Article In Brief
A study of collegiate football and volleyball players found that longitudinal increases in fractional anisotropy and axonal water fraction and decreases in radial/mean diffusivity were present on average in the volleyball cohort but absent on average in the football cohort. The findings suggest that these alterations could leave athletes more vulnerable to future injury, affect their cognitive reserve, and exacerbate the cognitive sequelae of subsequent concussions.
Advanced MRI scans showed significantly divergent microstructural brain changes among college football players, particularly those who experienced concussive blows, and college volleyball players over four years.
The longitudinal study, published July 21 in Neurology, found a consistent pattern across the two groups on advanced diffusion MRI and automated fiber quantification, including diffusion tensor imaging (DTI): longitudinal increases in fractional anisotropy and axonal water fraction and decreases in radial/mean diffusivity were present on average in the volleyball cohort but absent on average in the football cohort (all findings p<0.0001). These longitudinal differences were more prominent and observed in more tracts in football players who experienced concussion (p<0.0001).
These alterations could, in theory, leave athletes more vulnerable to future injury, affect cognitive reserve, and exacerbate the cognitive sequelae of subsequent concussions, the authors suggest.
Approximately 9 to 14 percent of athletes have multiple concussions during college, according to data from the NCAA Injury Surveillance Program. Diffusion MRI has proven useful in studying the effects of repeated impacts in high-contact sports on the brain’s microstructure, but most previous imaging studies have been cross-sectional and/or did not include low-contact players as controls.
“We aimed to investigate longitudinal changes in high-contact collegiate athletes compared to low-contact controls using advanced diffusion MRI and automated fiber quantification,” said lead author Michael Zeineh, MD, PhD, associate professor of radiology (neuroimaging and neurointervention) at Stanford University Medical Center. “Relatively few longitudinal studies have investigated these changes in sports. Even fewer studies incorporate baseline imaging, and studies with a duration of more than one year are even more scarce given their logistical complexity.
“Although we did everything possible to control for confounding factors, it’s important to keep in mind that these are group results, not individual results, and represent the overall pattern of the groups as a whole.
“We also have to be careful about making any definitive statements with regard to causality. In our study, we were just observing, and there are many factors that can result in brain changes. It is compelling to see these differences between the football and volleyball cohorts and the fact that they are more exacerbated in the concussed population, but we nonetheless need to be reserved in drawing conclusions on the basis of observational study.”
Besides the trauma of the concussive and subconcussive blows, what else could account for the differing trajectories in brain microstructure? “We did our best to match the cohorts, but they were not perfectly matched and could have evolved differently over time,” Dr. Zeineh said. “It’s possible that there were other environmental factors or social determinants of health involved, or brain changes related to physical/cognitive activity.”
Study Details
Dr. Zeineh and co-investigators prospectively enrolled a cohort of 49 college football and 24 college volleyball players in their study. Players underwent MRI scans annually at the beginning of every season, within 24 to 96 hours following a concussion (when possible), and at the end of their final athletic season. Each player had one to eight imaging time points throughout a maximum of four playing years.
“Looking at individual players over time is so important, because there is a great deal of variability in brain microstructural anatomy from athlete to athlete,” Dr. Zeineh explained.
For the longitudinal analyses, the investigators only included players with two or more scans that were at least six months apart, which resulted in 271 scans from 73 subjects, 193 scans from 49 football players, and 78 scans from 24 volleyball players. Of 49 football players, 25 did not report any concussions, 11 had prior concussions, eight had in-study concussions, and five had concussions before and during the study.
“At this age range—our study participants were about 19 at baseline—significant maturation is still going on in the brain. We found that the volleyball players, in aggregate, showed imaging findings that could represent maturation of their diffusion metrics, while the football group overall did not show the same level of presumed maturation,” Dr. Zeineh said.
He speculated that these findings could suggest delayed myelination, altered axonal caliber, or depressed pruning processes leading to increased axonal dispersion. “This potential delayed maturation in the white matter parallels our prior finding [reported in 2020 in Neuroimage] of divergent trajectories in the gray matter (cortical thinning) in football vs. volleyball players.”
The brain’s white matter can be thought of as the “cabling” connecting its processing power, Dr. Zeineh said. “It’s also the shielding for that cabling, and it evolves over time, can change with training, and be affected by injury. The key for neural synergy is connectivity, and disruptions to that connectivity are thought to happen with trauma. So the possible effects of these concussive and subconcussive impacts on the white matter could be significant.”
The study did have some limitations, Dr. Zeineh acknowledged. The investigators followed the players for up to four years, but they only enrolled male athletes from one institution, and the number of in-study concussions was limited and self-reported.
The current study also did not include longitudinal neurobehavioral metrics, so it is impossible to assess whether any of the differences in brain structure seen on DTI manifested in any clinical way.
“These are simply brain imaging findings, and future work will need to be done to tell if they are clinically significant,” Dr. Zeineh said. In ongoing work, he and colleagues are combining imaging with neurobehavioral metrics in a different cohort that includes both genders and multiple sports, including other higher-contact pursuits, such as rugby.
Alterations in Normal Structural Integrity
“This study has a number of strengths, including the longitudinal design and follow-up with the same individuals, as opposed to the merging of data with cross-sectional studies,” said James Kelly, MD, FAAN, professor of neurology and executive director of the Marcus Institute for Brain Health at the University of Colorado Anschutz Medical Campus.
“The use of this advanced diffusion imaging is a major contributor to our ability to understand what is happening to the brain on a cellular level as a result of repeated concussions and even sub-concussive blows. These imaging findings of alterations in what is assumed to be normal anatomical structural cellular integrity over time, in areas of the brain you might consider vulnerable to this kind of biomechanical force, verifies in some ways what we have observed clinically.”
Dr. Kelly acknowledged that some of these conclusions are speculative. “Do these differing trajectories result from demyelination of the white matter itself, or alterations of the axon fibers underneath or internal to the myelin wrapping? They could also reflect decreased ‘pruning,’ the maturing changes of how the neurons connect to one another over time,” he said. “This is all happening in a brain that is changing during this age span anyway. So yes, there is some uncertainty involved, but it does look like these are anatomical alterations related to a sport that involves blows to the head.”
Christopher M. Filley, MD, FAAN, director of the behavioral neurology section and professor of neurology and psychiatry at the University of Colorado, is an expert in the behavioral neurology of white matter.
“This study highlights the important role of white matter, which is not always fully appreciated in neurologic disease. We know that, during normal development, brain white matter increases in volume until a person reaches the mid-40s,” he said. “We see here that football, in particular, affects white matter development compared with volleyball; in addition, severity of brain injury is relevant because football players who experienced concussions had more damage than those who only had subconcussive blows. This observation supports the idea that there is a form of head injury somewhere between a concussion and no injury at all.”
Several other DTI studies have documented white matter abnormalities in high-contact athletes compared with low-contact controls in the context of a single athletic season, including decreased fractional anisotropy in tracts including the corpus callosum and cingulum hippocampus, associated with worsening impulse control and memory scores, and elevated mean and/or radial diffusivity in the corpus callosum and the corticospinal tract.
The findings could be considered in the context of other recent research involving postmortem studies of athletes in high-impact sports with chronic traumatic encephalopathy (CTE), said Stephanie Alessi-LaRosa, MD, director of the Hartford HealthCare sports neurology program. “All of this evidence strongly suggests that even exposure to low-impact hits to the head that do not result in concussion, on a regular basis, can be significant.”
“Other sports could be studied as well, including soccer, skiing, and hockey, comparing the various risks for concussion with imaging and clinical metrics over time,” Dr. Filley noted. “When feasible, it would be helpful to combine these findings with histopathological data from autopsy studies. These MRI/DTI metrics are suggestive of an injury process affecting the white matter, but we’re not yet sure exactly what that is. Among several possibilities are diminished myelination and changes in axonal caliber. Knowing more about this could lead to a better understanding about how much recovery can occur and how clinical outcomes might be improved.”
And that’s a key question, Dr. Filley said: If these differing trajectories of brain microstructure development are indeed the result of repeated concussive and subconcussive blows, can that damage be reversed or at least arrested if the source of the damage is eliminated? In other words, if someone stops playing football in their early 20s, will these metrics of brain microstructure and white matter development ever return to a more “normal” trajectory?
“Does time alone heal the brain? Is there treatment that could heal it faster? Would injured athletes resume normal white matter development after some time has passed and no further head injury has occurred? How long would that process take, and how extensive would recovery be? Those are all questions that need to be considered,” Dr. Filley said.
The questions would be difficult to answer within the parameters of a research study, Dr. Zeineh said. “Even if you have absolute ideal circumstances, you would need a considerable population to ensure that you have sufficient numbers in each group. My intuitive feeling is that, logically speaking, if the source of the blows is eliminated, that it would be likely that these alterations from typical brain development would decrease. That’s indirectly supported by our data correlating history of concussion with the level of changes. If that correlation is meaningful, then it does seem at least likely that reducing impacts would mean less of these changes down the line. Whether those changes could actually be reversed is another question.
The Long-Term Clinical Consequences
What might be the long-term clinical consequences of these alterations in brain development? “Obviously, our paper can’t say anything about CTE; that’s more long-term and different in terms of physiology,” Dr. Zeineh said. “So the range of possible consequences are anywhere from nothing to having less cognitive reserve in the future, and where someone might be in that range could be quite variable. These are all high-performing college students at an academically competitive institution; these impacts could affect their cognitive abilities down the line, but that is speculative.”
Neurologists who manage patients involved in high-impact sports should discuss this study in the context of the larger literature, he said. “This is a systematically conducted study where they observed people and saw differences over time in the football population compared with the control population,” Dr. Zeineh said. “We don’t know exactly what it means, but there could be potential consequences to consider down the line.”
The detailed longitudinal imaging data adds further weight to the growing move around the country in organized sports, particularly at the youth and collegiate level, to reduce the amount of preventable blows to the head in practices, as well as to mitigate head trauma in other ways in sports that involve collisions, Dr. Kelly said.
“The body of literature suggests that the more that you can reduce subconcussive or concussive blows to the head, in any manner, the better off these athletes are,” he said. “There’s not really any mystery to that anymore; it’s just a matter of adding further scientific information to support these more practical decisions.”
For example, the National Federation of High School Sports (NFHS) has changed several rules for football, banning certain full-contact drills and enforcing new penalties; many schools have implemented their own safety precautions by limiting the amount of players on the field and in pads during practice, as well as eliminating contact in two-a-day practices.
After a 2014 rule was adopted in Wisconsin athletics limiting the amount and duration of full-contact activities during high school football practice sessions, a 2019 study in the American Journal of Sports Medicine found that the rate of concussion sustained in high school football practice decreased by 57 percent.
“With the college students in this study, you can assume that they were playing at least in high school and maybe at the youth level to be competing at the college level,” Dr. Alessi-LaRosa said. “With my patients, I am a big advocate of not playing tackle football until at least high school.”
Data from the National Federation of State High School Associations shows that the 2021-22 school year was the first on record with fewer than a million players participating in 11-player high school football since the turn of the century, with that year’s total of 976,886 participants representing a 12.2 percent decrease from its peak in 2008-09.
The decline is even more dramatic at the youth level. The Aspen Institute’s State of Play report, based on data from the Sports & Fitness Industry Association, shows that from 2020 to 2021, participation in tackle football for children ages 6 to 12 declined nearly 18 percent. Since 2016, tackle football participation rates for this age group have decreased 29 percent, while flag football rates have gone up 15 percent. In 2021, youth flag football players outnumbered tackle players by more than 300,000.
“I’m in Hartford, CT, so the culture around football is probably different here than in the South or Midwest, but here at least we are definitely seeing less contact practices in high school and more popularity of flag football,” Dr. Alessi-LaRosa said.
“I do think people have become more receptive to this message, especially the coaches, referees, and parents. Honestly, the students are the biggest challenge: they want to play, they want to be in the playoffs, and they don’t want to tell anybody. They are focused on playing and being tough and staying in the game. But the culture of the coaches and leadership has definitely changed, and I think a lot of it has to do with studies like this one and the kind of education that we as sports neurologists can provide.”
Travis Burnett
A pioneer in the flag football community, Travis helped co-found the Flag Football World Championship Tour, FlagSpin and USA Flag. Featuring 15+ years of content creation for the sport of flag football, creating and managing the largest flag football tournaments on the planet, coaching experience at the youth and adult level as well as an active player with National and World Championship level experience.
