Lifetime exposure to cumulative force of repeated head impacts is strongly associated with CTE

This week's lead article, Lifetime exposure to cumulative force of repeated head impacts is strongly associated with CTE, is in the CTE and Neurodegeneration Issues category.

In this newsletter: Opportunities, Sports, Pathophysiology, Therapies & Diagnostic Tools Under Research, Veterans and Service Members, Mental Health, and CTE and Neurodegeneration Issues.

This is the third newsletter produced by interns participating in our Summer 2023 Concussion Education & Advocacy Internship.

Writers: Kat Kresse, Keya Mookencherry, Zoe Cronin, Zach Napora, Ike Smalley, and Maya Chawla,

Editors: Kira Kunzman, Conor Gormally, and Malayka Gormally

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Opportunities

Wednesday, July 19, 12:00 pm PST: a free webinar, How Sensory Sensitivities Impact Relationships & Mood, presented by Maria Dalbotten, a mental health therapist and a TBI survivor. Hosted by the Brain Injury Alliance of WA State and open to the public. Register in advance.

Video: Lead author Daniel H. Daneshvar discusses his team’s study on the cumulative force of head impacts and CTE: CLF Presents: New Research on CTE Risk & Prevention.

Podcast: Dr. Steve Broglio discusses the development process and key takeaways of the new 6th International Consensus on Concussion in Sport on the Youth Sports Safety podcast.

Podcast: Highlights from the 6th International Consensus on Concussion in Sport with Kathryn Scheider and Jon Patricios, hosted by the British Journal of Sports Medicine.

Sports

Early exercise post-concussion accelerates return-to-play recovery for collegiate student-athletes

Research by Lempke et al. indicates light exercise under clinician supervision within 48 hours post-concussion is associated with lower post-concussive symptom prevalence and faster return-to-play recovery for collegiate student-athletes. The study was published in Sports Medicine and involved "1228 participants enrolled in the NCAA–DoD CARE Consortium." In a University of Michigan press release, Lempke states that this study's "findings and many other studies indicate exercise can be started before symptoms resolve, if done in a safe and controlled manner as guided by a trained clinician." Lempke et al. also recommend changes to the RTP guidelines, arguing to replace 'no exercise within 24-48 hours' recommendations with "consider light exercise during this time," as long as the exercise is done safely in a way that reduces fall risk, such as a stationary bicycle.

The study compares symptom recovery time, clinical recovery time, and persisting post-concussion symptom prevalence across four groups: an early exercise group (less than two days post-concussion), a typical exercise group (3-7 days post-concussion), a late exercise group (more than a week post-concussion), and a no-exercise group who did not exercise prior to the beginning of the return-to-play (RTP) protocol. The study authors define symptom recovery and clinical recovery as follows: "Symptom recovery (days from injury to symptom resolution) and clinical recovery (days from injury to return to play protocol completion) was determined by the student-athletes' clinicians."

Among the 1228 participants, those who began light exercise were almost twice as likely to reach clinal recovery and almost 3 days faster to see their symptoms resolve compared to the non-exercise group. In contrast, athletes in the late-exercise group, compared to the no-exercise group, were about half as likely to reach symptom recovery and clinical recovery and "took 5.3 days [symptom] and 5.7 days [clinical] more to recover, respectively." The authors are unsure of the explanation behind this finding, though one theory is that the late-exercise group was engaging in exercise as a treatment for atypical symptom recovery. This observational study does not identify the intensity, type, or duration of exercise but does suggest a clear positive correlation between early exercise and concussion recovery times.

It is important to keep in mind that these findings don't mean collegiate student-athletes should return to play sooner. According to the above findings, implementing safe and controlled early exercise into clinical practice as treatment may improve student-athlete recovery time and decrease the likelihood of persistent symptoms.

Pathophysiology

Heading a soccer ball can cause concussive symptomatology and alter brain-muscle communication

A study published in Frontiers of Neurobiology found that a "short bout of soccer heading may impair cognitive function and disrupt the organization of efficient neural processes that typically accompany motor skill proficiency." In this study by Parr et al., 90% of participants in the experimental group tasked with heading a soccer ball reported experiencing symptoms related to concussion (such as confusion, headache, and dizziness). Conversely, only 10% of the control group, who headed a soccer ball using virtual reality, reported similar symptoms. This study showed findings that a bout of 20 headers resulted in significant brain-related changes across several kinds of tests.

Compared to the control group, experimental group participants (who performed twenty sequential headers with a soccer ball) showed more corticomuscular coherence, meaning that neuronal communication between the motor cortex in the brain and the body's muscles was elevated in participants heading a real soccer ball. This has neuromuscular implications; previous studies have proposed that hyperconnectivity represents the brain's natural repair response to injury as it compensates for reduced cognitive function. On the King-Devick test, a neurophysiological test of saccadic eye movement and cognitive function, the control group completed the test much faster post-test (as expected), but the experimental group had no improvement and made more errors on the test. "These impairments in the ability to improve on the King-Devick test have been reported in previous research and have been suggested to highlight an impairment in cognitive function that reduces the ability to learn such tasks."

The participants consisted of 60 soccer players, 15 male and 15 female, in both an experimental group and a control group. The playing level of the participants varied from recreational to semi-professional and encompassed a wide range of positions from goalkeeper to forward. The experimental group participated in heading a standard size 5 soccer ball, inflated to 16.2 psi, 20 times (uncommon in a soccer game, however 20 headers "is aligned with the upper range of headers previously recorded from training sessions with adolescent players.”) Meanwhile, the control group participated in "heading a soccer ball" using a virtual reality device. "The ball was projected to the players from a virtual ball machine, and they were required to perform a defensive header, heading the ball back as far past the virtual ball machine as possible whilst keeping both feet on the floor (i.e., jumping was not permitted)."

The experimental and control groups were assessed before and after engaging in the real or virtual bout of heading with a short questionnaire to determine concussive symptomatology, a neurophysiological assessment of maximum voluntary contraction of the hand (MVC), and the King-Devick test. The King-Devick test's purpose is to measure "saccadic eye speed" and provide "an immediate, low-cost indicator of head trauma or suspected concussion" while testing for suboptimal cognitive function. The self-reported symptom questionnaire asked patients to report their level of confusion, discomfort, drowsiness, ringing in ears, and pain and to pick the most prevalent of those symptoms at that time.

The neurophysiological assessment focused on an "isometric force precision task" that involved the study participants being connected to EEG and EMG equipment while performing 2 MVCs that indicate the maximum force one can generate within a muscle group. Then using the EEG and EMG equipment, participants squeezed a dynamometer (a tool to measure force) to get kinetic and physiological data surrounding the MVC.

Overall, this study has shown that short bouts of soccer heading can impair both cognitive functioning and alter corticomuscular control of movement. There have been a growing number of studies surrounding neurophysiological changes due to heading, and more research will help determine the short and long-term effects of heading.

Therapies & Diagnostic Tools Under Research

IV ketamine significantly reduces pain in pediatric patients with refractory migraine

A Neurology Live article describes a study by Dr. Scott Rosenthal and colleagues that was presented at the June 2023 American Headache Society (AHS) Annual Meeting. The study, not yet published, found that children aged 5 to 21 years treated with intravenous ketamine for refractory headaches had a 50% median pain reduction at discharge. Refractory headaches are headaches that fail to respond to most treatments, so advances in refractory headache treatment are important because patients "often have few options for treatment despite ongoing pain and significant disability." This study does not explicitly address concussion or post-traumatic headache, but intractable (>72 hours) headache is a common post-concussion symptom, so we think it is relevant to our readers.

Dr. Scott Rosenthal and colleagues at Children's Hospital Colorado, University of Colorado School of Medicine conducted a retrospective chart review of visits by 38 pediatric patients who received ketamine for refractory headache to determine the effectiveness of IV ketamine for headache pain reduction. The researchers reviewed the effectiveness of the treatment by considering the percentage of pain reduction at discharge in addition to any serious adverse events, medication side effects, and headache recurrence at time points 72 hours and 30 days following discharge. Dr. Rosenthal and colleagues hoped to demonstrate the usefulness of ketamine for the treatment of this condition that is resistant to most treatments.

The study found that intravenous ketamine significantly reduced patients' reported pain at discharge and yielded no serious adverse events, the latter of which the article does not define. Dr. Rosenthal notes that intravenous ketamine is effective for refractory headache pain because it works as an NMDA receptor antagonist. NMDA receptors are ion channels that respond to the neurotransmitter glutamate, making them particularly responsive to pain and implicated in the neuroinflammatory response. Inhibiting these receptors with an NMDA receptor antagonist such as ketamine can reduce the pain response. Scientists are researching IV ketamine as an alternative treatment to intravenous dihydroergotamine (IV DHE), a drug not tolerated by all refractory migraine patients.

Key findings of this study include a 50% median pain reduction at discharge, no serious adverse events, a 7% attrition rate due to side effects, a 9% rate of headache recurrence 72 hours after discharge, and a 36% rate of headache recurrence 30 days after discharge. The most common side effects were dizziness, nausea, hallucinations, blurry vision, cognitive fog, dysphoria, and vomiting. Each side effect occurred in 4% to 19% of patients.

Dr. Rosenthal notes, "These results suggest that intravenous ketamine is an effective, safe, and well-tolerated option for treating refractory pediatric headaches and status migrainosus." Additional research on IV ketamine for refractory migraine is needed.

Veterans & Service Members

PTSD and poor sleep quality associated with white matter alterations in the brains of veterans

A study published in the Journal of Clinical Medicine has shed light on the impact of sleep disturbances on brain health in veterans with comorbid PTSD and mTBI. They observed that "Veterans with PTSD and comorbid PTSD+mTBI reported poorer sleep quality than those with mTBI or no history of PTSD or mTBI" and "Poor sleep quality was associated with abnormal WM microstructure in veterans with comorbid PTSD+mTBI." Most notably, the research by Martha E Shenton and Inga K. Koerte et al. unveiled that poor sleep quality was a necessary link between more severe PTSD symptoms and impaired white matter microstructure.

In essence, it illuminated the pivotal role of sleep quality in how psychological trauma affects the brain. As lead researcher Koerte stated in a press release for the Brain and Behaviour Research Foundation, the results show "that sleep plays a central role in how psychological trauma affects brain health."

The study's participants, 180 male post-9/11 veterans, were divided into four groups: PTSD only, mTBI only, both PTSD and mTBI, and a control group without either condition. It's important to note that participants with both PTSD and mTBI had more instances of mTBI compared to the other groups. To evaluate the white matter microstructure, the authors used an advanced imaging technique, diffusion-weighted magnetic resonance imaging (dMRI). Additionally, the Pittsburgh Sleep Quality Index (PSQI) was utilized to assess sleep quality.

Nearly one-fourth of military service members returning from deployments to Iraq and Afghanistan receive a PTSD diagnosis. Additionally, 12% to 35% of these individuals sustain mTBI during their deployment, which increases the risk of developing or exacerbating PTSD symptoms. Poor sleep quality is a hallmark symptom of PTSD and is highly prevalent following mTBI, often leading to more severe symptoms and slower recovery from both conditions. Poor sleep can lead to impaired clearance of neurotoxins, which can then lead to impaired myelination. Future research should look at the effectiveness of insomnia treatments for PTSD in veteran populations.

For more information, see our resource Sleep and Sleep Problems following mild traumatic brain injuries.

Mental Health

Researchers outline five psychological factors contributing to persistent postconcussion symptoms

A recent article published in Physical Therapy & Rehabilitation proposes a model for understanding the psychological factors that contribute to the incidence of persistent postconcussion symptoms (PPCS) in adults. The authors Faulkner and Snell outline five tenents that may influence whether someone develops PPCS after a concussion:

preexisting psychological vulnerabilities, such as mental health conditions or certain personality traits
psychological distress, including both distress caused by the concussion neurologically and distress due to the event that caused the concussion or subsequent consequences of the event or injury
environmental and contextual factors, such as worry about work or a failure to follow rehabilitation and reintegration plans
underlying thought and behavioral patterns such as catastrophizing and avoidance, which can impede recovery, referred to as "transdiagnostic processes"
the subconscious and conscious learning of harmful behaviors such as avoiding too many activities, referred to as "learning principles"

The authors note that "a generic approach to mental health management without awareness of context is unlikely to be optimal…The proposed framework guides clinicians to go further and tease out the specific psychological processes that drive mental distress." The authors argue that their model fits within an accepted biopsychosocial approach to healthcare and stresses the necessity of a multidisciplinary approach to rehabilitation.

PPCS is defined as "the presence of any symptom that cannot be attributed to a preexisting condition, that appeared within hours of concussion, that is still present every day 3 months after the trauma, and has an impact on at least 1 aspect of a person's life." PPCS is incredibly widespread; a separate study found that nearly half of its participants were experiencing four or more postconcussion symptoms a year after their injury, and another identified that the majority of participants were still experiencing at least 3 symptoms after a year.

The development of this model was based on the facets of concussion recovery, the physiology of a concussion, and findings from chronic pain research, which is similar to PPCS in a variety of ways. The model is developed to understand the causes of PPCS "from a psychological perspective within current biopsychosocial models." Biopsychosocial approaches are a generally accepted framework within psychology to study and understand mental illnesses and other psychological and medical topics from biological, psychological, and social perspectives. Faulkner and Snell's framework can be used to guide treatment and recovery and exists as a resource for clinicians to help patients. The authors describe how "addressing psychological factors in rehabilitation can take several different forms from identification of psychological risk, assessment of current mental health status, education, the implementation of strategies to manage psychological symptoms, and, when indicated, referral for specialized mental health treatment."

There is strong evidence for the role of psychological factors in the development of persistent postconcussion symptoms. The term PPCS, and an even newer term from the 6th consensus on concussion in sport, "persisting symptoms after concussion," imply a constellation of factors (including psychosocial factors beyond the injury) contributing to patients' symptoms. Postconcussion syndrome, an older term, implies the existence of an underlying physical syndrome that causes all symptoms, which is not the case. (Concussion Alliance also finds the term postconcussion syndrome to be less conducive to empowering patients to take action to rehabilitate their symptoms; a syndrome is less concrete than a set of persisting postconcussion symptoms, each of which is treatable individually.)

Previous models have tried to describe the psychological factors contributing to PPCS, but they are often complex, and patients find them challenging to understand. These previous models also describe psychological factors as diagnostic groups without accounting for how these diagnostic groups (for ex., anxiety and depression) can develop during recovery or influence recovery, which can leave patients confused and “prevent clinicians from providing optimal support and treatment."

Check out Concussion Alliance's resources for more information on PPCS and its causes and symptoms.

CTE and Neurodegeneration Issues

Lifetime exposure to cumulative force of repeated head impacts is strongly associated with CTE

While brain injury prevention in sports has largely focused on concussion, a groundbreaking study published in Nature Communications revealed that the development and severity of CTE are associated with the duration of play and the cumulative force of all repetitive head impacts (RHIs). The charts from the study were reproduced in a New York Times article, in which authors Ken Belson and Benjamin Mueller note that "Those players who absorbed the most cumulative force from head hits had the worst forms of C.T.E.." For one element of the study, authors Daniel H. Daneshvar et al. looked at the concussion history of the brain donors in the study; they found no association between CTE status and the number of concussions they self-reported. There was no association between the number of self-reported concussions and CTE severity for those who had CTE.

Daneshvar and colleagues designed the first "position exposure matrix" (PEM) for American football using data from 34 accelerometer studies. They applied the PEM to the brains of 631 deceased football players diagnosed with CTE who had donated their brains to the Boston University Unite Brain Bank. The PEM retrospectively quantifies the cumulative RHI exposure of football players by position via approximating the total linear and rotational acceleration from impact forces in addition to the total number of RHIs. In addition to their PEM analysis, the study authors looked at stand-alone metrics in relationship to CTE pathology, including position played, duration of playing career, and number of concussions. The only factors with a statistically significant association with CTE pathogenesis were duration of play and PEM-derived measures of cumulative head impact intensity.

A more refined understanding of the aspects of RHI force involved in CTE can guide us in improving care and protection of our athletes. Possible manifestations of this include treating subconcussive hits with more caution in sideline assessments or, as described in the New York Times article, reducing or eliminating contact from practice. Keeping track of head impact history, especially information related to impact forces, may be useful in monitoring athletes' risk, and a PEM such as the one used in this study may be used to do so. Beyond athletics, this study's implications can potentially protect many more populations who experience RHIs, including individuals experiencing intimate partner violence and military personnel exposed to repeated blasts.

This study is evidence that repetitive subconcussive head impacts are implicated in CTE development and should be given more gravity. Repetitive occurrence of force imparted to the brain tissue increases the risk for CTE, regardless of whether the magnitude of each is enough to cause a concussion. Future research should continue expanding the demographics beyond male football players at high levels of competition. Still, this study reflects great progress in our ability to characterize CTE and predict risk, giving us valuable insights to protect the safety of athletes' careers and lives.