(3/9/23 Newsletter) Neuroprotective properties of CBD may support TBI recovery

This week's lead article, Neuroprotective properties of CBD may support TBI recovery, is in the Cannabis & Psychedelics category.

In this newsletter: Opportunities, Cannabis & Psychedelics, Mental Health, Statistics, Youth, Culture, and CTE & Neurodegeneration Issues.

We appreciate the Concussion Alliance Interns and staff who created this edition:
Writers: Minhong Kim, Susan Klein, Nancy Cullen, Sravya Valiveti, Aamy Woldesenbet, Conor Gormally, and Malayka Gormally

Editors: Conor Gormally and Malayka Gormally

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Opportunities

Tuesday, March 21, 6 pm EST: a free webinar, Anxiety, Depression and PTSD: Before and After Concussion, presented by Dr. Abe Snaiderman and hosted by the Canadian Concussion Centre. Register in advance.

Researchers at Massachusetts General Hospital and Harvard Medical School are offering a free program to help optimize your recovery from a recent concussion.

Who can participate?

Ages 18-24 years old
Have a concussion from the previous 10 weeks
English fluency

What does it involve?

Participate in 4 virtual sessions (45 minutes each)
The sessions will take place from the comfort of your own home using secure live-video
Complete 3 sets of questionnaires online through secure link about your emotional functioning and concussion symptoms.
You can receive up to $90 for participating in the program and answering questionnaires.

No cost, no medication and no travel. Want to learn more? Email MGHConcussionToolkit@partners.org

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.

Cannabis & Psychedelics

Neuroprotective properties of CBD may support TBI recovery

A recent review article published in Frontiers in Neurology examines the neuroprotective properties of cannabidiol (CBD) and its potential for treating traumatic brain injuries.

Authors Mackenzie M. Aychman et al. highlight that while “the complexity of cellular, molecular, physiological, and neurometabolic mechanisms associated with different stages post-TBI makes it particularly difficult to treat,” research into CBD has revealed unique neuroprotective properties of the chemical that may be useful for supporting TBI recovery.

CBD can target the “cellular, molecular, and biochemical changes” associated with mild, moderate, and severe TBI. Pre-clinical studies have revealed CBD’s role in reducing cognitive and physiological symptoms of TBI, such as changes to memory, attention, and mood. Additionally, CBD has been shown to improve cerebral (brain) blood flow and the treatment of seizures.

Despite these promising properties of CBD, the authors also bring up several challenges researchers face when conducting pre-clinical and clinical studies into CBD. First, identifying safe and effective dosing strategies for CBD to optimize therapeutic benefits remains a significant challenge. CBD dosing, administration method, and exposure duration are complicated factors that researchers need to consider when studying CBD. Second, research suggests potential “biological sex and hormone-based differences” in the body’s response to CBD, necessitating further examination.

Perhaps most importantly, the authors note that because the “current state of the research field is mostly derived from rodent studies,” clinical trials are needed to better evaluate CBD’s potential for TBI treatment. The authors conclude that “upcoming clinical trials sponsored by major professional sports leagues are the first attempts to test the efficacy of CBD in head injury treatment protocols.” These studies may equip the TBI community with better knowledge of the potential of CBD in treating brain injuries. We are aware of NFL-funded studies at the University of Regina and UCSD, and a study collaboration between the National Hockey League Alumni Association and NEEKA Health Canada.

Mental Health

Change needed to improve outcomes for children with mental health emergencies

A study published in Pediatrics has found that less than a third of children in the US who visit emergency departments (EDs) for mental health issues are receiving follow-up care within seven days of being discharged. This retrospective study, conducted by Jennifer Hoffman et al., analyzed data from the IBM Watson MarketScan Medicaid database on 28,551 children aged 6 to 17 years with mental health ED discharges between January 2018 to June 2019. This study was inspired by Hoffman's experiences as an attending pediatrician in the ER, as she has seen a steady rise in the number of children annually admitted to the ER for mental health issues over the course of her career.

The results showed that 31.2% and 55.8% of children had an outpatient follow-up mental health visit within 7 and 30 days, respectively. The rate at which children received follow-up care progressively increased with the number of previous-year mental health outpatient visits. Notably, the rate of follow-up care was lower for Black children and children with fee-for-service insurance. Rates of timely follow-up were also particularly low for black children, which highlights the urgent need to remove barriers to mental health care. Among all demographics, timely follow-up was associated with decreased risk of returning to the hospital within 5 days of the index ED discharge but an increased likelihood to need to go back beyond that 5-day timeframe.

The study suggests that EDs may not be effective sources of care for managing mental health crises for children and adolescents. Hoffman proposes that interventions to improve follow-up after mental health ED visits should focus on children with new mental health diagnoses who have not previously engaged in outpatient mental health care. These interventions have important implications, as research has shown that following up with a mental health provider can help lower an individual's suicide risk as well as raise the chances that they will take prescription medication. Follow-ups can also lower the likelihood that patients will take repeated trips to the ER. Hoffman urges those in the field and its funders to “come together to launch the next wave of bold mental health research,“ as “there is an urgent need for a dramatic change in our pediatric mental health care system,” particularly if we want to see an improvement in outcomes among pediatric mental health patients in the near future. The study also had some limitations, including the potential for misclassification and incomplete adjustment for illness severity.

Statistics

Meta-analysis: prescribed rest worsens symptom burden

Findings from a systematic meta-analysis published in The American Journal of Sports Medicine revealed that prescribed rest had a negative effect on symptoms following a concussion in studies totaling 4,329 patients. The authors found limited support for a negative effect on recovery time. Authors Anthony P. Contos et al. compared the effects of prescribed rest to the effects of active interventions on patients’ symptom resolution and time needed for recovery post-concussion.

Although the studies varied in how they defined rest and what the criteria for rest were, the researchers hypothesized that “rest may have a negative effect on symptoms following a concussion.”

The authors collected data from 19 randomized controlled trials and cohort studies that involved 4329 participants assessed for a concussion/mild traumatic brain injury, were assigned rest or an active intervention, and included tracking symptoms and days to recovery at a minimum of two time points.

Subgroup analyses were carried out to evaluate the impact and significance of prescribed rest with regard to symptoms and recovery time across patient subgroups. Results suggested that prescribed rest had a statistically significant negative effect on symptoms, meaning that prescribed rest negatively impacted symptom burden in adolescents. However, there was a lower and not statistically significant negative effect observed between prescribed rest and recovery time. In the subgroup analyses, the authors found larger negative effect sizes for prescribed rest in studies with shorter duration (<28 days), younger aged participants, and sports-related concussion. Effect size measures the strength between variables, and research findings with a higher effect size are associated with greater meaningful and practical significance.

Current limitations brought forth by the research team include the relatively small quantity of eligible research studies and concerns about the rigor of clinical trials, making it challenging to draw firm conclusions.

Youth

“Adolescent cognitive function is impaired by SRC even 1 to 6 months after injury”

Hou and colleagues posed three research questions about cognitive functioning in adolescents who have experienced sport-related concussion (SRC) in their 2023 systematic review: Does SRC cause cognitive impairment? Which cognitive functions are critical to include in assessments? What additional factors affect low cognitive performance after SRC? Published in the American Journal of Sports Medicine, the study found that SRC was associated with worse performance in tests of cognitive function and higher symptom burdens acutely–and that these cognitive impairments persisted 1-6 months after injury. Multitasking, female sex, younger age, and a history of prior concussions were associated with lower cognitive scores. The authors judged that comparison to normative data was more informative than repeated testing in determining when concussed athletes were ready to return to play.

Trends across 16 studies (31,860 total subjects, of whom 8,877 were concussed) suggested lower performance on cognitive test batteries in concussed subjects for the first 7 days after injury, with gradual improvement over time. Concussed patients generally scored lower on all cognitive dimensions (reaction time, processing speed, verbal memory, visual memory, executive function, symptom score) on the various neurocognitive assessments, though effect sizes differed. (More than half the studies used ImPACT, SCAT5, etc. – see Appendix Table 2 for details1).

This systematic review provides additional data for a standardized approach to SRC in the first weeks after concussion. It will be interesting to see whether clinicians will use this approach, comparing concussed athletes to published or clinical norms rather than the athlete's baseline and/or progression over time on standardized screening inventories. (The authors highlight the need for caution when using athletes' baseline-to-post concussion progression in return-to-play decisions.) This review's findings that symptoms and cognitive challenges regularly persist for more than a few months after SRCsuggest that providers should consider individualized, in-depth assessment sooner to help these adolescents learn cognitive strategies.

1. Tests used in the reviewed articles: ANAM: Automated Neuropsychological Assessment Metrics, ANT: Attentional Network Test, Beery VMI-6: Beery Visual-Motor Integration-Sixth Edition, BYMT-R: Brief Visual Spatial Memory Test-Revised, BYMT-R: Brief Visual Spatial Memory Test-Revised, CCTT: Children's Color Trails A and B, ChiPASAT: Children's Paced Serial Attention Task, CHQ: Concussion History Questionnaire; CMS: Children's Memory Scale, COWAT: Controlled Oral Word Association Test, DANA: Defense Automated Neurobehavioral Assessment, D-KEFS: Design Fluency Subtest-DelisKaplan Executive Function System, DMSPT: Detroit Motor Speed and Precision test, DST: Digit Spanning Test, HVLT: Hopkins Verbal Learning Test-Revised, ImPACT: Immediate Post-Concussion Assessment and Cognitive Test, PSU: Pennsylvania State University Cancellation Task, RAVLT: Rey Auditory Verbal Learning Test, RPCSQ: Rivermead Post-concussion Symptoms Assessment Metrics, SCAT: Sport Concussion Assessment Tool, SDMT: Symbol Digit Modality Test, Stroop: Stroop Color and Word Test, TMTA, TMTB: Trail Making Test Parts A and B, WEAT-4: Word Reading Subtest-Wide Range Achievement Test-Fourth Edition, VIGIL-CPT: Vigil Continuous Performance Test, WISC-III: Wechsler Intelligence Scale for Children 3rd Edition, WMS-III: The Wechsler Memory Scale III

Culture

The dangerous history of concussions and CTE, and how it’s affecting us today

Dr. Stephen Casper is a historian of neuroscience and neurology at Clarkson University in New York. A New Yorker article by Ingfei Chen focuses on Dr. Casper’s knowledge of the history of concussions and chronic traumatic encephalopathy (CTE). Dr. Casper has been an expert witness in multiple lawsuits against major professional sports leagues that involve past players suing the league for not informing them of the risks of CTE. Because of his involvement in these lawsuits, Dr. Casper has created a 150-page document on the history of brain injury and repetitive head impacts and their relationship to CTE. Not all experts agree with Dr. Casper, but those who don’t often hold ties to leagues like the NCAA and the NHL.

Dr. Casper found evidence that even back in 1872, some doctors warned that concussion–especially multiple concussions–“could result in mental infirmity and ‘moral delinquency.” The connection between sports and concussions was established as early as the 1880s. Even though people were calling for the end of football and other harmful sports (e.g., boxing and hockey), these sports were normalized, with the addition (for some) of protective gear–even though helmets prevent skull fractures, not concussions. By the 1930s-50s, a theory was clearly described regarding what we now call CTE. Dr. Casper points out that in 1928, pathologist Harrison Martland studied “punchdrunk syndrome.” Mild symptoms of “punchdrunk syndrome” included unsteadiness, or difficulty keeping equilibrium, while more serious ones included staggering, vertigo, and tremors. Martland concluded that this syndrome was due to repeated head injuries and identified brain degeneration in a way that clearly describes CTE.

Most support for the contemporary view that we “don’t know for sure” that blows to the head in sports can lead to CTE “has been stoked by researchers affiliated with the sports industry.” They often counter claims that Dr. Casper and others make by declaring that we need scientific evidence from very high-standard studies, such as longitudinal studies that would take many decades to conduct, before we can be confident of the relationship between multiple blows to the head and CTE. Of course, while those studies continue, children and adults continue hitting each other’s heads. Dr. Casper is exasperated with these claims, asserting (in this article and on Twitter) that the science was convincing enough in the 1950s to act on this relationship between blows to the head and CTE. And, as Ms. Chen mentions, because of the popularity of these sports, this debate is more than just about medicine – it is about public health. Adam M. Finkel, an environmental-risk expert, told Ms. Chen, “the responsible approach [from health officials] is to ‘warn people, inform people, protect people.’” Even if one takes the view of the researchers who call for studies following the highest standard before they believe there is a verified relationship between head blows and CTE, public health officials should keep the public informed on the “possible” connection between the two. As everyone knows, “better safe than sorry.”

CTE & Neurodegeneration Issues

Review of CTE’s relationship with repeated head impacts, history of clinical diagnosis, and case study findings

A review article published in Acta Neuropathologica by Ann C. McKee et al. provides a sweeping exploration of chronic traumatic encephalopathy (CTE) research, focusing on criteria for diagnosis and the condition’s relationship to repetitive head impacts (RHI). We include this passage from the conclusion below:

“The preponderance of the evidence suggests a high likelihood of a causal relationship between RHI and CTE, a conclusion that is strengthened by the absence of any evidence for plausible alternative hypotheses. There is no other common variable, aside than RHI, that explains why so many contact sports players worldwide, playing diverse sports, have been diagnosed with CTE, while individuals without RHI exposure have not.“

The article summarizes the case for a causal relationship between RHI and CTE, first noting that the “ideal study” to combat scientific uncertainty around RHI and CTE would require 6-7 decades of observation and would unethically impose risk on participants. Given that, the article supports the recent review article by Nowinksi et al. demonstrating a high likelihood of a causal relationship through the Bradford Hill Criteria, “the most frequently cited framework for causal inference in epidemiologic studies.” (See our newsletter synopsis.) McKee et al. outline studies showing significantly increased risk for CTE in those with a history of RHI and studies finding an association between multiple types of RHI exposure and CTE pathology. They point out that “RHI exposure is the only known unifying factor (present in 97%) among the over 600 CTE cases reported in the literature to date,” and that there is no conflicting evidence that RHI does not influence the development of CTE pathology.

McKee et al. cover the development of criteria for traumatic encephalopathy syndrome (TES), a clinical syndrome associated with CTE pathology. An NINDS consensus established four primary criteria for TES, the first of which is “substantial exposure to RHI.” The other criteria are progressively worsening cognitive impairment (memory and/or executive function) and/or “neurobehavioral dysregulation (explosiveness, impulsivity, rage, violent outbursts, and emotional lability), clinical features not fully accounted for by other disorders,” and some level of functional impairment or dementia. The article references a study finding that CTE with a particular damage pathology (hippocampal sclerosis) was associated with RHI. Several other studies found that NFL players were diagnosed with ALS at 3-4 times the rate of their demographic peers. Further, NFL players diagnosed with ALS had longer careers than players not diagnosed, “suggesting an association between NFL duration of play or RHI exposure and ALS.”

The article also explains how researchers developed criteria for the current neuropathological diagnosis–spanning from case reviews in the 1950s, to Bennett Omalu’s discovery of CTE in an American football player in 2005, to the 2014 and 2016 NINDS–NIBIB (National Institute of Neurological Diseases and Stroke–National Institute of Biomedical Imaging and Bioengineering) consensus panels creating criteria. The study then summarizes findings from retrospective cohort studies examining different populations using the criteria. This section outlines the high rates of CTE discovery in studies examining American football and–with much smaller sample sizes–soccer, rugby, ice hockey, and Australian rules football players. The article also explains that observed CTE rates in military personnel studies are much lower than in contact sport athletes (4.4% in one study) but still “many times” higher than the observed rate in community-based and brain bank studies. The authors advocate for longitudinal observational studies of those at risk for CTE (such as former contact sports athletes), along with robust fluid and biomarker studies.