Bifactor Model of the Sport Concussion Assessment Tool Symptom Checklist: Replication and Invariance Across Time in the CARE Consortium Sample

Background: Identifying separate dimensions of concussion symptoms may inform a precision medicine approach to treatment. It was previously reported that a bifactor model identified distinct acute postconcussion symptom dimensions. Purpose: To replicate previous findings of a bifactor structure of concussion symptoms in the Concussion Assessment Research and Education (CARE) Consortium sample, examine measurement invariance from pre- to postinjury, and evaluate whether factors are associated with other clinical and biomarker measures. Study design: Cohort study (Diagnosis); Level of evidence, 2. Methods: Collegiate athletes were prospectively evaluated using the Sport Concussion Assessment Tool-3 (SCAT-3) during preseason (N = 31,557); 2789 were followed at <6 hours and 24 to 48 hours after concussion. Item-level SCAT-3 ratings were analyzed using exploratory and confirmatory factor analyses. Bifactor and higher-order models were compared for their fit and interpretability. Measurement invariance tested the stability of the identified factor structure across time. The association between factors and criterion measures (clinical and blood-based markers of concussion severity, symptom duration) was evaluated. Results: The optimal structure for each time point was a 7-factor bifactor model: a General factor, on which all items loaded, and 6 specific factors-Vestibulo-ocular, Headache, Sensory, Fatigue, Cognitive, and Emotional. The model manifested strict invariance across the 2 postinjury time points but only configural invariance from baseline to postinjury. From <6 to 24-48 hours, some dimensions increased in severity (Sensory, Fatigue, Emotional), while others decreased (General, Headache, Vestibulo-ocular). The factors correlated with differing clinical and biomarker criterion measures and showed differing patterns of association with symptom duration at different time points. Conclusion: Bifactor modeling supported the predominant unidimensionality of concussion symptoms while revealing multidimensional properties, including a large dominant General factor and 6 independent factors: Headache, Vestibulo-ocular, Sensory, Cognitive, Fatigue, and Emotional. Unlike the widely used SCAT-3 symptom severity score, which declines gradually after injury, the bifactor model revealed separable symptom dimensions that have distinct trajectories in the acute postinjury period and different patterns of association with other markers of injury severity and outcome. Clinical relevance: The SCAT-3 total score remains a valuable, robust index of overall concussion symptom severity, and the specific factors identified may inform management strategies. Because some symptom dimensions continue to worsen in the first 24 to 48 hours after injury (ie, Sensory, Fatigue, Emotional), routine follow-up in this time frame may be valuable to ensure that symptoms are managed effectively

Using Serum Amino Acids to Predict Traumatic Brain Injury: A Systematic Approach to Utilize Multiple Biomarkers

Traumatic brain injury (TBI) can cause biochemical and metabolomic alterations in the brain tissue and serum. These alterations can be used for diagnosis and prognosis of TBI. Here, the serum concentrations of seventeen amino acids (AA) were studied for their potential utility as biomarkers of TBI. Twenty-five female, 4-week-old piglets received diffuse (n = 13) or focal (n = 12) TBI. Blood samples were obtained both pre-injury and at either 24-h or 4-days post-TBI. To find a robust panel of biomarkers, the results of focal and diffuse TBIs were combined and multivariate logistic regression analysis, coupled with the best subset selection technique and repeated k-fold cross-validation method, was used to perform a thorough search of all possible subsets of AAs. The combination of serum glycine, taurine, and ornithine was optimal for TBI diagnosis, with 80% sensitivity and 86% overall prediction rate, and showed excellent TBI diagnostic performance, with 100% sensitivity and 78% overall prediction rate, on a separate validation dataset including four uninjured and five injured animals. We found that combinations of biomarkers outperformed any single biomarker. We propose this 3-AA serum biomarker panel to diagnose mild-to-moderate focal/diffuse TBI. The systematic approaches implemented herein can be used for combining parameters from various TBI assessments to develop/evaluate optimal multi-factorial diagnostic/prognostic TBI metrics

Pupillary Light Response Deficits in 4-Week-Old Piglets and Adolescent Children after Low-Velocity Head Rotations and Sports-Related Concussions

Neurological disorders and traumatic brain injury (TBI) are among the leading causes of death and disability. The pupillary light reflex (PLR) is an emerging diagnostic tool for concussion in humans. We compared PLR obtained with a commercially available pupillometer in the 4 week old piglet model of the adolescent brain subject to rapid nonimpact head rotation (RNR), and in human adolescents with and without sports-related concussion (SRC). The 95% PLR reference ranges (RR, for maximum and minimum pupil diameter, latency, and average and peak constriction velocities) were established in healthy piglets (N = 13), and response reliability was validated in nine additional healthy piglets. PLR assessments were obtained in female piglets allocated to anesthetized sham (N = 10), single (sRNR, N = 13), and repeated (rRNR, N = 14) sagittal low-velocity RNR at pre-injury, as well as days 1, 4, and 7 post injury, and evaluated against RRs. In parallel, we established human PLR RRs in healthy adolescents (both sexes, N = 167) and compared healthy PLR to values obtained <28 days from a SRC (N = 177). In piglets, maximum and minimum diameter deficits were greater in rRNR than sRNR. Alterations peaked on day 1 post sRNR and rRNR, and remained altered at day 4 and 7. In SRC adolescents, the proportion of adolescents within the RR was significantly lower for maximum pupil diameter only (85.8%). We show that PLR deficits may persist in humans and piglets after low-velocity head rotations. Differences in timing of assessment after injury, developmental response to injury, and the number and magnitude of impacts may contribute to the differences observed between species. We conclude that PLR is a feasible, quantifiable involuntary physiological metric of neurological dysfunction in pigs, as well as humans. Healthy PLR porcine and human reference ranges established can be used for neurofunctional assessments after TBI or hypoxic exposures (e.g., stroke, apnea, or cardiac arrest)

Associations of Sex and Sport Contact-Level with Recovery Timelines Among Collegiate Athletes with Sport-Related Concussion

Abstract Background Growing interest has motivated recent studies to examine differences in recovery after sport-related concussion (SRC) by sex. However, heterogeneity in study design, participants, and recovery outcomes has led to mixed findings. Further work is needed to evaluate potential differences by sex and to investigate the role of related characteristics, such as sport contact-level, in recovery timelines. This study aimed to investigate whether concussion recovery trajectories differ by sex, considering a priori clinical and demographic covariates, and accounting for the sequence of recovery outcomes. Our secondary question was whether sport contact-level modifies the relationship between sex and time to outcomes. Using data from the Ivy League–Big Ten Epidemiology of Concussion Study, we included SRCs reported across five academic years; 2015–2020 (February 2020). We used Cox proportional hazards regressions to estimate associations between sex and time from injury to three outcomes: (1) symptom resolution, (2) return to academics, (3) return to full play, accounting for measured confounders. Results Among 1160 SRCs (male, n = 667; female, n = 493) with complete data, median age overall was 20 years (25th-75th percentiles:19–21), and most occurred among athletes playing high-contact sports (78.0%). Males were slightly more likely to complete symptom resolution over time compared to females (HR = 1.18, 95%CI = 1.05–1.33), but results were attenuated in fully adjusted models (HR 1.13, 95%CI = 0.99–1.29). Similarly, the HR of full academic return for males compared to females was 1.22 (95%CI = 1.07–1.38), but was attenuated in fully adjusted models (HR = 1.11, 95%CI = 0.97–1.28). The HR of full return to play for males compared to females was 1.14 (95%CI = 1.02–1.28), and was attenuated after adjustment (HR = 1.06, 95%CI = 0.93–1.20) as well. The interaction between sex and playing a high/low-contact sport was not statistically significant across models, though differences were apparent. Conclusions Among a cohort of collegiate athletes with SRC, recovery timelines appeared similar between male and female athletes, adjusting for measured confounders. Differences by sex, considering sport contact-level, were evident and may be important clinically and in future studies. This study used robust methods, accounting for nesting in the sequence of RTP outcomes. Results inform concussion management protocols and planned qualitative work to further elucidate how collegiate athletes experience concussion recovery. Key Points Heterogeneity in study design, participants, and recovery outcomes has led to mixed findings in determining differences in recovery trajectories after concussion by sex. We found that having longer time to symptom resolution, and also the sequence of having academic return before symptoms resolve and longer time to academic return were confounders in the relationship between sex and RTP timelines. Time to sequential recovery outcomes appeared similar between male and female athletes, adjusting for observable confounders. Further differences by sex were evident when considering contact-level, and may be important to consider clinically and in future research. Results indicate that differences in concussion recovery trajectories by sex may be largely attributed to and driven by differences in sports with a men’s or women’s team only, such as football, and this should be explored further