A gray matter

Concussion and its consequences are complex, but fear has surged ahead of science. To catch up, researchers nationwide have joined to undertake the largest concussion study in history.

Michael McCrea suspected that, when he and his wife sat together in their Milwaukee home in the fall of 2013 and watched “League of Denial,” the PBS documentary on concussions in football, they would be viewing it through a prism unique from thousands of other parents who tuned in that night.

McCrea, a neuropsychologist at the Medical College of Wisconsin, has played a part in some of the most important advancements in sport concussion research in the past two decades. But when his wife, Ann Marie, soaked in the stories of former NFL players whose brains had betrayed them later in life – players who battled depression and rage and confusion and memory loss – she turned to her husband and said she would be reluctant to let their 6-year-old son, Joe, play football when he became old enough. McCrea was appalled that, in the mind of the person who knew him best, a few jarring anecdotes rendered moot much of the work he had spent his career advancing.

“What the hell have I been doing for the past 20 years?” McCrea thought that night. “She has lived this life. She has lived through all of this agonizing work with me.”

What happened to his wife during those two hours, McCrea and several other notable concussion researchers say, is a microcosm of what has happened in American living rooms throughout the past decade as public perception and media discourse have altered the conversation surrounding concussion. For many people, a lack of understanding of concussion rocketed past awareness and landed squarely at angst. Participation rates have fallen in both high school (2 percent) and youth football (10 percent) in recent years, according to data from the National Federation of State High School Associations and Pop Warner. Young players like ex-San Francisco 49ers linebacker Chris Borland cut careers short because of uncertainty about long-term consequences. And retired NFL luminaries like Kurt Warner have publicly questioned whether their children should play the game.

These are important – and personal – discussions and decisions, but researchers worry that many of those choices are being informed by stories, not science. They don’t admonish those who choose not to play, but want them to be armed with accurate information when they make a decision. Lines in the sand are being drawn prematurely, researchers say, and what should be nuanced discussions about gray matter have been rendered black and white. A decade ago, McCrea frequently encountered people at dinner parties whose eyes would glaze over when he mentioned his work. Now, they are incredulous when he explains why he thinks his children should be allowed to play contact sports.

The root of that abrupt reversal, McCrea and many of his peers at institutions across the nation note, are the findings that have emerged from Boston University over the past seven years. Dr. Ann McKee, an experienced neuropathologist, dissects and analyzes the brains of former football players, often finding chronic traumatic encephalopathy, or CTE, a condition that can cause depression and significant cognitive problems. Her work was the centerpiece of “League of Denial,” and she has frequently been the focus of media reports about the state of concussion research.

At a glance, the findings that have poured out of McKee’s lab are terrifying to any parent or athlete. That it’s only a glance, McCrea and other top researchers attest, is the problem. Yes, this can happen in some players, they say, but we don’t know why it happens to some and not to so many others.

McKee agrees. Her work has undoubtedly called important attention to concussion, but the results of her research are not as definitive as many believe them to be. “There’s no question this is a very biased study,” McKee says of her own work.

What is often missing or buried in media reports and public opinions about McKee’s findings is that, almost always, she examines the brains of former professional players whose lives ended tragically or in despair – a tiny sliver of the overall population of former football players and athletes in other contact sports – because tormented spouses and children are quick to come to her to find meaning and answers. The families of athletes whose minds stayed sturdy rarely seek her out when their loved one passes away. That leaves a significant gap in the research.

“I’m relieved to see people taking it seriously,” McKee says. “There’s a certain level of, I don’t know, it’s just sensationalism or it’s what sells. I think there are times when it’s overblown. I do think we need to be concerned. … Sometimes it goes a little far.”

The question about long-term effects has yielded hundreds of headlines and millions of research dollars. It’s the question that has driven the public narrative beyond the science, forming the double-edged sword that has both heightened awareness and fostered paranoia. And yet, given enough years and enough patience, it’s the question that holds the ultimate answer for future generations – one the public, and Ann Marie, so desperately crave now.

So what, really, do we know about concussion? What can we be certain of?

Not as much as you probably assume.

Go ask the top minds in the field to simplify it for us – the journalists, the concerned parents, the athletes. Ask them, on a one-to-10 scale, just how far we have come in the decades spent studying the injury.

Most put our understanding around a five – we have only made it halfway to truly grasping the condition and its consequences. And for all the certainty a handful of personal narratives suggest, the true list of proven information that accounts for that five is relatively short. Peruse many concussion-centric research papers, and you will find conclusions littered with phrases like “warrants further investigation.”

So researchers hope to change “may” and “might” into “does” and “will” in their findings by asking more questions. There are a seemingly infinite number of granular queries, but three overarching mysteries drive their work. How and why does recovery differ for various subsets of people? How does the brain heal physiologically relative to the abatement of a person’s outward symptoms, and how can we track that healing process? And why do detrimental chronic effects – those correlated with CTE, for instance – present themselves in a minute portion of former athletes, but not others?

A landmark new study has the potential to answer those questions, but the solutions won’t come quickly. McCrea joined forces last year with Indiana University neuropsychiatrist Dr. Tom McAllister and University of Michigan associate professor of kinesiology Steven Broglio to lead a team of roughly 100 researchers and clinicians nationwide, including a slew of the top minds in the field, in a partnership to undertake the largest study of concussion in sport ever conducted.

The Concussion Assessment Research and Education Consortium, or CARE, began its work in the summer of 2014. Twenty-one schools are currently taking part, but the study will eventually gather data from roughly 35,000 athletes and military academy cadets across all sports at 30 campuses in hopes of answering those three questions that are at the core of modern concussion research.

It’s groundbreaking, but only a start. When crafting the study, researchers hoped it would provide the infrastructure needed – a massive cohort of athletes – to become a decades-long investigation into why some suffer later in life and many others don’t.

Together, NCAA Chief Medical Officer Brian Hainline and Col. Dallas Hack, former director of the combat casualty care research program for the Department of Defense, facilitated the study’s launch. Both yearn for the CARE Consortium study to become concussion’s equivalent of the Framingham Heart Study, which has tracked thousands of people from Framingham, Massachusetts, since 1948 and unlocked much of what we now consider to be common sense about heart maladies, such as the risks of smoking and high blood pressure. “Big shoes to fill,” Broglio says. An “audacious” goal, McAllister adds.

Yes, it’s audacious, but it’s precisely the type of study McKee says we need to answer the questions raised by her own work. To get there, the study will need to extend beyond the three years and $30 million that the Department of Defense and the NCAA have already provided. The answers that could emerge, though, would help parents and athletes make informed decisions about what sports they’re willing to play and for how long, rather than relying on small, biased samples and a handful of anecdotes about worst-case scenarios.

“The fact of the matter is that we have a population of former athletes walking the earth who are CEOs and teachers and engineers and astronauts and go on to live completely normal and incredibly productive lives. It’s only been of late that we have these very small reference points now suggesting the possibility of a link,” McCrea says. “Ultimately, even if that association exists, we know that it’s happening an incredibly small percentage of the time.

“I think the public is making pretty broad decisions based on the story, and I think there’s a call here to deliver the science that is then the basis for the story instead of the other way around.”

 

People have understood concussion, on a basic level, since ancient Greeks made efforts to characterize head injuries. It wasn’t until the 1920s that scientists began tying later-life memory problems or tremors in boxers, crudely dubbed dementia pugilistica, to the head trauma they sustained during their careers. Research into concussion in other sports began in earnest in the 1980s, and many significant breakthroughs have come just in the last 20 years.

McCrea has played a role in many of those discoveries. He entered the field in 1994 and made his first contribution when he sketched questions for a primitive concussion assessment tool on a napkin at a Northwestern Memorial Hospital lunch table. A decade later, he and Kevin Guskiewicz, now director of the Matthew Gfeller Sport-Related Traumatic Brain Injury Research Center at the University of North Carolina, Chapel Hill, produced a study of more than 2,900 college football players that had a significant impact on return-to-play standards. It revealed that most athletes’ clinical symptoms abate within seven to 10 days of injury and that suffering a repeat concussion often prolongs recovery time.

In a study of former NFL players, Guskiewicz found that suffering multiple concussions can make athletes more vulnerable to depression later in life and, last year, data revealed that retired NFL players suffered from higher rates of dementia and Alzheimer’s than the general population.

These were important breakthroughs, yet are also emblematic of key uncertainties. Research has been capable of establishing relationships between concussion and chronic effects. Yet the actual causes, why it occurs in some but not in many others, remain elusive.

Guskiewicz, staring out his window on a snowy March day at his North Carolina home, compares the injury to the snowflakes falling outside. No two are alike. More than 40 attempts to define concussion have been published by scientists in recent years, which makes treatments and recovery protocols difficult to formulate. Given that challenge, Guskiewicz surmises, we may never advance past an eight on the theoretical 10-point scale.

Still, researchers haven’t stopped trying to uncover a one-size-fits-all solution. In his former role with the U.S. Department of Defense, Hack was charged with assigning about $840 million to subsidize roughly 600 brain trauma studies after Congress approved an initial wave of funding in 2007. Why the deluge of the public funding? Because the injury impacts so many lives, on and off the field. Datalys, the firm that tracks NCAA injury data, estimates that, on average, college athletes suffered 10,500 concussions per year through the past five years, with roughly 3,400 coming in football alone. American service members, however, have suffered more than 320,000 brain injuries since 2000 – and more than 80 percent of those occurred away from combat. Nationally, a 2006 study estimates that between 1.6 million and 3.8 million recreation-related concussions occur annually.

Many of the early research dollars, Hack says, were spent trying to find a diagnostic imaging tool that could either definitively detect concussion or identify one drug that could counter a concussion’s effects. After a few years of failed attempts to develop either, Hack realized the need to take a more meticulous approach to understanding the complexities of the injury.

“A lot of people were trying to hit the one home run that is going to solve it all with a magic drug or magic device,” he says. “We were too naïve. We didn’t know.”

Scientists may only be halfway through the race to uncover major solutions, but their pace is quickening. An important step was taken last year in a paper authored by a pair of University of California, Los Angeles, neuroscientists, Dr. Christopher Giza and David Hovda. It relied on animal studies and examinations of more severe human brain trauma to piece together a complex cascade of what occurs at the cellular level in the aftermath of a concussion (see diagram).

A concussion can occur when the brain accelerates because of an impact, often colliding with the interior of the skull. Giza and Hovda’s paper suggests that neurons, specialized cells that transmit impulses throughout the brain and body, become stretched due to the acceleration, allowing calcium ions that can harm the cell’s structure and function to rush into the cell unchecked. Neurons then burn through their energy as they scramble to pump out calcium and restore balance. Overworked, the neurons suffer an energy crisis, leaving them in a depressed state for several days. The cells’ axons, the long arms that neurons use to communicate with each other and where the bulk of concussive damage is believed to occur, become clogged and swollen by the calcium-induced changes to their structure, impeding their ability to transmit signals to other cells.

The result: symptoms such as headaches, memory problems and cognitive issues, and cells left vulnerable to injury as they recover. Taking another concussive blow while the neurons are in a depressed state – not to be confused with second-impact syndrome, an exceedingly rare and often fatal condition in youth that involves other factors – could lead to longer-lasting damage, particularly in the axon. Those repeated impacts, whether diagnosable concussions or lesser blows to the head, Giza says, could lead to exacerbated problems in the short or long term.

“If you were a caveman and got a bad head injury, you’d probably hang out in your cave for a while,” Giza says. “We go right back out there and maybe hit our head again; or hit our head again 10 times. That’s probably where we run into the snafu – the brain is not ready for that.”

That is why allowing adequate recovery time may be so crucial to better outcomes. In a study that will likely be published later this year, for instance, Giza and colleagues found that animals who suffer a second concussion soon after the first show signs of neurodegeneration a year later, while those that are given adequate time to recover before suffering a second injury returned to normal a year removed from the experiment.

Giza speculates that youth may be at greater risk for more severe damage from concussion because developing brains lack myelin, the covering that protects axons. In other words, their cells are playing without helmets. But Giza insists more work needs to be done to prove this theory.

 

So how can the medical community reach a point that would allow a physician to, with a great deal of confidence, tell a women’s soccer player who has suffered her first concussion what her recovery timeline for both her symptoms and her brain function will be? About the risk she will have for another injury, or for depression, or for other effects later in life?

The solution is simultaneously simple and daunting: Just solve those three key questions CARE is designed to answer.

The first question, researchers say, is to determine what happens between the time the concussion occurs and the time of recovery. It sounds simple, but it can differ by gender, by sport, by each athlete’s injury history or by medical or mental health history and many other factors. But solving that question will allow medical staff to treat each person uniquely through the recovery process, whether it’s a female soccer player with a history of depression who has suffered her first injury or a football player who drinks heavily two nights a week and has suffered his fourth.

Broglio is coordinating the clinical work dedicated to finding the answer. Athletes at 30 campuses will be put through a barrage of baseline tests that, together, take roughly an hour. Given the volume – there are more than 900 athletes at Michigan, for instance – athletic trainers and research staffers often perform what looks to be an assembly line of exams.

Determine a baseline

Michigan researcher Dr. James T. Eckner and a research assistant demonstrate concussion tests. They may look simple, but each has been crafted through careful research.

More than 100 football players at Michigan crammed into a hotel ballroom last summer to take baseline tests – computerized drills that assess cognitive function, checking balance by standing on one leg in several awkward positions on a foam pad, examining memory by asking players to recall sequences of words or numbers and analyzing their physical reaction time by asking them to catch a large hammer that is dropped in front of them as fast as they can.

The tests start as a baseline before the season and are then repeated six times at various intervals if they suffer a concussion. Team physicians will use the results to monitor and treat injured players, but the thorough data collection will also provide researchers with an unprecedented level of detail about the aftermath of a concussion.

Broglio and his team estimate that of the 35,000 participants in the CARE study, roughly 750 will suffer a concussion. Researchers will also be able to study fresh baseline data every year that they can use to track changes in players who don’t report concussions. A steady stream of research papers tackling questions large and small will arise from that data. Broglio estimates that, in just three years, he and his team will be able to answer the first major question – detailing the acute effects and symptoms of concussion in several different subsets of athletes – because of the data’s scope.

The study’s findings may also affect the sports themselves. Hainline hopes to use the clinical study’s results to influence rule changes and return-to-play recommendations.

“Will there be changes in sport? Yes,” Broglio says. “Do I think it’s going to change the fundamental nature of those sports? No.”

If successful, answering the first question will help clinicians like Dr. Margot Putukian, team physician at Princeton University, assuage the increasing worries about concussion among the athletes she treats. When she explains recovery protocols and can’t give athletes a set timeline for returning to play, like she might with a broken bone or torn knee ligament, the conversations become “emotionally charged,” Putukian says.

“If we could provide that to our athletes with some level of confidence, it would go a long way,” she says. “It’s part of what makes it so damned challenging.”

And it’s a challenge with two edges. Researchers and clinicians are happy that increased concern about concussion has drummed up more research dollars and made athletes more attuned to the risk – developments that were necessary to make progress. But they cite unfounded panic about long-term consequences, a byproduct of the spike in awareness, as the biggest hindrance they encounter in their work.

“It’s hard for me to be absolutely critical, because I’ve benefited,” Broglio says. “But at the same time, I do think it’s gone a little bit too far, where now you’ll get a high school kid that has one injury, it’s managed really well, and he’ll say, ‘Oh, I might get CTE when I’m 35.’”

Putukian says encounters like those have begun happening more frequently at Princeton. In the past few years, she says, a few Princeton football, ice hockey and lacrosse players have given up their sports after suffering a concussion, concerned that their mental acuity will diminish or that they will eventually be subject to depression or thoughts of suicide. They have a prominent concussion researcher at their disposal, yet they often disregard her guidance because the public narrative has already codified their opinions about CTE.

“That is what every one of our college athletes is worried about,” Putukian says. “When they have this diagnosis, it’s like a death sentence. They don’t understand.”

 

Abetter understanding of concussion’s acute effects would be a breakthrough, but it’s only one element of the larger quandary. While changes in symptoms an athlete displays outwardly may indicate they are recovering, there is a second key question that needs to be answered: Are the cells in their brains recovering at the same pace?

In other words, when an athlete can move at full speed without a headache or trouble balancing, when he returns to baseline levels on computerized tests or in his ability to recall strings of words and numbers, is his brain truly better?

So far, research suggests that the window of vulnerability may persist beyond the time when tests show that cognitive and motor skills seem to be functioning normally. So McCrea and others are working to find signs in the blood or via advanced imaging techniques of the brain’s subtle changes to ensure that athletes don’t risk returning to play before it heals.

The CARE study’s advanced research core, helmed by McCrea with assistance from concussion experts at North Carolina, UCLA, Virginia Polytechnic Institute and State University and the University of Wisconsin-Madison, will seek to address that question. Roughly 1,600 athletes spread across seven contact sports at those four schools will be put through a series of advanced baseline and post-injury assessments: blood draws, genetic testing and neuroimaging – in addition to the clinical tests that will fuel Broglio’s work. The researchers hope to uncover barometers that physicians can rely on to determine what, exactly, is occurring inside the brain after a concussion, and how long the recovery process can be expected to take for different groups of athletes.

Engineering a better helmet

Just as vexing for researchers trying to understand what happens when a concussion occurs is understanding how to decrease the risk of them occurring in the first place. A helmet’s primary function is to prevent skull fractures, severe brain injury and death; there is no way to prevent the brain from accelerating and decelerating at forces that can cause an injury.

But that doesn’t preclude helmets from being designed to lessen concussion risk, as well. Stefan Duma, a mechanical engineer who is head of the Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, translated his experience conducting vehicle safety tests to helmets. He used data from accelerometers in Virginia Tech football players’ helmets to create realistic impacts in the lab, putting helmets through a barrage of tests designed to imitate what they would experience on the field. From that, he produced a five-star helmet ratings system in 2011.

Duma simulates a season’s worth of wear and tear on helmets. Accelerometers that measure impacts in real time are tucked between the padding. Photo by Virginia Polytechnic Institute and State University

The top-rated helmets – typically larger models with more padding – can cause the head to accelerate 50 percent slower than the worst-performing designs. Initially, only one helmet received a five-star rating. Now every major helmet manufacturer has changed its designs and boasts at least one five-star offering. Duma’s ratings system has come under fire for not adequately simulating real-world impacts, but he has tweaked his equation and testing so that rotational acceleration – which occurs during blows that cause the head to turn – will be taken into account in the ratings that will be released next year. Duma will release hockey, baseball, lacrosse and softball helmet ratings by 2017.

Cars with five-star safety ratings reduce risks of fatal crashes, but can’t promise to prevent them. Much the same, risk can’t be completely engineered or legislated out of contact sports, particularly football, Duma says. He strives only to create systems that help mitigate that inherent risk.

“We make sure they have the right equipment, and you do whatever you can to minimize their risk,” he says. “But there is a risk in any of these sports, and unless we talk about it in that light, we’re going to be stuck with tennis and golf and that’s all we’re going to play.”

Additionally, all athletes in the seven sports will be equipped with devices that measure head and body acceleration during impacts, which will enable researchers to identify correlations between those figures and their findings in imaging scans and blood work.

The data collection begins this spring and will run through the end of 2017. McCrea estimates that roughly 90 of the 1,600 athletes will suffer a concussion. Also, data from athletes in contact sports who don’t suffer concussions will be compared with athletes in noncontact sports, who will serve as a control group that will help researchers determine what effect mere exposure to sports like football – the collisions routine to football linemen, for instance – can have on the brain.

Though magnetic resonance imaging machines have failed to become definitive diagnostic tools, they have shown some promise as technology has improved. Depending on how MRI machines are programmed, they can track myriad problems in the brain: changes in structure, blood flow, connectivity and disruptions in the brain’s white matter. (White matter irregularities indicate axon damage, which inhibits brain cells’ abilities to communicate and is thought to be the root of many concussion symptoms.)

The lure of imaging as an answer is understandable: MRI machines are well-known for definitively diagnosing afflictions such as knee injuries. But diagnosing problems in the knee and its four ligaments is a simple undertaking compared with determining issues among the brain’s 86 billion neurons. Despite some athletics departments’ efforts to make imaging a part of their process for diagnosis, it has yet to find a place beyond a researcher’s toolkit.

The University of New Mexico, which is not part of the CARE study, began using MRI scans in 2013 as part of its regular baseline testing and for treatments after injuries occurred. The scans, dubbed the Brain Safe Project, can help team physicians as they monitor recovery, says Kent Kiehl, director of Brain Safe. Thus far, Kiehl’s team has done baseline testing on hundreds of New Mexico athletes, but post-injury exams have been performed on only about 10 who actually suffered a concussion.

Those MRI scans have yet to influence return-to-play decisions. And yet Kiehl says several other athletics departments, eager to do anything they can to address concussion, have expressed their interest in setting up similar baseline tests for their athletes.

“I just think that it’s a very elegant solution to such a complex problem,” Kiehl says.

McCrea and McAllister, though, aren’t convinced.

They insist imaging hasn’t come far enough to influence clinical decision-making. They don’t want any of the imaging they’re doing for the CARE study, for instance, to hold sway over return-to-play decisions as they collect information. They do laud programs such as Brain Safe for gathering more data, but warn against putting too much stock in imaging for recovery decisions.

Imaging techniques like functional MRI, which tracks blood flow and changes in blood oxygen levels in the brain, and diffusion tensor imaging, which examines white matter integrity, have shown changes in brain activity before and after an injury. But there are many other factors that could influence the results, McAllister says: lack of sleep, previous injury history, alcohol consumption, medication use, stress and others factors can contribute to the variation in imaging findings.

The machines can be extremely sensitive. But sensitivity, for now, often comes at the expense of specificity. The scans may be sensitive enough to detect a change, but they aren’t specific enough to explain why that change happened. And when examining something as complex as the brain, why always matters most.

McCrea hopes the imaging performed during the CARE study, which will be captured at four intervals over a six-month period after injuries occur, will help researchers build more specificity into imaging techniques, helping them know not only that a brain’s function is changing, but why it is changing.

“We find it to be very sensitive in brain-injured individuals, but it also turns out that we find it in a lot of people that don’t have brain injury,” McCrea says. “That waters down the ability to use it at the individual patient level.”

In addition to spending time in MRI machines, athletes at the four advanced research schools are being asked to offer up a few ounces of their blood to help identify what protein levels, among other substances, change in the bloodstream after a concussion, and when. Researchers are searching for a simple gauge that can be used the way levels of the protein troponin are measured to help physicians diagnose heart attacks. Other proteins and enzyme levels are used to detect a litany of other diseases and maladies. So why can’t the same logic be applied to concussion?

The hardest hits

The annual national estimate of reported concussions in NCAA sports during 2009-10 to 2013-14 academic years.

1 Football 3,417
2
Women’s soccer 1,113
3 Women’s basketball 998
4 Men’s basketball
773
5 Wrestling 617
6 Men’s soccer 576
7 Softball 540
8 Women’s volleyball 455
9 Women’s lacrosse 332
10 Men’s lacrosse 324

McCrea is relying, in part, on the complex release of ions and proteins after the injury that Giza illustrated in his research at UCLA to target what to test and when.

Other researchers have seen promise in this area: A 2014 study of 288 Swedish hockey players examined the levels of the protein tau in their blood after injuries. Tau helps provide structure to brain cells, is a marker for axonal damage – and is also what McKee finds spotted throughout the brains she examines in her Boston U. lab. The study found that tau levels spiked after concussion and gradually receded through the rest and rehabilitation process.

McCrea, though, says that measuring a single substance, such as tau, likely won’t be the final answer that governs return-to-play decisions because the chain of events after a concussion is multifaceted, and various substances are released into the bloodstream at various intervals after the injury. McCrea will be testing for several markers – mostly proteins – that can be used to measure immediate, intermediate and long-term effects of a concussion.

“If you aim from the outset at only one target, you’re destined to fail because the likelihood that a single image biomarker or a single blood protein biomarker or a single clinical test is going to be the ideal tool in all injuries at all time points is a faulty strategy,” McCrea says.

Those proteins could prove to be powerful allies. Broglio envisions a world, perhaps decades from now, in which mouth guards illuminate when triggered by a substance that enters the saliva after a brain injury. Or perhaps it will be sideline blood tests that reveal a concussion after a significant hit. Along those lines, blood tests could be particularly useful to detect concussion in athletes who try to conceal their injury. And if separate markers for recovery can be identified, subsequent blood or saliva or imaging tests could be administered throughout the recovery period to paint a clearer picture of what’s occurring inside the brain.

 

This is the big question, the one that scares McCrea’s wife, Ann Marie: What are the long-term effects of concussion or of simply playing contact sports?

Many, researchers say, seem to think those consequences are inevitably dire. As of September 2014, McKee had found CTE in 101 of the 128 football players’ brains she had examined – on the surface, a frightening ratio. What is missing, McKee says, is a thorough study of a wider population of athletes, including the many who suffered no ill effects later in life. In her published papers and in interviews, she is quick to note these holes exist and need, badly, to be filled. But comments like those have often gone overlooked.

“We have a need to understand why they’re doing well just as much as we need to understand why someone else is not doing well,” McKee says.

The CARE study has the potential to fill that gap. If it receives the requisite funding to continue its work beyond the three years the Department of Defense and the NCAA have provided to get it started, then it could become what Hainline believes is the brain’s direly needed equivalent to the Framingham study. That study was funded by the National Institutes of Health, which would likely need to provide financial assistance for the CARE study to reach its potential. That would allow researchers to check in on segments of the 35,000-strong cohort every three to five years to maintain accurate depictions of their medical history from college through death.

That painstaking work, and the decades it would require, is the only way answers to the third question, the biggest question, can materialize. Researchers could identify genes that make people more susceptible to head trauma or its detrimental long-term effects. They could determine whether those chronic symptoms are linked to the number of concussions suffered, when the injuries occurred, the total exposure to subconcussive head trauma, genetic makeup, mental health problems or some mix of them all. They could discover why some former athletes’ brains age gracefully while others end up in McKee’s lab – and pinpoint the many different outcomes in between.

Brain tissue collection and examination would be the study’s endpoint. Rather than gather brains from the grieving families of athletes who suffered severe long-term symptoms, they could have samples from hundreds or thousands of athletes, each brain matched with a well-documented medical history. Such a study would enable researchers to determine which variables lead to CTE and which do not.

Study findings would enable physicians to look at an athlete’s life story and tell them how much risk they could expect for developing chronic symptoms. They could help players who have suffered multiple head injuries make smarter choices about their careers and players who pursue professional sports to be acutely aware of the potential consequences.

“There’s no other way to really answer, ‘What are the long-term effects?’” Broglio says. “It’s difficult for people to accept that it’s going to take 20 years to get that answer, but that’s how science is done. You can’t just say this injury happens now, therefore this result happens 20 years from now. You can’t do it. We have to start tracking people.”

McKee’s son is now 25. She wanted him to play football in high school, but his father forbade it because he worried it was too dangerous – even before she had started her work. Now, having grown intimate with the brains of so many former football players, she says she has reversed course. If he were a high school freshman today, begging for a pair of cleats, she would say no.

“In the interim, we have to use our best judgment,” McKee says. “We have to use common sense. That’s all we’ve got until we have time to really conduct these very thorough scientific studies.”

In those few words, McKee defines the murky middle where we’re stuck for the next two, three, perhaps four decades, before science comes back with definitive answers. Until that happens, best judgment and common sense for Michael McCrea might differ from best judgment and common sense for his wife.

When Ann Marie insists that their son not play football because of what has emerged from McKee’s lab, her husband retorts with the strongest evidence he has: himself. He is a former high school football player turned world-renowned neuropsychologist. He points to the hundreds of thousands of others who played contact sports at various levels without having their lives marred by the type of symptoms that have led troubled widows to McKee’s doorstep.

That logic, he fears, may not be enough to convince even his own wife.

Joe, now 8 years old, yearns to play football in his teenage years, and McCrea would like to cheer for his son on Friday nights. But the concussion researcher worries the anxiety in his home has outpaced the findings in his lab.

His only recourse is to take the long road demanded by science. All he can do to turn fear into knowledge is to get up every morning, the three questions in his mind, and go to work.