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Since the original descriptions of postconcussive pathophysiology, there has been a significant increase in interest and ongoing research to study the biological underpinnings of concussion. The initial ionic flux and glutamate release result in significant energy demands and a period of metabolic crisis for the injured brain. These physiological perturbations can now be linked to clinical characteristics of concussion, including migrainous symptoms, vulnerability to repeat injury, and cognitive impairment. Furthermore, advanced neuroimaging now allows a research window to monitor postconcussion pathophysiology in humans noninvasively. There is also increasing concern about the risk for chronic or even progressive neurobehavioral impairment after concussion/mild traumatic brain injury. Critical studies are underway to better link the acute pathobiology of concussion with potential mechanisms of chronic cell death, dysfunction, and neurodegeneration. This "new and improved" article summarizes in a translational fashion and updates what is known about the acute neurometabolic changes after concussive brain injury. Furthermore, new connections are proposed between this neurobiology and early clinical symptoms as well as to cellular processes that may underlie long-term impairment.

BackgroundTraumatic experience can result in life-long changes in the ability to cope with future stressors and emotionally salient events. These experiences, particularly during early development, are a significant risk factor for later life anxiety disorders such as posttraumatic stress disorder (PTSD). However, because traumatic experience typically results in strong episodic memories, it is not known whether such long-term memories are necessary for particular features of PTSD, such as enhanced fear and anxiety. Here, we used a fear conditioning procedure in juvenile rats before maturation of the neural systems supporting declarative memory to assess the necessity of early memory to the later life development of PTSD-related symptoms.MethodsNineteen-day old rats were exposed to unpredictable and inescapable footshocks, and fear memory for the shock context was assessed during adulthood. Thereafter, adult animals were either exposed to single-trial fear conditioning or elevated plus maze or sacrificed for basal diurnal corticosterone and quantification of neuronal glucocorticoid and neuropeptide Y receptors.ResultsEarly trauma exposed rats displayed stereotypic footshock reactivity, yet by adulthood, hippocampus-dependent contextual fear-related memory was absent. However, adult rats showed sensitized fear learning, aberrant basal circadian fluctuations of corticosterone, increased amygdalar glucocorticoid receptors, decreased time spent in the open arm of an elevated plus maze, and an odor aversion associated with early-life footshocks.ConclusionsThese results suggest that traumatic experience during developmental periods of hippocampal immaturity can promote lifelong changes in symptoms and neuropathology associated with human PTSD, even if there is no explicit memory of the early trauma.

PurposeTraumatic brain injury (TBI) is an important cause of morbidity and mortality in children, and early posttraumatic seizures (EPTS) are a contributing factor to ongoing acute damage. Continuous video-EEG monitoring (cEEG) was utilized to assess the burden of clinical and electrographic EPTS.MethodsEighty-seven consecutive, unselected (mild - severe), acute TBI patients requiring pediatric intensive care unit (PICU) admission at two academic centers were monitored prospectively with cEEG per established clinical TBI protocols. Clinical and subclinical seizures and status epilepticus (SE, clinical and subclinical) were assessed for their relation to clinical risk factors and short-term outcome measures.Key findingsOf all patients, 42.5% (37/87) had seizures. Younger age (p = 0.002) and injury mechanism (abusive head trauma - AHT, p < 0.001) were significant risk factors. Subclinical seizures occurred in 16.1% (14/87), while 6.9% (6/87) had only subclinical seizures. Risk factors for subclinical seizures included younger age (p < 0.001), AHT (p < 0.001), and intraaxial bleed (p < 0.001). SE occurred in 18.4% (16/87) with risk factors including younger age (p < 0.001), AHT (p < 0.001), and intraaxial bleed (p = 0.002). Subclinical SE was detected in 13.8% (12/87) with significant risk factors including younger age (p < 0.001), AHT (p = 0.001), and intraaxial bleed (p = 0.004). Subclinical seizures were associated with lower discharge King's Outcome Scale for Childhood Head Injury (KOSCHI) score (p = 0.002). SE and subclinical SE were associated with increased hospital length of stay (p = 0.017 and p = 0.041, respectively) and lower hospital discharge KOSCHI (p = 0.007 and p = 0.040, respectively).SignificancecEEG monitoring significantly improves detection of seizures/SE and is the only way to detect subclinical seizures/SE. cEEG may be indicated after pediatric TBI, particularly in younger children, AHT cases, and those with intraaxial blood on computerized tomography (CT).

ObjectiveTo update the 1997 American Academy of Neurology (AAN) practice parameter regarding sports concussion, focusing on 4 questions: 1) What factors increase/decrease concussion risk? 2) What diagnostic tools identify those with concussion and those at increased risk for severe/prolonged early impairments, neurologic catastrophe, or chronic neurobehavioral impairment? 3) What clinical factors identify those at increased risk for severe/prolonged early postconcussion impairments, neurologic catastrophe, recurrent concussions, or chronic neurobehavioral impairment? 4) What interventions enhance recovery, reduce recurrent concussion risk, or diminish long-term sequelae? The complete guideline on which this summary is based is available as an online data supplement to this article.MethodsWe systematically reviewed the literature from 1955 to June 2012 for pertinent evidence. We assessed evidence for quality and synthesized into conclusions using a modified Grading of Recommendations Assessment, Development and Evaluation process. We used a modified Delphi process to develop recommendations.ResultsSpecific risk factors can increase or decrease concussion risk. Diagnostic tools to help identify individuals with concussion include graded symptom checklists, the Standardized Assessment of Concussion, neuropsychological assessments, and the Balance Error Scoring System. Ongoing clinical symptoms, concussion history, and younger age identify those at risk for postconcussion impairments. Risk factors for recurrent concussion include history of multiple concussions, particularly within 10 days after initial concussion. Risk factors for chronic neurobehavioral impairment include concussion exposure and APOE ε4 genotype. Data are insufficient to show that any intervention enhances recovery or diminishes long-term sequelae postconcussion. Practice recommendations are presented for preparticipation counseling, management of suspected concussion, and management of diagnosed concussion.

Treatment of youth concussion during the acute phase continues to evolve, and this has led to the emergence of guidelines to direct care. While symptoms after concussion typically resolve in 14-28 days, a portion (∼20%) of adolescents endorse persistent post-concussive symptoms (PPCS) beyond normal resolution. This report outlines a study implemented in response to the National Institute of Neurological Diseases and Stroke call for the development and initial clinical validation of objective biological measures to predict risk of PPCS in adolescents. We describe our plans for recruitment of a Development cohort of 11- to 17-year-old youth with concussion, and collection of autonomic, neurocognitive, biofluid, and imaging biomarkers. The most promising of these measures will then be validated in a separate Validation cohort of youth with concussion, and a final, clinically useful algorithm will be developed and disseminated. Upon completion of this study, we will have generated a battery of measures predictive of high risk for PPCS, which will allow for identification and testing of interventions to prevent PPCS in the most high-risk youth. [ABSTRACT FROM AUTHOR]

Background: Growing evidence indicates early exercise may improve symptoms and reduce clinical recovery time after concussion, but research examining collegiate student-athletes is scarce. Objective: The aim of this study was to compare symptom recovery time, clinical recovery time, and persisting post-concussion symptom (i.e., symptoms ≥ 28 days) prevalence by the timing of light exercise initiation before the graded return to play (RTP) protocol among concussed participants. Methods: Collegiate student-athletes (n = 1228; age 18.4 ± 0.9 years; 56.5% male, 76.3% division I; 33.7% ≥ 1 prior concussion) across 30 institutions enrolled in the CARE Consortium completed post-concussion assessments and were monitored over time. Symptom recovery (days from injury to symptom resolution) and clinical recovery (days from injury to return to play protocol completion) was determined by the student-athletes' clinicians. Student-athletes were categorized by timing of light exercise initiation. Early (< 2 days post-concussion; n = 161), typical (3–7 days post-concussion; n = 281), and late exercise (≥ 8 days post-concussion; n = 169) groups were compared with the no-exercise group (n = 617; i.e., did not exercise prior to beginning the RTP protocol) for all analyses. Multivariable Cox regression models with hazard ratios (HR) and survival curves and a multivariable binomial regression model with prevalence ratios (PR) compared recovery outcomes between exercise groups while accounting for covariates. Results: Compared to the no-exercise group, the early exercise group was 92% more probable to experience symptom recovery (HR 1.92; 95% CI 1.57–2.36), 88% more probable to reach clinical recovery (HR 1.88; 95% CI 1.55–2.28) and took a median of 2.4 and 3.2 days less to recover, respectively. The late exercise group relative to the no-exercise group was 57% less probable to reach symptom recovery (HR 0.43; 95% CI 0.35–0.53), 46% less probable to achieve clinical recovery (HR 0.54; 95% CI 0.45–0.66) and took 5.3 days and 5.7 days more to recover, respectively. The typical exercise group did not differ in hazard for symptom or clinical recovery (p ≥ 0.329) compared with the no-exercise group. The prevalence of persisting post-concussion symptoms in the combined sample was 6.6%. Early exercise had 4% lower prevalence (PR 0.96, 95% CI 0.94–0.99) and typical exercise had 3% lower prevalence (PR 0.97, 95% CI 0.94–0.99) of persisting post-concussion symptoms, while the late exercise group had an elevated prevalence (PR 1.11, 95% CI 1.04–1.18) compared with the no-exercise group. Conclusion: Exercise < 2 days post-concussion was associated with more probable and faster symptom and clinical recovery, and lower persisting post-concussion symptom prevalence. When considering our findings and existing literature, qualified clinicians may implement early exercise into their clinical practice to provide therapeutic treatment and improve student-athlete recovery. [ABSTRACT FROM AUTHOR]

Background: Previous sport-related concussion research highlights post-injury characteristics that influence recovery trajectories; however, there is limited information regarding premorbid factors that affect sport-related concussion risk. Objective: We aimed to (a) compare premorbid demographic factors among a large cohort of collegiate student athletes who did or did not sustain a sport-related concussion and (b) assess differences in acute injury characteristics based on biological sex and contact level. Methods: We conducted a cohort study of university student athletes from 22 sports enrolled in the Concussion Assessment, Research, and Education (CARE) Consortium study from 2014 to 2021 (n = 1804 student athletes with sport-related concussions; n = 21,702 student athletes without sport-related concussions). Results: Statistical analyses indicated student athletes who self-identified as Black (odds ratio [OR] = 1.61; 95% confidence interval [CI] = 1.42, 1.81) or multiracial (OR = 1.32; 95% CI 1.10, 1.59) demonstrated greater odds of experiencing sport-related concussions than White-identifying student athletes. Additional findings suggest male athletes (OR = 1.47; 95% CI 1.20, 1.81) and contact sport student athletes (OR = 1.40; 95% CI 1.16, 1.70) may be at increased odds for sport-related concussions if they were previously diagnosed with attention deficit hyperactive disorder. Notable post-injury characteristics across sexes included differences in the incident loss of consciousness (male: 5.9%, female: 2.6%; p < 0.001), post-traumatic amnesia (male: 13.6%, female: 5.1%; p < 0.001), and retrograde amnesia (male: 6.8%, female: 2.8%; p < 0.001). A greater proportion of contact-sport student athletes experienced an altered mental status (52.7%) than limited contact (36.2%) and non-contact (48.6%) [p < 0.001]. Last, student athletes participating at lower contact levels were more likely to have a longer delay in removal from activity following injury (contact: 73.6 ± 322.2 min; limited contact: 139.1 ± 560.0 min; non-contact: 461.4 ± 1870.8 min; p = 0.005). Conclusions: The present study provides contemporary pre- and post-sport-related concussion injury characteristics using a considerably sized cohort of collegiate student athletes. These findings support previous work suggesting sport-related concussion results in complex individualized clinical presentations, which may influence management strategies. [ABSTRACT FROM AUTHOR]

• Feasibility of multiplexed blood-based protein levels in sport-related concussion. • Identify novel blood-based biomarkers for concussed athletes. • Dysregulation of blood-based proteins provides a better understanding of human response to injury. • EPB41 and alpha synuclein distinguish concussed athletes from non-concussed athletes. Current protein biomarkers are only moderately predictive at identifying individuals with mild traumatic brain injury or concussion. Therefore, more accurate diagnostic markers are needed for sport-related concussion. This was a multicenter, prospective, case-control study of athletes who provided blood samples and were diagnosed with a concussion or were a matched non-concussed control within the National Collegiate Athletic Association–Department of Defense Concussion Assessment, Research, and Education Consortium conducted between 2015 and 2019. The blood was collected within 48 h of injury to identify protein abnormalities at the acute and subacute timepoints. Athletes with concussion were divided into 6 h post-injury (0–6 h post-injury) and after 6 h post-injury (7–48 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. 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. 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. [Display omitted] [ABSTRACT FROM AUTHOR]