Acute Phase Of Traumatic Brain Injury Research Articles

Investigating the Effect of High-Dose Vitamin D3 Administration on Inflammatory Biomarkers in Patients with Moderate to Severe Traumatic Brain Injury: A Randomized Clinical Trial.

Traumatic brain injury (TBI) is one of the most common neurological disorders worldwide. We aimed to investigate the efficacy of high-dose vitamin D3 on inflammatory biomarkers in patients with moderate to severe TBI. Thirty-five moderate to severe TBI patients were randomly assigned to intervention and control groups. Patients in the intervention group received a single intramuscular (IM) dose of 300,000 IU vitamin D. The primary endpoints were interleukin levels (IL-1β and IL-6), and the secondary endpoints were changes in neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), Glasgow Coma scale (GCS), and Glasgow Outcome Scale-Extended (GOS-E) scores compared between intervention and control arms of the study. The linear Generalized Estimating Equations were used for trend analysis and evaluating the association of independent factors to each outcome. The results revealed a significant decrease in IL-1β levels (-2.71±3.02, in the intervention group: P=0.001 vs. -0.14±3.70, in the control group: P=0.876) and IL-6 (-88.05±148.45, in the intervention group: P=0.0001 vs. -35.54±175.79, in the control groupL P=0.325) 3 days after the intervention. The improvement in the GCS score (P=0.001), reduction in NLR (P=0.001) and PLR (P=0.002), and improvement in the GOS-E score (P=0.039) was found to be greater in the vitamin D3 arm of the study than the control group. Administration of high-dose vitamin D3 in the acute phase of TBI could be effective in lowering the inflammatory markers and improving the level of consciousness and long-term performance outcomes.Trial Registration Number: IRCT20180522039777N2.

Traumatic brain injury and prolactin.

Traumatic brain injury (TBI) is a well-known etiologic factor for pituitary dysfunctions, with a prevalence of 15% during long-term follow-up. The most common hormonal disruption is growth hormone deficiency, followed by central adrenal insufficiency, central hypogonadism, and central hypothyroidism in varying order across studies. The prevalence of serum prolactin disturbances ranged widely from 0 to 85%. Prolactin release is mainly regulated by hypothalamic dopamine inhibition, and mediators such as TRH, serotonin, cytokines, and neurotransmitters have modulatory effects. Many factors, such as hypothalamic and/or pituitary gland injuries, as well as fluctuations in dopaminergic activity and other mediators and stress response, may cause derangements in serum prolactin levels after TBI. Although it is challenging to investigate the direct effects of TBI on serum prolactin levels due to many confounders, basal prolactin measurements and stimulation tests provide insight into the functionality of the hypothalamus and pituitary gland after TBI. Moreover, during the acute phase of TBI, prolactin levels appear to correlate with TBI severity. In contrast, in the chronic phase, hypoprolactinemia may function as an indirect indicator of pituitary dysfunction and reduced pituitary volume. Further investigations are needed to elucidate the pathophysiologic mechanisms underlying the prolactin trend following TBI, its significance, and its associations with other pituitary hormone dysfunctions. In this article, we re-evaluated our patients' TBI data regarding prolactin levels during prospective long-term follow-up, and reviewed the literature regarding the prevalence, pathophysiology, and clinical implications of serum prolactin disturbances during acute and chronic phases following TBI.

CGRP as a potential mediator for the sexually dimorphic responses to traumatic brain injury

BackgroundThe outcomes of traumatic brain injury (TBI) exhibit variance contingent upon biological sex. Although female sex hormones exert neuroprotective effects, the administration of estrogen and progesterone has not yielded conclusive results. Hence, it is conceivable that additional mediators, distinct from female sex hormones, merit consideration due to their potential differential impact on TBI outcomes. Calcitonin gene-related peptide (CGRP) exhibits sexually dimorphic expression and demonstrates neuroprotective effects in acute brain injuries. In this study, we aimed to examine sex-based variations in TBI structural and functional outcomes with respect to CGRP expression.MethodsMale and female Sprague Dawley rats were exposed to controlled cortical impact to induce severe TBI, followed by interventions with and without CGRP inhibition. In the acute phase of TBI, the study centered on elucidating the influence of CGRP on oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) and endothelial nitric oxide synthase (eNOS) signaling in the peri-impact tissue. Subsequently, during the chronic phase of TBI, the investigation expanded to evaluate CGRP expression in relation to lesion volume, microvascular dysfunction, and white matter injury, as well as working and spatial memory, anxiety-like, and depression-like behaviors in subjects of both sexes.ResultsFemale rats exhibited elevated levels of CGRP in the peri-impact brain tissue during both baseline conditions and in the acute and chronic phases of TBI, in comparison to age-matched male counterparts. Enhanced CGRP levels in specific brain sub-regions among female rats correlated with superior structural and functional outcomes following TBI compared to their male counterparts. CGRP inhibition induced heightened oxidative stress and a reduction in the expression of Nrf2 and eNOS in both male and female rats, with the observed alteration being more pronounced in females than in males.ConclusionsThis study marks the inaugural identification of CGRP as a downstream mediator contributing to the sexually dimorphic response observed in TBI outcomes.

Role of mitochondrial dysfunction in acute traumatic brain injury: Evidence from bioinformatics analysis

BackgroundThe intricate regulatory relationship between mitochondrial dysfunction, apoptosis, and immune cells remains largely elusive following traumatic brain injury (TBI). MethodsThe GSE45997 dataset from the Gene Expression Omnibus database and utilized GEO2R to screen for differentially expressed genes (DEGs). Functional enrichment analyses were performed. Mitochondrial gene data from the MitoCarta3.0 database were combined with the DEGs to identify mitochondria-related DEGs (MitoDEGs). The hub MitoDEGs related to apoptosis were further screened. Animal models of TBI were established to investigate the mechanisms underlying mitochondrial dysfunction regulation of apoptosis. Furthermore, we explored the relationship between MitoDEGs/hub MitoDEGs and immune cells using the Spearman correlation method. ResultsFifty-seven MitoDEGs were significantly enriched in pathways related to fatty acid degradation and metabolism. We identified three upregulated hub MitoDEGs, namely Dnm1l, Mcl1 and Casp3, were associated with apoptosis. In the animal experiments, we observed significant expression levels of microtubule-associated protein 1 light chain 3 beta (LC3B) surrounding the injury site. Most LC3B-expressing cells exhibited positive staining for Beclin 1 and colocalization analysis revealed the simultaneous presence of Beclin 1 and caspase-3. The Western blot analysis further unveiled a significant upregulation of cleaved caspase-3 levels and LC3B II/LC3B I ratio after TBI. Moreover, the quantity of myeloid cell leukaemia-1 immunoreactive cells was notably higher than that in the control group. Spearman correlation analysis demonstrated strong associations between plasma cells, marginal zone B cells, native CD4 T cells, monocytes, and MitoDEGs/hub MitoDEGs. ConclusionsThis study sheds light on enhanced fatty acid metabolism following mitochondrial dysfunction and its potential association with apoptosis and immune cell activation, thereby providing new mechanistic insights into the acute phase of TBI.

Computed Tomography of Cerebral Contusions in Children Younger Than 3 Years

Background: Cerebral contusions occur in approximately 43% of blunt head trauma cases. The gyri are predominantly affected, although severe traumatic brain injury (TBI) may damage the subcortical white matter and deep structures within the brain. Computed tomography (CT) of the brain is used to evaluate all forms of intracranial injuries, fractures, cerebral edema, and other associated injuries.Objective: To analyze the CT potential in the diagnosis of cerebral contusions during the acute phase of TBI in children younger than 3 years.Materials and methods: In 2021-2022 we performed CT using a Philips Ingenuity Elite 128 slice CT scanner in 1334 children with TBI (730 boys and 604 girls younger than 3 years). The area of interest in the examined children was the skull and cervical spine. We did not use enhancement. The effective dose range varied from 1.27 to 1.91 mSv.Results: Of 510 children, 448 (87.84%) patients had skull fractures that combined with intracranial injuries in 366 (81.7%) children, with 262 (71.58%) of them having severe injuries (Glasgow Coma Scale ≤ 8) and 36 (9.83%) of them undergoing surgery. Cerebral contusions were diagnosed in 58.5% (214 of 366) of children. Contusions (98% of which were hemorrhagic) had different volumes and degrees of hemorrhage and edema. The foci of contusions were in the frontal (37.1%), temporal (34.3%), parietal (20.6%), and, less often, occipital (8%) lobes.Conclusions: CT is the preferred imaging modality in acute TBI, which enables to accurately detect and adequately treat cerebral contusions, preventing secondary injuries. CT is the main diagnostic tool and should be performed in all children with TBI within the first hours after injury.

Metabotropic glutamate receptor 5 promotes blood-brain barrier recovery after traumatic brain injury

Blood-brain barrier (BBB) impairment and glutamate release are two pathophysiological features of traumatic brain injury (TBI), contributing to secondary brain damage and neuroinflammation. However, our knowledge of BBB integrity damage and dysfunction are still limited due to the diverse and fluctuating expression of glutamate receptors after trauma. Here, we confirmed the downregulation of metabotropic glutamate receptor 5 (mGluR5) on microvascular endothelial cell within the acute phase of TBI, and the recovered mGluR5 levels on BBB was positively associated with blood perfusion and neurological recovery. In whole body mGluR5-knockout mice, BBB dysfunction and neurological deficiency were exacerbated after TBI compared with wild type mice. In terms of mechanism, the amino acid sequence 201–259 of cytoskeletal protein Alpha-actinin-1 (ACTN1) interacted with mGluR5, facilitating mGluR5 translocation from cytoplasmic compartment to plasma membrane in endothelial cells. Activation of plasma membrane mGluR5 triggers the PLC/PKCμ/c-Jun signaling pathway, leading to increased expression of the tight junction-actin cytoskeleton connecting protein zonula occludens-1 (ZO-1). Our findings uncover a novel mechanism mediated by membrane and cytoplasmic mGluR5 in endothelial cell integrity maintenance and repair, providing the potential therapeutic target for TBI treatment targeting at mGluR5 and mGluR5/ACTN1 complex in BBB.

HET0016 inhibits neuronal pyroptosis in the immature brain post-TBI via the p38 MAPK signaling pathway

Traumatic brain injury (TBI) is a serious health threat worldwide, especially for the younger demographic. Our previous study demonstrated that HET0016 (a specific inhibitor of 20-hydroxyeicosatetraenoic acid synthesis) can decrease the lesion volume in the immature brain post-TBI; however, its mechanism of action and its association with pyroptosis post-TBI are unclear. In this study, we established a controlled cortical impact (CCI) injury rat model (postnatal day 9–10) and observed that increased expression of indicators for pyroptosis, including NLR family pyrin domain containing 3 (NLRP3), caspase-1 and gasdermin D (GSDMD) proteins and interleukin (IL)-18/IL-1β mRNA during the acute phase of TBI, especially on post-injury day (PID) 1. Additionally, we found that caspase-1 was primarily expressed in the neurons and microglia. HET0016 (1 mg/kg/d, ip, 3 consecutive days since TBI) reduced the lesion volume; neuronal death; expression of NLRP3, caspase-1, and GSDMD; and expression of IL-18/IL-1β mRNA. Bioinformatics analysis suggested involvement of mitogen-activated protein kinase (MAPK) signaling pathway in the HET0016-mediated neuroprotective role against TBI in the immature brain. Western blot analysis revealed reduced expression of p-p38 MAPK and nuclear factor-kappa B (NF-κB) p65 in the neurons and microglia upon HET0016 treatment in TBI rats. In cultured primary cortical neurons subjected to oxygen-glucose deprivation/re-oxygenation (OGD) + (lipopolysaccharide) LPS, HET0016-induced the reduction of p-p38 MAPK, NLRP3, cleaved-caspase-1, GSDMD, IL-18, and IL-1β was reversed by co-treatment with p38 MAPK activator as well as NLRP3 agonist. Therefore, we conclude that pyroptosis is involved in neuronal death in the immature brains post-TBI and that HET0016 administration can alleviate neuronal pyroptosis possibly via inhibiting the phosphorylation of p38 MAPK.

Pre-traumatic antibiotic-induced microbial depletion reduces neuroinflammation in acute murine traumatic brain injury

The connection between dysbiosis of the gut microbiome and diseases and injuries of the brain has attracted considerable interest in recent years. Interestingly, antibiotic-induced microbial dysbiosis has been implicated in the pathogenesis of traumatic brain injury (TBI), while early administration of antibiotics associates with improved survival in TBI patients. In animal models of TBI, short- or long-term administration of antibiotics, both peri- or post-operatively, were shown to induce gut microbiome dysbiosis but also anti-inflammatory and neuroprotective effects. However, the acute consequences of microbial dysbiosis on TBI pathogenesis after discontinuation of antibiotic treatment are elusive. In this study, we tested whether pre-traumatic antibiotic-induced microbial depletion by vancomycin, amoxicillin, and clavulanic acid affects pathogenesis during the acute phase of TBI in adult male C57BL/6 mice. Pre-traumatic microbiome depletion did not affect neurological deficits over 72 h post injury (hpi) and brain histopathology, including numbers of activated astrocytes and microglia, at 72 hpi. However, astrocytes and microglia were smaller after pre-traumatic microbiome depletion compared to vehicle treatment at 72 hpi, indicating less inflammatory activation. Accordingly, TBI-induced gene expression of the inflammation markers Interleukin-1β, complement component C3, translocator protein TSPO and the major histocompatibility complex MHC2 was attenuated in microbiome-depleted mice along with reduced Immunoglobulin G extravasation as a proxy of blood-brain barrier (BBB) impairment. These results suggest that the gut microbiome contributes to early neuroinflammatory responses to TBI but does not have a significant impact on brain histopathology and neurological deficits.This article is part of the Special Issue on “Microbiome & the Brain: Mechanisms & Maladies”.

Roles of Astrocytic Endothelin ETB Receptor in Traumatic Brain Injury.

Traumatic brain injury (TBI) is an intracranial injury caused by accidents, falls, or sports. The production of endothelins (ETs) is increased in the injured brain. ET receptors are classified into distinct types, including ETA receptor (ETA-R) and ETB receptor (ETB-R). ETB-R is highly expressed in reactive astrocytes and upregulated by TBI. Activation of astrocytic ETB-R promotes conversion to reactive astrocytes and the production of astrocyte-derived bioactive factors, including vascular permeability regulators and cytokines, which cause blood-brain barrier (BBB) disruption, brain edema, and neuroinflammation in the acute phase of TBI. ETB-R antagonists alleviate BBB disruption and brain edema in animal models of TBI. The activation of astrocytic ETB receptors also enhances the production of various neurotrophic factors. These astrocyte-derived neurotrophic factors promote the repair of the damaged nervous system in the recovery phase of patients with TBI. Thus, astrocytic ETB-R is expected to be a promising drug target for TBI in both the acute and recovery phases. This article reviews recent observations on the role of astrocytic ETB receptors in TBI.

Neurointensive Care of Traumatic Brain Injury Patients Based on Coagulation and Fibrinolytic Parameter Monitoring.

Coagulopathy, a common complication of traumatic brain injury (TBI), is characterized by a hypercoagulable state developing immediately after injury, with hyperfibrinolysis and bleeding tendency peaking 3 h after injury, followed by fibrinolysis shutdown. Reflecting this timeframe, the coagulation factor fibrinogen is first consumed and then degraded after TBI, its concentration rapidly decreasing by 3 h post-TBI. The fibrinolytic marker D-dimer reaches its maximum concentration at the same time. Hyperfibrinolysis in the acute phase of TBI is associated with poor prognosis via hematoma expansion. In the acute phase, the coagulation and fibrinolysis parameters must be monitored to determine the treatment strategy. The combination of D-dimer plasma level at admission and the level of consciousness upon arrival at the hospital can be used to predict the patients who will "talk and deteriorate." Fibrinogen and D-dimer levels should determine case selection and the amount of fresh frozen plasma required for transfusion. Surgery around 3 h after injury, when fibrinolysis and bleeding diathesis peak, should be avoided if possible. In recent years, attempts have been made to estimate the time of injury from the time course of coagulation and fibrinolysis parameter levels, which has been particularly useful in some cases of pediatric abusive head trauma patients.

Surface-fill H2S-releasing silk fibroin hydrogel for brain repair through the repression of neuronal pyroptosis

Traumatic brain injury (TBI) remains the major cause of disability and mortality worldwide due to the persistent neuroinflammation and neuronal death induced by TBI. Among them, pyroptosis, a specific type of programmed cell death (PCD) triggered by inflammatory signals, plays a significant part in the pathological process after TBI. Inhibition of neuroinflammation and pyroptosis is considered a possible strategy for the treatment of TBI. In our previous study, exogenous hydrogen sulfide(H2S) exerted a neuroprotective effect after TBI. Here, we developed a surface-fill H2S-releasing silk fibroin (SF) hydrogel (H2S@SF hydrogel) to achieve small-dose local administration and avoid volatile and toxic side effects. We used a controlled cortical impact (CCI) to establish a mild TBI model in mice to examine the effect of H2S@SF hydrogel on TBI-induced pyroptosis. We found that H2S@SF hydrogel inhibited the expression of H2S synthase in neurons after TBI and significantly inhibited TBI-induced neuronal pyroptosis. In addition, immunofluorescence staining results showed that the necroptosis protein receptor-interacting serine/threonine-protein kinase 1 (RIPK1) partially colocalized with the pyroptosis protein Gasdermin D (GSDMD) in the same cells. H2S@SF hydrogel can also inhibit the expression of the necroptosis protein. Moreover, H2S@SF hydrogel also alleviates brain edema and the degree of neurodegeneration in the acute phase of TBI. The neuroprotective effect of H2S@SF hydrogel was further confirmed by wire-grip test, open field test, Morris water maze, beam balance test, radial arm maze, tail suspension, and forced swimming test. Lastly, we also measured spared tissue volume, reactive astrocytes and activated microglia to demonstrate H2S@SF hydrogel impacts on long-term prognosis in TBI. Our study provides a new theoretical basis for the treatment of H2S after TBI and the clinical application of H2S@SF hydrogel. Statement of significanceSilk fibroin (SF) hydrogel controls the release of hydrogen sulfide (H2S) to inhibit neuronal pyroptosis and neuroinflammation in injured brain tissue. In this study, we synthesized a surface-fill H2S-releasing silk fibroin hydrogel, which could slowly release H2S to reshape the homeostasis of endogenous H2S in injured neurons and inhibit neuronal pyroptosis in a mouse model of traumatic brain injury. Meanwhile, H2S@SF hydrogel could alleviate brain edema and the degree of neurodegeneration, improve motor dysfunction, anxious behavior and memory impairment caused by TBI, reduce tissue loss and ameliorate neuroinflammation. Our study provides a new theoretical basis for the treatment of H2S after TBI and the clinical application of H2S@SF hydrogel.

Hyperfibrinolysis and fibrinolysis shutdown in patients with traumatic brain injury

Traumatic brain injury (TBI) is associated with coagulation/fibrinolysis disorders. We retrospectively evaluated 61 TBI cases transported to hospital within 1 h post-injury. Levels of thrombin-antithrombin III complex (TAT), D-dimer, and plasminogen activator inhibitor-1 (PAI-1) were measured on arrival and 3 h, 6 h, 12 h, 1 day, 3 days and 7 days after injury. Multivariate logistic regression analysis was performed to identify prognostic factors for coagulation and fibrinolysis. Plasma TAT levels peaked at admission and decreased until 1 day after injury. Plasma D-dimer levels increased, peaking up to 3 h after injury, and decreasing up to 3 days after injury. Plasma PAI-1 levels increased up to 3 h after injury, the upward trend continuing until 6 h after injury, followed by a decrease until 3 days after injury. TAT, D-dimer, and PAI-1 were elevated in the acute phase of TBI in cases with poor outcome. Multivariate logistic regression analysis showed that D-dimer elevation from admission to 3 h after injury and PAI-1 elevation from 6 h to 1 day after injury were significant negative prognostic indicators. Post-TBI hypercoagulation, fibrinolysis, and fibrinolysis shutdown were activated consecutively. Hyperfibrinolysis immediately after injury and subsequent fibrinolysis shutdown were associated with poor outcome.

The negative influence of chronic alcohol abuse on acute cognitive recovery after a traumatic brain injury

ABSTRACT Objective Cognitive recovery after a traumatic brain injury (TBI) may be negatively affected by a prior alcohol use disorder (AUD). This study aims to compare the cognitive recovery of patients who had comorbid TBI and AUD relative to TBI alone and investigate the influence of blood alcohol level (BAL) at hospital admission on this recovery. Method The sample consisted of 42 patients who had sustained a TBI (mild or moderate) and had an AUD diagnosis (TBI+AUD), and 42 patients who had sustained a TBI alone (TBI). The Brief Cognitive Exam in Traumatology (EXACT), designed to evaluate cognitive functions in the acute phase of TBI was administered (± 2 weeks post-injury). Results After controlling for BAL at admission, the TBI+AUD group had a lower EXACT total score compared to the TBI group. The negative influence of age on the results was more pronounced in the TBI+AUD group. The number of intoxicated patients at admission was also higher in this group, although there was no correlation between BAL at admission and cognitive outcome. Conclusion The presence of an AUD diagnosis seems to exert a greater negative influence on cognitive recovery following a mild/moderate TBI than BAL at admission, especially in older patients.

Association between cerebrovascular reactivity in adult traumatic brain injury and improvement in patient outcome over time: an exploratory analysis.

Impaired cerebrovascular reactivity following moderate/severe traumatic brain injury (TBI) has emerged as a key potential driver of morbidity and mortality. However, the major contributions to the literature so far have been solely focused on single point measures of long-term outcome. Therefore, it remains unknown whether cerebrovascular reactivity impairment, during the acute phase of TBI, is associated with failure to improve in outcome across time. Cerebrovascular reactivity was measured using three intracranial pressure-based surrogate metrics. For each patient, % time spent above various literature-defined thresholds was calculated. Patients were dichotomized based on outcome transition into Improved vs Not Improved between 1 and 3months, 3 and 6months, and 1 and 6months, based on the Glasgow Outcome Scale-Extended (GOSE). Univariate and multivariable logistic regression analyses were performed, adjusting for the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) variables. Seventy-eight patients from the Winnipeg Acute TBI Database were included in this study. On univariate logistic regression analysis, higher % time with cerebrovascular reactivity metrics above clinically defined thresholds was associated with a lack of clinical improvement between 1 and 3months and 1 and 6months post injury (p < 0.05). These relationships held true on multivariable logistic regression analysis. Our study demonstrates that impaired cerebrovascular reactivity, during the acute phase of TBI, is associated with failure to improve clinically over time. These preliminary findings highlight the significance that cerebrovascular reactivity monitoring carries in outcome recovery association in moderate/severe TBI.

Downregulation of Sepina3n Aggravated Blood–Brain Barrier Disruption after Traumatic Brain Injury by Activating Neutrophil Elastase in Mice

Traumatic brain injury (TBI) is the leading cause of death in young adults and the main cause of mortality and disability across all ages worldwide. We previously analyzed the expression profile data of TBI models obtained from the Gene Expression Omnibus (GEO) database and found that the seripina3n mRNA was markedly upregulated in the acute phase of TBI in four mRNA expression profile data sets, indicating that serpina3n may be involved in the pathophysiological process of TBI. Therefore, we further investigated the biological role and molecular mechanism of serpina3n in traumatic brain injury in this study. As a result, the endogenous level of sepina3n was markedly elevated in the cortex around the contusion sit in mice at day 1 and day 3 after TBI. Inhibiting the expression of serpina3n caused aggravation of neutrophil elastase (NE) expression, BBB disruption, and neurological deficit. With the inactivation of NE, even if serpina3n was silenced, the disruption of the BBB was not further aggravated. In vitro experiments further proved that recombinant serpina3n dose-dependently inhibited the activity of recombinant NE. Based on the above, this study demonstrated that the endogenous level of sepina3n was significantly elevated in the cortex around the contusion sit after TBI in mice, which reduced the secondary blood–brain barrier disruption by inhibiting the activity of neutrophil elastase.

Single-Cell RNA Sequencing Reveals Cellular and Transcriptional Changes Associated With Traumatic Brain Injury

Traumatic brain injury (TBI) is currently a substantial public health problem and one of the leading causes of morbidity and mortality worldwide. However, the cellular and transcriptional changes in TBI at single-cell level have not been well characterized. In this study, we reanalyzed a single-cell RNA sequencing (scRNA-seq) dataset of mouse hippocampus to identify the key cellular and transcriptional changes associated with TBI. Specifically, we found that oligodendrocytes were the most abundant cell type in mouse hippocampus, and detected an expanded astrocyte population, which was significantly activated in TBI. The enhanced activity of inflammatory response-related pathways in the astrocytes of TBI samples suggested that the astrocytes, along with microglia, which were the major brain-resident immune cells, were responsible for inflammation in the acute phase of TBI. Hormone secretion, transport, and exocytosis were found upregulated in the excitatory neurons of TBI, which gave us a hint that excitatory neurons might excessively transport and excrete glutamate in response to TBI. Moreover, the ependymal subpopulation C0 was TBI-specific and characterized by downregulated cilium movement, indicating that the attenuated activity of cilium movement following TBI might decrease cerebrospinal fluid flow. Furthermore, we observed that downregulated genes in response to candesartan treatment were preferentially expressed in excitatory neurons and were related to pathways like neuronal systems and neuroactive ligand-receptor interaction, indicating that candesartan might promote recovery of neurons after traumatic brain injury via mediating neuroactive ligand-receptor interactions and reducing excitotoxicity. In conclusion, our study identified key cell types in TBI, which improved our understanding of the cellular and transcriptional changes after TBI and offered an insight into the molecular mechanisms that could serve as therapeutic targets.

The Role of Neuroinflammatory Mediators in the Pathogenesis of Traumatic Brain Injury: A Narrative Review.

Traumatic brain injury (TBI) is a debilitating acquired neurological disorder that afflicts nearly 74 million people worldwide annually. TBI has been classified as more than just a single insult because of its associated risk toward various long-term neurological and neurodegenerative disorders. This risk may be triggered by a series of postinjury secondary molecular and cellular pathology, which may be dependent on the severity of the TBI. Among the secondary injury mechanisms, neuroinflammation may be the most crucial as it may exacerbate brain damage and lead to fatal consequences when prolonged. This Review aimed to elucidate the influence of neuroinflammatory mediators on the TBI functional and pathological outcomes, particularly focusing on inflammatory cytokines which were associated with neuronal dysfunctions in the acute and chronic stages of TBI. These cytokines include interleukins (IL) such as IL-1(beta)β, IL-4, IL-6, IL8, IL-10, IL-18, IL-33 and tumor necrosis factor alpha (TNF-α), which have been extensively studied. Apart from these, IL-2, interferon gamma (IFN-γ), and transforming growth factor-beta (TGF-β) may also play a significant role in the pathogenesis of TBI. These neuroinflammatory mediators may trigger a series of pathological events such as cell death, microglial suppression, and increased catecholaminergic activity. Interestingly, in the acute phase of TBI, most of these mediators may also play a neuroprotective role by displaying anti-inflammatory properties, which may convert to a pro-inflammatory action in the chronic stages post TBI. Early identification and treatment of these mediators may help the development of more effective treatment options for TBI.

Predictive Value of a New Brief Cognitive Test for Long-term Functional Outcome in Acute Traumatic Brain Injury

ObjectiveTo determine how results on the EXAmen Cognitif abrégé en Traumatologie (EXACT), a new test specifically designed to briefly assess global cognitive functioning during the acute phase of traumatic brain injury (TBI), can predict long-term functional outcome compared with length of posttraumatic amnesia (PTA), a well-established predictor. DesignInception cohort. SettingsLevel 1 trauma center. ParticipantsA total of 90 patients (N=90) hospitalized for a moderate or severe TBI. InterventionsNot applicable. Main Outcome MeasuresPerformance on the EXACT in the first 3 months after injury and results on the Disability Rating Scale (DRS) at follow-up 1-2 years later. ResultsEXACT scores were all correlated with length of PTA and DRS result. Compared with length of PTA, the EXACT added significantly to the regression and improved prediction of functional outcome. More specifically, a total score ≤80 on the EXACT was associated with a higher rate of long-term disability because of more severe TBI consequences. Behavioral regulation and executive functions were the cognitive domains that showed the most impairment, followed by attention and working memory as well as episodic memory. Except for length of PTA and hospital stay, the DRS score was not correlated with other demographic (age, education) or clinical variables (Glasgow Coma Scale and maximum score on the Therapy Intensity Level Scale). ConclusionsThe EXACT can be administered to most patients early in the acute phase of TBI, and results could be used, along with other predictors such as PTA, to estimate their long-term functional sequelae. The EXACT may be a promising brief cognitive instrument for future studies investigating recovery after TBI.

Neuroendocrine Changes are common during the acute Phase of Traumatic Brain Injury and Subarachnoid Hemorrhage

Background and aims of the study: Traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) can cause death and long-term morbidity. Studies indicate that both TBI and SAH may affect pituitary function in both the acute and the chronic phase. The aims of this study were firstly to evaluate the nature of neuroendocrine changes in the acute phase of moderate and severe TBI and all SAH, to evaluate association between neuroendocrine disturbance and indicators of severity of insult as well as hypotension, desaturation and anemia and to evaluated the incidence of neuroendocrine changes after moderate and severe TBI and SAH in the acute phase. Purpose: To explore neuroendocrine disturbances in moderate traumatic brain injury (mTBI), severe TBI (sTBI) and subarachnoid hemorrhage (SAH) in the acute phase. Methods: The study was a prospective single-center study. Anterior hypothalamic-pituitary (HP) hormone axis were assessed on admission (day 0) with baseline hormone levels and on day 6 post insult with baseline hormone levels and a Synacthen test. From patient charts we recorded for all patients GCS, APACHEII score, length of ICU stay, pupil dilatation, documented hypotension, desaturation and hemoglobin value &lt;80 g/dL. Hunt and Hess grade for SAH group and Injury severity score for TBI group. S100b was measured in all patients on admission. We included 21 TBI patient, 6 moderate TBI and 15 severe TBI, and 19 SAH patients. Anterior hypothalamic-pituitary (HP) hormone axis were assessed on day 0 and 6 post insult in Twenty-one TBI patient and 19 SAH patients. Results: HP-adrenal axis: The TBI group had significantly lower mean cortisol than the SAH group on day 0, 23.8% of TBI patients had low cortisol and 0% of SAH patients. On day 6, one patient in each group had low cortisol, 6.7% of TBI and 9.1% of SAH. HP-gonadal axis: In males on day 0, 52.9% of TBI patients and 57.1% of SAH patients had suppressed HP-gonadal axis and on day 6, 84.6% of TBI patients and 90% of SAH patients. There was a greater suppression of LH/FSH in the TBI group. HP-thyroid axis: Only one TBI patient (5.9%) had secondary hypothyroidism on day 6. HP-somatotroph axis: On day 0, 52.4% of TBI patients and 35.7% of SAH patients had low IGF-1. On day 6 all but one TBI patient (5.9%) had normalized their IGF-1 but 25% of SAH patients still had low IGF-1. In general, when evaluating association there seemed to more suppression of the hypothalamic-pituitary (HP) gonadal and thyroid axis with more severe insult and adequately more activation of the hypothalamic-pituitary adrenal axis. Conclusion: Neuroendocrine disturbances in the acute phase of TBI and SAH are common and seem to differ between the two groups. The clinical significance of these disturbances is uncertain.

Intracranial Densitometry-Augmented Machine Learning Enhances the Prognostic Value of Brain CT in Pediatric Patients With Traumatic Brain Injury: A Retrospective Pilot Study.

Background: The inter- and intrarater variability of conventional computed tomography (CT) classification systems for evaluating the extent of ischemic-edematous insult following traumatic brain injury (TBI) may hinder the robustness of TBI prognostic models.Objective: This study aimed to employ fully automated quantitative densitometric CT parameters and a cutting-edge machine learning algorithm to construct a robust prognostic model for pediatric TBI.Methods: Fifty-eight pediatric patients with TBI who underwent brain CT were retrospectively analyzed. Intracranial densitometric information was derived from the supratentorial region as a distribution representing the proportion of Hounsfield units. Furthermore, a machine learning-based prognostic model based on gradient boosting (i.e., CatBoost) was constructed with leave-one-out cross-validation. At discharge, the outcome was assessed dichotomously with the Glasgow Outcome Scale (favorability: 1–3 vs. 4–5). In-hospital mortality, length of stay (>1 week), and need for surgery were further evaluated as alternative TBI outcome measures.Results: Densitometric parameters indicating reduced brain density due to subtle global ischemic changes were significantly different among the TBI outcome groups, except for need for surgery. The skewed intracranial densitometry of the unfavorable outcome became more distinguishable in the follow-up CT within 48 h. The prognostic model augmented by intracranial densitometric information achieved adequate AUCs for various outcome measures [favorability = 0.83 (95% CI: 0.72–0.94), in-hospital mortality = 0.91 (95% CI: 0.82–1.00), length of stay = 0.83 (95% CI: 0.72–0.94), and need for surgery = 0.71 (95% CI: 0.56–0.86)], and this model showed enhanced performance compared to the conventional CRASH-CT model.Conclusion: Densitometric parameters indicative of global ischemic changes during the acute phase of TBI are predictive of a worse outcome in pediatric patients. The robustness and predictive capacity of conventional TBI prognostic models might be significantly enhanced by incorporating densitometric parameters and machine learning techniques.