Comparación de la efectividad entre distintas intervenciones en los síntomas posconmoción en adolescentes y jóvenes: una revisión bibliográfica / Comparison of effectiveness between different interventions in postconcussive symptoms in adolescents and young people: A literature review

Introducción: Actualmente la conmoción cerebral se considera un problema de gran magnitud, siendo los adolescentes y jóvenes la población de riesgo, ya que se encuentran en proceso de maduración. Nuestro objetivo ha sido comparar la eficacia de diferentes intervenciones (ejercicio físico terapéutico, terapia vestibular y descanso) en adolescentes y jóvenes con conmoción cerebral.Desarrollo: Se realizó una búsqueda bibliográfica en las principales bases de datos. Una vez aplicados los criterios de inclusión/exclusión y la escala metodológica Physiotherapy Evidence Database PEDro, fueron revisados seis artículos. Los resultados apoyan la utilización del ejercicio y la terapia vestibular en las etapas iniciales para disminuir los síntomas posconmoción. Según la mayoría de los autores, el ejercicio físico terapéutico y la terapia vestibular reportan mayores beneficios, aunque se necesitaría un protocolo que unificara escalas de valoración, variables de estudio y parámetros de análisis para poder realizar la inferencia en la población diana.Conclusión: Desde el momento del alta hospitalaria del paciente, la aplicación combinada de ejercicio físico y terapia vestibular, podría considerarse como la mejor opción para disminuir los síntomas posconmoción.(AU)

Introduction: Currently, concussion considers a problem of great magnitude, adolescents and young people being the population at risk, since it is in the process of maturation. Our goal has been to compare the effectiveness of different interventions (exercise therapy, vestibular rehabilitation and rest) in adolescents and young people with concussion. Development: A bibliographic search was carried out in the main databases. Once the inclusion / exclusion criteria and the PEDro methodological scale were applied, 6 articles were reviewed. The results support the use of exercise and vestibular rehabilitation in the initial stages to reduce post-concussion symptoms. According to most authors, therapeutic physical exercise and vestibular rehabilitation report greater benefits, although a protocol that unifies assessment scales, study variables and analysis parameters would be needed to be able to make the inference in the target population. Conclusión: From the moment of hospital discharge, the combined application of exercise and vestibular rehabilitation could be the best option to reduce post-concussion symptoms.(AU)

[Injury mechanism, clinical status and prospects of traumatic brain injury].

Traumatic brain injury (TBI) is an important in the world's public health and an important subject of basic and clinical research in the medical field. In the past 30 years, the epidemiology, injury mechanism, safety prevention, medical strategies, nursing measures and other aspects of TBI have made great progress, and the level of treatment has also been continuously improved, but it still faces many challenges. The focus of research on the injury mechanism of TBI has gradually shifted from the classic signaling pathways of primary injury to the study of secondary injury mechanisms. Pharmacological research on various therapeutic targets has also made significant progress, which is expected to be transformed into new TBI therapeutic drugs. On the other hand, many new clinical concepts, new systems, and new methods are constantly being integrated into the diagnosis and treatment of TBI, which has gradually transformed from the original treatment of acute neurological injury to the comprehensive treatment of chronic systemic diseases. This paper is based on the latest research progress in the basic and clinical aspects of TBI, and provides a review of its current status and development trends, providing reference for the medical treatment and research of TBI.

FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury.

BACKGROUND: Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury (TBI). However, the heterogeneity, multifunctionality, and time-dependent modulation of brain damage and outcome mediated by neutrophils after TBI remain poorly understood. METHODS: Using the combined single-cell transcriptomics, metabolomics, and proteomics analysis from TBI patients and the TBI mouse model, we investigate a novel neutrophil phenotype and its associated effects on TBI outcome by neurological deficit scoring and behavioral tests. We also characterized the underlying mechanisms both in vitro and in vivo through molecular simulations, signaling detections, gene expression regulation assessments [including dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays], primary cultures or co-cultures of neutrophils and oligodendrocytes, intracellular iron, and lipid hydroperoxide concentration measurements, as well as forkhead box protein O1 (FOXO1) conditional knockout mice. RESULTS: We identified that high expression of the FOXO1 protein was induced in neutrophils after TBI both in TBI patients and the TBI mouse model. Infiltration of these FOXO1high neutrophils in the brain was detected not only in the acute phase but also in the chronic phase post-TBI, aggravating acute brain inflammatory damage and promoting late TBI-induced depression. In the acute stage, FOXO1 upregulated cytoplasmic Versican (VCAN) to interact with the apoptosis regulator B-cell lymphoma-2 (BCL-2)-associated X protein (BAX), suppressing the mitochondrial translocation of BAX, which mediated the antiapoptotic effect companied with enhancing interleukin-6 (IL-6) production of FOXO1high neutrophils. In the chronic stage, the "FOXO1-transferrin receptor (TFRC)" mechanism contributes to FOXO1high neutrophil ferroptosis, disturbing the iron homeostasis of oligodendrocytes and inducing a reduction in myelin basic protein, which contributes to the progression of late depression after TBI. CONCLUSIONS: FOXO1high neutrophils represent a novel neutrophil phenotype that emerges in response to acute and chronic TBI, which provides insight into the heterogeneity, reprogramming activity, and versatility of neutrophils in TBI.

Bi-directional neuro-immune dysfunction after chronic experimental brain injury.

BACKGROUND: It is well established that traumatic brain injury (TBI) causes acute and chronic alterations in systemic immune function and that systemic immune changes contribute to posttraumatic neuroinflammation and neurodegeneration. However, how TBI affects bone marrow (BM) hematopoietic stem/progenitor cells chronically and to what extent such changes may negatively impact innate immunity and neurological function has not been examined. METHODS: To further understand the role of BM cell derivatives on TBI outcome, we generated BM chimeric mice by transplanting BM from chronically injured or sham (i.e., 90 days post-surgery) congenic donor mice into otherwise healthy, age-matched, irradiated CD45.2 C57BL/6 (WT) hosts. Immune changes were evaluated by flow cytometry, multiplex ELISA, and NanoString technology. Moderate-to-severe TBI was induced by controlled cortical impact injury and neurological function was measured using a battery of behavioral tests. RESULTS: TBI induced chronic alterations in the transcriptome of BM lineage-c-Kit+Sca1+ (LSK+) cells in C57BL/6 mice, including modified epigenetic and senescence pathways. After 8 weeks of reconstitution, peripheral myeloid cells from TBI→WT mice showed significantly higher oxidative stress levels and reduced phagocytic activity. At eight months after reconstitution, TBI→WT chimeric mice were leukopenic, with continued alterations in phagocytosis and oxidative stress responses, as well as persistent neurological deficits. Gene expression analysis revealed BM-driven changes in neuroinflammation and neuropathology after 8 weeks and 8 months of reconstitution, respectively. Chimeric mice subjected to TBI at 8 weeks and 8 months post-reconstitution showed that longer reconstitution periods (i.e., time post-injury) were associated with increased microgliosis and leukocyte infiltration. Pre-treatment with a senolytic agent, ABT-263, significantly improved behavioral performance of aged C57BL/6 mice at baseline, although it did not attenuate neuroinflammation in the acutely injured brain. CONCLUSIONS: TBI causes chronic activation and progressive dysfunction of the BM stem/progenitor cell pool, which drives long-term deficits in hematopoiesis, innate immunity, and neurological function, as well as altered sensitivity to subsequent brain injury.

Extracellular vesicles as carriers for noncoding RNA-based regulation of macrophage/microglia polarization: an emerging candidate regulator for lung and traumatic brain injuries.

Macrophage/microglia function as immune defense and homeostatic cells that originate from bone marrow progenitor cells. Macrophage/microglia activation is historically divided into proinflammatory M1 or anti-inflammatory M2 states based on intracellular dynamics and protein production. The polarization of macrophages/microglia involves a pivotal impact in modulating the development of inflammatory disorders, namely lung and traumatic brain injuries. Recent evidence indicates shared signaling pathways in lung and traumatic brain injuries, regulated through non-coding RNAs (ncRNAs) loaded into extracellular vesicles (EVs). This packaging protects ncRNAs from degradation. These vesicles are subcellular components released through a paracellular mechanism, constituting a group of nanoparticles that involve exosomes, microvesicles, and apoptotic bodies. EVs are characterized by a double-layered membrane and are abound with proteins, nucleic acids, and other bioactive compounds. ncRNAs are RNA molecules with functional roles, despite their absence of coding capacity. They actively participate in the regulation of mRNA expression and function through various mechanisms. Recent studies pointed out that selective packaging of ncRNAs into EVs plays a role in modulating distinct facets of macrophage/microglia polarization, under conditions of lung and traumatic brain injuries. This study will explore the latest findings regarding the role of EVs in the progression of lung and traumatic brain injuries, with a specific focus on the involvement of ncRNAs within these vesicles. The conclusion of this review will emphasize the clinical opportunities presented by EV-ncRNAs, underscoring their potential functions as both biomarkers and targets for therapeutic interventions.

Cutoff of the reverse shock index multiplied by the Glasgow coma scale for predicting in-hospital mortality in adult patients with trauma: a retrospective cohort study.

BACKGROUND: Early identification of patients at risk of potential death and timely transfer to appropriate healthcare facilities are critical for reducing the number of preventable trauma deaths. This study aimed to establish a cutoff value to predict in-hospital mortality using the reverse shock index multiplied by the Glasgow Coma Scale (rSIG). METHODS: This multicenter retrospective cohort study used data from 23 emergency departments in South Korea between January 2011 and December 2020. The outcome variable was the in-hospital mortality. The relationship between rSIG and in-hospital mortality was plotted using the shape-restricted regression spline method. To set a cutoff for rSIG, we found the point on the curve where mortality started to increase and the point where the slope of the mortality curve changed the most. We also calculated the cutoff value for rSIG using Youden's index. RESULTS: A total of 318,506 adult patients with trauma were included. The shape-restricted regression spline curve showed that in-hospital mortality began to increase when the rSIG value was less than 18.86, and the slope of the graph increased the most at 12.57. The cutoff of 16.5, calculated using Youden's index, was closest to the target under-triage and over-triage rates, as suggested by the American College of Surgeons, when applied to patients with an rSIG of 20 or less. In addition, in patients with traumatic brain injury, when the rSIG value was over 25, in-hospital mortality tended to increase as the rSIG value increased. CONCLUSIONS: We propose an rSIG cutoff value of 16.5 as a predictor of in-hospital mortality in adult patients with trauma. However, in patients with traumatic brain injury, a high rSIG is also associated with in-hospital mortality. Appropriate cutoffs should be established for this group in the future.

Applicability and clinical utility of the German rivermead post-concussion symptoms questionnaire in proxies of children after traumatic brain injury: an instrument validation study.

BACKGROUND: The German Rivermead Post-Concussion Symptoms Questionnaire (RPQ) can be used to assess post-concussion symptoms (PCS) after traumatic brain injury (TBI) in adults, adolescents, and children. METHODS: In this study, we examined the psychometric properties of the German RPQ proxy version (N = 146) for children (8-12 years) after TBI at the item, total and scale score level. Construct validity was analyzed using rank correlations with the proxy-assessed Post-Concussion Symptoms Inventory (PCSI-P), the Patient Health Questionnaire 9 (PHQ-9), and the Generalized Anxiety Disorder Scale 7 (GAD-7). Furthermore, sensitivity testing was performed concerning subjects' sociodemographic and injury-related characteristics. Differential item functioning (DIF) was analyzed to assess the comparability of RPQ proxy ratings for children with those for adolescents. RESULTS: Good internal consistency was demonstrated regarding Cronbach's α (0.81-0.90) and McDonald's ω (0.84-0.92). The factorial validity of a three-factor model was superior to the original one-factor model. Proxy ratings of the RPQ total and scale scores were strongly correlated with the PCSI-P (ϱ = 0.50-0.69), as well as moderately to strongly correlated with the PHQ-9 (ϱ = 0.49-0.65) and the GAD-7 (ϱ = 0.44-0.64). The DIF analysis revealed no relevant differences between the child and adolescent proxy versions. CONCLUSIONS: The German RPQ proxy is a psychometrically reliable and valid instrument for assessing PCS in children after TBI. Therefore, RPQ self- and proxy-ratings can be used to assess PCS in childhood as well as along the lifespan of an individual after TBI.

Establishment of a model to predict mortality after decompression craniotomy for traumatic brain injury.

BACKGROUND: The mortality rate of patients with traumatic brain injury (TBI) is still high even while undergoing decompressive craniectomy (DC), and the expensive treatment costs bring huge economic burden to the families of patients. OBJECTIVE: The aim of this study was to identify preoperative indicators that influence patient outcomes and to develop a risk model for predicting patient mortality by a retrospective analysis of TBI patients undergoing DC. METHODS: A total of 288 TBI patients treated with DC, admitted to the First Affiliated Hospital of Shantou University Medical School from August 2015 to April 2021, were used for univariate and multivariate logistic regression analysis to determine the risk factors for death after DC in TBI patients. We also built a risk model for the identified risk factors and conducted internal verification and model evaluation. RESULTS: Univariate and multivariate logistic regression analysis identified four risk factors: Glasgow Coma Scale, age, activated partial thrombin time, and mean CT value of the superior sagittal sinus. These risk factors can be obtained before DC. In addition, we also developed a 3-month mortality risk model and conducted a bootstrap 1000 resampling internal validation, with C-indices of 0.852 and 0.845, respectively. CONCLUSIONS: We developed a risk model that has clinical significance for the early identification of patients who will still die after DC. Interestingly, we also identified a new early risk factor for TBI patients after DC, that is, preoperative mean CT value of the superior sagittal sinus (p < .05).

PECARN prediction rules for CT imaging of children presenting to the emergency department with blunt abdominal or minor head trauma: a multicentre prospective validation study.

BACKGROUND: The intra-abdominal injury and traumatic brain injury prediction rules derived by the Pediatric Emergency Care Applied Research Network (PECARN) were designed to reduce inappropriate use of CT in children with abdominal and head trauma, respectively. We aimed to validate these prediction rules for children presenting to emergency departments with blunt abdominal or minor head trauma. METHODS: For this prospective validation study, we enrolled children and adolescents younger than 18 years presenting to six emergency departments in Sacramento (CA), Dallas (TX), Houston (TX), San Diego (CA), Los Angeles (CA), and Oakland (CA), USA between Dec 27, 2016, and Sept 1, 2021. We excluded patients who were pregnant or had pre-existing neurological disorders preventing examination, penetrating trauma, injuries more than 24 h before arrival, CT or MRI before transfer, or high suspicion of non-accidental trauma. Children presenting with blunt abdominal trauma were enrolled into an abdominal trauma cohort, and children with minor head trauma were enrolled into one of two age-segregated minor head trauma cohorts (younger than 2 years vs aged 2 years and older). Enrolled children were clinically examined in the emergency department, and CT scans were obtained at the attending clinician's discretion. All enrolled children were evaluated against the variables of the pertinent PECARN prediction rule before CT results were seen. The primary outcome of interest in the abdominal trauma cohort was intra-abdominal injury undergoing acute intervention (therapeutic laparotomy, angiographic embolisation, blood transfusion, intravenous fluid for ≥2 days for pancreatic or gastrointestinal injuries, or death from intra-abdominal injury). In the age-segregated minor head trauma cohorts, the primary outcome of interest was clinically important traumatic brain injury (neurosurgery, intubation for >24 h for traumatic brain injury, or hospital admission ≥2 nights for ongoing symptoms and CT-confirmed traumatic brain injury; or death from traumatic brain injury). FINDINGS: 7542 children with blunt abdominal trauma and 19 999 children with minor head trauma were enrolled. The intra-abdominal injury rule had a sensitivity of 100·0% (95% CI 98·0-100·0; correct test for 145 of 145 patients with intra-abdominal injury undergoing acute intervention) and a negative predictive value (NPV) of 100·0% (95% CI 99·9-100·0; correct test for 3488 of 3488 patients without intra-abdominal injuries undergoing acute intervention). The traumatic brain injury rule for children younger than 2 years had a sensitivity of 100·0% (93·1-100·0; 42 of 42) for clinically important traumatic brain injuries and an NPV of 100·0%; 99·9-100·0; 2940 of 2940), whereas the traumatic brain injury rule for children aged 2 years and older had a sensitivity of 98·8% (95·8-99·9; 168 of 170) and an NPV of 100·0% (99·9-100·0; 6015 of 6017). The two children who were misclassified by the traumatic brain injury rule were admitted to hospital for observation but did not need neurosurgery. INTERPRETATION: The PECARN intra-abdominal injury and traumatic brain injury rules were validated with a high degree of accuracy. Their implementation in paediatric emergency departments can therefore be considered a safe strategy to minimise inappropriate CT use in children needing high-quality care for abdominal or head trauma. FUNDING: The Eunice Kennedy Shriver National Institute of Child Health and Human Development.

GPT-agents based on medical guidelines can improve the responsiveness and explainability of outcomes for traumatic brain injury rehabilitation.

This study explored the application of generative pre-trained transformer (GPT) agents based on medical guidelines using large language model (LLM) technology for traumatic brain injury (TBI) rehabilitation-related questions. To assess the effectiveness of multiple agents (GPT-agents) created using GPT-4, a comparison was conducted using direct GPT-4 as the control group (GPT-4). The GPT-agents comprised multiple agents with distinct functions, including "Medical Guideline Classification", "Question Retrieval", "Matching Evaluation", "Intelligent Question Answering (QA)", and "Results Evaluation and Source Citation". Brain rehabilitation questions were selected from the doctor-patient Q&A database for assessment. The primary endpoint was a better answer. The secondary endpoints were accuracy, completeness, explainability, and empathy. Thirty questions were answered; overall GPT-agents took substantially longer and more words to respond than GPT-4 (time: 54.05 vs. 9.66 s, words: 371 vs. 57). However, GPT-agents provided superior answers in more cases compared to GPT-4 (66.7 vs. 33.3%). GPT-Agents surpassed GPT-4 in accuracy evaluation (3.8 ± 1.02 vs. 3.2 ± 0.96, p = 0.0234). No difference in incomplete answers was found (2 ± 0.87 vs. 1.7 ± 0.79, p = 0.213). However, in terms of explainability (2.79 ± 0.45 vs. 07 ± 0.52, p < 0.001) and empathy (2.63 ± 0.57 vs. 1.08 ± 0.51, p < 0.001) evaluation, the GPT-agents performed notably better. Based on medical guidelines, GPT-agents enhanced the accuracy and empathy of responses to TBI rehabilitation questions. This study provides guideline references and demonstrates improved clinical explainability. However, further validation through multicenter trials in a clinical setting is necessary. This study offers practical insights and establishes groundwork for the potential theoretical integration of LLM-agents medicine.

Implementation of a strengths-based approach in a traumatic brain injury community service; perspectives of community workers.

Background The strengths-based approach (SBA) was initially developed for people living with mental health issues but may represent a promising support option for community participation of people living with a traumatic brain injury (TBI). A community-based organisation working with people living with TBI is in the process of adapting this approach to implement it in their organisation. No studies explored an SBA implementation with this population. This study explores the implementation of key components of the SBA in a community-based organisation dedicated to people living with TBI. Methods A qualitative descriptive design using semi-structured interviews (n = 10) with community workers, before and during implementation, was used. Transcripts were analysed inductively and deductively. Deductive coding was informed by the SBA fidelity scale. Results Group supervision and mobilisation of personal strengths are key SBA components that were reported as being integrated within practice. These changes led to improved team communication and cohesiveness in and across services, more structured interventions, and greater engagement of clients. No changes were reported regarding the mobilisation of environmental strengths and the provision of individual supervision. Conclusion The implementation of the SBA had positive impacts on the community-based organisation. This suggests that it is valuable to implement an adaptation of the SBA for people living with TBI.

Co-designing for behavioural change: understanding barriers and enablers to addressing sexuality after traumatic brain injury and mapping intervention strategies in a multi-disciplinary rehabilitation unit.

Background Persistent changes in sexuality often follow traumatic brain injury (TBI). However, health professionals remain reticent about discussing sexuality and have reported barriers including uncertainties around whose role it is and limited educational and institutional support. This study employed a co-design and implementation process, aiming to promote team-wide behavioural change, whereby health professionals at a TBI rehabilitation unit would attempt to address sexuality with patients routinely. Methods Focus group sessions with multidisciplinary health professionals were conducted to identify barriers and enablers to behavioural change, identify areas for development, and co-design intervention options. Implementation deliverables were then finalised and provided to the team. The Theoretical Domains Framework was used to map factors influencing behaviours and the Behaviour Change Wheel was used to map interventions. Thematic analysis was used to further analyse barrier themes. Results Thirty-five barriers and eight enablers falling within 12 theoretical domains to behavioural change were identified. Thematic analysis revealed highly correlated barriers in initiating and sustaining change. Nine co-designed intervention options aligned with five intervention functions of the Behaviour Change Wheel, resulting in six final implementation deliverables. Conclusions Barriers were highly interrelated, influencing the approach to implementation deliverables. Simultaneously addressing multiple barriers could potentially alleviate discomfort associated with discussing sexuality. Concerns around initiating change were related to confidence in achieving sustainable changes. Achieving change requires organisational and team-level environmental restructuring and enablement. The next step involves evaluating the effectiveness of the co-design and implementation process in driving behavioural change and potential impacts on patient satisfaction and sexuality outcomes.

Implementation of activities of daily living retraining for individuals in post-traumatic amnesia.

Background Despite evidence of the efficacy of activities of daily living (ADL) retraining during post-traumatic amnesia (PTA) following traumatic brain injury (TBI), utilisation of this intervention in practice is unclear. Utilising an implementation science framework, the Consolidated Framework for Implementation Research, this study explored efforts to translate ADL retraining during PTA into the clinical practice of occupational therapists (OTs) working in TBI rehabilitation settings across Australia. Methods Participants were 44 OTs who attended a day-long training workshop that included knowledge and skill-based content regarding ADL retraining during PTA. Baseline and post-training ratings were completed including evaluation of workshop utility, and skill and knowledge-based competencies relevant to the intervention. Approximately 2 years later, nine trained OTs and two administrators were interviewed to explore the results of implementing the intervention. Results Overall, the training workshop was rated as being helpful and OT ratings of confidence (P P Conclusion Multiple barriers were identified in implementation of ADL retraining during PTA and require consideration to facilitate translation and promote best practice.

Oxygen Straight to the Brain: An Overview of Hyperbaric Oxygen Therapy for a Variety of Brain Morbidities.

ABSTRACT: Hyperbaric oxygen therapy as a treatment for conditions like traumatic brain injury, posttraumatic stress disorder, and migraines would seem intuitive, given its effect on condition-related ischemia and inflammation. However, hyperbaric therapeutic impacts for these in acute and chronic, or prolonged symptoms are elusive. This narrative review of hyperbaric's utility provided in sections per disease renders first a review of conventional pathological mechanisms and then articulates hyperbaric treatment targets versus their respective impacts. Multiple challenges exist using hyperbaric oxygen therapy for each morbidity, even in tertiary and adjunctive treatments. An almost universal shortfall across studies includes a lack of consistent, appropriate patient selection criteria intersected with delivery timing of therapy to symptomatic target, necessary to provide a higher fidelity in treatment metrics. Further research into these respective conditions is needed along with a revisitation of hyperbaric oxygen therapy's application to their conventional pathological mechanisms, lending new perspective to their employment and efficacy.

A Novel Experimental Approach for the Measurement of Vibration-Induced Changes in the Rheological Properties of Ex Vivo Ovine Brain Tissue.

Increased incidence of traumatic brain injury (TBI) imposes a growing need to understand the pathology of brain trauma. A correlation between the incidence of multiple brain traumas and rates of behavioural and cognitive deficiencies has been identified amongst people that experienced multiple TBI events. Mechanically, repetitive TBIs may affect brain tissue in a similar way to cyclic loading. Hence, the potential susceptibility of brain tissue to mechanical fatigue is of interest. Although temporal changes in ovine brain tissue viscoelasticity and biological fatigue of other tissues such as tendons and arteries have been investigated, no methodology currently exists to cyclically load ex vivo brain tissue. A novel rheology-based approach found a consistent, initial stiffening response of the brain tissue before a notable softening when subjected to a subsequential cyclic rotational shear. History dependence of the mechanical properties of brain tissue indicates susceptibility to mechanical fatigue. Results from this investigation increase understanding of the fatigue properties of brain tissue and could be used to strengthen therapy and prevention of TBI, or computational models of repetitive head injuries.

Long-Term Impact of Diffuse Traumatic Brain Injury on Neuroinflammation and Catecholaminergic Signaling: Potential Relevance for Parkinson's Disease Risk.

Traumatic brain injury (TBI) is associated with an increased risk of developing Parkinson's disease (PD), though the exact mechanisms remain unclear. TBI triggers acute neuroinflammation and catecholamine dysfunction post-injury, both implicated in PD pathophysiology. The long-term impact on these pathways following TBI, however, remains uncertain. In this study, male Sprague-Dawley rats underwent sham surgery or Marmarou's impact acceleration model to induce varying TBI severities: single mild TBI (mTBI), repetitive mild TBI (rmTBI), or moderate-severe TBI (msTBI). At 12 months post-injury, astrocyte reactivity (GFAP) and microglial levels (IBA1) were assessed in the striatum (STR), substantia nigra (SN), and prefrontal cortex (PFC) using immunohistochemistry. Key enzymes and receptors involved in catecholaminergic transmission were measured via Western blot within the same regions. Minimal changes in these markers were observed, regardless of initial injury severity. Following mTBI, elevated protein levels of dopamine D1 receptors (DRD1) were noted in the PFC, while msTBI resulted in increased alpha-2A adrenoceptors (ADRA2A) in the STR and decreased dopamine beta-hydroxylase (DßH) in the SN. Neuroinflammatory changes were subtle, with a reduced number of GFAP+ cells in the SN following msTBI. However, considering the potential for neurodegenerative outcomes to manifest decades after injury, longer post-injury intervals may be necessary to observe PD-relevant alterations within these systems.

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.

Fibrin promotes oxidative stress and neuronal loss in traumatic brain injury via innate immune activation.

BACKGROUND: Traumatic brain injury (TBI) causes significant blood-brain barrier (BBB) breakdown, resulting in the extravasation of blood proteins into the brain. The impact of blood proteins, especially fibrinogen, on inflammation and neurodegeneration post-TBI is not fully understood, highlighting a critical gap in our comprehension of TBI pathology and its connection to innate immune activation. METHODS: We combined vascular casting with 3D imaging of solvent-cleared organs (uDISCO) to study the spatial distribution of the blood coagulation protein fibrinogen in large, intact brain volumes and assessed the temporal regulation of the fibrin(ogen) deposition by immunohistochemistry in a murine model of TBI. Fibrin(ogen) deposition and innate immune cell markers were co-localized by immunohistochemistry in mouse and human brains after TBI. We assessed the role of fibrinogen in TBI using unbiased transcriptomics, flow cytometry and immunohistochemistry for innate immune and neuronal markers in Fggγ390-396A knock-in mice, which express a mutant fibrinogen that retains normal clotting function, but lacks the γ390-396 binding motif to CD11b/CD18 integrin receptor. RESULTS: We show that cerebral fibrinogen deposits were associated with activated innate immune cells in both human and murine TBI. Genetic elimination of fibrin-CD11b interaction reduced peripheral monocyte recruitment and the activation of inflammatory and reactive oxygen species (ROS) gene pathways in microglia and macrophages after TBI. Blockade of the fibrin-CD11b interaction was also protective from oxidative stress damage and cortical loss after TBI. CONCLUSIONS: These data suggest that fibrinogen is a regulator of innate immune activation and neurodegeneration in TBI. Abrogating post-injury neuroinflammation by selective blockade of fibrin's inflammatory functions may have implications for long-term neurologic recovery following brain trauma.