Simon Bruty/The MMQB
Simon Bruty/The MMQB

If You Give a Mouse a Concussion . . .

Using a novel technique to peer through the skulls of living mice, researchers at the National Institutes of Health in Maryland are observing concussed brains in real time, transforming ideas of what happens at the molecular level and pointing the way to possible treatment for mild brain trauma

By
Robert Klemko
· More from Robert·

LAB PHOTOS BY SIMON BRUTY/THE MMQB

BETHESDA, Md. – One of the most important recent developments in the treatment of brain trauma—and by extension, the future of football—may have been discovered by a clumsy intern. 

Theo Roth is a St. Louis-born, Alabama-raised Stanford graduate who finagled his way into a National Institutes of Health internship in the summer of 2010, after his senior year of high school. Bored after graduation, he appealed to Dr. Dorian McGavern with a personal email and the recommendation of a mentor of his parents, both doctors. McGavern, new at the NIH’s suburban Maryland health campus, allowed the 18-year-old to sidestep the pool of more than 10,000 college kids gunning for 1,000 spots and took him on. McGavern and his team were using a new research tool, pioneered in 2007 at New York University, which involved shaving down a small portion of a mouse’s skull to shine light into the brain and record its processes. McGavern wanted to study how meningitis affected the brain, but his new intern couldn’t handle the tiny ballpoint saw without concussing the mice and muddling the results. 

“He was really bad at performing skull-thinning surgery,” McGavern says of Roth. “Just couldn’t get the hang of it.” 

It was—and remains—a difficult thing to accept for a kid who scored 35 out of 36 on his ACTs and 2350 out of 2400 on his SAT. “It’s really hard to do, and they only gave me a week to learn,” Roth says of the procedure. “They have neurosurgeons come in and get it wrong.”

Theo Roth.
Theo Roth.

Mouse after mouse was concussed, but something valuable did come of the process. Roth and McGavern observed in the subsequent images of the rodents’ brains a flurry of action—leakage from blood vessels lining the skull seeping down and causing brain damage. Towards the end of the summer, the two started talking about what they had seen in the concussed mice. Roth, a former high school wrestler and a Rams fan, connected the dots. “We saw the brain operating in ways no one had ever recorded before, and right around the same time, traumatic brain injury was becoming a hot topic,” Roth says. “People were starting to realize how detrimental it was in the NFL and for guys coming back from Iraq and Afghanistan.” 

Roth and McGavern were chatting one morning in the cramped computer room in McGavern’s lab when something clicked. “It was like, wait a minute, we’re actually recreating what happens in a mild traumatic brain injury,” Roth says. “This may actually be very important.” 

The wheels started spinning. It became Roth’s personal project to study concussed mice—after all, he was the best in the lab at injuring them. Rather than take his time while sawing down the skull, Roth buzzed through the process in 45 seconds, shaving the bone from a density of one millimeter to 30 microns, about the width of a human hair. The anesthetized mouse was then strapped under a two-photon microscope, a four-foot tall machine that allows for imaging of living tissue. Over the rest of the summer and the summer after that, the bright blue, green and purple images relayed to the computer gave McGavern and his team an outline for the mechanism of damage from minor head trauma. Here’s a thumbnail of what happens:

  1. A mild brain injury occurs, in this case, when skull is pressed into brain.
  2. The impact damages blood vessels lining the skull, causing some to burst or leak.
  3. The body responds, in part, by producing molecules called reactive oxygen species (ROS), which mistake the injury for the intrusion of a foreign body.
  4. Useful in fighting bacterial infections such as E. coli, the ROS swarm around the injury and cause damage by tearing up the glial limitans, the thin membrane separating the brain from the fluids around it.
  5. Fluids from the damaged blood vessels leak through the new holes in the membrane and come into contact with brain tissue, destroying it.

McGavern believes this process could play a fundamental role in the development of chronic traumatic encephalopathy (CTE), the disease that has been found in the brains of deceased former football players. CTE has shown up in the autopsied brains of former Bear Dave Duerson and former Charger Junior Seau, both of whom committed suicide. It’s also listed as evidence in the case made against the NFL by thousands of former players who sued over decades of alleged mistreatment of concussions by NFL doctors. CTE and the concussion epidemic are the reason the NFL agreed last year to pay $765 million to those players, plus $30 million to the NIH to fund studies on the biggest problem confronting football at all levels of the game. 

But the NFL wasn’t funding this project. This was an NIH undertaking being performed by a researcher whose main interest was viral infection and an intern with shaky hands and a special mind. Roth became obsessed. He went to Palo Alto with mice on his mind. He joined the marching band, and it became his distraction, but as soon as winter and spring breaks began, he was on a plane to the East Coast. “I was much more excited to be doing the research than I was to be taking classes,” he says. “It was a little rough to be studying for a midterm when I was thinking about the next experiment we could do. I was doing work that was brand new, as opposed to learning things from a book that people already learned long ago.”

Next, having observed the process of concussion in real time, the researchers brainstormed ways to treat the injury. McGavern remembered that in grad school at the Mayo Clinic, his wife had worked on ROS and ways to block them, for an unrelated study. Her group had used an antioxidant called glutathione. McGavern’s team obtained the readily available organic chemical, and Roth tried it out on mice. He injured the mouse, placed a small quantity of the drug on top of the mouse skull and observed it under the microscope. “You think of the skull as a bone that keeps everything out, but it is a porous filter,” McGavern says. 

The morning after their first experiment with glutathione, McGavern arrived at 9 a.m. and found Roth grinning, having slept at the computer. “I saw him, and I already knew that we had it,” McGavern says. “He showed me the result, and the cells look like they were totally naïve. It looks like there’s no injury that’s happened whatsoever. It looks like a normal brain. 

Dorian McGavern. (Simon Bruty/The MMQB)
Dorian McGavern believes the same treatment his team found reduced brain damage in concussed mice might be effective in people.

“After that Theo lived in the laboratory, 16, 18, 20 hours at a time. He laid his pillow out on the keyboard and would just sleep between experiments. He was a man possessed.”

McGavern reached out to a doctor working a floor below who had been studying concussions in human patients for years. At two local hospitals, concussion patients were given the choice of joining an NIH study for which they were injected with dye and an MRI was taken of the brain. In half of all patients with mild brain injuries, the dye showed up in the brain tissue, which meant the same processes observed in mice were happening in humans.

“You can’t get down to the resolution we can see with the mice, but if you look at the human brain you saw the leakage,” McGavern says. 

Roth became the lead researcher on a paper that made national headlines last fall. He reported, among other findings, that passing an antioxidant through the skull immediately after a concussion reduced brain tissue damage by an average of 70%. 

(The mice used in the study are able to live normally with their thinned skulls, but typically they’re killed and dissected afterward to further examine the brain tissue. That was no doubt on the mind of dozens of online commenters who threatened McGavern and his team with violence as retribution when The New York Times reported on his research. McGavern has no qualms about using mice in his studies. “When you consider the possible benefit for our species,” he says. “It’s an easy call.”)

Head Trauma in Football


In October The MMQB devoted a week to the most pressing problem facing the game. READ THE SERIES.

Roth was elated. All those spring breaks spent in a lab devoid of daylight, staring at a computer; it meant something now. This was not a cure for brain injury, but it might lead the way to a concussion treatment

“I don’t know if I’ve ever had a person better than him in my lab in 10 years of doing this,” McGavern says. “He’s just brilliant. The amount of information he can collect is ridiculous. And the dedication—think of all the spring break destinations; Cabo, Florida—and instead he was at the lab.” 

“An incredible feeling,” Roth says. 

Next up for Roth is grad school, after graduation this spring. He applied to 20 graduate programs and got into every one, choosing UC-San Francisco. As for the research, McGavern and Roth’s work spawned two more studies. McGavern’s lab will look into the long-term effects of multiple brain injuries, with and without antioxidant treatment. Within the next several weeks, another researcher at NIH, with McGavern’s help, will study the treatment on pigs, who have skull thicknesses very similar to humans’. Someday, McGavern says, humans could be treated with a dose of antioxidant pressed to the scalp immediately after brain trauma. There’d be no clear telling if it worked, short of the dye MRI and, for football players, a decrease over time in the number of players who suffer loss of brain function, and the degree of that loss. 

No doubt Roth would like to get in on subsequent research, though he’s not sure he’s capable of devoting 16 hours at a time to the cause. “I was young and had plenty of energy then,” says Roth, 22. “It feels like I’m getting old.”

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49 comments
bodino
bodino

They should study woodpeckers.

Acanuts
Acanuts

And here we go again, we have not learned a thing other than cruelty to animals, in this case mice, is being rewarded with academic advancement, accolades and career success. I couldn't even read through the entire article without feeling appalled. Shame on research torturing animals when a much better approach would be finally compiling and consolidating all research that has already been done instead of repeating the same, stupid experiments causing pain and suffering to helpless animals. I wonder who among those who caused concussions in an endless number of mice would volunteer for such horrific experiments? Oh nobody? I wonder why... shame on all of those so-called scientists advancing their careers by displaying such inhumaneness. Shame also on the author of this article for displaying the same ignorance and detachment from other beings.

JuliaMackenzie
JuliaMackenzie

We used to strap monkeys in cars and smash them against walls to "research" car crashes until people woke up to the ugly cruelty of that. This is another case of legalized animal abuse and is sickening. Football is a choice and  a GAME, why should any animal be used in such experiments because a bunch of fools want to run around smashing into one another. 

DrDeckerWeiss
DrDeckerWeiss

Humans are not mice, so there is no direct translation, killing mice will not help the effort


MadoneRider
MadoneRider

Very interesting article, especially as I'm reading "League of Denial" about the NFL and it's attempts to deny the fact of concussions and subsequent brain injury being caused by playing football.  This work being done by the NIH (and not funded by the NFL) could lead to great things, not only for football players, but hockey, soccer, our veterans, car accident victims, etc.

Redskins
Redskins

Of Mice and Men. Mice shouldn't play professional football.

murryjcohen
murryjcohen

An article already ridiculous from a scientific point of view degenerates further into a discussion of needless head trauma caused by playing professional football. The idea that mice given a head injury called a “concussion” has anything to do with human concussion sustained by playing professional football is laughable.

The tone of the article reads like an upbeat propaganda piece….a “wow look what I found” adventure story, culminating in the absurd conclusion that something of scientific merit was discovered. This adventurous tone is necessary to sustain interest in the subject matter since the actual events are without genuine scientific interest or merit.

 In reality, especially being published in a sports magazine, the purpose of the piece is to defend the violence inherent in professional football by promising us future cures based on serendipitous but, in reality, worthless mouse experiments. This reminds one of the tobacco smoking experiments which were performed in mice which showed that smoking tobacco does NOT cause cancer. Those experiments were paid for by the tobacco companies, knowing that the public would be deceived into thinking that smoking was innocuous, in order to continue selling their deadly products and continuing to profit.

 Likewise, these ludicrous mouse experiments are being supported by organized professional football in order to offer false hope for humans whose heads get bashed in the game so as to be able to continue the sport and continue raking in profits.

Achim
Achim

hello i'm from germany, so excuse misspelling. okay, lets make it clear. you invent a form of sport whereby people run on each other to stop the opposition, by whatever it takes from the physical standpoint. then people begin to wonder 'why on earth could it possibly damage my body?'. okay...

and even used for other cases where people have a concussion, its dirty work to kill animals for research. switch the perspective and imagine they would come to your house, handcuff you an drive you to an unknown place. you would be concussed by someone for research to possibly find something.

mice have a heart, like you and i. they are creatures with a right to live, like you and i. and we should think, if our ability of free thinking and doing, could be aresponsibility to the world and nature.

maybe we better invest every spark we have in research to stop air pollution and melting of the polar ice caps to save the planet before it is to late and our children will live a really dark life, don't even knowing what the meaning of the term "american football" is. 

BatyaBauman
BatyaBauman

I really don't know why animals should suffer because humans do stupid and dangerous things to themselves.


sporthero
sporthero

Aside from any other considerations, just think for a moment what kind of individual would or could do this to little helpless beings. This is not the kind of person I want working on my behalf. 

veda9sports
veda9sports

There are hundreds of former athletes (football, baseball, soccer, etc.) who ARE willing to be subjects to study results of and cures for concussion. But of course they would most likely either volunteer or require a small stipend, thus depriving the sadists the opportunity to torture animals and depriving the laboratory taxpayer funding. What century is this again? 

CharlesPerrySwenson
CharlesPerrySwenson

Control of the ROS. Could be good, but needs to be applied immediately. Cruel way to find out. 

BarbaraStagno
BarbaraStagno

This would be totally ludicrous were it not so egregiously cruel.  Bashing in the heads of mice with their skulls ground down to a sliver is not the answer for how to address head injury in humans. It’s an artificial creation of something that doesn’t exist in reality.  Just like all the cancer cures in mice that have not materialized, this bogus research will not help people suffering from traumatic brain injuries. 

As Dr. Elias Zerhouni, the past director of NIH has said, it’s time to stop “dancing around the issue” with animal experiments and address human medical issues through clinical studies. It didn’t take these animal experiments to reveal that glutathione reverses cell degeneration or that ROS is a key part of cell injury. These things have been documented in the scientific literature for decades. So now they can watch as it happens. Yippee. More ways to torture animals.

All these animal experiments really prove is that there is big money to be made killing animals, especially with “hot button” issues like the NFL’s debate over head injury. The NFL is only too happy to throw money at the problem it perceives as a threat to its multi-billion dollar enterprise, and scientists are only too happy to get on the band wagon.  The brain-injured patients and the animals lose while the others get rich.

GaryOkie
GaryOkie

This could be game changing.  I'm a man who suffers from a TBI  almost17 years ago...I wish for others the brain can be treated and possibly healed.

MarkPitcavage
MarkPitcavage

You know, I am not at all an animal rights activist, but all I could think of reading that article is that intern torturing one mouse after another.

rwmurch
rwmurch

I love that I can read something so informative and so relevant to a sport I love. I've become conflicted over the  last few years in my enjoyment of the sport due to seeing the damage being caused on the field and the lasting effects seen on former players, I hope that these findings and the continued research by all can help mitigate the damage that is caused by concussions not just for the players, but for the soldiers and anyone else that suffers a concussion. As an engineer, I understand that the study of science is not always perfect, however the ability of Roth and Dr. McGavern to not dismiss the valuable information that was right in front of them It is a reminder to us all to not dismiss what is often right in front of our eyes.

theboneman21
theboneman21

Lol

New York Times commenters threatening for using mice.

As I have gotten older and moved to a more rural area and become a parent I have come to realize that kost of the mouths probably are city folk who have never had to consider pest problems and probably do not have kids.

If testing on rodents saves human lives I say throw em in a pillow case, toss em in the trunk of a car and fo for a ride on a bumpy road.

This was a great article and offers hope.

KeysSteven
KeysSteven

Informative write, Bob, nice change of pace.  Could've done w/out the mouse photo at top, though.  Some images are best left to the doctors and interns.

dtwin
dtwin

Mice don't wear helmets so they don't hit things with their heads.  This is why mice in the wild get very few concussions.  When we humans played tackle football as kids in our backyards with our friends we played with no helmets and NEVER got concussions because we wouldn't dream of using our heads to tackle an opponent.  We TACKLED them.  We didn't HIT them.  It is since the emphasis on HITTING that this has become an issue and the use of a TACKLE has faded over time.  I am not saying that the NFL in the 40's and 50's never had a concussion, but certainly far fewer.  Head slapping was banned so folks like Deacon Jones and such had to find other ways to intimdate.  Fred Williamson's forearm to the head was banned, etc...  The evolution of the helmet has contributed as much to the problem as anything else.  Give them back the leather helmets and they will stop leading with their heads.  Rugby is a pretty violent game, but concussions are few and far between.  We could take a lesson from those folks.


Dtwin.

BrianK
BrianK

Wow. That was fascinating. Can I buy stock in MMQB yet?

ohiojim44
ohiojim44

Another terrific article on the MMQB.

giwan1259
giwan1259

@bodino  Woodpeckers have a special built in shock absorber in their beak.

Bongo
Bongo

@murryjcohen :  I don't think it says anywhere that the NFL is funding this research.  And surely you can see that there would be benefits to medical breakthroughs regarding head injuries far beyond any imagined benefits to football players?  


I'm as cynical as the next person about corporate greed and doing anything for a profit, but anything to help the players with concussions is worthwhile, as far as I'm concerned.  We're talking about players in many different sports going down to youth sports, as well.  Seems like a good thing to research.

CharlesBarnard
CharlesBarnard

@BarbaraStagno  Do you read English? Do you understand that the mice are not aware of the procedure at all?

You are benefiting from such experiments daily, are you willing to stop using any medical treatment based upon animal experimentation? Please do so. It will increase the human average intelligence slightly if you do.

Experimentation is directly related to money only because that is the way our 'capitalists' have decided things should work. The rest of humanity doesn't necessarily act that way.

How do you feel about the millions of rodents that are killed daily using poisons, drowning, and predators to ensure that you have food to eat?

el80ne
el80ne

@BarbaraStagno  Ridiculous. The discoveries to science and medicine from animal experimentation is immeasurable. To dismiss the step of experimentation and say we could just jump to clinical trials just isn't cognizant of the realities. In order to get a study approved for the expense of a clinical trial it requires promise backed by hard data. The pace of medical advance would slow to a crawl without being able to recreate such trauma in a controlled environment. This is where research into affects on laboratory rats comes in. Maybe not in this case but some experiments require experimental procedures or drugs that have demonstrated their safety in a lab environment prior to human experimentation. Who are you to say that it's not the answer when the results from experimentation have been been the basis for so many medical breakthroughs? I trust the scientists that the brain trauma created is similar enough to human brain trauma to be useful more than I trust your unsupported opinion.


PeterHaag
PeterHaag

@rwmurch  We should probably stop encouraging children to use their heads as battering rams. There are much healthier sports and outlets for youth and yet we spend money on grooming children to destroy their bodies for entertainment purposes, just plain dumb.

Bongo
Bongo

@rwmurch:  I agree.  Growing up loving football, it becomes tough to watch some of the big hits now.  I'm seriously waiting for the day when a player dies during a game, because it seems inevitable.  There is constant talk in comment sections about how athletes are highly paid and "know what they're getting into".  To me that's pure nonsense.  It doesn't matter what an athlete is paid - they deserve to be protected and they don't deserve to have their longevity compromised by playing a sport.  How much they are paid is irrelevant.

I hope that the NFL is really, truly taking this topic seriously, and that this kind of research leads to true breakthroughs to help anyone, anywhere who has a concussion.  Of course the next step is to get the NCAA on board, and high school football, and peewee, etc.

CMFJ
CMFJ

@theboneman21  


I grew up in the country on a farm and now live in a major metropolitan area.  On the farm we worried about squirrels, some raccoons, and the odd coyote and deer.  Unfortunately, in several of the places I have lived here in the city I have had to worry about pest problems, mostly rats and raccoons.   Rats are a not an uncommon problem in big cities.  


Of the animal rights activists I have known over the years, about half were raised in the city and half in the country.  In fact, the person I know that has been most involved in animal rights activities was raised on a ranch. 


So I think your "city folks" argument is not a solid one.  I think the reason the NYT article attracted more of that is that it is read by a much larger audience and probably noted by other major national media outlets.  


ManticorePinion
ManticorePinion

What does having kids have to do with being against animal research? I hate kids, love animals and even I think this kind of research is necessary at worst.

CharlesBarnard
CharlesBarnard

@dtwin  Please share the source of your data supporting "mice in the wild get very few concussions."

A concussed wild mouse is food for something else.

Helmets do not cause concussions, although using your head as a battering ram often does.

How do you KNOW none of you got concussed? Not all brain trauma is noticeable at the time.

Better protective gear invariably results in more aggressive actions in sports. 

But sports is not the only or even main human activity which results in brain trauma, merely the one fools know best, because they pay little attention to the real world while involved in their fantasy world of organized rules and play.

Bongo
Bongo

@dtwin :  I remember very clearly from playing HS how the helmet and pads made us feel "invincible".  Kids think "I'm protected, so I can throw my body into this".  Or at least we did.  Does anyone else remember coaches yelling "put a hat on somebody!" during plays?  Meaning "hit somebody!".  We were taught that helmet to helmet contact was normal, but that your helmet should slide off to the side of the other guy's. (I played on the line so this was specific to that situation).


I then played rugby in college and learned how to tackle properly.  So, I agree, Dtwin.   99% of the "poor tackling" or "broken tackles" in the NFL and college involve defenders just hitting the ball carrier and not using their arms at all.  Like you said, it's not tackling, it's hitting.  If you have to wrap a guy up then you need to get your head out of the way and do it properly.  Sure, injuries can still happen, but it's much less likely.

murryjcohen
murryjcohen

@CharlesBarnard @CharlesPerrySwensonYes, there IS a possible treatment included in the results.....a treatment for mice, not humans. Repeatedly treatments that were successful in mice, in many different fields of medicine, failed in humans, When you are sick, do you see a veterinarian or an M.D.? When your companion animal is sick, do you bring him/her to an M.D. or to a veterinarian?

JuliaMackenzie
JuliaMackenzie

@CharlesBarnard @BarbaraStagno  So you read an article and believe that the mice "are not aware of the procedure at all" ? Really? Just like your body is not aware is has a brain it could use?? Read the facts before you post un educated comments. Animal experiments DON'T WORK and by chasing this medieval research we delay real medical advancements. How come cancer, heart disease, Alzheimer's isn't cured yet since we spend so much and kill so many animals trying to find the cure. How come it's actually INCREASED. If people are against animal experiments what do you THINK they feel about using animals to test poisons. Animal predators has NOTHING to do with the industrialized animal exploitation industry. Honestly..why am i even replying to such ignorance???  

rwmurch
rwmurch

@PeterHaag @rwmurch  Playing football in high school my coach would sideline a player in practice or on the field if they were leading with their heads and that was 19 years ago (Including myself a couple of times) I know are coaches stayed up to date on player safety and techniques right down to the types of stretches that were "standard" but actually had become obsolete because they caused more harm than good. I agree that many top state high school divisions the winning has become a business like college and NFL. I think the solutions don't need to be complicated. I think parents just need to be parents and demand from their Athletic Directors and coaches to be trained to coach properly. And if that isn't available for their child to say no. I think football was a great sport for me to play, however if my son wishes to play it will need to be for a system where sportsmanship and technique is prioritized over winning. Whether I support him playing as he gets older is still another story.

CharlesBarnard
CharlesBarnard

@Bongo @rwmurch  Having had to spend nearly a billion dollars last year because of this, plus the loss of many players who could have brought even more money, they are serious.

theboneman21
theboneman21

Thanks for weighing in. I can rest easier now.

theboneman21
theboneman21

Toddlers, climbing and falling is another way.

Playing king of the hill as a kid. Street fights. Wrestling.

Just some of the non sport ways a brain can be concussed.

theboneman21
theboneman21

This. As a Canadian where the playing field is bigger there is a greater emphasis on athleticism and tackling. We also have 12 men on the field at that. We use the whole field and it is not all about north and south. As a result you see fewer things like 400 pound "athletes" sprinting 18 feet then waddling off in a desperate search for oxygen.

Also a point of note - touchbacks count as a point surrendered here which means any catchable kick is returned. And still we do not have the concussion problems. Again, larger field.

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