Altered pattern of theta and gamma oscillation to visual stimuli in patients with postconcussion syndrome.

Although many patients with mild traumatic brain injury (mTBI) suffer from postconcussional syndrome (PCS) including abnormal emotional responses, most conventional imaging studies fail to detect any causative brain lesion. We hypothesized that event-related electroencephalography (EEG) recordings with time-frequency analysis would show a distinguishable pattern in patients with mTBI with PCS compared with normal healthy controls. EEG signals were collected from a total of 18 subjects: eight patients with mTBI with PCS and 10 healthy control subjects. The signals were recorded while the subjects were presented with affective visual stimuli, including neutral, pleasant, and unpleasant emotional cues. Event-related spectral perturbation analysis was performed to calculate frontal midline theta activity and posterior midline gamma activity, followed by statistical analysis to identify whether patients with mTBI with PCS have distinct patterns of theta or gamma oscillations in response to affective stimuli. Compared with the healthy control group, patients with mTBI with PCS did not show a significant increase in the power of frontal theta activity in response to the pleasant stimuli, indicating less susceptibility toward pleasant cues. Moreover, the patient group showed attenuated gamma oscillatory activity, with no clear alteration in gamma oscillations in response to either pleasant or unpleasant cues. This study demonstrates that patients with mTBI with PCS exhibited altered patterns of oscillatory activities in the theta and gamma bands in response to affective visual stimuli compared with the normal control group. The current finding implicates that these distinguishable patterns of brain oscillation may represent the mechanism behind various psychiatric symptoms in patients with mTBI.NEW & NOTEWORTHY Patients with mild traumatic brain injury (mTBI) with postconcussional syndrome (PCS) exhibited altered patterns of changes in oscillatory activities in the theta and gamma bands in response to visual affective stimuli. Distinguishable patterns of brain oscillation may represent the mechanism behind various psychiatric symptoms in patients with mTBI.

Functional connectivity-hemodynamic (un)coupling changes in chronic mild brain injury are associated with mental health and neurocognitive indices: a resting state fMRI study.

PURPOSE: To examine hemodynamic and functional connectivity alterations and their association with neurocognitive and mental health indices in patients with chronic mild traumatic brain injury (mTBI). METHODS: Resting-state functional MRI (rs-fMRI) and neuropsychological assessment of 37 patients with chronic mTBI were performed. Intrinsic connectivity contrast (ICC) and time-shift analysis (TSA) of the rs-fMRI data allowed the assessment of regional hemodynamic and functional connectivity disturbances and their coupling (or uncoupling). Thirty-nine healthy age- and gender-matched participants were also examined. RESULTS: Patients with chronic mTBI displayed hypoconnectivity in bilateral hippocampi and parahippocampal gyri and increased connectivity in parietal areas (right angular gyrus and left superior parietal lobule (SPL)). Slower perfusion (hemodynamic lag) in the left anterior hippocampus was associated with higher self-reported symptoms of depression (r = - 0.53, p = .0006) and anxiety (r = - 0.484, p = .002), while faster perfusion (hemodynamic lead) in the left SPL was associated with lower semantic fluency (r = - 0.474, p = .002). Finally, functional coupling (high connectivity and hemodynamic lead) in the right anterior cingulate cortex (ACC)) was associated with lower performance on attention and visuomotor coordination (r = - 0.50, p = .001), while dysfunctional coupling (low connectivity and hemodynamic lag) in the left ventral posterior cingulate cortex (PCC) and right SPL was associated with lower scores on immediate passage memory (r = - 0.52, p = .001; r = - 0.53, p = .0006, respectively). Uncoupling in the right extrastriate visual cortex and posterior middle temporal gyrus was negatively associated with cognitive flexibility (r = - 0.50, p = .001). CONCLUSION: Hemodynamic and functional connectivity differences, indicating neurovascular (un)coupling, may be linked to mental health and neurocognitive indices in patients with chronic mTBI.

Patient-centered mild traumatic brain injury interventions in the emergency department.

INTRODUCTION: Traumatic brain injury (TBI) results in 2.5 million emergency department (ED) visits per year in the US, with mild traumatic brain injury (mTBI) accounting for 90% of cases. There is considerable evidence that many experience chronic symptoms months to years later. This population is rarely represented in interventional studies. Management of adult mTBI in the ED has remained unchanged, without consensus of therapeutic options. The aim of this review was to synthesize existing literature of patient-centered ED treatments for adults who sustain an mTBI, and to identify practices that may offer promise. METHODS: A systematic review was conducted using the PubMed and Cochrane databases, while following PRISMA guidelines. Studies describing pediatric patients, moderate to severe TBI, or interventions outside the ED were excluded. Two reviewers independently performed title and abstract screening. A third blinded reviewer resolved discrepancies. The Mixed Methods Appraisal Tool (MMAT) was employed to assess the methodological quality of the studies. RESULTS: Our search strategy generated 1002 unique titles. 95 articles were selected for full-text screening. The 26 articles chosen for full analysis were grouped into one of the following intervention categories: (1) predictive models for Post-Concussion Syndrome (PCS), (2) discharge instructions, (3) pharmaceutical treatment, (4) clinical protocols, and (5) functional assessment. Studies that implemented a predictive PCS model successfully identified patients at highest risk for PCS. Trials implementing discharge related interventions found the use of video discharge instructions, encouragement of daily light exercise or bed rest, and text messaging did not significantly reduce mTBI symptoms. The use of electronic clinical practice guidelines (eCPG) and longer leaves of absence from work following injury reduced symptoms. Ondansetron was shown to reduce nausea in mTBI patients. Studies implementing ED Observation Units found significant declines in inpatient admissions and length of hospital stay. The use of tablet-based tasks was found to be superior to many standard cognitive assessments. CONCLUSION: Validated instruments are available to aid clinicians in identifying patients at risk for PCS or serious cognitive impairment. EDOU management and evidence-based modifications to discharge instructions may improve mTBI outcomes. Additional research is needed to establish the therapeutic value of medications and lifestyle changes for the treatment of mTBI in the ED.

Quantitative pupillometry as a biomarker for prediction of return to play in mild traumatic brain injury: a Military Traumatic Brain Injury Initiative study.

OBJECTIVE: This study aimed to determine the validity of quantitative pupillometry to predict the length of time for return to full activity/duty after a mild traumatic brain injury (mTBI) in a cohort of injured cadets at West Point. METHODS: Each subject received baseline (T0) quantitative pupillometry, in addition to evaluation with the Balance Error Scoring System (BESS), Standardized Assessment of Concussion (SAC), and Sport Concussion Assessment Tool 5th Edition Symptom Survey (SCAT5). Repeat assessments using the same parameters were conducted within 48 hours of injury (T1), at the beginning of progressive return to activity (T2), and at the completion of progressive return to activity protocols (T3). Pupillary metrics were compared on the basis of length of time to return to full play/duty and the clinical scores. RESULTS: The authors' statistical analyses found correlations between pupillometry measures at T1, including end-initial diameter and maximum constriction velocity, with larger change and faster constriction predicting earlier return to play. There was also an association with maximum constriction velocity at baseline (T0), predicting faster return to play. CONCLUSIONS: The authors conclude that that pupillometry may be a valuable tool for assessing time to return to duty from mTBI by providing a measure of baseline resiliency to mTBI and/or autonomic dysfunction in the acute phase after mTBI.

Long-term cognitive and affective consequences of mild traumatic brain injury: comparison with older adults.

OBJECTIVE: Memory and affective processing were compared in young adults with a remote mild traumatic brain injury (mTBI), to healthy younger and older adults. We evaluated memory performance when encoding was done under multi-tasking (divided attention) conditions, likely to exacerbate cognitive and psychological symptoms in mTBI. METHODS: Participants studied pairs of unrelated words under either full or divided attention conditions. Memory for single words (item memory) and for pairs of words (associative memory) was then assessed in sequential independent recognition tests, under full attention. RESULTS: Associative memory was poorer than item memory, and worse when encoding was done under divided than full attention. The decline in recognition accuracy from full to divided attention conditions on the associative memory test was significantly greater in mTBI compared to young adults and was similar in magnitude to that observed in older adults under full attention. Self-reported mental and total fatigue increased significantly as performance on the memory tests, following the divided attention condition, decreased, but only in the mTBI group. CONCLUSIONS: Results show lingering memory deficits, and suggest that cognitive tasks may be experienced as psychologically more demanding in those with a mTBI, even months or years after injury.

Co-existence of depression and post-concussion syndrome one month after mild traumatic brain injury.

BACKGROUND: Previous studies suggest an association between Post-concussion syndrome (PCS) and depression, both highly prevalent after mTBI. OBJECTIVE: To assess the prevalence and risk-factors of depression among patients with PCS 1 month after mTBI. METHODS: We prospectively screened 372 mTBI patients admitted in two academic Emergency Departments between 2017 and 2019. One month after mTBI, we administered the Rivermead Post-concussion symptoms Questionnaire (RPQ) and the Patient Health Questionnaire (PHQ-9) questionnaires over the telephone. PCS and depression were defined by RPQ ≥ 12 and PHQ-9 ≥ 10. Multivariate multinomial regression identified baseline factors associated with PCS and depression. RESULTS: Two hundred and eight completed RPQ and PHQ-9. Forty-seven patients (22.5%) met criteria for PCS, among which 22 (46.8%) met criteria for depression (PCS+D+). Patients with PCS but without depression were less likely to present with an associated injury (Coefficient = -1.6, p = 0.047) and to report initial sadness (Coefficient = -2.5, p = 0.03). Initial sadness (Coefficient = -1.3, p = 0.047), associated injury (Coefficient = -1.9, p = 0.008), as well as initial nausea (Coefficient = -1.8, p = 0.002), and male sex (Coefficient = 1.8, p = 0.002), were associated with the absence of depression and PCS in comparison with PCS+D+ patients. CONCLUSION: Among patients with PCS 1 month after mTBI, those with depression are more likely to present with initial sadness and with an associated injury.

Longitudinal neurocognitive trajectories and risk factors in the first three months following pediatric concussion.

OBJECTIVE: To identify differential trajectories of neurocognitive outcomes following pediatric concussion and investigate predictors associated with patterns of recovery up to 3 months. METHODS: 74 participants aged 8-17 years completed attention/working memory, processing speed, and executive function measures at 2 weeks, 1 month, and 3 months post-injury. We used principal component analysis to generate a composite of information processing. Group-based trajectory modeling identified latent trajectories. Multinominal logistic regression was used to examine associations between risk factors and trajectory groups. RESULTS: We identified three trajectories of neurocognitive outcomes. The medium (54.6%) and high improving groups (35.8%) showed ongoing increase in information processing, while the low persistent group showed limited change 3 months post-injury. This group recorded below average scores on Digit Span Forward and Backward at 3 months. History of pre-injury headache was significantly associated with the persistent low scoring group, relative to the medium improving (p = 0.03) but not the high improving group (p = 0.09). CONCLUSIONS: This study indicates variability in neurocognitive outcomes according to three differential trajectories, with groups partially distinguished by preexisting child factors (history of frequent headaches). Modelling that accounts for heterogeneity in individual outcomes is essential to identify clinically meaningful indices that are indicative of children requiring intervention.

Convergence insufficiency in patients with post-concussion syndrome is accompanied by a higher symptom load: a cross-sectional study.

OBJECTIVE: To estimate the prevalence of convergence insufficiency (CI) in adult patients with post-concussion syndrome and determine the impact of CI on symptom load. METHODS: Cross-sectional study of 103 patients with neurological symptoms 2-6 months after a concussion. Symptoms were assessed with the Rivermead Post Concussion Symptoms Questionnaire (RPQ), and CI was diagnosed using near point of convergence, vergence facility, and the Convergence Insufficiency Symptom Survey. The RPQ score for patients with and without CI was compared, and sensitivity, specificity, and area under the receiver operating characteristic curve for the two visually related RPQ questions as indicators of CI were calculated. RESULTS: The proportion of patients diagnosed with symptomatic CI was 20.4% (95% confidence interval: 13.1-29.5%). The RPQ score was significantly higher for patients with symptomatic CI both before (p = .01) and after removal of the two visually related questions in the RPQ-questionnaire (p = .03). The two visually related RPQ questions were unable to detect CI. CONCLUSION: In patients with post-concussion syndrome, the load of nonvisual symptoms is higher in the presence of CI. A prospective interventional study on CI is required to study the relationship between CI and other post-concussion symptoms.

Relationships between vestibular issues, noise sensitivity, anxiety and prolonged recovery from mild traumatic brain injury among adults: a scoping review.

BACKGROUND: We investigated the extent of literature and findings on relationships between vestibular issues, noise sensitivity (NS), and anxiety. We were interested in how relationships among these factors impacted adults' recovery three months or more after mild traumatic brain injury (mTBI). METHODS: We conducted a scoping review to evaluate the extent of evidence linking relationships between vestibular issues, NS and anxiety with recovery after mTBI. Data relating to study characteristics and key findings were extracted and used to inform a critical narrative synthesis of findings. RESULTS: After screening and full-text review, we included two studies. Both studies considered the combination of vestibular issues, NS and anxiety and mTBI recovery. Vestibular issues, NS and anxiety were all significantly associated with one another and their presence was the strongest indicator that symptoms would extend beyond three-months after mTBI. CONCLUSION: Few studies have focused on the relationships that vestibular issues, NS and anxiety have with one another and recovery after mTBI. Given the apparent strong relationships between these factors and prolonged recovery, we highlight this as an area warranting further investigation.

Vestibular issues, noise sensitivity and anxiety all appear to impact on recovery from mild traumatic brain injury.There appear to be quite strong relationships between vestibular, noise sensitivity and anxiety symptoms following mild traumatic brain injury.More work exploring these key symptoms and how they impact recovery from mild traumatic brain injury using a wide range of study methods and approaches are needed to advance the field.

Concussion diagnosis and recovery in relation to collegiate athletic department classification: a LIMBIC MATARS consortium investigation.

PURPOSE: We investigated time to reach concussion diagnosis and recovery milestones in collegiate athletes relative to their schools' National Collegiate Athletic Association (NCAA) classification. METHODS: We retrospectively examined 849 (43.1% female) concussion cases from 11 NCAA institutions (Division I Power 5 [n = 4], Division I Non-Power 5 [n = 4], and Division II/III [n = 3]) from the 2015-16 to 2019-20 athletic seasons. Our primary outcome measures were days to reach specific clinical milestones following concussion. RESULTS: Median (IQR) time from injury to diagnosis was significantly longer at Division II/III institutions (1 [0-4] days) compared to Division I Power 5 (0 [0-1] days) and Division I Non-Power 5 (0 [0-1] days) institutions (p < 0.001). Likewise, Division II/III athletes (15 [11-22] days) took significantly longer to return to sport after concussion than Division I Power 5 (10 [7-16] days) and Division I Non-Power 5 (11 [7-18.5] days) athletes (p < 0.001). CONCLUSION: Division II/III athletes had delayed concussion diagnoses and return to sport timelines compared to Division I athletes. Our results suggest that differences in sports medicine resources across NCAA divisions may influence injury recognition and recovery in collegiate athletes with concussion.

Physical activity and recovery following concussion in collegiate athletes: a LIMBIC MATARS Consortium Investigation.

OBJECTIVE: To investigate whether routine daily activities (RDA), non-prescribed exercise (Non-ERx), or prescribed exercise (ERx) were associated with recovery from sport-related concussion (SRC) in collegiate athletes. MATERIALS AND METHODS: Data for this cross-sectional, retrospective chart review of collegiate athletes diagnosed with SRC (n = 285[39.6% female], age = 19.5 ± 1.4 years) were collected during the 2015-16 to 2019-20 athletic seasons. The independent variable was group (RDA, Non-ERx, ERx). Dependent variables included days from date of diagnosis to symptom resolution (Dx-SR) and SR to return to sport (SR-RTS). RESULTS: Those in the Non-ERx group took nearly 1.3 times longer to achieve SR (IRR = 1.28, 95% CI: 1.11, 1.46) and, 1.8 times longer for RTS (IRR = 1.82, 95% CI: 1.11, 2.71) when compared to those in the RDA group. No other comparisons were significant. CONCLUSION: Collegiate athletes in the Non-ERx group took approximately 1 week longer to achieve SR as compared to the RDA and ERx groups. Our findings suggest that if exercise is recommended following SRC, it must be clearly and specifically prescribed. If exercise parameters cannot be prescribed, or monitored, RDA appear to be similarly beneficial during recovery for collegiate athletes with concussion.

Academic adjustments and concussion recoveries in NCAA student-athletes: a LIMBIC MATARS investigation.

OBJECTIVE: The aim of this study was to investigate the association between academic adjustments and recovery from sport-related concussions (SRCs) in collegiate athletes. MATERIALS AND METHODS: A retrospective medical chart review was performed between the 2015-2016 and 2019-2020 sport seasons at 11 Long-term Impact of Military-relevant Brain Injury Consortium Military and Tactical Athlete Research Study (LIMBIC MATARS) sites. Days between injury and symptom resolution, and injury and return to sport (dependent variables) for collegiate athletes who did or did not receive academic adjustments (independent variable) were analyzed using Mann-Whitney U tests. RESULTS: The number of days between date of injury and symptom-resolution between those who did (median = 9 [interquartile range = 5,16]) and did not have (7[3,12]) academic adjustments were statistically different (z=-2.76, p < 0.01, r=-0.17). However, no differences were observed between days to return to sport among those who did (14[10,22]) and did not (13[8,20]) receive assigned academic adjustments (z= -1.66, p = 0.10, r= -.10). CONCLUSIONS: Recovery trajectories were similar between athletes diagnosed with a SRC who did or did not receive academic adjustments.. Our findings suggest academic adjustments supported recovery for those who needed academic adjustments. Clinicians and healthcare professionals should assist and support collegiate athletes after SRCs on an individual basis, including academic adjustments when appropriate based on patient presentation.

Access to athletic trainers and sex as modifiers of time to reach clinical milestones after sport-related concussion in collegiate athletes.

OBJECTIVE: Investigate whether an athlete's biological sex and exposure to a dedicated athletic trainer (AT) were related to clinical milestones after a sports-related concussion (SRC). DESIGN: Retrospective chart review. METHODS: Medical charts of collegiate athletes (n = 196 [70.9% female]) diagnosed with SRC were reviewed to extract: biological sex, dedicated AT exposure for their sport (yes/no), and time (days) to reaching clinical milestones (diagnosis, symptom resolution, unrestricted return to sport [RTS]). Mann-Whitney U tests were used to determine whether time to clinical milestones differed by sex, AT exposure, or their interaction. Proportions of same-day diagnoses and times to diagnosis, symptom resolution, and unrestricted RTS were evaluated with chi-squared and spearman's rank correlations, respectively. RESULTS: There were no significant differences in times to reaching any clinical milestone by sex, AT exposure, or their interaction (ps > 0.05). Forty-three percent of participants were diagnosed on the day of their SRC. This did not differ by sex or AT exposure (ps > 0.29). Longer times to SRC diagnosis were associated with more days to symptom resolution (ρ = 0.236, p = 0.001) and unrestricted RTS (ρ = 0.223, p < 0.001). CONCLUSIONS: Athlete sex and AT exposure were not associated with times to reach any clinical milestone; however, delayed diagnosis was associated with longer times to reach clinical recovery.

Smart Textile Impact Sensor for e-Helmet to Measure Head Injury.

Concussions, a prevalent public health concern in the United States, often result from mild traumatic brain injuries (mTBI), notably in sports such as American football. There is limited exploration of smart-textile-based sensors for measuring the head impacts associated with concussions in sports and recreational activities. In this paper, we describe the development and construction of a smart textile impact sensor (STIS) and validate STIS functionality under high magnitude impacts. This STIS can be inserted into helmet cushioning to determine head impact force. The designed 2 × 2 STIS matrix is composed of a number of material layered structures, with a sensing surface made of semiconducting polymer composite (SPC). The SPC dimension was modified in the design iteration to increase sensor range, responsiveness, and linearity. This was to be applicable in high impact situations. A microcontroller board with a biasing circuit was used to interface the STIS and read the sensor's response. A pendulum test setup was constructed to evaluate various STISs with impact forces. A camera and Tracker software were used to monitor the pendulum swing. The impact forces were calculated by measuring the pendulum bob's velocity and acceleration. The performance of the various STISs was measured in terms of voltage due to impact force, with forces varying from 180 to 722 N. Through data analysis, the threshold impact forces in the linear range were determined. Through an analysis of linear regression, the sensors' sensitivity was assessed. Also, a simplified model was developed to measure the force distribution in the 2 × 2 STIS areas from the measured voltages. The results showed that improving the SPC thickness could obtain improved sensor behavior. However, for impacts that exceeded the threshold, the suggested sensor did not respond by reflecting the actual impact forces, but it gave helpful information about the impact distribution on the sensor regardless of the accurate expected linear response. Results showed that the proposed STIS performs satisfactorily within a range and has the potential to be used in the development of an e-helmet with a large STIS matrix that could cover the whole head within the e-helmet. This work also encourages future research, especially on the structure of the sensor that could withstand impacts which in turn could improve the overall range and performance and would accurately measure the impact in concussion-causing impact ranges.

Association of Blast Exposure in Military Breaching with Intestinal Permeability Blood Biomarkers Associated with Leaky Gut.

Injuries and subclinical effects from exposure to blasts are of significant concern in military operational settings, including tactical training, and are associated with self-reported concussion-like symptomology and physiological changes such as increased intestinal permeability (IP), which was investigated in this study. Time-series gene expression and IP biomarker data were generated from "breachers" exposed to controlled, low-level explosive blast during training. Samples from 30 male participants at pre-, post-, and follow-up blast exposure the next day were assayed via RNA-seq and ELISA. A battery of symptom data was also collected at each of these time points that acutely showed elevated symptom reporting related to headache, concentration, dizziness, and taking longer to think, dissipating ~16 h following blast exposure. Evidence for bacterial translocation into circulation following blast exposure was detected by significant stepwise increase in microbial diversity (measured via alpha-diversity p = 0.049). Alterations in levels of IP protein biomarkers (i.e., Zonulin, LBP, Claudin-3, I-FABP) assessed in a subset of these participants (n = 23) further evidenced blast exposure associates with IP. The observed symptom profile was consistent with mild traumatic brain injury and was further associated with changes in bacterial translocation and intestinal permeability, suggesting that IP may be linked to a decrease in cognitive functioning. These preliminary findings show for the first time within real-world military operational settings that exposures to blast can contribute to IP.

Brain metabolites measured with magnetic resonance spectroscopy in pediatric concussion and orthopedic injury: An Advancing Concussion Assessment in Pediatrics (A-CAP) study.

Millions of children sustain a concussion annually. Concussion disrupts cellular signaling and neural pathways within the brain but the resulting metabolic disruptions are not well characterized. Magnetic resonance spectroscopy (MRS) can examine key brain metabolites (e.g., N-acetyl Aspartate (tNAA), glutamate (Glx), creatine (tCr), choline (tCho), and myo-Inositol (mI)) to better understand these disruptions. In this study, we used MRS to examine differences in brain metabolites between children and adolescents with concussion versus orthopedic injury. Children and adolescents with concussion (n = 361) or orthopedic injury (OI) (n = 184) aged 8 to 17 years were recruited from five emergency departments across Canada. MRS data were collected from the left dorsolateral prefrontal cortex (L-DLPFC) using point resolved spectroscopy (PRESS) at 3 T at a mean of 12 days post-injury (median 10 days post-injury, range 2-33 days). Univariate analyses for each metabolite found no statistically significant metabolite differences between groups. Within each analysis, several covariates were statistically significant. Follow-up analyses designed to account for possible confounding factors including age, site, scanner, vendor, time since injury, and tissue type (and interactions as appropriate) did not find any metabolite group differences. In the largest sample of pediatric concussion studied with MRS to date, we found no metabolite differences between concussion and OI groups in the L-DLPFC. We suggest that at 2 weeks post-injury in a general pediatric concussion population, brain metabolites in the L-DLPFC are not specifically affected by brain injury.

Repeated closed-head mild traumatic brain injury-induced inflammation is associated with nociceptive sensitization.

BACKGROUND: Individuals who have experienced mild traumatic brain injuries (mTBIs) suffer from several comorbidities, including chronic pain. Despite extensive studies investigating the underlying mechanisms of mTBI-associated chronic pain, the role of inflammation in long-term pain after mTBIs is not fully elucidated. Given the shifting dynamics of inflammation, it is important to understand the spatial-longitudinal changes in inflammatory processes following mTBIs and their effects on TBI-related pain. METHODS: We utilized a recently developed transgenic caspase-1 luciferase reporter mouse model to monitor caspase-1 activation through a thinned skull window in the in vivo setting following three closed-head mTBI events. Organotypic coronal brain slice cultures and acutely dissociated dorsal root ganglion (DRG) cells provided tissue-relevant context of inflammation signal. Mechanical allodynia was assessed by mechanical withdrawal threshold to von Frey and thermal hyperalgesia withdrawal latency to radiant heat. Mouse grimace scale (MGS) was used to detect spontaneous or non-evoked pain. In some experiments, mice were prophylactically treated with MCC950, a potent small molecule inhibitor of NLRP3 inflammasome assembly to inhibit injury-induced inflammatory signaling. Bioluminescence spatiotemporal dynamics were quantified in the head and hind paws, and caspase-1 activation was confirmed by immunoblot. Immunofluorescence staining was used to monitor the progression of astrogliosis and microglial activation in ex vivo brain tissue following repetitive closed-head mTBIs. RESULTS: Mice with repetitive closed-head mTBIs exhibited significant increases of the bioluminescence signals within the brain and paws in vivo for at least one week after each injury. Consistently, immunoblotting and immunofluorescence experiments confirmed that mTBIs led to caspase-1 activation, astrogliosis, and microgliosis. Persistent changes in MGS and hind paw withdrawal thresholds, indicative of pain states, were observed post-injury in the same mTBI animals in vivo. We also observed enhanced inflammatory responses in ex vivo brain slice preparations and DRG for at least 3 days following mTBIs. In vivo treatment with MCC950 significantly reduced caspase-1 activation-associated bioluminescent signals in vivo and decreased stimulus-evoked and non-stimulus evoked nociception. CONCLUSIONS: Our findings suggest that the inflammatory states in the brain and peripheral nervous system following repeated mTBIs are coincidental with the development of nociceptive sensitization, and that these events can be significantly reduced by inhibition of NLRP3 inflammasome activation.

Repeated mild traumatic brain injury causes sex-specific increases in cell proliferation and inflammation in juvenile rats.

Childhood represents a period of significant growth and maturation for the brain, and is also associated with a heightened risk for mild traumatic brain injuries (mTBI). There is also concern that repeated-mTBI (r-mTBI) may have a long-term impact on developmental trajectories. Using an awake closed head injury (ACHI) model, that uses rapid head acceleration to induce a mTBI, we investigated the acute effects of repeated-mTBI (r-mTBI) on neurological function and cellular proliferation in juvenile male and female Long-Evans rats. We found that r-mTBI did not lead to cumulative neurological deficits with the model. R-mTBI animals exhibited an increase in BrdU + (bromodeoxyuridine positive) cells in the dentate gyrus (DG), and that this increase was more robust in male animals. This increase was not sustained, and cell proliferation returning to normal by PID3. A greater increase in BrdU + cells was observed in the dorsal DG in both male and female r-mTBI animals at PID1. Using Ki-67 expression as an endogenous marker of cellular proliferation, a robust proliferative response following r-mTBI was observed in male animals at PID1 that persisted until PID3, and was not constrained to the DG alone. Triple labeling experiments (Iba1+, GFAP+, Brdu+) revealed that a high proportion of these proliferating cells were microglia/macrophages, indicating there was a heightened inflammatory response. Overall, these findings suggest that rapid head acceleration with the ACHI model produces an mTBI, but that the acute neurological deficits do not increase in severity with repeated administration. R-mTBI transiently increases cellular proliferation in the hippocampus, particularly in male animals, and the pattern of cell proliferation suggests that this represents a neuroinflammatory response that is focused around the mid-brain rather than peripheral cortical regions. These results add to growing literature indicating sex differences in proliferative and inflammatory responses between females and males. Targeting proliferation as a therapeutic avenue may help reduce the short term impact of r-mTBI, but there may be sex-specific considerations.

Cognitive performance in older people after mild traumatic brain injury: Trauma effects and other risk factors.

OBJECTIVE: Cognitive symptoms are common in the initial weeks after mTBI, but recovery is generally expected within three months. However, there is limited information about recovery specifically in older age cohorts. Therefore, this study investigated cognitive outcome three months after mTBI in older adults (≥ 65 years) compared to trauma and community age-matched controls and explored risk factors for outcome after traumatic injury. METHODS: Older mTBI patients (n = 40) and older adults with mild traumatic injury but without head injury (n = 66) were compared to a noninjured community control group (n = 47). Cognitive assessment included neuropsychological and computerized tests. Group differences were compared on individual tasks and overall cognitive performances using composite scores. Regression analyses identified predictors of outcome for trauma patients and moderator analyses explored possible interactions of mTBI severity with age and cognition. RESULTS: As well as lower performances in processing speed and memory, both trauma groups had significantly lower performance on composite neuropsychological (d = .557 and .670) and computerized tasks (d = .783 and .824) compared to noninjured controls. Age, education, and history of depression were direct predictors of cognitive performance after mild traumatic injury (with or without head injury). Further moderation analysis demonstrated that mTBI severity (Glasgow Coma Scale < 15) moderated the impact of older age on computerized assessment (ß = -.138). CONCLUSIONS: Three months after mild trauma (regardless of head injury), older people demonstrate lower cognition compared to noninjured peers. However, severity of mTBI (Glasgow Coma Scale < 15) can interact with older age to predict poorer cognitive outcomes.

A dominance analysis of subjective cognitive complaint comorbidities in former professional football players with and without mild cognitive impairment.

OBJECTIVES: Subjective cognitive difficulties (SCDs) are associated with factors commonly reported in older adults and former contact sport athletes, regardless of objective cognitive decline. We investigated the relative contribution of these factors to SCD in former National Football League (NFL)-players with and without a diagnosis of mild cognitive impairment (MCI). METHODS: Former NFL players (n = 907) aged ≥ 50 years (mean = 64.7 ± 8.9), with (n = 165) and without (n = 742) a diagnosis of MCI completed health questionnaires. Multivariable regression and dominance analyses determined the relative importance of SCD factors on SCD: 1) depression, 2) anxiety, 3) sleep disturbance, 4) pain interference, 5) ability to participate in social roles and activities, 6) stress-related events, 7) fatigue, 8) concussion history, and 9) education. SCD outcomes included Neuro-QoL Emotional-Behavioral Dyscontrol and the PROMIS Cognitive Function. Fisher's z-transformation compared comorbid contributing factors to SCD across MCI and non-MCI groups. RESULTS: Complete dominance of anxiety was established over most comorbid factors across the MCI and non-MCI groups. Fatigue also exhibited complete dominance over most comorbid factors, though its influence in the MCI group was less robust (general dominance). Average contributions to variance accounted for by comorbid factors to ratings of SCD across MCI and non-MCI groups did not statistically differ (Z-statistics <1.96, ps>.05). CONCLUSIONS: Anxiety and fatigue are the most robust factors associated with SCD in former professional football players across various combinations of clinical presentations (different combinations of comorbid factors), regardless of documented cognitive impairment. Self-reported deficits may be less reliable in detecting objective impairment in the presence of these factors, with multidimensional assessment being ideal.