ZL006 mitigates anxiety-like behaviors induced by closed head injury through modulation of the neural circuit from the medial prefrontal cortex to amygdala.

Closed head injury is a prevalent form of traumatic brain injury with poorly understood effects on cortical neural circuits. Given the emotional and behavioral impairments linked to closed head injury, it is vital to uncover brain functional deficits and their driving mechanisms. In this study, we employed a robust viral tracing technique to identify the alteration of the neural pathway connecting the medial prefrontal cortex to the basolateral amygdala, and we observed the disruptions in neuronal projections between the medial prefrontal cortex and the basolateral amygdala following closed head injury. Remarkably, our results highlight that ZL006, an inhibitor targeting PSD-95/nNOS interaction, stands out for its ability to selectively reverse these aberrations. Specifically, ZL006 effectively mitigates the disruptions in neuronal projections from the medial prefrontal cortex to basolateral amygdala induced by closed head injury. Furthermore, using chemogenetic approaches, we elucidate that activating the medial prefrontal cortex projections to the basolateral amygdala circuit produces anxiolytic effects, aligning with the therapeutic potential of ZL006. Additionally, ZL006 administration effectively mitigates astrocyte activation, leading to the restoration of medial prefrontal cortex glutamatergic neuron activity. Moreover, in the context of attenuating anxiety-like behaviors through ZL006 treatment, we observe a reduction in closed head injury-induced astrocyte engulfment, which may correlate with the observed decrease in dendritic spine density of medial prefrontal cortex glutamatergic neurons.

Aberrant cortical spine dynamics after concussive injury are reversed by integrated stress response inhibition.

Traumatic brain injury (TBI) is a leading cause of long-term neurological disability in the world and the strongest environmental risk factor for the development of dementia. Even mild TBI (resulting from concussive injuries) is associated with a greater than twofold increase in the risk of dementia onset. Little is known about the cellular mechanisms responsible for the progression of long-lasting cognitive deficits. The integrated stress response (ISR), a phylogenetically conserved pathway involved in the cellular response to stress, is activated after TBI, and inhibition of the ISR-even weeks after injury-can reverse behavioral and cognitive deficits. However, the cellular mechanisms by which ISR inhibition restores cognition are unknown. Here, we used longitudinal two-photon imaging in vivo after concussive injury in mice to study dendritic spine dynamics in the parietal cortex, a brain region involved in working memory. Concussive injury profoundly altered spine dynamics measured up to a month after injury. Strikingly, brief pharmacological treatment with the drug-like small-molecule ISR inhibitor ISRIB entirely reversed structural changes measured in the parietal cortex and the associated working memory deficits. Thus, both neural and cognitive consequences of concussive injury are mediated in part by activation of the ISR and can be corrected by its inhibition. These findings suggest that targeting ISR activation could serve as a promising approach to the clinical treatment of chronic cognitive deficits after TBI.

Repetitive Mild Closed Head Injury in Adolescent Mice Is Associated with Impaired Proteostasis, Neuroinflammation, and Tauopathy.

Repetitive mild traumatic brain injury (mTBI) in children and adolescents leads to acute and chronic neurologic sequelae and is linked to later life neurodegenerative disease. However, the biological mechanisms connecting early life mTBI to neurodegeneration remain unknown. Using an adolescent mouse repetitive closed head injury model that induces progressive cognitive impairment in males and anxiety in females in the absence of overt histopathology, we examined transcriptional and translational changes in neurons isolated from sham and injured brain in the chronic phase after injury. At 14 months, single-nuclei RNA sequencing of cortical brain tissue identified disruption of genes associated with neuronal proteostasis and evidence for disrupted ligand-receptor signaling networks in injured mice. Western blot analysis of isolated neurons showed evidence of inflammasome activation and downstream IL-1ß processing, as previously demonstrated in acute CNS injury models, and accumulation of misfolded, hyperphosphorylated tau, and changes in expression of proteins suggestive of impaired translation in males but not in females. At 6 months, injured IL-1 receptor 1 (IL-1R1) KO mice, which are protected from postinjury cognitive deficits, had decreased accumulation of pro-IL-1ß and misfolded tau in cortex and cerebellum, suggesting that IL-1R1 is upstream of inflammasome priming (defined as increase in pro-IL-1ß) and abnormal tau phosphorylation. Together, our findings provide evidence for neuronal inflammasome activation and impaired proteostasis as key mechanisms linking repetitive mTBI in adolescence to later life neurologic dysfunction and neurodegeneration.SIGNIFICANCE STATEMENT Repetitive mild closed head injury in adolescent male mice leads to impaired proteostasis, tau phosphorylation, and inflammasome activation in neurons later in adulthood through mechanisms involving IL-1 receptor 1. The data are the first to link repetitive mild traumatic brain injury in adolescence to neurodegeneration and suggest molecular targets and pathways to prevent neurologic sequelae in the chronic period after injuries.

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.

Sirt1 attenuates astrocyte activation via modulating Dnajb1 and chaperone-mediated autophagy after closed head injury.

Our previous study indicates that Silent information regulator 1 (Sirt1) is involved in macroautophagy by upregulating light chain 3 (LC3) expression in astrocyte to exert a neuroprotective effect. Chaperon-mediated autophagy (CMA), another form of autophagy, is also upregulated after brain injury. However, little is known about the role of Sirt1 in regulation of the CMA. In the present study, an in vivo model of closed head injury (CHI) and an in vitro model of primary cortical astrocyte stimulated with interleukin-1ß were employed to mimic the astrocyte activation induced by traumatic brain injury. Lentivirus carrying target complementary DNA (cDNA) or short hairpin RNA (shRNA) sequence was used to overexpress Sirt1 or knockdown DnaJ heat shock protein family member B1 (Dnajb1) (a molecular chaperone). We found that Sirt1 overexpression ameliorated neurological deficits, reduced tissue loss, and attenuated astrocyte activation after CHI, which was reversed by Dnajb1-shRNA administration. The upregulation of CMA activity induced by CHI in vivo and in vitro was inhibited after Dnajb1 knockdown. Sirt1 potently promoted CMA activity via upregulating Dnajb1 expression. Mechanically, Sirt1 could interact with Dnajb1 and modulate the deacetylation and ubiquitination of Dnajb1. These findings collectively suggest that Sirt1 plays a protective role against astrocyte activation, which may be associated with the regulation of the CMA activity via modulating the deacetylation and ubiquitination of Dnajb1 after CHI.

TDP-43 drives synaptic and cognitive deterioration following traumatic brain injury.

Traumatic brain injury (TBI) has been recognized as an important risk factor for Alzheimer's disease (AD). However, the molecular mechanisms by which TBI contributes to developing AD remain unclear. Here, we provide evidence that aberrant production of TDP-43 is a key factor in promoting AD neuropathology and synaptic and cognitive deterioration in mouse models of mild closed head injury (CHI). We observed that a single mild CHI is sufficient to exacerbate AD neuropathology and accelerate synaptic and cognitive deterioration in APP transgenic mice but repeated mild CHI are required to induce neuropathological changes and impairments in synaptic plasticity, spatial learning, and memory retention in wild-type animals. Importantly, these changes in animals exposed to a single or repeated mild CHI are alleviated by silencing of TDP-43 but reverted by rescue of the TDP-43 knockdown. Moreover, overexpression of TDP-43 in the hippocampus aggravates AD neuropathology and provokes cognitive impairment in APP transgenic mice, mimicking single mild CHI-induced changes. We further discovered that neuroinflammation triggered by TBI promotes NF-κB-mediated transcription and expression of TDP-43, which in turn stimulates tau phosphorylation and Aß formation. Our findings suggest that excessive production of TDP-43 plays an important role in exacerbating AD neuropathology and in driving synaptic and cognitive declines following TBI.

Cortical Spreading Depolarization, Blood Flow, and Cognitive Outcomes in a Closed Head Injury Mouse Model of Traumatic Brain Injury.

BACKGROUND: Cortical spreading depolarizations (CSDs) are associated with worse outcomes in many forms of acute brain injury, including traumatic brain injury (TBI). Animal models could be helpful in developing new therapies or biomarkers to improve outcomes in survivors of TBI. Recently, investigators have observed CSDs in murine models of mild closed head injury (CHI). We designed the currently study to determine additional experimental conditions under which CSDs can be observed, from mild to relatively more severe TBI. METHODS: Adult male C57Bl/6J mice (8-14 weeks old) were anesthetized with isoflurane and subjected to CHI with an 81-g weight drop from 152 or 183 cm. CSDs were detected with minimally invasive visible light optical intrinsic signal imaging. Cerebral blood flow index (CBFi) was measured in the 152-cm drop height cohort using diffuse correlation spectroscopy at baseline before and 4 min after CHI. Cognitive outcomes were assessed at 152- and 183-cm drop heights for the Morris water maze hidden platform, probe, and visible platform tests. RESULTS: CSDs occurred in 43% (n = 12 of 28) of 152-cm and 58% (n = 15 of 26) of 183-cm drop height CHI mice (p = 0.28). A lower baseline preinjury CBFi was associated with development of CSDs in CHI mice (1.50 ± 0.07 × 10-7 CHI without CSD [CSD-] vs. 1.17 ± 0.04 × 10-7 CHI with CSD [CSD+], p = 0.0001). Furthermore, in CHI mice that developed CSDs, the ratio of post-CHI to pre-CHI CBFi was lower in the hemisphere ipsilateral to a CSD compared with non-CSD hemispheres (0.19 ± 0.07 less in the CSD hemisphere, p = 0.028). At a 152-cm drop height, there were no detectable differences between sham injured (n = 10), CHI CSD+ (n = 12), and CHI CSD- (n = 16) mice on Morris water maze testing at 4 weeks. At a 183-cm drop height, CHI CSD+ mice had worse performance on the hidden platform test at 1-2 weeks versus sham mice (n = 15 CHI CSD+, n = 9 sham, p = 0.045), but there was no appreciable differences compared with CHI CSD- mice (n = 11 CHI CSD-). CONCLUSIONS: The data suggest that a lower baseline cerebral blood flow prior to injury may contribute to the occurrence of a CSD. Furthermore, a CSD at the time of injury can be associated with worse cognitive outcome under the appropriate experimental conditions in a mouse CHI model of TBI.

Total Isolated Monocular Vision Loss in a Patient Who Suffered Closed Head Injury.

BACKGROUND: Head injuries are an important cause of morbidity and mortality in children and young adults. There are multiple sight-threatening complications of head injury, even in closed head injury without visible violation of the globe or orbits. One such entity is traumatic optic neuropathy. CASE REPORT: Herein we describe a case of traumatic optic neuropathy in an otherwise healthy teenage patient who suffered total monocular vision loss after a fall and without any other injuries on examination. Unfortunately, the prognosis for this condition is relatively poor in terms of visual recovery. Though much research has been conducted attempting to treat this condition, to date there have been no studies showing a clear benefit of medical or surgical intervention. Why Should an Emergency Physician Be Aware of This? Although there is no proven treatment for traumatic optic neuropathy, emergency physicians may encounter this in their practice while caring for both pediatric and adult patients presenting with head injury. Having more background knowledge on this condition will enhance emergency physicians' ability to consult with subspecialist providers as well as to educate patients and their families on their condition and prognosis.

Diagnosing skull fracture in children with closed head injury using point-of-care ultrasound vs. computed tomography scan.

Diagnostic and therapeutic interventions in children for traumatic brain injury, which is known as the most important complication in trauma, require special attention. This study aimed to evaluate the accuracy of point-of-care ultrasound (POCUS) in diagnosing skull fracture in children with closed head injury in comparison with computed tomography (CT) scan. The current prospective cross-sectional study was conducted on children (0-14 years old), who were referred to the emergency department of a general teaching hospital in Shiraz, southern Iran (January-March 2018), with close head injury and were suspected of bone fracture. The participants were selected using a convenience sampling. The results of POCUS performed by emergency medicine (EM) residents were compared with the results of CT scan, which was reported by radiologists and considered a gold standard. Then, diagnostic tests were calculated. A total of 168 children were enrolled, with the mean ± standard deviation age of 6.21 ± 3.99. The most affected areas in the skull were the frontal (34.5%) and occipital areas (33.3%). POCUS had a sensitivity and specificity of 81.8% (95%CI, 48.2-97.7%) and 100% (95%CI, 97.7-100%), respectively. Positive and negative predictive values were 100% and 98.7%, with an accuracy of 98.8% in comparison with CT scan in the diagnosis of skull fracture.Conclusion: The results showed that POCUS with a portable ultrasonography machine, performed by the EM's physicians, have high diagnostic precision and can be considered a tool in the management of patients with closed head injury. What is Known: • Some studies have investigated the accuracy of ultrasound in diagnosing skull bone fractures in children with closed head injury, but before conducting this survey, no definite evidence recommended POCUS for skull fracture in children with closed head trauma in the ED. What is New: • POCUS with a portable ultrasonography machine, performed by the EM's physicians, has high diagnostic precision and can be considered a tool in the management of patients with closed head injury.

Amelioration of Cognitive and Behavioral Deficits after Traumatic Brain Injury in Coagulation Factor XII Deficient Mice.

Based on recent findings that show that depletion of factor XII (FXII) leads to better posttraumatic neurological recovery, we studied the effect of FXII-deficiency on post-traumatic cognitive and behavioral outcomes in female and male mice. In agreement with our previous findings, neurological deficits on day 7 after weight-drop traumatic brain injury (TBI) were significantly reduced in FXII-/- mice compared to wild type (WT) mice. Also, glycoprotein Ib (GPIb)-positive platelet aggregates were more frequent in brain microvasculature of WT than FXII-/- mice 3 months after TBI. Six weeks after TBI, memory for novel object was significantly reduced in both female and male WT but not in FXII-/- mice compared to sham-operated mice. In the setting of automated home-cage monitoring of socially housed mice in IntelliCages, female WT mice but not FXII-/- mice showed decreased exploration and reacted negatively to reward extinction one month after TBI. Since neuroendocrine stress after TBI might contribute to trauma-induced cognitive dysfunction and negative emotional contrast reactions, we measured peripheral corticosterone levels and the ration of heart, lung, and spleen weight to bodyweight. Three months after TBI, plasma corticosterone levels were significantly suppressed in both female and male WT but not in FXII-/- mice, while the relative heart weight increased in males but not in females of both phenotypes when compared to sham-operated mice. Our results indicate that FXII deficiency is associated with efficient post-traumatic behavioral and neuroendocrine recovery.

Sports-related concussions in high school females: an epidemiologic analysis of twenty-year national trends.

The epidemiology of sports-related concussions (SRCs) and closed head injuries (CHIs) in high school females remains undefined at the national level, especially for unorganized sports and recreational activities. This study examines 1,176,092 national weighted estimates of SRCs or CHIs in female patients 14-18 years of age presenting to United States (US) emergency departments (EDs) between 2000 and 2019 in the National Electronic Injury Surveillance System (NEISS). The national weighted estimate of female patients in our study increased significantly (p < 0.001) between 2000 (9,835; 95% Confidence Interval [CI] 7,105-12,566) and 2019 (31,751; CI 26,392-37,110). The top five ranked sports and recreational activities most commonly associated with concussions and CHIs in female patients 14-18 years of age were: soccer (20.6%; CI 17.6%-23.6%); basketball (18.5%; CI 16.9%-20.1%); cheerleading (10.4%; CI 8.9%-11.9%); softball (10.1%; CI 9.0%-11.3%); volleyball (6.5%; CI 5.7%-7.2%). Simple univariate regression models showed that an increase of 10,000 annual female participants across all high school sports and recreational activities was associated with 308.7 (SE = 20.8, p < 0.001, R2 = 0.92) additional annual SRCs and CHIs presenting to US EDs. The promotion of concussion awareness and educational programs may help minimize SRCs and CHIs.

Investigation of the effect of dietary intake of omega-3 polyunsaturated fatty acids on trauma-induced white matter injury with quantitative diffusion MRI in mice.

Previous studies suggest that long-term supplementation and dietary intake of omega-3 polyunsaturated fatty acids (PUFAs) may have neuroprotective effects following brain injury. The objective of this study was to investigate potential neuroprotective effects of omega-3 PUFAs on white matter following closed-head trauma. The closed-head injury model of engineered rotational acceleration (CHIMERA) produces a reproducible injury in the optic tract and brachium of the superior colliculus in mice. Damage is detectable using diffusion tensor imaging (DTI) metrics, particularly fractional anisotropy (FA), with sensitivity comparable to histology. We acquired in vivo (n = 38) and ex vivo (n = 41) DTI data in mice divided into sham and CHIMERA groups with two dietary groups: one deficient in omega-3 PUFAs and one adequate in omega-3 PUFAs. We examined injury effects (reduction in FA) and neuroprotection (FA reduction modulated by diet) in the optic tract and brachium. We verified that diet did not affect FA in sham animals. In injured animals, we found significantly reduced FA in the optic tract and brachium (~10% reduction, p < 0.001), and Bayes factor analysis showed strong evidence to reject the null hypothesis. However, Bayes factor analysis showed substantial evidence to accept the null hypothesis of no diet-related FA differences in injured animals in the in vivo and ex vivo samples. Our results indicate no neuroprotective effect from adequate dietary omega-3 PUFA intake on white matter damage following traumatic brain injury. Since damage from CHIMERA mainly affects white matter, our results do not necessarily contradict previous findings showing omega-3 PUFA-mediated neuroprotection in gray matter.

Spermidine Exhibits Protective Effects Against Traumatic Brain Injury.

Traumatic brain injury (TBI) causes permanent neurological and cognitive impairments. Effective pharmacological interventions remain elusive. Spermidine is a polyamine compound found in our body that may play a role in brain development and congenital function. In this study, we aimed to investigate the therapeutic potential of spermidine for TBI. We employed experimental closed head injury (CHI) model to evaluate the protective function of spermidine on brain injury. We assessed the neurobehavioral function recovery using Neurologic Severity Score (NSS) and Morris water maze test. At histological level, we evaluated the improvement on brain edema, brain-blood barrier integrity, and cell apoptosis. We also measured inflammatory cytokines and brain injury biomarkers to monitor the treatment outcomes. Last, we correlated the level of spermidine with CHI animal model and TBI patients with different levels of severity. Spermidine administration post-CHI was found effectively to accelerate NSS improvement and shorten latency in maze test. We observed consistent improvements in brain edema, BBB function, and cell death in spermidine-treated group. Inflammatory cytokines and TBI biomarkers, e.g., S100B, MBP and CFAP were reduced significantly in treatment group. Interestingly, inhibiting spermidine synthesis influenced the neurobehavioral recovery in CHI mice. ODC1, a rate-limiting enzyme for spermidine synthesis, was found lower in CHI mice. Serum level of spermidine was significantly lower in TBI patients with severe pathological scores. Spermidine pathway may carry an endogenous role in pathophysiological process of CHI. For the first time, we demonstrated that administrating spermidine may provide a new treatment for TBI.

Development and Implementation of a Pilot Radiation Reduction Protocol for Pediatric Head Injury.

BACKGROUND: Traumatic brain injury is the leading cause of morbidity and mortality for children in the United States. The aim of this study was to develop and implement a guideline to reduce radiation exposure in the pediatric head injury patient by identifying the patient population where repeat imaging is necessary and to establish rapid brain protocol magnetic resonance imaging as the first-line modality. METHODS: A retrospective chart review of trauma patients between 0 and 14 y of age admitted at a pediatric level 2 trauma center was performed between January 2013 and June 2019. The guideline established the appropriateness of repeat scans for patients with Glasgow Coma Scale >13 with clinical neurological deterioration or patients with Glasgow Coma Scale ≤13 and intracranial hemorrhagic lesion on initial head computed tomography (CT). RESULTS: Our trauma registry included 592 patients during the study period, 415 before implementation and 161 after implementation. A total of 132 patients met inclusion criteria, 116 pre-guideline and 16 post-guideline. The number of patients receiving repeat head CTs significantly decreased from 34.5% to 6.3% (P < 0.02). There was also a significant decrease in the mean number of head CT/patient pre-guideline 1.63 (range 1-7) compared with post-guideline 1.06 (range 1-2) (P < 0.02). CONCLUSIONS: CT head imaging is invaluable in the initial trauma evaluation of pediatric patients. However, it can be overused, and the radiation may lead to long-term deleterious effects. Establishing a head imaging guideline which limits use with clinical criteria can be effective in reducing radiation exposure without missing injuries.

A secondary analysis to inform a clinical decision rule for predicting skull fracture and intracranial injury in children under age 2.

The purpose of this study was to identify factors associated with the risk of closed head injury (CHI) in children under age 2 years with suspected minor head injuries based on age-appropriate, or near age-appropriate, mental status on an exam. The study was a secondary data analysis of a public-use dataset from the largest prospective, multicenter pediatric head injury study found in the current literature. An existing, validated clinical decision rule was examined using a sample of 3,329 children under age 2 to determine whether it, or the individual variables within it, could be utilized alone, or in conjunction with other variables to accurately predict the risk of underlying CHI in this sample. Results indicated that the keys to an accurate triage assessment for children under age 2 with suspected minor head injuries include the ability to identify the specific skull region injured, the ability to assess for the presence and size of any scalp hematoma, the ability to identify signs of altered mental status in this age group, and having access to accurate information regarding the child's age and the details of the injury mechanism. The findings from this study add to the body of knowledge regarding what factors are associated with CHI in children under age 2 with suspected minor head injuries and could be used to inform age-specific recommendations for children under age 2 in triage, educational resources, and national trauma criteria.

Behavior, protein, and dendritic changes after model traumatic brain injury and treatment with nanocoffee particles.

BACKGROUND: Traumatic brain injury (TBI) is a widespread public health problem and a signature injury of our military in modern conflicts. Despite the long-term effects of even mild brain injuries, an effective treatment remains elusive. Coffee and several of its compounds, including caffeine, have been identified as having neuroprotective effects in studies of neurodegenerative disease. Given the molecular similarities between TBI and neurodegenerative disease, we have devised a study to test a nanocoffee extract in the treatment of a mouse model of mild TBI. RESULTS: After a single injury and two subsequent injections of nanocoffee, we identified treatment as being associated with improved behavioral outcomes, favorable molecular signaling changes, and dendritic changes suggestive of improved neuronal health. CONCLUSIONS: We have identified coffee extracts as a potential viable multifaceted treatment approach to target the secondary injury associated with TBI.

Cerebral blood flow in children and adolescents several years after concussion.

OBJECTIVES: The long-term effects of concussion in youth remain poorly understood. The objective of this study was to determine the association between history of concussion and cerebral blood flow (CBF) in youth. METHODS: A total of 53 children and adolescents with a history of concussion (n = 37) or orthopaedic injury (OI; n = 16) were considered. Measures included pseudo-continuous arterial spin labelling magnetic resonance imaging to quantify CBF, post-concussion symptoms, psychological symptoms, and cognitive testing. RESULTS: Participants (mean age: 14.4 years, 95% CI = 13.8-15.4, range = 8-19) were on average 2.7 years (95% CI = 2.2-3.1) post-injury. Youth with a history of concussion had higher parent-reported physical, cognitive, anxiety, and depression symptoms than children with OI, but the groups did not differ on self-reported symptoms (post-concussive or psychological) or cognitive testing. Global CBF did not differ between groups. Regional CBF analyses suggested that youth with a history of concussion had hypoperfusion in posterior and inferior regions and hyperperfusion in anterior/frontal/temporal regions as compared to those with OI. However, neither global nor regional CBF were significantly associated with demographics, pre-injury functioning, number of concussions, time since injury, post-concussive symptoms, psychological symptoms, or cognitive abilities. CONCLUSIONS: Youth with a history of concussion demonstrate differences in regional CBF (not global CBF), but without clear clinical expression.

Blood-brainbarrier disruption dictates nanoparticle accumulation following experimental brain injury.

Clinically, traumatic brain injury (TBI) results in complex heterogeneous pathology that cannot be recapitulated in single pre-clinical animal model. Therefore, we focused on evaluating utility of nanoparticle (NP)-based therapeutics following three diffuse-TBI models: mildclosed-head injury (mCHI), repetitive-mCHI and midline-fluid percussion injury (FPI). We hypothesized that NP accumulation after diffuse TBI correlates directly with blood-brainbarrier permeability. Mice received PEGylated-NP cocktail (20-500 nm) (intravenously) after single- or repetitive-(1 impact/day, 5 consecutive days) CHI (immediately) and midline-FPI (1 h, 3 h and 6 h). NPs circulated for 1 h before perfusion/brain extraction. NP accumulation was analyzed using fluorescent microscopy in brain regions vulnerable to neuropathology. Minimal/no NP accumulation after mCHI/RmCHI was observed. In contrast, midlineFPI resulted in significant peak accumulation of up to 500 nm NP at 3 h post-injury compared to sham, 1 h, and 6 h groups in the cortex. Therefore, our study provides the groundwork for feasibility of NP-delivery based on NPinjection time and NPsize after mCHI/RmCHI and midline-FPI.

Platelet transfusion does not improve outcomes in patients with brain injury on antiplatelet therapy.

INTRODUCTION: Platelet dysfunction following traumatic brain injury (TBI) is associated with worse outcomes. The efficacy of platelet transfusion to reverse antiplatelet medication (APM) remains unknown. Thrombelastography platelet mapping (TEG-PM) assesses platelet function. We hypothesize that platelet transfusion can reverse the effects of APM but does not improve outcomes following TBI. METHODS: An observational study at six US trauma centres was performed. Adult patients on APM with CT evident TBI after blunt injury were enrolled. Demographics, brain CT and TEG-PM results before/after platelet transfusion, length of stay (LOS), and injury severity score (ISS) were abstracted. RESULTS: Sixty six patients were enrolled (89% aspirin, 50% clopidogrel, 23% dual APM) with 23 patients undergoing platelet transfusion. Transfused patients had significantly higher ISS and admission CT scores. Platelet transfusion significantly reduced platelet inhibition due to aspirin (76.0 ± 30.2% to 52.7 ± 31.5%, p < 0.01), but had a non-significant impact on clopidogrel-associated inhibition (p = 0.07). Platelet transfusion was associated with longer length of stay (7.8 vs. 3.5 days, p < 0.01), but there were no differences in mortality. CONCLUSION: Platelet transfusion significantly decreases platelet inhibition due to aspirin but is not associated with change in outcomes in patients on APM following TBI.

Bilateral Lower Cranial Nerve Palsy after Closed Head Injury: A Case Report and Review of Literature.

Paralysis of the lower cranial nerves is uncommon after closed head injuries. Most cases reported are unilateral and associated with base of skull fractures, usually involving the occipital condyles. Bilateral lower cranial nerve palsy is even less common, with only a handful of cases reported in literature. A 17-year-old girl presented to us after she was involved in a side-on collision with a car while driving a scooter. She sustained traumatic brain injury requiring mechanical ventilation. Detailed neurological evaluation revealed bilateral paralysis of the IXth, Xth, and XIIth cranial nerves with no evidence of a fracture of the base of skull or brain stem injury. A traction type of injury to the nerves arising from a whiplash mechanism may have led to paralysis of the lower cranial nerves in our patient. An exhaustive review of literature revealed 11 reports of bilateral lower cranial nerve palsy associated with closed head injuries; there were only four cases without underlying fracture of the occipital condyles. Our patient made a complete recovery over a period of 4 months. A traction type of injury to the lower cranial nerves may occur due to a whiplash mechanism. This type of injury may be associated with a favorable outcome.