Age dictates brain functional connectivity and axonal integrity following repetitive mild traumatic brain injuries in mice.

Traumatic brain injuries (TBI) present a major public health challenge, demanding an in-depth understanding of age-specific symptoms and risk factors. Aging not only significantly influences brain function and plasticity but also elevates the risk of hospitalizations and death following TBIs. Repetitive mild TBIs (rmTBI) compound these issues, resulting in cumulative and long-term brain damage in the brain. In this study, we investigate the impact of age on brain network changes and white matter properties following rmTBI by employing a multi-modal approach that integrates resting-state functional magnetic resonance imaging (rsfMRI), graph theory analysis, diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI). Our hypothesis is that the effects of rmTBI are worsened in aged animals, with this group showing more pronounced alterations in brain connectivity and white matter structure. Utilizing the closed-head impact model of engineered rotational acceleration (CHIMERA) model, we conducted rmTBIs or sham (control) procedures on young (2.5-3-months-old) and aged (22-months-old) male and female mice to model high-risk groups. Functional and structural imaging unveiled age-related reductions in communication efficiency between brain regions, while injuries induced opposhigh-risking effects on the small-world index across age groups, influencing network segregation. Functional connectivity analysis also identified alterations in 79 out of 148 brain regions by age, treatment (sham vs. rmTBI), or their interaction. Injuries exerted pronounced effects on sensory integration areas, including insular and motor cortices. Age-related disruptions in white matter integrity were observed, indicating alterations in various diffusion directions (mean diffusivity, radial diffusivity, axial diffusivity, and fractional anisotropy) and density neurite properties (dispersion index, intracellular and isotropic volume fraction). Neuroinflammation, assessed through Iba-1 and GFAP markers, correlated with higher dispersion in the optic tract, suggesting a neuroinflammatory response in injured aged animals compared to sham aged. These findings offer insight into the interplay between age, injuries, and brain connectivity, shedding light on the long-term consequences of rmTBI.

Chronic immunosuppression across 12 months and high ability of acute and subacute CNS-injury biomarker concentrations to identify individuals with complicated mTBI on acute CT and MRI.

BACKGROUND: Identifying individuals with intracranial injuries following mild traumatic brain injury (mTBI), i.e. complicated mTBI cases, is important for follow-up and prognostication. The main aims of our study were (1) to assess the temporal evolution of blood biomarkers of CNS injury and inflammation in individuals with complicated mTBI determined on computer tomography (CT) and magnetic resonance imaging (MRI); (2) to assess the corresponding discriminability of both single- and multi-biomarker panels, from acute to chronic phases after injury. METHODS: Patients with mTBI (n = 207), defined as Glasgow Coma Scale score between 13 and 15, loss of consciousness < 30 min and post-traumatic amnesia < 24 h, were included. Complicated mTBI - i.e., presence of any traumatic intracranial injury on neuroimaging - was present in 8% (n = 16) on CT (CT+) and 12% (n = 25) on MRI (MRI+). Blood biomarkers were sampled at four timepoints following injury: admission (within 72 h), 2 weeks (± 3 days), 3 months (± 2 weeks) and 12 months (± 1 month). CNS biomarkers included were glial fibrillary acidic protein (GFAP), neurofilament light (NFL) and tau, along with 12 inflammation markers. RESULTS: The most discriminative single biomarkers of traumatic intracranial injury were GFAP at admission (CT+: AUC = 0.78; MRI+: AUC = 0.82), and NFL at 2 weeks (CT+: AUC = 0.81; MRI+: AUC = 0.89) and 3 months (MRI+: AUC = 0.86). MIP-1ß and IP-10 concentrations were significantly lower across follow-up period in individuals who were CT+ and MRI+. Eotaxin and IL-9 were significantly lower in individuals who were MRI+ only. FGF-basic concentrations increased over time in MRI- individuals and were significantly higher than MRI+ individuals at 3 and 12 months. Multi-biomarker panels improved discriminability over single biomarkers at all timepoints (AUCs > 0.85 for admission and 2-week models classifying CT+ and AUC ≈ 0.90 for admission, 2-week and 3-month models classifying MRI+). CONCLUSIONS: The CNS biomarkers GFAP and NFL were useful single diagnostic biomarkers of complicated mTBI, especially in acute and subacute phases after mTBI. Several inflammation markers were suppressed in patients with complicated versus uncomplicated mTBI and remained so even after 12 months. Multi-biomarker panels improved diagnostic accuracy at all timepoints, though at acute and 2-week timepoints, the single biomarkers GFAP and NFL, respectively, displayed similar accuracy compared to multi-biomarker panels.

Defining Mild Traumatic Brain Injury: From Research Definition to Clinical Practice.

INTRODUCTION: Approximately 75% of traumatic brain injuries (TBIs) qualify as mild. However, there exists no universally agreed upon definition for mild TBI (mTBI). Consequently, treatment guidelines for this group are lacking. The Center for Disease Control (CDC), American College of Rehabilitation Medicine (ACRM), Veterans Affairs and Department of Defense (VA/DoD), Eastern Association for the Surgery of Trauma (EAST), and the University of Arizona's Brain Injury Guidelines (BIG) have each published differing definitions for mTBI. The aim of this study was to compare the ability of these definitions to correctly classify mTBI patients in the acute care setting. METHODS: A single-center, retrospective cohort study comparing the performance of the varying definitions of mTBI was performed at a Level I trauma center from August 2015 to December 2018. Definitions were compared by sensitivity, specificity, positive predictive value, negative predictive value, as well as overtriage and undertriage rates. Finally, a cost-savings analysis was performed. RESULTS: We identified 596 patients suffering blunt TBI with Glasgow Coma Scale 13-15. The CDC/ACRM definitions demonstrated 100% sensitivity but 0% specificity along with the highest rate of undertriage and TBI-related mortality. BIG 1 included nearly twice as many patients than EAST and VA/DoD while achieving a superior positive predictive value and undertriage rate. CONCLUSIONS: The BIG definition identified a larger number of patients compared to the VA/DoD and EAST definitions while having an acceptable and more accurate overtriage and undertriage rate compared to the CDC and ACRM. By eliminating undertriage and minimizing overtriage rates, the BIG maintains patient safety while enhancing the efficiency of healthcare systems. Using the BIG definition, a cost savings of $395,288.95-$401,263.95 per year could be obtained at our level 1 trauma facility without additional mortality.

Traumatic brain injury heterogeneity affects cell death and autophagy.

Traumatic brain injury (TBI) mechanism and severity are heterogenous clinically, resulting in a multitude of physical, cognitive, and behavioral deficits. Impact variability influences the origin, spread, and classification of molecular dysfunction which limits strategies for comprehensive clinical intervention. Indeed, there are currently no clinically approved therapeutics for treating the secondary consequences associated with TBI. Thus, examining pathophysiological changes from heterogeneous impacts is imperative for improving clinical translation and evaluating the efficacy of potential therapeutic strategies. Here we utilized TBI models that varied in both injury mechanism and severity including severe traditional controlled cortical impact (CCI), modified mild CCI (MTBI), and multiple severities of closed-head diffuse TBI (DTBI), and assessed pathophysiological changes. Severe CCI induced cortical lesions and necrosis, while both MTBI and DTBI lacked lesions or significant necrotic damage. Autophagy was activated in the ipsilateral cortex following CCI, but acutely impaired in the ipsilateral hippocampus. Additionally, autophagy was activated in the cortex following DTBI, and autophagic impairment was observed in either the cortex or hippocampus following impact from each DTBI severity. Thus, we provide evidence that autophagy is a therapeutic target for both mild and severe TBI. However, dramatic increases in necrosis following CCI may negatively impact the clinical translatability of therapeutics designed to treat acute dysfunction in TBI. Overall, these results provide evidence that injury sequalae affiliated with TBI heterogeneity is linked through autophagy activation and/or impaired autophagic flux. Thus, therapeutic strategies designed to intervene in autophagy may alleviate pathophysiological consequences, in addition to the cognitive and behavioral deficits observed in TBI.

Understanding microglial responses in large animal models of traumatic brain injury: an underutilized resource for preclinical and translational research.

Traumatic brain injury (TBI) often results in prolonged or permanent brain dysfunction with over 2.8 million affected annually in the U.S., including over 56,000 deaths, with over 5 million total survivors exhibiting chronic deficits. Mild TBI (also known as concussion) accounts for over 75% of all TBIs every year. Mild TBI is a heterogeneous disorder, and long-term outcomes are dependent on the type and severity of the initial physical event and compounded by secondary pathophysiological consequences, such as reactive astrocytosis, edema, hypoxia, excitotoxicity, and neuroinflammation. Neuroinflammation has gained increasing attention for its role in secondary injury as inflammatory pathways can have both detrimental and beneficial roles. For example, microglia-resident immune cells of the central nervous system (CNS)-influence cell death pathways and may contribute to progressive neurodegeneration but also aid in debris clearance and neuroplasticity. In this review, we will discuss the acute and chronic role of microglia after mild TBI, including critical protective responses, deleterious effects, and how these processes vary over time. These descriptions are contextualized based on interspecies variation, sex differences, and prospects for therapy. We also highlight recent work from our lab that was the first to describe microglial responses out to chronic timepoints after diffuse mild TBI in a clinically relevant large animal model. The scaled head rotational acceleration of our large animal model, paired with the gyrencephalic architecture and appropriate white:gray matter ratio, allows us to produce pathology with the same anatomical patterns and distribution of human TBI, and serves as an exemplary model to examine complex neuroimmune response post-TBI. An improved understanding of microglial influences in TBI could aid in the development of targeted therapeutics to accentuate positive effects while attenuating detrimental post-injury responses over time.

Persistent hypersomnia following repetitive mild experimental traumatic brain injury: Roles of chronic stress and sex differences.

Traumatic brain injury (TBI) is often more complicated than a single head injury. An extreme example of this point may be military service members who experience a spectrum of exposures over a prolonged period under stressful conditions. Understanding the effects of complex exposures can inform evaluation and care to prevent persistent symptoms. We designed a longitudinal series of non-invasive procedures in adult mice to evaluate the effects of prolonged mild stress and head injury exposures. We assessed anxiety, depression, and sleep-wake dysfunction as symptoms that impact long-term outcomes after mild TBI. Unpredictable chronic mild stress (UCMS) was generated from a varied sequence of environmental stressors distributed within each of 21 days. Subsequently, mice received a mild blast combined with closed-head mild TBI on 5 days at 24-h intervals. In males and females, UCMS induced anxiety without depressive behavior. A major finding was reproducible sleep-wake dysfunction through 6- to 12-month time points in male mice that received UCMS with repetitive blast plus TBI events, or surprisingly after just UCMS alone. Specifically, male mice exhibited hypersomnia with increased sleep during the active/dark phase and fragmentation of longer wake bouts. Sleep-wake dysfunction was not found with TBI events alone, and hypersomnia was not found in females under any conditions. These results identify prolonged stress and sex differences as important considerations for sleep-wake dysfunction. Furthermore, this reproducible hypersomnia with impaired wakefulness is similar to the excessive daytime sleepiness reported in patients, including patients with TBI, which warrants further clinical screening, care, and treatment development.

Cross-spectral analysis of cerebral autoregulation after mild traumatic brain injury.

Severe traumatic brain injury (TBI) disrupts cerebral autoregulation (CAR), which may increase the risk of secondary neuronal damage in victims with large fluctuations in blood pressure (BP). CAR is also impaired in mild TBI. Given that mild TBI accounts for up to 70% of cases, this issue needs to be addressed. Physiological and non-invasive methods are now required to study CAR without the sharp fluctuations in blood pressure that underlie CAR tests. The cross-spectral analysis of fluctuations between cerebral blood flow and blood pressure discussed in the article is truly non-invasive and physiological. Forty-eight victims with mild traumatic brain injury were studied. CAR was assessed using two methods. The cuff test was used as a control method to assess autoregulation (RoR). Non-invasive cross-spectral analysis with phase shift (PS) detection was performed. The RoR values were normal, but there were cases within the group with varying severity of symptoms of the acute period of mild TBI. For example, the RoR was significantly higher (p < 0.001) in 32 patients with regression of symptoms than in 16 with persistence of symptoms. Their RoR and PS indicated a violation of the CAR, which required correction of the treatment. It was found that in 1/3 of the patients with mild TBI, a different state of CAR required individual tactics. RoR and PS correlated well.

Fear avoidance and return to work after mild traumatic brain injury.

OBJECTIVES: Fear avoidance is associated with symptom persistence after mild traumatic brain injury (mTBI). In this study, we investigated whether fear avoidance was associated with other outcomes such as return to work-related activity (RTW). MATERIALS AND METHODS: We analyzed associations between fear avoidance and RTW 6-9 months after mTBI, in two merged prospective mTBI cohorts. Adult participants aged 16 or over (n=175), presenting to outpatient services in New Zealand within 3 months of their injury, who were engaged in work-related activity at the time of injury, were included. Participants completed the Fear Avoidance Behavior after Traumatic Brain Injury (FAB-TBI) questionnaire at enrollment and 6 months later. Associations between FAB-TBI scores and RTW outcome were analyzed using multivariate approaches. RESULTS: Overall, 53% of participants had RTW by 6-9 months after mTBI. While early fear avoidance was weakly associated with RTW, persistent high fear avoidance between study assessments or increasing avoidance with time were associated with greater odds of still being off work 6-9 months after injury. CONCLUSIONS: Pervasive and increasing avoidance of symptom triggers after mTBI were associated with lower rates of RTW 6-9 months after mTBI. Further research is needed to better understand transition points along the recovery trajectory where fear avoidance behaviors fade or increase after mTBI.

Utility of Person-Environment-Occupation model in exploring sex-specific causes of work-related traumatic brain injury: a retrospective chart review.

BACKGROUND: Work-related traumatic brain injury (wr-TBI) is on the rise. The pre-injury period, a significant consideration for preventive initiatives, is largely unexplored. OBJECTIVES: To identify Person-Environment-Occupation (PEO) variables associated with wr-TBI to inform sex-specific primary prevention. METHODS: Retrospective chart review data were analyses. Two-tailed t-test and chi-squared tests were used to study sex differences. Multivariate logistic regression models of wr-TBI were fit with a priori defined PEO variables. RESULTS: The sample comprised 330 consecutive workers with wr-TBI (40.8 ± 11.1 years old, 71% male). Sex differences were observed across PEO variables. In multivariable logistic regression analyses the odds of sustaining a wr-TBI from a fall increased with the presence of a mood disorder and participation in non-labourer occupations (odds ratio (OR) 2.89 (95% CI 1.06-7.89) and OR 2.89 (95% CI 1.06-7.89), respectively) and decreased being a male (OR 0.31 (95% CI 0.17-0.54)). The odds of sustaining a wr-TBI from being striken by an object was greater in workers with prior head injury (OR 2.8 (95% CI 1.24-6.45)). None of the variables studied were associated with wr-TBI sustained from being striken against an object. CONCLUSIONS: Workers' health status pre-injury is associated with external causes of wr-TBI. Sex differences across PEO categories warrant further study.

Behaviour outcomes three months after mild TBI in preschool children.

This study examined parents' report of behaviour in preschoolers after a mild traumatic brain injury (mTBI), compared the proportion of preschoolers with elevated behaviour ratings between the mTBI and limb injury (LI) groups, and explored injury, premorbid child, and parent variables that may be associated with parents' report of behaviour at three months post-injury. Children aged 2-5 years with a mTBI (n = 13) or mild LI (n = 6) were recruited from the emergency department. Behaviour was assessed using the Child Behaviour Checklist. Preliminary findings showed that post-injury behaviour ratings remained in the normal range. The mTBI group had higher scores than the LI group at three months post-injury in terms of sleep; however, this may have been pre-existing. Two children with mTBI received borderline-clinically significant ratings on diagnostic-level anxiety problems at the three-month follow-up, while none of the limb-injured controls obtained elevated behaviour ratings. Parent-rated post-injury behaviour was significantly associated with premorbid child functioning and parental stress, which needs to be explored in greater detail using larger preschool mTBI samples.

Classification Criteria and Rates of Persistent Postconcussive Symptoms in Children: A Systematic Review and Meta-Analysis.

OBJECTIVE: To provide a systematic review of studies examining the proportion of children with persistent postconcussive symptoms (PPCS) and to examine potential moderators of prevalence. STUDY DESIGN: Searches were conducted in MEDLINE, Embase, PsycINFO, Scopus, and Cochrane Central Register of Controlled Trials on April 16, 2020. Criteria for study inclusion were children aged <18 years with concussion or mild traumatic brain injury, operational definition of PPCS, assessment of postconcussive symptoms at least 4 weeks postinjury, sample sizes and proportion with PPCS available, and study published in English. Definition of PPCS, sample size, proportion of participants identified with PPCS, child sex and age at injury, time postinjury, premorbid symptoms, diagnosis (concussion or mild traumatic brain injury), and study publication year were extracted from each article. Study quality was assessed using the Newcastle-Ottawa Scale. RESULTS: Thirteen studies, with a total of 5307 participants, were included in our analysis. The proportion of children identified with PPCS was 35.1% (weighted average; 95% CI, 26.3%-45.0%). The prevalence of PPCS was higher in older and female children who presented for care at concussion clinics, and in more recent publications. CONCLUSIONS: Approximately one-third of children with concussion/mild traumatic brain injury will experience PPCS. Age, sex, and point of care could help identify children at high risk for PPCS.

New diagnosis of cancer in mild and moderate/severe traumatic brain injury patients in a 12-year population-based study.

BACKGROUND: Traumatic brain injury (TBI) has been reported as a risk factor for brain cancer development. However, the magnitude of the impact of TBI on systemic cancer development has not been clarified. METHODS: A retrospective longitudinal cohort study was conducted using the Taiwan Longitudinal Health Insurance Database between January 2000 and December 2011. A total of 35,306 patients were initially enrolled, and 14,795 patients with mild TBI and 14,795 patients with moderate/severe TBI were matched using the National Health Insurance Research Database in Taiwan. The Cox proportional hazard regression model was used to estimate the hazard ratio (HR) of TBI adjusted for potential confounding factors. RESULTS: After matching, the results showed that patients with moderate/severe TBI had a high mortality rate (17.7% vs. 10.4%) and shorter time interval from TBI to death (mean 3.6 years vs. 5.8 years). No differences were observed in cancer incidence (4.1% vs. 4.1%) or risk factors for mortality between mild and moderate/severe TBI patients. However, patients aged between 46 and 55 years, female patients, and patients with pre-existing renal disease had a significant higher cancer incidence risk in moderate/severe TBI compared with mild TBI patients. The top 15 most common cancers showed that mild TBI patients had a higher percentage of head and neck cancer. The overall mortality rate in all TBI patients diagnosed with cancer was about 50%, and the cancer-specific mortality is approximately 85% in death of TBI patients with cancer. CONCLUSIONS: We concluded that the incidence risk of a new cancer diagnosis and mortality risk of TBI patients with cancer between the mild TBI and moderate/severe TBI patients were not significantly different.

Rehabilitation and outcomes after complicated vs uncomplicated mild TBI: results from the CENTER-TBI study.

BACKGROUND: Despite existing guidelines for managing mild traumatic brain injury (mTBI), evidence-based treatments are still scarce and large-scale studies on the provision and impact of specific rehabilitation services are needed. This study aimed to describe the provision of rehabilitation to patients after complicated and uncomplicated mTBI and investigate factors associated with functional outcome, symptom burden, and TBI-specific health-related quality of life (HRQOL) up to six months after injury. METHODS: Patients (n = 1379) with mTBI from the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study who reported whether they received rehabilitation services during the first six months post-injury and who participated in outcome assessments were included. Functional outcome was measured with the Glasgow Outcome Scale - Extended (GOSE), symptom burden with the Rivermead Post Concussion Symptoms Questionnaire (RPQ), and HRQOL with the Quality of Life after Brain Injury - Overall Scale (QOLIBRI-OS). We examined whether transition of care (TOC) pathways, receiving rehabilitation services, sociodemographic (incl. geographic), premorbid, and injury-related factors were associated with outcomes using regression models. For easy comparison, we estimated ordinal regression models for all outcomes where the scores were classified based on quantiles. RESULTS: Overall, 43% of patients with complicated and 20% with uncomplicated mTBI reported receiving rehabilitation services, primarily in physical and cognitive domains. Patients with complicated mTBI had lower functional level, higher symptom burden, and lower HRQOL compared to uncomplicated mTBI. Rehabilitation services at three or six months and a higher number of TOC were associated with unfavorable outcomes in all models, in addition to pre-morbid psychiatric problems. Being male and having more than 13 years of education was associated with more favorable outcomes. Sustaining major trauma was associated with unfavorable GOSE outcome, whereas living in Southern and Eastern European regions was associated with lower HRQOL. CONCLUSIONS: Patients with complicated mTBI reported more unfavorable outcomes and received rehabilitation services more frequently. Receiving rehabilitation services and higher number of care transitions were indicators of injury severity and associated with unfavorable outcomes. The findings should be interpreted carefully and validated in future studies as we applied a novel analytic approach. TRIAL REGISTRATION: ClinicalTrials.gov NCT02210221.

Pathway of care for visual and vestibular rehabilitation after mild traumatic brain injury: a critical review.

PRIMARY OBJECTIVE: To review the pathway to care for treatment and management of patients receiving visual and vestibular rehabilitation after mild traumatic brain injury (mTBI). METHODS & PROCEDURES: English scientific peer-reviewed articles from PubMed, CINAHL, Embase, and PsycINFO between 2000 and 2020 were first screened by title and abstract, then those selected underwent full-text review and analysis. MAIN OUTCOMES & RESULTS: The database search yielded 1640 results and after title and abstract review, 75 articles were selected for full-text screening, from which 8 were included in the qualitative synthesis. Current evidence includes a limited number of retrospective cohort studies and case studies. CONCLUSIONS: Many patients with visual and vestibular deficits following mTBI do not receive rehabilitation services until months following their injury as there is no standardized pathway to care for patients for visual and vestibular rehabilitation. Barriers to establishing a standardized pathway are the lack of natural history data for visual and vestibular function following mTBI and the lack of randomized clinical trials establishing the efficacy of rehabilitation in patients following mTBI.

The role of AT-SLP collaborations in return to academics following mTBI: A scoping review.

Return-to-academics (RTA) for student-athletes with mild traumatic brain injury (mTBI) is crucial, but relatively understudied compared to return-to-play (RTP). The transient and unpredictable nature of symptoms surrounding mTBI often results in underreporting of neurocognitive symptoms, leading to a greater susceptibility for repeated TBIs, as well as posing impediments to the process of RTA. Athletic Trainers (ATs) and Speech-Language Pathologists (SLPs) are in a unique position to help student-athletes achieve a safe, timely, and effective RTA following mTBI. They typically work in middle/high schools and collegiate-level academic settings and often serve as members of concussion management teams. Compared to other allied health professions, ATs and SLPs are relatively new professions with evolving scopes of practice. Despite established guidelines and recommendations for their scope of practice in treating student-athletes with mTBI, there is a lacuna in research regarding their individual and collaborative roles in achieving RTA. The current scoping review was conducted with the main goal of exploring published literature pertaining to the roles of ATs and SLPs in achieving RTA for student-athletes with mTBI. Current implications, recommendations for integrating pre-service interprofessional education (IPE) experiences, and future directions for AT-SLP collaborations are discussed.

Elevated Intraindividual Variability in Executive Functions and Associations with White Matter Microstructure in Veterans with Mild Traumatic Brain Injury.

OBJECTIVE: We examined whether intraindividual variability (IIV) across tests of executive functions (EF-IIV) is elevated in Veterans with a history of mild traumatic brain injury (mTBI) relative to military controls (MCs) without a history of mTBI. We also explored relationships among EF-IIV, white matter microstructure, and posttraumatic stress disorder (PTSD) symptoms. METHOD: A total of 77 Veterans (mTBI = 43, MCs = 34) completed neuropsychological testing, diffusion tensor imaging (DTI), and PTSD symptom ratings. EF-IIV was calculated as the standard deviation across six tests of EF, along with an EF-Mean composite. DSI Studio connectometry analysis identified white matter tracts significantly associated with EF-IIV according to generalized fractional anisotropy (GFA). RESULTS: After adjusting for EF-Mean and PTSD symptoms, the mTBI group showed significantly higher EF-IIV than MCs. Groups did not differ on EF-Mean after adjusting for PTSD symptoms. Across groups, PTSD symptoms significantly negatively correlated with EF-Mean, but not with EF-IIV. EF-IIV significantly negatively correlated with GFA in multiple white matter pathways connecting frontal and more posterior regions. CONCLUSIONS: Veterans with mTBI demonstrated significantly greater IIV across EF tests compared to MCs, even after adjusting for mean group differences on those measures as well as PTSD severity. Findings suggest that, in contrast to analyses that explore effects of mean performance across tests, discrepancy analyses may capture unique variance in neuropsychological performance and more sensitively capture cognitive disruption in Veterans with mTBI histories. Importantly, findings show that EF-IIV is negatively associated with the microstructure of white matter pathways interconnecting cortical regions that mediate executive function and attentional processes.

Plasma miR-9-3p and miR-136-3p as Potential Novel Diagnostic Biomarkers for Experimental and Human Mild Traumatic Brain Injury.

Noninvasive, affordable circulating biomarkers for difficult-to-diagnose mild traumatic brain injury (mTBI) are an unmet medical need. Although blood microRNA (miRNA) levels are reportedly altered after traumatic brain injury (TBI), their diagnostic potential for mTBI remains inconclusive. We hypothesized that acutely altered plasma miRNAs could serve as diagnostic biomarkers both in the lateral fluid percussion injury (FPI) model and clinical mTBI. We performed plasma small RNA-sequencing from adult male Sprague-Dawley rats (n = 31) at 2 days post-TBI, followed by polymerase chain reaction (PCR)-based validation of selected candidates. miR-9a-3p, miR-136-3p, and miR-434-3p were identified as the most promising candidates at 2 days after lateral FPI. Digital droplet PCR (ddPCR) revealed 4.2-, 2.8-, and 4.6-fold elevations in miR-9a-3p, miR-136-3p, and miR-434-3p levels (p < 0.01 for all), respectively, distinguishing rats with mTBI from naïve rats with 100% sensitivity and specificity. DdPCR further identified a subpopulation of mTBI patients with plasma miR-9-3p (n = 7/15) and miR-136-3p (n = 5/15) levels higher than one standard deviation above the control mean at <2 days postinjury. In sTBI patients, plasma miR-9-3p levels were 6.5- and 9.2-fold in comparison to the mTBI and control groups, respectively. Thus, plasma miR-9-3p and miR-136-3p were identified as promising biomarker candidates for mTBI requiring further evaluation in a larger patient population.

Outcome measures from experimental traumatic brain injury in male rats vary with the complete temporal biomechanical profile of the injury event.

Millions suffer a traumatic brain injury (TBI) each year wherein the outcomes associated with injury can vary greatly between individuals. This study postulates that variations in each biomechanical parameter of a head trauma lead to differences in histological and behavioral outcome measures that should be considered collectively in assessing injury. While trauma severity typically scales with the magnitude of injury, much less is known about the effects of rate and duration of the mechanical insult. In this study, a newly developed voice-coil fluid percussion injury system was used to investigate the effects of injury rate and fluid percussion impulse on a collection of post-injury outcomes in male rats. Collectively the data suggest a potential shift in the specificity and progression of neuronal injury and function rather than a general scaling of injury severity. While a faster, shorter fluid percussion first presents as a mild TBI, neuronal loss and some behavioral tasks were similar among the slower and faster fluid percussion injuries. This study concludes that the sequelae of neuronal degeneration and behavioral outcomes are related to the complete temporal profile of the fluid percussion and do not scale only with peak pressure.

Separate N-acetyl aspartyl glutamate, N-acetyl aspartate, aspartate, and glutamate quantification after pediatric mild traumatic brain injury in the acute phase.

PURPOSE: To separately measure N-acetyl aspartul glutamate (NAAG), N-acetyl aspartate (NAA), aspartate (Asp), and glutamate (Glu) concentrations in white matter (WM) using J-editing techniques in patients with mild traumatic brain injury (mTBI) in the acute phase. METHODS: Twenty-four patients with closed concussive head injury and 29 healthy volunteers were enrolled in the current study. For extended 1 H MRS examination, patients and controls were equally divided into two subgroups. In subgroup 1 (12 patients/15 controls), NAAG and NAA concentrations were measured in WM separately with MEGA-PRESS (echo time/repetition time [TE/TR] = 140/2000 ms; δONNAA / δOFFNAA = 4.84/4.38 ppm, δONNAAG / δOFFNAAG = 4.61/4.15 ppm). In subgroup 2 (12 patients/14 controls), Asp and Glu concentrations were acquired with MEGA-PRESS (TE/TR = 90/2000 ms; δONAsp / δOFFAsp = 3.89/5.21 ppm) and TE-averaged PRESS (TE from 35 ms to 185 ms with 2.5-ms increments; TR = 2000 ms) pulse sequences, respectively. RESULTS: tNAA and NAAG concentrations were found to be reduced, while NAA concentrations were unchanged, after mild mTBI. Reduced Asp and elevated myo-inositol (mI) concentrations were also found. CONCLUSION: The main finding of the study is that the tNAA signal reduction in WM after mTBI is associated with a decrease in the NAAG concentration rather than a decrease in the NAA concentration, as was thought previously. This finding highlights the importance of separating these signals, at least for WM studies, to avoid misinterpretation of the results. NAAG plays an important role in selectively activating mGluR3 receptors, thus providing neuroprotective and neuroreparative functions immediately after mTBI. NAAG shows potential for the development of new therapeutic strategies for patients with injuries of varying severity.

A Longitudinal Investigation of Symptom Recovery following Concussion in Youth Soccer.

OBJECTIVE: To prospectively evaluate symptom outcomes after youth soccer-related concussion. STUDY DESIGN: Using a prospective cohort design, we enrolled male and female competitive soccer players age 8-17 years into 3 groups: concussed (n = 23), matched control (n = 23), and orthopedic injury (n = 24). Postconcussive symptoms were monitored serially via both athlete and parent report at days 1-2, 4, 7, 10, 30, and 90. RESULTS: Repeated-measures analyses revealed a significant time by group interaction (F [12, 402] = 19.91, P < .001). In the initial days postinjury, the concussed group reported greater symptoms than the comparison groups, with more symptoms reported by athletes on average than parents. By 10 days, concussed athletes did not differ from the matched controls by either rater's report, but they did differ from the orthopedic injury group by parent report. At 30 days, no differences were apparent among groups. At 30 days, 100% of concussed youth and 91% of parents rated symptoms as back to preinjury levels using reliable change indices. At 30 days, 86% of athletes had been cleared to return to full game play. CONCLUSIONS: The natural clinical history of concussion symptoms in youth competitive soccer players was similar to that seen in older athletes, with resolution in days to a few weeks. Additional study will be required to investigate which factors best predict symptom outcomes for individual athletes and how symptom report relates to performance-based outcome measures and underlying neurophysiologic recovery.