Diagnostic Accuracy of Mental Health Screening Tools After Mild Traumatic Brain Injury.

Importance: Mental health disorders are common after mild traumatic brain injury (mTBI) and likely exacerbate postconcussive symptoms and disability. Early detection could improve clinical outcomes, but the accuracy of mental health screening tools in this population has not been well established. Objective: To determine the diagnostic accuracy of the Patient Health Questionnaire-9 (PHQ-9), Generalizaed Anxiety Disorder-7 (GAD-7), and Primary Care PTSD (Posttramatic Stress Disorder) Screen for Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) (PC-PTSD-5) in adults with mTBI. Design, Setting, and Participants: This diagnostic study was performed as a secondary analysis of a cluster randomized clinical trial. Self-report mental health screening tools (PHQ-9, GAD-7, and PC-PTSD-5) were administered online 12 weeks after mTBI and compared against a structured psychodiagnostic interview (Mini-International Neuropsychiatric Interview for DSM-5 (MINI) over videoconference at the same time. Adults with mTBI (N = 537) were recruited from February 1, 2021, to October 25, 2022. Main Outcomes and Measures: Presence of a major depressive episode, anxiety disorders, and PTSD were determined by a blinded assessor with the MINI. Diagnostic accuracy statistics were derived for the PHQ-9, GAD-7, and PC-PTSD-5. Findings were disaggregated for participants with and without persistent postconcussion symptoms (PPCS) by International and Statistical Classification of Diseases, Tenth Revision criteria. Results: Data were available for 499 of 537 trial participants, 278 (55.7%) of whom were female; the mean (SD) age was 38.8 (13.9) years. Each screening questionnaire had strong diagnostic accuracy in the overall sample for optimal cut points (area under the curve [AUC], ≥0.80; sensitivity, 0.55-0.94; specificity, 0.64-0.94). The AUC (difference of 0.01-0.13) and specificity (difference, 5-65 percentage points) were lower in those with PPCS present compared with PPCS absent, but the prevalence of at least 1 mental health disorder was 3 to 5 times higher in patients with PPCS present. The GAD-7 had slightly better performance than the PC-PTSD-5 for detecting PTSD (AUC, 0.85 [95% CI, 0.80-0.89] vs 0.80 [95% CI, 0.72-0.87]). The optimal cutoff on the PHQ-9 was 5 or more symptoms experienced on more than half of days; on the GAD-7, a total score of at least 7. Conclusions and Relevance: The findings of this diagnostic study suggest that the PHQ-9, GAD-7 and PC-PTSD-5 accurately screen for mental health disorders in patients with mTBI. Future research should corroborate optimal test cutoffs for this population.

Investigation of Mild Traumatic Brain Injury Home Cage Behavior: The Home Cage Assay Advantages.

This study utilized the Noldus PhenoTyper Home Cage Monitoring system (HCM) to assess the behavioral and cognitive changes of experimental closed-head mild traumatic brain injury (mTBI). Seventy-nine adult male Institute of Cancer Research (ICR) mice were subjected to either a sham procedure or closed-head mTBI using the weight-drop model. Seven days post-injury, separate cohorts of mice underwent either a non-cognitive or a cognitive home cage assessment, a treadmill fatigue test, or the Open Field Test. mTBI significantly influenced habituation behavior and circadian wheel-running activity. Notably, mTBI mice exhibited an increased frequency of visits to the running wheel, but each visit was shorter than those of controls. No significant differences between the groups in discrimination or reversal learning performance were observed. However, during the reversal learning stage, mTBI mice performed similarly to their initial discrimination learning levels, suggesting an abnormally faster rate of reversal learning. Home cage monitoring is a valuable tool for studying the subtle effects of mTBI, complementing traditional assays. The automated evaluation of habituation to novel stimuli (e.g., novel environment) could serve as a potentially sensitive tool for assessing mTBI-associated behavioral deficits.

Median Time to Return to Sports After Concussion Is Within 21 Days in 80% of Published Studies.

PURPOSE: To perform a systematic review of the literature and evaluate the return to play (RTP) time frame after a concussion diagnosis. Our secondary purpose was to analyze and compare different prognostic variables affecting concussions, time to return to school, time to symptom resolution of concussive symptoms, and time each patient spent in the RTP protocol. METHODS: A PubMed, Scopus, Medline, Embase, and Cochrane Library database literature review was performed in August 2022. The studies needed to report, in days, the length of time a patient/athlete was removed from play due to concussion management. The Risk of Bias in Non-Randomized Studies of Interventions tool was used for risk of bias for each study, and Methodological Index for Non-Randomized Studies criteria were used for quality assessment. RESULTS: There were 65 studies included in the systematic review and a total of 21,966 patients evaluated. The RTP time intervals ranged from 1 to 1,820 days, with 80.7% of the median RTP time frames for each study within 21 days. Preconcussion risk factors for prolonged RTP included female sex, younger age, presence of psychiatric disorders, and history of previous concussion. Postconcussion risk factors included severe symptom scores at initial clinic visit, loss of consciousness, nonelite athletes, and delayed removal from competition. The most common sports resulting in concussion were contact sports, most commonly football and soccer. Median time to return to school was 3 to 23 days. Median time to symptom resolution ranged from 2 to 11 days. Median time in RTP protocol was 1 to 6 days. CONCLUSIONS: Median time to return to sports after concussion is within 21 days in 80% of published studies. LEVEL OF EVIDENCE: IV, systematic review of Level I to IV studies.

N -acetylcysteine is associated with reduction of postconcussive symptoms in elderly patients: A pilot study.

INTRODUCTION: N -acetylcysteine (NAC) may be neuroprotective by minimizing postconcussion symptoms after mild traumatic brain injury (TBI), but limited data exist. This study evaluated the effects of NAC on postconcussion symptoms in elderly patients diagnosed with mild TBI. METHODS: This prospective, quasirandomized, controlled trial enrolled patients 60 years or older who suffered mild TBI. Patients were excluded if cognitive function could not be assessed within 3-hours postinjury. Patients were allocated to receive NAC plus standard care, or standard care alone, based on the trauma center where they presented. The primary study outcome was the severity of concussive symptoms measured using the Rivermeade Postconcussion Symptoms Questionnaire (RPQ). Symptoms were evaluated on days 0, 7, and 30. The RPQ scores were compared both within and between treatment groups. RESULTS: There were 65 patients analyzed (NAC, n = 34; control, n = 31) with an average age of 76 ± 10 years. Baseline demographics and clinical variables were similar. No group differences in head Abbreviated Injury Scale score or Glasgow Coma Scale score were observed. Baseline RPQ scores (6 [0-20] vs. 11 [4-20], p = 0.300) were indistinguishable. The RPQ scores on day 7 (2 [0-8] vs. 10 [3-18], p = 0.004) and 30 (0 [0-4] vs. 4 [0-13], p = 0.021) were significantly lower in the NAC group. Within-group differences were significantly lower in the NAC ( p < 0.001) but not control group ( p = 0.319). CONCLUSION: N -acetylcysteine was associated with significant improvements in concussion symptoms in elderly patients with mild TBI. These results justify further research into using NAC to treat TBI. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Plasma biomarkers associated with deployment trauma and its consequences in post-9/11 era veterans: initial findings from the TRACTS longitudinal cohort.

Mild traumatic brain injury (mTBI) is among the most common injuries sustained by post-9/11 veterans; however, these injuries often occur within the context of psychological trauma. Blast exposure, even in the absence of a diagnosable TBI, leads to changes in neural connectivity and congitive functioning. Therefore, considering clinical comorbidities and injury characteristics is critical to understanding the long-term effects of mTBI. Research is moving towards identifying diagnostic and prognostic blood-based biomarkers for TBI; however, few studies include other prevalent clinical and medical comorbidities related to deployment. Here, we present the initial cross-sectional relationships between plasma biomarkers, clinical, and medical comorbidities in a well-characterized longitudinal sample of 550 post-9/11 veteran men and women. We examined biomarkers associated with inflammation (interleukin 6 and 10, tumor necrosis factor α, and eotaxin) and neurodegeneration (neurofilament light, glial fibrillary acidic protein (GFAP), tau, brain derived neurotrophic factor, amyloid ß 40 and 42, phosphorylated neurofilament heavy chain, and neuron specific enolase). Univariate analyses of covariance (ANCOVA) were conducted to determine mean level differences between close blast (blasts that occur within 0-10 meters) and mTBI groups. Our primary findings were twofold: (1) Inflammatory markers were consistently higher in participants exposed to close blasts and were strongly related to deployment-related psychopathology. (2) GFAP was consistently lower in participants exposed to blast and mTBI and lower GFAP was associated with more severe psychological symptoms. More research is clearly needed; however, our findings indicate that chronic increased inflammation and decreased GFAP may be related to close blast exposure.

Psychosocial impairment following mild blast-induced traumatic brain injury in rats.

Traumatic brain injury (TBI) is associated with increased risk for mental health disorders, impacting post-injury quality of life and societal reintegration. TBI is also associated with deficits in psychosocial processing, defined as the cognitive integration of social and emotional behaviors, however little is known about how these deficits manifest and their contributions to post-TBI mental health. In this pre-clinical investigation using rats, a single mild blast TBI (mbTBI) induced impairment of psychosocial processing in the absence of confounding physical polytrauma, post-injury motor deficits, affective abnormalities, or deficits in non-social behavior. Impairment severity correlated with acute upregulations of a known oxidative stress metabolite, 3-hydroxypropylmercapturic acid (3-HPMA), in urine. Resting state fMRI alterations in the acute post-injury period implicated key brain regions known to regulate psychosocial behavior, including orbitofrontal cortex (OFC), which is congruent with our previous report of elevated acrolein, a marker of neurotrauma and 3-HPMA precursor, in this region following mbTBI. OFC of mbTBI-exposed rats demonstrated elevated mRNA expression of metabotropic glutamate receptors 1 and 5 (mGluR1/5) and injection of mGluR1/5-selective agonist in OFC of uninjured rats approximated mbTBI-induced psychosocial processing impairment, demonstrating a novel role for OFC in this psychosocial behavior. Furthermore, OFC may serve as a hotspot for TBI-induced disruption of psychosocial processing and subsequent mental health disorders.

Preliminary Report: Localized Cerebral Blood Flow Mediates the Relationship between Progesterone and Perceived Stress Symptoms among Female Collegiate Club Athletes after Mild Traumatic Brain Injury.

Female athletes are under-studied in the field of concussion research, despite evidence of higher injury prevalence and longer recovery time. Hormonal fluctuations caused by the natural menstrual cycle (MC) or hormonal contraceptive (HC) use impact both post-injury symptoms and neuroimaging findings, but the relationships among hormone, symptoms, and brain-based measures have not been jointly considered in concussion studies. In this preliminary study, we compared cerebral blood flow (CBF) measured with arterial spin labeling between concussed female club athletes 3-10 days after mild traumatic brain injury (mTBI) and demographic, HC/MC matched controls (CON). We tested whether CBF statistically mediates the relationship between progesterone serum levels and post-injury symptoms, which may support a hypothesis for progesterone's role in neuroprotection. We found a significant three-way relationship among progesterone, CBF, and perceived stress score (PSS) in the left middle temporal gyrus for the mTBI group. Higher progesterone was associated with lower (more normative) PSS, as well as higher (more normative) CBF. CBF mediates 100% of the relationship between progesterone and PSS (Sobel p value = 0.017). These findings support a hypothesis for progesterone having a neuroprotective role after concussion and highlight the importance of controlling for the effects of sex hormones in future concussion studies.

Health-promoting behaviours and concussion history are associated with cognitive function, mood-related symptoms and emotional-behavioural dyscontrol in former NFL players: an NFL-LONG Study.

OBJECTIVES: To examine the relationships among self-reported sport-related concussion (SRC) history and current health-promoting behaviours (exercise frequency, diet quality and sleep duration) with self-reported measures of brain health (cognitive function, symptoms of depression and anxiety and emotional-behavioural dyscontrol) in former NFL players. METHODS: In this cross-sectional study, a questionnaire was sent to former NFL players. Respondents reported SRC history (categorical: 0; 1-2; 3-5; 6-9; 10+ concussions), number of moderate-to-vigorous aerobic and resistance exercise sessions per week, diet quality (Rapid Eating Assessment for Participants-Shortened) and average nightly sleep duration. Outcomes were Patient-Reported Outcomes Measurement Information System Cognitive Function, Depression, and Anxiety, and Neuro-QoL Emotional-Behavioral Dyscontrol domain T-scores. Multivariable linear regression models were fit for each outcome with SRC history, exercise frequency, diet quality and sleep duration as explanatory variables alongside select covariates. RESULTS: Multivariable regression models (n=1784) explained approximately 33%-38% of the variance in each outcome. For all outcomes, SRC history (0.144≤|ß|≤0.217) was associated with poorer functioning, while exercise frequency (0.064≤|ß|≤0.088) and diet quality (0.057≤|ß|≤0.086) were associated with better functioning. Sleeping under 6 hours per night (0.061≤|ß|≤0.093) was associated with worse depressive symptoms, anxiety and emotional-behavioural dyscontrol. CONCLUSION: Several variables appear to be associated with mood and perceived cognitive function in former NFL players. SRC history is non-modifiable in former athletes; however, the effects of increasing postplaying career exercise frequency, making dietary improvements, and obtaining adequate sleep represent important potential opportunities for preventative and therapeutic interventions.

Modifiable Risk Factors for Poor Cognitive Function in Former American-Style Football Players: Findings from the Harvard Football Players Health Study.

Recent attention to consequences of head trauma among former professional American-style football players has increased the likelihood that former players and their healthcare providers attribute neurocognitive effects to these exposures. In addition to head trauma, however, many potentially modifiable risk factors are associated with cognitive impairment. We examined the association of self-reported risk factors for cognitive impairment (e.g., cardiovascular health, sleep, pain, depression, anxiety, smoking, physical impairment, and physical activity) with cognition-related quality of life, measured by the Quality of Life in Neurological Disorders, Applied Cognition-General Concerns (Neuro-QOL) among 3803 former National Football League (NFL) players. We examined the prevalence of risk factors among men who had experienced a high number of concussion symptoms during playing years, comparing men with good current cognition-related QOL, the "healthy concussed," to men with poor cognition-related QOL, the "unhealthy concussed." Physical functioning, pain, depression, and anxiety were very strongly associated with poor cognitive-related QOL (risk ratio range, 2.21-2.70, p < 0.0001 for all). Short sleep duration and low physical activity were also strongly associated (RR = 1.69 and 1.57, respectively, p < 0.0001 for both). The largest differences between healthy and unhealthy concussed were in chronic pain (72.0% vs. 21.2%), depressive symptoms (50.3% vs. 6.3%), anxiety symptoms (53.4% vs. 11.6%), and physical impairment (52.4% vs. 12.5%). Substantial differences also existed in prevalence of sleep apnea, short sleep duration, high-intensity exercise, weight training, high blood pressure, and body mass index ≥35 kg/m2 (all differences >10 percentage points). We identified cognitive risk factors, including chronic pain, mood problems, sleep problems, obesity, and lack of exercise, that were commonly present in former football players with cognition-related impairment. Better treatment for these factors may reduce cognitive problems in this population.

Utility of 1 Measurement Versus Multiple Measurements of Near Point of Convergence After Concussion.

CONTEXT: Increased near point of convergence (NPC) distance is a common finding after concussion and is associated with physical symptoms and worsened neurocognitive performance. Vestibular/Ocular Motor Screening measures NPC distance across 3 trials and uses the average measurement to inform clinical care. However, whether 3 trials are necessary, are consistent, or add clinical utility is unknown. OBJECTIVE: To investigate the consistency across 3 trials of NPC and establish the classification accuracy (ie, clinical utility) of 1 or 2 trials compared with the standardized average of 3 trials. DESIGN: Retrospective cohort study. SETTING: Sports medicine clinic and research laboratory. PATIENTS OR OTHER PARTICIPANTS: Consecutively enrolled patients aged 10 to 22 years with diagnosed concussions (74% sport related; n = 380). MAIN OUTCOME MEASURE(S): The previously reported clinical cutoff value of ≥5 cm across 3 trials was used. Pearson correlation and intraclass correlation coefficients were used to evaluate agreement between trials and average scores. Reliable change indices (RCIs) using 95% confidence intervals were also calculated. RESULTS: The Pearson correlation (r = .98) and intraclass correlation (0.98) coefficients revealed excellent agreement between the first measurement and average NPC distance across 3 measurements. The RCI across all trials was 2 cm. When the first NPC measurement was ≤3 cm or ≥7 cm, agreement existed within the RCI between the first measurement and the average of 3 measurements in 99.6% of cases. When we averaged the first and second measurements, 379/380 (99.7%) participants had the same classification (ie, <5 cm = normal, ≥5 cm = abnormal) as the average NPC distance across 3 measurements. CONCLUSIONS: Our findings suggest limited utility of multiple or average NPC distance measurements when the initial NPC distance is outside of RCI clinical cutoffs (ie, ≤3 cm or ≥7 cm). Given the high consistency between the first measurement and average NPC distance across 3 trials, only 1 measurement of NPC distance is warranted unless the first measurement is between 3 and 7 cm.

A randomized, double-blind, placebo-controlled trial of blue wavelength light exposure on sleep and recovery of brain structure, function, and cognition following mild traumatic brain injury.

Sleep and circadian rhythms are among the most powerful but least understood contributors to cognitive performance and brain health. Here we capitalize on the circadian resetting effect of blue-wavelength light to phase shift the sleep patterns of adult patients (aged 18-48 years) recovering from mild traumatic brain injury (mTBI), with the aim of facilitating recovery of brain structure, connectivity, and cognitive performance. During a randomized, double-blind, placebo-controlled trial of 32 adults with a recent mTBI, we compared 6-weeks of daily 30-min pulses of blue light (peak λ = 469 nm) each morning versus amber placebo light (peak λ = 578 nm) on neurocognitive and neuroimaging outcomes, including gray matter volume (GMV), resting-state functional connectivity, directed connectivity using Granger causality, and white matter integrity using diffusion tensor imaging (DTI). Relative to placebo, morning blue light led to phase-advanced sleep timing, reduced daytime sleepiness, and improved executive functioning, and was associated with increased volume of the posterior thalamus (i.e., pulvinar), greater thalamo-cortical functional connectivity, and increased axonal integrity of these pathways. These findings provide insight into the contributions of the circadian and sleep systems in brain repair and lay the groundwork for interventions targeting the retinohypothalamic system to facilitate injury recovery.

Modest utility of brief oculomotor test for concussion screening in military mixed-martial arts training.

Primary Objective: To assess a rapid concussion screening tool in Service members participating in combatives (mixed martial arts; MMA) training school.Research Design: This prospective study included baseline and either post-training or post-injury assessments.Methods and Procedures: Baseline (N = 152) and post-assessments (n = 129) of Service members included symptom reporting and the King-Devick (KD) oculomotor test.Outcomes and Results: Headache, balance problems, and dizziness were the most severe concussive symptoms. KD scores for those who sustained a concussion (n = 31) were significantly worse compared to baseline, but not for participants who finished the course with no concussion (n = 98). For concussed, 74.2% had scores that were worse from baseline (slower) compared to 39.8% of the post-training group. KD scores were worse 34.4% more in individuals who sustained a concussion compared to those who did not. However, there was poor discriminant ability of the KD test (AUC = .60, sensitivity/specificity) to distinguish between concussed and non-concussed participants.Conclusions: The KD test should not be used in isolation as a sideline or field concussion assessment during training scenarios. Rather, it has potential utility for evaluating individual cases to supplement decision making when an established baseline is available.

Mild traumatic brain injuries with loss of consciousness are associated with increased inflammation and pain in military personnel.

Mild traumatic brain injuries (mTBI) are a pervasive concern for military personnel. Determining the impact of injury severity, including loss of consciousness (LOC) may provide important insights into the risk of psychological symptoms and inflammation commonly witnessed in military personnel and veterans following mTBI. US military personnel and veterans were categorized into three groups; TBI with LOC (n = 36), TBI without LOC (n = 25), Controls (n = 82). Participants reported their history of mTBI, psychological symptoms (post-traumatic stress disorder [PTSD] and depression), health-related quality of life (HRQOL), and underwent a blood draw. ANCOVA models which controlled for insomnia status and combat exposure indicated that both mTBI groups (with/without LOC) reported significantly greater depression and PTSD symptoms compared to controls; however, they did not differ from each other. The mTBI with LOC did report greater pain than both controls and mTBI without LOC. The TBI with LOC group also had significantly elevated IL-6 concentrations than both TBI without LOC and control groups. Within the mTBI groups, increased TNFα concentrations were associated with greater PTSD symptoms. These findings indicate that sustaining an mTBI, with or without LOC is detrimental for psychological wellbeing. However, LOC may be involved in perceptions of pain and concentrations of IL-6.

Affective profiling for anxiety-like behavior in a rodent model of mTBI.

Mild traumatic brain injury is a common outcome of blast exposure, and current literature indicates high rates of comorbid posttraumatic stress disorder (PTSD) in military personnel. Blast-exposed rats display PTSD-like behavior, suggesting relationships may exist between PTSD and blast exposure. Other studies demonstrate the roles of stathmin and corticosterone associated with fear- and anxiety-like behaviors in rodent models. Furthermore, studies have observed ranges of responses to both physical and psychological trauma in animal populations (Elder 2012, Ritov 2016). This study exposed rodents to repeated blast overpressure (BOP) and analyzed behavioral responses and molecular variables at 3 weeks and 6 months after exposure. We applied a modified version of a previously reported behavioral profiling approach that separates "affected" and "unaffected" rats based on the presence of anxiety-like behaviors (Ritov, 2016). We report that "affected" 3 week animals showed higher plasma corticosterone and amygdalar stathmin levels, while "affected" 6 month animals had lower prefrontal cortex stathmin. Higher corticosterone also paralleled anxiety behavior in "affected" 3 week animals, which was not observed in 6 month animals, indicating possible negative feedback loop mechanisms. Elevated levels of amygdalar stathmin correlated with anxiety behaviors in "affected" 3 week and 6 month animals, indicating sustained molecular changes. We conclude that this unique analysis may provide more information about response to blast. This type of analysis should also be considered when treating clinical populations, since individual differences may affect behavioral and long-term outcomes. Future studies should elucidate relationships of stress and fear responses in the context of BOP.

Sex-dependent and chronic alterations in behavior and mitochondrial function in a rat model of pediatric mild traumatic brain injury.

OBJECTIVE: To determine if chronic changes in mitochondrial function occur following a mild traumatic brain injury in young rats. RESEARCH DESIGN: Closed-head, weight drop model was used to cause mTBI by applying rotational forces to the brain without surgery. Behavioral battery was used to assess multiple dimensions of impairment across time. Analysis of brain tissue carried out at three-weeks post-injury represents a chronic time point to complement previous work examining acute time points. METHODS AND PROCEDURES: Twenty-three male and 22 female rats one month of age were divided equally into sham and mTBI groups with the latter undergoing the weight drop. Multiple behavioral tests in combination with energetic (oxygen consumption), molecular (immunoblotting), and imaging (electron microscopy) characterization of brain mitochondria were performed. MAIN OUTCOMES AND RESULTS: Mitochondria isolated from sham juvenile female rats had higher basal oxygen consumption compared to juvenile male rats (514.875 ± 171.091 pmol/min vs. 267 ± 73.906 pmol/min, p < 0.0001). Chronic sex-dependent differences were observed in females after mTBI in basal (514.875 ± 171.091 pmol/min vs. 600.688 ± 124.422 pmol/min, p = 0.0264) and maximal oxygen consumption (298.938 ± 119.964 pmol/min vs. 403.281 ± 112.922 pmol/min, p = 0.0001) and proton leak (59.46 ± 7.807 vs. 84.32 ± 5.80 pmol/min, p = 0.0001). CONCLUSIONS: The juvenile rat brain displays sex differences in mitochondrial function at (1) baseline and (2) in long-term outcomes after mTBI. These results offer new insight into a potential mechanism for persistent, individualized impairments following pediatric mTBI.

Video and clinical screening of national rugby league players suspected of sustaining concussion.

PRIMARY OBJECTIVE: This study reviewed the available sideline Sport Concussion Assessment Tool-Third Edition (SCAT3) performance of players who were removed from play using the 'concussion interchange rule' (CIR), the available video footage of these incidences, and associated return to play and concussion diagnosis decisions. RESEARCH DESIGN: Descriptive, observational case series. METHODS AND PROCEDURES: Data were collected from all NRL players who used the CIR during the 2014 season. MAIN OUTCOMES AND RESULTS: Complete SCAT3 and video analysis data were available for 38 (23%) of 167 uses of the concussion interchange rule, of which 20 (52.6%) players were medically diagnosed with concussion. Those with video evidence of unresponsiveness performed more poorly on the modified Balance Error Scoring System (M-BESS; p = .04; Cohen's d = .69) and reported greater symptoms (p = .03; d = .51). Similarly, players with a vacant stare reported greater symptoms (p = .05; d = .78). Those who demonstrated three signs (unresponsiveness, vacant stare and gait ataxia) performed more poorly on the M-BESS (p = .03; d = 1.4) and reported greater symptoms than those with no observable signs (p = .03; d = 1.4). CONCLUSIONS: The SCAT3 is sensitive to the acute effects of concussion in professional athletes; however, a minority of injured athletes might go undetected by this test.

The accumulation of brain injury leads to severe neuropathological and neurobehavioral changes after repetitive mild traumatic brain injury.

Traumatic brain injury (TBI) is a major public health problem with long-term neurobehavioral sequela. The evidences have revealed that TBI is a risk factor for later development of neurodegenerative disease and both the single and repetitive brain injury can lead to the neurodegeneration. But whether the effects of accumulation play an important role in the neurodegenerative disease is still unknown. We utilized the Sprague Dawley (SD) rats to develop the animal models of repetitive mild TBI and single mild TBI in order to detect the neurobehavioral changes. The results of neurobehavioral test revealed that the repetitive mild TBI led to more severe behavioral injuries than the single TBI. There were more activated microglia cells and astrocytes in the repetitive mild TBI group than the single TBI group. In consistent with this, the levels of TNF-α and IL-6 were higher and the expression of IL-10 was lower in the repetitive mild TBI group compared with the single TBI group. The expression of amyloid precursor protein (APP) increased in the repetitive TBI group detected by ELISA and western blot. But the levels of total tau (Tau-5) and P-tau (ser202) seem no different between the two groups in most time point. In conclusion, repetitive mild TBI could lead to more severe neurobehavioral impairments and the effects of accumulation may be associated with the increased inflammation in the brain.

A model of recurrent concussion that leads to long-term motor deficits, CTE-like tauopathy and exacerbation of an ALS phenotype.

BACKGROUND: Concussion injury is the most common form of traumatic brain injury (TBI). How recurrent concussions alter long-term outcomes is poorly understood, especially as related to the development of neurodegenerative disease. We evaluated the functional and pathological consequences of repeated TBI over time in wild type (WT) rats as well as rats harboring the human SOD1 mutation ("SOD1"), a model of familial amyotrophic lateral sclerosis (ALS). METHODS: A total of 42 rats, 26 WT and 16 SOD1, were examined over a study period of 25 weeks (or endpoint). At postnatal day 60, 20 WT and 7 SOD1 rats were exposed to mild, bilateral TBI once per week for either 2 weeks (2×TBI) or 5 weeks (5×TBI) using a controlled cortical impact device. Six WT and nine SOD1 rats underwent sham injury with anesthesia alone. Twenty WT rats were euthanized at 12 weeks after first injury and six WT rats were euthanized at 25 weeks after first injury. SOD1 rats were euthanized when they reached ALS disease endpoint. Weekly body weights and behavioral assessments were performed. Tauopathy in brain tissue was analyzed using immunohistochemistry. RESULTS: 2XTBI injured rats initially demonstrated recovery of motor function but failed to recover to baseline within the 12-week study period. Relative to both 2XTBI and sham controls, 5XTBI rats demonstrated significant deficits that persisted over the 12-week period. SOD1 5XTBI rats reached a peak body weight earlier than sham SOD1 rats, indicating earlier onset of the ALS phenotype. Histologic examination of brain tissue revealed that, in contrast with sham controls, SOD1 and WT TBI rats demonstrated cortical and corpus collosum thinning and tauopathy, which increased over time. CONCLUSIONS: Unlike previous models of repeat brain injury, which demonstrate only transient deficits in motor function, our concussion model of repeat, mild, bilateral TBI induced long-lasting deficits in motor function, decreased cortical thickness, shrinkage of the corpus callosum, increased brain tauopathy, and earlier onset of ALS symptoms in SOD1 rats. This model may allow for a greater understanding of the complex relationship between TBI and neurodegenerative diseases and provides a potential method for testing novel therapeutic strategies.

Thioredoxin-Mimetic-Peptides Protect Cognitive Function after Mild Traumatic Brain Injury (mTBI).

Mild traumatic brain injury (mTBI) is recognized as a common injury among children, sportsmen, and elderly population. mTBI lacks visible objective structural brain damage but patients frequently suffer from long-lasting cognitive, behavioral and emotional difficulties associated with biochemical and cellular changes. Currently there is no effective treatment for patients with mTBI. The thioredoxin reductase/thioredoxin pathway (TrxR/Trx1) has both anti-inflammatory and anti-oxidative properties. If the system is compromised, Trx1 remains oxidized and triggers cell death via an ASK1-Trx1 signal transduction mechanism. We previously showed tri and tetra peptides which were derived from the canonical -CxxC- motif of the Trx1-active site, called thioredoxin mimetic (TXM) peptides, reversed inflammatory and oxidative stress damage mimicking Trx1 activity. Here, TXM-peptides were examined for protecting cognitive function following weight drop closed-head injury in a mouse model of mTBI. TXM-CB3 (AcCys-Pro-CysNH2), TXM-CB13 (DY-70; AcCys-Met-Lys-CysNH2) or AD4 (ACysNH2) were administered at 50 mg/kg, 60 min after injury and cognitive performance was monitored by the novel-object-recognition and Y-maze tests. Behavioral deficits subsequent to mTBI injury were reversed by a single dose of TXM-CB3, TXM-CB13 and, to a lesser extent, by AD4. TXM-CB13 similar to TXM-CB3 and AD4 reversed oxidative stress-induced phosphorylation of mitogen-activated kinases, p38MAPK and c-Jun N-terminal kinase, (JNK) in human neuronal SH-SY5Y cells. We conclude that significantly improved cognitive behavior post mTBI by the TXM-peptides could result from anti-apoptotic, and/or anti-inflammatory activities. Future preclinical studies are required to establish the TXM-peptides as potential therapeutic drugs for brain injuries.

Glucose-Dependent Insulinotropic Polypeptide Ameliorates Mild Traumatic Brain Injury-Induced Cognitive and Sensorimotor Deficits and Neuroinflammation in Rats.

Mild traumatic brain injury (mTBI) is a major public health issue, representing 75-90% of all cases of TBI. In clinical settings, mTBI, which is defined as a Glascow Coma Scale (GCS) score of 13-15, can lead to various physical, cognitive, emotional, and psychological-related symptoms. To date, there are no pharmaceutical-based therapies to manage the development of the pathological deficits associated with mTBI. In this study, the neurotrophic and neuroprotective properties of glucose-dependent insulinotropic polypeptide (GIP), an incretin similar to glucagon-like peptide-1 (GLP-1), was investigated after its steady-state subcutaneous administration, focusing on behavior after mTBI in an in vivo animal model. The mTBI rat model was generated by a mild controlled cortical impact (mCCI) and used to evaluate the therapeutic potential of GIP. We used the Morris water maze and novel object recognition tests, which are tasks for spatial and recognition memory, respectively, to identify the putative therapeutic effects of GIP on cognitive function. Further, beam walking and the adhesive removal tests were used to evaluate locomotor activity and somatosensory functions in rats with and without GIP administration after mCCI lesion. Lastly, we used immunohistochemical (IHC) staining and Western blot analyses to evaluate the inflammatory markers, glial fibrillary acidic protein (GFAP), amyloid-ß precursor protein (APP), and bone marrow tyrosine kinase gene in chromosome X (BMX) in animals with mTBI. GIP was well tolerated and ameliorated mTBI-induced memory impairments, poor balance, and sensorimotor deficits after initiation in the post-injury period. In addition, GIP mitigated mTBI-induced neuroinflammatory changes on GFAP, APP, and BMX protein levels. These findings suggest GIP has significant benefits in managing mTBI-related symptoms and represents a novel strategy for mTBI treatment.