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Traumatic brain injury is a major public health problem in the pediatric population. Previously, management was acute emergency department/primary care evaluation with follow-up by primary care. However, persistent symptoms after traumatic brain injury are common, and many do not have access to a specialized traumatic brain injury clinic to manage chronic issues. The goal of this study was to determine the factors related to outcomes, and identify the interventions provided in this subspecialty clinic. Data were extracted from medical records of 151 retrospective and 403 prospective patients. Relationships between sequelae, injury characteristics, and clinical interventions were analyzed. Most patients returning to clinic were not fully recovered from their injury. Headaches were more common after milder injuries, and seizures were more common after severe. The majority of patients received clinical intervention. The presence of persistent sequelae for traumatic brain injury patients can be evaluated and managed by a specialty concussion/traumatic brain injury clinic ensuring that medical needs are met. [ABSTRACT FROM AUTHOR]

Benzofuran, 2-methyl-3-carboxy-5-hydroxy benzofuran and several of its derivatives were studied as growth regulators in germination and seedling growth of turnip, rye and alfalfa. Stimulation was observed in most cases for the benzofuran derivatives, but the patterns of response were varied. [ABSTRACT FROM AUTHOR]

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., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This secondary analysis project was funded by the National Institute of Neurological Disorders and Stroke (R03NS100691 and R01NS110856). The Concussion Assessment, Research and Education (CARE) Consortium studies were supported in part by the National Collegiate Athletic Association and the DOD. The US Army Medical Research Acquisition Activity 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 Combat Casualty Care Research Program, endorsed by the DOD, through the Joint Program Committee 6/Combat Casualty Care Research Program–Psychological Health and Traumatic Brain Injury Research Program (W81XWH1420151 and W81XWH1820047). AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Privilege and marginalization associated with racial background have been posited as contributors to why Black athletes face disparities within their care, treatment, and recovery from sport-related concussion (SRC). However, empirical findings have limited exploration on how disparate outcomes have emerged, and the interaction with systems of biases, power and disenfranchisement. To understand concussion care disparities, a qualitative content analysis was conducted in three phases: [I] identifying salient literature on racial differences for Black athletes with SRC ( N  = 29), [II] qualitative analysis of literature to determine salient topics, themes and patterns within the literature, and [III] constructing a novel ecological-systems framework that encapsulates the 'why' and 'how' related to psychosocial and sociocultural experiences of power, access, and biases for Black athletes. The content analysis yielded two patterns, where concussion care decisions are influenced by (1) biased, unconscious beliefs that posit Black athletes as uniquely invincible to injury and pain, and (2) inadequate access to concussion knowledge and resources, which both moderate SRC injury risk, diagnosis, recovery and outcomes. Ultimately, our novel framework provides a clear thread on how historical, macro-level policy and perceptions can impact micro-level clinical care and decision-making for Black athletes with SRC.

Background and Objectives: After a concussion diagnosis, the most important issue for patients and loved ones is how long it will take them to recover. The main objective of this study is to develop a prognostic model of concussion recovery. This model would benefit many patients worldwide, allowing for early treatment intervention., Methods: The Concussion Assessment, Research and Education (CARE) consortium study enrolled collegiate athletes from 30 sites (NCAA athletic departments and US Department of Defense service academies), 4 of which participated in the Advanced Research Core, which included diffusion-weighted MRI (dMRI) data collection. We analyzed the dMRI data of 51 injuries of concussed athletes scanned within 48 h of injury. All athletes were cleared to return-to-play by the local medical staff following a standardized, graduated protocol. The primary outcome measure is days to clearance of unrestricted return-to-play. Injuries were divided into early (return-to-play < 28 days) and late (return-to-play >= 28 days) recovery based on the return-to-play clinical records. The late recovery group meets the standard definition of Persisting Post-Concussion Symptoms (PPCS). Data were processed using automated, state-of-the-art, rigorous methods for reproducible data processing using brainlife.io. All processed data derivatives are made available at https://brainlife.io/project/63b2ecb0daffe2c2407ee3c5/dataset. The microstructural properties of 47 major white matter tracts, 5 callosal, 15 subcortical, and 148 cortical structures were mapped. Fractional Anisotropy (FA) and Mean Diffusivity (MD) were estimated for each tract and structure. Correlation analysis and Receiver Operator Characteristic (ROC) analysis were then performed to assess the association between the microstructural properties and return-to-play. Finally, a Logistic Regression binary classifier (LR-BC) was used to classify the injuries between the two recovery groups., Results: The mean FA across all white matter volume was negatively correlated with return-to-play (r = -0.38, p = 0.00001). No significant association between mean MD and return-to-play was found, neither for FA nor MD for any other structure. The mean FA of 47 white matter tracts was negatively correlated with return-to-play (rμ = -0.27; rσ = 0.08; r min  = -0.1; r max  = -0.43). Across all tracts, a large mean ROC Area Under the Curve (AUC FA ) of 0.71 ± 0.09 SD was found. The top classification performance of the LR-BC was AUC = 0.90 obtained using the 16 statistically significant white matter tracts., Discussion: Utilizing a free, open-source, and automated cloud-based neuroimaging pipeline and app (https://brainlife.io/docs/tutorial/using-clairvoy/), a prognostic model has been developed, which predicts athletes at risk for slow recovery (PPCS) with an AUC=0.90, balanced accuracy = 0.89, sensitivity = 1.0, and specificity = 0.79. The small number of participants in this study (51 injuries) is a significant limitation and supports the need for future large concussion dMRI studies and focused on recovery., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Broglio has current or past research funding from the National Institutes of Health; Centers for Disease Control and Prevention; Department of Defense – USA Medical Research Acquisition Activity, National Collegiate Athletic Association; National Athletic Trainers’ Association Foundation; National Football League/Under Armour/GE; Simbex; and ElmindA. He has consulted for US Soccer (paid), US Cycling (unpaid), University of Calgary SHRed Concussions external advisory board (unpaid), medico-legal litigation, and received speaker honorarium and travel reimbursements for talks given. He is co-author of “Biomechanics of Injury (3rd edition)” and has a patent on “Brain Metabolism Monitoring Through CCO Measurements Using All-Fiber-Integrated Super-Continuum Source” (U.S. 11,529,091 B2). He is on the and is/was on the editorial boards (all unpaid) for Journal of Athletic Training (2015 to present), Concussion (2014 to present), Athletic Training & Sports Health Care (2008 to present), British Journal of Sports Medicine (2008 to 2019). Thomas McAllister has Concussion Research Grants from NIH; US Dept. of Defense; US Dept. of Energy; and the NCAA. He also has Royalties from American Psychiatric Assoc. Publishing for Textbook of TBI. He is part of the Concussion Scientific Advisory Committee; Australian Football League – uncompensated. Michael McCrea has Research funding to Medical College of Wisconsin from US Dept. of Defense (DoD) and NCAA; Research funding to Medical College of Wisconsin from NIH, VA, DoD, CDC, NFL, NCAA, Abbott Laboratories; Book royalties from Oxford University Press. He is Consultant, Neurotrauma Sciences, Inc.; Consultant, Green Bay Packers; Medical legal consulting. He receives Honoraria and travel support for professional speaking engagements and for professional meetings., (Copyright © 2024. Published by Elsevier Inc.)

Background: The prevalence of unreported concussions is high, and undiagnosed concussions can lead to worse postconcussion outcomes. It is not clear how those with a history of undiagnosed concussion perform on subsequent standard concussion baseline assessments., Purpose: To determine if previous concussion diagnosis status was associated with outcomes on the standard baseline concussion assessment battery., Study Design: Cross-sectional study; Level of evidence, 3., Methods: Concussion Assessment, Research, and Education (CARE) Consortium participants (N = 29,934) self-reported concussion history with diagnosis status and completed standard baseline concussion assessments, including assessments for symptoms, mental status, balance, and neurocognition. Multiple linear regression models were used to estimate mean differences and 95% CIs among concussion history groups (no concussion history [n = 23,037; 77.0%], all previous concussions diagnosed [n = 5315; 17.8%], ≥1 previous concussions undiagnosed [n = 1582; 5.3%]) at baseline for all outcomes except symptom severity and Brief Symptom Inventory-18 (BSI-18) score, in which negative binomial models were used to calculate incidence rate ratios (IRRs). All models were adjusted for sex, race, ethnicity, sport contact level, and concussion count. Mean differences with 95% CIs excluding 0.00 and at least a small effect size (≥0.20), and those IRRs with 95% CIs excluding 1.00 and at least a small association (IRR, ≥1.10) were considered significant., Results: The ≥1 previous concussions undiagnosed group reported significantly greater symptom severity scores (IRR, ≥1.38) and BSI-18 (IRR, ≥1.31) scores relative to the no concussion history and all previous concussions diagnosed groups. The ≥1 previous concussions undiagnosed group performed significantly worse on 6 neurocognitive assessments while performing better on only 2 compared with the no concussion history and all previous concussions diagnosed groups. There were no between-group differences on mental status or balance assessments., Conclusion: An undiagnosed concussion history was associated with worse clinical indicators at future baseline assessments. Individuals reporting ≥1 previous undiagnosed concussions exhibited worse baseline clinical indicators. This may suggest that concussion-related harm may be exacerbated when injuries are not diagnosed.

Pediatric traumatic brain injury (TBI) is a public health crisis, with neurobehavioral morbidity observed years after an injury associated with changes in related brain structures. A substantial literature base has established family environment as a significant predictor of neurobehavioral outcomes following pediatric TBI. The neural mechanisms linking family environment to neurobehavioral outcomes have, however, received less empiric study in this population. In contrast, limbic structural differences as well as challenges with emotional adjustment and behavioral regulation in non-TBI populations have been linked to a multitude of family environmental factors, including family stress, parenting style, and adverse childhood experiences. In this article, we systematically review the more comprehensive literature on family environment and neurobehavioral outcomes in pediatric TBI and leverage the work in both TBI and non-TBI populations to expand our understanding of the underlying neural mechanisms. Thus, we summarize the extant literature on the family environment's role in neurobehavioral sequelae in children with TBI and explore potential neural correlates by synthesizing the wealth of literature on family environment and limbic development, specifically related to the amygdala. This review underscores the critical role of environmental factors, especially those predating the injury, in modeling recovery outcomes post-TBI in childhood, and discusses clinical and research implications across pediatric populations. Given the public health crisis of pediatric TBI, along with the context of sparse available medical interventions, a broader understanding of factors contributing to outcomes is warranted to expand the range of intervention targets., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Sport-related concussion has garnered increasing scientific attention and research over the last decade. Collegiate student-athletes represent an important cohort in this field. As such, the Pac-12 CARE-Affiliated Program (CAP) was formed in 2017 as a regional hub of the Concussion Assessment, Research and Education (CARE) consortium. CAP is multisite, prospective, longitudinal study that aims to improve student-athlete health by identifying factors associated with concussion incidence and recovery and using this knowledge to inform best clinical practices and policy decisions. CAP employed a staggered rollout across the Pac-12, with the first four institutions enrolling in fall 2018. After receiving institutional review board (IRB) approval, these institutions began consenting student-athletes to share clinical concussion and baseline data for research purposes. Athletes completed baseline testing that included a medical questionnaire, concussion history and a battery for clinical concussion assessments. Concussed student-athletes were given the same battery of assessments in addition to full injury and return to play reports. Clinicians at each university worked with a data coordinator to ensure appropriate reporting, and the Pac-12 Concussion Coordinating Unit at the University of Colorado Boulder provided oversight for quality control of the data study wide. During year 1, CAP consented 2181 student-athletes and tracked 140 concussions. All research was conducted with the appropriate IRB approval across the participating Pac-12 institutions. Data security and dissemination are managed by the Presagia Sports Athlete Electronic Health Record software (Montreal, Quebec, Canada) and QuesGen Systems (San Francisco, California, USA)., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The Ice Hockey Summit III provided updated scientific evidence on concussions in hockey to inform these 5 objectives: (1) describe sport related concussion (SRC) epidemiology; (2) classify prevention strategies; (3) define objective, diagnostic tests; (4) identify treatment; and (5) integrate science and clinical care into prioritized action plans and policy., Methods: Our action plan evolved from 40 scientific presentations. The 155 attendees (physicians, athletic trainers, physical therapists, nurses, neuropsychologists, scientists, engineers, coaches, and officials) voted to prioritize these action items in the final Summit session., Results: To (1) establish a national and international hockey database for SRCs at all levels; (2) eliminate body checking in Bantam youth hockey games; (3) expand a behavior modification program (Fair Play) to all youth hockey levels; (4) enforce game ejection penalties for fighting in Junior A and professional hockey leagues; (5) establish objective tests to diagnose concussion at point of care; and (6) mandate baseline testing to improve concussion diagnosis for all age groups., Conclusions: Expedient implementation of the Summit III prioritized action items is necessary to reduce the risk, severity, and consequences of concussion in the sport of ice hockey., Competing Interests: The authors report no conflicts of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Traumatic brain injury (TBI)-induced disruptions in synaptic function within brain regions and across networks in the limbic system may underlie a vulnerability for maladaptive plasticity and contribute to behavioral comorbidities. In this study we measured how synaptic proteins respond to lateral fluid percussion injury (FPI) brain regions known to regulate emotion and memory, including the basolateral amygdala (BLA), dorsal and ventral hippocampus (DH, VH), and medial prefrontal cortex (PFC). We investigated proteins involved in regulating plasticity, including synaptic glutamatergic a-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid (AMPA; GluA1, GluA2) and N- methyl-D-aspartate (NMDA; NR1, NR2A, NR2B) receptor subunits as well as inhibitory gamma-aminobutyric acid (GABA) synthetic enzymes (GAD67, GAD65) via western blot. Adult male rats received a mild-moderate lateral FPI or sham surgery and ipsi- and contralateral BLA, DH, VH, and PFC were collected 6 h, 24 h, 48 h, and 7 days post-injury. In the ipsilateral BLA, there was a significant decrease in NR1 and GluA2 24 h after injury, whereas NR2A and NR2B were increased in the contralateral BLA at 48 h compared with sham. GAD67 was increased ipsilaterally at 24 h, but decreased contralaterally at 48 h in the BLA. In the DH, both NMDA (NR2A, NR2B) and GABA-synthetic (GAD65, GAD67) proteins were increased acutely at 6 h compared with sham. GAD67 was also robustly increased in the ipsilateral VH at 6 h. In the contralateral VH, NR2A significantly increased between 6 h and 24 h after FPI, whereas GAD65 was decreased across the same time-points in the contralateral VH. In the medial PFC at 24 h we saw bilateral increases in GAD67 and a contralateral decrease in GluA1. Later, there was a significant decrease in GAD67 in contralateral PFC from 48 h to 7 days post-injury. Collectively, these data suggest that lateral FPI causes a dynamic homeostatic response across limbic networks, leading to an imbalance of the proteins involved in plasticity in neural systems underlying cognitive and emotional regulation., Competing Interests: M.S.F. is director of research for Neurovation Labs. C.C.G. has research grants funded by the National Collegiate Athletic Association (NCAA) and the U.S. Department of Defense; is a clinical consultant for the National Football League (NFL)-Neurological Care Program, the National Hockey League Players' Association (NHLPA), and the LA Lakers; serves on advisory panels for Major League Soccer, the National Basketball Association (NBA), the U.S. Soccer Federation, and Highmark Interactive; has stock options from Highmark Interactive; and has received book royalties from Blackwell/Wiley Publishing (Prioritized Neurological Differential Diagnosis)., (© Ann N. Hoffman et al., 2021; Published by Mary Ann Liebert, Inc.)

Dysregulation of the autonomic nervous system (ANS) may play an important role in the development and maintenance of persistent post-concussive symptoms (PPCS). Post-injury breathing dysfunction, which is influenced by the ANS, has not been well-studied in youth. This study evaluated cardiorespiratory functioning at baseline in youth patients with PPCS and examined the relationship of cardiorespiratory variables with neurobehavioral outcomes. Participants were between the ages of 13-25 in two groups: (1) Patients with PPCS (concussion within the past 2-16 months; n = 13) and (2) non-injured controls ( n = 12). Capnometry was used to obtain end-tidal CO 2 (EtCO 2 ), oxygen saturation (SaO 2 ), respiration rate (RR), and pulse rate (PR) at seated rest. PPCS participants exhibited a reduced mean value of EtCO 2 in exhaled breath (M = 36.3 mmHg, SD = 2.86 mmHg) and an altered inter-correlation between EtCO 2 and RR compared to controls. Neurobehavioral outcomes including depression, severity of self-reported concussion symptoms, cognitive catastrophizing, and psychomotor processing speed were correlated with cardiorespiratory variables when the groups were combined. Overall, results from this study suggest that breathing dynamics may be altered in youth with PPCS and that cardiorespiratory outcomes could be related to a dimension of neurobehavioral outcomes associated with poorer recovery from concussion.

Background: Identifying separate dimensions of concussion symptoms may inform a precision medicine approach to treatment. It was previously reported that a bifactor model identified distinct acute postconcussion symptom dimensions., Purpose: To replicate previous findings of a bifactor structure of concussion symptoms in the Concussion Assessment Research and Education (CARE) Consortium sample, examine measurement invariance from pre- to postinjury, and evaluate whether factors are associated with other clinical and biomarker measures., Study Design: Cohort study (Diagnosis); Level of evidence, 2., Methods: Collegiate athletes were prospectively evaluated using the Sport Concussion Assessment Tool-3 (SCAT-3) during preseason (N = 31,557); 2789 were followed at <6 hours and 24 to 48 hours after concussion. Item-level SCAT-3 ratings were analyzed using exploratory and confirmatory factor analyses. Bifactor and higher-order models were compared for their fit and interpretability. Measurement invariance tested the stability of the identified factor structure across time. The association between factors and criterion measures (clinical and blood-based markers of concussion severity, symptom duration) was evaluated., Results: The optimal structure for each time point was a 7-factor bifactor model: a General factor, on which all items loaded, and 6 specific factors-Vestibulo-ocular, Headache, Sensory, Fatigue, Cognitive, and Emotional. The model manifested strict invariance across the 2 postinjury time points but only configural invariance from baseline to postinjury. From <6 to 24-48 hours, some dimensions increased in severity (Sensory, Fatigue, Emotional), while others decreased (General, Headache, Vestibulo-ocular). The factors correlated with differing clinical and biomarker criterion measures and showed differing patterns of association with symptom duration at different time points., Conclusion: Bifactor modeling supported the predominant unidimensionality of concussion symptoms while revealing multidimensional properties, including a large dominant General factor and 6 independent factors: Headache, Vestibulo-ocular, Sensory, Cognitive, Fatigue, and Emotional. Unlike the widely used SCAT-3 symptom severity score, which declines gradually after injury, the bifactor model revealed separable symptom dimensions that have distinct trajectories in the acute postinjury period and different patterns of association with other markers of injury severity and outcome., Clinical Relevance: The SCAT-3 total score remains a valuable, robust index of overall concussion symptom severity, and the specific factors identified may inform management strategies. Because some symptom dimensions continue to worsen in the first 24 to 48 hours after injury (ie, Sensory, Fatigue, Emotional), routine follow-up in this time frame may be valuable to ensure that symptoms are managed effectively.

Importance: Identifying plasma biomarkers associated with the amount of time an athlete may need before they return to sport (RTS) following a sport-related concussion (SRC) is important because it may help to improve the health and safety of athletes., Objective: To examine whether plasma biomarkers can differentiate collegiate athletes who RTS in less than 14 days or 14 days or more following SRC., Design, Setting, and Participants: This multicenter prospective diagnostic study, conducted by the National Collegiate Athletics Association-Department of Defense Concussion Assessment, Research, and Education Consortium, included 127 male and female athletes who had sustained an SRC while enrolled at 6 Concussion Assessment, Research, and Education Consortium Advanced Research Core sites as well as 2 partial-Advanced Research Core military service academies. Data were collected between February 2015 and May 2018. Athletes with SRC completed clinical testing and blood collection at preseason (baseline), postinjury (0-21 hours), 24 to 48 hours postinjury, time of symptom resolution, and 7 days after unrestricted RTS., Main Outcomes and Measures: A total of 3 plasma biomarkers (ie, total tau protein, glial fibrillary acidic protein [GFAP], and neurofilament light chain protein [Nf-L]) were measured using an ultrasensitive single molecule array technology and were included in the final analysis. RTS was examined between athletes who took less than 14 days vs those who took 14 days or more to RTS following SRC. Linear mixed models were used to identify significant interactions between period by RTS group. Area under the receiver operating characteristic curve analyses were conducted to examine whether these plasma biomarkers could discriminate between RTS groups., Results: The 127 participants had a mean (SD) age of 18.9 (1.3) years, and 97 (76.4%) were men; 65 (51.2%) took less than 14 days to RTS, and 62 (48.8%) took 14 days or more to RTS. Linear mixed models identified significant associations for both mean (SE) plasma total tau (24-48 hours postinjury, <14 days RTS vs ≥14 days RTS: -0.65 [0.12] pg/mL vs -0.14 [0.14] pg/mL; P = .008) and GFAP (postinjury, 14 days RTS vs ≥14 days RTS: 4.72 [0.12] pg/mL vs 4.39 [0.11] pg/mL; P = .04). Total tau at the time of symptom resolution had acceptable discrimination power (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.63-0.86; P < .001). We also examined a combined plasma biomarker panel that incorporated Nf-L, GFAP, and total tau at each period to discriminate RTS groups. Although the analyses did reach significance at each time period when combined, results indicated that they were poor at distinguishing the groups (area under the receiver operating characteristic curve, <0.7)., Conclusions and Relevance: The findings of this study suggest that measures of total tau and GFAP may identify athletes who will require more time to RTS. However, further research is needed to improve our ability to determine recovery following an SRC.

Background: Organizations recommend that athletes should be asymptomatic or symptom-limited before initiating a graduated return-to-play (GRTP) protocol after sports-related concussion, although asymptomatic or symptom-limited is not well-defined., Hypotheses: (1) There will be a range (ie, beyond zero as indicator of "symptom-free") in symptom severity endorsement when athletes are deemed ready to initiate a GRTP protocol. (2) Baseline symptom severity scores and demographic/preinjury medical history factors influence symptom severity scores at the commencement of the GRTP protocol. (3) Greater symptom severity scores at GRTP protocol initiation will result in longer protocol duration. (4) Symptom severity scores will not differ between those who did and did not sustain a repeat injury within 90 days of their initial injury., Study Design: Cohort study; Level of evidence, 2., Methods: Across 30 universities, athletes (N = 1531) completed assessments at baseline and before beginning the GRTP protocol, as determined by local medical staff. Symptom severity scores were recorded with the symptom checklist of the Sport Concussion Assessment Tool-3rd Edition. Nonparametric comparisons were used to examine the effect of medical, demographic, and injury factors on symptom endorsement at GRTP protocol initiation, as well as differences in symptom severity scores between those who did and did not sustain a repeat injury within 90 days. A Cox regression was used to examine the association between symptom severity scores at GRTP protocol initiation and protocol duration., Results: Symptom severity scores at the time when the GRTP protocol was initiated were as follows: 0 to 5 (n = 1378; 90.0%), 6 to 10 (n = 76; 5.0%), 11 to 20 (n = 42; 3.0%), and ≥21 (n = 35; 2.0%). Demographic (sex and age), medical (psychiatric disorders, attention-deficit/hyperactivity disorder, learning disorder), and other factors (baseline symptom endorsement and sleep) were significantly associated with higher symptom severity scores at the GRTP initiation ( P < .05). The 4 GRTP initiation time point symptom severity score groups did not significantly differ in total time to unrestricted RTP, χ 2 (3) = 1.4; P = .73. When days until the initiation of the GRTP protocol was included as a covariate, symptom severity scores between 11 and 20 ( P = .02; hazard ratio = 1.44; 95% CI, 1.06-1.96) and ≥21 ( P < .001; hazard ratio = 1.88; 95% CI, 1.34-2.63) were significantly associated with a longer GRTP protocol duration as compared with symptom severity scores between 0 and 5. Symptom severity scores at GRTP initiation did not significantly differ between those who sustained a repeat injury within 90 days and those who did not ( U = 29,893.5; P = .75)., Conclusion: A range of symptom severity endorsement was observed at GRTP protocol initiation, with higher endorsement among those with higher baseline symptom endorsement and select demographic and medical history factors. Findings suggest that initiation of a GRTP protocol before an absolute absence of all symptoms is not associated with longer progression of the GRTP protocol, although symptom severity scores >10 were associated with longer duration of a GRTP protocol. Results can be utilized to guide clinicians toward optimal GRTP initiation (ie, balancing active recovery with avoidance of premature return to activity).

Increased task-related blood oxygen level dependent (BOLD) activation is commonly observed in functional magnetic resonance imaging (fMRI) studies of moderate/severe traumatic brain injury (msTBI), but the functional relevance of these hyperactivations and how they are linked to more direct measures of neuronal function remain largely unknown. Here, we investigated how working memory load (WML)-dependent BOLD activation was related to an electrophysiological measure of interhemispheric transfer time (IHTT) in a sample of 18 msTBI patients and 26 demographically matched controls from the UCLA RAPBI (Recovery after Pediatric Brain Injury) study. In the context of highly similar fMRI task performance, a subgroup of TBI patients with slow IHTT had greater BOLD activation with higher WML than both healthy control children and a subgroup of msTBI patients with normal IHTT. Slower IHTT treated as a continuous variable was also associated with BOLD hyperactivation in the full TBI sample and in controls. Higher WML-dependent BOLD activation was related to better performance on a clinical cognitive performance index, an association that was more pronounced within the patient group with slow IHTT. Our previous work has shown that a subgroup of children with slow IHTT after pediatric msTBI has increased risk for poor white matter organization, long-term neurodegeneration, and poor cognitive outcome. BOLD hyperactivations after msTBI may reflect neuronal compensatory processes supporting higher-order capacity demanding cognitive functions in the context of inefficient neuronal transfer of information. The link between BOLD hyperactivations and slow IHTT adds to the multi-modal validation of this electrophysiological measure as a promising biomarker.

Researchers have been collecting head impact data from instrumented football players to characterize the biomechanics of concussion for the past 15 years, yet the link between biomechanical input and clinical outcome is still not well understood. We have previously shown that even though concussive biomechanics might be unremarkable in large datasets of head impacts, the impacts causing injury are of high magnitude for the concussed individuals relative to their impact history. This finding suggests a need to account for differences in tolerance at the individual level. In this study, we identified control subjects for our concussed subjects who demonstrated traits we believed were correlated to factors thought to affect injury tolerance, including height, mass, age, race, and concussion history. A total of 502 college football players were instrumented with helmet-mounted accelerometer arrays and provided complete baseline assessment data, 44 of which sustained a total of 49 concussion. Biomechanical measures quantifying impact frequency and acceleration magnitude were compared between groups. On average, we found that concussed subjects experienced 93.8 more head impacts (p = 0.0031), 10.2 more high magnitude impacts (p = 0.0157), and 1.9 × greater risk-weighted exposure (p = 0.0175) than their physically matched controls. This finding provides further evidence that head impact data need to be considered at the individual level and that cohort wide assessments may be of little value in the context of concussion.

The Ice Hockey Summit III provided updated scientific evidence on concussions in hockey to inform these five objectives: 1) describe sport-related concussion (SRC) epidemiology, 2) classify prevention strategies, 3) define objective, diagnostic tests, 4) identify treatment, and 5) integrate science and clinical care into prioritized action plans and policy. Our action plan evolved from 40 scientific presentations. The 155 attendees (physicians, athletic trainers, physical therapists, nurses, neuropsychologists, scientists, engineers, coaches, and officials) voted to prioritize these action items in the final Summit session. 1) Establish a national and international hockey data base for SRC at all levels, 2) eliminate body checking in Bantam youth hockey games, 3) expand a behavior modification program (Fair Play) to all youth hockey levels, 4) enforce game ejection penalties for fighting in Junior A and professional hockey leagues, 5) establish objective tests to diagnose concussion at point of care (POC), and 6) mandate baseline testing to improve concussion diagnosis for all age groups. Expedient implementation of the Summit III prioritized action items is necessary to reduce the risk, severity, and consequences of concussion in the sport of ice hockey.

Through a partnership with the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, and Department of Defense, the development of Sport-Related Concussion (SRC) Common Data Elements (CDEs) was initiated. The aim of this collaboration was to increase the efficiency and effectiveness of clinical research studies and clinical treatment outcomes, increase data quality, facilitate data sharing across studies, reduce study start-up time, more effectively aggregate information into metadata results, and educate new clinical investigators. The SRC CDE Working Group consisted of 32 worldwide experts in concussion from varied fields of related expertise divided into three Subgroups: Acute (<72 h post-concussion), Subacute (3 days-3 months post-concussion) and Persistent/Chronic (>3 months post-concussion). To develop CDEs, the Subgroups reviewed various domains, then selected from, refined, and added to existing CDEs, case report forms and field-tested data elements from national registries and funded research studies. Recommendations were posted to the NINDS CDE Website for Public Review from February 2017 to April 2017. Following an internal Working Group review of recommendations, along with consideration of comments received from the Public Review period, the first iteration (Version 1.0) of the NINDS SRC CDEs was completed in June 2017. The recommendations include Core and Supplemental-Highly Recommended CDEs for cognitive data elements and symptom checklists, as well as other outcomes and end-points (e.g., vestibular, oculomotor, balance, anxiety, depression), and sample case report forms (e.g., injury reporting, demographics, concussion history) for domains typically included in clinical research studies. The NINDS SRC CDEs and supporting documents are publicly available on the NINDS CDE website www.commondataelements.ninds.nih.gov . Widespread use of CDEs by researchers and clinicians will facilitate consistent SRC clinical research and trial design, data sharing, and metadata retrospective analysis.

The majority of the 3.8 million estimated annual traumatic brain injuries (TBI) in the United States are mild TBIs, or concussions, and they occur primarily in adolescents and young adults. A concussion is a brain injury associated with rapid brain movement and characteristic clinical symptoms, with no associated objective biomarkers or overt pathologic brain changes, thereby making it difficult to diagnose by neuroimaging or other objective diagnostic tests. Most concussion symptoms are transient and resolve within 1-2 weeks. Concussions share similar acute pathophysiologic perturbations to more severe TBI: there is a rapid release of neurotransmitters, which causes ionic disequilibrium across neuronal membranes. Re-establishing ionic homeostasis consumes energy and leads to dynamic changes in cerebral glucose uptake. The magnitude and duration of these changes are related to injury severity, with milder injuries showing faster normalization. Cerebral sex differences add further variation to concussion manifestation. Relative to the male brain, the female brain has higher overall cerebral blood flow, and demonstrates regional differences in glucose metabolism, inflammatory responses, and connectivity. Understanding the pathophysiology and clinical translation of concussion can move research towards management paradigms that will minimize the risk for prolonged recovery and repeat injury., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: In the treatment of pediatric traumatic brain injury (TBI), timely treatment of patients can affect the outcome. Our objectives were to examine the treatment process of acute pediatric TBI and the impact of non-value-added time (NVAT) on patient outcomes., Methods: Data for 136 pediatric trauma patients (age < 18 years) with severe TBI from 2 trauma centers in the United States were collected. A process flow and value stream map identified NVATs and their sources in the treatment process. Cluster and regression analysis were used to examine the relationship between NVAT, as a percentage of the patient's length of stay (LOS), and the patient outcome, measured by their corresponding Glasgow outcome scale., Results: There were 14 distinct sources of NVAT identified. A regression analysis showed that increased NVAT was associated with less favorable outcomes (relative ratio = 1.015, confidence interval = [1.002-1.029]). Specifically, 1% increase in the NVAT-to-LOS ratio was associated with a 1.5% increase in the chance of a less favorable outcome (i.e., death or vegetative state)., Conclusion: The NVAT has a significant impact on the outcome of pediatric TBI, and every minute spent on performing non-value-added processes can lead to an increase in the likelihood of less favorable outcomes.

Traumatic brain injury (TBI) frequently results in diffuse axonal injury and other white matter damage. The corpus callosum (CC) is particularly vulnerable to injury following TBI. Damage to this white matter tract has been associated with impaired neurocognitive functioning in children with TBI. Event-related potentials can identify stimulus-locked neural activity with high temporal resolution. They were used in this study to measure interhemispheric transfer time (IHTT) as an indicator of CC integrity in 44 children with moderate/severe TBI at 3-5 months post-injury, compared with 39 healthy control children. Neurocognitive performance also was examined in these groups. Nearly half of the children with TBI had IHTTs that were outside the range of the healthy control group children. This subgroup of TBI children with slow IHTT also had significantly poorer neurocognitive functioning than healthy controls-even after correction for premorbid intellectual functioning. We discuss alternative models for the relationship between IHTT and neurocognitive functioning following TBI. Slow IHTT may be a biomarker that identifies children at risk for poor cognitive functioning following moderate/severe TBI.

Traumatic brain injury is a major public health problem in the pediatric population. Previously, management was acute emergency department/primary care evaluation with follow-up by primary care. However, persistent symptoms after traumatic brain injury are common, and many do not have access to a specialized traumatic brain injury clinic to manage chronic issues. The goal of this study was to determine the factors related to outcomes, and identify the interventions provided in this subspecialty clinic. Data were extracted from medical records of 151 retrospective and 403 prospective patients. Relationships between sequelae, injury characteristics, and clinical interventions were analyzed. Most patients returning to clinic were not fully recovered from their injury. Headaches were more common after milder injuries, and seizures were more common after severe. The majority of patients received clinical intervention. The presence of persistent sequelae for traumatic brain injury patients can be evaluated and managed by a specialty concussion/traumatic brain injury clinic ensuring that medical needs are met., (© The Author(s) 2015.)

Professional boxing is associated with a risk of chronic neurological injury, with up to 20-50% of former boxers exhibiting symptoms of chronic brain injury. Chronic traumatic brain injury encompasses a spectrum of disorders that are associated with long-term consequences of brain injury and remains the most difficult safety challenge in modern-day boxing. Despite these concerns, traditional guidelines used for return to sport participation after concussion are inconsistently applied in boxing. Furthermore, few athletic commissions require either formal consultation with a neurological specialist (i.e. neurologist, neurosurgeon, or neuropsychologist) or formal neuropsychological testing prior to return to fight. In order to protect the health of boxers and maintain the long-term viability of a sport associated with exposure to repetitive head trauma, we propose a set of specific requirements for brain safety that all state athletic commissions would implement.

Dizziness and vertigo are common symptoms following minor head trauma. Although these symptoms resolve within a few weeks in many patients, in some the symptoms may last much longer and impede ability to return to work and full functioning. Causes of persisting or recurrent dizziness may include benign paroxysmal positional vertigo, so-called labyrinthine concussion, unilateral vestibular nerve injury or damage to the utricle or saccule, perilymphatic fistula, or less commonly traumatic endolymphatic hydrops. Some dizziness after head trauma is due to nonlabyrinthine causes that may be related to structural or microstructural central nervous system injury or to more complicated interactions between migraine, generalized anxiety, and issues related to patients self-perception, predisposing psychological states, and environmental and stress-related factors. In this article, the authors review both the inner ear causes of dizziness after concussion and also the current understanding of chronic postconcussive dizziness when no peripheral vestibular cause can be identified., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

The Center for Disease Control estimates that there are 1.7 million brain injuries in the US each year with 51% of these injuries occurring during periods of cerebral development. Among this population there is a growing population of individuals with repeat traumatic brain injury (RTBI). While the exact incidence is unknown, estimates range from 5.6 to 36% of the TBI population. This review summarizes the clinical problems/challenges and experimental research models that currently exist. It is intended to reveal the critical areas that need to be addressed so that age-relevant clinical management guidelines can be established to protect this population., (Published by Elsevier Ltd.)

In this fMRI study, the functions of the anterior cingulate cortex (ACC) were studied in a group of adolescents who had sustained a moderate to severe traumatic brain injury (TBI). A spatial working memory task with varying working memory loads, representing experimental conditions of increasing difficulty, was administered. In a cross-sectional comparison between the patients and a matched control group, patients performed worse than Controls, showing longer reaction times and lower response accuracy on the spatial working memory task. Brain imaging findings suggest a possible double-dissociation: activity of the ACC in the TBI group, but not in the Control group, was associated with task difficulty; conversely, activity of the left sensorimotor cortex (lSMC) in the Control group, but not in the TBI group, was correlated with task difficulty. In addition to the main cross-sectional study, a longitudinal study of a group of adolescent patients with moderate to severe TBI was done using fMRI and the same spatial working memory task. The patient group was studied at two time-points: one time-point during the post-acute phase and one time-point 12 months later, during the chronic phase. Results indicated that patients' behavioral performance improved over time, suggesting cognitive recovery. Brain imaging findings suggest that, over this 12-month period, patients recruited less of the ACC and more of the lSMC in response to increasing task difficulty. The role of ACC in executive functions following a moderate to severe brain injury in adolescence is discussed within the context of conflicting models of the ACC functions in the existing literature.

Among the enormous population of head-injured children and young adults are a growing subpopulation who experience repeat traumatic brain injury (RTBI). The most common cause of RTBI in this age group is sports-related concussions, and athletes who have experienced a head injury are at greater risk for subsequent TBI, with consequent long-term cognitive dysfunction. While several animal models have been proposed to study RTBI, they have been shown to either produce injuries too severe, were conducted in adults, involved craniotomy, or failed to show behavioral deficits. A closed head injury model for postnatal day 35 rats was established, and single and repeat TBI (1-day interval) were examined histologically for axonal injury and behaviorally by the novel object recognition (NOR) task. The results from the current study demonstrate that an experimental closed head injury in the rodent with low mortality rates and absence of gross pathology can produce measurable cognitive deficits in a juvenile age group. The introduction of a second injury 24 h after the first impact resulted in increased axonal injury, astrocytic reactivity and increased memory impairment in the NOR task. The histological evidence demonstrates the potential usefulness of this RTBI model for studying the impact and time course of RTBI as it relates to the pediatric and young adult population. This study marks the first critical step in experimentally addressing the consequences of concussions and the cumulative effects of RTBI in the developing brain., (Copyright © 2010 S. Karger AG, Basel.)

Following CNS injury there is a period of vulnerability when cells will not easily tolerate a secondary insult. However recent studies have shown that following traumatic brain injury (TBI), as well as hypoxic-ischemic injuries, the CNS may experience a period of protection termed "preconditioning." While there is literature characterizing the properties of vulnerability and preconditioning in the adult rodent, there is an absence of comparable literature in the developing rat. To determine if there is a window of vulnerability in the developing rat, post-natal day 19 animals were subjected to a severe lateral fluid percussion injury followed by pilocarpine (Pc)-induced status epilepticus at 1, 6 or 24 h post TBI. During the first 24 h after TBI, the dorsal hippocampus exhibited less status epilepticus-induced cell death than that normally seen following Pc administration alone. Instead of producing a state of hippocampal vulnerability to activation, TBI produced a state of neuroprotection. However, in a second group of animals evaluated 20 weeks post injury, double-injured animals were statistically indistinguishable in terms of seizure threshold, mossy fiber sprouting and cell survival when compared to those treated with Pc alone. TBI, therefore, produced a temporary state of neuroprotection from seizure-induced cell death in the developing rat; however, this ultimately conferred no long-term protection from altered hippocampal circuit rearrangements, enhanced excitability or later convulsive seizures.

Based on recent work demonstrating age-dependent ketogenic neuroprotection after traumatic brain injury (TBI), it was hypothesized that the neuroprotection among early post-weaned animals was related to induced cerebral transport of ketones after injury. Regional changes in monocarboxylate transporter 2 (MCT2) were acutely examined with immunohistochemistry after sham surgery or controlled cortical impact injury among postnatal day 35 and adult rats. Both ages showed elevated MCT2 expression in the ipsilateral cerebral vasculature after TBI. Using Western blotting, MCT2 expression was 80-88% greater in microvessels isolated from postnatal day 35 rats at all time points relative to adults. The increased MCT2 expression was temporally correlated with an age-related increase in cerebral uptake of ketones, when ketones were made available after injury., (Copyright (c) 2006 S. Karger AG, Basel.)

Cells that survive traumatic brain injury are exposed to changes in their neurochemical environment. One of these changes is a prolonged (48 h) uptake of calcium which, by itself, is not lethal. The N-methyl-D-aspartate receptor (NMDAR) is responsible for the acute membrane flux of calcium following trauma; however, it is unclear if it is involved in a flux lasting 2 days. We proposed that traumatic brain injury induced a molecular change in the NMDAR by modifying the concentrations of its corresponding subunits (NR1 and NR2). Changing these subunits could result in a receptor being more sensitive to glutamate and prolong its opening, thereby exposing cells to a sustained flux of calcium. To test this hypothesis, adult rats were subjected to a lateral fluid percussion brain injury and the NR1, NR2A and NR2B subunits measured within different regions. Although little change was seen in NR1, both NR2 subunits decreased nearly 50% compared with controls, particularly within the ipsilateral cerebral cortex. This decrease was sustained for 4 days with levels returning to control values by 2 weeks. However, this decrease was not the same for both subunits, resulting in a decrease (over 30%) in the NR2A:NR2B ratio indicating that the NMDAR had temporarily become more sensitive to glutamate and would remain open longer once activated. Combining these regional and temporal findings with 45calcium autoradiographic studies revealed that the degree of change in the subunit ratio corresponded to the extent of calcium accumulation. Finally, utilizing a combination of NMDAR and NR2B-specific antagonists it was determined that as much at 85% of the long term NMDAR-mediated calcium flux occurs through receptors whose subunits favor the NR2B subunit. These data indicate that TBI induces molecular changes within the NMDAR, contributing to the cells' post-injury vulnerability to glutamatergic stimulation.

The mechanisms underlying neurotrophin dependence, and cellular dependent states in general, are unknown. We show that a 29 amino acid region in the intracellular domain of the common neurotrophin receptor, p75NTR, is required for the mediation of apoptosis by p75NTR. Furthermore, contrary to results obtained with Fas, monomeric p75NTR is required for apoptosis induction, whereas multimerization inhibits the pro-apoptotic effect. Within the 29-residue domain required for apoptosis induction by p75NTR, a 14-residue region is sufficient as a peptide inducer of apoptosis. This 14-residue peptide requires the positively charged carboxyterminal residues for its effect on cell death, and these same residues are required by the full-length p75NTR. These studies define a novel type of domain that mediates neurotrophin dependence, and suggest that other cellular dependent states may be mediated by proteins displaying similar domains.

To determine if a moderate traumatic brain injury (TBI) sustained early in life alters the capacity for developmental plasticity, 17-20-day-old rat pups received a lateral fluid percussion and then reared in an enriched environment for 17 days. Compared to sham-injured controls, this moderate TBI prevented the increase in cortical thickness (1.48 vs. 1.68 mm, p < 0.01) as well as the corresponding enhancement in cognitive performance in the Morris Water Maze (39 vs. 25 trials to criterion, p < 0.05). These injured animals exhibited no significant neuronal degeneration and no evidence of neurologic or motor deficits. These findings strongly support the conclusion that a diffuse brain injury is capable of inhibiting both anatomical and cognitive manifestations of experience-dependent developmental plasticity.

Purpose: Young children with refractory symptomatic epilepsy are at risk for developing neurologic and cognitive disabilities. Stopping the seizures may prevent these disabilities, but it is unclear whether resective surgery is associated with adequate long-term seizure control., Methods: This study determined pre- and postsurgery seizure frequency and antiepileptic drug (AED) use (6 months to 10 years) in children with symptomatic seizures from unilateral cortical dysplasia (CD; n = 64) and non-CD etiologies (i.e., ischemia, infection; n = 71), and compared them with older temporal lobe epilepsy (TLE; n = 31) patients with complex partial seizures., Results: Compared with presurgery, postsurgery seizure frequencies were decreased for CD, non-CD, and TLE patients (p < 0.002), and there were no differences between the three groups from 6 to 24 months after surgery (p > 0.12). At 5 years after surgery, seizure frequencies were greater in CD compared with TLE cases (p = 0.009). Compared with presurgery, the number of AEDs declined after surgery in all three groups (p < 0.002), and positively correlated with seizure frequencies (p = 0.0001)., Conclusions: This study indicates that seizure relief and AED use after resective surgery for symptomatic CD and non-CD etiologies was comparable with complex partial TLE cases up to 2 years after surgery. Furthermore, at 5 years after surgery, CD patients had outcomes better than those before surgery, but worse than TLE cases. In young children, these findings support the concept that early removal of symptomatic pathologic substrates is associated with seizure control and reduced AED use, similar to that noted in older TLE cases up to 2 years after surgery. Seizure control may reduce the risk of developing the seizure-related encephalopathy associated with severe symptomatic early-onset childhood epilepsy.

A young female presented with an epileptic syndrome resembling childhood absence epilepsy, a normal neurologic examination, generalized 3-Hz spike-and-wave discharges, and clinical absences. Her seizures responded to treatment with valproic acid. Other abnormalities in her electroencephalogram prompted neuroimaging studies, which demonstrated periventricular nodular heterotopia. Review of published reports confirmed this presentation to be atypical of this developmental lesion. The authors describe their patient and discuss this unexpected association and the relevant reports briefly.