Mild Blast Exposure Dysregulates Metabolic Pathways and Correlation Networking as Evident from LC-MS-Based Plasma Profiling.

Blast-induced trauma is emerging as a serious threat due to its wide pathophysiology where not only the brain but also a spectrum of organs is being affected. In the present study, we aim to identify the plasma-based metabolic dysregulations along with the associated temporal changes at 5-6 h, day 1 and day 7 post-injury in a preclinical animal model for blast exposure, through liquid chromatography-mass spectrometry (LC-MS). Using significantly advanced metabolomic and statistical bioinformatic platforms, we were able to elucidate better and unravel the complex networks of blast-induced neurotrauma (BINT) and its interlinked systemic effects. Significant changes were evident at 5-6 h with maximal changes at day 1. Temporal analysis also depicted progressive changes which continued till day 7. Significant associations of metabolic markers belonging to the class of amino acids, energy-related molecules, lipids, vitamin, hormone, phenolic acid, keto and histidine derivatives, nucleic acid molecules, uremic toxins, and uronic acids were observed. Also, the present study is the first of its kind where comprehensive, detailed pathway dysregulations of amino acid metabolism and biosynthesis, perturbed nucleotides, lipid peroxidation, and nucleic acid damage followed by correlation networking and multiomics networking were explored on preclinical animal models exposed to mild blast trauma. In addition, markers for systemic changes (renal dysfunction) were also observed. Global pathway predictions of unannotated peaks also presented important insights into BINT pathophysiology. Conclusively, the present study depicts important findings that might help underpin the biological mechanisms of blast-induced brain or systemic trauma.

Temporary ambiguity and memory for the context of spoken language in adults with moderate-severe traumatic brain injury.

Language is processed incrementally, with addressees considering multiple candidate interpretations as speech unfolds, supporting the retention of these candidate interpretations in memory. For example, after interpreting the utterance, "Click on the striped bag", listeners exhibit better memory for non-mentioned items in the context that were temporarily consistent with what was said (e.g., dotted bag), vs. not consistent (e.g., dotted tie), reflecting the encoding of linguistic context in memory. Here, we examine the impact of moderate-severe traumatic brain injury (TBI) on memory for the contexts of language use. Participants with moderate-severe TBI (N=71) and non-injured comparison participants (NC, N=85) interpreted temporarily ambiguous utterances in rich contexts. A subsequent memory test demonstrated that participants with TBI exhibited impaired memory for context items and an attenuated memory advantage for mentioned items compared to NC participants. Nonetheless, participants with TBI showed similar, although attenuated, patterns in memory for temporarily-activated items as NC participants.

Attrition, adherence, and compliance to exercise training interventions in persons with traumatic brain injury: a systematic review of training studies.

BACKGROUND: Exercise training (ET) is a promising rehabilitation approach for long-term negative consequences of traumatic brain injury (TBI). However, little is known regarding overall rates of attrition, adherence, and compliance to ET in TBI. OBJECTIVE: The purpose of this systematic review was to estimate average attrition, adherence, and compliance rates in ET studies in persons with TBI. METHODS: Databases were searched from inception to April 15, 2024. Two authors independently extracted data related to attrition, adherence, compliance, and possible moderators identified a priori. RESULTS: The average rate of attrition from 45 studies was 14.4%, although the majority of studies had small sample sizes (i.e. n < 42). Based on hierarchical linear regression, the most influential predictors of attrition were sample size and study design. A minority of studies reported adherence (44.4%) or compliance (22.2%) but those that did reported good average adherence (85.1%) and compliance (77.7%). These studies support the ability of persons with TBI to complete an ET intervention as prescribed. CONCLUSIONS: Researchers can use this information to ensure adequate power to detect a true effect of ET in persons with TBI. Researchers conducting ET studies in persons with TBI should clearly and thoroughly report data on attrition, adherence, and compliance.

A Systematic Review of the Relationship Between Traumatic Brain Injury and Disruptions in Heart Rate Variability.

Autonomic nervous system dysfunction is increasingly recognized as a common sequela of traumatic brain injury (TBI). Heart rate variability (HRV) is a specific measure of autonomic nervous system functioning that can be used to measure beat-to-beat changes in heart rate following TBI. The objective of this systematic review was to determine the state of the literature on HRV dysfunction following TBI, assess the level of support for HRV dysfunction following TBI, and determine if HRV dysfunction predicts mortality and the severity and subsequent recovery of TBI symptoms. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two raters coded each article and provided quality ratings with discrepancies resolved by consensus. Eighty-nine papers met the inclusion criteria. Findings indicated that TBI of any severity is associated with decreased (i.e., worse) HRV; the severity of TBI appears to moderate the relationship between HRV and recovery; decreased HRV following TBI predicts mortality beyond age; HRV disturbances may persist beyond return-to-play and symptom resolution following mild TBI. Overall, current literature suggests HRV is decreased following TBI and may be a good indicator of physiological change and predictor of important outcomes including mortality and symptom improvement following TBI.

Neuroimmune and neuroinflammation response for traumatic brain injury.

Traumatic brain injury (TBI) is one of the major diseases leading to mortality and disability, causing a serious disease burden on individuals' ordinary lives as well as socioeconomics. In primary injury, neuroimmune and neuroinflammation are both responsible for the TBI. Besides, extensive and sustained injury induced by neuroimmune and neuroinflammation also prolongs the course and worsens prognosis of TBI. Therefore, this review aims to explore the role of neuroimmune, neuroinflammation and factors associated them in TBI as well as the therapies for TBI. Thus, we conducted by searching PubMed, Scopus, and Web of Science databases for articles published between 2010 and 2023. Keywords included "traumatic brain injury," "neuroimmune response," "neuroinflammation," "astrocytes," "microglia," and "NLRP3." Articles were selected based on relevance and quality of evidence. On this basis, we provide the cellular and molecular mechanisms of TBI-induced both neuroimmune and neuroinflammation response, as well as the different factors affecting them, are introduced based on physiology of TBI, which supply a clear overview in TBI-induced chain-reacting, for a better understanding of TBI and to offer more thoughts on the future therapies for TBI.

Chronic glial activation and behavioral alterations induced by acute/subacute pioglitazone treatment in a mouse model of traumatic brain injury.

Traumatic brain injury (TBI) is a disabling neurotraumatic condition and the leading cause of injury-related deaths and disability in the United States. Attenuation of neuroinflammation early after TBI is considered an important treatment target; however, while these inflammatory responses can induce secondary brain injury, they are also involved in the repair of the nervous system. Pioglitazone, which activates peroxisome proliferator-activated receptor gamma, has been shown to decrease inflammation acutely after TBI, but the long-term consequences of its use remain unknown. For this reason, the impacts of treatment with pioglitazone during the acute/subacute phase (30 min after injury and each subsequent 24 h for 5 days) after TBI were interrogated during the chronic phase (30- and 274-days post-injury (DPI)) in mice using the controlled cortical impact model of experimental TBI. Acute/subacute pioglitazone treatment after TBI results in long-term deleterious consequences, including disruption of tau homeostasis, chronic glial cell activation, neuronal pathology, and worsened injury severity particularly at 274 DPI, with male mice being more susceptible than female mice. Further, male pioglitazone-treated TBI mice exhibited increased dominant and offensive-like behavior while having a decreased non-social exploring behavior at 274 DPI. After TBI, both sexes exhibited glial activation at 30 DPI when treated with pioglitazone; however, while injury severity was increased in females it was not impacted in male mice. This work reveals that although pioglitazone has been shown to lead to attenuated TBI outcomes acutely, sex-based differences, timing and long-term consequences of treatment with glitazones must be considered and further studied prior to their clinical use for TBI therapy.

Characterization of an Advanced Blast Simulator for Investigation of Large Scale Blast Traumatic Brain Injury Studies.

Blast traumatic brain injury (bTBI) is a prominent military health concern. The pervasiveness and long-term impacts of this injury highlight the need for investigation of the physiological outcomes of bTBI. Preclinical models allow for the evaluation of behavioral and neuropathological sequelae associated with bTBI. Studies have implemented rodent models to investigate bTBI due to the relative small size and low cost; however, a large animal model with similar neuroanatomical structure to humans is essential for clinical translation. Small blast simulators are used to induce bTBI in rodents, but a large animal model demands a larger device. This study describes a large advanced blast simulator (ABS4) that is a gas-detonation-driven system consisting of 5 sections totaling 40 ft in length with a cross-section of 4 × 4 ft at the test section. It is highly suitable for large animals and human surrogate investigations. This work characterized the ABS4 in preparation of large-scale bTBI testing. An array of tests were conducted with target overpressures in the test section ranging from 10 to 50 psi, and the pressure-time profiles clearly illustrate the essential characteristics of a free-field blast wave, specifically a sharp peak pressure and a defined negative phase. Multiple blast tests conducted at the same target pressure produced very similar pressure profiles, exhibiting the reproducibility of the ABS4 system. With its extensive range of pressures and substantial size, the ABS4 will permit military-relevant translational blast testing.

"Biomarkers in severe traumatic brain injury: enhancing prognostic accuracy and therapeutic strategies".

This study examines the emerging role of biomarkers in the prognosis and management of severe traumatic brain injury (sTBI). Key findings highlight the significance of serum RIP-3, STC1, Nrf2, and cerebrospinal fluid galectin-3 and cytokines in predicting disease severity, mortality, and functional outcomes in sTBI patients. Elevated levels of RIP-3 and STC1 were linked to poor prognosis and increased mortality, with RIP-3 associated with necroptosis and inflammation, and STC1 with neuroprotective properties. Nrf2 was found to correlate with oxidative stress and adverse outcomes, while elevated CSF galectin-3 and IL-6 indicated neuroinflammation and neurodegeneration. These biomarkers show promise not only as prognostic tools but also as potential therapeutic targets. The study suggests further validation through multicenter research to enhance clinical applications and improve treatment strategies for sTBI.

Assessing the Predictive Utility of the C-Reactive Protein-to-Lymphocyte Ratio for Mortality in Isolated Traumatic Brain Injury: A Single-Center Retrospective Analysis.

Introduction: Early identification of high-risk traumatic brain injury (TBI) patients is crucial for optimizing treatment strategies and improving outcomes. The C-reactive protein-to-lymphocyte ratio (CLR) reflects systemic immunology and inflammation function and serves as a new biomarker for patient stratification. This study aimed to assess the predictive value of the CLR for mortality in patients with isolated moderate to severe TBI. Methods: A retrospective analysis of trauma registry data from 2009 to 2022 was conducted, including 1641 adult patients with isolated moderate to severe TBI. Patient demographics, the CLR, injury characteristics, and outcomes were compared between deceased and surviving patients. Univariate and multivariate analyses were performed to identify mortality risk factors. The optimal CLR cut-off value for predicting mortality was determined using receiver operating characteristic (ROC) curve analysis. Results: The CLR was significantly higher in deceased patients compared to survivors (60.1 vs. 33.9, p < 0.001). The optimal CLR cut-off value for predicting mortality was 54.5, with a sensitivity of 0.328 and a specificity of 0.812. The area under the ROC curve was 0.566, indicating poor discriminative ability. In the multivariate analysis, the CLR was not a significant independent predictor of mortality (OR 1.03, p = 0.051). After propensity score matching to attenuate the difference in baseline characteristics, including sex, age, comorbidities, conscious level, and injury severity, the high-CLR group (CLR ≥ 54.5) did not have significantly higher mortality compared to the low-CLR group (CLR < 54.5). Conclusion: While the CLR was associated with mortality in TBI patients, it demonstrated poor discriminative ability as a standalone predictor. The association between a high CLR and worse outcomes may be primarily due to other baseline patient and injury characteristics, rather than the CLR itself.

Longitudinal Outcomes of Neurofeedback and Hyperbaric Oxygen Therapy in Treating a Traumatic Brain Injury Patient: A Case Report.

Severe Traumatic Brain Injury (TBI) is a significant health issue, with neurofeedback and Hyperbaric Oxygen Therapy (HBOT) as potentially effective treatments. Neurofeedback uses operant conditioning for real-time psychological and physiological awareness, and HBOT increases blood oxygen levels, potentially enhancing cognitive abilities and the body's innate healing processes and reducing symptoms. On July 30, 2018, a 33-year-old female runner was hit by a car going 40 mph and thrown 30 feet, resulting in a severe TBI and a seven-week coma. After seven months of intensive rehabilitation, she started HBOT and neurofeedback treatments in November 2021, as recommended by her neuropsychiatrist. These treatments led to noticeable improvements in her cognition, sleep, conversation skills, emotional control, and relationships by January 2022. By December 2023, after 195 neurofeedback and over 300 HBOT sessions, she reported further improvements in various cognitive and emotional aspects and daily activities like feeding, toileting, grooming, and communication. Post-treatment quantitative electroencephalogram (qEEG) results in June 2024 showed moderate to large effects on her brain's average frequency band parameters (g = .612) and small to moderate average effects on 19 scalp electrode placement sites outcomes (uV2 g=.339 and Hz g=.333). This indicates significant progress in her recovery journey over a 31-month treatment period. This patient's case demonstrated noteworthy improvements in cognitive variables, namely, feeding (p=0.046), toileting (p=0.046), grooming (p=0.046), and communication abilities (p=0.046) per the objective measures, Disability Rating Scale (DRS) and the Glasgow Outcome Scale Extended (GOSE). Based on the qEEG effect sizes, DRS, and GOSE results from the pretest (2021) and posttest (2024), the patient has made noteworthy gains in brain recovery and overall quality of life.

Unveiling the performance of the prehospital Rapid Emergency Medicine Score (pREMS): How the predictive score impacts in-hospital outcomes in traumatic brain injury (TBI): A retrospective observational cohort study.

INTRODUCTION: This study aimed to evaluate the predictive accuracy of the prehospital rapid emergency medicine score (pREMS) for predicting the outcomes of hospitalized patients with traumatic brain injury (TBI) who died, were discharged, were admitted to the intensive care unit (ICU), or were admitted to the operating room (OR) within 72 h. METHODS: A retrospective cohort analysis was performed on a sample of 513 TBI patients admitted to the emergency department (ED) of Besat Hospital in 2023. Only patients of both sexes aged 18 years or older who were not pregnant and had adequate documentation of vital signs were included in the analysis. Patients who died during transport and patients who were transferred from other hospitals were excluded. The predictive power of the pREMS for each outcome was assessed by calculating the sensitivity and specificity curves and by analyzing the area under the receiver operating characteristic curve (AUROC). RESULTS: The mean pREMS scores for hospital discharge, death, ICU admission and OR admission were 11.97 ± 3.84, 6.32 ± 3.15, 8.24 ± 5.17 and 9.88 ± 2.02, respectively. pREMS accurately predicted hospital discharge and death (AOR = 1.62, P < 0.001) but was not a good predictor of ICU or OR admission (AOR = 1.085, P = 0.603). The AUROCs for the ability of the pREMS to predict outcomes in hospitalized TBI patients were 0.618 (optimal cutoff point = 7) for ICU admission and OR and 0.877 (optimal cutoff point = 9.5) for hospital discharge and death at 72 h. CONCLUSION: The results indicate that the pREMS, a new preclinical trauma score for traumatic brain injury, is a useful tool for prehospital risk stratification (RST) in TBI patients. The pREMS showed good discriminatory power for predicting in-hospital mortality within 72 h in patients with traumatic brain injury.

Probiotics in Traumatic Brain Injury: New Insights into Mechanisms and Future Perspectives.

Traumatic brain injury (TBI) is a serious global public health issue, recognized as a chronic and progressive disease that can affect multiple organs, including the gastrointestinal (GI) tract. Research shows that there is a specific link between the GI tract and the central nervous system, termed the gut-brain axis, which consists of bidirectional exchange between these two. Several preclinical and clinical studies have demonstrated intestinal barrier dysfunction, intestinal inflammation and gut dysbiosis in patients with TBI. It is proven that probiotics can modulate the inflammatory process and modify gut microbiota. Numerous animal studies and human clinical trials have proven the effectiveness of selected bacterial strains as an adjuvant treatment in reducing inflammation, infection rates and time spent in intensive care of hospitalized patients suffering from brain injury. Thus, this review summarizes the current evidence regarding the beneficial effects of probiotic administration in patients suffering from TBI-related complications. This review will help identify novel therapeutic strategies in the future as probiotics have an extensive history of apparently safe use.

Decompressive Craniectomy: From Ancient Practices to Modern Neurosurgery.

Decompressive craniectomy (DC) is a neurosurgical strategy that expels a parcel of the cranium to relieve pressure on a swollen or herniating brain. This review article explores the history of DC, from its ancient roots in trepanning to its contemporary applications. It then examines the mechanisms by which DC reduces intracranial pressure (ICP) and improves cerebral blood flow. The article highlights the efficacy of DC in treating patients with severe traumatic brain injury (TBI), stroke, and other conditions that cause increased ICP. However, it also acknowledges the potential complications of DC, such as infection and bleeding. The ethical considerations surrounding DC are explored in detail, particularly the challenging decision-making process for patients who are unable to give consent. A specific focus is given to the use of DC in pediatric patients, where the developing brain is especially vulnerable to pressure changes.

The predicative value of early quantitative electroencephalograph in epilepsy after severe traumatic brain injury in children.

Objective: To explore whether early quantitative electroencephalograph (EEG) can predict the development of epilepsy in pediatric patients with severe traumatic brain injury (TBI). Methods: A total of 78 children with severe TBI who were admitted to our hospital were divided into post-traumatic epilepsy (PTE) and non-PTE groups according to whether or not they developed PTE. EEGs of frontal, central and parietal lobes were recorded at the time of their admission. The power values of each frequency band, odds ratio and peak envelope power values of each brain region were statistically analyzed. In addition, the patients were followed up for two years, and the occurrence of PTE was documented. Results: During the follow-up period, PTE occurred in 8 patients. Analysis of EEG signals across different brain regions (frontal, central, and parietal lobes) revealed significant differences between the PTE and non-PTE groups. Patients with PTE exhibited significantly higher δ and θ power values (P < 0.01), lower α/θ ratios (P < 0.01), and elevated θ/ß, (δ + θ)/(α + ß), and peak envelope power (P < 0.01) compared to those in the non-PTE group. Conclusion: In children with severe TBI, the parameter characterization of early quantitative EEG has potential application in predicting PTE.

The death of a neurotrauma trial lessons learned from the prematurely halted randomized evaluation of surgery in elderly with traumatic acute subdural hematoma (RESET-ASDH) trial.

Introduction: Acute subdural hematoma (ASDH) due to traumatic brain injury (TBI) constitutes an increasing global health problem, especially in the elderly population. Treatment decisions on surgical versus conservative management pose a neurosurgical dilemma. Large practice variation exists between countries, hospitals, and individual neurosurgeons, illustrating the presence of 'clinical equipoise'. The RESET-ASDH trial aimed to address this dilemma but was terminated prematurely due to insufficient patient recruitment. Research question: What factors may have contributed to the premature discontinuation of the RESET-ASDH trial? Materials and methods: The RESET-ASDH was a multicenter randomized controlled trial (RCT) comparing functional outcome at 1 year after early surgery or an initial conservative treatment in elderly patients (≥65 years) with a traumatic ASDH. Logs of registry data, medical-ethical approval timelines and COVID-19 related research documents were analyzed. Furthermore, non-structured interviews with involved clinical research personnel were conducted. Results: The concept of clinical equipoise was broadly misinterpreted by neurosurgeons as individual uncertainty, hampering patient recruitment. Also, the elderly target population complicated the inclusion process as elderly and their informal caregivers were hesitant to participate in our acute surgical trial. Moreover, the COVID-19 pandemic added additional hurdles like delayed medical-ethical approval, a decline in eligible patients and repeated trial halts during the peaks of the pandemic. Discussion and conclusion: The premature termination of the RESET-ASDH study may have been related to the trial's methodology and target population with an additional impact of COVID-19. Future acute neurosurgical trials in elderly may consider these challenges to prevent premature trial termination.

Geriatric Trauma Outcome Score as a Mortality Predictor in Isolated Moderate to Severe Traumatic Brain Injury: A Single-Center Retrospective Study.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide, with severe cases significantly increasing the risk of complications and long-term mortality. The Geriatric Trauma Outcome Score (GTOS), based on age, injury severity, and transfusion need, has been validated for predicting mortality in older trauma patients, but its utility in predicting mortality for TBI patients remains unexplored. METHODS: This retrospective study included 5543 adult trauma patients with isolated moderate to severe TBI, defined by head Abbreviated Injury Scale (AIS) scores of ≥ 3, from 1998 to 2021. GTOS was calculated with the following formula: age + (Injury Severity Score × 2.5) + 22 (if transfused within 24 h). The area under the receiver operating characteristic curve (AUROC) assessed GTOS's ability to predict mortality. The optimal GTOS cutoff value was determined using Youden's index. Mortality rates were compared between high- and low-GTOS groups, separated by the optimal GTOS cutoff value, including a propensity score-matched analysis adjusting for baseline characteristics. RESULTS: Among 5543 patients, mortality was 8.3% (462 deaths). Higher mortality is correlated with male sex, older age, higher GTOS, and comorbidities like hypertension, coronary artery disease, and end-stage renal disease. The optimal GTOS cut-off for mortality prediction was 121.5 (AUC = 0.813). Even when the study population was matched by propensity score, patients with GTOS ≥121.5 had much higher odds of death (odds ratio 2.64, 95% confidence interval 1.93-3.61, p < 0.001) and longer hospital stays (mean 16.7 vs. 12.2 days, p < 0.001) than those with GTOS < 121.5. CONCLUSIONS: These findings support the idea that GTOS is a useful tool for risk stratification of in-hospital mortality in isolated moderate to severe TBI patients. However, we encourage further research to refine GTOS for better applicability in TBI patients.

Who is seeking information about traumatic brain injury? Characterizing online course participants.

Accessible, up-to-date information on traumatic brain injury (TBI) can be challenging to find and is needed to address TBI knowledge gaps and improve outcomes for people who experience a TBI. The Understanding TBI Massive Open Online Course (TBI MOOC) was developed to increase TBI knowledge across a diverse global audience. We sought to characterize the TBI MOOC participant cohort, to understand the reach of the course among this target audience. Examining the characteristics of TBI MOOC enrollees showed that participants came from a wide range of demographic backgrounds, had a variety of TBI experiences and had multiple reasons for enrolling in the MOOC. The majority of course participants shared some characteristics with other groups of health information seekers. Four distinct demographic profiles were identified among TBI MOOC participants (education seekers, TBI-aware participants, TBI care providers and retirees) using a novel approach combining chi-squared tests and network modularity. Participants assigned to the TBI-aware and retiree profiles were most likely to complete all modules of the MOOC, and the TBI-aware profile was more highly represented in more recent iterations of the MOOC. Together, these data indicate that the TBI MOOC provided information to a wide range of people, and particularly engaged participants with personal or family experience of TBI. However, engagement with this course was minimal among some hard-to-reach populations, including men and people with low levels of education, indicating that additional strategies are needed to ensure equity in health promotion.

Letter to the editor: Brain tissue oxygen partial pressure monitoring and prognosis of patients with traumatic brain injury: a meta-analysis.

The meta-analysis by Shen et al. in Neurosurgical Review highlights the benefits of brain tissue oxygen partial pressure (PbtO2) monitoring in reducing mortality and intracranial pressure in severe traumatic brain injury (TBI) patients. However, it also associates PbtO2 monitoring with prolonged hospital stays. Future research should focus on standardizing PbtO2 protocols, integrating with advanced neuroimaging, exploring long-term outcomes, evaluating combination therapies, and conducting cost-benefit analyses. Addressing these areas could further enhance the clinical application and efficacy of PbtO2 monitoring in improving patient outcomes.