Mechanisms Of Brain Injury Research Articles

Ly6C-high monocytes alleviate brain injury in experimental subarachnoid hemorrhage in mice

BackgroundSubarachnoid hemorrhage (SAH) is an uncommon type of potentially fatal stroke. The pathophysiological mechanisms of brain injury remain unclear, which hinders the development of drugs for SAH. We aimed to investigate the pathophysiological mechanisms of SAH and to elucidate the cellular and molecular biological response to SAH-induced injury.MethodsA cross-species (human and mouse) multiomics approach combining high-throughput data and bioinformatic analysis was used to explore the key pathophysiological processes and cells involved in SAH-induced brain injury. Patient data were collected from the hospital (n = 712). SAH was established in adult male mice via endovascular perforation, and flow cytometry, a bone marrow chimera model, qPCR, and microglial depletion experiments were conducted to explore the origin and chemotaxis mechanism of the immune cells. To investigate cell effects on SAH prognosis, murine neurological function was evaluated based on a modified Garcia score, pole test, and rotarod test.ResultsThe bioinformatics analysis confirmed that inflammatory and immune responses were the key pathophysiological processes after SAH. Significant increases in the monocyte levels were observed in both the mouse brains and the peripheral blood of patients after SAH. Ly6C-high monocytes originated in the bone marrow, and the skull bone marrow contribute a higher proportion of these monocytes than neutrophils. The mRNA level of Ccl2 was significantly upregulated after SAH and was greater in CD11b-positive than CD11b-negative cells. Microglial depletion, microglial inhibition, and CCL2 blockade reduced the numbers of Ly6C-high monocytes after SAH. With CCR2 antagonization, the neurological function of the mice exhibited a slow recovery. Three days post-SAH, the monocyte-derived dendritic cell (moDC) population had a higher proportion of TNF-α-positive cells and a lower proportion of IL-10-positive cells than the macrophage population. The ratio of moDCs to macrophages was higher on day 3 than on day 5 post-SAH.ConclusionsInflammatory and immune responses are significantly involved in SAH-induced brain injury. Ly6C-high monocytes derived from the bone marrow, including the skull bone marrow, infiltrated into mouse brains via CCL2 secreted from microglia. Moreover, Ly6C-high monocytes alleviated neurological dysfunction after SAH.

Structural and functional changes in the brain after chronic complete thoracic spinal cord injury

This study aimed to investigate whether brain anatomical structures and functional network connectivity are altered after chronic complete thoracic spinal cord injury (cctSCI) and to determine how these changes impact clinical outcomes. Structural and resting-state functional MRI was performed for 19 cctSCI patients (18 for final statistics) and 19 healthy controls. Voxel-based morphometry (VBM) was used to assess gray matter volume (GMV) with differences between cctSCI patients and controls. VBM results were used as seeds for whole-brain functional connectivity (FC) analysis. The relationship between brain changes and clinical variables was investigated. Compared with those of the control group, the left triangular inferior frontal gyrus, middle frontal gyrus, orbital inferior frontal gyrus, precuneus and parietal superior gyrus volumes of SCI patients decreased, while the left superior frontal gyrus and supplementary motor area volumes increased. Additionally, when the regions with increased GMV were used as seeds, the FC of the parahippocampus and thalamus increased. Subsequent partial correlation analysis showed a positive correlation between FC and total sensorimotor score based on the ASIA criteria (p = 0.001, r = 0.746). Overall, the structural and functional changes in the brain after cctSCI occurred in some visual and cognitive areas and sensory or motor control areas. These findings aid in improving our understanding of the underlying brain injury mechanisms and the subsequent structural and functional reorganization to reveal potential therapeutic targets and track treatment outcomes.

Abstract 17490: Impaired Cerebrovascular Oxygen Delivery, Reserve, and Metabolism in Adult Fontan Patients

Introduction: Patients with univentricular hearts undergo a three-stage surgical palliation, culminating in total caval-pulmonary connection (Fontan procedure), maximizing delivery of oxygenated blood to the systemic circulation. Prior brain research in this population has highlighted genetic predisposition, in-utero oxygen delivery, surgical insults, and pre-Fontan cyanosis as possible mechanisms of brain injury, but none have examined the impact of the Fontan repair on brain hemodynamics. Study Purpose: To determine the sufficiency of brain O 2 delivery, cerebrovascular reserve (CVR), brain O 2 extraction fraction (OEF), and cerebral metabolic rate of O 2 (CMRO 2 ) in adult Fontan patients, compared to permeability-surface area (PS) of blood brain barrier (BBB) integrity to water, and endothelin levels. Hypothesis: We hypothesized that brain O 2 delivery, CVR, PS, and CMRO 2 would be decreased in Fontan patients, proportional to endothelin levels, an established surrogate for low cardiac output. Methods: We have enrolled 35 Fontan patients (age 20.8 ± 2.5 years, 21M) and 24 control subjects (age 23.4 ± 4.8 years, 9M) to undergo brain MRI, excluding all subjects with known stroke, seizure, or genetic abnormalities. We collected total cerebral blood flow (CBF), OEF, CVR, and PS using 3T MRI. Results: Table 1 summarizes differences in O 2 delivery, CBF, OEF, CMRO 2 , CVR, PS, and endothelin levels in the study cohort. O 2 delivery, CBF, CVR, and CMRO 2 were decreased in Fontan patients; OEF and PS were not different. Endothelin was increased but uncorrelated with the brain metrics. CMRO 2 was correlated with PS (r 2 = 0.19, p<0.001). Conclusion: Adult survivors of Fontan palliation have decreased brain O 2 delivery and reserve, without compensatory OEF increases, leading to lower CMRO 2 . Decreased CMRO 2 was associated with decreased PS, but not endothelin, suggesting microvascular dysfunction rather than low cardiac output as the fundamental etiology.

Methods matter: Mechanism of traumatic brain injury drives substantial post-traumatic sleep differences

Methods matter: Mechanism of traumatic brain injury drives substantial post-traumatic sleep differences

Methods matter: Mechanism of traumatic brain injury drives substantial post-traumatic sleep differences

Methods matter: Mechanism of traumatic brain injury drives substantial post-traumatic sleep differences

Dynamic strain fields of the mouse brain during rotation.

Mouse models are used to better understand brain injury mechanisms in humans, yet there is a limited understanding of biomechanical relevance, beginning with how the murine brain deforms when the head undergoes rapid rotation from blunt impact. This problem makes it difficult to translate some aspects of diffuse axonal injury from mouse to human. To address this gap, we present the two-dimensional strain field of the mouse brain undergoing dynamic rotation in the sagittal plane. Using a high-speed camera with digital image correlation measurements of the exposed mid-sagittal brain surface, we found that pure rotations (no direct impact to the skull) of 100-200rad/s are capable of producing complex strain fields that evolve over time with respect to rotational acceleration and deceleration. At the highest rotational velocity tested, the largest tensile strains (≥ 21% elongation) in selected regions of the mouse brain approach strain thresholds previously associated with axonal injury in prior work. These findings provide a benchmark to validate the mechanical response in biomechanical computational models predicting diffuse axonal injury, but much work remains in correlating tissue deformation patterns from computational models with underlying neuropathology.

Nano-selenium alleviates cadmium-induced neurotoxicity in cerebrum via inhibiting gap junction protein connexin 43 phosphorylation.

Cadmium (Cd) as a ubiquitous toxic heavy metal is reported to affect the nervous system. Selenium (Se) has been shown to have antagonistic effects against heavy metal toxicity. In addition, it shows potential antioxidant and anti-inflammatory properties. Thus, the purpose of this study was to determine the possible mechanism of brain injury after high Cd exposure and the mitigation of Nano-selenium (Nano-Se) against Cd-induced brain injury. In this study, the Cd-treated group showed a decrease in the number of neurons in brain tissue, swelling of the endoplasmic reticulum and mitochondria, and the formation of autophagosomes. Nano-Se intervention restored Cd-caused alterations in neuronal morphology, endoplasmic reticulum, and mitochondrial structure, thereby reducing neuronal damage. Furthermore, we found that some differentially expressed genes were involved in cell junction and molecular functions. Subsequently, we selected eleven (11) related differentially expressed genes for verification. The qRT-PCR results revealed the same trend of results as determined by RNA-Seq. Our findings also showed that Nano-Se supplementation alleviated Cx43 phosphorylation induced by Cd exposure. Based on immunofluorescence colocalization it was demonstrated that higher expression of GFAP and lower expressions of Cx43 were restored by Nano-Se supplementation. In conclusion, the data presented in this study establish a direct association between the phosphorylation of Cx43 and the occurrence of autophagy and neuroinflammation. However, it is noteworthy that the introduction of Nano-Se supplementation has been observed to mitigate these alterations. These results elucidate the relieving effect of Nano-Se on Cd exposure-induced brain injury.

Role of SIRT1 in sepsis-induced encephalopathy: Molecular targets for future therapies.

Sepsis induces neuroinflammation, BBB disruption, cerebral hypoxia, neuronal mitochondrial dysfunction, and cell death causing sepsis-associated encephalopathy (SAE). These pathological consequences lead to short- and long-term neurobehavioural deficits. Till now there is no specific treatment that directly improves SAE and its associated behavioural impairments. In this review, we discuss the underlying mechanisms of sepsis-induced brain injury with a focus on the latest progress regarding neuroprotective effects of SIRT1 (silent mating type information regulation-2 homologue-1). SIRT1 is an NAD+ -dependent class III protein deacetylase. It is able to modulate multiple downstream signals (including NF-κB, HMGB, AMPK, PGC1α and FoxO), which are involved in the development of SAE by its deacetylation activity. There are multiple recent studies showing the neuroprotective effects of SIRT1 in neuroinflammation related diseases. The proposed neuroprotective action of SIRT1 is meant to bring a promising therapeutic strategy for managing SAE and ameliorating its related behavioural deficits.

A - 156 History of Mild Traumatic Brain Injury Is Not Associated with worse Neuropsychological Functioning in Amnestic Mild Cognitive Impairment.

The mechanisms for traumatic brain injury (TBI) being a risk factor for Alzheimer's disease is unclear, and whether mild TBI (mTBI) may relate to decreased neural circuit functioning in the prodromal phase is unknown. This study examined whether a history of mTBI was associated with lower functioning of neural circuits, measured with neuropsychological tasks, in amnestic Mild Cognitive Impairment (aMCI). Twenty older adults (MAge = 71years; 70% Male; 90% White) with aMCI were recruited to complete a detailed TBI interview and were classified based on the presence (mTBI+ n = 13) or absence (mTBI- n = 7) of past mTBI. Most mTBI+ participants (n = 11) had multiple mTBIs, and on average were 32years from last injury. A comprehensive neuropsychological assessment was administered, and composite T-scores were calculated for the domains of attention, executive functioning, memory, and language. One-tailed T-tests were conducted to compare the means between groups. No statistically significant differences (p's = 0.06-0.09) were found between the groups in memory (mTBI+ M = 38.11; mTBI- M = 33.19), executive function (mTBI+ M = 48.79; mTBI- M = 43.09), language (mTBI+ M = 48.12; mTBI- M = 43.09), or attention (mTBI+ M = 40.54; mTBI- M = 35.57). Nonetheless, medium effect sizes were seen for the mTBI+ group performing better than the mTBI- group on all composite scores (Cohen's d = 0.45-0.66). A history of mTBI was not associated with poorer neuropsychological performance in aMCI, often a prodromal stage of Alzheimer's disease. While concerns about later-in-life effects from multiple mTBIs is prevalent, repetitive mTBI may not be related to lower neural circuit functioning in aMCI, though further evaluation with larger samples is needed.

Optimal rehabilitation strategies for early postacute stroke recovery: An ongoing inquiry.

Early rehabilitation is crucial in reducing stroke-related disability, but the optimal training model remains unclear. We conducted a trial comparing different initiation timings and intensities of mobilization strategies after stroke. Results showed that early intensive mobilization had favorable outcomes at 3 months post-stroke, while very early intensive mobilization had poorer chances of favorable outcomes. Our investigation into brain injury mechanisms induced by very early exercise within 24 hours of stroke onset aligned with guidelines advising against high-dose very early mobilization. Additionally, we are studying the effects of various exercise intensities and frequencies on early stroke rehabilitation. Integrated rehabilitation models, such as combining remote ischemic conditioning (RIC) with exercise (RICE), hold promise. Our study found RICE to be safe and feasible for early rehabilitation of acute ischemic stroke patients, and further research is underway to determine its efficacy in a larger sample size. Despite extensive research, identifying the most effective early recovery strategies remains a complex challenge, necessitating ongoing work in the field of early rehabilitation after stroke.

Ion Channel Dysregulation Following Intracerebral Hemorrhage.

Injury to the brain after intracerebral hemorrhage (ICH) results from numerous complex cellular mechanisms. At present, effective therapy for ICH is limited and a better understanding of the mechanisms of brain injury is necessary to improve prognosis. There is increasing evidence that ion channel dysregulation occurs at multiple stages in primary and secondary brain injury following ICH. Ion channels such as TWIK-related K+ channel 1, sulfonylurea 1 transient receptor potential melastatin 4 and glutamate-gated channels affect ion homeostasis in ICH. They in turn participate in the formation of brain edema, disruption of the blood-brain barrier, and the generation of neurotoxicity. In this review, we summarize the interaction between ions and ion channels, the effects of ion channel dysregulation, and we discuss some therapeutics based on ion-channel modulation following ICH.

Basic Mechanisms of Brain Injury and Cognitive Decline in Hypertension.

Dementia affects almost 50 million adults worldwide, and remains a major cause of death and disability. Hypertension is a leading risk factor for dementia, including Alzheimer disease and Alzheimer disease-related dementias. Although this association is well-established, the mechanisms underlying hypertension-induced cognitive decline remain poorly understood. By exploring the mechanisms mediating the detrimental effects of hypertension on the brain, studies have aimed to provide therapeutic insights and strategies on how to protect the brain from the effects of blood pressure elevation. In this review, we focus on the basic mechanisms contributing to the cerebrovascular adaptions to elevated blood pressure and hypertension-induced microvascular injury. We also assess the cellular mechanisms of neurovascular unit dysfunction, focusing on the premise that cognitive impairment ensues when the dynamic metabolic demands of neurons are not met due to neurovascular uncoupling, and summarize cognitive deficits across various rodent models of hypertension as a resource for investigators. Despite significant advances in antihypertensive therapy, hypertension remains a critical risk factor for cognitive decline, and several questions remain about the development and progression of hypertension-induced cognitive impairment.

Outcomes After the Surgical Evacuation of Traumatic Acute Subdural Hematomas: The tASDH Risk Score

Acute subdural hematoma (ASDH) is a common pathology following traumatic brain injury (TBI). There is sparse data on the prediction of clinical outcomes following traumatic ASDH (tASDH) evacuation. We investigated prognosticators of outcome following evacuation of tASDHs, with subset analysis in a cohort of octogenarians. We developed a scoring system for stratifying the risk of in-hospital mortality for patients undergoing tASDH evacuation. A retrospective chart review was performed to identify all patients who underwent tASDH evacuation. Baseline clinical and demographic data including age, traumatic brain injury mechanism, admission Glasgow Coma Scale (GCS), and Rotterdam computed tomography Scale (RCS) were collected. In-hospital outcomes such as mortality and discharge disposition were collected. A scoring system (tASDH Score) which incorporates RCS (1-2 points), admissions GCS (0-1 points), and age (0-1 point) was created to predict the risk of in-hospital mortality following tASDH evacuation. Being an octogenarian (OR=6.91 [2.20-21.71], P= 0.0009), having a GCS of 9-12 (OR=1.58 [1.32-4.12], P= 0.027) or 3-8 (OR=2.07 [1.41-10.38], P= 0.018), and having an RCS of 4-6 (OR=3.49 [1.45-8.44], P= 0.0055) were independently predictive of in-hospital mortality. The in-hospital mortality rate was lower for those with a tASDH score of 1 (10%), compared to those with a score of 2 (12%), 3 (42%), and 4 (100%). Octogenarians with an RCS of 4-6 and an admission GCS <13 have a high risk of mortality following tASDH evacuation. Knowledge of which patients are unlikely to survive ASDH evacuation may help guide neurosurgeons in prognostication and goals of care discussions.

Optimization of Nutrition after Brain Injury: Mechanistic and Therapeutic Considerations.

Emerging science continues to establish the detrimental effects of malnutrition in acute neurological diseases such as traumatic brain injury, stroke, status epilepticus and anoxic brain injury. The primary pathological pathways responsible for secondary brain injury include neuroinflammation, catabolism, immune suppression and metabolic failure, and these are exacerbated by malnutrition. Given this, there is growing interest in novel nutritional interventions to promote neurological recovery after acute brain injury. In this review, we will describe how malnutrition impacts the biomolecular mechanisms of secondary brain injury in acute neurological disorders, and how nutritional status can be optimized in both pediatric and adult populations. We will further highlight emerging therapeutic approaches, including specialized diets that aim to resolve neuroinflammation, immunodeficiency and metabolic crisis, by providing pre-clinical and clinical evidence that their use promotes neurologic recovery. Using nutrition as a targeted treatment is appealing for several reasons that will be discussed. Given the high mortality and both short- and long-term morbidity associated with acute brain injuries, novel translational and clinical approaches are needed.

COVID-19 and the Nervous System from a Cuban Experience.

Neuropsychiatric manifestations of viral infections (both per se and secondary to the neuroinflammatory reaction of the host) are mainly attributed to immunological reactions, so many aspects of their pathogenesis are still nuclear. Some novel therapeutic strategies are progressively emerging in which a vaccination may be having a particular impact on recovery and reduction of death. In this context, it is accepted that the SARS-CoV-2 virus is profoundly neurotropic and neuroinvasive, with various effects on the nervous system, although there is no complete understanding of the mechanism of neuroinvasion, brain injury, or short- or long-term neuropsychiatric sequelae. Therefore, it is necessary to understand the post-infectious manifestations of COVID-19 to guide the management of neuropsychiatric diseases. Thus, based on different research groups focused on this field, in this manuscript we summarize papers on COVID-19 and the nervous system (NS) published in a series of articles by Cuban authors. This review focuses on cognitive and affective emotional states, pathogenesis, biomarkers, clinical manifestations, and intervention strategies.

Oxidative stress and early mortality in acute ischemic stroke: A prospective cohort study

ABSTRACT Background Malondialdehyde (MDA) is an oxidative stress biomarker, which represents a unifying mechanism of brain injury that occurs throughout the ischemic stroke cascade. The current study aimed to examine whether or not acute ischemic stroke (AIS) patients who had elevated serum MDA levels at admission had an increased risk of mortality and a worse functional outcome three months later. Methods An observational, prospective cohort study that enrolled 90 patients with AIS. The patients were examined in the first 24 hours and then followed up for three months to assess mortality, short-term neurological functional outcome, and neurological disability by the Modified Rankin Scale (MRS). Results The mean of serum MDA level among AIS patients was 6.3 ± 3.7 nmol/ml. Non-survivor cases were associated with statistically significantly higher serum MDA levels compared to survivors (9.7 ± 4.3 vs. 5.3 ± 2.8, p < 0.001), respectively. Patients with severe stroke, according to NIHSS score, were associated with significantly (p < 0.05) higher MDA levels compared to moderate and mild cases (7.4 ± 4.3 vs. 5.4 ± 2.6 vs. 3.3 ± .6). At a cutoff point of ≥ 6.7 nmol/ml, the area under the curve (AUC) for serum MDA levels as a predictor of mortality was 0.8 (0.69–0.91; p < 0.05). The sensitivity, specificity, positive predictive value, and negative predictive value were 77%, 80%, 89.5%, and 48.5%, respectively. Multivariate regression demonstrated that MDA level was a significant independent predictor of mortality among patients with AIS (OR = 1.29, 95% CI: 1.01 to 1.65; p = 0.041). Conclusion MDA serum level was significantly higher in non-survivors than in survivors patients, so MDA could be used as a predictor for early mortality and short-term outcome of cases with AIS.

Inflammasome Activation Mediates Apoptotic and Pyroptotic Death in Astrocytes Under Ischemic Conditions.

Inflammation is a hallmark mechanism of ischemic stroke-induced brain injury. Recent studies have shown that an intracellular multimeric protein complex known as an inflammasome is a key factor for inducing an inflammatory response, and apoptotic and pyroptotic cell death in ischemic stroke. Inflammasome assembly leads to the activation of pro-inflammatory caspases, and the maturation and secretion of pro-inflammatory cytokines IL-1β and IL-18. While the role of inflammasomes in ischemic stroke-induced neuronal death, and microglial activation and cell death have been established, little is known about the role of inflammasomes in astrocytes under ischemic conditions. In this study, we investigated the expression and activation of inflammasome components in protoplasmic and fibrous astrocytes under ischemic conditions. We found that both protoplasmic and fibrous astrocytes expressed a differential increase in inflammasome protein components, and that their activation promoted maturation of IL-1β and IL-18, and secretion of IL-1β, as well as initiating apoptotic and pyroptotic cell death. Pharmacological inhibition of caspase-1 decreased expression of cleaved caspase-1 and production of mature IL-1β, and protected against inflammasome-mediated apoptotic and pyroptotic cell death. Overall, this study provides novel insights into the role of inflammasome signaling in astrocytes under ischemic conditions.

Activation of autophagy after blast-induced traumatic brain injury in mice.

Injury mechanism and treatment of blast-induced traumatic brain injury (bTBI) has not made a breakthrough so far. Previous reports demonstrate autophagy is involved in regulating the pathophysiological process after TBI. Therefore, this study explored whether autophagy was activated after bTBI. A total of 108 mice were divided randomly into six groups: 6 h, 1 d, 3 d, 7 d, 14 d after bTBI groups and sham group. The protein levels of anti-microtubule associated protein 1 light chain 3B (LC3B, hereafter referred to as LC3), beclin1 and p62 were detected using western blot. Moreover, HO-1 and Nrf2 were localized using histologic staining. Immunofluorescence of LC3 and immunohistochemistry of beclin1 were performed. The autophagy-related ultrastructure was observed by TEM. LC3-II and beclin1 reached their peak on day 3 after bTBI, while p62 showed a continuous downward trend. Immunofluorescence and immunohistochemistry also confirmed that the expression levels of LC3 and beclin1 were the highest at 3 days after bTBI. Autophagic vesicles containing lysosomes or digestive residual structures were observed then. Autophagy was induced in the frontal lobe tissues of bTBI mice induced by moderate-intensity explosion, with a peak at 3d and a gradual decline thereafter.

Morpho-mechanical mapping of human dura mater microstructure

The human dura mater is known to impact vastly traumatic brain injury mechanopathology. In spite of this involvement, dura mater is typically neglected in computational and physical human head models. The lack of location-dependent microstructural and related mechanical data of dura mater may be considered a rationale behind this simplification. The anisotropic nature of dura mater under various loading conditions so far remains unelucidated. Furthermore, principal collagen fiber orientation is yet to be quantified for a morpho-mechanically-informed material model on the dura mater. This study aims to assess how location-dependent mechanical anisotropy is linked to principal collagen fiber orientation. Uniaxial extension tests were performed in a heated tissue bath for 60 samples from six individuals and correlated to the three-dimensional collagen structure in four individuals using second-harmonic generation (SHG) imaging. Failure stress and stretch at failure, elastic modulus, and a microstructurally motivated material model were integrated to examine local differences in dura mater morpho-mechanics. The quantitative observation of collagen fiber orientation and dispersion confirmed that collagen is highly aligned in the human dura mater and that both fiber orientation and dispersion differ depending on the location investigated. This observation provides a possible explanation for the previously observed isotropic mechanical behavior, as the main collagen fiber direction is not oriented along the anterior-posterior or medial-lateral direction at most of the mapped locations. Additionally, these site-dependent structural properties have implications for the mechanical load response and therefore potentially for the regional functions dura mater has to fulfill. The here chosen non-symmetrical fiber dispersion material model fits the data well and provides a comprehensive parameter base for further studies and future finite element models. Statement of significanceThe human dura mater greatly affects traumatic brain injury mechanisms, but it is often ignored in computational and physical head models. This is because there is a lack of detailed microstructural and mechanical data specific to the dura mater. Its anisotropic nature and collagen fiber orientation have not been fully understood, hindering the development of an accurate material model. Hence, this study combines morphological data on collagen fiber orientation and dispersion at multiple locations of human cranial dura mater, and links microstructure to location-specific load-displacement behavior. It provides microstructurally informed mechanical information towards realistic head models for predicting location-dependent tissue behavior and failure for assessing brain injury and graft material development.

Paediatric organ donation following neurological determinants of death in intensive care units in Saudi Arabia: a retrospective cross-sectional study

ObjectivesThe aim of this retrospective cross-sectional study was to assess the performance of paediatric organ donation in intensive care units following neurological determinants of death in Saudi Arabia.DesignRetrospective cross-sectional study.SettingPaediatric...