Brain Injury Research Articles

Metabolic-driven analytics of traumatic brain injury and neuroprotection by ethyl pyruvate

Abstract Background Research on traumatic brain injury (TBI) highlights the significance of counteracting its metabolic impact via exogenous fuels to support metabolism and diminish cellular damage. While ethyl pyruvate (EP) treatment shows promise in normalizing cellular metabolism and providing neuroprotection, there is a gap in understanding the precise metabolic pathways involved. Metabolomic analysis of the acute post-injury metabolic effects, with and without EP treatment, aims to deepen our knowledge by identifying and comparing the metabolite profiles, thereby illuminating the injury's effects and EP's therapeutic potential. Methods In the current study, an untargeted metabolomics approach was used to reveal brain metabolism changes in rats 24 h after a controlled cortical impact (CCI) injury, with or without EP treatment. Using principal component analysis (PCA), volcano plots, Random Forest and pathway analysis we differentiated the brain metabolomes of CCI and sham injured animals treated with saline (Veh) or EP, identifying key metabolites and pathways affected by injury. Additionally, the effect of EP on the non-injured brain was also explored. Results PCA showed a clear separation of the four study groups (sham-Veh, CCI-Veh, sham-EP, CCI-EP) based on injury. Following CCI injury (CCI-Veh), 109 metabolites belonging to the amino acid, carbohydrate, lipid, nucleotide, and xenobiotic families exhibited a twofold change at 24 h compared to the sham-Veh group, with 93 of these significantly increasing and 16 significantly decreasing (p < 0.05). CCI animals were treated with EP (CCI-EP) showed only 5 metabolites in the carbohydrate, amino acids, peptides, nucleotides, lipids, and xenobiotics super families that exhibited a twofold change, compared to the CCI-Veh group (p < 0.05). In the non-injured brain, EP treatment (sham-EP) resulted in a twofold change in 6 metabolites within the amino acid, peptide, nucleotide, and lipid super families compared to saline treated sham animals (sham-Veh, p < 0.05). Conclusions This study delineates the unique metabolic signatures resulting from a CCI injury and those related to EP treatment in both the injured and non-injured brain, underscoring the metabolic adaptations to brain injury and the effects of EP. Our analysis uncovers significant shifts in metabolites associated with inflammation, energy metabolism, and neuroprotection after injury, and demonstrates how EP intervention after injury alters metabolites associated with mitigating inflammation and oxidative damage.

Timing of Neonatal Discharge and Unplanned Readmission to PICUs Among Infants Born Preterm

ImportanceChildren born very preterm (<32 weeks) are at risk of ongoing morbidity and admission to pediatric intensive care units (PICUs) in childhood. However, the influence of the timing of neonatal discharge on unplanned PICU admission has not been established.ObjectiveTo examine whether the timing of neonatal discharge (postmenstrual age and season) is associated with subsequent unplanned PICU admission.Design, Setting, and ParticipantsThis retrospective cohort study used linked national data from the National Neonatal Research Database and Paediatric Intensive Care Audit Network (PICANet) for children born from January 2013 to December 2018 at 22 to 31 weeks’ gestational age who were admitted to a neonatal unit in England and Wales and were discharged home at 34 weeks’ postmenstrual age or later. All National Health Service (NHS) neonatal units and PICUs in England and Wales were included. Children were followed up until 2 years of chronological age. Data analysis was conducted from October 2023 to August 2024.ExposuresTiming of discharge.Main Outcomes and MeasuresThe primary outcome was unplanned PICU admission between neonatal discharge and chronological age 2 years to any PICU within England and Wales. Survival analysis using a flexible parametric model was conducted with season of discharge (time-dependent factor), gestation, sex, birth weight less than the 10th centile, bronchopulmonary dysplasia, necrotizing enterocolitis, brain injury, and earlier neonatal discharge (lower quartile of postmenstrual age at discharge for gestation) as variables.ResultsOf 39 938 children discharged home (median [IQR] gestational age, 29 [27-31] weeks; 21 602 [54.1%] male), 1878 (4.7%) had unplanned PICU admission. More than half of admissions occurred within 50 days of neonatal discharge (1080 [57.5%]). Compared with summer, the risk of unplanned PICU admission following neonatal discharge was 2.58 times higher in winter and 2.35 times higher in autumn (winter: adjusted hazard ratio [aHR], 2.58; 95% CI, 1.68-3.95; autumn: aHR, 2.35; 95% CI, 1.84-2.99). Among children born at 28 to 31 weeks’ gestational age, earlier neonatal discharge was associated with increased risk (aHR, 1.30; 95% CI, 1.13-1.49), but this was not true for children born younger than 28 weeks’ gestational age.Conclusions and RelevanceIn this retrospective cohort study of preterm children, autumn and winter discharge were associated with the highest risk of unplanned PICU admission following neonatal discharge. For children born at 28 to 31 weeks’ gestational age, discharge at lower postmenstrual age was also associated with increased risk. Further work is required to understand whether delaying neonatal discharge for some children born at 28 to 31 weeks’ gestational age is beneficial and to consider the wider costs and implications of prolonging neonatal care.

Neurological Surgery Manpower Training and Density in Islamic Republic of Iran: A Population Study

BACKGROUND AND OBJECTIVES: Significant disparities in worldwide neurosurgical training and workforce distribution are prominent primarily in low-income and middle-income countries. Although Iran is considered a lower middle–income country, neurosurgical density and distribution in Iran has surpassed the recommended ratio of 1 neurosurgeon for every 100 000 population. The objective was to determine neurological surgery density and distribution in Iran and the factors significant in the relative success in training and allocation of neurosurgeons in Iran. METHODS: Review of PubMed and administration of site surveys of multiple data sources including Neurosurgical Society of Iran, Iranian Board of Neurological Surgery, Medical Council of Islamic Republic of Iran, Universities of Medical Sciences in Iran, and Ministry of Health and Higher Education of Iran. RESULTS: Over the 72-year period from 1952 to 2024, 1200 neurosurgeons have been trained and distributed in 31 provinces in Iran, attaining a ratio of 1.4/100 000 population. All but 40 neurosurgeons were trained after 1981, which coincided with the Iran-Iraq War. Decentralization of medical and neurosurgical residency training programs, resolving the immediate need for neurosurgeons managing penetrating traumatic brain and spinal cord injuries during the 1980 to 1988 Iran-Iraq War, and active participation of legislative and executive branches of government in solving health care disparities were major factors in meeting the needs of the country. At the present time, more than 555 neurosurgeons are practicing in Tehran Province, a proportion of 3.8 neurosurgeons for every 100 000 population, which indicates an element of disparity in density distribution across Iranian land. CONCLUSION: Legislative initiatives and government support of public health care delivery and decentralization of medical and residency training programs after the Iran-Iraq War and introduction of the Ministry of Health and Medical Education are considered the main reasons for the relative success in meeting the neurosurgical demand and manpower density. Still, further adjustment of distribution of manpower is needed.

Traumatic Brain Injury as a Public Health Issue: Epidemiology, Prognostic Factors and Useful Data from Forensic Practice

Traumatic brain injury (TBI) represents a major public health problem, being a leading cause of disability and mortality among young people in developed countries. Head trauma occurs across all age groups, each experiencing consistently high rates of mortality and disability. This review aims to present an overview of TBI epidemiology and its socioeconomic impact, alongside data valuable for prevention, clinical management, and research efforts. Methods: A narrative review of TBI was performed with a particular focus on forensic pathology and public health. In fact, this review highlighted the economic and epidemiological aspects of TBI, as well as autopsy, histology, immunohistochemistry, and miRNA. Results: These data, together with immunohistochemical markers, are crucial for histopathological diagnosis and to determine the timing of injury onset, a fundamental aspect in forensic pathology practice. There is compelling evidence that brain injury biomarkers may enhance predictive models for clinical and prognostic outcomes. By clarifying the cause of death and providing details on survival time after trauma, forensic tools offer valuable information to improve the clinical management of TBI and guide preventive interventions. Conclusions: TBI is one of the most common causes of death today, with high costs for health care spending. Knowing the different mechanisms of TBI, reduces health care costs and helps improve prognosis.

Impact of fever on the outcome non-anoxic acute brain injury patients: a systematic review and meta-analysis

Impact of fever on the outcome non-anoxic acute brain injury patients: a systematic review and meta-analysis

An increase of lysosomes through EGF-triggered endocytosis attenuated zinc-mediated lysosomal membrane permeabilization and neuronal cell death

AbstractIn the context of acute brain injuries, where zinc neurotoxicity and oxidative stress are acknowledged contributors to neuronal damage, we investigated the pivotal role of lysosomes as a potential protective mechanism. Our research commenced with an exploration of epidermal growth factor (EGF) and its impact on lysosomal dynamics, particularly its neuroprotective potential against zinc-induced cytotoxicity. Using primary mouse cerebrocortical cultures, we observed the rapid induction of EGFR endocytosis triggered by EGF, resulting in a transient increase in lysosomal vesicles. Furthermore, EGF stimulated lysosomal biogenesis, evident through elevated expression of lysosomal-associated membrane protein 1 (LAMP-1) and the induction and activation of prominent lysosomal proteases, particularly cathepsin B (CTSB). This process of EGFR endocytosis was found to promote lysosomal augmentation, thus conferring protection against zinc-induced lysosomal membrane permeabilization (LMP) and subsequent neuronal death. Notably, the neuroprotective effects and lysosomal enhancement induced by EGF were almost completely reversed by the inhibition of clathrin-mediated and caveolin-mediated endocytosis pathways, along with the disruption of retrograde trafficking. Furthermore, tyrosine kinase inhibition of EGFR nullified EGFR endocytosis, resulting in the abrogation of EGF-induced lysosomal upregulation and neuroprotection. An intriguing aspect of our study is the successful replication of EGF’s neuroprotective effects through the overexpression of LAMP-1, which significantly reduced zinc-induced LMP and cell death, demonstrated in both primary mouse cerebrocortical neuronal cultures and human embryonic kidney (HEK) cells. Our research extended beyond zinc-induced neurotoxicity, as we observed EGF’s protective effects against other oxidative stressors linked to intracellular zinc release, including hydrogen peroxide (H2O2) and 1-methyl-4-phenylpyridinium ion (MPP+). Collectively, our findings unveil the intricate interplay between EGF-triggered EGFR endocytosis, lysosomal upregulation, an increase in the regulatory capacity for zinc homeostasis, and the subsequent alleviation of zinc-induced neurotoxicity. These results present promising avenues for therapeutic interventions to enhance neuroprotection by targeting lysosomal augmentation.

Optimal functioning after early mild traumatic brain injury: Evolution and predictors

Abstract Introduction and objectives: Early mild traumatic brain injury (mTBI or concussion sustained between 0 and 5 years old) can lead to post-concussive symptoms, behavioral changes, and cognitive difficulties. Although school-age children (6–17 years old) experience similar consequences, severe neuropsychological deficits are not common, and the majority have no persisting symptoms after one month. Thus, there may be value in focusing on what characterizes optimal functioning (or wellness) after mTBI, but this has not been explored in young children. This study documents the evolution and predictors of optimal functioning after early mTBI. Method: Participants were 190 children aged 18 – 60 months with mTBI (n = 69), orthopedic injury (OI; n = 50), or typical development (TDC; n = 71). Optimal functioning was defined as: (1) no clinically significant behavioral problems; (2) no cognitive difficulties; (3) no persisting post-concussive symptoms; (4) average quality of life or better. Predictors related to sociodemographic, injury, child, and caregiver characteristics included number of acute symptoms, child sex, age, temperament, maternal education, parent-child attachment and interaction quality, and parenting stress. Results: Fewer children with mTBI had optimal functioning over 6 and 18-months post-injury compared to those with OI and TDC. Higher parent-child interaction quality and lower child negative affectivity temperament independently predicted optimal functioning. Conclusion: Children who sustain early mTBI are less likely to exhibit optimal functioning than their peers in the long-term. Parent-child interaction quality could be a potential intervention target for promoting optimal function.

Collaborative Care to Improve Quality of Life for Anxiety and Depression in Posttraumatic Epilepsy (CoCarePTE): Protocol for a Randomized Hybrid Effectiveness-Implementation Trial

Background Anxiety and depression in people with epilepsy are common and associated with poor outcomes; yet, they often go untreated due to poor mental health specialist access. Collaborative care is an integrated care model with a strong evidence base in primary care and medical settings, but it has not been evaluated in neurology clinics. Evaluating implementation outcomes when translating evidence-based interventions to new clinical settings to inform future scaling and incorporation into real-world practice is important. Objective The Collaborative Care for Posttraumatic Epilepsy (CoCarePTE) trial aims to evaluate the effectiveness (improvement in emotional quality of life) and implementation of a collaborative care intervention for people with anxiety or depressive symptoms and posttraumatic epilepsy. Methods CoCarePTE is a 2-site, randomized, single-blind, hybrid type 1 effectiveness-implementation trial that will randomize 60 adults to receive either neurology-based collaborative care or usual care. Adults receiving neurological care at participating centers with anxiety or depressive symptoms and a history of at least mild traumatic brain injury before epilepsy onset will be enrolled. The collaborative care intervention is a 24-week stepped-care model with video or telephone calls every 2 weeks by a care manager for measurement-based anxiety and depression care, seizure care monitoring, and brief therapy intervention delivery. This is supplemented by antidepressant prescribing recommendations by psychiatrists for neurologists via case conferences and care manager–facilitated team communication. In step 2 of the intervention, individuals with <50% symptom reduction by 10 weeks will receive an added 8-session remote cognitive behavioral therapy program. The study is powered to detect a moderate improvement in emotional quality of life. As a hybrid type 1 trial, effectiveness is the primary focus, with the primary outcome being a change in emotional quality of life at 6 months in the intervention group compared to control. Secondary effectiveness outcomes are 6-month changes in depression, anxiety, and overall quality of life. Implementation outcomes, including fidelity, acceptability, feasibility, and appropriateness, are evaluated before implementation and at 3 months. The primary effectiveness analysis will compare changes in emotional quality of life scores from baseline to 6 months between the intervention and control arms using multiple linear regression modeling, adjusting for study site and using an intent-to-treat approach. Results Enrollment commenced in 2023, with modifications in the inclusion and exclusion made after the first 6 enrollees due to slow recruitment. Enrollment is expected to continue at least into early 2025. Conclusions The CoCarePTE trial is novel in its use of a hybrid effectiveness-implementation design to evaluate an evidence-based mental health intervention in epilepsy, and by incorporating seizure care into a collaborative care model. If a significant improvement in emotional quality of life is found in the intervention group compared to usual care, this would support next step scaling or clinical implementation. Trial Registration ClinicalTrials.gov NCT05353452; https://www.clinicaltrials.gov/study/NCT05353452 International Registered Report Identifier (IRRID) DERR1-10.2196/59329

The Intersection of Traumatic Brain Injury, Substance Abuse, and Mental Health Disorders in Incarcerated Women Addressing Intergenerational Trauma through Neuropsychological Rehabilitation

The intersection of traumatic brain injury (TBI), substance abuse, and mental health disorders presents a significant challenge within the incarcerated female population, where rates of these conditions are alarmingly high. This paper explores the multifaceted relationships among TBI, substance abuse, and mental health disorders, emphasizing the impact of intergenerational trauma on this vulnerable group. Women in correctional facilities often experience a history of trauma, exacerbating their mental health challenges and increasing the likelihood of substance use as a maladaptive coping mechanism. The cumulative effects of TBI can further complicate their psychological and emotional well-being, leading to a cycle of trauma that is perpetuated across generations. Through a review of current literature and case studies, this paper advocates for the implementation of neuropsychological rehabilitation programs that address the unique needs of incarcerated women. Such interventions are crucial not only for improving individual outcomes but also for breaking the cycle of trauma that affects families and communities. Recommendations for policy reforms and future research directions are provided to enhance the efficacy of rehabilitation efforts and support the reintegration of these women into society.

Pharmacogenomic screening identifies and repurposes leucovorin and dyclonine as pro-oligodendrogenic compounds in brain repair

AbstractOligodendrocytes are critical for CNS myelin formation and are involved in preterm-birth brain injury (PBI) and multiple sclerosis (MS), both of which lack effective treatments. We present a pharmacogenomic approach that identifies compounds with potent pro-oligodendrogenic activity, selected through a scoring strategy (OligoScore) based on their modulation of oligodendrogenic and (re)myelination-related transcriptional programs. Through in vitro neural and oligodendrocyte progenitor cell (OPC) cultures, ex vivo cerebellar explants, and in vivo mouse models of PBI and MS, we identify FDA-approved leucovorin and dyclonine as promising candidates. In a neonatal chronic hypoxia mouse model mimicking PBI, both compounds promote neural progenitor cell proliferation and oligodendroglial fate acquisition, with leucovorin further enhancing differentiation. In an adult MS model of focal de/remyelination, they improve lesion repair by promoting OPC differentiation while preserving the OPC pool. Additionally, they shift microglia from a pro-inflammatory to a pro-regenerative profile and enhance myelin debris clearance. These findings support the repurposing of leucovorin and dyclonine for clinical trials targeting myelin disorders, offering potential therapeutic avenues for PBI and MS.

Timing Matters: A Comprehensive Meta-Analysis on the Optimal Period for Cranioplasty After Severe Traumatic Brain Injury

BACKGROUND AND OBJECTIVES: Craniectomy is a commonly performed procedure in severe traumatic brain injury (TBI) to control intracranial hypertension and reduce mortality. The optimal timing for cranioplasty after craniectomy remains a topic of debate. The aim of this study was to investigate the ideal timing for cranioplasty after severe TBI, focusing on complications associated with temporal aspects and materials used in cranioplasty. METHODS: Multiple databases, including PubMed, Embase, Cochrane, and Web of Science, were searched for studies reporting on the subject. Inclusion criteria involved randomized and observational studies comparing early and late cranioplasty procedures. Quality assessment was performed using the Methodological Index for Non-Randomized Studies scale. Results were pooled in a single-arm meta-analysis and presented as mean and 95% confidence interval. RESULTS: Early cranioplasty was associated with a lower likelihood of subdural effusion (odds ratio [OR] 0.3735 [0.1643; 0.8490], P = .0187). However, no differences were detected for the presence of infection between both groups (OR 0.7460 [0.2065; 2.6945], P = .6548). Cranioplasties performed within or equal to 3 months from the TBI incident were associated with a reduced likelihood of minor complications (OR 0.4471 [0.2467; 0.8102], P = .0080). Paradoxically, this time frame exhibited an elevated risk of hydrocephalus (OR 3.2035 [1.4860; 6.9059], P = .0030), as well as total complications (OR 1.4190 [1.0453; 1.9262] P = .0248). CONCLUSION: This comprehensive review highlights the current lack of consensus on the optimal timing for cranioplasty after severe TBI. Early cranioplasty, within 35 days, showed a reduced risk of subdural effusion, but no disparity in the odds of infection was found. A reduced incidence of minor complications was observed in the earlier approach, however with an elevated risk for hydrocephalus and total complications. The association between timing and complications, including hydrocephalus, highlights the need for further research and standardization in this critical aspect of TBI management.

Concussion leads to opposing sensorimotor effects of habituation deficit and fatigue in zebrafish larvae

Abstract Concussion, or mild traumatic brain injury, is caused by sudden mechanical forces impacting the brain either directly or through inertial loading. This can lead to physical, behavioural, and cognitive impairments 1. Despite concussion being a significant health issue, our understanding of the relationship between initial impact force and the subsequent neurological consequences is not well understood. Previously, we established a model of concussion in zebrafish larvae 2. Here we further investigate concussions of varying severities in zebrafish larvae using linear deceleration. Using an acoustic assay to monitor the larval sensorimotor behaviour 3, we found that different parameters of the resulting escape behaviour are modulated by the impact force of the preceding concussive insult. To investigate the relative contributions of habituation performance and fatigue on the escape response behaviour, we constructed a neurocomputational model. Our findings suggest that a concussive impact initially affects habituation performance at first and, as the impact force increases, fatigue is induced. Fatigue then alters the escape response behaviour in an opposing manner.

Cerebrovascular markers of WMH and infarcts in ADNI: A historical perspective and future directions

AbstractWhite matter hyperintensities (WMH) and infarcts found on magnetic resonance imaging (MR infarcts) are common biomarkers of cerebrovascular disease. In this review, we summarize the methods, publications, and conclusions stemming from the Alzheimer's Disease Neuroimaging Initiative (ADNI) related to these measures. We combine analysis of WMH and MR infarct data from across the three main ADNI cohorts with a review of existing literature discussing new methodologies and scientific findings derived from these data. Although ADNI inclusion criteria were designed to minimize vascular risk factors and disease, data across all the ADNI cohorts found consistent trends of increasing WMH volumes associated with advancing age, female sex, and cognitive impairment. ADNI, initially proposed as a study to investigate biomarkers of AD pathology, has also helped elucidate the impact of asymptomatic cerebrovascular brain injury on cognition within a cohort relatively free of vascular disease. Future ADNI work will emphasize additional vascular biomarkers.Highlights White matter hyperintensities (WMHs) are common to advancing age and likely reflect brain vascular injury among older individuals. WMH and to a lesser extent, magnetic resonance (MR) infarcts, affect risk for transition to cognitive impairment. WMHs and MR infarcts are present, even among Alzheimer's Disease Neuroimaging Initiative (ADNI) participants highly selected to have Alzheimer's disease (AD) as the primary pathology. WMH burden in ADNI is greater among individuals with cognitive impairment and has been associated with AD neurodegenerative markers and cerebral amyloidosis. The negative additive effects of cerebrovascular disease appear present, even in select populations, and future biomarker work needs to further explore this relationship.

Calcium bridges built by mitochondria-associated endoplasmic reticulum membranes: potential targets for neural repair in neurological diseases

The exchange of information and materials between organelles plays a crucial role in regulating cellular physiological functions and metabolic levels. Mitochondria-associated endoplasmic reticulum membranes serve as physical contact channels between the endoplasmic reticulum membrane and the mitochondrial outer membrane, formed by various proteins and protein complexes. This microstructural domain mediates several specialized functions, including calcium (Ca2+) signaling, autophagy, mitochondrial morphology, oxidative stress response, and apoptosis. Notably, the dysregulation of Ca2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes is a critical factor in the pathogenesis of neurological diseases. Certain proteins or protein complexes within these membranes directly or indirectly regulate the distance between the endoplasmic reticulum and mitochondria, as well as the transduction of Ca2+ signaling. Conversely, Ca2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes influences other mitochondria-associated endoplasmic reticulum membrane-associated functions. These functions can vary significantly across different neurological diseases–such as ischemic stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease–and their respective stages of progression. Targeted modulation of these disease-related pathways and functional proteins can enhance neurological function and promote the regeneration and repair of damaged neurons. Therefore, mitochondria-associated endoplasmic reticulum membranes-mediated Ca2+ signaling plays a pivotal role in the pathological progression of neurological diseases and represents a significant potential therapeutic target. This review focuses on the effects of protein complexes in mitochondria-associated endoplasmic reticulum membranes and the distinct roles of mitochondria-associated endoplasmic reticulum membranes-mediated Ca2+ signaling in neurological diseases, specifically highlighting the early protective effects and neuronal damage that can result from prolonged mitochondrial Ca2+ overload or deficiency. This article provides a comprehensive analysis of the various mechanisms of Ca2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes in neurological diseases, contributing to the exploration of potential therapeutic targets for promoting neuroprotection and nerve repair.

Self-reported dizziness, balance, and multisensory impairment following mild traumatic brain injury: an exploratory study

Self-reported dizziness, balance, and multisensory impairment following mild traumatic brain injury: an exploratory study

Cortical structural network characteristics in non-cognitive impairment end-stage renal disease

ObjectiveExplore alterations in topological features of gray matter volume (GMV) and structural networks in non-cognitive impairment end-stage renal disease (Non-CI ESRD).Materials and methodsUtilizing graph theory, we collected structural magnetic resonance imaging (sMRI) data from 38 Non-CI ESRD patients and 50 normal controls (NC). We compared, and extracted the GMV across subject groups, constructed corresponding structural covariance networks (SCNs), and investigated the alterations in SCNs feature parameters between groups.ResultsIn Non-CI ESRD patients, The GMV were reduced in several brain regions, predominantly on the left side (p < 0.05, FWE correction). The small-world network characteristics of the patient group’s brain networks showed a tendency toward regular. In a few densities, global network parameters, transitivity, (p < 0.05) was significantly increased in the ESRD group. Regional network measurements revealed inconsistent changes in regional efficiency across different brain areas. In the analysis of network hubs, the right temporal pole is likely a compensatory hub for Non-CI ESRD patients. The SCNs in Non-CI ESRD patients demonstrated reduced topological stability against targeted attacks.ConclusionThis study reveals that patients with renal failure exhibited subtle changes in brain network characteristics even before a decline in cognitive scores. These changes involve compensatory activation in certain brain regions, which enhances network transitivity to maintain the efficiency of whole-brain network information integration without significant loss. Additionally, the SCNs characteristics can serve as a neuroanatomical marker for brain alterations in Non-CI ESRD patients, offering new insights into the mechanisms of early brain injury in ESRD patients.

Epigenetic regulation of the inflammatory response in stroke

Stroke is classified as ischemic or hemorrhagic, and there are few effective treatments for either type. Immunologic mechanisms play a critical role in secondary brain injury following a stroke, which manifests as cytokine release, blood–brain barrier disruption, neuronal cell death, and ultimately behavioral impairment. Suppressing the inflammatory response has been shown to mitigate this cascade of events in experimental stroke models. However, in clinical trials of anti-inflammatory agents, long-term immunosuppression has not demonstrated significant clinical benefits for patients. This may be attributable to the dichotomous roles of inflammation in both tissue injury and repair, as well as the complex pathophysiologic inflammatory processes in stroke. Inhibiting acute harmful inflammatory responses or inducing a phenotypic shift from a pro-inflammatory to an anti-inflammatory state at specific time points after a stroke are alternative and promising therapeutic strategies. Identifying agents that can modulate inflammation requires a detailed understanding of the inflammatory processes of stroke. Furthermore, epigenetic reprogramming plays a crucial role in modulating post-stroke inflammation and can potentially be exploited for stroke management. In this review, we summarize current findings on the epigenetic regulation of the inflammatory response in stroke, focusing on key signaling pathways including nuclear factor-kappa B, Janus kinase/ signal transducer and activator of transcription, and mitogen-activated protein kinase as well as inflammasome activation. We also discuss promising molecular targets for stroke treatment. The evidence to date indicates that therapeutic targeting of the epigenetic regulation of inflammation can shift the balance from inflammation-induced tissue injury to repair following stroke, leading to improved post-stroke outcomes.

Psychological correlates of the good old days bias in mild traumatic brain injury

ABSTRACT Non-neurological factors such as the “expectation as etiology” or the “good old days” bias (EE/GOD bias) may partially explain persistent symptoms following mild traumatic brain injury (MTBI). What is less clear from existing research is the degree to which EE/GOD bias is related to other psychological correlates of persistent post-concussive symptoms (PPCS). We examined whether the EE/GOD bias was related to illness perception beliefs, intolerance of uncertainty, suggestibility, and domain identification. Participants with MTBI history and without (controls) reported frequency and severity of current PPCS; the MTBI group additionally reported premorbid PPCS. Participants also completed measures of psychological factors potentially associated with PPCS. Consistent with previous studies of the EE/GOD bias, the MTBI group endorsed less premorbid PPCS than current PPCS and when compared to the current symptom report of the control group. The MTBI group also endorsed more current PPCS than the control group. Higher EE/GOD bias was associated with several aspects of illness identity, including belief that symptoms would be more chronic, greater illness-related psychological distress, and greater cogniphobia. Higher EE/GOD bias was also related to higher intolerance of uncertainty and stronger personal identification with memory abilities. Regression showed that perceived symptom timeline, cogniphobia, and domain identification were unique predictors of EE/GOD bias. Findings confirm that the EE/GOD bias is seen in individuals with self-reported history of MTBI and corresponds to other psychological processes that potentially explain ongoing MTBI symptoms, providing greater insight into the potential mechanisms of PPCS. Future studies should examine the EE/GOD bias and associated psychological correlates in a clinical population and also assess for potential neuropsychological correlates. Findings suggest that psychological factors and premorbid symptom report should be considered in clinical assessment and also suggest potential mechanisms of treatment of individuals with acute MTBI or prolonged MTBI symptoms.

Preterm Brain Injury: Mechanisms and Challenges

Preterm fetuses and newborns have a high risk of neural injury and impaired neural maturation, leading to neurodevelopmental disability. Developing effective treatments is rather challenging, as preterm brain injury may occur at any time during pregnancy and postnatally, and many cases involve multiple pathogenic factors. This review examines research on how the preterm fetus responds to hypoxia-ischemia and how brain injury evolves after hypoxia-ischemia, offering windows of opportunity for treatment and insights into the mechanisms of injury during key phases. We highlight research showing that preterm fetuses can survive hypoxia-ischemia and continue development in utero with evolving brain injury. Early detection of fetal brain injury would provide an opportunity for treatments to reduce adverse neurodevelopmental outcomes, including cerebral palsy. However, this requires that we can detect injury using noninvasive methods. We discuss how circadian changes in fetal heart rate variability may offer utility as a biomarker for detecting injury and phases of injury.

The Impact of the Histone Deacetylase Inhibitor—Sodium Butyrate on Complement-Mediated Synapse Loss in a Rat Model of Neonatal Hypoxia–Ischemia

AbstractPerinatal asphyxia is one of the most important causes of morbidity and mortality in newborns. One of the key pathogenic factors in hypoxic-ischemic (HI) brain injury is the inflammatory reaction including complement system activation. Over-activated complement stimulates cells to release inflammatory molecules and is involved in the post-ischemic degradation of synaptic connections. On the other hand, complement is also involved in regenerative processes. The histone deacetylase inhibitor (HDACi)—sodium butyrate (SB)—provides reduction of inflammation by decreasing the expression of the proinflammatory factors. The main purpose of this study was to examine the effect of SB treatment on complement activation and synapse elimination after HI. Neonatal HI was induced in Wistar rats pups by unilateral ligation of the common carotid artery followed by 60-min hypoxia (7.6% O2). SB (300 mg/kg) was administered on a 5-day regimen. Our study has shown decreased levels of synapsin I, synaptophysin, and PSD-95 in the hypoxic-ischemic hemisphere, indicating synaptic loss after neonatal HI. Transmission electron microscopy revealed injury of the synaptic structures in the brain after HI. SB treatment increased the level of the synaptic proteins, improved tissue ultrastructure, and reduced degradation of the synapses. Neonatal HI induced mRNA expression of the complement C1q, C3, C5, and C9, and their receptors C3aR and C5aR. The effect of SB was different depending on the time after induction of hypoxic-ischemic damage. Our study demonstrated that neuroprotective effect of SB may be related to the modulation of complement activity after HI brain injury.