Optimizing Concussion Care Seeking: Using Machine Learning to Predict Delayed Concussion Reporting.

BACKGROUND: Early medical attention after concussion may minimize symptom duration and burden; however, many concussions are undiagnosed or have a delay in diagnosis after injury. Many concussion symptoms (eg, headache, dizziness) are not visible, meaning that early identification is often contingent on individuals reporting their injury to medical staff. A fundamental understanding of the types and levels of factors that explain when concussions are reported can help identify promising directions for intervention. PURPOSE: To identify individual and institutional factors that predict immediate (vs delayed) injury reporting. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: This study was a secondary analysis of data from the Concussion Assessment, Research and Education (CARE) Consortium study. The sample included 3213 collegiate athletes and military service academy cadets who were diagnosed with a concussion during the study period. Participants were from 27 civilian institutions and 3 military institutions in the United States. Machine learning techniques were used to build models predicting who would report an injury immediately after a concussive event (measured by an athletic trainer denoting the injury as being reported "immediately" or "at a delay"), including both individual athlete/cadet and institutional characteristics. RESULTS: In the sample as a whole, combining individual factors enabled prediction of reporting immediacy, with mean accuracies between 55.8% and 62.6%, depending on classifier type and sample subset; adding institutional factors improved reporting prediction accuracies by 1 to 6 percentage points. At the individual level, injury-related altered mental status and loss of consciousness were most predictive of immediate reporting, which may be the result of observable signs leading to the injury report being externally mediated. At the institutional level, important attributes included athletic department annual revenue and ratio of athletes to athletic trainers. CONCLUSION: Further study is needed on the pathways through which institutional decisions about resource allocation, including decisions about sports medicine staffing, may contribute to reporting immediacy. More broadly, the relatively low accuracy of the machine learning models tested suggests the importance of continued expansion in how reporting is understood and facilitated.

Diffusion tensor analysis of white matter tracts is prognostic of persisting post-concussion symptoms in collegiate athletes.

BACKGROUND AND OBJECTIVES: After a concussion diagnosis, the most important issue for patients and loved ones is how long it will take them to recover. The main objective of this study is to develop a prognostic model of concussion recovery. This model would benefit many patients worldwide, allowing for early treatment intervention. METHODS: The Concussion Assessment, Research and Education (CARE) consortium study enrolled collegiate athletes from 30 sites (NCAA athletic departments and US Department of Defense service academies), 4 of which participated in the Advanced Research Core, which included diffusion-weighted MRI (dMRI) data collection. We analyzed the dMRI data of 51 injuries of concussed athletes scanned within 48 h of injury. All athletes were cleared to return-to-play by the local medical staff following a standardized, graduated protocol. The primary outcome measure is days to clearance of unrestricted return-to-play. Injuries were divided into early (return-to-play < 28 days) and late (return-to-play >= 28 days) recovery based on the return-to-play clinical records. The late recovery group meets the standard definition of Persisting Post-Concussion Symptoms (PPCS). Data were processed using automated, state-of-the-art, rigorous methods for reproducible data processing using brainlife.io. All processed data derivatives are made available at https://brainlife.io/project/63b2ecb0daffe2c2407ee3c5/dataset. The microstructural properties of 47 major white matter tracts, 5 callosal, 15 subcortical, and 148 cortical structures were mapped. Fractional Anisotropy (FA) and Mean Diffusivity (MD) were estimated for each tract and structure. Correlation analysis and Receiver Operator Characteristic (ROC) analysis were then performed to assess the association between the microstructural properties and return-to-play. Finally, a Logistic Regression binary classifier (LR-BC) was used to classify the injuries between the two recovery groups. RESULTS: The mean FA across all white matter volume was negatively correlated with return-to-play (r = -0.38, p = 0.00001). No significant association between mean MD and return-to-play was found, neither for FA nor MD for any other structure. The mean FA of 47 white matter tracts was negatively correlated with return-to-play (rµ = -0.27; rσ = 0.08; rmin = -0.1; rmax = -0.43). Across all tracts, a large mean ROC Area Under the Curve (AUCFA) of 0.71 ± 0.09 SD was found. The top classification performance of the LR-BC was AUC = 0.90 obtained using the 16 statistically significant white matter tracts. DISCUSSION: Utilizing a free, open-source, and automated cloud-based neuroimaging pipeline and app (https://brainlife.io/docs/tutorial/using-clairvoy/), a prognostic model has been developed, which predicts athletes at risk for slow recovery (PPCS) with an AUC=0.90, balanced accuracy = 0.89, sensitivity = 1.0, and specificity = 0.79. The small number of participants in this study (51 injuries) is a significant limitation and supports the need for future large concussion dMRI studies and focused on recovery.

Prior traumatic brain injury is a risk factor for in-hospital mortality in moderate to severe traumatic brain injury: a TRACK-TBI cohort study.

Objectives: An estimated 14-23% of patients with traumatic brain injury (TBI) incur multiple lifetime TBIs. The relationship between prior TBI and outcomes in patients with moderate to severe TBI (msTBI) is not well delineated. We examined the associations between prior TBI, in-hospital mortality, and outcomes up to 12 months after injury in a prospective US msTBI cohort. Methods: Data from hospitalized subjects with Glasgow Coma Scale score of 3-12 were extracted from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study (enrollment period: 2014-2019). Prior TBI with amnesia or alteration of consciousness was assessed using the Ohio State University TBI Identification Method. Competing risk regressions adjusting for age, sex, psychiatric history, cranial injury and extracranial injury severity examined the associations between prior TBI and in-hospital mortality, with hospital discharged alive as the competing risk. Adjusted HRs (aHR (95% CI)) were reported. Multivariable logistic regressions assessed the associations between prior TBI, mortality, and unfavorable outcome (Glasgow Outcome Scale-Extended score 1-3 (vs. 4-8)) at 3, 6, and 12 months after injury. Results: Of 405 acute msTBI subjects, 21.5% had prior TBI, which was associated with male sex (87.4% vs. 77.0%, p=0.037) and psychiatric history (34.5% vs. 20.7%, p=0.010). In-hospital mortality was 10.1% (prior TBI: 17.2%, no prior TBI: 8.2%, p=0.025). Competing risk regressions indicated that prior TBI was associated with likelihood of in-hospital mortality (aHR=2.06 (1.01-4.22)), but not with hospital discharged alive. Prior TBI was not associated with mortality or unfavorable outcomes at 3, 6, and 12 months. Conclusions: After acute msTBI, prior TBI history is independently associated with in-hospital mortality but not with mortality or unfavorable outcomes within 12 months after injury. This selective association underscores the importance of collecting standardized prior TBI history data early after acute hospitalization to inform risk stratification. Prospective validation studies are needed. Level of evidence: IV. Trial registration number: NCT02119182.

Research Letter: Relationship of Blood Biomarkers of Inflammation With Acute Concussion Symptoms and Recovery in the CARE Consortium.

OBJECTIVE: Determine the association of inflammatory biomarkers with clinical measures and recovery in participants with concussion. SETTING: Multicenter study in National Collegiate Athletic Association member institutions including military service academies. PARTICIPANTS: Four hundred twenty-two participants with acute concussion. DESIGN: Clinical visits and blood draws were completed preinjury and at multiple visits postconcussion (0-12 hours, 12-36 hours, and 36-60 hours postinjury). Clinical measures included Sport Concussion Assessment Tool (SCAT) symptom severity, Balance Error Scoring System, Standardized Assessment of Concussion (SAC), Brief Symptom Inventory-18 (BSI-18) scores, time to initiation of graduated return-to-play (RTP) protocol, and time to RTP. Interleukin (IL)-6, IL-10, IL-8, IL-1 receptor antagonist (RA), tumor necrosis factor (TNF), c-reactive protein, and vascular endothelial growth factor (VEGF) were measured in serum. Prespecified analyses focused on IL-6 and IL-1RA at 0 to 12 hours; exploratory analyses were conducted with false discovery rate correction. RESULTS: For prespecified analyses, IL-1RA at 0 to 12 hours in female participants was positively associated with more errors on the SAC (B(standard error, SE) = 0.58(0.27), P < .05) and worse SCAT symptom severity (B(SE) = 0.96(0.44), P < .05). For exploratory analyses, higher levels of IL-1RA at 12 to 36 hours were associated with higher global (B(SE) = 0.55(0.14), q < 0.01), depression (B(SE) = 0.45(0.10), q < 0.005), and somatization scores on the BSI (B(SE) = 0.46(0.12), q < 0.01) in participants with concussion; Higher TNF at 12 to 36 hours was associated with fewer errors on the SAC (B(SE) = - 0.46(0.14), q < 0.05). Subanalyses showed similar results for male participants and participants who were athletes. No associations were discovered in nonathlete cadets. Higher IL-8 at 0 to 12 hours was associated with slower RTP in female participants (OR = 14.47; 95% confidence interval, 2.96-70.66, q < 0.05); no other associations with recovery were observed. CONCLUSIONS: Peripheral inflammatory markers are associated with clinical symptoms following concussion and potentially represent one mechanism for psychological symptoms observed postinjury. Current results do not provide strong support for a potential prognostic role for these markers.

Latent Profiles of Acute Symptoms, Cognitive Performance, and Balance in Sport-Related Concussions.

BACKGROUND: A sport-related concussion (SRC) is a common injury that affects multiple clinical domains such as cognition, balance, and nonspecific neurobehavioral symptoms. Although multidimensional clinical assessments of concussion are widely accepted, there remain limited empirical data on the nature and clinical utility of distinct clinical profiles identified by multimodal assessments. PURPOSE: Our objectives were to (1) identify distinct clinical profiles discernible from acute postinjury scores on the Sport Concussion Assessment Tool (SCAT), composed of a symptom checklist, a cognitive assessment (Standardized Assessment of Concussion), and a balance assessment (Balance Error Scoring System), and (2) evaluate the clinical utility of the identified profiles by examining their association with injury characteristics, neuropsychological outcomes, and clinical management-related outcomes. STUDY DESIGN: Cohort study (Prognosis); Level of evidence, 2. METHODS: Up to 7 latent profiles were modeled for 1885 collegiate athletes and/or military cadets who completed the SCAT at 0 to 12 hours after an injury. Chi-square tests and general linear models were used to compare identified profiles on outcomes at 12 to 72 hours after the injury. Kaplan-Meier analysis was used to investigate associations between clinical profiles and time to return to being asymptomatic and to return to play. RESULTS: There were 5 latent profiles retained: low impairment (65.8%), high cognitive impairment (5.4%), high balance impairment (5.8%), high symptom severity (16.4%), and global impairment (6.5%). The latent profile predicted outcomes at 12 to 72 hours in expectable ways (eg, the high balance impairment profile demonstrated worse balance at 12 to 72 hours after the injury). Time to return to being asymptomatic and to return to play were different across profiles, with the high symptom severity and global impairment profiles experiencing the longest recovery and the high balance impairment profile experiencing an intermediate-length recovery (vs low impairment profile). CONCLUSION: An SRC is a heterogeneous injury that presents in varying ways clinically in the acute injury period and results in different recovery patterns. These data support the clinical prognostic value of diverse profiles of impairment across symptom, cognitive, and balance domains. By identifying distinct profiles of an SRC and connecting them to differing outcomes, the findings support more evidence-based use of accepted multimodal clinical assessment strategies for SRCs.

Longitudinal Characterization of Pain Interference and Influential Factors in Former National Football League (NFL) Players Over a 19-Year Period: An NFL-LONG Study.

Previous studies on pain experiences in retired contract sport athletes have been cross-sectional, leaving gaps in our understanding of the evolution of pain interference (PI) and factors that influence trajectories decades after sport discontinuation. This study investigated the longitudinal course of PI in former male National Football League (NFL) players over a 19-year period following sport discontinuation and examined factors influencing overall levels and trajectories of PI. Former NFL players completed health surveys in 2001, 2010, and 2019, with PI ratings measured using the 36-Item Short Form Health Survey (2001 and 2010) and the Patient-Reported Outcomes Measurement Information System (2019). Unconditional latent growth curve models analyzed overall PI severity and trajectories. Conditional latent growth curve models explored the influence of musculoskeletal injuries, osteoarthritis (OA), and depression diagnosis on PI. Over 19 years (N = 338; mean age = 48.96 ± 9.35), PI significantly increased (slope = .179, P < .001; mean Patient-Reported Outcomes Measurement Information System PI t-scores 2001 = 54.19, 2010 = 54.64, 2019 = 57.38). Cumulative musculoskeletal injuries (B = .092, P < .001) and baseline depression diagnosis (B = 4.463, P < .001) were associated with overall PI levels but not change over time. OA was significantly associated with overall PI levels (B = 6.536, P < .001) and trajectory (B = -.253, P < .001); those endorsing OA in 2001 had lower PI increases over 19 years. The body region of injury and level of play during injuries mirrored overall injury effects. PI mildly increased over 19 years, with multiple factors independently influencing overall PI levels. Enhancing former contact sport athletes' daily functionality may be achieved through holistic biopsychosocial interventions addressing musculoskeletal injuries, OA, and depression. Future research should identify factors influencing elevated trajectories of long-term PI post-sport discontinuation. PERSPECTIVE: This study assessed PI in former NFL athletes over 2 decades, revealing notable interindividual variability in trajectories over time. Musculoskeletal injuries, depression, and OA correlated with overall PI. Prevention and intervention in these 3 areas present the potential to improve disruptions in daily living due to pain in former athletes.

Symptom Exacerbation and Adverse Events during a Randomized Trial of Early-stage Concussion Rehabilitation.

CONTEXT: Few studies utilize randomized clinical trials (RCT) to quantify clinical intervention safety of rehabilitation after sport-related concussion across sport levels. OBJECTIVE: Describe symptom exacerbation and adverse events (AEs) associated with two concussion rehabilitation interventions. DESIGN: Cluster Randomized Controlled Trial (XXX). SETTING: Sports medicine clinic and field settings. PARTICIPANTS: The RCT enrolled 251 concussed athletes (median age=20 years; female n=48) across 28 sites from New Zealand professional rugby (n=31), Canadian professional football (n=52), United States (U.S.)/Canadian colleges (n=128) and U.S. high schools (n=40). INTERVENTIONS: Two medically supervised interventions: 1) Enhanced Graded Exertion (EGE): international return to sport strategy and sport specific activities only (EGE-only n=119) and 2) Multidimensional Rehabilitation (MDR) followed by EGE: early symptom-directed exercises once symptoms were stable, followed by EGE after symptoms resolved (MDR+EGE n=132). MAIN OUTCOME MEASURES: Primary outcomes were intrasession total symptom severity score exacerbation and significant intersession (increase 10+ severity points) sustained total symptom severity exacerbation, each measured with a Postconcussion Symptom Scale (132 total severity points on scale). Reported AEs were also described. Activity-based rehabilitation sessions (n=1437) were the primary analysis unit. Frequencies, proportions, medians, and Interquartile Ranges (IQRs) were calculated for outcomes by treatment group. RESULTS: The 251 post-injury participants completed 1437 (MDR+EGE=819, EGE-only=618) activity-based intervention sessions. A total of 110 and 105 participants contributed data (those missing had no documented session data) to at least 1 activity-based session in the MDR+EGE and EGE-only arms respectively. Intrasession symptom exacerbations were equivilantly low in MDR+EGE and EGE-only arms (MDR+EGE: 16.7%, 95% CI:14.1%,19.1%; EGE-only: 15.7%, 95% CI: 12.8%,18.6%). In total, 9/819 MDR+EGE sessions (0.9%) and 1/618 EGE-only sessions (0.2%) resulted in a pre- to post-session symptom exacerbation beyond a 10+ severity point increase; 8/9 resolved to <10 points by the next session. Two study-related AEs (1 in each arm) were reported. CONCLUSIONS: Participants in MDR+EGE and EGE-only activities reported equivalently low rates of symptom exacerbation.

Mechanisms of Injury Leading to Concussions in Collegiate Soccer Players: A CARE Consortium Study.

BACKGROUND: Few previous studies have investigated how different injury mechanisms leading to sport-related concussion (SRC) in soccer may affect outcomes. PURPOSE: To describe injury mechanisms and evaluate injury mechanisms as predictors of symptom severity, return to play (RTP) initiation, and unrestricted RTP (URTP) in a cohort of collegiate soccer players. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: The Concussion Assessment, Research and Education (CARE) Consortium database was used. The mechanism of injury was categorized into head-to-ball, head-to-head, head-to-body, and head-to-ground/equipment. Baseline/acute injury characteristics-including Sports Concussion Assessment Tool-3 total symptom severity (TSS), loss of consciousness (LOC), and altered mental status (AMS); descriptive data; and recovery (RTP and URTP)-were compared. Multivariable regression and Weibull models were used to assess the predictive value of the mechanism of injury on TSS and RTP/URTP, respectively. RESULTS: Among 391 soccer SRCs, 32.7% were attributed to a head-to-ball mechanism, 27.9% to a head-to-body mechanism, 21.7% to a head-to-head mechanism, and 17.6% to a head-to-ground/equipment mechanism. Event type was significantly associated with injury mechanism [χ2(3) = 63; P < .001), such that more head-to-ball concussions occurred in practice sessions (n = 92 [51.1%] vs n = 36 [17.1%]) and more head-to-head (n = 65 [30.8%] vs n = 20 [11.1]) and head-to-body (n = 76 [36%] vs n = 33 [18.3%]) concussions occurred in competition. The primary position was significantly associated with injury mechanism [χ2(3) = 24; P < .004], with goalkeepers having no SRCs from the head-to-head mechanism (n = 0 [0%]) and forward players having the least head-to-body mechanism (n = 15 [19.2%]). LOC was also associated with injury mechanism (P = .034), with LOC being most prevalent in head-to-ground/equipment. Finally, AMS was most prevalent in head-to-ball (n = 54 [34.2%]) and head-to-body (n = 48 [30.4%]) mechanisms [χ2(3) = 9; P = .029]. In our multivariable models, the mechanism was not a predictor of TSS or RTP; however, it was associated with URTP (P = .044), with head-to-equipment/ground injuries resulting in the shortest mean number of days (14 ± 9.1 days) to URTP and the head-to-ball mechanism the longest (18.6 ± 21.6 days). CONCLUSION: The mechanism of injury differed by event type and primary position, and LOC and AMS were different across mechanisms. Even though the mechanism of injury was not a significant predictor of acute symptom burden or time until RTP initiation, those with head-to-equipment/ground injuries spent the shortest time until URTP, and those with head-to-ball injuries had the longest time until URTP.

Isolated Traumatic Subarachnoid Hemorrhage on Head Computed Tomography Scan May Not Be Isolated: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study (TRACK-TBI) Study.

Isolated traumatic subarachnoid hemorrhage (tSAH) after traumatic brain injury (TBI) on head computed tomography (CT) scan is often regarded as a "mild" injury, with reduced need for additional workup. However, tSAH is also a predictor of incomplete recovery and unfavorable outcome. This study aimed to evaluate the characteristics of CT-occult intracranial injuries on brain magnetic resonance imaging (MRI) scan in TBI patients with emergency department (ED) arrival Glasgow Coma Scale (GCS) score 13-15 and isolated tSAH on CT. The prospective, 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study (TRACK-TBI; enrollment years 2014-2019) enrolled participants who presented to the ED and received a clinically-indicated head CT within 24 h of TBI. A subset of TRACK-TBI participants underwent venipuncture within 24 h for plasma glial fibrillary acidic protein (GFAP) analysis, and research MRI at 2-weeks post-injury. In the current study, TRACK-TBI participants age ≥17 years with ED arrival GCS 13-15, isolated tSAH on initial head CT, plasma GFAP level, and 2-week MRI data were analyzed. In 57 participants, median age was 46.0 years [quartile 1 to 3 (Q1-Q3): 34-57] and 52.6% were male. At ED disposition, 12.3% were discharged home, 61.4% were admitted to hospital ward, and 26.3% to intensive care unit. MRI identified CT-occult traumatic intracranial lesions in 45.6% (26 of 57 participants; one additional lesion type: 31.6%; 2 additional lesion types: 14.0%); of these 26 participants with CT-occult intracranial lesions, 65.4% had axonal injury, 42.3% had subdural hematoma, and 23.1% had intracerebral contusion. GFAP levels were higher in participants with CT-occult MRI lesions compared with without (median: 630.6 pg/mL, Q1-Q3: [172.4-941.2] vs. 226.4 [105.8-436.1], p = 0.049), and were associated with axonal injury (no: median 226.7 pg/mL [109.6-435.1], yes: 828.6 pg/mL [204.0-1194.3], p = 0.009). Our results indicate that isolated tSAH on head CT is often not the sole intracranial traumatic injury in GCS 13-15 TBI. Forty-six percent of patients in our cohort (26 of 57 participants) had additional CT-occult traumatic lesions on MRI. Plasma GFAP may be an important biomarker for the identification of additional CT-occult injuries, including axonal injury. These findings should be interpreted cautiously given our small sample size and await validation from larger studies.

Performance of the IMPACT and CRASH prognostic models for traumatic brain injury in a contemporary multicenter cohort: a TRACK-TBI study.

OBJECTIVE: The International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) and Corticosteroid Randomization After Significant Head Injury (CRASH) prognostic models for mortality and outcome after traumatic brain injury (TBI) were developed using data from 1984 to 2004. This study examined IMPACT and CRASH model performances in a contemporary cohort of US patients. METHODS: The prospective 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study (enrollment years 2014-2018) enrolled subjects aged ≥ 17 years who presented to level I trauma centers and received head CT within 24 hours of TBI. Data were extracted from the subjects who met the model criteria (for IMPACT, Glasgow Coma Scale [GCS] score 3-12 with 6-month Glasgow Outcome Scale-Extended [GOSE] data [n = 441]; for CRASH, GCS score 3-14 with 2-week mortality data and 6-month GOSE data [n = 831]). Analyses were conducted in the overall cohort and stratified on the basis of TBI severity (severe/moderate/mild TBI defined as GCS score 3-8/9-12/13-14), age (17-64 years or ≥ 65 years), and the 5 top enrolling sites. Unfavorable outcome was defined as GOSE score 1-4. Original IMPACT and CRASH model coefficients were applied, and model performances were assessed by calibration (intercept [< 0 indicated overprediction; > 0 indicated underprediction] and slope) and discrimination (c-statistic). RESULTS: Overall, the IMPACT models overpredicted mortality (intercept -0.79 [95% CI -1.05 to -0.53], slope 1.37 [1.05-1.69]) and acceptably predicted unfavorable outcome (intercept 0.07 [-0.14 to 0.29], slope 1.19 [0.96-1.42]), with good discrimination (c-statistics 0.84 and 0.83, respectively). The CRASH models overpredicted mortality (intercept -1.06 [-1.36 to -0.75], slope 0.96 [0.79-1.14]) and unfavorable outcome (intercept -0.60 [-0.78 to -0.41], slope 1.20 [1.03-1.37]), with good discrimination (c-statistics 0.92 and 0.88, respectively). IMPACT overpredicted mortality and acceptably predicted unfavorable outcome in the severe and moderate TBI subgroups, with good discrimination (c-statistic ≥ 0.81). CRASH overpredicted mortality in the severe and moderate TBI subgroups and acceptably predicted mortality in the mild TBI subgroup, with good discrimination (c-statistic ≥ 0.86); unfavorable outcome was overpredicted in the severe and mild TBI subgroups with adequate discrimination (c-statistic ≥ 0.78), whereas calibration was nonlinear in the moderate TBI subgroup. In subjects ≥ 65 years of age, the models performed variably (IMPACT-mortality, intercept 0.28, slope 0.68, and c-statistic 0.68; CRASH-unfavorable outcome, intercept -0.97, slope 1.32, and c-statistic 0.88; nonlinear calibration for IMPACT-unfavorable outcome and CRASH-mortality). Model performance differences were observed across the top enrolling sites for mortality and unfavorable outcome. CONCLUSIONS: The IMPACT and CRASH models adequately discriminated mortality and unfavorable outcome. Observed overestimations of mortality and unfavorable outcome underscore the need to update prognostic models to incorporate contemporary changes in TBI management and case-mix. Investigations to elucidate the relationships between increased survival, outcome, treatment intensity, and site-specific practices will be relevant to improve models in specific TBI subpopulations (e.g., older adults), which may benefit from the inclusion of blood-based biomarkers, neuroimaging features, and treatment data.

Factors Influencing Time to Return to Learn Among NCAA Student-Athletes Enrolled in the Concussion Assessment, Research, and Education (CARE) Study.

PURPOSE: The aim was to describe the demographic and post-injury factors that influence time to return to learn (RTL) among student-athletes enrolled in the Concussion Assessment, Research and Education (CARE) Consortium. METHODS: A total of 47,860 student-athletes enrolled in the National Collegiate Athletic Association-Department of Defense (NCAA-DoD) CARE Consortium study from 2014 to 2020, with 1485 sport-related concussions (SRCs) analyzed in the present dataset. Demographic and post-injury characteristics were calculated using descriptive statistics, followed by Kaplan-Meier estimates to examine median time to return to normal academic performance (i.e., RTL) by sex (male, female), baseline psychiatric conditions (depression, anxiety) and/or learning disorder, NCAA division (I, II, III), SRC history (0, 1, 2, 3+), NCAA sport category (contact, limited contact, non-contact sport), and median difference in baseline/post-injury symptom severity scores (< 21, ≥ 21). Further, a multivariable zero-inflated negative binomial (ZINB) regression model was used to examine their association with RTL. RESULTS: Overall, time to RTL (mean = 4.96 ± 8.24 days, median = 3.0 [interquartile range = 0.0, 6.0] days) was found to be influenced by several factors resulting in earlier trajectories. Notably, nearly 25% of the sample demonstrated immediate RTL (i.e., 0 days). Among student-athletes who did not immediately RTL, males demonstrated a decreased rate in RTL (rate = 0.79; 95% CI 0.66-0.96) compared to females. Further, student-athletes with a ≥ 21 change in symptom severity score (post-injury baseline) demonstrated a higher rate of RTL (rate = 1.47; 95% CI 1.21-1.79) compared to student-athletes with a symptom severity change score < 21. Lastly, male student-athletes demonstrated two times higher odds (odds ratio = 1.95; 95% CI 1.02-3.73) of immediate RTL compared to female student-athletes. No other covariates were associated with time to RTL. CONCLUSION: Collectively, the present findings suggest a rapid return to the classroom following concussion. Specifically, males demonstrated higher odds of time to RTL, whereas those with greater differences in symptom severity resulted in a higher rate of time to RTL among those who did not immediately RTL. Ultimately, these findings support prior work emphasizing an individualized approach to SRC management.

Use of the Buffalo Concussion Treadmill Test in community adult patients with mild traumatic brain injury.

BACKGROUND: The Buffalo Concussion Treadmill Test (BCTT) is used to establish exercise tolerance for rehabilitation and identify injury subtypes for youth athletes after mild traumatic brain injury (mTBI). Its utility in adult community members is unknown. OBJECTIVE: Primary: To describe how adults with and without mTBI tolerate the BCTT. Secondary: To explore relationships between baseline factors, mTBI-related symptoms, and BCTT duration. DESIGN: Prospective, observational, longitudinal. SETTING: Academic medical center. PARTICIPANTS: Thirty-seven adults treated in a level 1 trauma center emergency department with mTBI; 24 uninjured controls (UC). INTERVENTIONS: N/A. MAIN MEASURES: Participants completed two visits 3 weeks apart (1 week and 1 month after mTBI) including a 15-minute BCTT, the Rivermead Post Concussion Symptoms Questionnaire (RPQ), and preinjury International Physical Activity Questionnaire. Analyses characterized BCTT response and associations between baseline factors, RPQ scores, and BCTT duration. RESULTS: Persons with mTBI discontinued earlier than UC at 1-week postinjury using standard discontinuation criteria for exercise intolerance. The percentage of mTBI participants with signs of possible mTBI-related intolerance was 55.6% at 1 week (36.1% for mTBI-related symptom exacerbation, 19.4% for exertion/fatigue before reaching 85% of one's age-predicted maximum heart rate [HR]) and 48.0% at 1 month (40.0% mTBI-related symptom exacerbation, 8.0% exertion without reaching the target HR). Thirty percent of UCs completed the BCTT at both assessments. UCs met discontinuation criteria for increased nonspecific symptoms (eg, pain/general discomfort and increased Visual Analog Scale ratings; 39-61%) and physical exertion (9-26%). Shorter duration was associated with higher body mass index (r = -0.42 - -0.45), shorter height (r = 0.22-0.29), female gender (r = -0.26 - -0.27), and greater RPQ symptoms (r = -0.28 - -0.47). CONCLUSION: The BCTT exacerbates mTBI-related symptoms in adult community members. Participant characteristics and noninjury factors influence performance. The findings imply the BCTT could be useful in clinical assessments of adults with mTBI. Interpretation should account for the unique characteristics of nonathletes.

Optimizing Concussion Care Seeking: Connecting Care-Seeking Behaviors and Neurophysiological States Through Blood Biomarkers.

BACKGROUND: Timely and appropriate medical care after concussion presents a difficult public health problem. Concussion identification and treatment rely heavily on self-report, but more than half of concussions go unreported or are reported after a delay. If incomplete self-report increases exposure to harm, blood biomarkers may objectively indicate this neurobiological dysfunction. PURPOSE/HYPOTHESIS: The purpose of this study was to compare postconcussion biomarker levels between individuals with different previous concussion diagnosis statuses and care-seeking statuses. It was hypothesized that individuals with undiagnosed concussions and poorer care seeking would show altered biomarker profiles. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Blood samples were collected from 287 military academy cadets and collegiate athletes diagnosed with concussion in the Advanced Research Core of the Concussion Assessment, Research and Education Consortium. The authors extracted each participant's self-reported previous concussion diagnosis status (no history, all diagnosed, ≥1 undiagnosed) and whether they had delayed or immediate symptom onset, symptom reporting, and removal from activity after the incident concussion. The authors compared the following blood biomarkers associated with neural injury between previous concussion diagnosis status groups and care-seeking groups: glial fibrillary acidic protein, ubiquitin c-terminal hydrolase-L1 (UCH-L1), neurofilament light chain (NF-L), and tau protein, captured at baseline, 24 to 48 hours, asymptomatic, and 7 days after unrestricted return to activity using tests of parallel profiles. RESULTS: The undiagnosed previous concussion group (n = 21) had higher levels of NF-L at 24- to 48-hour and asymptomatic time points relative to all diagnosed (n = 72) or no previous concussion (n = 194) groups. For those with delayed removal from activity (n = 127), UCH-L1 was lower at 7 days after return to activity than that for athletes immediately removed from activity (n = 131). No other biomarker differences were observed. CONCLUSION: Individuals with previous undiagnosed concussions or delayed removal from activity showed some different biomarker levels after concussion and after clinical recovery, despite a lack of baseline differences. This may indicate that poorer care seeking can create neurobiological differences in the concussed brain.

Profile of brief symptom inventory-18 (BSI-18) scores in collegiate athletes: A CARE Consortium study.

Objective: The goal of this study was to characterize normative scores for the Brief Symptom Inventory (BSI-18) in collegiate athletes to inform decision making about the need for psychological health services in this group. Methods: Collegiate student-athletes (N = 20,034) from 25 universities completed the BSI-18 at their preseason baseline assessment. A subgroup (n = 5,387) underwent multiple baseline assessments. Global Severity Index (GSI) scores were compared to community norms and across multiple timepoints. Results: Collegiate athletes reported significantly lower GSI scores than published community norms (p<.001). Published GSI threshold scores for "caseness", identified only 2 per 100 athletes (≥ the 98th percentile) as needing further evaluation. Using a GSI score ≥ than the cohort's 90th percentile, 11.4 per 100 athletes would merit additional evaluation. These individuals were more likely to report a history of psychiatric diagnosis (Odds ratio [95% CI] 2.745 [2.480, 3.039]), as well as ≥ 2 prior concussions (p<.001). GSI scores were not highly correlated across timepoints. Suicidal ideation was rare (n = 230; 1.15%). Conclusions: For collegiate student-athletes, published BSI-18 threshold scores identify only extreme outliers who might benefit from additional behavioral health evaluation. Alternatively, use of threshold scores ≥ the 90th percentile identifies a more realistic 11.4% of the population, with higher likelihood of prior concussion and/or psychiatric disorders.

Utility of Structured Oculomotor, Balance, and Exercise Testing in Civilian Adults With Mild Traumatic Brain Injury.

PURPOSE: Assessments of oculomotor, balance, and exercise function detect different responses to mild traumatic brain injury in sports-related mild traumatic brain injury. These assessments are understudied in the adult community mild traumatic brain injury population. We evaluated level 1 trauma center patients with nonsports-related mild traumatic brain injury on oculomotor functioning (near point of convergence and accommodation), balance (Balance Error Scoring System), and exercise tolerance (Buffalo Concussion Treadmill Test). METHODS: A prospective, cohort study of adults with mild traumatic brain injury ( n = 36) were assessed at 1 wk and 1-mo post-mild traumatic brain injury ( n = 26) using near point of convergence, near point of accommodation, Balance Error Scoring System, Buffalo Concussion Treadmill Test, and the Rivermead Post Concussion Symptoms Questionnaire. Prevalence of test impairment and association between performance and mild traumatic brain injury-related symptom burden (Rivermead Post Concussion Symptoms Questionnaire scores) were characterized. RESULTS: Participants demonstrated varying levels of impairment (e.g., 33.3% oculomotor, 44.1% balance, and 55.6% exercise impairment at 1 wk). Participants displayed diverse impairment profiles across assessments. We observed medium-to-large correlations between poorer near point of convergence and Buffalo Concussion Treadmill Test performance and greater mild traumatic brain injury symptom burden. CONCLUSIONS: Clinical examinations of oculomotor function, balance, and exercise adopted from sports-related concussion assessments detect impairment in adult community members with mild traumatic brain injury. While findings warrant larger-scale replication, they imply that incorporating these simple, structured examinations into the assessment of mild traumatic brain injury may facilitate more personalized management strategies.

Association of Blood Biomarkers of Inflammation With Acute Concussion in Collegiate Athletes and Military Service Academy Cadets.

BACKGROUND AND OBJECTIVES: The objective was to characterize the acute effects of concussion (a subset of mild traumatic brain injury) on serum interleukin (IL)-6 and IL-1 receptor antagonist (RA) and 5 additional inflammatory markers in athletes and military service academy members from the Concussion Assessment, Research, and Education Consortium and to determine whether these markers aid in discrimination of concussed participants from controls. METHODS: Athletes and cadets with concussion and matched controls provided blood at baseline and postinjury visits between January 2015 and March 2020. Linear models investigated changes in inflammatory markers measured using Meso Scale Discovery assays across time points (baseline and 0-12, 12-36, 36-60 hours). Subanalyses were conducted in participants split by sex and injury population. Logistic regression analyses tested whether acute levels of IL-6 and IL-1RA improved discrimination of concussed participants relative to brain injury markers (glial fibrillary acidic protein, tau, neurofilament light, ubiquitin c-terminal hydrolase-L1) or clinical data (Sport Concussion Assessment Tool-Third Edition, Standardized Assessment of Concussion, Balance Error Scoring System). RESULTS: Participants with concussion (total, N = 422) had elevated IL-6 and IL-1RA at 0-12 hours vs controls (n = 345; IL-6: mean difference [MD] (standard error) = 0.701 (0.091), p < 0.0001; IL-1RA: MD = 0.283 (0.042), p < 0.0001) and relative to baseline (IL-6: MD = 0.656 (0.078), p < 0.0001; IL-1RA: MD = 0.242 (0.038), p < 0.0001), 12-36 hours (IL-6: MD = 0.609 (0.086), p < 0.0001; IL-1RA: MD = 0.322 (0.041), p < 0.0001), and 36-60 hours (IL-6: MD = 0.818 (0.084), p < 0.0001; IL-1RA: MD = 0.317 (0.040), p < 0.0001). IL-6 and IL-1RA were elevated in participants with sport (IL-6: MD = 0.748 (0.115), p < 0.0001; IL-1RA: MD = 0.304 (0.055), p < 0.0001) and combative-related concussions (IL-6: MD = 0.583 (0.178), p = 0.001; IL-1RA: MD = 0.312 (0.081), p = 0.0001). IL-6 was elevated in male (MD = 0.734 (0.105), p < 0.0001) and female participants (MD = 0.600 (0.177), p = 0.0008); IL-1RA was only elevated in male participants (MD = 0.356 (0.047), p < 0.0001). Logistic regression showed the inclusion of IL-6 and IL-1RA at 0-12 hours improved the discrimination of participants with concussion from controls relative to brain injury markers (χ2(2) = 17.855, p = 0.0001; area under the receiver operating characteristic curve [AUC] 0.73 [0.66-0.80] to 0.78 [0.71-0.84]), objective clinical measures (balance and cognition; χ2(2) = 40.661, p < 0.0001; AUC 0.81 [0.76-0.86] to 0.87 [0.83-0.91]), and objective and subjective measures combined (χ2(2) = 13.456, p = 0.001; AUC 0.97 [0.95-0.99] to 0.98 [0.96-0.99]), although improvement in AUC was only significantly relative to objective clinical measures. DISCUSSION: IL-6 and IL-1RA (male participants only) are elevated in the early-acute window postconcussion and may aid in diagnostic decisions beyond traditional blood markers and common clinical measures. IL-1RA results highlight sex differences in the immune response to concussion which should be considered in future biomarker work.

The Longitudinal Relationship Between Concussion History, Years of American Football Participation, and Alcohol Use Among Former National Football League Players: an NFL-LONG Study.

OBJECTIVE: Investigate the relationships between concussion history and years of football participation (repetitive head impact proxy) with alcohol use across multiple decades in former professional football players. METHODS: Participants (n = 348; mean age = 49.0 ± 9.4) completed health questionnaires in 2001 and 2019, which included self-reported concussion history and years of participation. Alcohol use frequency and amount per occasion were reported for three timepoints: during professional career, 2001, and 2019. Ordinal logistic regression models were fit to test associations of concussion history and years of participation with alcohol use at each timepoint. RESULTS: There were no significant associations between either concussion history or years of football participation with alcohol use (frequency and amount per occasion) at any timepoint. Effect estimates for concussion history and years of football participation with alcohol use were generally comparable across timepoints. CONCLUSIONS: Later life alcohol use by former American football players is not associated with concussion history or years of exposure to football.

Concussion Risk and Recovery in Athletes With Psychostimulant-Treated Attention-Deficit/Hyperactivity Disorder: Findings From the NCAA-DOD CARE Consortium.

The aim of the present study was to examine the effects of attention-deficit/hyperactivity disorder (ADHD) -related psychostimulant use in the context of concussion risk and symptom recovery. Data were obtained from the National Collegiate Athletic Association Department of Defense Grand Alliance Concussion Assessment, Research, and Education (NCAA-DOD CARE) Consortium from 2014 to 2017. Relative to individuals without diagnosed ADHD (i.e., control), both ADHD diagnosis and the combination of ADHD diagnosis and psychostimulant use were associated with a greater risk of incurring a concussive injury. Following a concussive injury, ADHD diagnosis was associated with longer symptom recovery time relative to the control group. However, individuals with ADHD who use psychostimulants did not take longer to resolve symptoms than controls, suggesting that psychostimulants may have a positive influence on recovery. Regardless of time point, ADHD diagnosis was associated with an elevated number of concussion-related symptoms; however, this effect appears mitigated by having used ADHD-related psychostimulants.

Profiles of Cognitive Functioning at 6 Months After Traumatic Brain Injury Among Patients in Level I Trauma Centers: A TRACK-TBI Study.

Importance: Cognitive dysfunction is common after traumatic brain injury (TBI), with a well-established dose-response relationship between TBI severity and likelihood or magnitude of persistent cognitive impairment. However, patterns of cognitive dysfunction in the long-term (eg, 6-month) recovery period are less well known. Objective: To characterize the prevalence of cognitive dysfunction within and across cognitive domains (processing speed, memory, and executive functioning) 6 months after injury in patients with TBI seen at level I trauma centers. Design, Setting, and Participants: This prospective longitudinal cohort study used data from Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) and included patients aged 17 years or older presenting at 18 US level I trauma center emergency departments or inpatient units within 24 hours of head injury, control individuals with orthopedic injury recruited from the same centers, and uninjured friend and family controls. Participants were enrolled between March 2, 2014, and July 27, 2018. Data were analyzed from March 5, 2020, through October 3, 2023. Exposures: Traumatic brain injury (Glasgow Coma Scale score of 3-15) or orthopedic injury. Main Outcomes and Measures: Performance on standard neuropsychological tests, including premorbid cognitive ability (National Institutes of Health Toolbox Picture Vocabulary Test), verbal memory (Rey Auditory Verbal Learning Test), processing speed (Wechsler Adult Intelligence Scale [4th edition] Processing Speed Index), and executive functioning (Trail Making Test). Results: The sample included 1057 persons with TBI (mean [SD] age, 39.3 [16.4] years; 705 [67%] male) and 327 controls without TBI (mean [SD] age, 38.4 [15.1] years; 222 [68%] male). Most persons with TBI demonstrated performance within 1.5 SDs or better of the control group (49.3% [95% CI, 39.5%-59.2%] to 67.5% [95% CI, 63.7%-71.2%] showed no evidence of impairment). Similarly, 64.4% (95% CI, 54.5%-73.4%) to 78.8% (95% CI, 75.4%-81.9%) of participants demonstrated no evidence of cognitive decline (defined as performance within 1.5 SDs of estimated premorbid ability). For individuals with evidence of either cognitive impairment or decline, diverse profiles of impairment across memory, speed, and executive functioning domains were observed (ie, the prevalence was >0 in each of the 7 combinations of impairment across these 3 cognitive domains for most TBI subgroups). Conclusions and Relevance: In this cohort study of patients seen at level I trauma centers 6 months after TBI, many patients with TBI demonstrated no cognitive impairment. Impairment was more prevalent in persons with more severe TBI and manifested in variable ways across individuals. The findings may guide future research and treatment recommendations.

Network analysis and relationship of symptom factors to functional outcomes and quality of life following mild traumatic brain injury: a TRACK-TBI study.

Introduction: Mild traumatic brain injury (mTBI) is a heterogenous injury which can be difficult to characterize and manage. Using cross-sectional network analysis (NA) to conceptualize mTBI symptoms offers an innovative solution to identify how mTBI symptoms relate to each other. The centrality hypothesis of network theory posits that certain symptoms in a network are more relevant (central) or have above average influence over the rest of the network. However, no studies have used NA to characterize the interrelationships between symptoms in a cohort of patients who presented with mTBI to a U.S. Level 1 trauma center emergency department and how subacute central symptoms relate to long-term outcomes. Methods: Patients with mTBI (Glasgow Coma Scale = 13-15) evaluated across 18 U.S. Level 1 trauma centers from 2013 to 2019 completed the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) at 2 weeks (W2) post-injury (n = 1,593) and at 3 months (M3), 6 months (M6), and 12 months (M12) post-injury. Network maps were developed from RPQ subscale scores at each timepoint. RPQ scores at W2 were associated with M6 and M12 functional and quality of life outcomes. Results: Network structure did not differ across timepoints, indicating no difference in symptoms/factors influence on the overall symptom network across time. The cognitive factor had the highest expected influence at W2 (1.761), M3 (1.245), and M6 (1.349). Fatigue had the highest expected influence at M12 (1.275). The emotional factor was the only other node with expected influence >1 at any timepoint, indicating disproportionate influence of emotional symptoms on overall symptom burden (M3 = 1.011; M6 = 1.076). Discussion: Several symptom factors at 2-weeks post-injury were more strongly associated with incomplete recovery and/or poorer injury-related quality of life at 6 and 12 months post-injury than previously validated demographic and clinical covariates. The network analysis suggests that emotional, cognitive, and fatigue symptoms may be useful treatment targets in this population due to high centrality and activating potential of the overall symptom network.