The brain is a tough thing but not when it comes to football. Anyone with kids realizes that pretty early on. Our brains must possess some fairly robust protective mechanisms against physical shock or way fewer of us (especially boys) would survive to adulthood.
The brain resides in a shock-dampening fluid layer within the skull. If you hit your head in a particular way, you can actually feel your brain move within your skull, perhaps a half-second after the initial physical impact. That timing is why we see so many concussions from players’ heads hitting the ground; the brain is already moving in one direction from the initial hit and then bounces off the skull when the skull hits the ground and reverses direction.
Bouncing of the brain inside the skull is a known mechanism of brain injury. The initial hit is called the “coup”; the bounce on the opposite side is called the “contrecoup” injury.
At football speeds we call that a concussion. We used to think that a concussion was fundamentally different from severe traumatic brain injury (highway speed), and they’re obviously not the same thing, but they share a major physiologic consequence: inflammation.
That word, inflammation. It just refers to the body’s response to an injury, but as a system, it’s the most complex thing in human physiology. And the brain, just to make things even harder for researchers, has its own unique system that, under normal circumstances, doesn’t talk to the rest of the immune system.
That separation, and its destruction through repeated injury, is emerging as a major factor in chronic sports-related brain injury.
The Brain Microenvironment
The brain has its own resident population of white blood cells (WBCs), the cells in our body that attack invasive pathogens and drive the response to physical injury that results in healing (all of which is collectively called inflammation). These brain WBCs, called microglia, comprise as much as 10% of the total number of cells in the brain. That’s a lot.
In the first phase of healing, the microglia digest and destroy brain tissue which has been damaged by injury.
Microglia, like other WBCs, spend nearly all of their lifespan in a quiescent state and are not activated until there’s an injury. Once activated, microglia stay activated for weeks (even months) before they settle down again. If there’s a second injury stimulus while they’re still active, the response is much more explosive and long-lasting. This is why one week is never long enough to recover after a concussion; any additional injury will be much worse during this active inflammatory stage.
Because of this long-lasting injury response, the brain is separated from the rest of the body’s immune system (WBCs and the antibodies they produce) by what’s called the blood-brain barrier (BBB). The BBB surrounds every capillary in the brain. Because oxygen and nutrients have to diffuse through this barrier, it’s only a few cell layers thick. So despite the formidable sounding name, the barrier is easily susceptible to injury.
The blood-brain barrier is formed primarily by cells called astrocytes. The rest of the body doesn’t look like this. Photo credit: Wikimedia commons
If the BBB is disrupted, the blood WBCs get exposed to brain, recognize it as a foreign invader because they’ve never seen it before, and form antibodies to brain tissue. We know with 100% certainty that this occurs; these antibodies have been detected and quantified.
It is from these antibody studies that we know that even repetitive low-level brain impacts are not safe. These include offensive line impacts, and even heading the ball in soccer. To reemphasize, this is 100% certain. Because progesterone is known to be protective to brain injury, researchers have seen different levels of antibody production among high school female soccer players based on where in the menstrual cycle they happen to be.
We can reasonably infer that repeatedly banging one’s head into something is a new thing in human evolution; we aren’t designed for this. Concussions are worse in both severity of injury response and how long it lasts.
The Seeds of CTE
You can see here the outlines of what I strongly suspect is going to emerge as the cause of chronic sports related brain injury and its end-stage disease which we now call CTE. Once a person has circulating antibodies to their own brain tissue, any subsequent disruption of the BBB will expose those antibodies to the (uninjured) brain, which will activate the local microglia. Over time these microglia will destroy functional brain tissue that isn’t damaged; that’s what activated microglia do.
Some players will have so much damage to their BBB that they never stop getting microglial activation, or else their microglia enter a chronic state of activation where they never settle down again. Either way, this mechanism (chronic microglial activation) would explain why, long after they have stopped playing football, a subset of these players show progressively worsening symptoms of brain dysfunction. It would also explain the physical destruction of the brain seen at autopsy of those who have died of CTE.
Massive destruction of brain tissue is seen in advanced CTE.
Who’s Stopping Concussion Research: Parents
What I’ve outlined in the previous section seems quite reasonable but it’s not demonstrated science. It sure seems like a good plan would be to investigate this mechanism. We have, in 2024, a way to image the blood brain barrier (advanced MRI scan) and a way to image microglial activation (advanced PET scan). We do not have any idea what these images look like in concussion.
The obvious way to figure this imaging concussions stuff out, which we would do for any other disease process, would be to take a bunch of people with concussions and, you know, image them. See what’s up.
The largest group of potential patients is high school football players. Ask anyone in this field and I guarantee you they will tell you they’ve run into the same thing: parents who don’t want the certainty of a concussion diagnosis for fear of their child being “labeled” and losing the opportunity for scholarships, fame and fortune.
This is the most frustrating thing that physicians encounter with concussions. Parents bring their kid to the ER or the office because they know their kid has an injury. They get told the correct answer to the question “When can he play again?” The safe answer, based on our understanding of microglial activation, is unknown but is certainly longer than a week, and probably at least a month.
Parents will inevitably ask, “What can we do about it if this newfangled PET scan is bad?” Right now, the only answer would be to sit out and image again in three months. That’s the whole season. But it’s the right answer.
Parents don’t want to hear that. I get it. My son plays soccer. It’s not as bad as football, but there’s a reason why Abby Wambach has already bequeathed her brain to CTE research.
The problem of study participation gets orders of magnitude worse at the collegiate and professional levels, with escalating issues of liability and potential loss of tens (now hundreds) of millions of dollars in future earnings, all while the potential study population shrinks. There won’t be a study there.
There’s a related question of what to do with the antibody tests once they inevitably become widely available. What do you do if 75% of line of scrimmage players show antibodies halfway through a season? Shorten the season? Quit playing football?
I don’t have a great answer and I’m not sure any simple answers exist for a game as intrinsically violent as football. I watch the game because it’s violent.
I do think for the game to survive, there needs to be a better set of options for diagnosing and treating players who inhabit the susceptible brain injury niche. Prevention is obviously crucial but there aren’t many moves left from a rules standpoint; look at how bizarre targeting has become.
Those options won’t become available without proper research. I don’t see a way for the research to happen short of a community of parents, located near a major medical center, coming together to advocate for it to happen.
A few NFL players, or perhaps recent ex-NFL players who aren’t beholden to the owner group for their money, advocating or even funding such a study would be an enormous help. NFL owners could easily make this happen but they make this risk/benefit calculation on the basis of their investments, not their players. Proper brain injury protocol based on imaging would almost certainly make players sit out longer than they do now.
