Propofol Protects the Blood-Brain Barrier After Traumatic Brain Injury by Stabilizing the Extracellular Matrix via Prrx1: From Neuroglioma to Neurotrauma.

The purpose of this study is to explore the shared molecular pathogenesis of traumatic brain injury (TBI) and high-grade glioma and investigate the mechanism of propofol (PF) as a potential protective agent. By analyzing the Chinese glioma genome atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases, we compared the transcriptomic data of high-grade glioma and TBI patients to identify common pathological mechanisms. Through bioinformatics analysis, in vitro experiments and in vivo TBI model, we investigated the regulatory effect of PF on extracellular matrix (ECM)-related genes through Prrx1 under oxidative stress. The impact of PF on BBB integrity under oxidative stress was investigated using a dual-layer BBB model, and we explored the protective effect of PF on tight junction proteins and ECM-related genes in mice after TBI. The study found that high-grade glioma and TBI share ECM instability as an important molecular pathological mechanism. PF stabilizes the ECM and protects the BBB by directly binding to Prrx1 or indirectly regulating Prrx1 through miRNAs. In addition, PF reduces intracellular calcium ions and ROS levels under oxidative stress, thereby preserving BBB integrity. In a TBI mouse model, PF protected BBB integrity through up-regulated tight junction proteins and stabilized the expression of ECM-related genes. Our study reveals the shared molecular pathogenesis between TBI and glioblastoma and demonstrate the potential of PF as a protective agent of BBB. This provides new targets and approaches for the development of novel neurotrauma therapeutic drugs.

Headbutting through time: A review of this hypothesized behavior in "dome-headed" fossil taxa.

Headbutting is a combative behavior most popularly portrayed and exemplified in the extant bighorn sheep (Ovis canadensis). When behaviorally proposed in extinct taxa, these organisms are oft depicted Ovis-like as having used modified cranial structures to combatively slam into one another. The combative behavioral hypothesis of headbutting has a long and rich history in the vertebrate fossil literature (not just within Dinosauria), but the core of this behavioral hypothesis in fossil terrestrial vertebrates is associated with an enlarged osseous cranial dome-an osteological structure with essentially no current counterpart. One confounding issue found in the literature is that while the term "headbutting" sounds simplistic enough, little terminology has been used to describe this hypothesized behavior. And pertinent to this special issue, potential brain trauma and the merits of such proposed pugilism have been assessed largely from the potential deformation of the overlying osseous structure; despite the fact that extant taxa readily show that brain damage can and does occur without osteological compromise. Additionally, the extant taxa serving as the behavioral counterpart for comparison are critical, not only because of the combative behaviors and morphologies they display, but also the way they engage in such behavior. Sheep (Ovis), warthogs (Phacochoerus), and bison (Bison) all engage in various forms of "headbutting", but the cranial morphologies and the way each engages in combat is markedly different. To hypothesize that an extinct organism engaged in headbutting like an extant counterpart in theory implies specific striking:contacting surfaces, speed, velocity, and overall how that action was executed. This review examines the history and usage of the headbutting behavioral hypothesis in these dome-headed fossil taxa, their respective extant behavioral counterparts, and proposes a protocol for specific behavioral terms relating to headbutting to stem future confusion. We also discuss the disparate morphology of combative cranial structures in the fossil record, and the implications of headbutting-induced brain injury in extinct taxa. Finally, we conclude with some potential implications for artistic reconstructions of fossil taxa regarding this behavioral repertoire.

Heads up on concussion: Aboriginal and Torres Strait Islander peoples' knowledge and understanding of mild traumatic brain injury.

ISSUE ADDRESSED: Concussion awareness and knowledge among Aboriginal and Torres Strait Islander peoples residing in Perth, Western Australia and factors preventing presentation at a health service for assessment after such an injury. METHODS: Qualitative study with participants aged between 18 and 65 years. Recruitment was by Facebook advertising and snowball sampling. A semi-structured topic yarning guide was used to guide conversations through 1:1, multi-person or group yarns. Yarns were audio-recorded, transcribed and thematically analysed. RESULTS: Twenty-four participants were recruited. A good knowledge of modes of concussion injury was identified in these participants. However, they identified difficulty differentiating this injury from other injuries or medical conditions. Multiple factors contributed to a reluctance to seek assessment and further management of a potential concussion. Multiple strategies to enhance education and presentation for assessment were suggested by participants. CONCLUSIONS: Aboriginal and Torres Strait Islander-owned and led concussion education is the first step in enhancing understanding of this condition. Education must be coupled with improvements in the cultural safety of healthcare services, as without this, patients will continue to fail to present for assessment and management. SO WHAT?: It is recommended that concussion education focuses on the differentiation of concussion as a diagnosis from other injuries. Information regarding where and when to seek medical assessment is recommended, and this must be in a culturally safe environment. Typical recovery and potential sequelae must be explored, in programs led and devised by Aboriginal and Torres Strait Islander peoples engaged with the community for which the education is proposed.

On-road driving remediation following acquired brain injury: a randomized controlled trial.

OBJECTIVE: To investigate the relationship between on-road driving remediation and achieving fitness to drive following acquired brain injury. DESIGN: Randomized controlled trial. SETTING: Tertiary hospital outpatient driver assessment and rehabilitation service, Australia. PARTICIPANTS: Thirty-five participants (54.3% male), aged 18-65 years, 41 days-20 years post-acquired brain injury (including stroke, aneurysm, traumatic brain injury) recommended for on-road driving remediation following occupational therapy driver assessment were randomly assigned to intervention (n = 18) and waitlist control (n = 17) groups. INTERVENTION: Intervention group received on-road driving remediation delivered by a qualified driving instructor in a dual-control vehicle. The waitlist control group completed a 6 week period of no driving-related remediation. MAIN MEASURE: Fitness to drive rated following the conduct of an on-road occupational therapy driver assessment with a qualified driving instructor where outcome assessors were blinded to group allocation. RESULTS: The intervention group were significantly more likely to achieve a fit to drive recommendation than no driving specific intervention (p = 0.003). CONCLUSION: Following comprehensive assessment, individualized on-road driving remediation programs devised by an occupational therapist with advanced training in driver assessment and rehabilitation and delivered by a qualified driving instructor are significantly associated with achieving fitness to drive after acquired brain injury.

Evaluating the Impact of Point-of-Care Electroencephalography on Length of Stay in the Intensive Care Unit: Subanalysis of the SAFER-EEG Trial.

BACKGROUND: Electroencephalography (EEG) is needed to diagnose nonconvulsive seizures. Prolonged nonconvulsive seizures are associated with neuronal injuries and deleterious clinical outcomes. However, it is uncertain whether the rapid identification of these seizures using point-of-care EEG (POC-EEG) can have a positive impact on clinical outcomes. METHODS: In a retrospective subanalysis of the recently completed multicenter Seizure Assessment and Forecasting with Efficient Rapid-EEG (SAFER-EEG) trial, we compared intensive care unit (ICU) length of stay (LOS), unfavorable functional outcome (modified Rankin Scale score ≥ 4), and time to EEG between adult patients receiving a US Food and Drug Administration-cleared POC-EEG (Ceribell, Inc.) and those receiving conventional EEG (conv-EEG). Patient records from January 2018 to June 2022 at three different academic centers were reviewed, focusing on EEG timing and clinical outcomes. Propensity score matching was applied using key clinical covariates to control for confounders. Medians and interquartile ranges (IQRs) were calculated for descriptive statistics. Nonparametric tests (Mann-Whitney U-test) were used for the continuous variables, and the χ2 test was used for the proportions. RESULTS: A total of 283 ICU patients (62 conv-EEG, 221 POC-EEG) were included. The two populations were matched using demographic and clinical characteristics. We found that the ICU LOS was significantly shorter in the POC-EEG cohort compared to the conv-EEG cohort (3.9 [IQR 1.9-8.8] vs. 8.0 [IQR 3.0-16.0] days, p = 0.003). Moreover, modified Rankin Scale functional outcomes were also different between the two EEG cohorts (p = 0.047). CONCLUSIONS: This study reveals a significant association between early POC-EEG detection of nonconvulsive seizures and decreased ICU LOS. The POC-EEG differed from conv-EEG, demonstrating better functional outcomes compared with the latter in a matched analysis. These findings corroborate previous research advocating the benefit of early diagnosis of nonconvulsive seizure. The causal relationship between the type of EEG and metrics of interest, such as ICU LOS and functional/clinical outcomes, needs to be confirmed in future prospective randomized studies.

How to Define and Meet Blood Pressure Targets After Traumatic Brain Injury: A Narrative Review.

BACKGROUND: Traumatic brain injury (TBI) poses a significant challenge to healthcare providers, necessitating meticulous management of hemodynamic parameters to optimize patient outcomes. This article delves into the critical task of defining and meeting continuous arterial blood pressure (ABP) and cerebral perfusion pressure (CPP) targets in the context of severe TBI in neurocritical care settings. METHODS: We narratively reviewed existing literature, clinical guidelines, and emerging technologies to propose a comprehensive approach that integrates real-time monitoring, individualized cerebral perfusion target setting, and dynamic interventions. RESULTS: Our findings emphasize the need for personalized hemodynamic management, considering the heterogeneity of patients with TBI and the evolving nature of their condition. We describe the latest advancements in monitoring technologies, such as autoregulation-guided ABP/CPP treatment, which enable a more nuanced understanding of cerebral perfusion dynamics. By incorporating these tools into a proactive monitoring strategy, clinicians can tailor interventions to optimize ABP/CPP and mitigate secondary brain injury. DISCUSSION: Challenges in this field include the lack of standardized protocols for interpreting multimodal neuromonitoring data, potential variability in clinical decision-making, understanding the role of cardiac output, and the need for specialized expertise and customized software to have individualized ABP/CPP targets regularly available. The patient outcome benefit of monitoring-guided ABP/CPP target definitions still needs to be proven in patients with TBI. CONCLUSIONS: We recommend that the TBI community take proactive steps to translate the potential benefits of personalized ABP/CPP targets, which have been implemented in certain centers, into a standardized and clinically validated reality through randomized controlled trials.

Effect of l-oxiracetam and oxiracetam on memory and cognitive impairment in mild-to-moderate traumatic brain injury patients: Study protocol for a randomized controlled trial.

Objectives: Patients with traumatic brain injury (TBI) often suffer memory and cognitive impairments, and oxiracetam-like drugs are considered to have a positive impact on these symptoms potentially. However, the efficacy and safety of l-oxiracetam and oxiracetam in TBI patients have not been sufficiently investigated. Methods: The study adopts a multicenter, randomized, double-blind, parallel-group, phase 3 clinical trial design in 74 centers across 51 hospitals in China. A total of 590 TBI patients meeting criteria will be randomly allocated into three groups in a 2:2:1 ratio: l-oxiracetam group, oxiracetam group, and placebo group. The treatment period is 14 days, with a follow-up period of 90 days. The primary outcome measure is the change in the Loewenstein Occupational Therapy Cognitive Assessment score at 90 days after treatment. Secondary outcomes include changes in other cognitive assessments, neurological function, activities of daily living, and safety assessments. Discussion: There is no robust evidence to suggest that l-oxiracetam and oxiracetam can enhance memory and cognitive function in patients with mild to moderate TBI. This study has the potential to answer this crucial clinical question. Trial registration: chinadrugtrials.org.cn, identifier CTR20192539; ClinicalTrials.gov, identifier NCT04205565.

High Doses of Caffeine-Induced Cerebral Infarction Leading to Partial Locked-In Syndrome in a Young Adult: A Novel Association?

Introduction: This is a case of a 30-year-old male with no prior medical conditions presented to the emergency department for presumed seizures after ingesting 900 mg of caffeine via pre-workout drinks and pills. Case Presentation: The patient was described as having nearly 15 min of generalized seizure activity observed by emergency medical service, requiring midazolam. A head computerized tomography (CT) demonstrated a possible thrombus, and further, CT angiography and CT perfusion confirmed a basilar artery occlusion. He was treated with tissue plasminogen activator and underwent thrombectomy achieving TICI grade 3 in the left posterior cerebral artery and TICI grade 2b in the superior cerebellar artery. Unfortunately, the patient experienced a hemorrhagic conversion leading to an incomplete locked-in syndrome. Conclusion: This case report suggests a novel association between energy drinks and caffeine supplements as potential etiologies for rapid onset on cerebrovascular incidents.

Indications, results and consequences of electroencephalography in neurocritical care: A retrospective study.

PURPOSE: Electrocencephalography (EEG) is a tool to assess cerebral cortical activity. We investigated the indications and results of routine EEG recordings in neurocritical care patients and corresponding changes in anti-seizure medication (ASM). MATERIALS AND METHODS: This was a single-center, retrospective cohort study. We included all adult Intensive Care Unit (ICU) patients with severe acute brain injury who received a routine EEG (30-60 min). Indications, background patterns, presence of rhythmic and periodic patterns, seizures, and adjustments in ASM were documented. RESULTS: A total of 109 patients were included. The EEGs were performed primarily to investigate the presence of (non-convulsive) status epilepticus ((NC)SE) and/or seizures. A (slowed) continuous background pattern was present in 94%. Low voltage, burst-suppression and suppressed background patterns were found in six patients (5.5%). Seizures were diagnosed in two patients and (NC)SE was diagnosed in five patients (6.4%). Based on the EEG results, ASM was changed in 47 patients (43%). This encompassed discontinuation of ASM in 27 patients (24.8%) and initiation of ASM in 20 patients (18.3%). CONCLUSIONS: All EEGs were performed to investigate the presence of (NC)SE or seizures. A slowed, but continuous background pattern was found in nearly all patients and (NC)SE and seizures were rarely diagnosed. Adjustments in ASM were made in approximately half of the patients.

Restoring consciousness with pharmacologic therapy: Mechanisms, targets, and future directions.

Severe brain injury impairs consciousness by disrupting a broad spectrum of neurotransmitter systems. Emerging evidence suggests that pharmacologic modulation of specific neurotransmitter systems, such as dopamine, promotes recovery of consciousness. Clinical guidelines now endorse the use of amantadine in individuals with traumatic disorders of consciousness (DoC) based on level 1 evidence, and multiple neurostimulants are used off-label in clinical practice, including methylphenidate, modafinil, bromocriptine, levodopa, and zolpidem. However, the relative contributions of monoaminergic, glutamatergic, cholinergic, GABAergic, and orexinergic neurotransmitter systems to recovery of consciousness after severe brain injury are unknown, and personalized approaches to targeted therapy have yet to be developed. This review summarizes the state-of-the-science in the neurochemistry and neurobiology of neurotransmitter systems involved in conscious behaviors, followed by a discussion of how pharmacologic therapies may be used to modulate these neurotransmitter systems and promote recovery of consciousness. We consider pharmacologic modulation of consciousness at the synapse, circuit, and network levels, with a focus on the mesocircuit model that has been proposed to explain the consciousness-promoting effects of various monoaminergic, glutamatergic, and paradoxically, GABAergic therapies. Though fundamental questions remain about neurotransmitter mechanisms, target engagement and optimal therapy selection for individual patients, we propose that pharmacologic therapies hold great promise to promote recovery and improve quality of life for patients with severe brain injuries.

Retrospective evaluation of shock index and mortality in dogs with head trauma (2015-2020): 86 cases.

OBJECTIVE: To assess the relationship between shock index (SI) and mortality in dogs with head trauma (HT). A secondary objective was to compare SI with the animal trauma triage (ATT) score and Modified Glasgow Coma Scale (MCGS) score in HT cases. A tertiary aim was to assess if SI is predictive of survival to discharge or improvement in presenting neurologic signs. DESIGN: Retrospective study from January 2015 to December 2020. SETTING: Tertiary referral level II veterinary trauma center. ANIMALS: Eighty-six dogs with evidence of HT presenting through emergency for various traumas compared to 60 healthy control dogs. MEASUREMENTS AND MAIN RESULTS: SI was calculated using the quotient of heart rate over systolic blood pressure measured on presentation. SI was significantly higher in HT patients than healthy controls (P = 0.0019). SI was not significantly different between traumatic brain injury dogs that died or were euthanized and HT dogs that lived until the time of discharge (P = 0.98). SI was not significantly different between HT dogs that were neurologically normal at the time of discharge and HT dogs that were static or improved but not normal neurologically at the time of discharge (P = 0.84). In HT dogs, SI did not correlate with ATT score (P = 0.16) or MGCS score (P = 0.75). There was no significant difference in SI and length of hospitalization until death or discharge (P = 0.78). CONCLUSIONS: SI was significantly higher in HT patients compared to control patients. Interestingly, SI was not correlated with ATT score or MGCS score. The use of SI in HT patients warrants further investigation to assess the efficacy in predicting mortality.

In vivo neural regeneration via AAV-NeuroD1 gene delivery to astrocytes in neonatal hypoxic-ischemic brain injury.

BACKGROUND: Neonatal hypoxic-ischemic brain injury (HIBI) is a significant contributor to neonatal mortality and long-term neurodevelopmental disability, characterized by massive neuronal loss and reactive astrogliosis. Current therapeutic approaches for neonatal HIBI have been limited to general supportive therapy because of the lack of methods to compensate for irreversible neuronal loss. This study aimed to establish a feasible regenerative therapy for neonatal HIBI utilizing in vivo direct neuronal reprogramming technology. METHODS: Neonatal HIBI was induced in ICR mice at postnatal day 7 by permanent right common carotid artery occlusion and exposure to hypoxia with 8% oxygen and 92% nitrogen for 90 min. Three days after the injury, NeuroD1 was delivered to reactive astrocytes of the injury site using the astrocyte-tropic adeno-associated viral (AAV) vector AAVShH19. AAVShH19 was engineered with the Cre-FLEX system for long-term tracking of infected cells. RESULTS: AAVShH19-mediated ectopic NeuroD1 expression effectively converted astrocytes into GABAergic neurons, and the converted cells exhibited electrophysiological properties and synaptic transmitters. Additionally, we found that NeuroD1-mediated in vivo direct neuronal reprogramming protected injured host neurons and altered the host environment, i.e., decreased the numbers of activated microglia, reactive astrocytes, and toxic A1-type astrocytes, and decreased the expression of pro-inflammatory factors. Furthermore, NeuroD1-treated mice exhibited significantly improved motor functions. CONCLUSIONS: This study demonstrates that NeuroD1-mediated in vivo direct neuronal reprogramming technology through AAV gene delivery can be a novel regenerative therapy for neonatal HIBI.

Utility and rationale for continuous EEG monitoring: a primer for the general intensivist.

This review offers a comprehensive guide for general intensivists on the utility of continuous EEG (cEEG) monitoring for critically ill patients. Beyond the primary role of EEG in detecting seizures, this review explores its utility in neuroprognostication, monitoring neurological deterioration, assessing treatment responses, and aiding rehabilitation in patients with encephalopathy, coma, or other consciousness disorders. Most seizures and status epilepticus (SE) events in the intensive care unit (ICU) setting are nonconvulsive or subtle, making cEEG essential for identifying these otherwise silent events. Imaging and invasive approaches can add to the diagnosis of seizures for specific populations, given that scalp electrodes may fail to identify seizures that may be detected by depth electrodes or electroradiologic findings. When cEEG identifies SE, the risk of secondary neuronal injury related to the time-intensity "burden" often prompts treatment with anti-seizure medications. Similarly, treatment may be administered for seizure-spectrum activity, such as periodic discharges or lateralized rhythmic delta slowing on the ictal-interictal continuum (IIC), even when frank seizures are not evident on the scalp. In this setting, cEEG is utilized empirically to monitor treatment response. Separately, cEEG has other versatile uses for neurotelemetry, including identifying the level of sedation or consciousness. Specific conditions such as sepsis, traumatic brain injury, subarachnoid hemorrhage, and cardiac arrest may each be associated with a unique application of cEEG; for example, predicting impending events of delayed cerebral ischemia, a feared complication in the first two weeks after subarachnoid hemorrhage. After brief training, non-neurophysiologists can learn to interpret quantitative EEG trends that summarize elements of EEG activity, enhancing clinical responsiveness in collaboration with clinical neurophysiologists. Intensivists and other healthcare professionals also play crucial roles in facilitating timely cEEG setup, preventing electrode-related skin injuries, and maintaining patient mobility during monitoring.

Inflammasomes at the crossroads of traumatic brain injury and post-traumatic epilepsy.

Post-traumatic epilepsy (PTE) is one of the most debilitating consequences of traumatic brain injury (TBI) and is one of the most drug-resistant forms of epilepsy. Novel therapeutic treatment options are an urgent unmet clinical need. The current focus in healthcare has been shifting to disease prevention, rather than treatment, though, not much progress has been made due to a limited understanding of the disease pathogenesis. Neuroinflammation has been implicated in the pathophysiology of traumatic brain injury and may impact neurological sequelae following TBI including functional behavior and post-traumatic epilepsy development. Inflammasome signaling is one of the major components of the neuroinflammatory response, which is increasingly being explored for its contribution to the epileptogenic mechanisms and a novel therapeutic target against epilepsy. This review discusses the role of inflammasomes as a possible connecting link between TBI and PTE with a particular focus on clinical and preclinical evidence of therapeutic inflammasome targeting and its downstream effector molecules for their contribution to epileptogenesis. Finally, we also discuss emerging evidence indicating the potential of evaluating inflammasome proteins in biofluids and the brain by non-invasive neuroimaging, as potential biomarkers for predicting PTE development.

Mood Disorders in the Wake of Traumatic Brain Injury: A Systematic Review.

Traumatic brain injury (TBI) frequently leads to a myriad of long-term consequences, among which mood disorders present a significant challenge. This systematic review delves into the complex interplay between TBI and subsequent mood disorders, focusing on research studies conducted over the past decade. Encompassing an age range from 12 years old to older adults (60+ years), our review aims to elucidate the epidemiological patterns, neurobiological mechanisms, and psychosocial factors that contribute to the development of mood disorders following TBI. By synthesizing the current literature, we seek to uncover the prevalence and clinical implications of this often-under-recognized comorbidity. For the quality appraisal of the reviewed articles, the Newcastle-Ottawa risk-of-bias tool and Scale for the Assessment of Narrative Review Articles (SANRA) checklist were employed. Ultimately, this review endeavors to provide a comprehensive understanding of the intricate relationship between TBI and mood disorders, offering insights crucial for improved management and intervention strategies in affected individuals.

The Association Between Tranexamic Acid and Seizures in Moderate or Severe Traumatic Brain Injury.

INTRODUCTION: Tranexamic acid (TXA) administered within 2 h of injury reduces mortality in traumatic brain injury (TBI) with intracranial hemorrhage. TXA also reduces the seizure threshold in a dose-dependent manner. We examined whether a 2-g bolus of prehospital TXA administered in moderate or severe TBI is associated with seizure activity within 72 h of injury. METHODS: Patients from the prehospital TXA for TBI trial with Glasgow Coma Scale < 13, blunt head injury, and time-of-seizure data were included in this analysis. The original trial randomized patients with suspected TBI to placebo, 1-g TXA bolus + 1-g 8-h TXA infusion, or 2-g TXA bolus within 2 h of injury. In this secondary analysis, multivariable logistic regression was performed to examine the association of treatment group with seizure incidence. The model controlled for age, Glasgow Coma Scale, Injury Severity Score, intracranial hemorrhage, Abbreviated Injury Scale-head, and home antiseizure medication use. RESULTS: Of the 786 patients who met the inclusion criteria, 19 had seizures within 72 h (five in placebo, two in 1-g bolus/1-g infusion, and 12 in 2-g bolus). The 2-g TXA bolus was not associated with increased seizures compared to placebo (odds ratio 0.41, 95% confidence interval 0.12-1.18, P = 0.12). Home antiseizure medication use was associated with increased seizures (odds ratio 15.95, 95% confidence interval 3.79-60.57, P < 0.001). CONCLUSIONS: A prehospital 2-g TXA bolus in moderate or severe TBI was not associated with increased seizure activity during the first 72 h after injury; however, limited power, limited use of continuous electroencephalography, and unavailable seizure prophylaxis data highlight the need for further study.

Developmental Functions of Microglia: Impact of Psychosocial and Physiological Early Life Stress.

Microglia play numerous important roles in brain development. From early embryonic stages through adolescence, these immune cells influence neuronal genesis and maturation, guide connectivity, and shape brain circuits. They also interact with other glial cells and structures, influencing the brain's supportive microenvironment. While this central role makes microglia essential, it means that early life perturbations to microglia can have widespread effects on brain development, potentially resulting in long-lasting behavioral impairments. Here, we will focus on the effects of early life psychosocial versus physiological stressors in rodent models. Psychosocial stress refers to perceived threats that lead to stress axes activation, including prenatal stress, or chronic postnatal stress, including maternal separation and resource scarcity. Physiological stress refers to with physical threats, including maternal immune activation, postnatal infection, and traumatic brain injury. Differing sources of early life stress have varied impacts on microglia, and these effects are moderated by factors such as developmental age, brain region, and sex. Overall, these stressors appear to either 1) upregulate basal microglia numbers and activity throughout the lifespan, while possibly blunting their responsivity to subsequent stressors, or 2) shift the developmental curve of microglia, resulting in differential timing and function, impacting the critical periods they govern. Either could contribute to behavioral dysfunctions that occur after the resolution of early life stress. Exploring how different stressors impact microglia, as well as how the experience of multiple stressors interacts to alter microglia's developmental functions, could deepen our understanding of how early life stress changes the brain's developmental trajectory.

A Criteria to Reduce Interhospital Transfer of Traumatic Brain Injuries in Greater East Texas.

BACKGROUND: Traumatic brain injury (TBI) due to single-level falls (SLF) are frequent and often require interhospital transfer. This retrospective cohort study aimed to assess the safety of a criteria for non-transfer among a subset of TBI patients who could be observed at their local hospital, vs mandatory transfer to a level 1 trauma center (L1TC). METHODS: We conducted a 7-year review of patients with TBI due to SLF at a rural L1TC. Patients were classified as transfer/non-transfer according to the Brain Injuries in Greater East Texas (BIGTEX) criteria. The primary outcome measure was the occurrence of a critical event defined as deteriorating repeat head computed tomography (CT) scan or neurological status, neurosurgical intervention, or death. RESULTS: Of the 689 included patients, 63 (9.1%) were classified as non-transfer. Although there were 4 cases with a neurological change and one with a head CT change among the non-transfer group, there were no neurosurgical procedures or deaths. The Cox Proportional Hazard model showed a near 3-fold increased risk of experiencing a critical event if classified as a non-transfer. The multivariable regression model showed patients with an Abbreviated Injury Scale (AIS) of 3 was twice as likely to experience a critical event, with an AIS of 4, three times, and 3 times more likely to be classified to transfer. DISCUSSION: The BIGTEX criteria identify a subset of patients who can safely be observed at their local hospital. To confirm the safety and efficacy of this transfer criteria recommendation, a prospective study is warranted.

Essential role of p21Waf1/Cip1 in the modulation of post-traumatic hippocampal Neural Stem Cells response.

BACKGROUND: Traumatic Brain Injury (TBI) represents one of the main causes of brain damage in young people and the elderly population with a very high rate of psycho-physical disability and death. TBI is characterized by extensive cell death, tissue damage and neuro-inflammation with a symptomatology that varies depending on the severity of the trauma from memory loss to a state of irreversible coma and death. Recently, preclinical studies on mouse models have demonstrated that the post-traumatic adult Neural Stem/Progenitor cells response could represent an excellent model to shed light on the neuro-reparative role of adult neurogenesis following damage. The cyclin-dependent kinase inhibitor p21Waf1/Cip1 plays a pivotal role in modulating the quiescence/activation balance of adult Neural Stem Cells (aNSCs) and in restraining the proliferation progression of progenitor cells. Based on these considerations, the aim of this work is to evaluate how the conditional ablation of p21Waf1/Cip1 in the aNSCS can alter the adult hippocampal neurogenesis in physiological and post-traumatic conditions. METHODS: We designed a novel conditional p21Waf1/Cip1 knock-out mouse model, in which the deletion of p21Waf1/Cip1 (referred as p21) is temporally controlled and occurs in Nestin-positive aNSCs, following administration of Tamoxifen. This mouse model (referred as p21 cKO mice) was subjected to Controlled Cortical Impact to analyze how the deletion of p21 could influence the post-traumatic neurogenic response within the hippocampal niche. RESULTS: The data demonstrates that the conditional deletion of p21 in the aNSCs induces a strong increase in activation of aNSCs as well as proliferation and differentiation of neural progenitors in the adult dentate gyrus of the hippocampus, resulting in an enhancement of neurogenesis and the hippocampal-dependent working memory. However, following traumatic brain injury, the increased neurogenic response of aNSCs in p21 cKO mice leads to a fast depletion of the aNSCs pool, followed by declined neurogenesis and impaired hippocampal functionality. CONCLUSIONS: These data demonstrate for the first time a fundamental role of p21 in modulating the post-traumatic hippocampal neurogenic response, by the regulation of the proliferative and differentiative steps of aNSCs/progenitor populations after brain damage.

High-fat diet consumption negatively influences closed-head traumatic brain injury in a pediatric rodent model.

Traumatic brain injury (TBI) is one of the most common causes of emergency room visits in children, and it is a leading cause of death in juveniles in the United States. Similarly, a high proportion of this population consumes diets that are high in saturated fats, and millions of children are overweight or obese. The goal of the present study was to assess the relationship between diet and TBI on cognitive and cerebrovascular outcomes in juvenile rats. In the current study, groups of juvenile male Long Evans rats were subjected to either mild TBI via the Closed-Head Injury Model of Engineered Rotational Acceleration (CHIMERA) or underwent sham procedures. The animals were provided with either a combination of high-fat diet and a mixture of high-fructose corn syrup (HFD/HFCS) or a standard chow diet (CH) for 9 days prior to injury. Prior to injury, the animals were trained on the Morris water maze for three consecutive days, and they underwent a post-injury trial on the day of the injury. Immediately after TBI, the animals' righting reflexes were tested. Four days post-injury, the animals were euthanized, and brain samples and blood plasma were collected for qRT-PCR, immunohistochemistry, and triglyceride assays. Additional subsets of animals were used to investigate cerebrovascular perfusion using Laser Speckle and perform immunohistochemistry for endothelial cell marker RECA. Following TBI, the righting reflex was significantly increased in TBI rats, irrespective of diet. The TBI worsened the rats' performance in the post-injury trial of the water maze at 3 h, p(injury) < 0.05, but not at 4 days post-injury. Reduced cerebrovascular blood flow using Laser Speckle was demonstrated in the cerebellum, p(injury) < 0.05, but not foci of the cerebral cortices or superior sagittal sinus. Immunoreactive staining for RECA in the cortex and corpus callosum was significantly reduced in HFD/HFCS TBI rats, p < 0.05. qRT-PCR showed significant increases in APOE, CREB1, FCGR2B, IL1B, and IL6, particularly in the hippocampus. The results from this study offer robust evidence that HFD/HFCS negatively influences TBI outcomes with respect to cognition and cerebrovascular perfusion of relevant brain regions in the juvenile rat.