Acute Brain Trauma Research Articles

In the mouse cortex, oligodendrocytes regain a plastic capacity, transforming into astrocytes after acute injury.

Acute brain injuries evoke various response cascades directing the formation of the glial scar. Here, we report that acute lesions associated with hemorrhagic injuries trigger a re-programming of oligodendrocytes. Single-cell RNA sequencing highlighted a subpopulation of oligodendrocytes activating astroglial genes after acute brain injuries. By using PLP-DsRed1/GFAP-EGFP and PLP-EGFPmem/GFAP-mRFP1 transgenic mice, we visualized this population of oligodendrocytes that we termed AO cells based on their concomitant activity of astro- and oligodendroglial genes. By fate mapping using PLP- and GFAP-split Cre complementation and repeated chronic invivo imaging with two-photon laser-scanning microscopy, we observed the conversion of oligodendrocytes into astrocytes via the AO cell stage. Such conversion was promoted by local injection of IL-6 and was diminished by IL-6 receptor-neutralizing antibody as well as by inhibiting microglial activation with minocycline. In summary, our findings highlight the plastic potential of oligodendrocytes in acute brain trauma due to microglia-derived IL-6.

Transcranial Doppler ultrasound: Clinical applications from neurological to cardiological setting.

Transcranial Doppler (TCD) ultrasonography is a rapid, noninvasive, real-time, and low-cost imaging technique. It is performed with a low-frequency (2 MHz) probe in order to evaluate the cerebral blood flow (CBF) and its pathological alterations, through specific acoustic windows. In the recent years, TCD use has been expanded across many clinical settings. Actually, the most widespread indication for TCD exam is represented by the diagnosis of paradoxical embolism, due to patent foramen ovale, in young patients with cryptogenic stroke. In addition, TCD has also found useful applications in neurological care setting, including the following: cerebral vasospasm following acute subarachnoid hemorrhage, brain trauma, cerebrovascular atherosclerosis, and evaluation of CBF and cerebral autoregulation after an ischemic stroke event. The present review aimed to describe the most recent evidences of TCD utilization from neurological to cardiological setting.

Evidence of traumatic brain injury in headbutting bovids

Traumatic brain injury (TBI) is a leading cause of neurologic impairment and death that remains poorly understood. Rodent models have yet to produce clinical therapies, and the exploration of larger and more diverse models remains relatively scarce. We investigated the potential for brain injury after headbutting in two combative bovid species by assessing neuromorphology and neuropathology through immunohistochemistry and stereological quantification. Postmortem brains of muskoxen (Ovibos moschatus, n = 3) and bighorn sheep (Ovis canadensis, n = 4) were analyzed by high-resolution MRI and processed histologically for evidence of TBI. Exploratory histological protocols investigated potential abnormalities in neurons, microglia, and astrocytes in the prefrontal and parietal cortex. Phosphorylated tau protein, a TBI biomarker found in the cerebrospinal fluid and in neurodegenerative lesions, was used to detect possible cellular consequences of chronic or acute TBI. MRI revealed no abnormal neuropathological changes; however, high amounts of tau-immunoreactive neuritic thread clusters, neurites, and neurons were concentrated in the superficial layers of the neocortex, preferentially at the bottom of the sulci in the muskoxen and occasionally around blood vessels. Tau-immunoreactive lesions were rare in the bighorn sheep. Additionally, microglia and astrocytes showed no grouping around tau-immunoreactive cells in either species. Our preliminary findings indicate that muskoxen and possibly other headbutting bovids suffer from chronic or acute brain trauma and that the males’ thicker skulls may protect them to a certain extent.

An oligomeric semiconducting nanozyme with ultrafast electron transfers alleviates acute brain injury.

Artificial enzymes have attracted wide interest in disease diagnosis and biotechnology due to high stability, easy synthesis, and cost effectiveness. Unfortunately, their catalytic rate is limited to surface electron transfer, affecting the catalytic and biological activity. Here, we report an oligomeric nanozyme (O-NZ) with ultrafast electron transfer, achieving ultrahigh catalytic activity. O-NZ shows electron transfer of 1.8 nanoseconds in internal cores and 1.2 picoseconds between core and ligand molecule, leading to ultrahigh superoxidase dismutase–like and glutathione peroxidase–like activity (comparable with natural enzyme, Michaelis constant = 0.87 millimolars). Excitingly, O-NZ can improve the 1-month survival rate of mice with acute brain trauma from 50 to 90% and promote the recovery of long-term neurocognition. Biochemical experiments show that O-NZ can decrease harmful peroxide and superoxide via in vivo catalytic chain reaction and reduce acute neuroinflammation via nuclear factor erythroid-2 related factor 2–mediated up-regulation of heme oxygenase-1 expression.

Clinical outcomes and prognostic factors for prolonged mechanical ventilation in patients with acute stroke and brain trauma

Neurological dysfunction is a common condition necessitating prolonged mechanical ventilation (PMV). We investigated the clinical features and outcomes of patients with acute neurological diseases requiring PMV.This retrospective observational study was conducted at the Respiratory Care Center (RCC) of Chang Gung Memorial Hospital, Taiwan, between January 2011 and January 2014. The main outcome was weaning success, defined as successful withdrawal from mechanical ventilator support for more than 5 days.The study included 103 patients with acute stroke and brain trauma receiving PMV. Weaning success was reported in 63 (61%) patients and weaning failure was reported in 40 (39%) patients. Patients in the weaning failure group were older and had a lower RCC Glasgow Coma Scale (GCS) score (6.0 vs 7.9, p = 0.005), lower albumin level (2.8 vs 3.1, p = 0.015), longer RCC stay (28.7 vs 21.3 days, p = 0.017), and higher in-hospital mortality rate (47% vs 9%, p < 0.01). Multivariate analysis revealed that reduced RCC GCS score is an independent prognostic factor for weaning failure (odds ratio [OR] = 1.22, 95% confidence interval [CI] = 1.05-1.46, p = 0.016) and that per unit increase of RCC GCS score is associated with a lower risk of in-hospital mortality (OR = 0.83, 95% CI = 0.70-0.96, p = 0.019).Reduced RCC GCS score is an independent prognostic factor for weaning failure, and is associated with increased in-hospital mortality rates in patients with acute stroke and brain trauma requiring PMV.

Mismatch between Tissue Partial Oxygen Pressure and Near-Infrared Spectroscopy Neuromonitoring of Tissue Respiration in Acute Brain Trauma: The Rationale for Implementing a Multimodal Monitoring Strategy.

The brain tissue partial oxygen pressure (PbtO2) and near-infrared spectroscopy (NIRS) neuromonitoring are frequently compared in the management of acute moderate and severe traumatic brain injury patients; however, the relationship between their respective output parameters flows from the complex pathogenesis of tissue respiration after brain trauma. NIRS neuromonitoring overcomes certain limitations related to the heterogeneity of the pathology across the brain that cannot be adequately addressed by local-sample invasive neuromonitoring (e.g., PbtO2 neuromonitoring, microdialysis), and it allows clinicians to assess parameters that cannot otherwise be scanned. The anatomical co-registration of an NIRS signal with axial imaging (e.g., computerized tomography scan) enhances the optical signal, which can be changed by the anatomy of the lesions and the significance of the radiological assessment. These arguments led us to conclude that rather than aiming to substitute PbtO2 with tissue saturation, multiple types of NIRS should be included via multimodal systemic- and neuro-monitoring, whose values then are incorporated into biosignatures linked to patient status and prognosis. Discussion on the abnormalities in tissue respiration due to brain trauma and how they affect the PbtO2 and NIRS neuromonitoring is given.

Mechanism of Zinc Excitotoxicity: A Focus on AMPK.

Over the last 20 years, it has been shown that complex signaling cascades are involved in zinc excitotoxicity. Free zinc rapidly induces PKC activation, which causes reactive oxygen species (ROS) production at least in part through NADPH oxidase. It also promotes neuronal nitric oxide synthase, thereby increasing nitric oxide (NO) production. Extracellular signal-regulated kinase activation and Egr-1 transcription factor activity were quickly induced by zinc, too. These concurrent actions of kinases consequently produce oxygen free radical, ROS, and NO, which may cause severe DNA damage. Following the excessive activity of poly(ADP-ribose) polymerase-1 depletes NAD+/ATP in the cells. Zinc excitotoxicity exhibits distinct characteristics of apoptosis, too. Activation of caspase-3 is induced by liver kinase B1 (LKB1)-AMP-activated kinase (AMPK)-Bim cascade signaling and induction of p75NTR receptors and p75NTR-associated Death Executor. Thus, zinc excitotoxicity is a mechanism of neuronal cell death showing various cell death patterns. In addition to the above signaling cascades, individual intracellular organelles also play a crucial role in zinc excitotoxicity. Mitochondria and lysosomes function as zinc reservoirs, and as such, are capable of regulating zinc concentration in the cytoplasm. However, when loaded with too much zinc, they may undergo mitochondrial permeability transition pore (mPTP) opening, and lysosomal membrane permeabilization (LMP), both of which are well-established mechanisms of cell death. Since zinc excitotoxicity has been reported to be associated with acute brain injuries, including stroke, trauma, and epilepsy, we performed to find the novel AMPK inhibitors as therapeutic agents for these diseases. Since we thought acute brain injury has complicated neuronal death pathways, we tried to see the neuroprotection against zinc excitotoxicity, calcium-overload excitotoxicity, oxidative damage, and apoptosis. We found that two chemicals showed significant neuroprotection against all cellular neurotoxic models we tested. Finally, we observed the reduction of infarct volume in a rat model of brain injury after middle cerebral artery occlusion (MCAO). In this review, we introduced the AMPK-mediated cell death mechanism and novel strategy for the development of stroke therapeutics. The hope is that this understanding would provide a rationale for acute brain injury and eventually find new therapeutics.

Anatomical and histological observations on a musk ox brain (Ovibos moschatus)

Musk oxen are large tundra‐dwelling bovids that, when in rut, can strike heads at speeds around 30 mph. The wide base of their large horns armor their skull against such impacts, although it is unknown if they sustain brain trauma. There is no literature describing concussion, or other adverse repercussions of severe cranial contact in musk oxen. Our research explores the brain and skull anatomy of combative bovids, specifically focusing on whether these animals sustain brain injury after head‐butting, and if not, what features most likely provide protection. Achieving a better understanding of how these extreme animals may avoid brain injury will provide insight to develop strategies for the reduction of traumatic brain injury in humans.An archived brain of an adult male musk ox was used in this preliminary study. It had been collected after humane euthanasia and preserved in formalin following a goring injury in the wild where it had been observed clashing heads with another musk ox bull in the moments before its death. The brain was MR scanned and examined histologically for evidence of traumatic brain injury. The right hemisphere was fixed in paraformaldehyde (4%, buffered) and prepared using a variety of exploratory histological protocols, to investigate abnormalities in neurons, microglia, astrocytes, and blood vessels. Specifically, Tau protein, a biomarker found in the cerebrospinal fluid and in neurodegenerative lesions, was used to detect any brain trauma‐related cellular consequence of chronic or acute head clashing. Preliminary histological results indicate no apparent abnormalities. A high‐resolution 7‐T MRI scan additionally revealed no abnormal neuropathological changes. This brain being a single sample does not allow us to make sweeping assumptions. However, these preliminary investigations lead us to believe that musk oxen do not appear to suffer from chronic or acute brain trauma after head clashing. A more in‐depth exploration with a larger sample size is proposed to better understand the combination of anatomical structures contributing to brain protection in these animals.Support or Funding InformationNLA is a fellow of the Swiss National Science Foundation

Imaging Cerebral Haemorrhage using MRI: Improved Sensitivity of Susceptibility Weighted Imaging (SWI) Compared to Gradient Echo Sequences (GRE)

Background: The appearance of cerebral haemorrhage (CH) as common MR imaging findings raise the question of how MR image acquisition and haemorrhage area quantification can help in understanding brain pathological changes as the result of various disease conditions such as acute brain injury, hypertension amyloid angiopathy and other diverse pathology. Neuroimaging is essential for the clinician to identify the cause of haemorrhage. In this study, we examined 25 cerebral haemorrhage MR images with an objective of comparing two different sequences viz., susceptibility weighted imaging (SWI) and gradient recalled echo (GRE) on same patients and also to quantify the area of haemorrhage using manual selection and gray area threshold (automated selection) in the digital image. Materials and Methods: In this prospective study, MR images were acquired from 25 subjects with acute brain trauma (16) , hypertension (5), and amyloid angiopathy (4), using SWI and GRE MR Sequences, with section thicknesses (3- 5 mm), and magnetic field strengths (1.5T). Individual CH was manually identified and analyzed for haemorrhage area using signal intensity changes by manual and automatic selection of binary threshold hypointense signal by ImageJ software package. Results: By other parameters set as constant, we were able to quantify hypointense signal changes at regions of cerebral haemorrhage on SWI when compared to no such notable changes in GRE in the case of amyloid angiopathy patients. Apart from this, lesions prospectively identified on SWI had a significantly greater area measured on the SWI image than those not prospectively identified on GRE. Conclusions: There is an increased sensitivity in the CH detection in patients with amyloid angiopathy while using SWI sequence when compared to GRE in which we could not identify any signal changes in specific areas. Furthermore, the haemorrhage areas quantified by an automated cropping technique using ImageJ software yielded a precise lesion area method when compared to manual cropping. However, observation on increased sample size in this disease condition is required to confirm these preliminary findings to prognosticate CH.

Prognostic Value of Spreading Depolarizations in Patients With Severe Traumatic Brain Injury

Advances in treatment of traumatic brain injury are hindered by the inability to monitor pathological mechanisms in individual patients for targeted neuroprotective treatment. Spreading depolarizations, a mechanism of lesion development in animal models, are a novel candidate for clinical monitoring in patients with brain trauma who need surgery. To test the null hypothesis that spreading depolarizations are not associated with worse neurologic outcomes. This prospective, observational, multicenter cohort study was conducted from February 2009 to August 2013 in 5 level 1 trauma centers. Consecutive patients who required neurological surgery for treatment of acute brain trauma and for whom research consent could be obtained were enrolled; participants were excluded because of technical problems in data quality, patient withdrawal, or loss to follow-up. Primary statistical analysis took place from April to December 2018. Evaluators of outcome assessments were blinded to other measures. A 6-contact electrode strip was placed on the brain surface during surgery for continuous electrocorticography during intensive care. Electrocorticography was scored for depolarizations, following international consensus procedures. Six-month outcomes were assessed by the Glasgow Outcome Scale-Extended score. A total of 157 patients were initially enrolled; 19 were subsequently excluded. The 138 remaining patients (104 men [75%]; median [interquartile range] age, 45 [29-64] years) underwent a median (interquartile range) of 75.5 (42.2-117.1) hours of electrocorticography. A total of 2837 spreading depolarizations occurred in 83 of 138 patients (60.1% incidence) who, compared with patients who did not have spreading depolarizations, had lower prehospital systolic blood pressure levels (mean [SD], 133 [31] mm Hg vs 146 [33] mm Hg; P = .03), more traumatic subarachnoid hemorrhage (depolarization incidences of 17 of 37 [46%], 18 of 32 [56%], 22 of 33 [67%], and 23 of 30 patients [77%] for Morris-Marshall Grades 0, 1, 2, and 3/4, respectively; P = .047), and worse radiographic pathology (in 38 of 73 patients [52%] and 42 of 60 patients [70%] for Rotterdam Scores 2-4 vs 5-6, respectively; P = .04). Of patients with depolarizations, 32 of 83 (39%) had only sporadic events that induced cortical spreading depression of spontaneous electrical activity, whereas 51 of 83 patients (61%) exhibited temporal clusters of depolarizations (≥3 in a 2-hour span). Nearly half of those with clusters (23 of 51 [45%]) also had depolarizations in an electrically silent area of the cortex (isoelectric spreading depolarization). Patients with clusters did not improve in motor neurologic examinations from presurgery to postelectrocorticography, while other patients did improve. In multivariate ordinal regression adjusting for baseline prognostic variables, the occurrence of depolarization clusters had an odds ratio of 2.29 (95% CI, 1.13-4.65; P = .02) for worse outcomes. In this cohort study of patients with acute brain trauma, spreading depolarizations were predominant but heterogeneous and independently associated with poor neurologic recovery. Monitoring the occurrence of spreading depolarizations may identify patients most likely to benefit from targeted management strategies.

The Notch pathway in CNS homeostasis and neurodegeneration.

The role of the Notch signaling pathway in neural development has been well established over many years. More recent studies, however, have demonstrated that Notch continues to be expressed and active throughout adulthood in many areas of the central nervous system. Notch signals have been implicated in adult neurogenesis, memory formation, and synaptic plasticity in the adult organism, as well as linked to acute brain trauma and chronic neurodegenerative conditions. NOTCH3 mutations are responsible for the most common form of hereditary stroke, the progressive disorder cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Notch has also been associated with several progressive neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Although numerous studies link Notch activity with CNS homeostasis and neurodegenerative diseases, the data thus far are primarily correlative, rather than functional. Nevertheless, the evidence for Notch pathway activity in specific neural cellular contexts is strong, and certainly intriguing, and points to the possibility that the pathway carries therapeutic promise. This article is categorized under: Nervous System Development > Flies Signaling Pathways > Cell Fate Signaling Nervous System Development > Vertebrates: General Principles.

Association of Increased Serum S100B Levels With High School Football Subconcussive Head Impacts.

Astrocyte-enriched marker, S100B, shows promise for gauging the severity of acute brain trauma, and understanding subconcussive effects will advance its utility in tracking real-time acute brain damage. The aim of the study was to investigate whether serum S100B elevations were associated with frequency and magnitude of subconcussive head impacts in adolescents. This prospective cohort study of 17 high-school football players consisted of the following 12 time points: pre-season baseline, 5 in-season pre-post games, and post-season. A sensor-installed mouthguard recorded the number of head impacts, peak linear (PLA) and peak rotational (PRA) head accelerations from every practice and game. During the 5 games, players wore chest-strap heart-rate monitors to estimate players' excess post-exercise oxygen consumption (EPOC), accounting for physical exertion effects. At each time point, blood samples were obtained and assessed for S100B and creatine kinase levels to account for astrocyte damage/activation and muscle damage, respectively. Using k-means clustering on the impact data, players were categorized into high- or low-impact group. Two players withdrew during the first month of the study. A total of 156 blood samples from 15 players were assessed for S100B and creatine kinase levels and included in the analysis. A median value of 596 head impacts from 15 players were recorded during all practices and games in a season. S100B levels were significantly elevated in all post-game measures compared with the respective pre-game values (median-increase, 0.022 μg/L; interquartile-range, 0.011–0.043 μg/L, p < 0.05 for all games). Greater acute S100B increases were significantly associated with greater impact frequency, sum of PLA and PRA, with negligible contributions from physical exertion and muscle damage effects. The high-impact group exhibited greater increases in serum S100B levels at post-games than the low-impact group (high vs. low, 0.043 ± 0.035 μg/L vs. 0.019 ± 0.017 μg/L, p = 0.002). The degree of acute S100B increases was correlated with subconcussive head impact exposure, suggesting that acute astrocyte damage may be induced in an impact-dependent manner. Acute changes in serum S100B levels may become a useful tool in monitoring real-time brain damage in sports.

Abstract WP334: Brain Permeable Iron Chelator HBED Improves White Matter Integrity After Traumatic Brain Injury

Introduction: Traumatic brain injury (TBI) contributes significantly to the overall disabilities and mortality in the United States and worldwide. Many distinct pathophysiological processes follow brain trauma. Iron is postulated to contribute majorly to the secondary cascades after TBI. Therefore, the use of a potent iron chelator like N,N'-Di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid monohydrochloride (HBED) which has higher affinity, better permeability to BBB and longer half-life than most of the commonly used chelators is expected to improve outcomes after TBI. Methods: a controlled-cortical impact model of traumatic brain injury (TBI) was induced in two groups of WT male mice at 4.0±0.5mo of age (n=12/group). Mice were subcutaneously injected with HBED immediately after TBI, then at 12h after, followed by a twice-a-day regimen until the 3d end-point. Results: In addition to the overall anatomical and functional benefits, HBED-treated mice show a significantly thicker, more intact corpus callosum when compared with vehicle control mice (p&lt;0.05). HBED mice also demonstrate a significant decrease in Iba1 expression in the body of the corpus callosum when compared to controls (p&lt;0.05). More testing for the effect of HBED on iron susceptible oligodendrocyte and white matter affected proteins is under currently under investigation. Conclusion: HBED uniquely protects and maintains the integrity of the corpus callosum. This beneficial effect appears to be mediated through decreasing microglial activation and preserving the anatomical structure of corpus callosum. Such effects are being added to the previously published work on HBED role in mitigating oxidative stress injury and inflammation after TBI. HBED is clinically tested and proven to be safe in humans; thus, further strengthening its possible clinical use after acute brain trauma. [This work was supported in part by grants from the McKnight Brain Research Foundation, Brain and Spinal Cord Injury Research Trust Fund, AHA33450010, and NIH R21NS095166 (SD).]

Biomarkers in acute brain trauma: A narrative review

Biomarkers have been used to diagnose, prognose, evaluate, and identify the severity and outcomes in traumatic brain injury (TBI) patients. This study explored if it is possible to predict the outcome of TBI patients by estimating the biomarkers in cerebrospinal fluid and serum. We searched data bases and literature about biomarkers, and found forty epidemiologic studies from 92 potentially relevant articles. However, limited data are available about postanoxic encephalopathy. It showed that presently, neurofilament, S100B, glial fibrillary acidic protein, and ubiquitin carboxyl terminal hydrolase-L1 seemed to have the best potential as diagnostic biomarkers for distinguishing focal and diffuse injury, whereas C-Tau, neuron-specific enolase, S100B, glial fibrillary acidic protein, and spectrin breakdown products appear to be candidates for reflective biomarkers of TBI. Point-of-care biomarkers are needed in TBI which is one of the most important additional risk factors in road traffic injuries. In a holistic approach, more researches about biomarkers of TBI are required. These biomarkers are very useful for treatment of patients with TBI.

Neuroprotective effects of progesterone in acute brain trauma and its physiological mechanism

Traumatic brain injury (TBI) is the leading cause of death and neurological disability in young adults worldwide. This work aims to review the role of progesterone in traumatic brain injury and the usefulness as a possible treatment. We searched pubmed database (2000-2017) for articles containing “progesterone and brain traumatic injury”. Basic science studies have advanced knowledge of the mechanisms of secondary brain injury, creating prospects for the medical and pharmacological management of TBI. Although several comparative studies evaluated both the efficacy and safety of several groups of drugs, in which, corticosteroids, tranexamic acid, β receptor antagonists, erythropoiesis-stimulating agents, reductase inhibitors include hydroxymethyl glutaryl-CoA inhibitors (statins), among others. Several studies even evaluated the role of progesterone in the treatment of TBI, which is providing growing evidence about its potential neuroprotective mechanisms during the acute phase of trauma. Despite recent advances in the field of management of TBI care in the emergency units, intensive care and the multiple trials for more than 20 years to find useful pharmacological treatments, most of these efforts failed in pre-clinical stages (II and III).

Detection of American Football Head Impacts Using Biomechanical Features and Support Vector Machine Classification

Accumulation of head impacts may contribute to acute and long-term brain trauma. Wearable sensors can measure impact exposure, yet current sensors do not have validated impact detection methods for accurate exposure monitoring. Here we demonstrate a head impact detection method that can be implemented on a wearable sensor for detecting field football head impacts. Our method incorporates a support vector machine classifier that uses biomechanical features from the time domain and frequency domain, as well as model predictions of head-neck motions. The classifier was trained and validated using instrumented mouthguard data from collegiate football games and practices, with ground truth data labels established from video review. We found that low frequency power spectral density and wavelet transform features (10~30 Hz) were the best performing features. From forward feature selection, fewer than ten features optimized classifier performance, achieving 87.2% sensitivity and 93.2% precision in cross-validation on the collegiate dataset (n = 387), and over 90% sensitivity and precision on an independent youth dataset (n = 32). Accurate head impact detection is essential for studying and monitoring head impact exposure on the field, and the approach in the current paper may help to improve impact detection performance on wearable sensors.

Neuroinflammation and neurosteroidogenesis: Reciprocal modulation during injury to the adult zebra finch brain

Estrogens like estradiol (E2) via their receptors are pluripotent steroid hormones that exert a profound influence on the developing and adult brain in many vertebrates. In songbirds and mammals, acute brain injury resulting from mechanical damage, anoxia and ischemia rapidly upregulates aromatase and E2 synthesis. Interestingly, this E2 provision occurs due to the induction of aromatase expression in reactive astrocytes in areas surrounding brain injury. The resultant increase in E2 is neuroprotective with established influences on apoptosis, gliosis, cytogenesis, neurogenesis and neuroinflammation. Correspondingly, E2 decreases secondary damage following acute brain trauma and may improve recovery. Until very recently however, the signals responsible for the induction of astrocytic aromatase expression in reactive astrocytes were unknown. In the current review, we discuss what is known about the role of astrocytic E2 in neuroprotection with a particular emphasis on a recently discovered interaction between neuroinflammatory and steroidogenic signaling in the zebra finch. We first describe the role of acute inflammatory signaling in the regulation of astrocytic aromatase and central E2 levels. Next, we discuss the emerging role of central E2 in the control of chronic neuroinflammation. Finally, we provide a framework for further work investigating the important role of the interaction between inflammatory and steroidogenic signaling in the protection of neural circuits and behavior following traumatic brain injury (TBI). We also highlight dimorphisms that point to important aspects of sex-specific pathways that underlie the interactions of neuroinflammation and neurosteroidogenesis.

The Role of the Oligodendrocyte Lineage in Acute Brain Trauma.

An acute brain injury is commonly characterized by an extended cellular damage. The post-injury process of scar formation is largely determined by responses of various local glial cells and blood-derived immune cells. The role of astrocytes and microglia have been frequently reviewed in the traumatic sequelae. Here, we summarize the diverse contributions of oligodendrocytes (OLs) and their precursor cells (OPCs) in acute injuries. OLs at the lesion site are highly sensitive to a damaging insult, provoked by Ca2+ overload after hyperexcitation originating from increased levels of transmitters. At the lesion site, differentiating OPCs can replace injured oligodendrocytes to guarantee proper myelination that is instrumental for healthy brain function. In contrast to finally differentiated and non-dividing OLs, OPCs are the most proliferative cells of the brain and their proliferation rate even increases after injury. There exist even evidence that OPCs might also generate some type of astrocyte beside OLs. Thereby, OPCs can contribute to the generation and maintenance of the glial scar. In the future, detailed knowledge of the molecular cues that help to prevent injury-evoked glial cell death and that control differentiation and myelination of the oligodendroglial lineage will be pivotal in developing novel therapeutic approaches.

Acute brain trauma, lung injury, and pneumonia: more than just altered mental status and decreased airway protection.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Even when patients survive the initial insult, there is significant morbidity and mortality secondary to subsequent pulmonary edema, acute lung injury (ALI), and nosocomial pneumonia. Whereas the relationship between TBI and secondary pulmonary complications is recognized, little is known about the mechanistic interplay of the two phenomena. Changes in mental status secondary to acute brain injury certainly impair airway- and lung-protective mechanisms. However, clinical and translational evidence suggests that more specific neuronal and cellular mechanisms contribute to impaired systemic and lung immunity that increases the risk of TBI-mediated lung injury and infection. To better understand the cellular mechanisms of that immune impairment, we review here the current clinical data that support TBI-induced impairment of systemic and lung immunity. Furthermore, we also review the animal models that attempt to reproduce human TBI. Additionally, we examine the possible role of damage-associated molecular patterns, the chlolinergic anti-inflammatory pathway, and sex dimorphism in post-TBI ALI. In the last part of the review, we discuss current treatments and future pharmacological therapies, including fever control, tracheostomy, and corticosteroids, aimed to prevent and treat pulmonary edema, ALI, and nosocomial pneumonia after TBI.

Spreading depolarization monitoring in neurocritical care of acute brain injury.

Spreading depolarizations are unique in being discrete pathologic entities that are well characterized experimentally and also occur commonly in patients with substantial acute brain injury. Here, we review essential concepts in depolarization monitoring, highlighting its clinical significance, interpretation, and future potential. Cortical lesion development in diverse animal models is mediated by tissue waves of mass spreading depolarization that cause the toxic loss of ion homeostasis and limit energy substrate supply through associated vasoconstriction. The signatures of such deterioration are observed in electrocorticographic recordings from perilesional cortex of patients with acute stroke or brain trauma. Experimental work suggests that depolarizations are triggered by energy supply-demand mismatch in focal hotspots of the injury penumbra, and depolarizations are usually observed clinically when other monitoring variables are within recommended ranges. These results suggest that depolarizations are a sensitive measure of relative ischemia and ongoing secondary injury, and may serve as a clinical guide for personalized, mechanistically targeted therapy. Both existing and future candidate therapies offer hope to limit depolarization recurrence. Electrocorticographic monitoring of spreading depolarizations in patients with acute brain injury provides a sensitive measure of relative energy shortage in focal, vulnerable brains regions and indicates ongoing secondary damage. Depolarization monitoring holds potential for targeted clinical trial design and implementation of precision medicine approaches to acute brain injury therapy.