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.

Association of Premorbid Anxiety and Depression Symptoms in Concussion Recovery in Collegiate Student-Athletes.

BACKGROUND: Mental health disorders are linked to prolonged concussion symptoms. However, the association of premorbid anxiety/depression symptoms with postconcussion return-to-play timelines and total symptom burden is unclear. OBJECTIVE: To examine the association of self-reported premorbid anxiety/depression symptoms in collegiate student-athletes with (1) recovery times until asymptomatic, (2) return-to-play, and (3) postconcussion symptom burden. STUDY DESIGN: Athletes in the Concussion Assessment, Research and Education Consortium completed baseline concussion assessments (Sport Concussion Assessment Tool [SCAT3] and Brief Symptom Inventory-18 [BSI-18]). Athletes were tested postinjury at <6 hours, 24 to 48 hours, time of asymptomatic and start of return-to-play protocol, unrestricted return-to-play, and 6 months after injury. Injured athletes were categorized into 4 groups based on BSI-18 scores: (1) B-ANX, elevated anxiety symptoms only; (2) B-DEP, elevated depression symptoms only; (3) B-ANX&DEP, elevated anxiety and depression symptoms; and (4) B-NEITHER, no elevated anxiety or depression symptoms. Relationship between age, sex, BSI-18 group, SCAT3 total symptom and severity scores, and time to asymptomatic status and return-to-play was assessed with Pearson's chi-squared test and robust analysis of variance. LEVEL OF EVIDENCE: Level 3. RESULTS: Among 1329 athletes with 1352 concussions, no respondents had a self-reported premorbid diagnosis of anxiety/depression. There was no difference in time until asymptomatic or time until return-to-play between BSI-18 groups (P = 0.15 and P = 0.11, respectively). B-ANX, B-DEP, and B-ANX&DEP groups did not have higher total symptom or severity scores postinjury compared with the B-NEITHER group. CONCLUSION: Baseline anxiety/depression symptoms in collegiate student-athletes without a mental health diagnosis are not associated with longer recovery times until asymptomatic, longer time to return-to-play, or higher postconcussion total symptom and severity scores compared with athletes without baseline symptoms. CLINICAL RELEVANCE: Anxiety and depression symptoms without a clear mental health diagnosis should be considered differently from other comorbidities when discussing prolonged recovery in collegiate student-athletes.

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.

The Prevalence and Influence of New or Worsened Neck Pain After a Sport-Related Concussion in Collegiate Athletes: A Study From the CARE Consortium.

BACKGROUND: Neck pain in a concussion population is an emerging area of study that has been shown to have a negative influence on recovery. This effect has not yet been studied in collegiate athletes. HYPOTHESIS: New or worsened neck pain is common after a concussion (>30%), negatively influences recovery, and is associated with patient sex and level of contact in sport. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Varsity-level athletes from 29 National Collegiate Athletic Association member institutions as well as nonvarsity sport athletes at military service academies were eligible for enrollment. Participants completed a preseason baseline assessment and follow-up assessments at 6 and 24 to 48 hours after a concussion, when they were symptom-free, and when they returned to unrestricted play. Data collection occurred between January 2014 and September 2018. RESULTS: A total of 2163 injuries were studied. New or worsened neck pain was reported with 47.0% of injuries. New or worsened neck pain was associated with patient sex (higher in female athletes), an altered mental status after the injury, the mechanism of injury, and what the athlete collided with. The presence of new/worsened neck pain was associated with delayed recovery. Those with new or worsened neck pain had 11.1 days of symptoms versus 8.8 days in those without (P < .001). They were also less likely to have a resolution of self-reported symptoms in ≤7 days (P < .001). However, the mean duration of the return-to-play protocol was not significantly different for those with new or worsened neck pain (7.5 ± 7.7 days) than those without (7.4 ± 8.3 days) (P = .592). CONCLUSION: This novel study shows that neck pain was common in collegiate athletes sustaining a concussion, was influenced by many factors, and negatively affected recovery.

The Interval Between Concussions Does Not Influence Time to Asymptomatic or Return to Play: A CARE Consortium Study.

INTRODUCTION: The purpose of this study was to determine if the time interval between two concussive events influences the number of days to asymptomatic status, days to return to play, or performance on common post-concussion assessments following the second concussion. METHODS: Data from 448 collegiate athletes and service academy cadets with two concussions (time between concussions: median 295.0 days [interquartile range: 125.0-438.2]), 40.0% female) were analyzed from Concussion Assessment Research and Education (CARE) Consortium institutions between 2014 and 2020. Days between concussions was the primary predictor variable. Primary outcome measures included time to asymptomatic and time to return to play following the second concussion. Secondary outcome measures included total number of symptoms, total symptom severity, Balance Error Scoring System total score, and Standardized Assessment of Concussion total score within 48 h of their second concussion. RESULTS: Time between concussions did not significantly contribute to the multivariate time to asymptomatic (p = 0.390), time to return to play (p = 0.859), or the secondary outcomes (p-range = 0.165-0.477) models. Time to asymptomatic (p = 0.619) or return to play (p = 0.524) did not differ between same-season and different-season concussions. Sex significantly contributed to the return to play (p = 0.005) multivariate model. Delayed symptom onset and immediate removal from play/competition significantly contributed to the total number of symptoms (p = 0.001, p = 0.014) and symptom severity (p = 0.011, p = 0.022) multivariate models. CONCLUSION: These results suggest that in a population with a large period between injuries, the time between concussions may not be relevant to clinical recovery.

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.

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.

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.

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.

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.

Collegiate Athletes With Diabetes: Baseline Medical Comorbidities and Preseason Concussion Testing Performance.

CONTEXT: People with diabetes mellitus (DM) are at increased risk for adverse health events and complications throughout their lifetime. Whether DM significantly affects collegiate athletes' concussion baseline testing performance remains unclear. OBJECTIVES: To (1) describe the prevalence of DM and associated comorbidities and (2) compare concussion baseline testing performance between student-athletes with DM and student-athletes without DM (NoDM). DESIGN: Retrospective, cross-sectional study. SETTING: University. PATIENTS OR OTHER PARTICIPANTS: Using the Concussion, Assessment, Research and Education (CARE) Consortium research database, we matched athletes with self-reported DM (N = 229) by institution, sex, age, sport, position, testing year, and concussion history to athletes with NoDM (N = 229; total sample mean age = 19.6 ± 1.4 years, women = 42%). MAIN OUTCOME MEASURE(S): Descriptive statistics and χ2 tests of independence with subsequent odds ratios were calculated. Independent-samples t tests compared baseline symptoms, neurocognitive testing, and balance performance between athletes with DM and athletes with NoDM. Effect sizes were determined for significant group differences. RESULTS: At baseline, athletes with DM had higher rates of self-reported pre-existing balance disorders, sleep disorders, seizure disorders, motion sickness, learning disorders, vision and hearing problems, psychiatric disorders, depression, bipolar disorder, nonmigraine headaches, and meningitis than athletes with NoDM (P values < .05). We found balance differences between groups (P = .032, Cohen d = 0.17) such that, on average, athletes with DM had 1 additional error on the Balance Error Scoring System (DM = 13.4 ± 6.5; NoDM = 12.1 ± 5.9). No other comparisons yielded significant results. CONCLUSIONS: Although athletes with DM had high rates of self-reported balance disorders, sleep disorders, seizures, and meningitis, their baseline neurocognitive testing results were largely identical to those of athletes with NoDM. Our findings suggested that nonclinically meaningful differences were present in concussion baseline balance testing but no significant differences were noted in cognitive testing; however, the effect of DM on concussion recovery remains unknown.

Postinjury Alcohol Use Is Associated With Prolonged Recovery After Concussion in NCAA Athletes.

OBJECTIVE: To determine whether alcohol use leads to prolonged clinical recovery or increased severity of concussion symptoms in National Collegiate Athletic Association (NCAA) athletes. DESIGN: Prospective observational study. SETTING: Clinical institutions. PARTICIPANTS: Athletes from the NCAA Concussion Assessment Research and Education consortium who sustained a concussion from 2014 to 2021. INTERVENTIONS: Athletes were divided into 2 groups, those reporting alcohol use postinjury and those reporting no alcohol use postinjury. MAIN OUTCOME MEASURES: Symptom recovery was evaluated as time (in days) from injury to clearance to return to unrestricted play (days until URTP). Severity of concussion symptoms was assessed using the Standardized Sport Concussion Assessment Tool (SCAT3) symptom severity, headache severity, difficulty concentrating, and difficulty remembering scores. These scores were taken a median of 6.6 [interquartile range (IQR) = 4.0-10] and 6 (IQR = 4.0-9.0) days after injury for those who did and did not consume alcohol postinjury respectively and compared with baseline SCAT3 scores. RESULTS: Four hundred eighty four athletes from the data set had complete data for exposure and outcome. The adjusted mean number of days until URTP for athletes reporting alcohol use postinjury [23.3; 95% confidence interval (CI), 20.0-27.2; days] was incidence rate ratio (IRR) 1.32 (95% CI, 1.12-1.55; P < 0.001) times higher than for athletes who reported no alcohol use postinjury [17.7 (95% CI, 16.1-19.3) days]. Postinjury alcohol was not associated with severity of concussion symptoms ( P 's < 0.05). CONCLUSION: Self-reported postinjury alcohol use is associated with prolonged recovery but not severity of concussion symptoms in collegiate athletes. This may inform future clinical recommendations regarding alcohol consumption after concussion.

Postinjury Outcomes After Non-Sport-Related Concussion: A CARE Consortium Study.

CONTEXT: Concussion research has primarily focused on sport-related mechanisms and excluded non-sport-related mechanisms. In adult populations, non-sport-related concussions (non-SRCs) demonstrated worse clinical outcomes compared with sport-related concussions (SRCs); however, investigations of non-SRCs in college-aged patients are limited. OBJECTIVES: To examine clinical outcomes in collegiate athletes with non-SRCs compared with SRCs and explore sex differences in outcomes among collegiate athletes with non-SRCs. DESIGN: Prospective cohort study. SETTING: Clinical setting. PATIENTS OR OTHER PARTICIPANTS: A total of 3500 athletes were included (n = 555 with non-SRCs, 42.5% female) from colleges or universities and service academies participating in the National Collegiate Athletic Association Department of Defense Concussion Assessment, Research and Education (CARE) Consortium. MAIN OUTCOME MEASURE(S): Dichotomous outcomes (yes or no) consisted of immediate reporting, mental status alterations, loss of consciousness, posttraumatic amnesia, retrograde amnesia, motor impairments, delayed symptom presentation, and required hospital transport. Continuous outcomes were symptom severity, days with concussion symptoms, and days lost to injury. Data were collected within 24 to 48 hours of injury and at return to play. Adjusted relative risks (ARRs) compared the likelihood of dichotomous outcomes by mechanism and by sex within patients with non-SRCs. Multivariate negative binomial regressions were used to assess group differences in continuous variables. RESULTS: Athletes with non-SRCs were less likely to report immediately (ARR = 0.73, 95% CI = 0.65, 0.81) and more likely to report delayed symptom presentation (ARR = 1.17, 95% CI = 1.03, 1.32), loss of consciousness (ARR = 3.15, 95% CI = 2.32, 4.28), retrograde amnesia (ARR = 1.77, 95% CI = 1.22, 2.57), and motor impairment (ARR = 1.45, 95% CI = 1.14, 1.84). Athletes with non-SRCs described greater symptom severity, more symptomatic days, and more days lost to injury (P < .001) compared with those who had SRCs. Within the non-SRC group, female athletes indicated greater symptom severity, more symptomatic days, and more days lost to injury (P < .03) than male athletes. CONCLUSIONS: Athletes with non-SRCs had worse postinjury outcomes compared with those who had SRCs, and female athletes with non-SRCs had worse recovery metrics than male athletes. Our findings suggest that further investigation of individuals with non-SRCs is needed to improve concussion reporting and management.

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.

Sex Differences in Recovery Trajectories of Assessments for Sport-Related Concussion Among NCAA Athletes: A CARE Consortium Study.

OBJECTIVES: The purpose of this study was to determine sex differences in recovery trajectories of assessments for sport-related concussion using Concussion Assessment, Research and Education (CARE) Consortium data. METHODS: National Collegiate Athletic Association athletes (N = 906; 61% female) from sex-comparable sports completed a pre-season baseline assessment and post-sport-related concussion assessments within 6 h of injury, 24-48 h, when they initiated their return to play progression, when they were cleared for unrestricted return to play, and 6 months post-injury. Assessments included the Standardized Assessment of Concussion, Balance Error Scoring System, Brief Symptom Inventory-18, Immediate Post-concussion Assessment and Cognitive Testing (ImPACT), Sport Concussion Assessment Tool-3 symptom evaluation, Clinical Reaction Time, King-Devick test, Vestibular Ocular Motor Screen, 12-item Short-Form Health Survey, Hospital Anxiety and Depression Scale, and Satisfaction with Life Scale. RESULTS: Only the Vestibular Ocular Motor Screen Total Symptom Score at the 24-48 h timepoint (p = 0.005) was statistically significantly different between sexes. Specifically, female athletes (mean = 60.2, 95% confidence interval [CI] 51.5-70.4) had higher Vestibular Ocular Motor Screen Total Symptom Scores than male athletes (mean = 36.9, 95% CI 27.6-49.3), but this difference resolved by the time of return-to-play initiation (female athletes, mean = 1.8, 95% CI 1.1-2.9; male athletes, mean = 4.1, 95% CI 1.5-10.9). CONCLUSIONS: Sport-related concussion recovery trajectories for most assessments were similar for female and male National Collegiate Athletic Association athletes except for Vestibular Ocular Motor Screen symptoms within 48 h of sport-related concussion, which was greater in female athletes. Female athletes had a greater symptom burden across all timepoints, suggesting that cross-sectional observations may indicate sex differences despite similar recovery trajectories.

Sport-Specific Recovery Trajectories for NCAA Collegiate Athletes Following Concussion.

The recovery trajectories of collegiate athletes with sport-related concussion (SRC) are well characterized in contact/collision sports but are less well understood in limited contact sports with lower risk, reducing the ability of clinicians to effectively manage the return-to-play (RTP) process. The current study investigated the time to asymptomatic and RTP across a broad range of male and female collegiate sports and sought to group sports by recovery intervals. Data from the Concussion Assessment, Research and Education (CARE) Consortium included 1049 collegiate athletes who sustained a SRC while participating in game or practice/training of their primary sport. Injury setting and subsequent clinical presentation data were obtained. Survival analysis using the Cox Proportional Hazard model estimated the median recovery times for each sport. Optimal univariate K-means clustering grouped sports into recovery categories. Across all sports, median time to asymptomatic following SRC ranged from 5.9 (female basketball) to 8.6 days (male wrestling). Median RTP protocol duration ranged from 4.9 days (female volleyball) to 6.3 days (male wrestling). Median total RTP days ranged from 11.2 days (female lacrosse) to 16.9 days (male wrestling). Sport clusters based on recovery differences in time to asymptomatic (3) and RTP protocol duration (2) were identified. The findings from this study of a large sample of more than 1000 NCAA collegiate athletes with SRC show there exists ranges in recovery trajectories. Clinicians can thus manage athletes with similar guidelines, with individualized treatment and recovery plans.

Gene Expression Alterations in Peripheral Blood Following Sport-Related Concussion in a Prospective Cohort of Collegiate Athletes: A Concussion Assessment, Research and Education (CARE) Consortium Study.

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.

Optimizing baseline and post-concussion assessments through identification, confirmation, and equivalence of latent factor structures: findings from the NCAA-DoD CARE Consortium.

Objective: Concussion evaluations use a multidimensional assessment to evaluate unique patient function dimensions (e.g., subjective symptoms differ from balance assessments), but the overarching latent factor structure has not been empirically substantiated. Our objective was to determine the cumulative latent factor structure of pre-injury baseline and acute (<48-h) post-concussion assessment battery outcomes, and determine measurement equivalence among common factors in collegiate student-athletes. Methods: Collegiate student-athletes at baseline (n = 21,865) and post-concussion (n = 1,537) across 25-institutions completed standardized assessments. Individual items were used from the baseline and post-concussion assessments and consisted of: Sport Concussion Assessment Tool, Brief Symptom Inventory-18, Standardized Assessment of Concussion, Balance Error Scoring System, Immediate Post-Concussion Assessment and Cognitive Test, and vestibular-ocular motor screening. Exploratory factor analysis was used on half the baseline data, and confirmatory factor analysis on the remaining baseline data and post-concussion data separately. Measurement equivalence was assessed between sex, sport contact classification, concussion history, and time. Results: A 10-factor exploratory model was established and comprised of: depression, somatic, vestibulo-ocular, headache, postural stability, neurocognition, emotional, fatigue, cognitive, consciousness clouding. The 10-factor model was confirmed at baseline and post-concussion with strong measurement equivalence between timepoints. Strong to strict measurement equivalence was observed for sex, sport contact classification, and concussion history at both timepoints separately. Conclusion: Our findings established a robust 10-factor latent factor model equivalent across timepoints and common factors among healthy and concussed collegiate athletes. Clinicians can use these findings to target specific factors while reducing redundant elements to provide efficient, comprehensive post-concussion assessments.

Initial Mild Traumatic Brain Injury Characteristics and Recovery Patterns Among Females Across the United States Military Service Academies: A Report from the NCAA-DoD CARE Consortium.

Mild traumatic brain injury (mTBI) has been described in the United States (US) military service academy cadet population, but female-specific characteristics and recovery outcomes are poorly characterized despite sex being a confounder. Our objective was to describe female cadets' initial characteristics, assessment performance, and return-to-activity outcomes post-mTBI. Female cadets (n = 472) from the four US military service academies who experienced a mTBI completed standardized mTBI assessments from pre-injury to acute initial injury and unrestricted return-to-duty (uRTD). Initial injury presentation characteristics (e.g., delayed symptoms, retrograde amnesia) and return-to-activity outcomes [i.e., return-to-learn, initiate return-to-duty protocol (iRTD), uRTD] were documented. Descriptive statistics summarized female cadets' injury characteristics, return-to-activity outcomes, and post-mTBI assessment performance change categorization (worsened, unchanged, improved) relative to pre-injury baseline using established change score confidence rank criteria for each assessment score. The median (interquartile range) days to return-to-learn (n = 157) was 7.0 (3.0-14.0), to iRTD (n = 412) was 14.7 (8.6-25.8), and to uRTD (n = 431) was 26.0 (17.7-41.8). The majority experienced worse SCAT total symptom severity (77.8%) and ImPACT reaction time (97.0%) acutely < 24-h versus baseline, but unchanged BESS total errors (75.2%), SAC total score (72%), BSI-18 total score (69.6%), and ImPACT verbal memory (62.3%), visual memory (58.4%), and visual motor speed (52.5%). We observed similar return-to-activity times in the present female cadet cohort relative to the existing female-specific literature. Confidence ranks categorizing post-mTBI performance were heterogenous and indicate multimodal assessments are necessary. Our findings provide clinically relevant insights to female cadets experiencing mTBI across the US service academies for stakeholders providing healthcare.