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BACKGROUND: Molecular-based approaches to understanding concussion pathophysiology provide complex biological information that can advance concussion research and identify potential diagnostic and/or prognostic biomarkers of injury. OBJECTIVE: The aim of this study was to identify gene expression changes in peripheral blood that are initiated following concussion and are relevant to concussion response and recovery. METHODS: We analyzed whole blood transcriptomes in a large cohort of concussed and control collegiate athletes who were participating in the multicenter prospective cohort Concussion Assessment, Research, and Education (CARE) Consortium study. Blood samples were collected from collegiate athletes at preseason (baseline), within 6 h of concussion injury, and at four additional prescribed time points spanning 24 h to 6 months post-injury. RNA sequencing was performed on samples from 230 concussed, 130 contact control, and 102 non-contact control athletes. Differential gene expression and deconvolution analysis were performed at each time point relative to baseline. RESULTS: Cytokine and immune response signaling pathways were activated immediately after concussion, but at later time points these pathways appeared to be suppressed relative to the contact control group. We also found that the proportion of neutrophils increased and natural killer cells decreased in the blood following concussion. CONCLUSIONS: Transcriptome signatures in the blood reflect the known pathophysiology of concussion and may be useful for defining the immediate biological response and the time course for recovery. In addition, the identified immune response pathways and changes in immune cell type proportions following a concussion may inform future treatment strategies.

BACKGROUND AND OBJECTIVES: To study longitudinal associations between blood-based neural biomarkers (including total tau, neurofilament light [NfL], glial fibrillary acidic protein [GFAP], and ubiquitin C-terminal hydrolase-L1) and white matter neuroimaging biomarkers in collegiate athletes with sport-related concussion (SRC) from 24 hours postinjury to 1 week after return to play. METHODS: We analyzed clinical and imaging data of concussed collegiate athletes in the Concussion Assessment, Research, and Education (CARE) Consortium. The CARE participants completed same-day clinical assessments, blood draws, and diffusion tensor imaging (DTI) at 3 time points: 24-48 hours postinjury, point of becoming asymptomatic, and 7 days after return to play. DTI probabilistic tractography was performed for each participant at each time point to render 27 participant-specific major white matter tracts. The microstructural organization of these tracts was characterized by 4 DTI metrics. Mixed-effects models with random intercepts were applied to test whether white matter microstructural abnormalities are associated with the blood-based biomarkers at the same time point. An interaction model was used to test whether the association varies across time points. A lagged model was used to test whether early blood-based biomarkers predict later microstructural changes. RESULTS: Data from 77 collegiate athletes were included in the following analyses. Among the 4 blood-based biomarkers, total tau had significant associations with the DTI metrics across the 3 time points. In particular, high tau level was associated with high radial diffusivity (RD) in the right corticospinal tract (β = 0.25, SE = 0.07, p FDR-adjusted = 0.016) and superior thalamic radiation (β = 0.21, SE = 0.07, p FDR-adjusted = 0.042). NfL and GFAP had time-dependent associations with the DTI metrics. NfL showed significant associations only at the asymptomatic time point (|β|s > 0.12, SEs 0.14, SEs

CONTEXT: Increasing attention has been directed toward identifying aspects of football participation for targeted policy change that reduces the concussion risk. Prior researchers evaluated concussion risks during the preseason and regular seasons, leaving the spring season largely unexplored. DESIGN: In this nationally representative observational investigation of 19 National Collegiate Athletic Association Division I collegiate football programs, we assessed concussion rates and head impact exposures during the preseason, regular season, and spring practices from 2014 to 2019. All participating programs recorded the incidence of concussions, and a subset (n = 6) also measured head impact exposures. RESULTS: Analyses by time of year and session type indicated that concussion rates and head impact exposures during all practice sessions and contact practices were higher in the spring and preseason than those in the regular season (P < .05). Concussion rates during the spring season and preseason were statistically similar. CONCLUSIONS: We identified comparable concussion risks in the spring season and preseason, highlighting the need for targeted policy interventions to protect athlete health and safety.

CONTEXT: The King-Devick (K-D) test is used to identify oculomotor impairment after concussion. However, the diagnostic accuracy of the K-D test over time has not been evaluated. OBJECTIVES: To (1) examine the sensitivity and specificity of the K-D test at 0 to 6 hours postinjury, 24 to 48 hours postinjury, the beginning of a return-to-play (RTP) protocol (asymptomatic), unrestricted RTP, and 6 months postconcussion and (2) compare outcomes between athletes with and those without concussion across confounding factors (sex, age, sport contact level, academic year, learning disorder, attention-deficit/hyperactivity disorder, migraine history, concussion history, and test administration mode). DESIGN: Retrospective, cross-sectional design. SETTING: Multiple institutions in the Concussion Assessment, Research and Education Consortium. PATIENTS OR OTHER PARTICIPANTS: A total of 320 athletes with a concussion (162 men, 158 women; age = 19.80 ± 1.41 years) were compared with 1239 total collegiate athletes without a concussion (646 men, 593 women; age = 20.31 ± 1.18 years). MAIN OUTCOME MEASURE(S): We calculated the K-D test time difference (in seconds) by subtracting the baseline from the most recent time. Receiver operator characteristic (ROC) curve and area under the curve (AUC) analyses were used to determine the diagnostic accuracy across time points. We identified cutoff scores and corresponding specificity at both the 80% and 70% sensitivity levels. We repeated ROC with AUC analyses using confounding factors. RESULTS: The K-D test predicted positive results at the 0- to 6-hour (AUC = 0.724, P < .001), 24- to 48-hour (AUC = 0.701, P < .001), RTP (AUC = 0.640, P < .001), and 6-month postconcussion (AUC = 0.615, P < .001) tim points but not at the asymptomatic time point (AUC = 0.513, P = .497). The 0- to 6-hour and 24- to 48-hour time points yielded 80% sensitivity cutoff scores of -2.6 and -3.2 seconds (ie, faster), respectively, but 46% and 41% specificity, respectively. The K-D test had a better AUC when administered using an iPad (AUC = 0.800, 95% CI = 0.747, 0.854) compared with the spiral-bound card system (AUC = 0.646, 95% CI = 0.600, 0.692; P < .001). CONCLUSIONS: The diagnostic accuracy of the K-D test was greatest at 0 to 6 hours and 24 to 48 hours postconcussion but declined across subsequent postconcussion time points. The AUCs did not differentiate between groups across confounding factors. Our negative cutoff scores indicated that practice effects contributed to improved performance, requiring athletes to outperform their baseline scores.

Sport-related concussion (SRC) is an important public health issue. White-matter alterations after SRC are widely studied by neuroimaging approaches, such as diffusion magnetic resonance imaging (MRI). Although the exact anatomical location of the alterations may differ, significant white-matter alterations are commonly observed in long fiber tracts, but are never proven. In the present study, we performed streamline tractography to characterize the association between tract length and white-matter microstructural alterations after SRC. Sixty-eight collegiate athletes diagnosed with acute concussion (24-48 h post-injury) and 64 matched contact-sport controls were included in this study. The athletes underwent diffusion tensor imaging (DTI) in 3.0 T MRI scanners across three study sites. DTI metrics were used for tract-based spatial statistics to map white-matter regions-of-interest (ROIs) with significant group differences. Whole-brain white-mater streamline tractography was performed to extract affected white-matter streamlines (i.e., streamlines passing through the identified ROIs). In the concussed athletes, streamline counts and DTI metrics of the affected white-matter fiber tracts were summarized and compared with unaffected white-matter tracts across tract length in the same participant. The affected white-matter tracts had a high streamline count at length of 80-100 mm and high length-adjusted affected ratio for streamline length longer than 80 mm. DTI mean diffusivity was higher in the affected streamlines longer than 100 mm with significant associations with the Brief Symptom Inventory score. Our findings suggest that long fibers in the brains of collegiate athletes are more vulnerable to acute SRC with higher mean diffusivity and a higher affected ratio compared with the whole distribution.

Sport-related concussions can result from a single high magnitude impact that generates concussive symptoms, repeated subconcussive head impacts aggregating to generate concussive symptoms, or a combined effect from the two mechanisms. The array of symptoms produced by these mechanisms may be clinically interpreted as a sport-related concussion. It was hypothesized that head impact exposure resulting in concussion is influenced by severity, total number, and frequency of subconcussive head impacts. The influence of total number and magnitude of impacts was previously explored, but frequency was investigated to a lesser degree. In this analysis, head impact frequency was investigated over a new metric called 'time delta', the time difference from the first recorded head impact of the day until the concussive impact. Four exposure metrics were analyzed over the time delta to determine whether frequency of head impact exposure was greater for athletes on their concussion date relative to other dates of contact participation. Those metrics included head impact frequency, head impact accrual rate, risk weighted exposure (RWE), and RWE accrual rate. Athletes experienced an elevated median number of impacts, RWE, and RWE accrual rate over the time delta on their concussion date compared to non-injury sessions. This finding suggests elevated frequency of head impact exposure on the concussion date compared to other dates that may precipitate the onset of concussion.

ObjectiveTo examine the association between estimated age at first exposure (eAFE) to American football and clinical measures throughout recovery following concussion.MethodsParticipants were recruited across 30 colleges and universities as part of the National Collegiate Athletic Association (NCAA)-Department of Defense Concussion Assessment, Research and Education Consortium. There were 294 NCAA American football players (age 19 ± 1 years) evaluated 24-48 hours following concussion with valid baseline data and 327 (age 19 ± 1 years) evaluated at the time they were asymptomatic with valid baseline data. Participants sustained a medically diagnosed concussion between baseline testing and postconcussion assessments. Outcome measures included the number of days until asymptomatic, Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) composite scores, Balance Error Scoring System (BESS) total score, and Brief Symptom Inventory 18 (BSI-18) subscores. The eAFE was defined as participant's age at the time of assessment minus self-reported number of years playing football.ResultsIn unadjusted regression models, younger eAFE was associated with lower (worse) ImPACT Visual Motor Speed (R 2 = 0.031, p = 0.012) at 24-48 hours following injury and lower (better) BSI-18 Somatization subscores (R 2 = 0.014, p = 0.038) when the athletes were asymptomatic. The effect sizes were very small. The eAFE was not associated with the number of days until asymptomatic, other ImPACT composite scores, BESS total score, or other BSI-18 subscores.ConclusionEarlier eAFE to American football was not associated with longer symptom recovery, worse balance, worse cognitive performance, or greater psychological distress following concussion. In these NCAA football players, longer duration of exposure to football during childhood and adolescence appears to be unrelated to clinical recovery following concussion.

BackgroundIdentifying 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.PurposeTo 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 designCohort study (Diagnosis); Level of evidence, 2.MethodsCollegiate athletes were prospectively evaluated using the Sport Concussion Assessment Tool-3 (SCAT-3) during preseason (N = 31,557); 2789 were followed at

Objective: A recent systematic review determined that the physiological effects of concussion may persist beyond clinical recovery. Preclinical models suggest that ongoing physiological effects are accompanied by increased cerebral vulnerability that is associated with risk for subsequent, more severe injury. This study examined the association between signal alterations on diffusion tensor imaging following clinical recovery of sport-related concussion in athletes with and without a subsequent second concussion. Methods: Average mean diffusivity (MD) was calculated in a region of interest (ROI) in which concussed athletes (n = 82) showed significantly elevated MD acutely after injury (

Prior studies have reported long-term differences in brain structure (brain morphometry) as being associated with cumulative concussion and contact sport participation. There is emerging evidence to suggest that similar effects of prior concussion and contact sport participation on brain morphometry may be present in younger cohorts of active athletes. We investigated the relationship between prior concussion and primary sport participation with subcortical and cortical structures in active collegiate contact sport and non-contact sport athletes. Contact sport athletes (CS; N = 190) and matched non-contact sport athletes (NCS; N = 95) completed baseline clinical testing and participated in up to four serial neuroimaging sessions across a 6-months period. Subcortical and cortical structural metrics were derived using FreeSurfer. Linear mixed-effects (LME) models examined the effects of years of primary sport participation and prior concussion (0, 1+) on brain structure and baseline clinical variables. Athletes with prior concussion across both groups reported significantly more baseline concussion and psychological symptoms (all ps < 0.05). The relationship between years of primary sport participation and thalamic volume differed between CS and NCS (p = 0.015), driven by a significant inverse association between primary years of participation and thalamic volume in CS (p = 0.007). Additional analyses limited to CS alone showed that the relationship between years of primary sport participation and dorsal striatal volume was moderated by concussion history (p = 0.042). Finally, CS with prior concussion had larger hippocampal volumes than CS without prior concussion (p = 0.015). Years of contact sport exposure and prior concussion(s) are associated with differences in subcortical volumes in young-adult, active collegiate athletes, consistent with prior literature in retired, primarily symptomatic contact sport athletes. Longitudinal follow-up studies in these athletes are needed to determine clinical significance of current findings.

There has been a recent call for longitudinal cohort studies to track the physiological recovery of sport-related concussion (SRC) and its relationship with clinical recovery. Resting-state functional magnetic resonance imaging (rs-fMRI) has shown potential for detecting subtle changes in brain function after SRC. We investigated the effects of SRC on rs-fMRI metrics assessing local connectivity (regional homogeneity; REHO), global connectivity (average nodal strength), and the relative amplitude of slow oscillations of rs-fMRI (fractional amplitude of low-frequency fluctuations; fALFF). Athletes diagnosed with SRC (n = 92) completed visits with neuroimaging at 24-48 h post-injury (24 h), after clearance to begin the return-to-play (RTP) progression (asymptomatic), and 7 days following unrestricted RTP (post-RTP). Non-injured athletes (n = 82) completed visits yoked to the schedule of matched injured athletes and served as controls. Concussed athletes had elevated symptoms, worse neurocognitive performance, greater balance deficits, and elevated psychological symptoms at the 24-h visit relative to controls. These deficits were largely recovered by the asymptomatic visit. Concussed athletes still reported elevated psychological symptoms at the asymptomatic visit relative to controls. Concussed athletes also had elevated REHO in the right middle and superior frontal gyri at the 24-h visit that returned to normal levels by the asymptomatic visit. Additionally, REHO in these regions at 24 h predicted psychological symptoms at the asymptomatic visit in concussed athletes. Current results suggest that SRC is associated with an acute alteration in local connectivity that follows a similar time course as clinical recovery. Our results do not indicate strong evidence that concussion-related alterations in rs-fMRI persist beyond clinical recovery.

Repetitive head impact exposure sustained by athletes of contact sports has been hypothesized to be a mechanism for concussion and a possible explanation for the high degree of variability in sport-related concussion biomechanics. In an attempt to limit repetitive head impact exposure during the football preseason, the NCAA eliminated two-a-day practices in 2017, while maintaining the total number of team practice sessions. The objective of this study was to quantify head impact exposure during the preseason and regular season in Division I college football athletes to determine whether the 2017 NCAA ruling decreased head impact exposure. 342 unique athletes from five NCAA Division I Football Bowl Subdivision (FBS) programs were consented and enrolled. Head impacts were recorded using the Head Impact Telemetry (HIT) System during the entire fall preseasons and regular seasons in 2016 and 2017. Despite the elimination of two-a-day practices, the number of preseason contact days increased in 2017, with an increase in average hourly impact exposure (i.e., contact intensity), resulting in a significant increase in total head impact burden (+ 26%) for the 2017 preseason. This finding would indicate that the 2017 NCAA ruling was not effective at reducing the head impact burden during the football preseason. Additionally, athletes sustained a significantly higher number of recorded head impacts per week (+ 40%) during the preseason than the regular season, implicating the preseason as a time of elevated repetitive head impact burden. With increased recognition of a possible association between repetitive head impact exposure and concussion, increased preseason exposure may predispose certain athletes to a higher risk of concussion during the preseason and regular season. Accordingly, efforts at reducing concussion incidence in contact sports should include a reduction in overall head impact exposure.

Studies of football athletes have implicated repetitive head impact exposure in the onset of cognitive and brain structural changes, even in the absence of diagnosed concussion. Those studies imply accumulating damage from successive head impacts reduces tolerance and increases risk for concussion. Support for this premise is that biomechanics of head impacts resulting in concussion are often not remarkable when compared to impacts sustained by athletes without diagnosed concussion. Accordingly, this analysis quantified repetitive head impact exposure in a cohort of 50 concussed NCAA Division I FBS college football athletes compared to controls that were matched for team and position group. The analysis quantified the number of head impacts and risk weighted exposure both on the day of injury and for the season to the date of injury. 43% of concussed athletes had the most severe head impact exposure on the day of injury compared to their matched control group and 46% of concussed athletes had the most severe head impact exposure for the season to the date of injury compared to their matched control group. When accounting for date of injury or season to date of injury, 72% of all concussed athletes had the most or second most severe head impact exposure compared to their matched control group. These trends associating cumulative head impact exposure with concussion onset were stronger for athletes that participated in a greater number of contact activities. For example, 77% of athletes that participated in ten or more days of contact activities had greater head impact exposure than their matched control group. This unique analysis provided further evidence for the role of repetitive head impact exposure as a predisposing factor for the onset of concussion. The clinical implication of these findings supports contemporary trends of limiting head impact exposure for college football athletes during practice activities in an effort to also reduce risk of concussive injury.

Previous studies have shown that mild traumatic brain injury (mTBI) can cause abnormalities in clinically relevant magnetic resonance imaging (MRI) sequences. No large-scale study, however, has prospectively assessed this in athletes with sport-related concussion (SRC). The aim of the current study was to characterize and compare the prevalence of acute, trauma-related MRI findings and clinically significant, non-specific MRI findings in athletes with and without SRC. College and high-school athletes were prospectively enrolled and participated in scanning sessions between January 2015 through August 2017. Concussed contact sport athletes (n = 138; 14 female [F]; 19.5 ± 1.6 years) completed up to four scanning sessions after SRC. Non-concussed contact (n = 135; 15 F; 19.7 ± 1.6) and non-contact athletes (n = 96; 15 F; 20.0 ± 1.7) completed similar scanning sessions and served as controls. Board-certified neuroradiologists, blinded to SRC status, reviewed T1-weighted and T2-weighted fluid-attenuated inversion recovery and T2*-weighted and T2-weighted images for acute (i.e., injury-related) or non-acute findings that prompted recommendation for clinical follow-up. Concussed athletes were more likely to have MRI findings relative to contact (30.4% vs. 15.6%; odds ratio [OR] = 2.32; p = 0.01) and non-contact control athletes (19.8%; OR = 2.11; p = 0.04). Female athletes were more likely to have MRI findings than males (43.2% vs. 19.4%; OR = 2.62; p = 0.01). One athlete with SRC had an acute, injury-related finding; group differences were largely driven by increased rate of non-specific white matter hyperintensities in concussed athletes. This prospective, large-scale study demonstrates that

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Although preseason baseline testing is a commonly recommended part of the concussion management process, its "value-added" contribution to the diagnosis of acute concussion compared with normative reference values remains in question. Purpose: This research aimed to evaluate the diagnostic benefits of baseline testing in acute concussion assessment compared with normative reference values and characterize the athletes who receive the most diagnostic utility from baseline testing. Study Design: Cohort study (Diagnosis); Level of evidence, 2. Methods: The investigators selected athletes from the National Collegiate Athletic Association—Department of Defense (NCAA-DoD) Concussion Assessment, Research, and Education (CARE) Consortium with at least 2 baseline assessments and 1 concussion. Two predictive models were developed that mimic acute concussion assessment using multivariate logistic regression based on a battery of postural control, neurocognitive status, and symptom assessments. The first predictive model gives a concussion status prediction based on change scores computed using individualized baseline testing information, whereas the second model uses normative reference values. The investigators defined and computed a novel metric called the Diagnostic Utility of Baseline Testing by comparing the concussion status predicted by each of these predictive models. The Diagnostic Utility of Baseline distribution was analyzed across athlete demographic characteristics and medical history. Results: The study included 1081 collegiate athletes (43.9% female) with 1279 acute concussion assessments (24- to 48-hour postinjury assessments) and 1551 reference assessments (baseline and 6-month assessments). Both the baseline and normative models exhibited notably high area under the curve values of.89 and.90, respectively. Most athletes (86.7%) did not gain additional diagnostic benefits from baseline testing versus normative values. Those with Hispanic ethnicity (P =.038) or a history of psychiatric disorders (P <.001) or depression (P =.002) were more likely to be correctly identified as having acute concussion when change scores were derived from normative values instead of individualized baseline values. Conclusion: This study highlights that the additional diagnostic benefit of preseason baseline testing over normative data is limited for most collegiate student-athletes. Thus, normative data can be used for most collegiate student-athletes in the absence of baseline testing. Moreover, these results can inform decisions on the allocation of baseline tests in resource-limited athletic settings, emphasizing the need for targeted concussion assessment strategies based on individual characteristics. [ABSTRACT FROM AUTHOR]