The lead article this week, Study finds traumatic brain injury (TBI) is a “significant risk factor” for cardiovascular disease (CVD) in study of post-9/11 Veterans, is in the Veterans & Service Members category.

In this newsletter: Opportunities, Education, Pathophysiology, Self-Care, Therapies & Diagnostic Tools Under Research, Veterans & Service Members, Mental Health, Women’s Health, & Culture.

We appreciate the Concussion Alliance Interns and staff who created this edition:
Writers: Lori Mae Yvette Calibuso Acob, Fadhil Hussain, Susan Klein, Sravya Valiveti, Amanda Cheney-Zitting, Conor Gormally, and Malayka Gormally

Editors: Conor Gormally and Malayka Gormally

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Opportunities

Thursday, September 29, 4:00 pm EST: A free online presentation, Tackling the Mechanisms and Aftermath of Concussion, with Doug Smith, MD, of the University of Pennsylvania. This speaker series is hosted by the Concussion Center of the University of Michigan. Register in advance.

Tuesday, October 11, 6 pm EST: A free webinar on Exercise Therapy presented by Dr. Mark Bayley, hosted by the Canadian Concussion Centre. Register in advance.

Thursday, October 13, 3 pm EST: A webinar for professionals presented by Jeffrey J Bazarian MD, MPH, Monitoring Brain Health in Individuals Exposed to Repetitive Head Impacts: Lessons Learned From Radiation Safety. Hosted by the Brain Injury Association of America, the $50 fee includes 1 ACBIS CEU. Registration closes at 11:59 pm EST on October 12.

Thursday, October 27, 10 am - 5:30p pm EST: A free virtual course, the 6th annual CTE Conference, will be hosted by the BU Alzheimer’s Disease Research Center. Speakers include Ann McKee, MD, and Robert Stern, PhD. For professionals, 7 CME credits are available for paid attendance. Register in advance.

The University of Michigan Concussion Center is offering a free online course and concussion training certification, providing "information for coaches, athletic trainers, parents, and athletes on the basics of concussion." The course is open to all and provides a certificate of completion for those in Michigan. Note: you will be first prompted to create an account before taking the course.

For school professionals: a free, online course, The Concussion Awareness Training Tool (CATT), for school professionals and administrators to provide "the information they need to take an evidence-based approach in responding to and managing concussion." Estimated time: 45 minutes.

Be part of a study on brain health and head impacts from sport: The Head Impact and Trauma Surveillance Study (HITTS) is recruiting study participants who will take a fully online, annual survey. "Anyone age 40 or older who played soccer or tackle football at any level (youth, high school, college, or pro/elite) can enroll."

Education

History of concussion associated with higher risk of poor academic standing in high school students

A study published in the British Medical Journal found that a history of concussion within the past 12 months was significantly associated with a substantially higher risk of poor academic standing among high school students. The findings point to a potential impact of concussions on academic performance.

The cross-sectional study used data from the 2019 Youth Risk Behaviour Survey (YRBS) to analyze how self-reported history of concussions in the past 12 months correlated with self-reported academic performance within the same period and whether any associations varied by sex, school grade, and race/ethnicity. Researchers included over 10,000 records in the study; about 15% of students reported at least one concussion within the past 12 months. Students who had at least one concussion were at a 25% higher risk of poor academic standing compared to those with no concussion history, and students with two or more concussions were at a 50% higher risk of poor academic standing. Poor academic standing was defined as grades consisting mainly of C’s, D’s, or F’s.

When stratified by race/ethnicity, authors Julian Takagi-Stewart et al. found a statistically significant association between concussion history within the past 12 months and poor academic standing among students who are white or of “other races/ethnicities” [the study did not elaborate on the “other races/ethnicities”]. The authors did not find this association in “Black or African American and Hispanic/Latino” students. The study outlines several potential explanations, including bias in self-reported outcomes or varying sample sizes across racial/ethnic groups. Overall, the study adds to a growing but still inconclusive body of evidence regarding how concussions may impact academic performance in adolescents.

Pathophysiology

Do the eyes have it? How on-site technology and machine learning can diagnose concussion and gauge recovery from it

A study from Divya Jain, Christina L Master et al. explores how a machine-learning algorithm applied to eye findings can diagnose concussion and may track why some youth recover more slowly than others from concussion.

A 9/13/22 tweet from this team reminded us that pupillary responses may aid concussion diagnosis. The tweet links to a video about a hand-held pupillometer (NPi -300, NeurOptics) that can record pupil size and the speed of pupil size changes in light and dark conditions–referred to as pupillary light reflex (PLR). A 2020 study by Christina L Master et al. used this hand-held pupillometer, whereas the new 2022 study used the EyeBOX (Oculogica) for pupillary measurements and machine learning which accurately diagnosed concussed individuals (acute and persistent) compared to control subjects.

To put the 2022 study in context, we will start by discussing the 2020 study by Christina L Master et al. In the 2020 study, the team found significant differences in PLR measurement in 98 adolescents within a median of 12 days after concussion, compared to a group of age and sex-matched controls. Based on pupillometer assessment, concussed subjects had significantly distinct findings compared to the control group in “8 of 9 metrics.” These findings included larger pupils, more pupil constriction, faster peak and average constriction speed, and faster peak and average dilation speed compared with 134 age- and sex-matched controls. The only variable that was unchanged between the two groups was latency (time delay) of pupil size change. In 35 subjects who had PLR assessment within 7 days of concussion, pupil dilation speed did not identify those with concussion, but the other seven metrics separated those with concussion from controls.

Females in the < 7-day subset who had concussion showed slower recovery speed of pupillary dilation (time to 75% dilation). Some control youth had a history of concussion, but their PLR measurements did not differ from those who had never had a concussion. These data suggest that pupillometry within the first 7-10 days can help quantify visual disturbances in youth with concussion, but how serial PLR measurement can inform recovery from concussion is unknown. Additionally, a set of youth norms by age and sex, specific to the site where the pupillometer is used, would be needed.

In the 2022 study, the researchers are now exploring other eye movement abnormalities after concussion to see whether a machine learning algorithm can be applied to identify subgroups of youth who have a slower recovery from concussion. In this new follow-up study, the team used the EyeBOX (Oculogica) to compare a group of 219 concussed adolescent athletes with 178 control athletes.

Subject characteristics were typical of a specialty-clinic recruited sample–athletes aged 13-17. The authors recruited 148 controls from a private suburban high school. Concussion diagnosis was made clinically in 207 patients by a sports medicine pediatrician, with standardized symptom inventories collected. For analysis, the group of concussed athletes was further subdivided into 122 who were seen < 28 days after concussion (“acute concussion”) and an additional 85 (“persistent concussion”) seen after 28 days. Those subjects with persistent concussion were more likely to be older and female. Youth reporting acute or persistent concussions were more likely to have had a prior concussion. The demographic ethnicity of the groups differed as well.

The EyeBOX yielded pupillary size data from the eye tracking task, which involved subjects following videos displayed in different places on the screen for a 220-second test interval. The authors used a machine learning algorithm, a data analysis technique separating data into groups with pattern recognition, to identify whether an individual was either in the concussion group (acute or persistent) or the uninjured group. Pupil size was larger and more asymmetric in the combined acute and persistent concussed patients compared with controls, which supported the 2020 observations from this research team.

As with all clinical measurements in children, norms on these measures to clarify age and sex differences (which change as part of normal development) will need to be developed thoughtfully. However, these techniques suggest that pupillary size changes might be a relatively cost-effective way to diagnose and track symptoms after concussion and figure out whether the recommended interventions help.

Self-Care

Concussion and telework: “your rights and options so you can return—or not—in your own way”

Do you have a concussion or persistent post-concussion symptoms (PPCS), also referred to as PCS, and have misgivings about giving up working remotely? An article in Brain & Life discusses the rights and options for those with neurologic conditions who may be reluctant to give up telework.

Working from home may mean avoiding office lighting (which may trigger light sensitivity problems), allowing a flexible schedule for working when you are most alert, and facilitating physical therapy appointments. Avoiding Covid exposure is another consideration.

Ask your employer about telework options; if a 5-day telework option is not available, “employees need to submit (verbally or in writing) official accommodations requests, which are governed under the ADA [Amercian Disabilities Act].”

While the article does not mention concussion or PPCS, the Mayo Clinic includes mild TBI, or concussion, in its definition of brain injury, covered in its pdf guide. “An employee may be eligible for accommodations under the law when a brain injury leads to impairment in major life activities, including work. Brain injury is considered a form of disability. It is covered by the provisions of the 1990 Americans with Disabilities Act (ADA).”

The ADA applies to employers with 14 or more employees; the employer “is required to make a ‘reasonable accommodation.’ However, the ADA leaves it up to the employer to decide the nature of that accommodation.”

The article suggests that employees don’t have to explain fully what their disability is to their employer and recommends that “employees focus on accomplishments rather than their medical conditions when submitting requests.” The article concludes with suggestions for making work healthier, including taking mini-breaks such as a 10-minute walk or meditation and being firm about your schedule to disconnect from work and screens after work hours.

Therapies & Diagnostic Tools Under Research

The potential of Resveratrol as a complimentary therapeutic option for TBI

Resveratrol, an antimicrobial, disease-resistant compound commonly found in many plants, could be a promising therapeutic alternative in TBI intervention by fostering neuroprotection. Joyobrato Nath et al. wrote an article about the molecular mechanism of resveratrol in TBI, published in Brain Disorders. The authors state, “Substantial preclinical evidence has associated Resveratrol with protection against TBI and subsequent secondary brain injury as it has significant anti-oxidant, anti-inflammatory, and anti-apoptotic properties, emphasizing its promising scope in the treatment of TBI.”

Resveratrol’s mechanism of action primarily consists of targeting oxidative stress associated with TBI-induced damage and involves scavenging free radicals produced at the site of secondary brain injury. This significant oxidative stress is due to the formation of free radicals produced by the activation of various intracellular enzymes due to excess Calcium influx. Resveratrol may confer neuroprotection by counteracting this activation or excess influx of intracellular enzymes and pro-inflammatory cytokine in injured brain tissues.

However, the authors note that “Resveratrol is not without limitations related to its pharmacokinetic properties, primarily attributed to its poor water solubility, fast metabolism and elimination, and low bioavailability depending on the route of administration… Therefore, further research focusing on improving its pharmacokinetic properties using strategies like encapsulated systems could lead to Resveratrol being a novel therapeutic choice for TBI neuroprotection.”

A second group of researchers, Yan Feng et al., published a recent article about Resveratrol attenuating autophagy (cleaning out damaged cells) and inflammation after TBI in rats, published in Folia Neuropathology.

A blog post published in JD SPURA by Downs Rachlin Martin PLLC, based on a review of evidence-based TBI literature, highlights the benefits of Resveratrol as a potential complementary therapeutic intervention to further support the recovery of TBI patients.

Downs Rachlin Martin points out that the research is still in the preclinical stages, and double-blind human clinical studies that are essential to ensure safety have not yet been conducted. Thus, they note that although the unregulated supplement is currently available on the market, it’s vital to consult with medical providers to make an informed decision on using Resveratrol as a complementary therapeutic option.

Veterans

Study finds traumatic brain injury (TBI) is a “significant risk factor” for cardiovascular disease (CVD) in study of post-9/11 Veterans

A study published in Jama Neurology found that veterans with a history of mild TBI were 62% more likely to have received a CVD diagnosis than veterans without recorded TBI. This association appears more robust with TBI severity, as veterans with moderate-to-severe TBI and veterans with penetrating TBI were 2.1 times and 4.6 times more likely to be diagnosed with CVD, respectively. According to authors Ian J Stewart et al., “All categories of TBI were significantly associated with stroke,” peripheral artery disease (PAD), and coronary artery disease (CAD). For each of these outcomes, there was the suggestion of a dose response whereby more severe TBI resulted in higher risk.” This population was predominantly young, with over 68% of veterans under 35 at time of injury.

While TBI was associated with all CVD subgroups, stroke associations were particularly substantial, ranging from 2.5 times higher risk for mTBI to 12.1 times risk for moderate-severe TBI. The authors also found that veterans were at increased risk for cardiovascular-related death, with mTBI and moderate-severe TBI veterans at 26% and 69% increased risk compared to no TBI, respectively. However, they did not find the same dose response in mortality due to CVD.

In a time-varying model, the authors found that the increased risk for CVD outcomes in veterans with mild and moderate-to-severe TBI was highest at three months but close to zero at eight years and no longer significant at nine years. Based on their results and mechanisms observed in other studies in mouse models, the authors speculate that “TBI results in an inflammatory state that may predispose individuals to atherosclerosis and subsequent CVD, independent of traditional pathways.” They also point to the potential role of autonomic nervous system (ANS) dysfunction causing heart rate variability and blood pressure regulation issues. Finally, the authors point to the role of mental health diagnoses such as PTSD; PTSD and CVD have been extensively linked in healthcare literature.

The retrospective study looked at data from 1999-2016 from the Long-term Impact of Military-Relevant Brain Injury Consortium–Chronic Effects of Neurotrauma Consortium, following up by looking at VA healthcare data through 2018. The veterans in the study were predominantly male (89%) but varied significantly in other demographic factors. “All variables examined were significantly different between the groups. Veterans with TBI were younger and more likely to be male than those without TBI history. A larger proportion of those without TBI history had post–high school education compared with those with TBI. Veterans with TBI were more likely to be active duty, in the Army or Marines, and have enlisted rank. They were also more likely to have deployed and have combat exposure.” Veterans with TBI were more likely to have a history of smoking, obesity, insomnia, depression, and anxiety.

Mental Health

Pediatric study links mild traumatic brain injuries with behavioral and developmental problems

A study published in NeuroImage by David A. Lopez et al. found further evidence that mild traumatic brain injury (mTBI) increases the risk of behavioral and emotional problems in adolescents. Upon comparing the imaging and behavioral data, Dr. Lopez et al. found evidence that supports the association between mTBI and deterioration in mental health. Compared to children with no history of TBI, children who experienced mTBI had a 15% increased risk of developing behavioral and emotional problems, and children with possible mTBI had a 7% increased risk.

The team also found that children with a possible mTBI showed a 17% increased risk of becoming distressed after experiencing a psychotic-like event (PLE). Despite their intense name, "PLEs can present as either benign or distressing events. Distress following a PLE can potentially distinguish between benign and clinically-relevant symptoms."

Prior research findings conclude that TBI can have long-lasting effects on children's behavioral and emotional domains. Although mTBIs account for about 75-90% of all TBIs, little is known about the impact of mTBIs on brain structure and mental health outcomes. To gain a deeper understanding of this association, Dr. Lopez and his team compared data of children who participated in the Adolescent Brain Cognitive Development (ABCD) Study. The ABCD Study is a prospective longitudinal study that enrolled 11,876 children ages 9-10 to track their brain and behavioral development throughout their adolescent years until they are 19-20.

Dr. Lopez and the team analyzed MRI imaging and behavioral data collected at baseline, one-year, and two-year follow-ups. Of the 11,876 children enrolled, there were 199 cases of mTBI (a loss of consciousness (LOC) of 30 minutes or less) and 527 cases of possible mTBI (no LOC but memory loss was present). To assess behavioral development, children completed a questionnaire to determine the presence of psychotic-like symptoms, such as auditory hallucinations, to evaluate the level of distress they felt. Parents also completed a questionnaire regarding their child's behavior to help determine if the child displayed anxious, withdrawn, aggressive, or similar behaviors.

It is essential to acknowledge the limitations of this study. The sample used in the ABCD study included a disproportionately low number of Black children with mTBI, which may affect the generalizability of this study. There is also cause for concern regarding recall bias due to the gap in data collection regarding when the injury occurred and injury severity. However, despite these limitations, Dr. Lopez et al. remain hopeful that with the time and resources, they will be able to better understand the long-term impact of mTBI.

Women’s Health

Study finds key consensus statements drew from research that under-represents female athletes

A study published in the British Journal of Sports Medicine analyzed the sex of subject samples of the research cited in the three pre-eminent concussion consensus statements. Christopher D’Lauro et al. found that the overall body of research cited in the consensus statements used samples that were 80.1% male. These findings indicate a severe lack of appropriate research on female athletes, which is particularly concerning in the context of the broad reach of the consensus statements, their influence on clinical care, and the resulting lack of guidance for female athletes and patients.

The National Athletic Trainer’s Association (NATA), the International Consensus Conference on Concussion in Sport (ICCCS)–sometimes called the Concussion in Sport Group (CISG), and the American Medical Society for Sports Medicine (AMSSM) produce the key consensus statements that inform care for sports concussion worldwide. The study authors state that “if female athletes are under-represented within the sports-related concussion (SRC) literature—particularly in key documents that inform clinical practices—clinicians would face considerable challenges in effectively treating female concussion patients.”

Female athletes are more likely to be injured when playing the same sports, face different barriers in healthcare systems and cultural norms around reporting symptoms, may have longer recovery trajectories and are more prone to cervical injuries. Additionally, research has indicated that concussion can cause abnormal menstrual cycles and sexual dysfunction in female athletes. See our newly updated ‘Populations’ page on Women & Girls. However, “Of the 171 studies analyzed across the three statements, 69 (40.3%) had all-male samples, but only two (2, 1.2%) had all-female samples… Each statement mentioned female athletes only briefly, typically when describing sex as a modifying factor for return-to-play time.”

The authors suggest that the “sport-as-laboratory” model of studying concussions initially used American football, as it was the most efficient sport to study concussions in–due to teams’ large roster sizes and the sport’s high collision rate. This bias in research pools is furthered by the fact that female athletes faced barriers to sports participation–especially in collision sports–and even after Title IX’s implementation, collision sports continue to be male-dominated. Additionally, most sponsor organizations supporting concussion research are all male or male-dominated, focusing research dollars on the athletes they represent. The authors point out that it’s not just subjects and funders that play a role in this, but also that the prevalence of male faculty–especially in research positions–may bias the selection of male athletes.

The authors identified the following strategies for supporting female athletes in concussion research:

“Balancing the representation of female, male, transgender and non-binary authors on consensus and position statement voting and authorship teams—as well as within editorial boards and research programme management.
Female athlete-focused sections of consensus and position statements should be included until the literature is robust enough for a standalone document for this population.
Consensus and position statements should acknowledge when predominantly male athlete samples inform recommendations.
Include a checkpoint within consensus/position statement processes for ensuring that cited research is as balanced as possible (similar to NIH’s ‘Inclusion of Women and Minorities’ requirements).
Create research funding opportunities that focus solely on women or non-binary and transgender athletes or, at a minimum, include a better balance between male and female athlete data.”

Culture

(Content Warning: discusses suicide) Did white matter damage due to concussions lead to Mac Parkman’s suicide?

Mac Parkman was a popular 17-year-old high school student, talented defensive lineman and wrestler, and a beloved family member. To some, it may have seemed like he had it all – until September 25, 2020, when Mac stepped off an 80-foot cliff and committed suicide. As the youngest, Mac left behind a grieving family who wanted answers.

Christopher O’Donnell of the Tampa Bay Times relays some of what his family went through after Mac’s suicide. “I was in an unbelievable hole of grief and despair and lack of knowledge,” said his father. As nothing from the postmortem exam explained why they had to lose their teenage son, Mac’s dad pushed for more from the coroner. The coroner inquired about Mac’s concussion history and suggested that CTE, chronic traumatic encephalopathy – a degenerative brain disease linked to frequent blows to the head, could have been behind Mac taking his life.

Since 2002, CTE has been found in more than 300 NFL players. There is so much unknown surrounding the disease, but symptoms may include memory loss, impaired judgment, impulsive behavior, aggression, depression, and thoughts of suicide. CTE has been discovered in people as young as 17, but symptoms usually aren’t apparent until far into the future. That the condition can’t be confirmed until a postmortem brain analysis makes CTE very hard to recognize.

Determined, Mac’s father didn’t want his son’s death to be in vain. Mac had played contact sports since he was four years old – rugby, football, hockey, snowboarding, and wrestling. During his adolescence, he suffered three concussions, none of which seemed serious. Mac’s brain was examined by Dr. Ann McKee, head of the Boston University CTE Research Center. Although the typical buildup of abnormal proteins used to diagnose CTE was absent, Dr. McKee found damage to the white matter of Mac’s brain, similar to what she had seen in older professional athletes.

Mac’s father said, “I made the mistake of allowing my son to hurt himself, to kill himself — I was uninformed. We’re doing the wrong thing as a society when we put these developing brains out on the field.” Mr. Parkman has established a foundation in his son’s honor, advocates for change in contact sports, and works to bring attention to the link between brain injuries and depression.