The Injury Bug: There’s growing evidence that genetics play a role in sports concussions.

The blow that knocked New York Giants quarterback Daniel Jones out of a game against the Dallas Cowboys looked innocuous enough. It did not look like a particularly vicious hit as far as NFL tackles go. It wasn’t a head on collision, though there was obvious helmet-to-helmet contact. There wasn’t a jarring snap of the head after being torpedoed. Jones’ head didn’t bounce on the ground upon impact. Nonetheless, he got up slowly with aid from his teammates. His eyes were blank.

Up until that play, the game was still up in the air. The Cowboys enjoyed a 10-3 lead but the Giants were on the verge of tying the game. Evening things up would have been big, almost a turning point in a disappointing season. It was a chance for some much needed positive momentum. The next couple of plays meant a lot. At 1-4, a loss would cement another season of failure. As Daniel Jones stepped behind his offensive line at 3rd and goal, there was only one thing on his mind. Get the ball into the endzone, no matter the cost. 

After the snap, the Giants’ quarterback turned and took a couple of steps back. He extended his arms down around waist-level while running back Devontae Booker ran in his direction. At the last moment, Jones pulled the football away, faking the handoff. While Booker sliced his way into the end zone, Jones turned to his left and, clutching the pigskin with one hand, took off for the endzone

The Cowboys’ rookie linebacker Jabril Cox and defensive end Chauncy Golston gave chase. Cox ran the diagonal, trying to cut off Jones before he reached the 1 yard line. Golston sprinted in parallel with the quarterback.

Cox reached Jones first at around the one yard line. As they neared each other and braced for contact, they lowered their shoulders. Jones took a lower position and once Cox began to lower his head, their helmets smashed together. Cox reached his arms around Jones and then brought him down. As they hit the ground, Jones also banged his head on the turf, inflicting another blow to the head.

Clearly dazed, Jones tried to move on to the next play. He lurched forward after a couple of steps and for a moment, it looked as if he would go back down. Cowboy Jayron Kearse moved quickly to prevent him from falling. One of the referees did the same. If it hadn’t been for them, Jones likely would have fallen over. Eventually, the disoriented quarterback was carted off the field. He was later diagnosed with a concussion. It was the first of his career.

***

Concussions like the one Jones suffered represent some of the most insidious injuries plaguing professional and amateur sports. Part of the problem with them is that they are fairly common. Head bumps in contact sports like boxing, mixed martial arts, rugby, American football or ice hockey are a dime a dozen. It goes without saying that more violent sports like MMA or boxing have more than their fair share of head injuries. 

Knocks to the head in professional sports vary in the degree of violence. MMA and boxing top the list, particularly when it comes to direct blows to the head. According to one study that tracked mild traumatic brain injuries (mTBIs) in MMA, “The injury rate per 100 athlete exposure (AE), the injury rate per 100 min of exposure and the concussion rate per 100 AE were 23.6 (95% CI 20.5 to 27.0), 4.1 (95% CI 3.48 to 4.70) and 14.7 (95% CI 11.8 to 17.2), respectively. The most common location of injury was the head and mTBI was the most common type of injury.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045699/ 

In the NFL, mild traumatic brain injuries come in two forms. There are the ones that result from major blows to the head and manifest almost immediately. The injury sustained by Daniel Jones belongs to this category. The other form is where things get truly insidious. Called sub-concussive injuries, they represent blows to the head that are not severe enough to knock a player out, yet beneath the hood, they cause incremental bits of damage that have been shown to cause a condition called Chronic Traumatic Encephalopathy (CTE). The same dynamic takes place in rugby, where concussions are even more frequent than in the NFL.


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In an article that compared in-game American football concussions with similar injuries in Mixed Martial Arts, Charles Bernick MD, MPH, a chief researcher at the Professional Fighters Brain Health Study told Bleacher Report,

“It may not be just the huge concussions. There are various sub-concussive injuries,” Bernick said. “You would need sensors inside their mouth guards, and even then you can’t know about the sub-concussive injuries or how it differs from person to person. You can get hit and have no symptoms. It’s a very nebulous field. We don’t know if it’s cumulative or if the major hits are the worst. That’s what we’re working to find out. But we simply don’t know.”

Of course, head injuries aren’t limited to Mixed Martial Arts, American football, and rugby. Ice hockey is right up there with them. World football (soccer), basketball, wrestling, and even cheerleading carry the threat of concussive injuries. The same goes for athletes participating in so-called non-contact sports like figure skating, bike riding, and bobsledding where participants are at risk of sustaining concussions. Ellie Furneaux (Sport: Skeleton), Joshua Farris (Sport: Figure skating), Gretchen Bleiler (Sport: Snowboarding), and Tory Nyhaug (Sport: BMX) have all had their careers stopped short due to mild traumatic brain injuries. 

mTBIs During Game Play

  1. Men’s rugby match play (3.00/1,000 AE)
  2. Men’s American football (2.5/1,000 AE)
  3. Women’s ice hockey (2.27/1,000 AE)
  4. Men’s Ice hockey (1.63/1,000 AE)
  5. Women’s soccer (1.48/1,000 AE)
  6. Men’s football (or soccer) (1.07/1,000 AE)

mTBIs During practice

  1. Men’s rugby (0.37/1,000 AE)
  2. Women’s ice hockey (0.31/1,000 AE)
  3. Men’s American football (0.30/1,000 AE)
  4. Women’s football (or soccer) (0.13/1,000 AE)
  5. Men’s ice hockey (0.12/1,000 AE)
  6. Men’s football (or soccer) (0.08/1,000 AE)

According to the U.S. Centers for Disease Control, there were approximately 223,050 TBI-related hospitalizations in 2018* and 60,611 TBI-related deaths in 2019. It also estimates that between 1.6 million to 3.8 million sports-related traumatic brain injuries occur every year. The figure is widely considered an underestimation due to a tendency to undercount TBIs in professional sports. 

In the NFL alone, at least 100 concussions went unreported between 1996 and 2001. For example, according to one report, “The Dallas Cowboys… didn’t list one concussion over the six-year period in the database. Quarterback Troy Aikman sustained four concussions during that span, according to the NFL’s league injury report or in news stories. 

In the sports world, concussions are defined as having any combination of the following criteria: a direct or indirect trauma anywhere on the body with a force transmitted to the head; Rapid (seconds to minutes) or delayed (minutes to hours) symptom presentation, typically with spontaneous resolution; Negative standard neuroimaging reflecting a functional rather than structural injury; with or without loss of consciousness, with stepwise resolution of symptoms.

Once an athlete is suspected of having a concussion, guidelines dictate that they be removed from play and prevented from returning for at least the remainder of the day. “When in doubt, sit them out.”

There are a number of tests that can be performed on the field, including having someone familiar with the player’s personality compare whether he or she is acting normal. A more extensive battery of exams can be performed off the field and in the medical room. 

Today, the best known and comprehensive evaluation of potential mTBIs is the sports cognitive assessment tool (SCAT). The SCAT5 is most recent and involves an immediate on-field assessment, including identification of red flags warranting immediate medical attention, observable signs, orientation assessment, postural stability, and a cervical spine assessment.

The immediate post-concussion assessment and cognitive testing test (ImPACT) is one of the most widely used neurocognitive assessment tools and has been demonstrated to have high sensitivity and specificity for detecting concussion and monitoring recovery. However, even with its effectiveness, ImPACT must be used with other tools to really make a difference. 

***

In the video above, Foxsports commentator Skip Bayless brings up a nagging question when it comes to concussions in sports, as well as many other injuries. Why do some athletes suffer mild TBIs more frequently than others and why are their reactions to concussions more severe? Tens of thousands of professional football players have played the game over the years, yet not every person who has stepped on the field suffered a concussion, even those who took big hits. It’s one of the big mysteries in sports injuries.

Evolution set up our heads in a way that was designed to protect the squishy command center where all of our thoughts and emotions originate and also regulates the functions of our organs. On its own, the brain is particularly vulnerable. It is fragile and susceptible to damage. Think of jello and how easy it is to poke a hole in it or pinch a chunk free. What’s more, its neurons are set up like a smartphone only with billions of electrical circuits delicately intertwined. A sudden violent shock can knock a mobile phone out, something those of us prone to dropping things know all too well. The same holds true for our grey matter.

In order to keep those circuits functional, our brains are nestled beneath a hard exterior (our skulls) and beneath that, a layer of cerebrospinal fluid that prevents our brains from banging against our skulls, under normal circumstances, at least.

During a concussion, the force of the blow shifts the brain’s position in its protective shell, turning safeguards on their heads. That’s because during a traumatic hit, the brain’s momentum is enough to overcome the cerebrospinal cushion and it basically bangs against the skull. It whips back and forth inside causing more internal collisions. Blows that involve the frontal and temporal fossae regions of the brain are particularly harmful.

The real damage to the brain occurs when its neurons are stretched suddenly and surpass what is known as the sublethal axonal injury threshold. Think of it like a point of no return. The violent extension of the neuron causes the release of potassium ions that depolarize the area around the neuron, unleashing a chain reaction of events. The disruption of the ionic balance eventually leads to an energy crisis inside the injured brain. This microstructural damage is believed to be the root cause of all forms of traumatic brain injuries, not just concussions.

Understanding exactly what happens at the moment a concussion occurs has been complicated, as noted by Charles Bernick earlier. Recent attempts at understanding why and when they occur have depended on new technology like mouthpiece or helmet sensors that allow scientists to measure the force of impact involved in concussive blows. Unfortunately, the data brings up more questions than it answers.

“Several investigators have examined the physical force necessary for an athlete to sustain a concussion using sensors that are placed in helmets or on the body,” says Scott Zuckerman and Douglas Terry from the Vanderbilt University Sports Concussion Center. “The results are complicated, such that some athletes sustain a concussion from moderately-high force, while other athletes are completely fine when they are hit with much more force.”

A recent study performed by researchers at Carnegie Mellon University attached accelerometers in the helmets of University of Rochester football players. Only two players suffered clinically diagnosed concussions during that time. However, post- and pre-season MRIs showed two-thirds of the players experienced a decrease in the structural integrity of their brains. The sub-concussive blows reduced white matter integrity in the midbrain after the season compared to before the season. Tantalizingly, the researchers also found the amount of white matter damage was correlated with the number of hits to the head players sustained.

Another of the study’s findings may shed some light on Daniel Jones’ concussion. The MRI scans measured structural changes in the brain that took place over the course of each season. They found that rotational acceleration (impact causing the head to twist) more so than linear acceleration (head-on impact) is correlated with the observed changes in the structural integrity of white matter in the midbrain.

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In more general terms, researchers have pinpointed a wide range of factors associated with concussion susceptibility. Some make sense. Some are real head-scratchers. (Hey, nobody said science had to make complete logical sense.) They include past history of concussions (makes sense), sex (makes sense to a degree), migraine headaches (kinda makes sense) learning disabilities or attention deficit hyperactivity disorder (not so sure about these), and psychiatric co-morbidities (how do psychological problems influence concussions?).  

The evidence for each of the susceptibility factors run from thin to almost negligible. The difficulties studying concussions very much come into plays. In particular, the nebulous nature of the injury makes it difficult to replicate the conditions that caused the concussions under investigation. As is, the injuries sustained in a single study vary in the force, angle, and location of the blows. That goes without factoring in everything from the athletes physique to the quality of protective gear (if any). In short, replicating studies, one of the bastions of modern science, is no easy task. Making matters worse, the methods employed by different researchers vary enough to further complicate the puzzle.

Prior concussions have the strongest correlation with susceptibility. Empirical and anecdotal evidence supports the idea. Gender also appears to be correlated with mTBI susceptibility. Even though males suffer higher TBI rates in general compared to females, studies indicate that female athletes suffer more sports related concussions than males in same-sex sports.

Beyond that, the water gets muddier. There is an obvious need for more studies as well as alternate approaches to understanding the problem.

Enter genetics.

***

There has always been an almost messianic quality to the expectation placed on genetics to not only explain the inner workings of organisms large and small, but also to rectify our contradictions. For men and women, the Human Genome Project was supposed to provide answers for the human body as well as a roadmap toward possible solutions to the ailments that plague them. Everything hinged on a one-gene-one-enzyme, DNA to RNA to protein paradigm that proved a bit simplistic. While occasionally providing complete answers, more often than not, the Human Genome Project only provides additional pieces of the puzzle. However, what genetics did was to provide researchers with slivers of clarity to spur their research in novel directions.

One of the issues researchers have in studying concussions is the variability of the injury, something Scott Zuckerman and Douglas Terry have seen first hand among their patients at the Vanderbilt Sports Concussion Center.

“There are genetic elements to several neurological and neurodegenerative diseases, like Alzheimer’s and Parkinson’s,” they explained over email. “While mild traumatic brain injury (also known as a concussion) is predominantly an injury, there may be certain people who are more susceptible to experiencing a concussion based on their genes. Additionally, certain genes may be associated with a prolonged recovery after a sport-related concussion.”

The general biology of the brain seems to support the idea that genes may play a role. It is estimated that roughly 90% of the brain’s structure and 60% of a person’s cognitive performance is inherited. Coupled with other observations regarding “inter-individual variability” of human traits, some researchers conclude: “It is likely that a substantial genetic component also applies to concussions.”

The human genome consists of between 20,000 to 25,000 genes. It’s not the smallest and it’s not the largest. Still, that’s a lot to choose from when trying to narrow down a search. Thankfully, scientists aren’t flying blind and have some idea what many of them do. This provides a starting point for investigations. The most common method for identifying genes that may play a role in injuries is called the candidate gene approach. This method takes advantage of the knowledge geneticists have accrued thanks to the efforts like Human Genome Project and the HapMap Project. 

In a way, the candidate gene approach works backwards (at least initially) in order to take constructive steps forward. It works by running through the entire list of genes and their functions, singling out ones that encode for a trait or process involved in the injury or the system that is harmed. For example, researchers wanting to find a gene that may play a role in Achilles tears might initially focus on snippets of code that play a role in collagen formation since tendons consist mostly of collagen. Of particular interest are polyporphisms that affect the function of a gene compared to its other forms.  The reason the process works is that it compensates for the overall dearth of concussion cases available to study.

“High level genetic studies involve thousands and in some cases millions of patients. Sport-related concussion is common, but not that common,” says Zuckerman. “Even though there are studies with this many patients, having genetic data on this many individuals can be challenging. To identify quality candidate genes, researchers need very high numbers of patients with genetic samples, and efforts remain ongoing in this area.”

Apolipoprotein E (APOE) is a class of proteins that plays a central role in the transportation of lipids throughout the body. More importantly for concussion purposes, APOE is believed to manage the nerve myelination of the brain. The protein also stimulates neurite extension and post-injury repair. The class is divided into three types APOE e2, APOE e3, and APOE e4. Various studies have linked APOE e4 with poor outcomes post-concussion. 

A study conducted by V.C. Merrit et al. looked at 57 college athletes who suffered concussions. They found that 40% of the people who carried the APOE e4 allele suffered more significant post-concussion impairment, compared to only 16.5% in athletes who lacked the polymorphism. 

Unfortunately, even though many studies support APOE e4’s role in concussion onset and rehabilitation, there are also studies that contradict the findings. At best, they indicate that current data regarding the gene’s role in TBI is inconsistent.

Another popular candidate gene is associated with a chemical involved in the body’s inflammation process, Interleukin 6. In this case, it is the IL-6 receptor that is implicated in adverse reactions once a concussion occurs. As with APOE e4, the positive findings are weakened somewhat by studies that contradict them.

The following table lists the genes considered leading candidates for further investigation.

Tables copied from “Genetic Factors That Could Affect Concussion Risk in Elite Rugby” M. Antrobas et al. (doi: 10.3390/sports9020019)

One of the weaknesses of the candidate gene approach is its inefficiency. While it yields a lot of potential targets, many of them are essentially low-quality search results. (Though nothing could be less efficient than tried-and-occasionally-true method of digging up a patch of soil and hoping to discover a new class of antibiotics.) 

Stuart Kim, a researcher at Stanford University, describes the problems facing the candidate gene approach in terms of building a race car. What makes a race car go fast? How can it be reverse engineered in order to learn where the speed comes from?

The candidate gene approach would be like asking, Does the car have a spoiler? Does it have rearview mirrors that are aerodynamically shaped? Is it painted red? Appearances can be deceiving. Red is a color that appears on a lot of sports cars but it has nothing to do with speed. And even when something does actually influence performance, it is not to the desired degree.

“The rearviews may help your car go faster” says Kim. “But it’s way down the list. The same goes for candidate genes. They are almost always way down the list. In fact, the candidate genes that had been tested [by the Kim lab]… We did not see any validation for them.”

Stuart Kim’s laboratory took a different approach toward the problem of isolating genes that may play a role in concussions. They conducted what is known as a genome-wide association study in order to search for genes that may predispose individuals to mild traumatic brain injuries.  

Generally, genome-wide association studies are conducted by collecting the genetic information from two groups: people with the disease in question and those without it. 

The saliva or blood sample is then purified, placed on tiny chips and scanned on automated laboratory machines. The machines quickly survey each participant’s genome for strategically selected markers of genetic variation, which are called single nucleotide polymorphisms (SNPs).

If certain alterations are found to be significantly more frequent in people with the disease compared to people without disease, the variations are said to be “associated” with the disease. The associated genetic variations can serve as indicators that point to the region of the human genome where the disease-causing problem resides.

Kim used genetic data from Kaiser Permanente Research Bank (KPRB) and the UK Biobank as gene sources. Kim’s analysis included 83,414 individuals of European ancestry from the KPRB and an additional 212,122 individuals from the UK Biobank. Out of that pool, 4064 cases of concussion were identified and 291,472 controls.

Two SNPs displayed significant association with concussions. In other words, a substitution of a single letter in a person’s genetic code could increase a person’s susceptibility to injury. Kim found that a polymorphism (rs144663795) is found on a strip of DNA known as SPATA5. Mutations to that patch of a person’s genes have been shown to cause intellectual disability, hearing loss, and vision loss. The other polymorphism, rs117985931, is located on a strip of DNA called PLXNA4 which plays an important role in axon outgrowth during neural development. Mutations in PLXNA4 are associated with increased Alzheimer’s disease risk. While further investigation of the two genes is still warranted, the SNPs represent potentially stronger contenders than those yielded by candidate gene approach.

The role of genetics in concussions is not limited to the biological realm. Shameemah Adams et al. investigated whether genes associated with certain personality traits may lead to behaviors conducive to traumatic brain injury. DRD2 and DRD4 genes specifically have caught scientists’ attention. The influence of those genes, if associated, indirectly affect susceptibility by predisposing individuals to riskier behavior that eventually results in a head injury.

The exploration of genetics in sports injuries is still in its infancy. As with other injuries such as tendinopathies, even the most compelling associations are tentative at best, requiring further investigation and stronger evidence. Not only that, in addition to identifying individual genes associated with concussions, they’ll need to decipher the way they function as a system. Still, there is a lot of promise.

“There are likely several genes that are associated with concussion,” says Zuckerman. “But it remains to be seen if one of these genes is more important than the others or if they are all equally important. In general, there is no one single ‘magic bullet’ in improving the care of sports concussion patients. As with many other disease entities, it will likely require a multi-pronged approach.”

For more information about the Vanderbilt Sports Concussion Center follow them on Twitter at @VUMC_Conussion.

For more information about Stuart Kim’s research visit his lab page.

WORDS: Marc Landas.


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