Transcranial Doppler Ultrasound and Concussion-Supplemental Symptoms with Physiology: A Systematic Review.

Sport-related concussion (SRC) can impair the cerebrovasculature both acutely and chronically. Transcranial Doppler (TCD) ultrasound assessment has the potential to illuminate the mechanisms of impairment and provide an objective evaluation of SRC. The current systematic review investigated studies employing TCD ultrasound assessment of intracranial arteries across three broad categories of cerebrovascular regulation: neurovascular coupling (NVC), cerebrovascular reactivity (CVR), and dynamic cerebral autoregulation (dCA). The current review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42021275627). The search strategy was applied to PubMed, as this database indexes all biomedical journals. Original articles on TCD for athletes with medically diagnosed SRC were included. Title/abstract and full-text screening were completed by three authors. Two authors completed data extraction and risk of bias using the Methodological Index for Non-Randomized Studies and Scottish Intercollegiate Guideline Network checklists. Of the 141 articles identified, 14 met the eligibility criteria. One article used an NVC challenge, eight assessed CVR, and six investigated dCA. Methodologies varied widely among studies, and results were heterogeneous. There was evidence of cerebrovascular impairment in all three domains roughly 2 days post-SRC, but the magnitude and recovery of these impairments were not clear. There was evidence that clinical symptom resolution occurred before cerebrovascular function, indicating that physiological deficits may persist despite clinical recovery and return to play. Collectively, this emphasizes an opportunity for the use of TCD to illuminate the cerebrovascular deficits caused by SRC. It also highlights that there is need for consistent methodological rigor when employing TCD in a SRC population.

Adolescent Sport-Related Concussion and the Associated Neurophysiological Changes: A Systematic Review.

BACKGROUND: Sport-related concussion (SRC) has been shown to induce cerebral neurophysiological deficits, quantifiable with electroencephalography (EEG). As the adolescent brain is undergoing rapid neurodevelopment, it is fundamental to understand both the short- and long-term ramifications SRC may have on neuronal functioning. The current systematic review sought to amalgamate the literature regarding both acute/subacute (≤28 days) and chronic (>28 days) effects of SRC in adolescents via EEG and the diagnostic accuracy of this tool. METHODS: The review was registered within the Prospero database (CRD42021275256). Search strategies were created and input into the PubMed database, where three authors completed all screening. Risk of bias assessments were completed using the Scottish Intercollegiate Guideline Network and Methodological Index for Non-Randomized Studies. RESULTS: A total of 128 articles were identified; however, only seven satisfied all inclusion criteria. The studies ranged from 2012 to 2021 and included sample sizes of 21 to 81 participants, albeit only ∼14% of the included athletes were females. The studies displayed low-to-high levels of bias due to the small sample sizes and preliminary nature of most investigations. Although heterogeneous methods, tasks, and analytical techniques were used, 86% of the studies found differences compared with control athletes, in both the symptomatic and asymptomatic phases of SRC. One study used raw EEG data as a diagnostic indicator demonstrating promise; however, more research and standardization are a necessity. CONCLUSIONS: Collectively, the findings highlight the utility of EEG in assessing adolescent SRC; however, future studies should consider important covariates including biological sex, maturation status, and development.

Use of Biostatistical Models to Manage Replicate Error in Concussion Biomarker Research.

Importance: Advancing research on fluid biomarkers associated with sport-related concussion (SRC) highlights the importance of detecting low concentrations using ultrasensitive platforms. However, common statistical practices may overlook replicate errors and specimen exclusion, emphasizing the need to explore robust modeling approaches that consider all available replicate data for comprehensive understanding of sample variation and statistical inferences. Objective: To evaluate the impact of replicate error and different biostatistical modeling approaches on SRC biomarker interpretation. Design, Setting, and Participants: This cross-sectional study within the Surveillance in High Schools to Reduce the Risk of Concussions and Their Consequences study used data from healthy youth athletes (ages 11-18 years) collected from 3 sites across Canada between September 2019 and November 2021. Data were analyzed from November 2022 to February 2023. Exposures: Demographic variables included age, sex, and self-reported history of previous concussion. Main Outcomes and Measures: Outcomes of interest were preinjury plasma glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament-light (NFL), total tau (t-tau) and phosphorylated-tau-181 (p-tau-181) assayed in duplicate. Bland-Altman analysis determined the 95% limits of agreement (LOAs) for each biomarker. The impact of replicate error was explored using 3 biostatistical modeling approaches assessing the associations of age, sex, and previous concussion on biomarker concentrations: multilevel regression using all available replicate data, single-level regression using the means of replicate data, and single-level regression with replicate means, excluding specimens demonstrating more than 20% coefficient variation (CV). Results: The sample included 149 healthy youth athletes (78 [52%] male; mean [SD] age, 15.74 [1.41] years; 51 participants [34%] reporting ≥1 previous concussions). Wide 95% LOAs were observed for GFAP (-17.74 to 18.20 pg/mL), UCH-L1 (-13.80 to 14.77 pg/mL), and t-tau (65.27% to 150.03%). GFAP and UCH-L1 were significantly associated with sex in multilevel regression (GFAP: effect size, 15.65%; ß = -0.17; 95% CI, -0.30 to -0.04]; P = .02; UCH-L1: effect size, 17.24%; ß = -0.19; 95% CI, -0.36 to -0.02]; P = .03) and single-level regression using the means of replicate data (GFAP: effect size, 15.56%; ß = -0.17; 95% CI, -0.30 to -0.03]; P = .02; UCH-L1: effect size, 18.02%; ß = -0.20; 95% CI, -0.37 to -0.03]; P = .02); however, there was no association for UCH-L1 after excluding specimens demonstrating more than 20% CV. Excluding specimens demonstrating more than 20% CV resulted in decreased differences associated with sex in GFAP (effect size, 12.29%; ß = -0.14; 95% CI, -0.273 to -0.004]; P = .04) and increased sex differences in UCH-L1 (effect size, 23.59%; ß = -0.27; 95% CI, -0.55 to 0.01]; P = .06), with the widest 95% CIs (ie, least precision) found in UCH-L1. Conclusions and Relevance: In this cross-sectional study of healthy youth athletes, varying levels of agreement between SRC biomarker technical replicates suggested that means of measurements may not optimize precision for population values. Multilevel regression modeling demonstrated how incorporating all available biomarker data could capture replicate variation, avoiding challenges associated with means and percentage of CV exclusion thresholds to produce more representative estimates of association.

Role of biomarkers and emerging technologies in defining and assessing neurobiological recovery after sport-related concussion: a systematic review.

OBJECTIVE: Determine the role of fluid-based biomarkers, advanced neuroimaging, genetic testing and emerging technologies in defining and assessing neurobiological recovery after sport-related concussion (SRC). DESIGN: Systematic review. DATA SOURCES: Searches of seven databases from 1 January 2001 through 24 March 2022 using keywords and index terms relevant to concussion, sports and neurobiological recovery. Separate reviews were conducted for studies involving neuroimaging, fluid biomarkers, genetic testing and emerging technologies. A standardised method and data extraction tool was used to document the study design, population, methodology and results. Reviewers also rated the risk of bias and quality of each study. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies were included if they: (1) were published in English; (2) represented original research; (3) involved human research; (4) pertained only to SRC; (5) included data involving neuroimaging (including electrophysiological testing), fluid biomarkers or genetic testing or other advanced technologies used to assess neurobiological recovery after SRC; (6) had a minimum of one data collection point within 6 months post-SRC; and (7) contained a minimum sample size of 10 participants. RESULTS: A total of 205 studies met inclusion criteria, including 81 neuroimaging, 50 fluid biomarkers, 5 genetic testing, 73 advanced technologies studies (4 studies overlapped two separate domains). Numerous studies have demonstrated the ability of neuroimaging and fluid-based biomarkers to detect the acute effects of concussion and to track neurobiological recovery after injury. Recent studies have also reported on the diagnostic and prognostic performance of emerging technologies in the assessment of SRC. In sum, the available evidence reinforces the theory that physiological recovery may persist beyond clinical recovery after SRC. The potential role of genetic testing remains unclear based on limited research. CONCLUSIONS: Advanced neuroimaging, fluid-based biomarkers, genetic testing and emerging technologies are valuable research tools for the study of SRC, but there is not sufficient evidence to recommend their use in clinical practice. PROSPERO REGISTRATION NUMBER: CRD42020164558.

Adjusting to Changing Environments: Virtual Preseason SCAT5 Assessment in Canadian Male Youth Football Players.

OBJECTIVE: To provide preseason reference scores for Canadian youth tackle football players on the Sport Concussion Assessment Tool 5 (SCAT5) and to examine whether age, concussion history, and self-reported medical diagnoses are associated with SCAT5 subcomponent performance. DESIGN: Cross-sectional study. SETTING: Calgary, Alberta. PARTICIPANTS: Five hundred one male youth football players (ages 13-18 years) participating in the 2021 season. ASSESSMENT OF RISK FACTORS: SCAT5 subcomponents were assessed by age group (13-14, 15-16, 17-18), concussion history (0, 1, 2+, and yes/no), and self-reported diagnoses (headache disorder, attention-deficit/hyperactive disorder, learning disability/dyslexia, and depression, anxiety, or other psychiatric disorder). MAIN OUTCOME MEASURES: Virtual video administration (vs traditional in-person testing) of the SCAT5 was completed, and subcomponent scores included total number of symptoms (/22), symptom-severity score (/132), Standardized Assessment of Concussion [orientation (/5), immediate memory (/30), concentration (/5), delayed recall (/10)], and modified Balance Error Scoring System (/30). Kruskal-Wallis, one-way analysis of variance , Mann-Whitney U , or independent t tests were used to assess possible associations depending on number of groups and data normality. RESULTS: Virtual SCAT5 assessment scores across all outcomes did not differ by age group or concussion history. The median number of symptoms and median symptom-severity score at baseline was 2, and 173 players (34.5%) reported no symptoms. Median total number of errors on the modified Balance Error Scoring System was 3. Participants with certain self-reported diagnoses (attention-deficit/hyperactive disorder, dyslexia) demonstrated poorer performance on some SCAT5 subcomponents (symptom reporting, Standardized Assessment of Concussion). CONCLUSIONS: Baseline SCAT5 performance did not differ by age group or concussion history in male youth football players. Diagnoses of the self-reported disorders examined may be important considerations for interpretation of the SCAT5 assessment.

Long-term heart transplant recipients: heart rate-related effects on augmented transfer function coherence during repeated squat-stand maneuvers in males.

Previous research has highlighted that squat-stand maneuvers (SSMs) augment coherence values within the cerebral pressure-flow relationship to ∼0.99. However, it is not fully elucidated if mean arterial pressure (MAP) leads to this physiological entrainment independently, or if heart rate (HR) and/or the partial pressure of carbon dioxide (Pco2) also have contributing influences. A 2:1 control-to-case model was used in the present investigation [participant number (n) = 40; n = 16 age-matched (AM); n = 16 donor control (DM); n = 8 heart transplant recipients (HTRs)]. The latter group was used to mechanistically isolate the extent to which HR influences the cerebral pressure-flow relationship. Participants completed 5 min of squat-stand maneuvers at 0.05 Hz (10 s) and 0.10 Hz (5 s). Linear transfer function analysis (TFA) examined the relationship between different physiological inputs (i.e., MAP, HR, and Pco2) and output [cerebral blood velocity (CBV)] during SSM; and cardiac baroreceptor sensitivity (BRS). Compared with DM, cardiac BRS was reduced in AM (P < 0.001), which was further reduced in HTR (P < 0.045). In addition, during the SSM, HR was elevated in HTR compared with both control groups (P < 0.001), but all groups had near-maximal coherence metrics ≥0.98 at 0.05 Hz and ≥0.99 at 0.10 Hz (P ≥ 0.399). In contrast, the mean HR-CBV/Pco2-CBV relationships ranged from 0.38 (HTR) to 0.81 (DM). Despite near abolishment of BRS and blunted HR following heart transplantation, long-term HTR exhibited near-maximal coherence within the MAP-CBV relationship, comparable with AM and DM. Therefore, these results show that the augmented coherence with SSM is driven by blood pressure, whereas elevations in TFA coherence as a result of HR contribution are likely correlational in nature.