sight of a mouse in a box, at this point blissfully unaware that it is about to feel the after-effects of an explosive charge. In real-time you don't see anything of note. At nearly a million frames per second, however, you see the head wobble quickly and violently.

"The sudden increase from zero to very fast, that's what causes the problem," Goldstein says. "The sudden acceleration of the head."

Sports like rugby and American football have cut down on the contact at training as a result of greater injury awareness. Photo / Brett Phibbs
Sports like rugby and American football have cut down on the contact at training as a result of greater injury awareness. Photo / Brett Phibbs

You feel compelled to ask, as politely as possible, how a mouse in a box feeling the after-effects of a blast can relate to a NFL linebacker executing a block, or an openside flanker hitting a ruck?

"It's the same story," he says with unwavering confidence. "We did the same thing with impact. The problem is the slow motion people get from football or rugby, it's not nearly slow enough. The frames on your TV, they're nowhere close.

"To answer your question… we had to build a new device. What we wanted to do was to get the head to move exactly as it did in the blast so we could compare them. The head, it turns out, moves identically.

"This is the equivalent of a flying tackle in football, someone coming in from the side, helmet to helmet, or a left hook to the right side of the face. From a physics standpoint, they're identical."

Even accelerometers used on players cannot react quickly enough to provide a full picture of head movement during contact, says scientist Dr Lee Goldstein. Photo / ODT
Even accelerometers used on players cannot react quickly enough to provide a full picture of head movement during contact, says scientist Dr Lee Goldstein. Photo / ODT

We are now watching mice get impacted on the side of their heads. It's grim viewing and some will feel squeamish even reading about it. After the impact, the mice take a while to find their feet again and when they do they wobble around, much like a rugby player after a big head clash.

Dr Ian Murphy, who heads up New Zealand Rugby's medical department, is by nature cautious. He knows that rodent studies inform human studies but also understands their shortcomings.

He does, however, acknowledge that anecdotal evidence points to rotational forces of Goldstein's experiments being a problem.

"Certainly, people have commented that those forces appear to be more problematic in terms of recovery.

"The cumulative-effect question is interesting. I'd be interested to see if any of the research we're involved with produces anything along the cumulative-effects line."
Murphy is a believer in consensus. It would be fair to characterise the Boston Group as believers in themselves and the work they are doing.

In a contentious, developing area of medical science like CTE, the Boston group feel they are well ahead of the curve in terms of their research and methodologies.

Goldstein points to the hundreds upon hundreds of tests he has done on rodents whose brain and skull characteristics he says are anatomically similar to humans.

"What [the tests] told us is the concussion can't be causing CTE because in the blast case we never see concussion. And even in the impact mice when we look at the degree of concussion, there's no correlation with degree of CTE.

"That tells me there cannot be a mechanistic relationship between concussion and CTE. We've proven they are unlinked. It's not speculation. I've proven it."

On this point, Goldstein becomes animated. Nobody, he says, has been more robust in critiquing his work than he has.

"I spent five years in a lab trying to prove myself wrong," he says.

"You can say, "I don't like the result.' I'm OK with that. But you can't say it is untrue."

The case against the Boston Group

The science around CTE remains contentious. While Boston University's researchers say the criticism often comes from uninformed sources who do not do their own laboratory science, others say the evaluation of their work is a normal part of the scientific process.

It is not easy to summarise the popular critiques of their work in a way that is easily understood, though it can be boiled down to the following questions, based off the Boston Group's claims that "CTE is a progressive neurodegenerative disease caused by exposure to repetitive head impacts", and that CTE clinically presents with a diverse combination of symptoms that manifests early in life as mood disorders and depression and later in life as cognitive impairments in executive function (dementia).

If the disease is progressive, how do we know that based on case-series studies of autopsies? In other words, to state that with such certitude, you'd need longitudinal studies with a control group.

If CTE pathology is based around the simple function of repetitive head impacts, wouldn't most contact-sport athletes who played through to adulthood have that pathology?

If a large chunk of adult contact-sport athletes have the pathology, why do only a fraction display the symptoms?

Somewhere along the chain the relation must be weak, critics argue, otherwise there would be literally thousands upon thousands of contact-sport athletes with early-onset dementia, and there just isn't.

To take the next logical step, you could propose that for some reason, only a subset of these players are vulnerable to the pathology.

If this is the case, are there other factors outside repetitive head impacts that contribute - anything from diet, to alcohol consumption to genetics or even steroid abuse?

This, potentially, is the next great leap for CTE science.

The search for CTE

The search for chronic traumatic encephalopathy starts with brains donated to brain banks.

Scientists look for obvious signs of the disease such as atrophy and shrinking in frontal and temporal lobes and the hippocampus. CTE is never diagnosed at this stage as these features are not unique to CTE, and many in the early stages of CTE have normal looking brains.

The brains are photographed. Parts are frozen for molecular and chemical studies and half of the brain will be dissected and placed on slides under microscopes.

Researchers are looking for tau protein, the key marker of CTE, which has a characteristic pattern upon accumulation.

Tau is part of the internal scaffolding of a cell. Just as a skeleton holds the body in a particular configuration, tau is a component of a cell that helps it maintain its integrity and function.

When tau becomes traumatised it falls off the scaffolding and accumulates in the cell in clumps. These clumps become toxic to the cell's normal functioning.

It is believed this sets off a cascade effect whereby abnormal protein is transmitted from one cell to the next, gradually destroying normal brain function.

* Dylan Cleaver travelled to Boston with the assistance of an nib scholarship.