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.

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.

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

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

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.

Increased [18F]Fluorodeoxyglucose Uptake in the Left Pallidum in Military Veterans with Blast-Related Mild Traumatic Brain Injury: Potential as an Imaging Biomarker and Mediation with Executive Dysfunction and Cognitive Impairment.

Blast-related mild traumatic brain injury (blast-mTBI) can result in a spectrum of persistent symptoms leading to substantial functional impairment and reduced quality of life. Clinical evaluation and discernment from other conditions common to military service can be challenging and subject to patient recall bias and the limitations of available assessment measures. The need for objective biomarkers to facilitate accurate diagnosis, not just for symptom management and rehabilitation but for prognostication and disability compensation purposes is clear. Toward this end, we compared regional brain [18F]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) intensity-scaled uptake measurements and motor, neuropsychological, and behavioral assessments in 79 combat Veterans with retrospectively recalled blast-mTBI with 41 control participants having no lifetime history of TBI. Using an agnostic and unbiased approach, we found significantly increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI versus control participants, p < 0.0001; q = 3.29 × 10-9 [Cohen's d, 1.38, 95% confidence interval (0.96, 1.79)]. The degree of left pallidum [18F]FDG-uptake correlated with the number of self-reported blast-mTBIs, r2 = 0.22; p < 0.0001. Greater [18F]FDG-uptake in the left pallidum provided excellent discrimination between Veterans with blast-mTBI and controls, with a receiver operator characteristic area under the curve of 0.859 (p < 0.0001) and likelihood ratio of 21.19 (threshold:SUVR ≥ 0.895). Deficits in executive function assessed using the Behavior Rating Inventory of Executive Function-Adult Global Executive Composite T-score were identified in Veterans with blast-mTBI compared with controls, p < 0.0001. Regression-based mediation analyses determined that in Veterans with blast-mTBI, increased [18F]FDG-uptake in the left pallidum-mediated executive function impairments, adjusted causal mediation estimate p = 0.021; total effect estimate, p = 0.039. Measures of working and prospective memory (Auditory Consonant Trigrams test and Memory for Intentions Test, respectively) were negatively correlated with left pallidum [18F]FDG-uptake, p < 0.0001, with mTBI as a covariate. Increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI compared with controls did not covary with dominant handedness or with motor activity assessed using the Unified Parkinson's Disease Rating Scale. Localized increased [18F]FDG-uptake in the left pallidum may reflect a compensatory response to functional deficits following blast-mTBI. Limited imaging resolution does not allow us to distinguish subregions of the pallidum; however, the significant correlation of our data with behavioral but not motor outcomes suggests involvement of the ventral pallidum, which is known to regulate motivation, behavior, and emotions through basal ganglia-thalamo-cortical circuits. Increased [18F]FDG-uptake in the left pallidum in blast-mTBI versus control participants was consistently identified using two different PET scanners, supporting the generalizability of this finding. Although confirmation of our results by single-subject-to-cohort analyses will be required before clinical deployment, this study provides proof of concept that [18F]FDG-PET bears promise as a readily available noninvasive biomarker for blast-mTBI. Further, our findings support a causative relationship between executive dysfunction and increased [18F]FDG-uptake in the left pallidum.

Cumulative Blast Impulse Is Predictive for Changes in Chronic Neurobehavioral Symptoms Following Low Level Blast Exposure during Military Training.

INTRODUCTION: Cumulative low-level blast exposure during military training may be a significant occupational hazard, increasing the risk of poor long-term outcomes in brain function. US Public Law 116-92 section 717 mandates that US Department of Defense agencies document the blast exposure of each Service member to help inform later disability and health care decisions. However, which empirical measures of training blast exposure, such as the number of incidents, peak overpressure, or impulse, best inform changes in the neurobehavioral symptoms reflecting brain health have not been established. MATERIALS AND METHODS: This study was approved by the US Army Special Operations Command, the University of North Carolina at Chapel Hill, and the VA Puget Sound Health Care System. Using methods easily deployable across different organizational structures, this study sought to identify and measure candidate risk factors related to career occupational blast exposure predictive of changes in neurobehavioral symptom burden. Blast dosimetry-symptom relationships were first evaluated in mice and then tested in a military training environment. In mice, the righting time neurobehavioral response was measured after exposure to a repetitive low-level blast paradigm modeled after Special Operations training. In the military training environment, 23 trainees enrolled in a 6-week explosive breaching training course, 13 instructors, and 10 Service member controls without blast exposure participated in the study (46 total). All participants provided weekly Neurobehavioral Symptom Inventory (NSI) surveys. Peak blast overpressure, impulse, total number of blasts, Time in Low-Level Blast Occupation, and Time in Service were analyzed by Bayesian analysis of regression modeling to determine their probability of influence on the post-training symptoms reported by participants. RESULTS: We tested the hypothesis that cumulative measures of low-level blast exposure were predictive of changes in neurobehavioral symptoms. In mice, repetitive blast resulted in reduced righting times correlated with cumulative blast impulse. In Service members, peak blast overpressure, impulse, total number of blasts, Time in Low-Level Blast Occupation, and Time in Service all showed strong evidence of influence on NSI scores after blast exposure. However, only models including baseline NSI scores and cumulative blast impulse provided significant predictive value following validation. CONCLUSIONS: These results indicate that measures of cumulative blast impulse may have utility in predicting changes in NSI scores. Such paired dosimetry-symptom measures are expected to be an important tool in safely guiding Service members' occupational exposure and optimizing force readiness and lethality.

Comparison of Kinematics for Head Impacts Initiated by Helmets and Shoulder Pads Among High School American Football Athletes.

Helmets and shoulder pads are required equipment intended to protect American football athletes by attenuating collision forces during participation. Surprisingly, research differentiating kinematics from head impacts initiated by helmets from those initiated by shoulder pads among adolescent athletes has not been completed. The current study's purpose was to determine the effects of equipment on head impact kinematics. Sixty-nine male American football athletes from three high schools wore helmets equipped with Head Impact Telemetry (HIT) System instrumentation to quantify peak linear (g) and rotational (rad/s2) accelerations. Data were extracted for video-confirmed impacts during two competitions. Separate multivariable linear regressions using ordinary least squares were conducted to determine if equipment type (helmet vs. shoulder pad) was associated with log-transformed linear and rotational accelerations. In total, 1150 video-confirmed impacts involved helmet (N = 960) or shoulder pad (N = 190) initiated contact. Linear (p = 0.809) and rotational (p = 0.351) acceleration were not associated with equipment type. Head impact kinematics were similar between impacts initiated by either helmets or shoulder pads and suggests an opponent's shoulder pads and helmet can deliver comparable forces to the struck player. Equipment manufacturers may need to consider the unintended role shoulder pads may contribute to head injury risk.

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.

Mild Traumatic Brain Injury and Career Stage Associate with Visible Perivascular Spaces in Special Operations Forces Soldiers.

Mild traumatic brain injury (mTBI) and occupational blast exposure in military Service Members may lead to impaired brain waste clearance which increases neurological disease risk. Perivascular spaces (PVS) are a key part of the glymphatic system which supports brain waste clearance, preferentially during sleep. Visible PVS on clinical magnetic resonance imaging have been previously observed in patients with neurodegenerative diseases and animal neurotrauma models. The purpose of this study was to determine associations between PVS morphological characteristics, military career stage, and mTBI history in Special Operations Forces (SOF) Soldiers. Participants underwent T2-weighed neuroimaging to capture three-dimensional whole brain volumes. Segmentation was performed using a previously validated, multi-scale deep convolutional encoder-decoder neural network. Only PVS clusters within the white matter mask were quantified for analyses. Due to non-normal PVS metric distribution, non-parametric Mann-Whitney U tests were used to determine group differences in PVS outcomes. In total, 223 healthy SOF combat Soldiers (age = 33.1 ± 4.3yrs) were included, 217 reported career stage. Soldiers with mTBI history had greater PVS number (z = 2.51, P = 0.013) and PVS volume (z = 2.42, P = 0.016). In-career SOF combat Soldiers had greater PVS number (z = 2.56, P = 0.01) and PVS volume (z = 2.28, P = 0.02) compared to a baseline cohort. Mild TBI history is associated with increased PVS burden in SOF combat Soldiers that are clinically recovered from mTBI. This may indicate ongoing physiological changes that could lead to impaired waste clearance via the glymphatic system. Future studies should determine if PVS number and volume are meaningful neurobiological outcomes for neurodegenerative disease risk and if clinical interventions such as improving sleep can reduce PVS burden.

Efficacy of Guardian Cap Soft-Shell Padding on Head Impact Kinematics in American Football: Pilot Findings.

Sport-related concussion prevention strategies in collision sports are a primary interest for sporting organizations and policy makers. After-market soft-shell padding purports to augment the protective capabilities of standard football helmets and to reduce head impact severity. We compared head impact kinematics [peak linear acceleration (PLA) and peak rotational acceleration (PRA)] in athletes wearing Guardian Cap soft-shell padding to teammates without soft-shell padding. Ten Division I college football players were enrolled [soft-shell padding (SHELL) included four defensive linemen and one tight end; non-soft-shell (CONTROL) included two offensive linemen, two defensive linemen, and one tight end]. Participants wore helmets equipped with the Head Impact Telemetry System to quantify PLA (g) and PRA (rad/s2) during 14 practices. Two-way ANOVAs were conducted to compare log-transformed PLA and PRA between groups across helmet location and gameplay characteristics. In total, 968 video-confirmed head impacts between SHELL (n = 421) and CONTROL (n = 547) were analyzed. We observed a Group x Stance interaction for PRA (F1,963 = 7.21; p = 0.007) indicating greater PRA by SHELL during 2-point stance and lower PRA during 3- or 4-point stances compared to CONTROL. There were no between-group main effects. Protective soft-shell padding did not reduce head impact kinematic outcomes among college football athletes.

Plasma phosphorylated tau181 as a biomarker of mild traumatic brain injury: findings from THINC and NCAA-DoD CARE Consortium prospective cohorts.

Objective: The aim of this study was to investigate phosphorylated tau (p-tau181) protein in plasma in a cohort of mild traumatic brain injury (mTBI) patients and a cohort of concussed athletes. Methods: This pilot study comprised two independent cohorts. The first cohort-part of a Traumatic Head Injury Neuroimaging Classification (THINC) study-with a mean age of 46 years was composed of uninjured controls (UIC, n = 30) and mTBI patients (n = 288) recruited from the emergency department with clinical computed tomography (CT) and research magnetic resonance imaging (MRI) findings. The second cohort-with a mean age of 19 years-comprised 133 collegiate athletes with (n = 112) and without (n = 21) concussions. The participants enrolled in the second cohort were a part of a multicenter, prospective, case-control study conducted by the NCAA-DoD Concussion Assessment, Research and Education (CARE) Consortium at six CARE Advanced Research Core (ARC) sites between 2015 and 2019. Blood was collected within 48 h of injury for both cohorts. Plasma concentration (pg/ml) of p-tau181 was measured using the Single Molecule Array ultrasensitive assay. Results: Concentrations of plasma p-tau181 in both cohorts were significantly elevated compared to controls within 48 h of injury, with the highest concentrations of p-tau181 within 18 h of injury, with an area under the curve (AUC) of 0.690-0.748, respectively, in distinguishing mTBI patients and concussed athletes from controls. Among the mTBI patients, the levels of plasma p-tau181 were significantly higher in patients with positive neuroimaging (either CT+/MRI+, n = 74 or CT-/MRI+, n = 89) compared to mTBI patients with negative neuroimaging (CT-/MRI-, n = 111) findings and UIC (P-values < 0.05). Conclusion: These findings indicate that plasma p-tau181 concentrations likely relate to brain injury, with the highest levels in patients with neuroimaging evidence of injury. Future research is needed to replicate and validate this protein assay's performance as a possible early diagnostic biomarker for mTBI/concussions.

Mild traumatic brain injury history is associated with lower brain network resilience in soldiers.

Special Operations Forces combat soldiers sustain frequent blast and blunt neurotrauma, most often classified as mild traumatic brain injuries. Exposure to repetitive mild traumatic brain injuries is associated with persistent behavioural, cognitive, emotional and neurological symptoms later in life. Identifying neurophysiological changes associated with mild traumatic brain injury exposure, in the absence of present-day symptoms, is necessary for detecting future neurological risk. Advancements in graph theory and functional MRI have offered novel ways to analyse complex whole-brain network connectivity. Our purpose was to determine how mild traumatic brain injury history, lifetime incidence and recency affected whole-brain graph theoretical outcome measures. Healthy male Special Operations Forces combat soldiers (age = 33.2 ± 4.3 years) underwent multimodal neuroimaging at a biomedical research imaging centre using 3T Siemens Prisma or Biograph MRI scanners in this cross-sectional study. Anatomical and functional scans were preprocessed. The blood-oxygen-level-dependent signal was extracted from each functional MRI time series using the Big Brain 300 atlas. Correlations between atlas regions were calculated and Fisher z-transformed to generate subject-level correlation matrices. The Brain Connectivity Toolbox was used to obtain functional network measures for global efficiency (the average inverse shortest path length), local efficiency (the average global efficiency of each node and its neighbours), and assortativity coefficient (the correlation coefficient between the degrees of all nodes on two opposite ends of a link). General linear models were fit to compare mild traumatic brain injury lifetime incidence and recency. Nonparametric ANOVAs were used for tests on non-normally distributed data. Soldiers with a history of mild traumatic brain injury had significantly lower assortativity than those who did not self-report mild traumatic brain injury (t148 = 2.44, P = 0.016). The assortativity coefficient was significantly predicted by continuous mild traumatic brain injury lifetime incidence [F1,144 = 6.51, P = 0.012]. No differences were observed between recency groups, and no global or local efficiency differences were observed between mild traumatic brain injury history and lifetime incidence groups. Brain networks with greater assortativity have more resilient, interconnected hubs, while those with lower assortativity indicate widely distributed, vulnerable hubs. Greater lifetime mild traumatic brain injury incidence predicted lower assortativity in our study sample. Less resilient brain networks may represent a lack of physiological recovery in mild traumatic brain injury patients, who otherwise demonstrate clinical recovery, more vulnerability to future brain injury and increased risk for accelerated age-related neurodegenerative changes. Future longitudinal studies should investigate whether decreased brain network resilience may be a predictor for long-term neurological dysfunction.

Longitudinal Associations Between Blood Biomarkers and White Matter MRI in Sport-Related Concussion: A Study of the NCAA-DoD CARE Consortium.

BACKGROUND AND OBJECTIVES: To study longitudinal associations between blood-based neural biomarkers (including total tau, neurofilament light [NfL], glial fibrillary acidic protein [GFAP], and ubiquitin C-terminal hydrolase-L1) and white matter neuroimaging biomarkers in collegiate athletes with sport-related concussion (SRC) from 24 hours postinjury to 1 week after return to play. METHODS: We analyzed clinical and imaging data of concussed collegiate athletes in the Concussion Assessment, Research, and Education (CARE) Consortium. The CARE participants completed same-day clinical assessments, blood draws, and diffusion tensor imaging (DTI) at 3 time points: 24-48 hours postinjury, point of becoming asymptomatic, and 7 days after return to play. DTI probabilistic tractography was performed for each participant at each time point to render 27 participant-specific major white matter tracts. The microstructural organization of these tracts was characterized by 4 DTI metrics. Mixed-effects models with random intercepts were applied to test whether white matter microstructural abnormalities are associated with the blood-based biomarkers at the same time point. An interaction model was used to test whether the association varies across time points. A lagged model was used to test whether early blood-based biomarkers predict later microstructural changes. RESULTS: Data from 77 collegiate athletes were included in the following analyses. Among the 4 blood-based biomarkers, total tau had significant associations with the DTI metrics across the 3 time points. In particular, high tau level was associated with high radial diffusivity (RD) in the right corticospinal tract (ß = 0.25, SE = 0.07, p FDR-adjusted = 0.016) and superior thalamic radiation (ß = 0.21, SE = 0.07, p FDR-adjusted = 0.042). NfL and GFAP had time-dependent associations with the DTI metrics. NfL showed significant associations only at the asymptomatic time point (|ß|s > 0.12, SEs <0.09, psFDR-adjusted < 0.05) and GFAP showed a significant association only at 7 days after return to play (ßs > 0.14, SEs <0.06, psFDR-adjusted < 0.05). The p values for the associations of early tau and later RD were not significant after multiple comparison adjustment, but were less than 0.1 in 7 white matter tracts. DISCUSSION: This prospective study using data from the CARE Consortium demonstrated that in the early phase of SRC, white matter microstructural integrity detected by DTI neuroimaging was associated with elevated levels of blood-based biomarkers of traumatic brain injury. Total tau in the blood showed the strongest association with white matter microstructural changes.

Optimizing Concussion Care Seeking: A Longitudinal Analysis of Recovery.

BACKGROUND: Approximately half of concussions go undisclosed and therefore undiagnosed. Among diagnosed concussions, 51% to 64% receive delayed medical care. Understanding the influence of undiagnosed concussions and delayed medical care would inform medical and education practices. PURPOSE: To compare postconcussion longitudinal clinical outcomes among (1) individuals with no concussion history, all previous concussions diagnosed, and ≥1 previous concussion undiagnosed, as well as (2) those who have delayed versus immediate symptom onset, symptom reporting, and removal from activity after concussion. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Participants included 2758 military academy cadets and intercollegiate athletes diagnosed with concussion in the CARE Consortium. We determined (1) each participant's previous concussion diagnosis status self-reported at baseline (no history, all diagnosed, ≥1 undiagnosed) and (2) whether the participant had delayed or immediate symptom onset, symptom reporting, and removal from activity. We compared symptom severities, cognition, balance, and recovery duration at baseline, 24 to 48 hours, date of asymptomatic status, and date of unrestricted return to activity using tests of parallel profiles. RESULTS: The ≥1 undiagnosed concussion group had higher baseline symptom burdens (P < .001) than the other 2 groups and poorer baseline verbal memory performance (P = .001) than the all diagnosed group; however, they became asymptomatic and returned to activity sooner than those with no history. Cadets/athletes who delayed symptom reporting had higher symptom burdens 24 to 48 hours after injury (mean ± SE; delayed, 28.8 ± 0.8; immediate, 20.6 ± 0.7), took a median difference of 2 days longer to become asymptomatic, and took 3 days longer to return to activity than those who had immediate symptom reporting. For every 30 minutes of continued participation after injury, days to asymptomatic status increased 8.1% (95% CI, 0.3%-16.4%). CONCLUSION: Clinicians should expect that cadets/athletes who delay reporting concussion symptoms will have acutely higher symptom burdens and take 2 days longer to become asymptomatic. Educational messaging should emphasize the clinical benefits of seeking immediate care for concussion-like symptoms.

Are EPB41 and alpha-synuclein diagnostic biomarkers of sport-related concussion? Findings from the NCAA and Department of Defense CARE Consortium.

BACKGROUND: 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. METHODS: 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 h 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. RESULTS: A total of 140 athletes with concussion (79.3% males; aged 18.71 ± 1.10 years, mean ± SD) and 21 non-concussed athletes (76.2% males; 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 (AUC) of 0.954 (95% confidence interval: 0.922‒0.986). Specifically, after 6 h of injury, the individual AUC of plasma erythrocyte membrane protein band 4.1 (EPB41) and alpha-synuclein (SNCA) were 0.956 and 0.875, respectively. The combination of EPB41 and SNCA provided the best AUC (1.000), which suggests this combination of candidate plasma biomarkers is the best for diagnosing concussion in athletes after 6 h of injury. CONCLUSION: Our data suggest that proteomic profiling may provide novel diagnostic protein markers and that a combination of EPB41 and SNCA is the most predictive biomarker of concussion after 6 h of injury.

Cumulative Blast Exposure Estimate Model for Special Operations Forces Combat Soldiers.

Special Operations Forces (SOF) Service members endure frequent exposures to blast and overpressure mechanisms given their high training tempo. The link between cumulative subconcussive blasts on short- and long-term neurological impairment is largely understudied. Neurodegenerative diseases such as brain dysfunction, cognitive decline, mild cognitive impairment, and dementia may develop with chronic exposures. This hypothesis remains unproven because of lack of ecologically valid occupational blast exposure surveillance among SOF Service members. The purpose of the study was to measure occupational blast exposures in a close quarter battle (CQB) training environment and to use those outcomes to develop a pragmatic cumulative blast exposure (CBE) estimate model. Four blast silhouettes equipped with a field-deployable wireless blast gauge system were positioned in breaching positions during CQB training scenarios. Silhouettes were exposed to flashbangs and three interior breaching charges (single strand roll-up interior charge, 300 grain (gr) explosive cutting tape (ECT), and Jelly charge). Mean blast measures were calculated for each silhouette for flashbangs (n = 93), single strand roll-up interior charge (n = 80), 300 gr ECT (n = 28), and Jelly charge (n = 71). Mean peak blast pressures per detonation are reported as follows: (1) flashbangs (1.97 pounds per square inch [psi]); (2) single strand roll-up interior charge (3.88 psi); (3) 300 gr ECT (2.78 psi); and (4) Jelly charge (1.89 psi). Pragmatic CBE estimates for SOF Service members suggest 36.8 psi, 184 psi, and 2760 psi may represent daily, weekly, and training cycle cumulative pressure exposures. Estimating blast exposures during routine CQB training can be determined from empirical measures taken in CQB environments. Factoring in daily, weekly, training cycle, or even career length may reasonably estimate cumulative occupational training blast exposures for SOF Service members. Future work may permit more granular exposure estimates based on operational blast exposures and those experienced by other military occupational specialties.

Consensus Head Acceleration Measurement Practices (CHAMP): Study Design and Statistical Analysis.

Head impact measurement devices enable opportunities to collect impact data directly from humans to study topics like concussion biomechanics, head impact exposure and its effects, and concussion risk reduction techniques in sports when paired with other relevant data. With recent advances in head impact measurement devices and cost-effective price points, more and more investigators are using them to study brain health questions. However, as the field's literature grows, the variance in study quality is apparent. This brief paper aims to provide a high-level set of key considerations for the design and analysis of head impact measurement studies that can help avoid flaws introduced by sampling biases, false data, missing data, and confounding factors. We discuss key points through four overarching themes: study design, operational management, data quality, and data analysis.

The Effect of Sex, Sport, and Preexisting Histories on Baseline Concussion Test Performance in College Lacrosse and Soccer Athletes.

OBJECTIVE: To study sex and sport differences in baseline clinical concussion assessments. A secondary purpose was to determine if these same assessments are affected by self-reported histories of (1) concussion; (2) learning disability; (3) anxiety and/or depression; and (4) migraine. DESIGN: Prospective cohort. SETTING: National Collegiate Athletic Association D1 Universities. PARTICIPANTS: Male and female soccer and lacrosse athletes (n = 237; age = 19.8 ± 1.3 years). ASSESSMENT OF RISK FACTORS: Sport, sex, history of (1) concussion; (2) learning disability; (3) anxiety and/or depression; and (4) migraine. MAIN OUTCOME MEASURES: Sport Concussion Assessment Tool 22-item symptom checklist, Standardized Assessment of Concussion, Balance Error Scoring System (BESS), Generalized Anxiety Disorder 7-item scale, and Patient Health Questionnaire. RESULTS: Female athletes had significantly higher total symptoms endorsed (P = 0.02), total symptom severity (P < 0.001), and BESS total errors (P = 0.01) than male athletes. No other sex, sport, or sex-by-sport interactions were observed (P > 0.05). Previous concussion and migraine history were related to greater total symptoms endorsed (concussion: P = 0.03; migraine: P = 0.01) and total symptom severity (concussion: P = 0.04; migraine: P = 0.02). Athletes with a migraine history also self-reported higher anxiety (P = 0.004) and depression (P = 0.01) scores. No other associations between preexisting histories and clinical concussion outcomes were observed (P > 0.05). CONCLUSIONS: Our findings reinforce the need to individualize concussion assessment and management. This is highlighted by the findings involving sex differences and preexisting concussion and migraine histories. CLINICAL RELEVANCE: Clinicians should fully inventory athletes' personal and medical histories to better understand variability in measures, which may be used to inform return-to-participation decisions following injury.

Active Warfighter Mental Health Lower in Mid-Career.

PURPOSE: The present study investigated Special Operations Forces (SOF) combat Servicemember mental health at different SOF career stages in association with resilience. METHODS: Fifty-eight SOF combat Service Members either entering SOF (career start; n=38) or multiple years with their SOF organization (mid-career; n=20) self-reported mild traumatic brain injury (TBI) history, resilience, subjective well-being, depression, anxiety, and posttraumatic stress. Poisson regression analyses were employed to test SOF career stage differences in each mental health symptom using resilience, while accounting for other pertinent military factors. RESULTS: There were significant interaction effects of SOF career stage and resilience on mental health symptoms. SOF career start combat Servicemembers endorsed lower depression and posttraumatic stress and higher subjective well-being with higher resilience, but these associations between resilience and mental health symptoms were not seen in SOF mid-career Servicemembers. CONCLUSIONS: Although preliminary, the adaptive association between resilience and mental health seemed to be blunted in combat Servicemembers having served multiple years in SOF. This information informs research to provide evaluation tools to support prophylactic performance and long-term health preservation in military populations.

Proteomic Profiling of Plasma Biomarkers Associated With Return to Sport Following Concussion: Findings From the NCAA and Department of Defense CARE Consortium.

Objective: To investigate the plasma proteomic profiling in identifying biomarkers related to return to sport (RTS) following a sport-related concussion (SRC). Methods: This multicenter, prospective, case-control study was part of a larger cohort study conducted by the NCAA-DoD Concussion Assessment, Research, and Education (CARE) Consortium, athletes (n = 140) with blood collected within 48 h of injury and reported day to asymptomatic were included in this study, divided into two groups: (1) recovery <14-days (n = 99) and (2) recovery ≥14-days (n = 41). We applied a highly multiplexed proteomic technique that uses DNA aptamers assay to target 1,305 proteins in plasma samples from concussed athletes with <14-days and ≥14-days. Results: We identified 87 plasma proteins significantly dysregulated (32 upregulated and 55 downregulated) in concussed athletes with recovery ≥14-days relative to recovery <14-days groups. The significantly dysregulated proteins were uploaded to Ingenuity Pathway Analysis (IPA) software for analysis. Pathway analysis showed that significantly dysregulated proteins were associated with STAT3 pathway, regulation of the epithelial mesenchymal transition by growth factors pathway, and acute phase response signaling. Conclusion: Our data showed the feasibility of large-scale plasma proteomic profiling in concussed athletes with a <14-days and ≥ 14-days recovery. These findings provide a possible understanding of the pathophysiological mechanism in neurobiological recovery. Further study is required to determine whether these proteins can aid clinicians in RTS decisions.