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Can Science Diagnose a Living Player's Brain?

Kyle Wagner has an in-depth piece up on Deadspin that goes into how far away we are from being able to limit and protect players from concussions.

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44 comments, Last at 29 Jun 2012, 7:45am

1 Re: Can Science Diagnose a Living Player's Brain?

Interesting article, but there's some things in it that are decidedly wrong, and others that are completely ridiculous. The idea that increasing intracranial pressure through trapped blood accumulation could somehow "cushion" the brain and reduce the impact force of the brain as it "sloshes" in side the skull was obviously dreamed up by someone that has no grounding in biomechanics whatsoever. First, many head "mild" injuries (the ones that don't involve skull fracture or haematoma) occur because of rotation of the head, not linear impacts, and suppressing brain motion relative to the skull won't do a thing to help that. Secondly, CSF is essentially water from a physical response standpoint--and if you have an object floating in water, increasing the pressure in the water doesn't do a single thing cushion the object floating in it.

The other major issue that I can see is, based on the doctors and biologists I've talked to, the accumulation of tau protein associated with CTE can take a minimum of many months, and more generally several years, to occur after the head traumas that triggered it. Also, apparently once you hit a critical threshold level of tau buildup, it becomes self propagating, even if you don't have any additional head trauma. So monitoring the increase in tau protein wouldn't be a good way to decide when to hang up the cleats...you could quit when you were still at a "healthy" level, it could take a couple of years to accumulate more, hit the threshold, and you could still end up with early onset of dementia or other lasting brain injury.

The article also touches briefly on, but glosses over, an alternative diagnosis technique that does show promise...diffusion tensor imagine MRI. Although poorly understood, there's some really promising research about using it to track the biomechanical insults that could lead to long term tau protein buildup.

4 Re: Can Science Diagnose a Living Player's Brain?

I work in a genetics lab that does Alzheimer's research (tau is one of the two key proteins in AD pathology)

Short answer: No

Longer answer: Tau is short for microtubule-binding protein-tau, it's a protein that's involved in cell stability. In AD the proteins are AB (amyloid-beta) and tau, the former being extracellular and the latter being intracellular. The difficulty of making a pill to clear tau would be: 1 - a drug that crosses the blood brain barrier, 2 - said drug also gaining access to damaged cells with misfolding/misexpressed tau, 3 - activating a clearance pathway and 4 - differentiating from normally expressed/properly folded forms of tau.

5 Re: Can Science Diagnose a Living Player's Brain?

Tau itself isn't necessarily the source of the problem, but more like the byproduct of the disease process. It's just the most consistent intrinsic biomarker available for these kinds of problems.

And any drug that "dissolves" something in the brain would worry me greatly. The side effects would be terrible and likely irreversible.

7 Re: Can Science Diagnose a Living Player's Brain?

Disclaimer: I'm a material scientist and mechanician who works in biomechanics of brain injury, not a biologist or an M.D. But I had heard from the doctors/biologists I work with that tau is both a symptom or indicator, and also a potential source of further problems (only the doctors alwasy use the word "pathology").

The way they explained it to me is that damage to the structures within the cell or resulting neurological degeneration liberates the tau proteins from the places they're supposed to be (like rebar breaking out of a concrete wall was the analogy used), so the tau is indeed a biomarker for neurological damage. But they also said that a buildup of tau itself can cause further damage--the free protein tangles mess up cell functions both structurally and biochemically, and that enough buildup of tau protein will reduce cell function and ultimately lead to death of the cell. Furthermore, they said that when tau protein concentrations become sufficiently large in damaged areas of the brain, they can become mobile and be transported to healthy areas of the brain, ultimately causing those areas to also lose functionality (and ultimately die). Hence there is a critical threshold of damage above which the disease becomes self-propagating (and irreversible, unless doctors find some way to eliminate the freed proteins).

Perhaps my understanding is oversimplistic or naieve, or perhaps I was misunderstanding what the neurologists and biologists I am working with were trying to explain to me, but that was my impression. They seemd to think that if there were some way of dealing with the tau protein tangles, the additional damage could be checked, and the brain could re-wire itself around the locally damaged areas that caused the tau buildup in the first place...

19 Re: Can Science Diagnose a Living Player's Brain?

It seems you're a lot closer to this than I am (my area is fMRI and non-proton MRI in the setting of normal brain function, stroke, and cancer). Everything you've described makes sense to me, but it seems that clearing the NFTs would provide symptomatic relief with diminishing returns over time (analogous to replacing dopamine in Parkinson's patients). The brain's ability to "rewire" around damaged areas is limited as well, depending on the damage already done. The root pathology is obviously not fully known--for example, we know that the event precipitating tauopathy is hyperphosphorylization of tau. Would a drug preventing that from happening be more effective?

Similarly, would phosphate-based MR (something I'm working on) be sensitive enough to detect these early changes? It's an interesting idea, one that I haven't really thought about.

3 Re: Can Science Diagnose a Living Player's Brain?

This entire article sounds like the author took the researchers' grant proposal and translated it into laymen terms. It also reads like a press release for UCLA's patent-protected tau PET marker. I especially love how the author uses a PET image for Down syndrome as a substitute for how the missing tau results would look like.

Any device that constantly presses on the jugular vein is going to create more problems than it solves. Constant pressure/weak trauma leads to bruising, inflammatory responses, and ultimately thrombi, increasing the risk of pulmonary embolism. If the device extends to pressuring the carotid (which could easily happen when it's constantly being jostled around), stroke is possible. In addition, the body self-regulates intercranial pressure. It's likely that long term use of the device would decrease the amount of CSF produced by the choiroid, defeating the purpose of the device.

You are right, tau buildup is typically a chronic process that usually takes years to develop. While this might be useful in early retirement as a guide to early treatment, an annual/biannual test while playing isn't likely to be very useful. The section covering clinical and neuropsych testing seems more promising as a early assessment for CTE risk.

My own expertise is in MRI, and I can tell you that the amount tau buildup required to see significant DTI-related changes is substantial and unlikely to be very useful for early diagnosis (or at least, not as sensitive/specific as tau-specific PET studies). In addition, the article talks about looking at changes in specific structures (the ones typically associated with AD/dementia patients). As a radiologist, I can tell you that those structure-specific size changes inform, but do not diagnose the disease. Brain scanning is typically performed to rule out other possibilities, but AD itself is primarily a clinical diagnosis. I've read many of those studies, and results are typically reported as something like "Overall, there was a 10% reduction in volume of the hippocampus over the 75 patients that were studied." The specificity of that kind of finding on an individual patient basis is unreliable at best.

I don't mean to sound so negative about the prospects in the article, but there's a reason this stuff is so hard. The brain is the most complicated and hardest to measure organ in the body. Macroscopic scans just don't do it justice, and microscopic tests are too invasive. We've got a long way to go. My own bias is that MRI-related improvements in technology will allow us to get to the microscopic/physiological level noninvasively before these other avenues pan out, but the more attention to the issue the better.

8 Re: Can Science Diagnose a Living Player's Brain?

My impression was that you wouldn't try to use changes visible with DTI to look for tau buildup, but rather to look for the basic axonal pathology that can lead to tau buildup. In other words, direct axonal damage (tearing, kinking, or swelling) caused by a head impact will ultimately lead to tau buildup, but in the short term such damage should cause a change (a reduction) in the anisotropy of the diffusion tensor within the white matter, and that this change of anisotropy is often discernable using DTI.

What I understood to be the problem is that healthy anisotropy levels naturally vary from person to person (and over time for a single person), so damaged tissue for me might look like healthy tissue in you, or like healthy tissue in me years ago. So the only way to reliably use DTI to spot injury is to have frequent "healthy" scans, and compare a post-impact scan to a relatively recent "healthy" scan for that specific patient. But if you're a radiologist, you probably know more about that then I do (I'm only using DTI to try to create tractography maps in order to orient material model anisotropy in brain impact simulations...)

15 Re: Can Science Diagnose a Living Player's Brain?

We generally model the interface between the brain and skull with a fluid layer (depending on the model, we may or may not get into all the fine details of the dura, arachnoid, and sub-arachnoid spaces), but we always allow some kind of fluid-filled slip boundary, as you say. In general, I think more relative motion between the brain and skull happens in the sub-arachnoid space than at the dura-skull interface. Discrete springs would only make sense if they are extremely weak (after all, there are structures like bridging veins that tie everything together in there, but those structures can't bear much load).

20 Re: Can Science Diagnose a Living Player's Brain?

As I said above, you're a lot closer to this than I am. I can tell you that the findings you're talking about haven't quite filtered down into regular radiology practice. In fact, DWI is not usually done for patients with mild brain trauma unless more significant injury is suspected (bleeding, etc.). For now, clinical exam and neuropsych testing remain the gold standard for evaluating concussions.

PS: I'll have to remember that there are a few guys studying this stuff on the board.

25 Re: Can Science Diagnose a Living Player's Brain?

I'm a little confused here. Setting aside the implausibility of his suggested method of controlling brain movement relative to the skull, why wouldn't that help? I was under the impression that the reason rotational movements were so bad is because the existing "cushioning" was bad at suppressing those movements, and so rotational movements tended to cause the brain to impact the skull. Is there something inherent in sudden rotation of the brain that causes damage even in the absence of contact?

26 Re: Can Science Diagnose a Living Player's Brain?

Short answer: yes.

Longer answer:

Brain tissue is "nearly incompressible" because it's filled with fluid. It has a consistency kind of like pudding. That means that it is very resistant to pressure-induced changes in volume, and very succeptible to shear-induced changes in shape. When you subject a brain to pure linear motion, absent contact (and despite what you year, it takes a *lot* of linear motion to cause the brain to collide with the skull...the cushioning in the head is actually pretty good. Remember, we evolved from monkeys who were falling out of trees!), all you get in the tissue is a buildup of pressure--which causes very little actual deformation of the brain. While pressure can cause injury, you have to have either a lot of it, it has to last a long time, or you have to have negative pressure ("suction"), to injury things.

But when you rotate the brain, that creates shear loads in the tissues, which causes shear deformation of the tissue. Shear is believed to be far more damaging because a little bit of shear load causes a lot of shear deformation, which in turn can tear or damage the cells.

For a reasonabl analogy, imagine filling a bowl with pudding, right up to the brim, and put some stripes of food coloring or another kind of pudding across the top so you can see what's going on. Put plastic wrap over it to keep it from sloshing. That's your brain in the skull. Now slide the bowl back and forth--not much will happen. Then spin the bowl. The pudding inside will get all mixed up.

13 Re: Can Science Diagnose a Living Player's Brain?

I'm sorry, wouldn't increasing intracranial pressure lead to more brain damage? Isn't swelling and increased pressure one of the causes of brain injury? I remember reading that head trauma resulting in open head wounds is actually less likely to cause damage than trauma without an open wound due to swelling and pressure.

14 Re: Can Science Diagnose a Living Player's Brain?

Yes and no. In the case your thinking of, where there is swelling or haematoma putting pressure on one local part of the brain, it can certainly cause injury. Localized pressure can cause shearing and stretching deformation of the brain, which can cause damage. This can certainly be detected via a rise in intracranial pressure that occurs due to local swelling, but it is the actual deformation of the brain that is the problem.

What this article is proposing is to increase intracranial pressure uniformly throughout the head by restricting blood flow. Since we are basically ugly bags of mostly water, our tissues are nearly incompressible (meaning that it's much easier to change their shape than their volume). Subject a nearly incompressible material to a uniform increase in pressure, and basically nothing happens. Subject it to a localized pressure in one spot, and it will change its shape. To use a rough analogy, if you take a water balloon and drop it to the bottom of the ocean, it will probably not deform or pop, although the pressure inside will certainly go up. But if you push on one side of it with your finger, you will deform it and maybe pop it (and the pressure inside will also go up).

(Of course, the water balloon will move through the water with the same level of ease regardless of the pressure on it, which is why the suggestion that increasing intracranial pressure will somehow cushion the brain better is just silly).

It is believed (although not known for certain) that uniform intra-cranial pressures that can directly cause injury are extremely high (I've heard various numbers ranging from 10 to 50 atmospheres, or more), although it does depend on duration. I think there's some evidence that small icreases in intracranial pressure that last a very long time (e.g. in people who have hydrocephalus), might be damaging. However, a significant body of animal tests and patient data from injured humans suggest that over short durations, increases in intracranial pressures of the order that you could cause with restricted blood flow (probably on the order of less than an atmosphere) do not cause brain injury.

21 Re: Can Science Diagnose a Living Player's Brain?

Two things:

1) Hydrocephalus is more a concern for infants and children, as the increased pressure (even if relatively mild) can have a profound impact on development. In adults, non-obstructing increases in pressure can lead to either pseudotumor cerebri (visual disturbances and headaches) or ventriculomegaly (dementia, gait disturbances and urinary incontinence), both of which are local injuries (despite a uniform increase in pressure). It doesn't take a large increase in pressure to cause this (>200 mmH20--appx .02 atm, but I don't know if the measure is the same as the 10-50 atm you refer to above for direct injury).

2) One big concern indirectly related to CSF pressure is rapid changes. It doesn't take a large pressure change to cause brain herniation, a potentially life threatening situation (if it involves the brainstem). Again, another reason not to be fooling around with devices that change intracranial pressure.

29 Re: Can Science Diagnose a Living Player's Brain?

High intracranial pressure isn't a direct injury. As a transient event, high pressure isn't that injurious -- the brain being basically a bag of water, it doesn't compess much. When your brain swells, the damage occurs because the rising pressure tourniquets the blood vessels in the brain, basically starving it. That's what causes the damage. It can also swell the brain sufficiently that it tries to force the midbrain back out of the foramen magnum (the hole from which your spinal cords exits), and directly injures it. (That's bad)

So while extended high pressure is bad, over the duration of an impact, it's typically not a huge deal. I don't see many brain contusions in the context of football, which is the injury you'd see from a traumatic over/under-pressure event.

17 Re: Can Science Diagnose a Living Player's Brain?

I have a question that I am sure one of the enormously brained commenting on this thread can help me with.

Is there any chance that the extremely irregular diets of NFL players play a role? I know someone who is a nutritional epidemiologist (my job description for them, not theirs') and they refer to Alzheimer's disease as 'Diabetes Type 3' and they are only slightly joking - I don't think the research they are involved in is finished but from what I am told the conclusions seem fairly evident. NFL players have to stuff themselves on a constant basis to keep their weight up and solid nutritional awareness is a relatively recent phenomena. I imagine most NFL players of say, twenty years ago will have been glugging down cup after cup of gatorade or similar and ingesting huge quantities of industrially created high fructose corn syrup. This stuff seems to be bad for just about every organ in the human body and if my friend's research group is correct (and I don't think this is thought of as being particularly wacky) the brain is on that list. Even if not a direct cause of neuron damage it could limit or stifle healing?

22 Re: Can Science Diagnose a Living Player's Brain?

There is work being done linking diabetes to AD, but diabetes is not really a concern for professional athletes, as their BMI's are so low that there is no decreased tolerance to insulin.

High fructose corn syrup isn't great for you, but non-obese 25 year old bodies aren't in much danger. An old professor from medical school used to say that teenagers and 20-somethings could eat Tupperware and still be okay. The problem rises when those teenagers and 20-something continue that behavior into their 30s and beyond.

28 Re: Can Science Diagnose a Living Player's Brain?

High fructose corn syrup "isn't great" for you in the same way that any sugar "isn't great" for you. Chemically it's just ~half glucose, half fructose. All of the "fructose is bad for you, therefore HFCS is bad for you!!!" are insane (and there are summary articles from the FDA and foreign equivalents basically saying exactly this), since HFCS has as much fructose as, well... sugar.

(And as a side point, for all of those people drinking Pepsi Throwback thinking oh, it's sugar, it's better for me... it's also got more sugar and is higher in calories. Not by much, but it's there.)

I don't mean to belabor this point, because it's off topic, but I don't understand why scientists aren't almost offended when people go "oh, bleah, HFCS, it's some industrial chemical thing!" This is insane. All food is 'some chemical thing' - I heard some nutcase calling HFCS bad because it's food that's been "chemically altered" - you know, like toasted bread.

Back to the original point, though, I'm not sure that the original poster might not have a bit of a point. It's not that their diet is bad - but their metabolism is so much higher than the average person, that you have to ask whether it could have an effect. I mean, you're talking about people that are probably on a ~4000 calorie/day diet.

30 Re: Can Science Diagnose a Living Player's Brain?

Yes I was referring to the huge metabolic load of eating enough to stay NFL football player shape. Even though in peak physical condition for the NFL, they only have a human pancreas, liver etc.

And yes I was being somewhat alarmist about HFCS but I really don't see the need for it in people's diets. I didn't stick with my biochemistry long enough to remember much about fructose's isomers and how its chemistry alters so I can't really comment too much about it. Not all things that seem very similar in chemical terms are similar in biological systems though. Look at thalidomide; one optical isomer was an incredibly effective pain killer with few side effects (thought to be very suitable for pregnant women), the other was not so suitable for pregnant women.

32 Re: Can Science Diagnose a Living Player's Brain?

Nono, literally: the first thing your body does with sucrose is break it down to fructose and glucose. Which is what HFCS is. Plus a lot of "sugar" in drinks is actually invert syrup, which is chemically identical to HFCS. Being opposed to HFCS because it's sugar is fine. Pretending it's different than sucrose because it has a funky name is insane. It's not "very similar" - it's identical. Really, of all of the things people can complain about in food, HFCS is the one that makes no sense.

The reason it gets used a bunch in the US is because it's cheaper because of corn subsidies (and being opposed to it because of that is fine too). Plus corn can grow in a lot of places that sugar-bearing plants can't.

38 Re: Can Science Diagnose a Living Player's Brain?

This is the only study which has shown this, and the FDA has criticized it in several review articles. There are ludicrous numbers of other studies that show that it is completely identical. At some point the number of studies gets large enough that you'll get a 3-sigma outlier just by chance.

In addition, the comparison you want is not HFCS and table sugar. It's HFCS and invert syrup, which is what many manufacturers use when they want to say "HFCS free!" Invert syrup is chemically identical to HFCS.

35 Re: Can Science Diagnose a Living Player's Brain?

All sugars are not alike. They are similar but may have different properties. How they are used in cells may be different (ie how they are stored may change due to them being different shapes, this can then affect chemical properties of said sugars). Having said this, you are probably right.

I wish I hadn't mentioned HFCS, it was just an example of how unaware people were 20 years ago of exactly what constituted good nutrition. I wish I had gone for palm oil, if bacteria don't like digesting that stuff what makes us think we do? Again though not really the point of what I was saying.

39 Re: Can Science Diagnose a Living Player's Brain?

Let me try to be very, very clear here. Corn syrup is very high in maltose, a dimer of glucose and glucose (at least in the higher grades used in industry). High-fructose corn syrup is corn syrup that they enzymatically process using alpha-amylase, then glucoamylase to get a pretty darn pure glucose mixture.

That glucose mixture is then inverted using glucose isomerase to make fructose, until you get ~55% fructose/45% glucose. The slight imbalance there is because a 50% glucose/fructose mix tastes different than sucrose, so you boost the fructose to make it taste equivalent (Note - invert syrup manufacturers do basically the same thing). What you end up with is essentially chemically identical to invert syrup. A difference could exist between sucrose and HFCS, but that same difference would exist between sucrose and invert syrup, which food manufacturers call "real sugar."

Also note that that same difference would exist between sucrose and honey, which is essentially chemically identical to 'HFCS' as listed in baking products.

I'm not talking about "different sugars." I'm talking about the exact same sugar mix, made in different processes. In the HFCS case the ratios are usually determined pretty darn precisely using chromatography because glucose isomerase is expensive.

That's why most of the comparisons you see for HFCS and other sweeteners are usually between sweeteners that are chemically different, like sucrose vs. HFCS, or sucrose vs. fructose (from researchers who don't understand that HFCS isn't actually high in fructose).

31 Re: Can Science Diagnose a Living Player's Brain?

Soccer players have extremely fast metabolisms demanding thousands of calories/day. Michal Phelps famously eats six 2000 calorie meals a day when training. Elite athletes in many sports go through a ton of calories--HFCS or otherwise. Yet the only common increased long term health risk all these athletes face is the same one that football players most commonly face--arthritis.

44 Re: Can Science Diagnose a Living Player's Brain?

Terry's lack of concern for damage to his head has lead to him flying head first into a goalpost hard enough to leave a blood spatter visible from the other end of the ground when a defender nicked the ball away in front of him (after which he hopped up and jogged off to get bandaged) and getting kicked in the face hard enough for him to be knocked out and swallow his tongue, probably coming within 30 seconds or so of death.

However, I'm not sure there was an enormous amount of brain in there to damage in the first place.

23 Re: Can Science Diagnose a Living Player's Brain?

"The logical place to stage a project like that would be one of those huge, überprofitable biomedical conglomerates."
The guy obviously doesn't know what golden toilet seats cost nowadays.