Search Results (104)

It is increasingly recognized that early perturbation of energy metabolism might have important implications in management and ultimately the neurological outcome in patients with traumatic brain injury (TBI). At the same time, treatments and screening tools successfully developed in preclinical TBI models have failed to translate to the clinic. As ferrets possess primate-like gyrencephalic brains that may better replicate the human response to neurologic injury, the goal of this study was to noninvasively measure brain energy metabolism after injury in a ferret model of TBI. To this end, metabolic imaging of hyperpolarized (HP) [1-¹³C]pyruvate (Pyr) and its conversion to lactate (Lac) and bicarbonate (Bic) was performed in ferrets before and after combined under-vehicle blast and controlled cortical impact injury. Reduced Bic/Pyr, reflecting reduced pyruvate dehydrogenase activity, was detected 8–10 days post-injury whereas no difference in Lac/Pyr was observed. These results demonstrate the feasibility of using metabolic imaging of HP [1-¹³C]Pyr to measure perturbations in brain energy metabolism in a novel highly translatable animal model of TBI. The method may contribute to both improved understanding of injury mechanisms and more effective drug development. Full article

The incidence of morbidity and mortality in patients who have suffered traumatic brain injury (TBI) is such that novel therapeutic strategies are currently required. There is good evidence that ischaemia is the primary, and sometimes the secondary, cause of brain damage in TBI. This ischaemia may lead to mitochondrial dysfunction, with associated oxidative stress and inflammation, in the pathogenesis of brain injury following head trauma. This, in turn, provides a rationale for the use of supplemental coenzyme Q10 (CoQ10) in the management of TBI, given its key roles in normal mitochondrial function and as an antioxidant and anti-inflammatory agent. In this article, we, therefore, review the use of supplemental CoQ10 in animal models of TBI and its potential application in the management of TBI patients. The problem of blood–brain barrier access is discussed, and how this might be circumvented via the use of an intranasal route to provide direct access of CoQ10 to the brain. In addition, there is evidence that TBI patients have an increased risk of developing cardiac dysfunction and that this may be mediated by aberrant immune action. Given the role of CoQ10 in promoting normal cardiac function and normal immune function, the administration of CoQ10 to prevent cardiovascular complications may improve outcomes in TBI patients. Full article

Mild traumatic brain injury (mTBI), a leading cause of disability in young adults, often results from external forces that damage the brain. Cellularly, mTBI induces oxidative stress, characterized by excessive reactive oxygen species (ROS) and diminished antioxidant capacity. This redox imbalance disrupts hippocampal glutamatergic transmission and synaptic plasticity, where NMDA receptors (NMDARs) are crucial. The exocyst, a vesicle tethering complex, is implicated in glutamate receptor trafficking. We previously showed that Exo70, a key exocyst subunit, redistributes within synapses and increases its interaction with the NMDAR subunit GluN2B following mTBI, suggesting a role in GluN2B distribution from synaptic to extrasynaptic sites. This study investigated whether Exo70 could mitigate mTBI pathology by modulating NMDAR trafficking under elevated oxidative stress. Using a modified Maryland mTBI mouse model, we overexpressed Exo70 in CA1 pyramidal neurons via lentiviral transduction. Exo70 overexpression prevented mTBI-induced cognitive impairment, assessed by the Morris water maze. Moreover, these mice exhibited basal and NMDAR-dependent hippocampal synaptic transmission comparable to sham animals, preventing mTBI-induced deterioration. Preserved long-term potentiation, abundant synaptic GluN2B-containing NMDARs, and downstream signaling indicated that Exo70 overexpression prevented mTBI-related alterations. Our findings highlight Exo70’s crucial role in NMDAR trafficking, potentially counteracting oxidative stress effects. The exocyst complex may be a critical component of the machinery regulating NMDAR distribution in health and disease, particularly in pathologies featuring oxidative stress and NMDAR dysfunction, like mTBI. Full article

Brain stimulation therapies may be used to correct motor, social, emotional, and cognitive consequences of traumatic brain injury (TBI). Neuromodulation applied with anatomical specificity can ameliorate desired symptoms while leaving functional circuits intact. Before applying precision medicine approaches, preclinical animal studies are needed to explore potential neurophysiological signatures that could be modulated with neurostimulation. This review discusses potential neural signatures of cognition, particularly reward processing, which is chronically impaired after brain injury. Electrophysiology, compared to other types of biomarkers, can detect deficits missed by structural measures, holds translational potential between humans and animals, and directly informs neuromodulatory treatments. Disturbances in oscillatory activity underscore structural, molecular, and behavioral impairments seen following TBI. For instance, cortico-striatal beta frequency activity (15–30 Hz) during reward processing represents subjective value and is chronically disturbed after frontal TBI in rodents. We use the example of evoked beta oscillations in the cortico-striatal network as a putative marker of reward processing that could be targeted with electrical stimulation to improve decision making after TBI. This review highlights the necessity of collecting electrophysiological data in preclinical models to understand the underlying mechanisms of cognitive behavioral deficits after TBI and to develop targeted stimulation treatments in humans. Full article

Recent U.S. military conflicts have underscored the knowledge gap regarding the neurological changes associated with blast-induced traumatic brain injury (bTBI). In vitro models of TBIs have the advantage of following the neuronal response to biomechanical perturbations in real-time, which can be exceedingly difficult in animal models. Here, we sought to develop an in vitro approach with controlled blast biomechanics to study the direct effects of the primary shock wave at the neuronal level. A blast injury apparatus mimicking the human skull and cerebrospinal fluid was developed. Primary neuronal cells were cultured inside the apparatus and exposed to a 70 kPa peak blast overpressure using helium gas in a blast tube. Neuronal viability was measured 24 h after blast exposure. The transmission of the pressure wave through the skull is believed to be a factor in injury to the cells of the brain. Three thicknesses in the apparatus wall were studied to represent the range of thicknesses in a human skull. To study the transmission of the shock wave to the neurons, the incident pressure at the apparatus location, as well as internal apparatus pressure, were measured. Analysis of the internal pressure wave revealed that wave oscillation frequency, not amplitude, was a significant factor in cell viability after a bTBI. This finding is related to the viscoelastic properties of the brain and suggests that the transmission of the shock wave through the skull is an important variable in blast injury. Full article

Background: Blast traumatic brain injury (bTBI) can result in depression-like behaviors in the acute and chronic phases. SSRIs have been shown to significantly alleviate depression-like behaviors in animal models of traumatic brain injury (TBI) by increasing serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) in the hippocampus. However, the therapeutic effects of SSRIs on depression caused by bTBI remain unclear. Objective: Therefore, this study was aimed at investigating the therapeutic effects of SSRIs on depression-like behaviors in bTBI models. Methods: We created a rat model to study mild TBI by subjecting rats to increased blast overpressures (BOP) and injecting fluoxetine and escitalopram SSRIs intraperitoneally for 28 days. Results: On day 14 post-BOP exposure, rats treated with SSRIs showed decreased depression-like behaviors. This finding was accompanied by higher 5-HT levels in the hippocampus and increased numbers of Nestin-positive cells in the dentate gyrus. Furthermore, rats treated with SSRIs exhibited increased pCREB and BDNF protein expression in the hippocampus on days 7, 14, and 28 after bTBI. Conclusions: Overall, our findings indicate that SSRI-induced recovery from depression-like behaviors after mild bTBI is associated with the upregulation of 5-HT levels, pCREB and BDNF expression, and neurogenesis in the hippocampus. Full article

Traumatic brain injury (TBI) is a disease resulting from external physical forces acting against the head, leading to transient or chronic damage to brain tissue. Primary brain injury is an immediate and, therefore, rather irreversible effect of trauma, while secondary brain injury results from a complex cascade of pathological processes, among which oxidative stress and neuroinflammation are the most prominent. As TBI is a significant cause of mortality and chronic disability, with high social costs all over the world, any form of therapy that may mitigate trauma-evoked brain damage is desirable. Melatonin, a sleep–wake-cycle-regulating neurohormone, exerts strong antioxidant and anti-inflammatory effects and is well tolerated when used as a drug. Due to these properties, it is very reasonable to consider melatonin as a potential therapeutic molecule for TBI treatment. This review summarizes data from in vitro studies, animal models, and clinical trials that focus on the usage of melatonin in TBI. Full article

Traumatic brain injury (TBI) remains one of the leading causes of death. Because of the individual nature of the trauma (brain, circumstances and forces), humans experience individual TBIs. This makes it difficult to generalise therapies. Clinical management issues such as whether intracranial pressure (ICP), cerebral perfusion pressure (CPP) or decompressive craniectomy improve patient outcome remain partly unanswered. Experimental drug approaches for the treatment of secondary brain injury (SBI) have not found clinical application. The complex, cellular and molecular pathways of SBI remain incompletely understood, and there are insufficient experimental (animal) models that reflect the pathophysiology of human TBI to develop translational therapeutic approaches. Therefore, we investigated different injury patterns after acute subdural hematoma (ASDH) as TBI in a post-hoc approach to assess the impact on SBI in a long-term, human-sized porcine TBI animal model. Post-mortem brain tissue analysis, after ASDH, bilateral ICP, CPP, cerebral oxygenation and temperature monitoring, and biomarker analysis were performed. Extracerebral, intraparenchymal–extraventricular and intraventricular blood, combined with brainstem and basal ganglia injury, influenced the experiment and its outcome. Basal ganglia injury affects the duration of the experiment. Recognition of these different injury patterns is important for translational interpretation of results in this animal model of SBI after TBI. Full article

Background/Objectives: Traumatic brain injury (TBI) can lead to substantial disability and health loss. Despite its importance and impact worldwide, no treatment options are currently available to help protect or preserve brain structure and function following injury. In this review, we discuss the potential benefits of using omega-3 polyunsaturated fatty acids (O3 PUFAs) as therapeutic agents in the context of TBI in the paediatric and adult populations. Methods: Preclinical and clinical research reports investigating the effects of O3 PUFA-based interventions on the consequences of TBI were retrieved and reviewed, and the evidence presented and discussed. Results: A range of animal models of TBI, types of injury, and O3 PUFA dosing regimens and administration protocols have been used in different strategies to investigate the effects of O3 PUFAs in TBI. Most evidence comes from preclinical studies, with limited clinical data available thus far. Overall, research indicates that high O3 PUFA levels help lessen the harmful effects of TBI by reducing tissue damage and cell loss, decreasing associated neuroinflammation and the immune response, which in turn moderates the severity of the associated neurological dysfunction. Conclusions: Data from the studies reviewed here indicate that O3 PUFAs could substantially alleviate the impact of traumatic injuries in the central nervous system, protect structure and help restore function in both the immature and adult brains. Full article

The noble gas argon is one of the most promising neuroprotective agents for hypoxic-reperfusion injuries of the brain. However, its effect on traumatic injuries has been insufficiently studied. The aim of this study was to analyze the effect of the triple inhalation of the argon-oxygen mixture Ar 70%/O₂ 30% on physical and neurological recovery and the degree of brain damage after traumatic brain injury and to investigate the possible molecular mechanisms of the neuroprotective effect. The experiments were performed in male Wistar rats. A controlled brain injury model was used to investigate the effects of argon treatment and the underlying molecular mechanisms. The results of the study showed that animals with craniocerebral injuries that were treated with argon inhalation exhibited better physical recovery rates, better neurological status, and less brain damage. Argon treatment significantly reduced the expression of the proinflammatory markers TNFα and CD68 caused by TBI, increased the expression of phosphorylated protein kinase B (pAKT), and promoted the expression of the transcription factor Nrf2 in intact animals. Treatment with an argon-oxygen breathing mixture after traumatic brain injury has a neuroprotective effect by suppressing the inflammatory response and activating the antioxidant and anti-ischemic system. Full article

Neuroplasticity and neuroinflammation are variables seen during recovery from traumatic brain injury (TBI), while biomarkers are useful in monitoring injury and guiding rehabilitation efforts. This systematic review examines how neuroinflammation affects neuroplasticity and recovery following TBI in animal models and humans. Studies were identified from an online search of the PubMed, Web of Science, and Embase databases without any search time range. This review has been registered on Open OSF (n) UDWQM. Recent studies highlight the critical role of biomarkers like serum amyloid A1 (SAA1) and Toll-like receptor 4 (TLR4) in predicting TBI patients’ injury severity and recovery outcomes, offering the potential for personalized treatment and improved neurorehabilitation strategies. Additionally, insights from animal studies reveal how neuroinflammation affects recovery, emphasizing targets such as NOD-like receptor family pyrin domain-containing 3 (NLRP3) and microglia for enhancing therapeutic interventions. This review emphasizes the central role of neuroinflammation in TBI, and its adverse impact on neuroplasticity and recovery, and suggests that targeted anti-inflammatory treatments and biomarker-based personalized approaches hold the key to improvement. Such approaches will need further development in future research by integrating neuromodulation and pharmacological interventions, along with biomarker validation, to optimize management in TBI. Full article

Background/Objectives: Sports-related concussions are a main cause of cognitive dysfunction and somatic complaints, particularly in youth. While the majority of concussion symptoms resolve within one week, cognitive effects may persist. In this study, we sought to study changes to cognition within this acute time frame. Methods: In this current study, we use an established swine model of traumatic brain injury (TBI) to study the effects of single and repeated head rotations on resting-state electroencephalography (rs-EEG) in awake piglets in the acute (within 7 days) time period after injury. We studied both healthy and experimental groups to (1) establish healthy reference ranges (RRs; N = 23) for one-minute rs-EEG in awake piglets, (2) compare the effects of single (N = 12) and repeated head rotations (N = 13) on rs-EEG, and (3) examine the acute time course (pre-injury and days 1, 4, and 7 post-injury) in animals administered single and repeated head rotations. EEG data were Fourier transformed, and total (1–30 Hz) and relative power in the alpha (8–12 Hz), beta (16.5–25 Hz), delta (1–4 Hz), and theta (4–7.5 Hz) bands were analyzed. Results: Total power and relative alpha, beta, delta, and theta power were consistent measures across days in healthy animals. We found a significant and transient increase in relative alpha power after repeated injury on day 1 in all regions and a rise above the healthy RR in the frontal and left temporal regions. Conclusions: Future studies will expand the study duration to investigate and inform clinical prognoses from acute measurements of rs-EEG. Full article

Background/Objectives: Traumatic brain injury (TBI) is a global healthcare concern affecting millions, with wide-ranging symptoms including sensory and behavioral changes that can persist long-term. Due to similarities with human brain cytoarchitecture and inflammation, minipig models are advantageous for translational TBI research. However, gaps in knowledge exist regarding their behavioral and sensory sequelae following injury. Methods: Therefore, in this study, we assessed changes in approachability using a forced human approach task (FHAT) and mechanical nociception using the von Frey test in adult male and female Yucatan minipigs for up to one week following a sham or central fluid percussion injury (cFPI). Specifically, the FHAT assessed each animal’s response to a forced interaction with either a known or unknown experimenter. To evaluate changes in nociceptive sensory sensitivity, von Frey monofilaments ranging from 0.008 to 300 g of force were applied to the pinna of the ear or base of the tail. Results: We found that forced approachability was affected by experimenter familiarity as well as cFPI in a sex-specific manner at subacute timepoints. We also found reductions in sensitivity following cFPI on the ear in male minipigs and on the tail in female minipigs. Conclusion: Overall, the current study demonstrates that cFPI produces both behavioral and sensory changes in minipigs up to one-week post-injury. Full article

According to the Centers for Disease Control and Prevention (CDC), the national public health agency of the United States, traumatic brain injury is among the leading causes of mortality and disability worldwide. The consequences of TBI include diffuse brain atrophy, local post-traumatic atrophy, arachnoiditis, pachymeningitis, meningocerebral cicatrices, cranial nerve lesions, and cranial defects. In 2019, the economic cost of injuries in the USA alone was USD 4.2 trillion, which included USD 327 billion for medical care, USD 69 billion for work loss, and USD 3.8 trillion for the value of statistical life and quality of life losses. More than half of this cost (USD 2.4 trillion) was among working-age adults (25–64 years old). Currently, the development of new diagnostic approaches and the improvement of treatment techniques require further experimental studies focused on modeling TBI of varying severity. Full article

Traumatic brain injury (TBI) is a public health concern, with an estimated 42 million cases globally every year. The majority of TBIs are mild TBIs, also known as concussion, and result from the application of mechanical forces on the head. Most patients make a complete recovery and mortality is rare; therefore, studies investigating cellular changes after mild TBI in a clinical setting are limited. To address this constraint, our group utilized a pig model of closed-head rotational acceleration-induced TBI, which recreated the biomechanical loading parameters associated with concussion on a large gyrencephalic brain similar to humans. While our previous research has focused on immunohistochemical characterization of neuropathology, the current study utilized transcriptomic assays to evaluate an array of TBI-induced neurodegenerative analytes. Pigs subjected to mild TBI were survived for 3 days post-injury (DPI) (n = 3), 30 DPI (n = 3), or 1 year post-injury (YPI) (n = 3) and compared to animals undergoing a sham procedure (n = 8). RNA was isolated from whole coronal sections of fixed tissue and multiplexed on a Nanostring neuropathology panel. Differential expression analysis revealed 11 differentially expressed genes at 3 DPI versus sham, including downregulation of the synaptotagmin calcium sensor gene (SYT1), upregulation of the neurofibromin gene (NF1), and upregulation of the Alzheimer’s disease-associated receptor gene (SORL1). There were no differentially expressed genes at 30 DPI or 1 YPI compared to shams. Additionally, high-magnitude undirected global significance scores (GSS) were detected at 3 DPI for chromatin modification and autophagy gene sets, and at 30 DPI for cytokine gene sets, while many dysregulated gene sets were highlighted by directed GSSs out to 1 YPI. This study adds to a growing body of literature on transcriptomic changes in a clinically relevant large animal model of closed-head TBI, which highlights potential therapeutic targets following mild TBI. Full article