(2/9/23 Newsletter) Significant improvements in 4 former football players with possible CTE: transcranial photobiomodulation case studies

This week's lead article, Significant improvements in 4 former football players with possible CTE: transcranial photobiomodulation case studies, is in the Therapies Currently Available category.

In this newsletter: Opportunities, Sports, Pathophysiology, Self Care, Therapies Currently Available, Therapies & Diagnostic Tools Under Research, Mental Health, Youth, and CTE & Neurodegeneration Issues.

We appreciate the Concussion Alliance Interns and staff who created this edition:
Writers: Minhong Kim, Susan Klein, Fadhil Hussain, Jemsy Mathew, Conor Gormally, and Malayka Gormally

Editors: Conor Gormally and Malayka Gormally

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Opportunities

Thursday, February 16, 2 pm EST: a free webinar, CTE 101, with Dr. Michael Alosco, covering “recent advances in CTE research and CTE causation. Hosted by the Concussion Legacy Foundation. Register in advance.

Thursday, February 16, 11 am - 1 pm EST: a free online education event, TBI Across the Lifespan, which will explore “clinical best practices for prevention, assessment, and treatment of mild TBI, also known as concussion, for military dependents. This event will cover pediatric treatments ages 0-12 and adolescent to adult treatment ages 12 and up.” The program is presented by the Traumatic Brain Injury Center of Excellence, but you do not need to be associated with the military to attend.

Thursday, February 16, 7:45 am - 5:40 pm, EST: 10th Annual Concussion Conference: From Cutting Edge to Practical Management, hosted by NYU Langone Health, $199 or $149 reduced fee. Register in advance.

Tuesday, February 21, 6 pm EST: a free webinar, Persisting Problems with Attention, Speed of Processing, Memory and Executive Functions, presented by Dr. Robin Green and hosted by the Canadian Concussion Centre. Register in advance.

Thursday, February 23, 1 pm EST: a free webinar on concussion with Dr. Carmela Tartaglia, Cognitive Neurologist, presented by uhnpatienteducation.com. The webinar addresses symptoms, risk factors for persistent concussion symptoms, and treatment and recovery, ending with a Q&A. Register in advance.

Female athletes wanted for a short online research survey. Researchers at Mount Sinai Icahn School of Medicine are working to understand menstrual cycle functioning in athletes who have experienced a sports-related concussion or orthopedic injury. Take the survey here.

Athlete participants wanted for a 1 hr Zoom interview with researchers at Simon Fraser University investigating sport-related concussion. Participants must have sustained a sport-related concussion in the past year. Contact Kyle Bergh, kyle_bergh@sfu.ca, 604-989-7887.

Sports

Is Dolphins QB Tua Tagovailoa at a greater risk for more concussions?

Miami Dolphins starting Quarterback Tua Tagovailoa sustained two diagnosed concussions during the 2022 NFL season, bringing public attention back to the issue of concussions in professional football. In the final press conference of the season, Dolphins GM Chris Grier was asked if concussions will be a recurring issue for Tua’s career. Citing conversations with team doctors and NFL Players Association consultants, Grier stated, “I don’t think he’s any more [concussion] prone than anyone else.” In an article from the South Florida Sun-Sentinel, author Chris Perkins spoke to four neurological experts to determine if Grier’s statement is true. All four experts, including two Concussion Alliance Expert Advisory Board members, agreed that Tua is at an increased risk for concussions.

Tua Tagovailoa sustained an apparent head injury in week 3 of the NFL season that was not ruled a concussion, followed by concussions in week 4 and week 16. He had also sustained a concussion in college. According to Dr. Nsini Umoh, program director of Traumatic Brain Injury research at the National Institutes of Health/National Institute of Neurological Disorders and Stroke, “research does show that someone who has already sustained a concussion is at an increased risk for additional concussions.” Researcher, athletic trainer, and assistant professor Dr. Julie Stamm, a member of the Concussion Alliance expert advisory board, said, “There is a lot of evidence that suggests that having a prior concussion increases the risk for another,” and “there’s evidence that if you go back too quickly, that your risk of concussion is higher…and we don’t really know exactly when that brain has truly healed”.

While the four experts consulted agreed that Tagovailoa is at a higher risk for concussions, research does not provide a “definitive answer” on the issue. Dr. Elizabeth Sandel, a brain injury medicine physician, and Concussion Alliance expert advisory board member, stated that in research, “sometimes there’s a bias…in general, follow the money.” She also explained that concussion recovery is symptom-based, but “there are imaging studies that show the brain actually is not completely recovered even after symptoms resolve.” This finding makes it difficult to predict when a player is truly ready to return to play, and more research is studying when the brain is truly healed.

Concussions continue to be a prominent issue in the NFL. According to an article in Reuters, the number of concussions in the 2022 NFL season jumped 18%. All players affected have to decide if and when they continue to play, so it is essential for them to understand their risk for additional concussions. While the NFL and NFLPA-associated experts seem to have one opinion on the matter, the four experts consulted in the Sun Sentinel article differ, further complicating the decision.

Pathophysiology

Increasing numbers of concussions, particularly 3 or more, result in worse cognition in later life

Do increasing numbers of concussions (when younger) worsen cognition in later life? The answer is "yes." A study by Matthew J. Lennon et al., published in the Journal of Neurotrauma, used the Brain Injury Screening Questionnaire to learn about self-reported TBIs (of all severities) in a cohort of 15,764 people in the UK. The individuals were ages 50-90 and had their most recent TBI, on average, 29 years prior. Their cognition was tested at baseline (when they entered the study) and each year for four years. A University of Exeter press release states, "Each additional concussion correlated with progressively worse cognitive deficits." The study authors found that individuals with three or more concussions "had significantly worse executive function and attention scores." Those with four or more concussions "had worsened attention, processing speed, and working memory."

When clinicians advise patients with recurrent concussions, the authors recommend that they "should be cognizant that some long-term cognitive deficits can be expected after three or more mTBIs." They note that people with three or more concussions "should be counseled on whether to continue high-risk activities," such as contact sports or dangerous work. On a positive note, the authors found that these chronic cognitive deficits did not increase during the four-year study but were fixed.

Attention and executive function were "the most sensitive cognitive domains," which were affected twice as much as processing speed and working memory. This finding led co-author Helen Brooker to suggest that "cognitive rehabilitation should focus on key functions such as concentration span and completion of complex tasks, which we found to be especially susceptible to long-term damage."

Limitations of the study include the reliance on elders' memory to report TBIs. Also, while controlling for some variables such as "age, sex, education, smoking and vascular risk," they were not able to control for other variables such as socioeconomic status.

Self Care

Identifying and Coping With Fatigue After Brain Injury

Fatigue is one of the most common symptoms after brain injury. The Brain Injury Association of America's article, Fatigue After Brain Injury, reports that "as many as 98% of people who have experienced a traumatic brain injury have some form of fatigue." Limitations caused by fatigue following a concussion may be challenging to understand and can appear to be laziness or an unwillingness to participate. The author states, "it is important to understand that lacking the mental energy needed to complete tasks does not equate to lacking the desire to complete those tasks."

Some coping strategies to ease symptoms of fatigue include

Having a healthy sleep routine by establishing a strict, daily sleep schedule and taking a 30-minute "power nap" when rest is needed)
Practicing energy conservation by prioritizing daily tasks and completing tasks that require the most mental effort earlier in the day with planned rest breaks in the afternoon or evening
Organizing daily activities by utilizing a checklist or planner and breaking up complex projects into manageable tasks
Improving overall health and wellness by aiming to exercise three to five times per week for a minimum of 30 minutes per session and maintaining a well-balanced diet rich in protein, fiber, and carbohydrates
Keeping a fatigue diary to monitor changes and energy levels before and after daily activities.

Other coping strategies to manage fatigue and decrease stress levels are to limit physically, cognitively, and emotionally draining tasks, such as working at a computer, watching television excessively, having a stimulating sensory environment, concentrating on paperwork, or reading for long periods.

To learn about a patient's fatigue levels, clinicians evaluate physical and mental changes that can commonly present as overwhelming fatigue. They also use self-report assessment tools, such as the Barrow Neurological Institute Fatigue Scale (BNI) and the Cause of Fatigue Questionnaire (COF). Fatigue, often described as mental or physical tiredness, may present in the form of various symptoms. Physical symptoms may include

Headaches
Tension in muscles
Shortness of breath
Slower movement and speech
Decreased coordination
Difficulty staying awake
Glazed eyes

Cognitive symptoms include:

increased forgetfulness
distractibility
decreased ability to follow directions
increased number of mistakes
reduced awareness of surroundings
or increased response time or lack of response

Social/Emotional symptoms include:

decreased ability to communicate effectively
reduced ability to engage in social activities
irritability
restlessness
emotional lability (changeability)
increased negative thoughts
withdrawal
short answers
dull tone of voice
lack of motivation and interest
or difficulty engaging in activities of daily living

While there is no cure for fatigue, awareness of and willingness to attempt coping strategies can alleviate the negative effects of fatigue, improve overall performance in activities, and allow for meaningful participation in life.

Therapies Currently Available

Significant improvements in 4 former football players with possible CTE: transcranial photobiomodulation case studies

In a study published in the Journal of Alzheimer's Disease Reports, researchers write that “this is the first report of a potential treatment modality to mitigate symptoms of Possible CTE.” The study is a case-series report of four former football players (3 professionals) who met the NIH criteria for Possible CTE and were treated with transcranial photobiomodulation (tPBM), a specific kind of light therapy. After treatment, all four demonstrated significant cognitive improvement in neuropsychological tests, including executive function, attention, verbal learning and memory, visuospatial memory, and verbal fluency. The participants’ scores on mood/behavior questionnaires significantly improved in domains of PTSD, depression, sleep, and pain. The researchers found that functional MRI imaging supported these clinical improvements and noted, “Instead of continuing to worsen over time, these cases improved with tPBM.”

For these case studies, the 18 in-office treatments involved either the MedX Health LED cluster heads that deliver red and near-infrared (the first player) or the Thor Photomedicine helmet that delivers near-infrared (three players). The in-office treatment lasted for six weeks, 3x a week, each lasting 22-40 minutes. All four players decided to do ongoing home treatments using the 40 Hz Vielight Neuro Gamma and the Vielight Red Intranasal. Our blog post, based on an earlier poster presentation, details the case studies of the first and third players in this study. Our page, Light Therapy/Photobiomodulation, provides background information on this therapy modality.

For two of the players, the improvements held after the cessation of in-office treatments–similar to findings in earlier open clinical trials with mTBI patients. Two players lost much of their gains after the cessation of the in-office treatments. However, they regained most or all their improvements with the implementation of at-home treatments. The researchers point out that the pattern with the latter two players “is similar to the pattern of response to tPBM in dementia, but not in chronic mTBI.” The need for long-term photobiomodulation “suggests presence of a neurodegenerative disease, e.g., possible CTE. Each case improved again, after tPBM home treatments.” The first player in this study made a video detailing his experience with tPBM.

The same group of researchers is recruiting study participants for an ongoing study, “Investigational Research Light Therapy to Improve Thinking and Memory for Traumatic Brain Injury.” People who have suffered at least one mild traumatic brain injury (a concussion) or moderate traumatic brain injury (TBI) at least six months ago are eligible for the study. The study is fully remote and open to U.S. citizens. See our blog post to learn more.

The researchers suggested several potential mechanisms for how tPBM might be having these positive effects:

Improved cellular oxygenation and respiration due to “increased production of ATP by mitochondria in cortical neurons.”
Increased vasodilation in brain blood and lymphatic vessels, plus “reduced inflammation and oxidative damage” due to “release of nitric oxide” from compromised brain cells.
Increased BDNF (brain-derived neurotrophic factor), a key molecule related to memory and learning.
Augmentation of brain glymphatic drainage. The glymphatic system is involved in waste clearance; improvements in this system may positively affect the clearance of p-tau, which is accumulated in the brain CTE patients.

The players were ages 55, 57, 65, and 74. Two study participants were former NFL players, one was a former Canadian Football league player, and one played through college; their years playing football ranged from 11 to 16, and their age of first exposure to football ranged from age 7 to 14. This study was not sham-controlled, meaning the players knew they were getting the tPBM treatments, and the researchers could not control for the placebo effect. They suggest future studies with sham and real tPBM devices used at home.

Lee Benson wrote an article for the Desert News in September 2022 about a related study of photobiomodulation by the University of Utah. (An abstract of the study’s findings, in the form of a poster, was published in the Archives of Clinical Neuropsychology.) “‘It’s not a miracle drug, I’m still not perfect,’ says the former boxer and football player [study participant Christian Smith] who spent years leading with his head. “But I’m in control again and I’m enjoying life. I feel positive that I can contribute, that I have value again, that I am worth something. To me it is a miracle. You don’t realize how bad you were until you get good again.” Lead researcher Dr. Elizabeth Wilde stated that “It wasn’t just an occasional here and there who indicated it worked for them. It was really consistent across the board. That’s exciting.” See our blog post to learn more.

Therapies & Diagnostic Tools Under Research

The promise of saliva microRNA to diagnose concussion–and maybe distinguish concussion subtypes

Journalist Allura Leggard from CNY Central in New York State updated us on using saliva as a concussion biomarker based on her visit to Quadrant Biosciences (Syracuse, NY). This company has developed a methodology for studying microRNA (miRNA) as biological markers in disorders, including concussion. Dr. Steven D.Hicks, one of 5 keynote speakers at the upcoming World Congress on Brain Injury (Dublin, Ireland), developed this methodology with colleagues at SUNY Upstate Medical University and Penn State College of Medicine; "the patent was awarded to Quadrant Biosciences, SUNY Research Foundation, and Penn State College of Medicine." The CNY Central article also stated that the Quadrant salivary biomarker test would be used for head-injured patients in upstate New York. Since the Quadrant Biosciences test is not yet available commercially, this would likely be through a clinical trial (such as this one, active at three sites, including SUNY Upstate).

We are excited that researchers are investigating concussion diagnostics that pair clinical observations of patients' concussion signs and symptoms with a biological pattern of microRNA. We previously reported on another team exploring saliva microRNA and concussion–our blog post provides a brief explanation of the methodology and a link to Atif and Hicks' 2019 scholarly review of microRNA in mTBI.

A 2022 report from Hicks and colleagues shows that the saliva microRNA approach is being explored actively. Hicks' team collaborated across seven institutions to study 22 salivary microRNAs of interest in TBI in 251 adolescents and adults with an acute concussion seen within 14 days of their head injury. The clinical variables were standardized symptom-rating scales, balance testing, and cognitive assessment sets. The researchers identified ten biological clusters of salivary microRNA, and these clusters contained microRNAs related to specific pathways that are disrupted after head injury. The clinical variables that differed across the 10 microRNA clusters were subject age, days after injury, and history of prior concussions; the authors suggest that microRNA profiles may be sensitive to these clinical variables and possibly the cumulative effects of concussions. The team found that "the clusters differentiated individuals with high levels of fatigue, confusion, difficulty remembering, and trouble falling asleep." They hypothesize, "These results provide a biological foundation for stratification of concussed individuals in future research."

We will continue to watch as these research teams scale up the use of microRNA to diagnose and track recovery from concussion. Amassing a clinical data set of informative measures collected systematically across a large sample is also a worthy goal and very hard to do. Dr. Hicks will likely have exciting insights next month in Dublin; we'll be there!

Mental Health

Literature review explores link between concussions and psychological health

In a literature review published in Head, Neck, and Spine, Matthew Barela et al. explored existing literature on the relationship between concussions and suicide, increased risk-taking behavior, mood and anxiety disorders, preexisting psychological traits, and treatments for these issues. After their review, they found “significant evidence that demonstrates an association of changes in mood and behavior, including new or worsening symptoms of anxiety, depression, and difficulty with attention and concentration in those recovering from a concussion.” They also found that prompt diagnosis of psychological symptoms following a concussion could aid in predicting long-term outcomes and determining if treatments for the psychological symptoms are necessary.

The authors found that concussions were associated with an increased risk of suicidal thoughts or behavior, regardless of sex. One study in their review found that female athletes had a higher risk of hopelessness, ideation, and planning, while males had higher self-reported mood scores but also a higher risk of attempting suicide. Concerning risk-taking behavior, one study in the review concluded “moderate association with concussions and being in a physical fight in both boys and girls, tobacco/e-cigarette use in boys, binge drinking in boys, and riding in a vehicle with a driver who has been drinking.” Another study found that some patients may self-medicate with alcohol and cannabis to modulate the psychological (depression, anxiety) effects of concussion.

The mood and anxiety portion of the review includes consideration of the overlap between symptoms of depression and concussion. Additionally, the authors found associations between having three or more concussions or a more severe concussion and an increased risk of developing depression or anxiety. However, they remark the evidence on the association between severity and psychological issues is mixed. Other studies show that pre-injury irritability, sadness, nervousness, and anger–as well as personal and family history of psychiatric disorder–were all predictive of worse outcomes following concussion.

The authors discuss regulated behavior plans, exposure models, cognitive behavioral therapy, psychoeducation and concussion education, and biofeedback. Regulated behavior plans like the one in the review, consisting of “adequate diet/hydration, sleep, noncontact daily activity, [and] stress management,” would likely benefit all concussion patients. Exposure models and psychoeducation could help patients understand their injury, expose them to things that temporarily exacerbate symptoms without leaving them worse off, and promote awareness and self-efficacy. The authors recommend cognitive behavioral therapy similarly could help patients with anxiety or depression recognize and disempower maladaptive thought patterns and catastrophization, set goals, and resume daily activities. The authors suggest that biofeedback could be helpful but may be financially or logistically inaccessible and recommend medications for severe or treatment-resistant symptoms.

Youth

Students experience problems in school after concussion, but rates decrease over time

A study by Carol A. DeMatteo et al. observed Ontario students aged 9-18 returning to school after a concussion. Of the students who had already returned to school by the time they had their first post-injury visit (median 7.7 days), 50% experienced new or worsening school problems–primarily headaches, inability to pay attention in class, and being overly tired. A larger group (55%) experienced trouble with their classes, with 16% reporting a drop in grades. Students who had returned to school at their follow-up visit (scheduled based on symptom recovery, at a median of 133 days) reported school problems at a lower but still substantial rate (18%), with 17% reporting a drop in grades. Among this group, the most common issues were an inability to pay attention in class, homework taking longer, and difficulty understanding the subject matter.

The study, published in Frontiers in Sports and Active Living, found that, similar to other studies in this area, problems in school tended to decrease over time. However, this did not extend to those whose grades were impacted; a similar proportion had a drop of at least one letter (A to B) at both the first post-injury visit and follow-up visit (16% at the first visit and 17% at follow-up). Interestingly, 50% of students and 26% of parents were concerned about school problems at the first visit, but these proportions more than reversed at the follow-up, with 20% of students and 96% of parents expressing concern about school problems.

The study recruited 139 students aged 9 to 18 in Ontario with a diagnosed concussion within the last year who were symptomatic. These students enrolled in the study at a median of 7.8 days after their injury (average: 34.8 days, minimum: 2.9 hours, and maximum: 320.9 days). Students whose symptoms resolved within 28 days had only a first post-injury visit and a follow-up visit. Students whose symptoms lasted longer also had a post-symptom resolution visit three months after their symptoms resolved.

The study did have several limitations. The authors included participants who had been injured as much as one year previously as long as they were experiencing symptoms. The study cohort included students with both subacute and long-persisting symptoms. Additionally, some students were recruited during summer holidays when schools were not in session. Also, not all students completed the school questionnaire at each visit, so the researchers could not capture all patients' experiences at each level.

CTE & Neurodegeneration Issues

Elevated neurodegenerative disease risk in rugby union players

A recent study published in the Journal of Neurology, Neurosurgery, and Psychiatry found that neurodegenerative disease risk was approximately 2.5 times higher among former rugby union (elite amateur) players than among the general population. The rate of hospitalizations and medication prescriptions for neurodegenerative disease were also higher among former rugby players compared to the general population. The researchers point out that while these amateur athletes participated “at an elite, international level,” this study is “the first demonstration that high neurodegenerative disease risk is not a phenomenon exclusive to professional athletes.”

Authors Emma R. Russell et al. studied a cohort of 412 male Scottish rugby union players, mainly consisting of amateur athletes. The researchers matched rugby union players with 1236 individuals in the general population by age, sex, and socioeconomic status. Analysis of both groups revealed that “47 (11.4%) former international rugby players and 67 (5.4%) of the matched, general population comparison group had an incident neurodegenerative disease diagnosis.”

Interestingly, a comparison of mortality rates revealed that all-cause mortality was lower among the rugby players than in the general population up to 70 years of age, “with no difference thereafter.” However, rugby players did face a higher risk of death from neurodegenerative disease than the general population.