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Military service members are at increased risk for mental health issues and comorbidity with mild traumatic brain injury (mTBI) is common. Largely overlapping symptoms between conditions suggest a shared pathophysiology. The present work investigates the associations between white matter microstructure, psychological functioning, and serum neuroactive steroids that are part of the stress-response system.Diffusion-weighted brain imaging was acquired from 163 participants (with and without military affiliation) and free-water-corrected fractional anisotropy (FAT) was extracted. Associations between serum neurosteroid levels of allopregnanolone (ALLO) and pregnenolone (PREGNE), psychological functioning, and whole-brain white matter microstructure were assessed using regression models. Moderation models tested the effect of mTBI and comorbid post-traumatic stress disorder (PTSD) and mTBI on these associations.ALLO is associated with whole-brain white matter FAT (β=.24, t=3.00, p= .006). This association is significantly modulated by PTSD+mTBI comorbidity (β=.01, t=3.07, p=.003) while an mTBI diagnosis alone did not significantly impact this association (p=.183). There was no significant association between PREGNE and FAT (p=.380). Importantly, lower FAT is associated with poor psychological functioning (β=-.19, t=-2.35, p=.020).This study provides novel insight into a potential common pathophysiological mechanism of neurosteroid dysregulation underlying the high risk for mental health issues in military service members. Further, comorbidity of PTSD and mTBI may bring the compensatory effects of the brain's stress response to their limit. Future research is needed to investigate whether neurosteroid regulation may be a promising tool for restoring brain health and improving psychological functioning.

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.

To assess whether the King-Devick (KD) test is useful as a prognostic test for prolonged concussion symptoms by examining the relationship between a) change in performance on KD test from baseline to within two days post-injury and b) the absolute KD time at post-concussion testing, with an outcome of time to return to play (RTP).Prospective Cohort Study.Collegiate varsity athletes in the Concussion Assessment, Research, and Education (CARE) Consortium completed baseline and post-injury King-Devick tests from 2014 to 2018. Two exposures were evaluated: 1) change in KD score from baseline to within two days post-injury and 2) absolute KD score within two days post-injury, adjusted for baseline KD. We used Cox proportional hazards models to analyze the relationships between these exposures and time to RTP post-concussion.A total of 309 concussion injuries were included. Median baseline KD score was 40.0 s (IQR: 35.8, 45.2). Median post-injury KD score was 45.8 s (IQR: 39.8, 57.1). Median number of days until RTP in this cohort was 11 (IQR: 8, 17). Post-injury KD score adjusted for baseline KD had a stronger association with time to RTP duration (HR: 0.99 (0.98, 1.00), p = 0.03) than the difference in KD score from baseline to post-injury (HR: 0.99 (0.99, 1.00), p = 0.07).Higher post-injury KD scores are associated with longer RTP. The association between KD post-concussion test and longer RTP warrants further investigation to assess the utility of the KD for prognostication in a clinical setting.

The purpose of this study was to determine changes in neurocognitive, psychosocial, and balance functioning in collegiate male and female soccer players across three consecutive years of baseline testing compared to a control group of non-contact athletes.Generalized estimating equations were used to compare changes in annual, pre-season baseline measures of neurocognitive function, neurobehavioral and psychological symptoms, and postural stability between collegiate soccer players (n = 75; 51 [68%] female soccer players) and non-contact athletes (n = 210; 133 [63%] female non-contact athletes) across three consecutive years.Among all participants, the group-by-time interaction was not significant for any outcome measures. Overall, soccer players reported lower (better) Brief Symptom Inventory 18 Depression (p = 0.004, Exp(B) = 0.36 [95% CI 0.18-0.73]), Global Severity Index (p = 0.006, Exp(B) = 0.53 [95% CI 0.33-0.84]), and Post-Concussion Symptom Scale (PCSS) Symptom Severity (p0.001, Exp(B) = 0.45 [95% CI 0.22-0.95]) scores than non-contact athletes. No other outcome measures were different between soccer players and non-contact athletes.Among collegiate athletes, soccer players report similar or better psychosocial functioning and symptom scores than non-contact athletes. Importantly, neurocognitive functioning, neurobehavioral and psychological symptoms, and postural stability does not worsen over time in collegiate soccer players relative to their non-contact counterparts. Our findings suggest that despite possible exposure to repetitive head impacts (RHIs), collegiate soccer players do not exhibit changes in observable function and symptoms across multiple seasons.

Concussions are common among youth athletes and could disrupt critical neurodevelopment. This study examined the association between age of first concussion (AFC) and neurocognitive performance, psychological distress, postural stability, and symptoms commonly associated with concussion in healthy collegiate men and women student athletes.Participants included 4267 collegiate athletes from various contact, limited-contact, and non-contact sports (1818 women and 2449 men) who completed baseline assessments as part of the Concussion Assessment, Research and Education (CARE) Consortium. Psychological distress was assessed with the Brief Symptom Inventory 18; neurocognitive performance was assessed with the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT); symptoms commonly associated with concussion were assessed with the ImPACT Post-Concussion Symptom Scale; postural stability was assessed with the Balance Error Scoring System. Generalized linear models were used to examine the effects of AFC on clinical outcomes separately in men and women.Later AFC was associated with lower global (Exp(B) = 0.96, P = 0.001) and somatic (Exp(B) = 0.96, P = 0.002) psychological distress on the Brief Symptom Inventory 18 and faster ImPACT reaction time (B = - 0.003, P = 0.001) in women. AFC was not associated with any clinical outcomes in men.Younger AFC was associated with some differences in psychological distress and reaction time among women but not men; however, these results are likely not clinically meaningful. Sociodemographic disparities, pre-existing conditions, and sport type may impact clinical and cognitive outcomes in collegiate athletes more than concussion history. Future work should examine the relationship between AFC and lifespan-related outcomes.

Background: The Vestibular/Ocular-Motor Screening (VOMS) is a valuable component of acute (Purpose: To analyze VOMS, SCAT3, and ImPACT to evaluate the test-retest reliability of consecutive-year preseason baseline assessments to directly compare the diagnostic utility of these tools when incorporating baseline assessments versus using postinjury data alone to identify acute SRC. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: Preseason and postinjury VOMS, SCAT3, ImPACT Post-Concussion Symptom Scale (PCSS), and ImPACT composite scores were analyzed for 3958 preseason (47.7% female) and 496 acute (≤48 hours) SRC (37.5% female) collegiate athlete evaluations in the National Collegiate Athletic Association—Department of Defense Concussion Assessment Research and Education Consortium. Descriptive statistics, Kolmogorov-Smirnov significance, and Cohen d effect size were calculated. Consecutive-year baseline reliability was evaluated for a subset of 447 athlete encounters using Pearson r, Cohen κ, Cohen d, and 2-way mixed intraclass correlation coefficients (ICCs). Wilcoxon signed rank tests were used to determine the statistical significance between population performances, and the 90% reliable change index (RCI) was calculated from the test-retest results. Preseason to postinjury change scores were then calculated from each tool’s RCI. Finally, receiver operating characteristic (ROC) curve analyses were conducted, and DeLong method was used to compare the area under the curve (AUC) of raw postinjury scores versus change scores from preseason baseline assessments. Potential effects of sex, medical history (learning disorders or attention-deficit/hyperactivity disorder), and outlier data were also explored. Results: Effect sizes were large, and overall predictive utilities were clinically useful for postinjury VOMS Total ( d = 2.44; AUC = 0.85), the SCAT3 Symptom Evaluation total severity score ( d = 1.74; AUC = 0.82), and the ImPACT PCSS total severity score ( d = 1.67; AUC = 0.80). Comparatively, effect sizes were small and predictive utilities were poor for Standardized Assessment of Concussion (SAC), modified Balance Error Scoring System (mBESS), and all ImPACT composites ( d = 0.11-0.46; AUC = 0.48-0.59). Preseason baseline test-retest reliability was poor to moderate ( r = 0.23-0.52; κ = 0.32-0.36; ICC = 0.36-0.68) for all assessments except ImPACT Visual Motion Sensitivity ( r = 0.73; ICC = 0.85). Incorporating baseline scores for VOMS Total, SCAT3 (Symptom Evaluation, SAC, mBESS), ImPACT PCSS, or ImPACT composites did not significantly improve AUCs. Conclusion: VOMS Total and symptom severity (SCAT3, PCSS) total scores had large effect sizes and clinically useful AUCs for identifying acute concussion. However, all tools demonstrated high within-patient test-retest variability, resulting in poor reliability. The findings in this sample of collegiate athletes suggest that incorporating baseline assessments does not significantly increase diagnostic yield for acute concussion.

Few studies have analyzed the Sport Concussion Assessment Tool's (SCAT) utility among athletes whose concussion assessment is challenging. Using a previously published algorithm, we identified possible and probable concussions at

Evidence suggests neurodevelopmental disorders (NDs) may be associated with an increased incidence of concussion, but no studies have cross-sectionally and longitudinally assessed the associations of NDs and sex with concussion in collegiate athletes. We sought to assess the odds and relative risk (RR) of concussion in athletes self-reporting a diagnosis of attention deficit/hyperactivity disorder (ADHD), learning disability (LD), and ADHD+LD. Data from the Concussion Assessment, Research and Education (CARE) Consortium (2014–2017) were used to evaluate the likelihood of concussion for male and female athletes with ADHD, LD, and ADHD+LD, relative to controls. Odds ratios (ORs) of concussion history prior to enrollment and relative risk ratios for incurring a concussion following enrollment, with and without concussion history were calculated for all groups. Athletes with self-reported diagnosis of ADHD, LD, and ADHD+LD were more likely to report a single concussion (OR range = 1.528 to 1.828) and multiple concussions (OR range = 1.849 to 2.365) prior to enrollment in the CARE Consortium, irrespective of sex compared with control athletes. While enrolled in CARE, male athletes with ADHD, LD, and ADHD+LD had greater risk of incurring a concussion (RR range = 1.369 to 2.243) than controls, irrespective of concussion history. Male athletes with ADHD+LD with concussion history (RR = 2.221) and without concussion history (RR = 1.835) had greater risk of incurring a concussion than controls. These results suggest NDs may be associated with increased odds of single and multiple concussions, irrespective of sex. However, when we accounted for concussion history, it appears only male athletes with ADHD+LD had greater risk than respective controls. There were no significant differences between females and males with ADHD, LD, or ADHD+LD for either odds of concussion history or risk for incurring concussion.

Sport-related concussion is recognized as a significant injury with variable recovery rates. This study defined the acute natural history of sport concussion in male and female collegiate athletes participating in a broad array of sports. We conducted a prospective, longitudinal investigation among collegiate student athletes (n = 34,709) from 30 academic institutions. Primary outcomes included the time (days) from injury until initiation of a return to participation (RTP) protocol and time from injury until medical clearance for unrestricted RTP. Concussed athletes (n = 1751, 19.2 years, 63.2% male) participating in 22 different sports began the RTP protocol in a median 6.4 (IQR 3.7–11.8) days. Time to initiate the RTP protocol was lengthened by less frequent post-injury assessments, greater initial post-injury symptom severity, limited contact sports participation, practice/training injuries, and three or more prior concussions. The median total RTP duration was 12.8 (IQR 8.7–20.1) days. Total RTP duration was shorter with ADHD medication usage, males, and greater assessment frequency; while greater initial post-injury symptom severity, practice-/training-related injuries, and three or more prior concussions had longer recoveries. Although median recovery times are consistent with previous guidelines, it was not until 1 month post-injury that a preponderance of collegiate athletes were cleared to begin the RTP protocol (92%) or cleared for unrestricted sport participation (85%). Intrinsic and extrinsic factors had a small effect, altering recovery trajectories by up to 2 days, suggesting a largely unified approach to post-injury monitoring and management across all athletes. These data represent a shift from previous classification parameters of normal clinical recovery.

Computer-based neurocognitive tests are widely used in sport-related concussion management, but the performance of these tests is not well understood in the participant population with attention-deficit/hyperactivity disorder (ADHD) and/or learning disorder (LD). This research estimates the sensitivity and specificity performance of the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) computer-based neurocognitive test in identifying concussion in this population.Study participants consisted of collegiate university athletes and military service academy cadets from the National Collegiate Athletic Association-Department of Defense CARE Consortium who completed the ImPACT test between 2014 and 2021. Participants who self-identified as belonging to one of the subgroups of interest (ADHD with or without LD [ADHD:LD+/-], LD with or without ADHD [LD:ADHD+/-], ADHD and/or LD [ADHD a/o LD]) and completed a baseline (1874 ADHD:LD+/-, 779 LD:ADHD+/-, 2338 ADHD a/o LD) or 24-48 h post-concussion (175 ADHD:LD+/-, 77 LD:ADHD+/-, 216 ADHD a/o LD) ImPACT assessment were included. Sensitivity and specificity were calculated using a normative data method and three machine learning classification methods: logistic regression, classification and regression tree, and random forest.Using the four methods, participants with ADHD:LD+/- had sensitivities that ranged from 0.474 to 0.697, and specificities that ranged from 0.538 to 0.686. Participants with LD:ADHD+/- had sensitivities that ranged from 0.455 to 0.688, and specificities that ranged from 0.456 to 0.588. For participants with ADHD a/o LD, sensitivities ranged from 0.542 to 0.755, and specificities ranged from 0.451 to 0.724.For all subgroups and analytical methods, the results illustrate sensitivity and specificity values below typically accepted levels indicative of clinical utility. These findings support that using ImPACT alone may be insufficient to inform concussion diagnoses and encourages the use of a multi-dimensional concussion assessment.

The purpose of this study was to describe the mechanism of injury (MOI) and examine factors associated with greater risk for specific MOIs involving concussions in collegiate soccer players.Participants included 3,288 collegiate soccer players from 28 institutions across four competitive seasons, 2014-17. MOIs were documented for 262 soccer-related concussions during the study and placed into one of four categories: collisions, unintentional contact, aerial challenges, and others.70% of the concussions occurred in DI soccer players. Collisions and unintentional contact were the MOIs that resulted in 66.5% of all concussions. DI and DIII soccer players sustained more concussions by unintentional contact versus collisions and aerial challenges when compared to their DII counterparts. Defenders were more likely than midfielders to sustain concussions by aerial challenges than collisions. As expected, the field players experienced more concussions as a result of collisions, unintentional contact, and aerial challenges when compared to goalkeepers.Future research should explore preventive strategies for decreasing collisions, especially during aerial challenges while heading the soccer ball, and unintentional contacts from errant balls in soccer in order to decrease concussion risk.

Prior research has found that individuals with a pre-injury psychiatric history report greater difficulty with executive functioning after mild traumatic brain injury (mTBI). The present study examined self-rated executive functioning after the acute phase of recovery in individuals with mTBI having no prior psychiatric history. Participants included 59 individuals with mTBI and 27 healthy comparison subjects (HC). They completed the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) and Beck Depression Inventory-II. Participants had no prior history of psychiatric diagnosis based on semi-structured interview. In those with a valid BRIEF-A, the mTBI group (n = 54; days since injury: M = 465.04, SD = 146.92, range = 315–1144) endorsed poorer executive functioning than the HC group (n = 24) on several BRIEF-A scales. Only the Working Memory and Inhibit scales remained significant after adjusting for group differences in education and depression score, but they did not survive adjustment for multiple comparisons. The mean standardized scores for the mTBI group were well within normal limits across scales. Furthermore, there were no group differences on any BRIEF-A scales for percentage of participants with clinically elevated scores. Individuals with mTBI and no prior psychiatric history did not endorse significant executive dysfunction. Our findings support previous literature indicating that self-rated executive dysfunction in those with mTBI after the acute phase of recovery is likely due to factors other than brain injury, such as subclinical symptoms of depression.

There is a growing literature on the impact of genetic variation on outcome in traumatic brain injury (TBI). Whereas a substantial proportion of these publications have focused on the apolipoprotein E (APOE) gene, several have explored the influence of other polymorphisms. We undertook a systematic review of the impact of single-nucleotide polymorphisms (SNPs) in non-apolipoprotein E (non-APOE) genes associated with patient outcomes in adult TBI). We searched EMBASE, MEDLINE, CINAHL, and gray literature from inception to the beginning of August 2017 for studies of genetic variance in relation to patient outcomes in adult TBI. Sixty-eight articles were deemed eligible for inclusion into the systematic review. The SNPs described were in the following categories: neurotransmitter (NT) in 23, cytokine in nine, brain-derived neurotrophic factor (BDNF) in 12, mitochondrial genes in three, and miscellaneous SNPs in 21. All studies were based on small patient cohorts and suffered from potential bias. A range of SNPs associated with genes coding for monoamine NTs, BDNF, cytokines, and mitochondrial proteins have been reported to be associated with variation in global, neuropsychiatric, and behavioral outcomes. An analysis of the tissue, cellular, and subcellular location of the genes that harbored the SNPs studied showed that they could be clustered into blood-brain barrier associated, neuroprotective/regulatory, and neuropsychiatric/degenerative groups. Several small studies report that various NT, cytokine, and BDNF-related SNPs are associated with variations in global outcome at 6-12 months post-TBI. The association of these SNPs with neuropsychiatric and behavioral outcomes is less clear. A definitive assessment of role and effect size of genetic variation in these genes on outcome remains uncertain, but could be clarified by an adequately powered genome-wide association study with appropriate recording of outcomes.

Highlights • Previous concussion was associated with 2 times increased odds of incident concussion, while wearing a mouthguard was protective against incident concussion, reducing odds by 57%. • Overall, concussion mechanisms did not significantly differ between sexes. • Females took significantly longer to reach asymptomatic and return-to-play clearance. Within the first 2 weeks post-concussion, 86.11% of males reached asymptomatic, while only 45.50% of females reached the same phase of recovery. • Most males (91.67%) were cleared for return-to-play within 3 weeks of their concussion, compared to less than one-half (45.50%) of females., Objective Since concussion is the most common injury in ice hockey, the objective of the current study was to elucidate risk factors, specific mechanisms, and clinical presentations of concussion in men's and women's ice hockey. Methods Ice hockey players from 5 institutions participating in the Concussion Assessment, Research, and Education Consortium were eligible for the current study. Participants who sustained a concussion outside of this sport were excluded. There were 332 (250 males, 82 females) athletes who participated in ice hockey, and 47 (36 males, 11 females) who sustained a concussion. Results Previous concussion (odds ratio (OR) = 2.00; 95% confidence interval (95% CI): 1.02‒3.91) was associated with increased incident concussion odds, while wearing a mouthguard was protective against incident concussion (OR = 0.43; 95%CI: 0.22‒0.85). Overall, concussion mechanisms did not significantly differ between sexes. There were specific differences in how concussions presented clinically across male and female ice hockey players, however. Females (9.09%) were less likely than males (41.67%) to have a delayed symptom onset (p = 0.045). Additionally, females took significantly longer to reach asymptomatic (p = 0.015) and return-to-play clearance (p = 0.005). Within the first 2 weeks post-concussion, 86.11% of males reached asymptomatic, while only 45.50% of females reached the same phase of recovery. Most males (91.67%) were cleared for return to play within 3 weeks of their concussion, compared to less than half (45.50%) of females. Conclusion The current study proposes possible risk factors, mechanisms, and clinical profiles to be validated in future concussions studies with larger female sample sizes. Understanding specific risk factors, concussion mechanisms, and clinical profiles of concussion in collegiate ice hockey may generate ideas for future concussion prevention or intervention studies., Graphical Abstract Image, graphical abstract

Symptom resolution is a key marker in determining fitness for return to activity following concussion, but in some cases, distinguishing persistent symptoms due to concussion versus symptoms related to other factors can be challenging. To determine base rates of postconcussional syndrome (PCS) diagnostic categorization in healthy cadets and student athletes with no recent concussion. 13,009 cadets and 21,006 student athletes completed baseline preseason testing. After inclusion/exclusion criteria were applied, the final sample included 12,039 cadets [9123 men (75.8%); 2916 women (24.2%)] and 18,548 student athletes [10,192 men (54.9%); 8356 women (45.1%)]. Participants completed the Sport Concussion Assessment Tool–3rd Edition (SCAT3) symptom evaluation as part of baseline preseason testing. The PCS diagnostic categorization was classified by the International Classification of Diseases, 10th Revision (ICD-10) symptom criteria for PCS. In the absence of recent concussion, subgroups of cadets (17.8% of men; 27.6% of women) and student athletes (11.4% of men; 20.0% of women) reported a cluster of symptoms that would meet the ICD-10 symptom criteria for PCS. Participants with insufficient sleep and/or preexisting conditions (e.g., mental health problems), freshmen cadets, and cadets at the U.S. Coast Guard Academy and at the U.S. Air Force Academy (freshmen were tested during basic cadet training) were more likely to report a cluster of symptoms that would meet the ICD-10 symptom criteria for PCS. The ICD-10 symptom criteria for PCS can be mimicked by preexisting conditions, insufficient sleep, and/or stress. Findings support person-specific assessment and management of symptoms following concussion.

Increasing attention is directed on identifying aspects of football participation for targeted policy change that reduces concussion risk. Prior work evaluated concussion risk during the pre- and regular-seasons, leaving the spring season largely unexplored. This nationally representative observational investigation of 19 Division I collegiate football programs evaluated concussion rates and head impact exposure during the pre-season, regular season, and spring practices from 2014-2019. All participating programs recorded incidence concussions and a subset (n=6) also measured head impact exposure. Analyses by time of year and session type indicated concussion rates and head impact exposure during all practice sessions and contact only practices were significantly higher in the spring and pre-season compared to the regular season (p's0.05). Concussion rates during the spring season and pre-season were statistically similar. This investigation identified comparable concussion risk between the spring and pre-seasons, highlighting the need for targeted policy intervention to protect athlete health and safety.

Recent literature has indicated altitude may be a protective factor for concussion but it is unknown whether altitude or heat index affects recovery. To examine whether on-field heat index and altitude at the time of injury alter acute (

To optimally care for concussed individuals, a multi-dimensional approach is critical and a key component of this assessment in the athletic environment is computer-based neurocognitive testing. However, there continues to be concerns about the reliability and validity of these testing tools. The purpose of this study was to determine the sensitivity and specificity of three common computer-based neurocognitive tests (Immediate Post-Concussion Assessment and Cognitive Testing [ImPACT], CNS Vital Signs, and CogState Computerized Assessment Tool [CCAT]), to provide guidance on their clinical utility. This study analyzed assessments from a cohort of collegiate athletes and non-varsity cadets from the NCAA-DoD CARE Consortium. The data were collected from 2014–2018. Study participants were divided into two testing groups [concussed, n = 1414 (baseline/24–48 h) and healthy, n = 8305 (baseline/baseline)]. For each test type, change scores were calculated for the components of interest. Then, the Normative Change method, which used normative data published in a similar cohort, and the Reliable Change Index (RCI) method were used to determine if the change scores were significant. Using the Normative Change method, ImPACT performed best with an 87.5%-confidence interval and 1 number of components failed (NCF; sensitivity = 0.583, specificity = 0.625, F1 = 0.308). CNS Vital Signs performed best with a 90%-confidence interval and 1 NCF (sensitivity = 0.587, specificity = 0.532, F1 = 0.314). CCAT performed best when using a 75%-confidence interval and 2 NCF (sensitivity = 0.513, specificity = 0.715, F1 = 0.290). When using the RCI method, ImPACT performed best with an 87.5%-confidence interval and 1 NCF (sensitivity = 0.626, specificity = 0.559, F1 = 0.297). When considering all three computer-based neurocognitive tests, the overall low sensitivity and specificity results provide additional evidence for the use of a multi-dimensional assessment for concussion diagnosis, including symptom evaluation, postural control assessment, neuropsychological status, and other functional assessments.

Concussion tolerance and head impact exposure are highly variable among football players. Recent findings highlight that head impact data analyses need to be performed at the subject level. In this paper, we describe a method of characterizing concussion risk between individuals using a new survival analysis technique developed with real-world head impact data in mind. Our approach addresses the limitations and challenges seen in previous risk analyses of football head impact data. Specifically, this demonstrative analysis appropriately models risk for a combination of left-censored recurrent events (concussions) and right-censored recurrent non-events (head impacts without concussion). Furthermore, the analysis accounts for uneven impact sampling between players. In brief, we propose using the Consistent Threshold method to develop subject-specific risk curves and then determine average risk point estimates between subjects at injurious magnitude values. We describe an approach for selecting an optimal cumulative distribution function to model risk between subjects by minimizing injury prediction error. We illustrate that small differences in distribution fit can result in large predictive errors. Given the vast amounts of on-field data researchers are collecting across sports, this approach can be applied to develop population-specific risk curves that can ultimately inform interventions that reduce concussion incidence.

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 (R2 = 0.031, p = 0.012) at 24–48 hours following injury and lower (better) BSI-18 Somatization subscores (R2 = 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.

INTRODUCTION: Concern surrounding short- and long-term consequences of participation in contact sports has become a significant public health topic. Previous literature utilizing diffusion tensor imaging in sports-related concussion has exhibited notable variety of analysis methods and analyzed regions of interest, and largely focuses on acute effects of concussion. The current study aimed to compare diffusivity metrics across a single season within athlete cohorts with no history of concussion. METHODS: A prospective cohort of 75 contact and 79 non-contact division I athletes were compared across diffusion tensor imaging metrics (i.e., TRACULA); examinations were also performed assessing the relationship between neuroimaging metrics, head impact exposure metrics (in-helmet accelerometer), and neurocognitive variables. Assessment occurred at pre-and post-season time points. RESULTS: Seasonal changes in fractional anisotropy and mean diffusivity values did not differ between athlete cohorts, nor did they differ within cohort groups, across pre- and post-season scans. Specific to contact athletes, positive associations were found between uncinate fasciculus mean diffusivity values and season linear acceleration (p = .018), season rotational acceleration (p = .017), and season hit severity (p = .021). CONCLUSIONS: Results suggest an influence of impact frequency, type, and severity on white matter integrity in select brain regions in contact athletes. Current findings expand our knowledge of anatomical changes over the course of a single season, and underscore the importance of considering methodology when interpreting findings in this population, as differing image analysis techniques may lead to different conclusions regarding significant effects.

ObjectiveTo study longitudinal recovery trajectories of white matter after sports-related concussion (SRC) by performing diffusion tensor imaging (DTI) on collegiate athletes who sustained SRC.MethodsCollegiate athletes (n = 219, 82 concussed athletes, 68 contact-sport controls, and 69 non–contact-sport controls) were included from the Concussion Assessment, Research and Education Consortium. The participants completed clinical assessments and DTI at 4 time points: 24 to 48 hours after injury, asymptomatic state, 7 days after return-to-play, and 6 months after injury. Tract-based spatial statistics was used to investigate group differences in DTI metrics and to identify white-matter areas with persistent abnormalities. Generalized linear mixed models were used to study longitudinal changes and associations between outcome measures and DTI metrics. Cox proportional hazards model was used to study effects of white-matter abnormalities on recovery time.ResultsIn the white matter of concussed athletes, DTI-derived mean diffusivity was significantly higher than in the controls at 24 to 48 hours after injury and beyond the point when the concussed athletes became asymptomatic. While the extent of affected white matter decreased over time, part of the corpus callosum had persistent group differences across all the time points. Furthermore, greater elevation of mean diffusivity at acute concussion was associated with worse clinical outcome measures (i.e., Brief Symptom Inventory scores and symptom severity scores) and prolonged recovery time. No significant differences in DTI metrics were observed between the contact-sport and non–contact-sport controls.ConclusionsChanges in white matter were evident after SRC at 6 months after injury but were not observed in contact-sport exposure. Furthermore, the persistent white-matter abnormalities were associated with clinical outcomes and delayed recovery time.

Context Assessments of the duration of concussion recovery have primarily been limited to sport-related concussions and male contact sports. Furthermore, whereas durations of symptoms and return-to-activity (RTA) protocols encompass total recovery, the trajectory of each duration has not been examined separately. Objective To identify individual (eg, demographics, medical history), initial concussion injury (eg, symptoms), and external (eg, site) factors associated with symptom duration and RTA-protocol duration after concussion. Design Cohort study. Setting Three US military service academies. Patients or Other Participants A total of 10 604 cadets at participating US military service academies enrolled in the study and completed a baseline evaluation and up to 5 postinjury evaluations. A total of 726 cadets (451 men, 275 women) sustained concussions during the study period. Main Outcome Measure(s) Number of days from injury (1) until the participant became asymptomatic and (2) to complete the RTA protocol. Results Varsity athlete cadets took less time than nonvarsity cadets to become asymptomatic (hazard ratio [HR] = 1.75, 95% confidence interval = 1.38, 2.23). Cadets who reported less symptom severity on the Sport Concussion Assessment Tool, third edition (SCAT3), within 48 hours of concussion had 1.45 to 3.77 times shorter symptom-recovery durations than those with more symptom severity. Similar to symptom duration, varsity status was associated with a shorter RTA-protocol duration (HR = 1.74, 95% confidence interval = 1.34, 2.25), and less symptom severity on the SCAT3 was associated with a shorter RTA-protocol duration (HR range = 1.31 to 1.47). The academy that the cadet attended was associated with the RTA-protocol duration (P < .05). Conclusions The initial total number of symptoms reported and varsity athlete status were strongly associated with symptom and RTA-protocol durations. These findings suggested that external (varsity status and academy) and injury (symptom burden) factors influenced the time until RTA.

Depression is common among patients with neurologic disorders, and it has long been considered more difficult to treat than depression in the general population. In this review, the authors consider challenges in the diagnosis and treatment of depression among patients with stroke, traumatic brain injury, Parkinson's disease, and multiple sclerosis. For each disorder, the authors discuss the epidemiology and time course of depression as well as review the physiologic and psychological etiologies of depression. In addition, for each disorder, they review screening tools and diagnostic considerations, including differential diagnosis; discuss etiological factors, both neurobiological and psychological; and assess evidence for various depression treatments, including pharmacologic, psychosocial, and neuromodulatory therapies. The evidence suggests that depression is common among patients with neurologic disorders and that it is crucial for general psychiatrists to provide treatment for this population.

Continued participation after sport-related concussion (SRC) worsens outcomes, but it is unknown if duration of continued participation after SRC impacts recovery outcomes, and which athletes who continue to participate are at greatest risk for poor SRC outcomes. The purpose of this National Collegiate Athletic Association/Department of Defense (NCAA/DoD) Concussion Assessment, Research, and Education (CARE) Consortium study was to evaluate the association of estimated duration of continued participation after SRC with symptom severity and recovery time in collegiate athletes.Clinicians estimated if/how long athletes continued participation after SRC. Collegiate athletes who continued participation after suspected SRC (n = 195/373, 52.3%) completed the Graded Symptom Checklist to evaluate the severity of total symptoms and migraine/fatigue, cognitive/ocular, and affective symptom clusters. Linear regression analyzed the associations between estimated duration of continued participation, symptom severity, and recovery time. Binary logistic regression examined the association of estimated duration of continued participation with the odds of recovery ≥ 14 and ≥ 21 days. Statistical significance was p 0.05.Athletes who continued to participate did so for 27.9 ± 25.3 min (mean ± standard deviation; range 1-90 min). Longer estimated continued participation (1-90 min) was associated with greater symptom severity (β = 0.122, p = 0.02), affective (β = 0.171, p = 0.001) and migraine/fatigue symptoms (β = 0.104, p = 0.049), longer symptom duration (β = 0.193, p 0.001), and longer time missed (β = 0.156, p = 0.003). Longer estimated continued participation positively interacted with female sex (cognitive/ocular: female RLonger estimated duration of continued participation after SRC was associated with higher symptom severity, particularly affective and migraine/fatigue; longer symptom duration; and more time missed from sport. SRC outcomes in those who continue to play may be especially severe for female athletes, athletes with migraine history, and athletes with prior concussion(s). The findings can help clinicians and administrators to educate athletes on the importance of immediate removal following a suspected SRC.

Current protein biomarkers are only moderately predictive at identifying individuals with mild traumatic brain injury or concussion. Therefore, more accurate diagnostic markers are needed for sport-related concussion.This was a multicenter, prospective, case-control study of athletes who provided blood samples and were diagnosed with a concussion or were a matched non-concussed control within the National Collegiate Athletic Association-Department of Defense Concussion Assessment, Research, and Education Consortium conducted between 2015 and 2019. The blood was collected within 48 h of injury to identify protein abnormalities at the acute and subacute timepoints. Athletes with concussion were divided into 6 h post-injury (0-6 h post-injury) and after 6 h post-injury (7-48 hours post-injury) groups. We applied a highly multiplexed proteomic technique that used a DNA aptamers assay to target 1305 proteins in plasma samples from athletes with and without sport-related concussion.A total of 140 athletes with concussion (79.3% male; aged 18.71 ± 1.10 years, mean ± SD) and 21 non-concussed athletes (76.2% male; 19.14 ± 1.10 years) were included in this study. We identified 338 plasma proteins that significantly differed in abundance (319 upregulated and 19 downregulated) in concussed athletes compared to non-concussed athletes. The top 20 most differentially abundant proteins discriminated concussed athletes from non-concussed athletes with an area under the curve of 0.954 (95% confidence interval: 0.922‒0.986). Specifically, after 6 h of injury, the individual area under the curve of plasma erythrocyte membrane protein band 4.1 (EPB41) and alpha-synuclein were 0.956 and 0.875, respectively. The combination of EPB41 and alpha-synuclein provided the best area under the curve (1.000), which suggests this combination of candidate plasma biomarkers is best for diagnosing concussion in athletes after 6 h of injury.Our data suggest that proteomic profiling may provide novel diagnostic protein markers and that a combination of EPB41 and alpha-synuclein is the most predictive biomarker of concussion after 6 h of injury.

Contact sport athletes are exposed to a unique environment where they sustain repeated head impacts throughout the season and can sustain hundreds of head impacts over a few months. Accordingly, recent studies outlined the role that head impact exposure (HIE) has in concussion biomechanics and in the development of cognitive and brain-based changes. Those studies focused on time-bound effects by quantifying exposure leading up to the concussion, or cognitive changes after a season in which athletes had high HIE. However, HIE may have a more prolonged effect. This study identified associations between HIE and concussion incidence during different periods of the college football fall season.This study included 1120 athlete seasons from six National Collegiate Athletic Association Division I football programs across 5 yr. Athletes were instrumented with the Head Impact Telemetry System to record daily HIE. The analysis quantified associations of preseason/regular season/total season concussion incidence with HIE during those periods.Strong associations were identified between HIE and concussion incidence during different periods of the season. Preseason HIE was associated with preseason and total season concussion incidence, and total season HIE was associated with total season concussion incidence.These findings demonstrate a prolonged effect of HIE on concussion risk, wherein elevated preseason HIE was associated with higher concussion risk both during the preseason and throughout the entire fall season. This investigation is the first to provide evidence supporting the hypothesis of a relationship between elevated HIE during the college football preseason and a sustained decreased tolerance for concussion throughout that season.

Background: Current consensus and position statements recommend that concussed patients be asymptomatic upon the initiation of the graduated return to activity (RTA) protocol. However, a significant number of concussed patients are beginning their RTA protocols while endorsing symptoms. Purpose: To characterize symptom endorsement at the beginning of the RTA protocol and examine the association between symptom endorsement and RTA protocol duration in service academy cadets. Study Design: Cohort study; Level of evidence, 2. Methods: A prospective cohort study was conducted with cadets at 3 US service academies. Postconcussion symptom inventories were recorded upon the initiation of an RTA protocol. The Sport Concussion Assessment Tool Symptom Inventory was used to classify participants into 3 groups (0 symptoms, 1 symptom, and ≥2 symptoms) upon the initiation of the RTA protocol. The primary outcome of interest was RTA protocol duration. Kaplan-Meier survival estimates were calculated to estimate RTA protocol duration by symptom endorsement, sex, varsity status, academic break, and time to graduated RTA initiation. Univariate and multivariable Cox proportional hazards models were used to estimate the association between symptom endorsement at the initiation of the RTA protocol and RTA protocol duration (α < .05). Results: Data were analyzed from 966 concussed cadets (36% women). Headache (42%) and faintness/dizziness (44%) were the most commonly endorsed symptoms on the Sport Concussion Assessment Tool-Third Edition and the Brief Symptom Inventory-18, respectively. Univariate results revealed a significant association between endorsing ≥2 symptoms and RTA protocol duration. In the multivariable model, endorsing ≥2 symptoms maintained a statistically significant association with RTA protocol duration. Significant associations were observed between RTA protocol duration and nonvarsity status (27% longer), women (15% longer), academic breaks (70% longer), and time to the initiation of the RTA protocol (1.1% longer daily incremental increase) after controlling for covariates. Conclusion: Symptom endorsement at the initiation of an RTA protocol was associated with RTA protocol duration. Cadets who had returned to preinjury baseline symptom burden or improved from baseline symptom burden and endorsed ≥2 symptoms at the initiation of the RTA protocol took longer to RTA.

Mild Traumatic brain injury (mTBI) is a signature wound in military personnel, and repetitive mTBI has been linked to age-related neurogenerative disorders that affect white matter (WM) in the brain. However, findings of injury to specific WM tracts have been variable and inconsistent. This may be due to the heterogeneity of mechanisms, etiology, and comorbid disorders related to mTBI. Non-negative matrix factorization (NMF) is a data-driven approach that detects covarying patterns (components) within high-dimensional data. We applied NMF to diffusion imaging data from military Veterans with and without a self-reported TBI history. NMF identified 12 independent components derived from fractional anisotropy (FA) in a large dataset (n= 1,475) gathered through the ENIGMA (Enhancing Neuroimaging Genetics through Meta-Analysis) Military Brain Injury working group. Regressions were used to examine TBI- and mTBI-related associations in NMF-derived components while adjusting for age, sex, post-traumatic stress disorder, depression, and data acquisition site/scanner. We found significantly stronger age-dependent effects of lower FA in Veterans with TBI than Veterans without in four components (q&nbsp

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. National Institute of Neurological Disorders and Stroke of the National Institutes of Health [1R01NS126449]; Grand Alliance Concussion Assessment, Research, and Education (CARE) Consortium - National Collegiate Athletic Association (NCAA); Department of Defense (DOD); Office of the Assistant Secretary of Defense for Health Affairs [W81XWH-14-2-0151]; Veterans Affairs Medical Research Published version Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number 1R01NS126449. This publication was also made possible with support from the Grand Alliance Concussion Assessment, Research, and Education (CARE) Consortium, funded in part by the National Collegiate Athletic Association (NCAA) and the Department of Defense (DOD). The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Psychological Health and Traumatic Brain Injury Program under Award NO W81XWH-14-2-0151. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense (DHP funds). This study was also supported by Veterans Affairs Medical Research. The authors would also like to thank Jody Harland, MS, Janetta Matesan, BA, Michael Menser, Larry Riggen, MS (Indiana University School of Medicine); Ashley Rettmann, BS, Nicole L'Heureux, MBA (University of Michigan); Melissa Koschnitzke, MA (Medical College of Wisconsin); Michael Jarrett, MBA, Vibeke Brinck, MS and Bianca Byrne, BA (Quesgen); Melissa Baker, BS (Datalys Center for Sports Injury Research and Prevention); and the research and medical staff at each of the CARE participation sites. The team would also like to acknowledge the HIT System operators that participated in this study: Julia Ford (UNC), Philippe Gagnon-Joseph (UNC), Miranda Kruse (UNC), Gus Hendricks (UCLA), Quinn Lukens (UW), Brett Griesemer (VT), Alex Black (VT), Lewis Young (VT), Dom Calhoun (USAFA), Mike Aderman (USMA), Sean Roach (USMA), and Jeremy Ross (USMA).

Key Points Question Are different patterns of intracranial injury on head computed tomography associated with prognosis after mild traumatic brain injury (mTBI)? Findings In this cohort study, subarachnoid hemorrhage, subdural hematoma, and contusion often co-occurred and were associated with both incomplete recovery and more severe impairment out to 12 months after injury, while intraventricular and/or petechial hemorrhage co-occurred and were associated with more severe impairment up to 12 months after injury; epidural hematoma was associated with incomplete recovery at some points but not with more severe impairment. Some intracranial hemorrhage patterns were more strongly associated with outcomes than previously validated demographic and clinical variables. Meaning In this study, different pathological features on head computed tomography carried different implications for mild traumatic brain injury prognosis to 1 year., The longitudinal, observational study aims to identify pathological computed tomography features associated with adverse outcomes after mild traumatic brain injury., Importance A head computed tomography (CT) with positive results for acute intracranial hemorrhage is the gold-standard diagnostic biomarker for acute traumatic brain injury (TBI). In moderate to severe TBI (Glasgow Coma Scale [GCS] scores 3-12), some CT features have been shown to be associated with outcomes. In mild TBI (mTBI; GCS scores 13-15), distribution and co-occurrence of pathological CT features and their prognostic importance are not well understood. Objective To identify pathological CT features associated with adverse outcomes after mTBI. Design, Setting, and Participants The longitudinal, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study enrolled patients with TBI, including those 17 years and older with GCS scores of 13 to 15 who presented to emergency departments at 18 US level 1 trauma centers between February 26, 2014, and August 8, 2018, and underwent head CT imaging within 24 hours of TBI. Evaluations of CT imaging used TBI Common Data Elements. Glasgow Outcome Scale–Extended (GOSE) scores were assessed at 2 weeks and 3, 6, and 12 months postinjury. External validation of results was performed via the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Data analyses were completed from February 2020 to February 2021. Exposures Acute nonpenetrating head trauma. Main Outcomes and Measures Frequency, co-occurrence, and clustering of CT features; incomplete recovery (GOSE scores

Context Preseason testing can be time intensive and cost prohibitive. Therefore, using normative data for postconcussion interpretation in lieu of preseason testing is desirable. Objective To establish the recovery trajectory for clinical reaction time (RTclin) and assess the usefulness of changes from baseline (comparison of postconcussion scores with individual baseline scores) and norm-based cutoff scores (comparison of postconcussion scores with a normative mean) for identifying impairments postconcussion. Design Case-control study. Setting Multisite clinical setting. Patients or Other Participants An overlapping sample of 99 participants (age = 19.0 ± 1.1 years) evaluated within 6 hours postconcussion, 176 participants (age = 18.9 ± 1.1 years) evaluated at 24 to 48 hours postconcussion, and 214 participants (age = 18.9 ± 1.1 years) evaluated once they were cleared to begin a return-to-play progression were included. Participants with concussion were compared with 942 control participants (age = 19.0 ± 1.0 years) who did not sustain a concussion during the study period but completed preseason baseline testing at 2 points separated by 1 year (years 1 and 2). Main Outcome Measure(s) At each time point, follow-up RTclin (ie, postconcussion or year 2) was compared with the individual year 1 preseason baseline RTclin and normative baseline data (ie, sex and sport specific). Receiver operating characteristic curves were calculated to compare the sensitivity and specificity of RTclin change from baseline and norm-based cutoff scores. Results Clinical reaction time performance declined within 6 hours (18 milliseconds, 9.2% slower than baseline). The decline persisted at 24 to 48 hours (15 milliseconds, 7.6% slower than baseline), but performance recovered by the time of return-to-play initiation. Within 6 hours, a change from baseline of 16 milliseconds maximized combined sensitivity (52%) and specificity (79%, area under the curve [AUC] = 0.702), whereas a norm-based cutoff score of 19 milliseconds maximized combined sensitivity (46%) and specificity (86%, AUC = 0.700). At 24 to 48 hours, a change from baseline of 2 milliseconds maximized combined sensitivity (64%) and specificity (61%, AUC = 0.666), whereas a norm-based cutoff score of 0 milliseconds maximized combined sensitivity (63%) and specificity (62%, AUC = 0.647). Conclusions Norm-based cutoff scores can be used for interpreting RTclin scores postconcussion in collegiate athletes when individual baseline data are not available, although low sensitivity and specificity limit the use of RTclin as a stand-alone test.