Diffuse Brain Injury Research Articles

CNSC-66. STRUCTURAL AND ELECTROPHYSIOLOGICAL CONNECTIVITY IN GLIOBLASTOMA IS MEDIATED BY TUMOR AND IMMUNE DERIVED CYTOKINES

Abstract BACKGROUND In glioblastomas (GBM), the pleiotropic cytokine interleukin-6 (IL-6) upregulates PD-L1 expression. This results in local immunosuppression favorable to tumor progression, and may account for the limited efficacy of immune checkpoint inhibition. Additionally, IL-6 increases synaptogenesis during development, and contributes to neuronal network remodeling following focal brain or spinal cord injury. Therefore, the aim was to determine whether IL-6 contributes to GBM-induced circuit remodeling from a structural and electrophysiological perspective. METHODS In magnetoencephalography (MEG)-based intratumoral regions of High- (HFC) and Low-Functional Connectivity (LFC) from GBM patients, the expression of IL-6 and GAP43 was compared using bulk and single-cell RNA sequencing and immunofluorescence staining in biological replicates (n=44). In mouse postnatal cortical neurons and primary patient-derived GBM cell cocultures, the expression of Ki67, GAP43, tumor connectivity and neuronal activity were monitored after exogenous application of recombinant human IL-6 (rIL-6) or microglial depletion using PLX5622. Results. IL-6 and GAP43 were overexpressed in HFC compared to LFC regions. In neuron-GBM cocultures, the tumour proliferation index was significantly increased by rIL-6 and decreased by PLX5622. Morphologically, the number of microtubes per tumor cell was significantly increased by rIL-6 and decreased by PLX5622. The expression of GAP43 was inconstantly increased by rIL-6, suggesting the regulation of other pathways involved in tumour microtube formation. Multielectrode array recordings showed a significant increase or decrease in the neuronal activity, following the addition of rIL-6 or microglial depletion, respectively. CONCLUSIONS IL-6-signaling increases proliferation, structural and electrophysiological connectivity in gliomas and may contribute to neuronal network hyper-excitability and synchrony. Microglial depletion provided opposite effects. Additional experiments are mandatory to determine whether the effects of IL-6 on GBM cells depend on the presence of microglial cells or not. These data will be critical to design new therapeutic options, likely to improve the oncological and functional outcomes of patients treated for GBM.

A Combination of Low Doses of Lithium and Valproate Improves Cognitive Outcomes after Mild Traumatic Brain Injury.

The prevalence of mild traumatic brain injury (mTBI) is high compared with moderate and severe TBI, comprising almost 80% of all brain injuries. mTBI activates a complex cascade of biochemical, molecular, structural, and pathological changes that can result in neurological and cognitive impairments. These impairments can manifest even in the absence of overt brain damage. Given the complexity of changes triggered by mTBI, a combination of drugs that target multiple TBI-activated cascades may be required to improve mTBI outcomes. It has been previously demonstrated that cotreatment with the U.S. Food and Drug Administration (FDA)-approved drugs lithium plus valproate (Li + VPA) for 3 weeks after a moderate-to-severe controlled cortical impact injury reduced cortical tissue loss and improved motor function. Since both lithium and valproate can exhibit toxicity at high doses, it would be beneficial to determine if this combination treatment is effective when administered at low doses and for a shorter duration, and if it can improve cognitive function, after a mild diffuse TBI. In the present study, we tested if the combination of low doses of lithium (1 mEq/kg or 0.5 mEq/kg) plus valproate (20 mg/kg) administered for 3 days after a mild fluid percussion injury can improve hippocampal-dependent learning and memory. Our data show that the combination of low-dose Li + VPA improved spatial learning and memory, effects not seen when either drug was administered alone. In addition, postinjury Li + VPA treatment improved recognition memory and sociability and reduced fear generalization. Postinjury Li + VPA also reduced the number of anti-ionized calcium binding adaptor molecule 1 (Iba1)-positive microglia counted using a convolutional neural network, indicating a reduction in neuroinflammation. These findings indicate that low-dose Li + VPA administered acutely after mTBI may have translational utility to reduce pathology and improve cognitive function.

Imaging the large-scale and cellular response to focal traumatic brain injury in mouse neocortex.

Traumatic brain injury (TBI) affects neural function at the local injury site and also at distant, connected brain areas. However, the real-time neural dynamics in response to injury and subsequent effects on sensory processing and behavior are not fully resolved, especially across a range of spatial scales. We used in vivo calcium imaging in awake, head-restrained male and female mice to measure large-scale and cellular resolution neuronal activation, respectively, in response to a mild/moderate TBI induced by focal controlled cortical impact (CCI) injury of the motor cortex (M1). Widefield imaging revealed an immediate CCI-induced activation at the injury site, followed by a massive slow wave of calcium signal activation that traveled across the majority of the dorsal cortex within approximately 30 s. Correspondingly, two-photon calcium imaging in primary somatosensory cortex (S1) found strong activation of neuropil and neuronal populations during the CCI-induced traveling wave. A depression of calcium signals followed the wave, during which we observed atypical activity of a sparse population of S1 neurons. Longitudinal imaging in the hours and days after CCI revealed increases in the area of whisker-evoked sensory maps at early time points, in parallel to decreases in cortical functional connectivity and behavioral measures. Neural and behavioral changes mostly recovered over hours to days in our M1-TBI model, with a more lasting decrease in the number of active S1 neurons. Our results in unanesthetized mice describe novel spatial and temporal neural adaptations that occur at cortical sites remote to a focal brain injury.

Traumatic Brain Injury Increasing Risk of Meningioma? From the Genetic Evidence

BackgroundNumerous studies have demonstrated a strong association between traumatic brain injury (TBI) and an increased risk of meningioma. However, this correlation remains controversial. This study utilized mendelian randomization to explore this relationship from perspective of genetic evidence. MethodsWe employed six traumatic brain injury genome-wide association study (GWAS) datasets from the IEU GWAS database. Summary statistics for meningioma were sourced from the FinnGen R10 database. We assessed heterogeneity and horizontal pleiotropy within the analyzed data. The primary method was inverse variance weighting (IVW) to investigate the causal relationship between TBI and meningioma, excluding cases with horizontal pleiotropy. Four supplementary analysis methods were also used, with abnormal results excluded based on leave-one-out sensitivity analysis. ResultsAll six Mendelian randomization analyses indicated no causal relationship between TBI and meningiomas (Focal brain injury IVW p-value = 0.98; Diffuse brain injury IVW p-value = 0.41; TBI without concussion IVW p-value = 0.45; Intracranial trauma IVW p-value = 0.34; Traumatic subdural hemorrhage IVW p-value = 0.80; Traumatic subarachnoid hemorrhage IVW p-value = 0.92). ConclusionsThe mendelian randomization study revealed that traumatic brain injury does not increase the risk of meningioma based on genetic evidence.

Relationship between Location of Focal Traumatic Brain Injury and Canal Involved in Benign Paroxysmal Positional Vertigo.

Benign paroxysmal positional vertigo (BPPV) has a prevalence of 58% in a traumatic brain injury (TBI) population. Research on idiopathic BPPV has demonstrated a higher prevalence of right-sided canal involvement. While many studies have investigated the epidemiology of canal involvement in BPPV in both idiopathic and traumatic BPPV (BPPV associated with a fall), there has been no assessment of trauma location as a predictor of the location of BPPV. The aim of this study was to assess the relationship between the location of a focal TBI and canal involvement in BPPV. Patients who were admitted to an inpatient rehabilitation unit with a diagnosis of TBI were screened for BPPV. The primary outcome of this study was the side of the TBI, the BPPV type (posterior, horizontal, or anterior canal), and the side of the BPPV (right, left, or bilateral). There were 42 people who had BPPV. Twenty-one had right-sided canal involvement, 14 had left-sided involvement, and 7 had bilateral involvement. Sixteen had right-side tissue involvement, 13 had left-side involvement, and 13 had bilateral involvement. There was no significant correlation between variables (χ2 = 1.70, p = 0.80). All patients with a TBI should have all canals assessed for BPPV as there is no relationship between the side of focal damage and canal involvement.

Post-injury treatment with 7,8-dihydroxyflavone attenuates white matter pathology in aged mice following focal traumatic brain injury

Traumatic brain injury (TBI) is a major cause of morbidity and mortality, not least in the elderly. The incidence of aged TBI patients has increased dramatically during the last decades. High age is a highly negative prognostic factor in TBI, and pharmacological treatment options are lacking. We used the controlled cortical impact (CCI) TBI model in 23-month-old male and female mice and analyzed the effect of post-injury treatment with 7,8 dihydroxyflavone (7,8-DHF), a brain-derived neurotrophic factor (BDNF)-mimetic compound, on white matter pathology. Following CCI or sham injury, mice received subcutaneous 7,8-DHF injections (5 ​mg/kg) 30 ​min post-injury and were sacrificed on 2, 7 or 14 days post-injury (dpi) for histological and immunofluorescence analyses. Histological assessment with Luxol Fast Blue (LFB)/Cresyl Violet stain showed that administration of 7,8-DHF resulted in preserved white matter tissue at 2 and 7 dpi with no difference in cortical tissue loss at all investigated time points. Treatment with 7,8-DHF led to reduced axonal swellings at 2 and 7 dpi, as visualized by SMI-31 (Neurofilament Heavy Chain) immunofluorescence, and reduced number of TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labelling)/CC1-positive mature oligodendrocytes at 2 dpi in the perilesional white matter. Post-injury proliferation of Platelet-derived Growth Factor Receptor (PDGFRα)-positive oligodendodrocyte progenitor cells was not altered by 7,8-DHF. Our results suggest that 7,8-DHF can attenuate white matter pathology by mitigating axonal injury and oligodendrocyte death in the aged mouse brain following TBI. These data argue that further exploration of 7,8-DHF towards clinical use is warranted.

Sex-dependent temporal changes in astrocyte-vessel interactions following diffuse traumatic brain injury in rats.

Traumatic brain injury (TBI) is associated with diffuse axonal injury (DAI), a primary pathology linked to progressive neurodegeneration and neuroinflammation, including chronic astrogliosis, which influences long-term post-TBI recovery and morbidity. Sex-based differences in blood-brain barrier (BBB) permeability increases the risk of accelerated brain aging and early-onset neurodegeneration. However, few studies have evaluated chronic time course of astrocytic responses around cerebrovascular in the context of aging after TBI and sex dependence. We observed increased glial fibrillary acidic protein (GFAP)-labeled accessory processes branching near and connecting with GFAP-ensheathed cortical vessels, suggesting a critical nuance in astrocyte-vessel interactions after TBI. To quantify this observation, male and female Sprague Dawley rats (∼3months old, n = 5-6/group) underwent either sham surgery or midline fluid percussion injury. Using immunohistochemical analysis, we quantified GFAP-labeled astrocyte primary and accessory processes that contacted GFAP-ensheathed vessels in the somatosensory barrel cortex at 7, 56, and 168days post-injury (DPI). TBI significantly increased GFAP-positive primary processes at 7 DPI (P < 0.01) in both sexes. At 56 DPI, these vessel-process interactions remained significantly increased exclusively in males (P < 0.05). At 168 DPI, both sexes showed a significant reduction in vessel-process interactions compared to 7 DPI (P < 0.05); however, a modest but significant injury effect reemerged in females (P < 0.05). A similar sex-dependent pattern in the number of accessory processes provides novel evidence of long-term temporal changes in astrocyte-vessel interactions. TBI-induced changes in astrocyte-vessel interactions may indicate chronic BBB vulnerability and processes responsible for early onset vascular and neurodegenerative pathology.

Dissecting causal relationships between gut microbiome, immune cells, and brain injury: A Mendelian randomization study.

Increasing literature has affirmed that changes in the gut microbiome (GM) composition were linked to distinct brain injury (BI) through the gut-brain axis, but it is uncertain if such links reflect causality. Further, the immune cell changes mediating the impact of GM on BI are not completely understood. We made use of the summary statistics of 211 GM (MiBioGen consortium), 731 immune cells, and 2 different BIs (FinnGen consortium), namely traumatic BI (TBI) and focal BI (FBI), from the extensive genome-wide association studies to date. We executed bidirectional Mendelian randomization (MR) analyses to ascertain the causal relationships between the GM and BI, and 2-step MR to validate possible mediating immune cells. Additionally, thorough sensitivity analyses verified the heterogeneity, robustness, as well as horizontal pleiotropy of the results. Based on the results of inverse-variance weighted (IVW) and sensitivity analyses, in MR analyses, 5 specific GM taxa and 6 specific GM taxa were causally associated with FBI and TBI, respectively; 27 immunophenotypes and 39 immunophenotypes were causally associated with FBI and TBI, respectively. Remarkably, Anaerofilum, LachnospiraceaeNC2004group, RuminococcaceaeUCG004, CCR2 on myeloid dendritic cell (DC), CD123 on CD62L+ plasmacytoid DC, and CD123 on plasmacytoid DC were causally associated with TBI and FBI (all P < .040). However, our reverse MR did not indicate any influence of TBI and FBI on the specific GM. In mediation analysis, we found that the associations between Escherichia.Shigella and FBI were mediated by CD123 on CD62L + plasmacytoid DC in addition to CD123 on plasmacytoid DC, each accounting for 4.21% and 4.21%; the association between FamilyXIIIAD3011group and TBI was mediated by CCR2 on myeloid DC, with mediated proportions of 5.07%. No remarkable horizontal pleiotropy or heterogeneity of instrumental variables was detected. Our comprehensive MR analysis first provides insight into potential causal links between several specific GM taxa with FBI/TBI. Additionally, CD123 on plasmacytoid DC in conjunction with CCR2 on myeloid DC may function in gut microbiota-host crosstalk in FBI and TBI, correspondingly. Further studies are critical to unravel the underlying mechanisms of the links between GM and BI.

How Well Do Popular Bicycle Helmets Protect from Different Types of Head Injury?

Bicycle helmets are designed to protect against skull fractures and associated focal brain injuries, driven by helmet standards. Another type of head injury seen in injured cyclists is diffuse brain injuries, but little is known about the protection provided by bicycle helmets against these injuries. Here, we examine the performance of modern bicycle helmets in preventing diffuse injuries and skull fractures under impact conditions that represent a range of real-world incidents. We also investigate the effects of helmet technology, price, and mass on protection against these pathologies. 30 most popular helmets among UK cyclists were purchased within 9.99-135.00 GBP price range. Helmets were tested under oblique impacts onto a 45° anvil at 6.5m/s impact speed and four locations, front, rear, side, and front-side. A new headform, which better represents the average human head's mass, moments of inertia and coefficient of friction than any other available headforms, was used. We determined peak linear acceleration (PLA), peak rotational acceleration (PRA), peak rotational velocity (PRV), and BrIC. We also determined the risk of skull fractures based on PLA (linear risk), risk of diffuse brain injuries based on BrIC (rotational risk), and their mean (overall risk). Our results show large variation in head kinematics: PLA (80-213g), PRV (8.5-29.9rad/s), PRA (1.6-9.7 krad/s2), and BrIC (0.17-0.65). The overall risk varied considerably with a 2.25 ratio between the least and most protective helmet. This ratio was 1.76 for the linear and 4.21 for the rotational risk. Nine best performing helmets were equipped with the rotation management technology MIPS, but not all helmets equipped with MIPS were among the best performing helmets. Our comparison of three tested helmets which have MIPS and no-MIPS versions showed that MIPS reduced rotational kinematics, but not linear kinematics. We found no significant effect of helmet price on exposure-adjusted injury risks. We found that larger helmet mass was associated with higher linear risk. This study highlights the need for a holistic approach, including both rotational and linear head injury metrics and risks, in helmet design and testing. It also highlights the need for providing information about helmet safety to consumers to help them make an informed choice.

Whole-brain model replicates sleep-like slow-wave dynamics generated by stroke lesions

Focal brain injuries, such as stroke, cause local structural damage as well as alteration of neuronal activity in distant brain regions. Experimental evidence suggests that one of these changes is the appearance of sleep-like slow waves in the otherwise awake individual. This pattern is prominent in areas surrounding the damaged region and can extend to connected brain regions in a way consistent with the individual's specific long-range connectivity patterns. In this paper we present a generative whole-brain model based on (f)MRI data that, in combination with the disconnection mask associated with a given patient, explains the effects of the sleep-like slow waves originated in the vicinity of the lesion area on the distant brain activity. Our model reveals new aspects of their interaction, being able to reproduce functional connectivity patterns of stroke patients and offering a detailed, causal understanding of how stroke-related effects, in particular slow waves, spread throughout the brain. The presented findings demonstrate that the model effectively captures the links between stroke occurrences, sleep-like slow waves, and their subsequent spread across the human brain.

Association of Gestational Age at Birth and Changes on MRI With Prevalence and Spectrum of Comorbidities in Children With Cerebral Palsy.

For individuals with cerebral palsy (CP) and caregivers, comorbidities may be a greater challenge than neuromotor impairment. Clinicians may make assumptions regarding risk of comorbidities based simply on term vs preterm birth, but this has not been well examined. To better understand factors affecting comorbidity pattern, we investigated the relationship between gestational age (GA) and imaging pattern on the presence of specific comorbidities. This is a cross-sectional study of data extracted from the Canadian Cerebral Palsy Registry of children with CP. Multivariable analysis was used to evaluate the relationship between brain injury, GA, and comorbidities. Comorbidities included in the analysis were communication, cognitive, visual, and auditory impairment, seizures in the past year, and gavage feeding. Each comorbidity was assessed as a separate nonexclusive outcome, with GA, MRI pattern, birth weight, postneonatal insult, 5-minute Apgar score, and male sex considered as potential modifiers. The only comorbidity affected by GA on multivariable analysis was seizures within the past year that were more prevalent in term children (odds ratio [OR] 1.1 95% CI 1.0-1.2) and was also affected by Apgar score (OR 0.9 95% CI 0.85-0.94), but not MRI pattern. MRI pattern appeared important for communication impairment (deep gray OR 4.2 95% CI 1.8-10.0; total brain injury OR 8.5, 95% CI 3.2-22.6; malformation OR 2.7, 95% CI 1.3-5.7) and cognitive impairment (deep gray OR 5.6, 95% CI 2.4-13.2; total brain injury OR 10.1, 95% CI 4.0-25.3; malformation OR 3.3, 95% CI 1.6-6.8; watershed OR 3.6, 95% CI 1.4-8.9). Focal injury compared with normal MRI was associated with reduced odds of visual impairment (OR 0.24, 95% CI 0.12-0.48), auditory impairment (OR 0.2195% CI 0.10-0.46) and communication impairment (OR 0.46, 95% CI 0.26-0.82), and overall number of comorbidities (coefficient -0.73, 95% CI -1.2 to -0.31). The number of comorbidities was increased by total brain injury pattern (coefficient 0.65, 95% CI 0.15-1.13) and reduced by focal brain injury (coefficient -0.73, 95% CI -1.2 to -0.31) and increasing 5-minute Apgar score (coefficient -0.11, 95% CI -0.16 to -0.07). In those with brain injuries sufficient to cause CP, development of additional comorbidities is less affected by GA at birth and more related to the underlying cause of CP as reflected by MRI patterns.

The structure of traumatic brain injury in the city of Rostov-on-Don during the new coronavirus infection COVID 19

Objective: to study the frequency and structure of traumatic brain injury in the pre-ovoid, covid and post-ovoid periods in Rostov-on-Don.Materials and methods: to study the frequency and structure of traumatic brain injury in three years from 2019 to 2021 (in the pre-ovoid, covid and post-ovoid periods) according to the neurosurgical department and the department of combined trauma of the Emergency Medical Hospital No. 2 in Rostov-on-Don. Data processing using the IBM SPSS Statictic program version 26.0 using the χ2-Pearson criterion, in pairwise a posteriori comparative analysis, the χ2-Pearson criterion with Yates correction and likelihood correction were used. If the significance level is p&lt;0.05, the differences are statistically significant.Results: in the pre-crisis period (2019), household trauma prevailed, the total number of hospitalized with TBI was 1,322. Of these, concussions accounted for 71%, brain contusions accounted for 28%, diffuse brain injury — 1%, street injury — 6.9%, transport injury — 6.81% and intentional injury — 24.1%. In the covid period (2020), the total number of patients admitted to the department decreased by 24%. The structure of the injury remained unchanged (concussions in 70% of cases, brain contusions in 28%, diffuse brain injury in 2%). In 2021 (completion of covid restrictions), the number of inpatient patients with TBI remained reduced (by 23%), the ratio of concussions, bruises, diffuse brain injuries remained the same.Conclusions: during the period of social isolation, there was a decrease in the number of hospitalized with TBI, which coincides with global indicators. The end of the restrictions associated with the pandemic is also characterized by a decrease in the number of patients admitted to the hospital with TBI. At the same time, a decrease in the ratio of the number of hospitalizations to the total number of deaths from head injury in 2019 and 2020 should be taken into account. from 19.83 to 14.98 in the Rostov region (according to the Federal State Statistics Service on the number of deaths from head injuries in 2019-2020), which reflects the level of accessibility of medical care. There was also a significant decrease in household, street, transport, school, sports and intentional types of TBI (p&lt;0.05), while occupational injuries and trauma, the circumstances of which are unknown, did not significantly differ from the pre-pandemic indicators. Taking into account these results will improve the organization of emergency and emergency medical care for patients with TBI.

A novel weight-drop closed head focal traumatic brain injury: A candidate to translational studies?

Traumatic brain injury (TBI) is a neurotrauma with a complex pathophysiology caused by an external mechanical force. This global public health problem is a leading cause of death and disability in young adults. In this scenario, many models were developed to try to simulate human TBI. The weight drop model allows the investigation of the pathophysiological cascades of TBI without surgical interference. In this protocol, a new closed-head weight-drop rat model consisting of a 48.5g weight projectile that free falls from 1.10m high onto the skull of the animals was built. We classify the present TBI model performed as moderately severe due to its mortality rate. Animals from TBI and Control (Sham) groups underwent weight for 7 days and temperature assessments within 1 hour after TBI and for 7 days. Results demonstrated that the TBI group showed less body weight gain in the days after the injury. Temperature oscillations within the first-hour post-injury and on the 3rd day after injury were observed. As the results of this study demonstrated similarity to human TBI vital parameters, this new adaptation of the Weight-drop model injury can be a suitable candidate for translational studies.•We developed a novel closed head focal traumatic brain injury using a projectile.•This TBI model does not require surgical intervention.•The validation of this method demonstrates that the vital parameters of the injured rats exhibit similarities with those of TBI patients.

Risk Factors for Perinatal Arterial Ischemic Stroke: A Machine Learning Approach.

Perinatal arterial ischemic stroke (PAIS) is a focal vascular brain injury presumed to occur between the fetal period and the first 28 days of life. It is the leading cause of hemiparetic cerebral palsy. Multiple maternal, intrapartum, delivery, and fetal factors have been associated with PAIS, but studies are limited by modest sample sizes and complex interactions between factors. Machine learning approaches use large and complex data sets to enable unbiased identification of clinical predictors but have not yet been applied to PAIS. We combined large PAIS data sets and used machine learning methods to identify clinical PAIS factors and compare this data-driven approach with previously described literature-driven clinical prediction models. Common data elements from 3 registries with patients with PAIS, the Alberta Perinatal Stroke Project, Canadian Cerebral Palsy Registry, International Pediatric Stroke Study, and a longitudinal cohort of healthy controls (Alberta Pregnancy Outcomes and Nutrition Study), were used to identify potential predictors of PAIS. Inclusion criteria were term birth and idiopathic PAIS (absence of primary causative medical condition). Data including maternal/pregnancy, intrapartum, and neonatal factors were collected between January 2003 and March 2020. Common data elements were entered into a validated random forest machine learning pipeline to identify the highest predictive features and develop a predictive model. Univariable analyses were completed post hoc to assess the relationship between each predictor and outcome. A machine learning model was developed using data from 2,571 neonates, including 527 cases (20%) and 2,044 controls (80%). With a mean of 21 features selected, the random forest machine learning approach predicted the outcome with approximately 86.5% balanced accuracy. Factors that were selected a priori through literature-driven variable selection that were also identified as most important by the machine learning model were maternal age, recreational substance exposure, tobacco exposure, intrapartum maternal fever, and low Apgar score at 5 minutes. Additional variables identified through machine learning included in utero alcohol exposure, infertility, miscarriage, primigravida, meconium, spontaneous vaginal delivery, neonatal head circumference, and 1-minute Apgar score. Overall, the machine learning model performed better (area under the curve [AUC] 0.93) than the literature-driven model (AUC 0.73). Machine learning may be an alternative, unbiased method to identify clinical predictors associated with PAIS. Identification of previously suggested and novel clinical factors requires cautious interpretation but supports the multifactorial nature of PAIS pathophysiology. Our results suggest that identification of neonates at risk of PAIS is possible.

Advancements in understanding the role of ferroptosis in hypoxia-associated brain injury: a narrative review.

Ferroptosis, a form of programmed cell death driven by lipid peroxidation and dependent on iron ions, unfolds through a sophisticated interplay of multiple biological processes. These include perturbations in iron metabolism, lipid peroxidation, aberrant amino acid metabolism, disruptions in hypoxia-inducible factor-prolyl hydroxylase (HIF-PHD) axis, and endoplasmic reticulum (ER) stress. Recent studies indicate that ferroptosis may serve as a promising therapeutic target for hypoxia-associated brain injury such as hypoxic-ischemic brain damage (HIBD) and cerebral ischemia-reperfusion injury (CIRI). HIBD is a neonatal disease that can be fatal, causing death or mental retardation in newborns. HIBD is a kind of diffuse brain injury, which is characterized by apoptosis of nerve cells and abnormal function and structure of neurons after cerebral hypoxia and ischemia. At present, there are no fundamental prevention and treatment measures for HIBD. The brain is the most sensitive organ of the human body to hypoxia. Cerebral ischemia will lead to the damage of local brain tissue and its function, and CIRI will lead to a series of serious consequences. We hope to clarify the mechanism of ferroptosis in hypoxia-associated brain injury, inhibit the relevant targets of ferroptosis in hypoxia-associated brain injury to guide clinical treatment, and provide guidance for the subsequent treatment of disease-related drugs. Our research incorporated data on "ferroptosis", "neonatal hypoxic ischemia", "hypoxic ischemic brain injury", "hypoxic ischemic encephalopathy", "brain ischemia-reperfusion injury", and "therapeutics", which were sourced from Web of Science, PubMed, and comprehensive reviews and articles written in English. This review delineates the underlying mechanisms of ferroptosis and the significance of these pathways in hypoxia-associated brain injury, offering an overview of therapeutic strategies for mitigating ferroptosis. Ferroptosis involves dysregulation of iron metabolism, lipid peroxidation, amino acid metabolism, dysregulation of HIF-PHD axis and endoplasmic reticulum stress (ERS). By reviewing the literature, we identified the involvement of the above processes in HIBD and CIRI, and summarized a series of therapeutic measures for HIBD and CIRI by inhibiting ferroptosis. We hope this study would provide guidance for the clinical treatment of HIBD and CIRI in the future.

Trends in mortality rates and correlations between intracranial injuries and external causes: A Japanese population study.

The age-standardized incidence of head trauma in 2016 was 369 per 100,000 people worldwide. The Western Pacific region, including Japan, had the highest incidence. This study aimed to extract ICD-10 code data for intracranial injury (S06) and external causes of morbidity and mortality (V01-Y89), analyze their characteristics and interrelationships, and contribute to these diseases' prevention, treatment, and prognosis. The number of deaths according to injury type and external cause type of intracranial injury published by the Japanese government was statistically analyzed using JoinPoint, and univariate distribution and multivariate correlation were conducted using JMP Software. From 1999-2021, there was a downward trend in the number of deaths because of intracranial injuries: mortality from intracranial injuries was higher among those aged ≥65 years. Conversely, mortality from intracranial injuries was lower among those aged ≤14 years. Among deaths from intracranial injury, mortality from diffuse brain injury and traumatic subdural hemorrhage was more common. Among deaths from external causes of intracranial injury, mortality from falls, transport accidents, and other unforeseen accidents was more common. Mortality because of intracranial injuries increased significantly during the 2011 Great East Japan Earthquake. For some age groups and sexes, there were significant inverse correlations of mortality with traumatic subdural hemorrhage and traumatic subarachnoid hemorrhage for transport accidents, intentional self-harm and assault, and diffuse brain injury and focal brain injury for falls. We believe that the data presented in this study will be useful for preventing and treating intracranial injuries and for developing administrative measures to reduce intracranial injuries.

Higher Discharge GCS Score is Associated with Both Survival and Long-term Functional Recovery in Patients with Clinically Defined Diffuse Axonal Injury

Abstract Background: Diffuse axonal injury (DAI) refers to widespread axonal damage due to traumatic brain injury. There are very few studies that have specifically looked at outcomes in patients with DAI, where the injury is not associated with accompanying focal lesions (such as haematomas and other mass lesions) or ischaemic brain injury. In this study, we assessed factors that predict mortality and long-term functional outcome of patients with DAI who underwent treatment and rehabilitation in a tertiary care hospital in South India. Methodology: Long-term outcome and neuropsychiatric sequelae were assessed in 160 patients with DAI, who underwent rehabilitation and were on regular follow-up for a median duration of 5 years (interquartile range = 3–6). Cox proportional hazards and logistic regression models were used to determine factors associated with mortality and functional outcome (Glasgow Outcome Scale-Extended [GOSE], Mayo-Portland Adaptability Inventory [MPAI] and Neuropsychiatric Inventory [NPI]). Results: Majority of the 160 patients included in this study were young males (92%) who presented with severe head injury (Glasgow Coma Scale [GCS] score of 5.6 ± 2.1). At the time of follow-up, 94 (58.75%) patients were alive, while 66 (41.25%) were dead. Patients who were alive at the time of follow-up were significantly younger, had higher GCS score and lower Rotterdam computed tomography (CT) grade at presentation compared to those who died. Compromised airway requiring tracheostomy (χ 2 = 21.3; P &lt; 0.001) and abnormal pupil reactivity (χ2 = 30.2, P &lt; 0.001) were significantly associated with mortality. GCS score at discharge was the single most important determinant of mortality (hazard ratio = 0.802, P &lt; 0.001). Among those who were alive, majority (73.4%) had good functional recovery (GOSE score 8). GCS scores (at admission and that at discharge) and Rotterdam CT score independently and significantly predicted MPAI, NPI and caregiver distress scores. Among them, GCS score at discharge was the strongest predictor. In-hospital improvement in GCS correlated with GOSE but not with MPAI and NPI. Conclusion: Higher GCS scores at discharge were strongly associated with both survival and functional recovery in patients with DAI.

Focal Traumatic Brain Injury Impairs the Integrity of the Basement Membrane of Hindlimb Muscle Fibers Revealed by Extracellular Matrix Immunoreactivity.

Traumatic brain injury (TBI) stands as a prominent global cause of disability, with motor deficits being a common consequence. Despite its widespread impact, the precise pathological mechanisms underlying motor deficits after TBI remain elusive. In this study, hindlimb postural asymmetry (HL-PA) development in rats subjected to focal TBI was investigated to explore the potential roles of collagen IV and laminin within the extracellular matrix (ECM) of selected hindlimb muscles in the emergence of motor deficits following TBI. A focal TBI was induced by ablating the left sensorimotor cortex in rats and motor deficits were assessed by measuring HL-PA. The expression of laminin and collagen IV in eight selected muscles on each side of the hindlimbs from both TBI- and sham-operated rats were studied using immunohistochemistry and semi-quantitatively analyzed. The results indicated that the TBI rats exhibited HL-PA, characterized by flexion of the contralateral (right) hindlimb. In the sham-operated rats, the immunoreactive components of laminin and collagen IV were evenly and smoothly distributed along the border of the muscle fibers in all the investigated muscles. In contrast, in the TBI rats, the pattern was broken into aggregated, granule-like, immunoreactive components. Such a labeling pattern was detected in all the investigated muscles both from the contra- and ipsilateral sides of the TBI rats. However, in TBI rats, most of the muscles from the contralateral hindlimb showed a significantly increased expression of these two proteins in comparison with those from the ipsilateral hindlimb. In comparison to sham-operated rats, there was a significant increase in laminin and collagen IV expression in various contralateral hindlimb muscles in the TBI rats. These findings suggest potential implications of laminin and collagen IV in the development of motor deficits following a focal TBI.

Establishing a 3-Tesla Magnetic Resonance Imaging Method for Assessing Diffuse Axonal Brain Injury in Rats.

Traumatic brain injury (TBI) significantly contributes to death and disability worldwide. However, treatment options remain limited. Here, we focus on a specific pathology of TBI, diffuse axonal brain injury (DABI), which describes the process of the tearing of nerve fibers in the brain after blunt injury. Most protocols to study DABI do not incorporate a specific model for that type of pathology, limiting their ability to identify mechanisms and comorbidities of DABI. In this study, we developed a magnetic resonance imaging (MRI) protocol for DABI in a rat model using a 3-T clinical scanner. We compared the neuroimaging outcomes with histologic and neurologic assessments. In a sample size of 10 rats in the sham group and 10 rats in the DABI group, we established neurological severity scores before the intervention and at 48 h following DABI induction. After the neurological evaluation after DABI, all rats underwent MRI scans and were subsequently euthanized for histological evaluation. As expected, the neurological assessment showed a high sensitivity for DABI lesions indicated using the β-APP marker. Surprisingly, however, we found that the MRI method had greater sensitivity in assessing DABI lesions compared to histological methods. Out of the five MRI parameters with pathological changes in the DABI model, we found significant changes compared to sham rats in three parameters, and, as shown using comparative tests with other models, MRI was the most sensitive parameter, being even more sensitive than histology. We anticipate that this DABI protocol will have a significant impact on future TBI and DABI studies, advancing research on treatments specifically targeted towards improving patient quality of life and long-term outcomes.

Transcriptomic alterations in cortical astrocytes following the development of post-traumatic epilepsy

Post-traumatic epilepsy (PTE) stands as one of the numerous debilitating consequences that follow traumatic brain injury (TBI). Despite its impact on many individuals, the current landscape offers only a limited array of reliable treatment options, and our understanding of the underlying mechanisms and susceptibility factors remains incomplete. Among the potential contributors to epileptogenesis, astrocytes, a type of glial cell, have garnered substantial attention as they are believed to promote hyperexcitability and the development of seizures in the brain following TBI. The current study evaluated the transcriptomic changes in cortical astrocytes derived from animals that developed seizures as a result of severe focal TBI. Using RNA-Seq and ingenuity pathway analysis (IPA), we unveil a distinct gene expression profile in astrocytes, including alterations in genes supporting inflammation, early response modifiers, and neuropeptide-amidating enzymes. The findings underscore the complex molecular dynamics in astrocytes during PTE development, offering insights into therapeutic targets and avenues for further exploration.