The Use of Biofluid Markers to Evaluate the Consequences of Sport-Related Subconcussive Head Impact Exposure: A Scoping Review.

BACKGROUND: Amidst growing concern about the safety of sport-related repetitive subconcussive head impacts (RSHI), biofluid markers may provide sensitive, informative, and practical assessment of the effects of RSHI exposure. OBJECTIVE: This scoping review aimed to systematically examine the extent, nature, and quality of available evidence from studies investigating the effects of RSHI on biofluid markers, to identify gaps and to formulate guidelines to inform future research. METHODS: PRISMA extension for Scoping Reviews guidelines were adhered to. The protocol was pre-registered through publication. MEDLINE, Scopus, SPORTDiscus, CINAHL, PsycINFO, Cochrane Library, OpenGrey, and two clinical trial registries were searched (until March 30, 2022) using descriptors for subconcussive head impacts, biomarkers, and contact sports. Included studies were assessed for risk of bias and quality. RESULTS: Seventy-nine research publications were included in the review. Forty-nine studies assessed the acute effects, 23 semi-acute and 26 long-term effects of RSHI exposure. The most studied sports were American football, boxing, and soccer, and the most investigated markers were (in descending order): S100 calcium-binding protein beta (S100B), tau, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), brain-derived neurotrophic factor (BDNF), phosphorylated tau (p-tau), ubiquitin C-terminal hydrolase L1 (UCH-L1), and hormones. High or moderate bias was found in most studies, and marker-specific conclusions were subject to heterogeneous and limited evidence. Although the evidence is weak, some biofluid markers-such as NfL-appeared to show promise. More markedly, S100B was found to be problematic when evaluating the effects of RSHI in sport. CONCLUSION: Considering the limitations of the evidence base revealed by this first review dedicated to systematically scoping the evidence of biofluid marker levels following RSHI exposure, the field is evidently still in its infancy. As a result, any recommendation and application is premature. Although some markers show promise for the assessment of brain health following RSHI exposure, future large standardized and better-controlled studies are needed to determine biofluid markers' utility.

Contrasting Characteristics and Outcomes of Sports-Related and Non-Sports-Related Traumatic Brain Injury.

Importance: Exposure to traumatic brain injury (TBI) has raised widespread concern over participation in sports, particularly over possible long-term consequences. However, little is known about the outcomes of individuals presenting to hospitals with sports-related TBI. Objective: To compare the characteristics and outcomes of individuals presenting to hospitals with sports-related and non-sports-related TBI. Design, Setting, and Participants: The CENTER-TBI (Collaborative European NeuroTrauma Effectiveness Research in TBI) observational cohort study was conducted at hospitals in 18 countries. The study enrolled 4509 patients who had TBI and had an indication for computed tomography (CT), of whom 4360 were 16 years or older. Outcomes were assessed at 3 and 6 months, and groups were compared using regression analyses adjusting for clinical and demographic differences. Data were collected between December 9, 2014, and December 17, 2017, and analyzed from August 2022 to March 2023. Exposure: Sports-related and non-sports-related TBI with subgroups selected by severity of injury. Main Outcomes and Measures: The main outcome was the Glasgow Outcome Scale-Extended (GOSE) at 6 months, with secondary outcomes covering postconcussion symptoms, health-related quality of life, and mental health. Results: A total of 4360 patients were studied, including 256 (6%) with sports-related TBI (mean [SD] age, 38.9 [18.1] years; 161 [63%] male) and 4104 with non-sports-related TBI (mean [SD] age, 51.0 [20.2] years; 2773 [68%] male). Compared with patients with non-sports-related TBI, patients with sports-related TBI were younger, more likely to have tertiary education, more likely to be previously healthy, and less likely to have a major extracranial injury. After adjustment, the groups did not differ in incomplete recovery (GOSE scores <8) at 6 months (odds ratio [OR], 1.27; 95% CI, 0.90-1.78; P = .22 for all patients; OR, 1.20; 95% CI, 0.83-1.73; P = .34 for those with mild TBI; and OR, 1.19; 95% CI, 0.74-1.92; P = .65 for those with mild TBI and negative CT findings). At 6 months, there was incomplete recovery in 103 of 223 patients (46%) with outcomes in the sports-related TBI group, 65 of 168 (39%) in those with mild sports-related TBI, and 30 of 98 (31%) in those with mild sports-related TBI and negative CT findings. In contrast, at 6 months, the sports-related TBI group had lower prevalence of anxiety, depression, posttraumatic stress disorder, and postconcussion symptoms than the non-sports-related group. Conclusions and Relevance: In this cohort study of 4360 patients with TBI, functional limitations 6 months after injury were common after sports-related TBI, even mild sports-related TBI. Persisting impairment was evident in the sports-related TBI group despite better recovery compared with non-sports-related TBI on measures of mental health and postconcussion symptoms. These findings caution against taking an overoptimistic view of outcomes after sports-related TBI, even if the initial injury appears mild.

Repeated Sub-Concussive Impacts and the Negative Effects of Contact Sports on Cognition and Brain Integrity.

Sports are yielding a wealth of benefits for cardiovascular fitness, for psychological resilience, and for cognition. The amount of practice, and the type of practiced sports, are of importance to obtain these benefits and avoid any side effects. This is especially important in the context of contact sports. Contact sports are not only known to be a major source of injuries of the musculoskeletal apparatus, they are also significantly related to concussion and sub-concussion. Sub-concussive head impacts accumulate throughout the active sports career, and thus can cause measurable deficits and changes to brain health. Emerging research in the area of cumulative sub-concussions in contact sports has revealed several associated markers of brain injury. For example, recent studies discovered that repeated headers in soccer not only cause measurable signs of cognitive impairment but are also related to a prolonged cortical silent period in transcranial magnetic stimulation measurements. Other cognitive and neuroimaging biomarkers are also pointing to adverse effects of heading. A range of fluid biomarkers completes the picture of cumulating effects of sub-concussive impacts. Those accumulating effects can cause significant cognitive impairment later in life of active contact sportswomen and men. The aim of this review is to highlight the current scientific evidence on the effects of repeated sub-concussive head impacts on contact sports athletes' brains, identify the areas in need of further investigation, highlight the potential of advanced neuroscientific methods, and comment on the steps governing bodies have made to address this issue. We conclude that there are indeed neural and biofluid markers that can help better understand the effects of repeated sub-concussive head impacts and that some aspects of contact sports should be redefined, especially in situations where sub-concussive impacts and concussions can be minimized.

Longer Neurophysiological vs. Clinical Recovery Following Sport Concussion.

Objectives: The objective of this study was to assess if injury-related alterations in the Sport Concussion Assessment Tool-5 (SCAT5) are matched by changes in transcranial magnetic stimulation-derived intracortical inhibition. We hypothesised that neurophysiological measures would take longer to return to normal than recovery assessed by the SCAT5 following sport related concussion (SRC). Methods: Thirteen male contact sport athletes (20.5 ± 4.5 years), who reported a concussion were recruited from local Rugby and American football clubs. Participants were tested at 4 timepoints throughout the concussion recovery period: within 24 h of concussion (day 0), and at 7, 9, and 11 days after concussion. All participants completed the SCAT5 and underwent TMS to assess cortical silent period duration (CSp), a measure of intracortical inhibition. Results: After concussion CSp significantly declined from day 0 (122 ± 28 ms) to day 11 (106 ± 15 ms) [F (3, 33) = 7.80, p < 0.001]. SCAT5 measures of symptom number and severity were significantly decreased [symptom number: χ ( 3 ) 2 = 30.44, p < 0.01; symptom severity: χ ( 3 ) 2 = 25.75, p < 0.001] between the day 0 timepoint and each of the other timepoints. SCAT5 balance errors (mBESS) decreased significantly [F (3, 33) = 19.55, p < 0.001] between the day 0 timepoint and each of the other timepoints. CSp and SCAT5 recovery patterns were different. SCAT5 domains recovered faster showing no further significant changes after day 7, whilst CSp was still decreasing between days 7 and 9. Due to the small sample size we also used a Bayesian linear model to investigate the recovery of CSp and mBESS. The posterior distribution of our Bayesian model provided evidence that CSp decreased at day 7 and it continued to decrease at day 9, unlike mBESS which decreased at day 7 and then reached a plateau. Conclusion: There are clinically important discrepancies between clinical and neurophysiological measures of concussion recovery. This finding has important implications for return to play (RTP) protocols and the prevention of complications after sport concussion.

Effects of sport-related repetitive subconcussive head impacts on biofluid markers: a scoping review protocol.

INTRODUCTION: Sport-related repetitive subconcussive head impacts (RSHIs) are increasingly thought to be associated with adverse long-term outcomes. However, owing to potentially subtle effects, accurate assessment of harm to the brain as a consequence of RSHI is a major challenge and an unmet need. Several studies suggest that biofluid markers can be valuable objective tools to aid the diagnosis and injury characterisation and help in medical decision-making. Still, by and large, the results have been limited, heterogeneous and inconsistent. The main aims of this scoping review are therefore (1) to systematically examine the extent, nature and quality of available evidence from studies investigating effects of RSHI on fluid biomarkers and (2) to formulate guidelines and identify gaps with the aim to inform future clinical studies and the development of research priorities. METHODS AND ANALYSES: We will use a comprehensive search strategy to retrieve all available and relevant articles in the literature. The following electronic databases will be systematically searched: MEDLINE (EBSCO host; from 1809 to 2020); Scopus (from 1788 to 2020); SPORTDiscus (from 1892 to 2020); CINAHL Complete (from 1937 to 2020); PsycINFO (from 1887 to 2020); Cochrane Library (to 2020); OpenGrey (to 2020); ClinicalTrials.gov (to 2020) and WHO International Clinical Trials Registry Platform (to 2020). We will consider primarily biomedical studies evaluating the biofluid markers following RSHI. Two independent reviewers will screen articles for inclusion using predefined eligibility criteria and extract data of retained articles. Disagreements will be resolved through consensus or arbitrated by a third reviewer if necessary. Data will be reported qualitatively given the heterogeneity of the included studies. In synthesising the evidence, we will structure results by markers, sample types, outcomes, sport and timepoints. ETHICS AND DISSEMINATION: Ethics approval is not required. We will submit results for peer-review publication, and present at relevant conferences.