Potential For Traumatic Brain Injury Research Articles

Research and Prospect of Visual Event-Related Potential in Traumatic Brain Injury and Visual Function Evaluation.

Visual event-related potential (ERP) is an electrophysiological technique that objectively reflects the cognitive processing of stimulus from the perspective of detecting and recording neural electrophysiology responses using different paradigms of visual stimuli. Its endogenous components are closely related to advanced psychological activities. This article introduces the characteristics of main endogenous components including visual mismatch negativity (vMMN), N200 and P300, reviews the research progress of visual ERP in the sequelae of brain injury and objective evaluation of visual function, and prospects the application prospect of visual ERP in the field of forensic medicine.

Post-acute blood biomarkers and disease progression in traumatic brain injury.

There is substantial interest in the potential for traumatic brain injury to result in progressive neurological deterioration. While blood biomarkers such as glial fibrillary acid protein (GFAP) and neurofilament light have been widely explored in characterizing acute traumatic brain injury (TBI), their use in the chronic phase is limited. Given increasing evidence that these proteins may be markers of ongoing neurodegeneration in a range of diseases, we examined their relationship to imaging changes and functional outcome in the months to years following TBI.Two-hundred and three patients were recruited in two separate cohorts; 6 months post-injury (n = 165); and >5 years post-injury (n = 38; 12 of whom also provided data ∼8 months post-TBI). Subjects underwent blood biomarker sampling (n = 199) and MRI (n = 172; including diffusion tensor imaging). Data from patient cohorts were compared to 59 healthy volunteers and 21 non-brain injury trauma controls. Mean diffusivity and fractional anisotropy were calculated in cortical grey matter, deep grey matter and whole brain white matter. Accelerated brain ageing was calculated at a whole brain level as the predicted age difference defined using T1-weighted images, and at a voxel-based level as the annualized Jacobian determinants in white matter and grey matter, referenced to a population of 652 healthy control subjects.Serum neurofilament light concentrations were elevated in the early chronic phase. While GFAP values were within the normal range at ∼8 months, many patients showed a secondary and temporally distinct elevations up to >5 years after injury. Biomarker elevation at 6 months was significantly related to metrics of microstructural injury on diffusion tensor imaging. Biomarker levels at ∼8 months predicted white matter volume loss at >5 years, and annualized brain volume loss between ∼8 months and 5 years. Patients who worsened functionally between ∼8 months and >5 years showed higher than predicted brain age and elevated neurofilament light levels.GFAP and neurofilament light levels can remain elevated months to years after TBI, and show distinct temporal profiles. These elevations correlate closely with microstructural injury in both grey and white matter on contemporaneous quantitative diffusion tensor imaging. Neurofilament light elevations at ∼8 months may predict ongoing white matter and brain volume loss over >5 years of follow-up. If confirmed, these findings suggest that blood biomarker levels at late time points could be used to identify TBI survivors who are at high risk of progressive neurological damage.

Cortical Electrical Stimulation Ameliorates Traumatic Brain Injury-Induced Sensorimotor and Cognitive Deficits in Rats.

Objective: Individuals with different severities of traumatic brain injury (TBI) often suffer long-lasting motor, sensory, neurological, or cognitive disturbances. To date, no neuromodulation-based therapies have been used to manage the functional deficits associated with TBI. Cortical electrical stimulation (CES) has been increasingly developed for modulating brain plasticity and is considered to have therapeutic potential in TBI. However, the therapeutic value of such a technique for TBI is still unclear. Accordingly, an animal model of this disease would be helpful for mechanistic insight into using CES as a novel treatment approach in TBI. The current study aims to apply a novel CES scheme with a theta-burst stimulation (TBS) protocol to identify the therapeutic potential of CES in a weight drop-induced rat model of TBI.Methods: TBI rats were divided into the sham CES treatment group and CES treatment group. Following early and long-term CES intervention (starting 24 h after TBI, 1 session/day, 5 days/week) in awake TBI animals for a total of 4 weeks, the effects of CES on the modified neurological severity score (mNSS), sensorimotor and cognitive behaviors and neuroinflammatory changes were identified.Results: We found that the 4-week CES intervention significantly alleviated the TBI-induced neurological, sensorimotor, and cognitive deficits in locomotor activity, sensory and recognition memory. Immunohistochemically, we found that CES mitigated the glial fibrillary acidic protein (GFAP) activation in the hippocampus.Conclusion: These findings suggest that CES has significant benefits in alleviating TBI-related symptoms and represents a promising treatment for TBI.

Argon Inhalation for 24h After Closed-Head Injury Does not Improve Recovery, Neuroinflammation, or Neurologic Outcome in Mice.

In recent years, the noble gas argon (Ar) has been extensively studied for its organ protection properties. While mounting in vitro and in vivo evidence indicates that argon provides neuroprotection in ischemic brain injury, its neuroprotective potential in traumatic brain injury (TBI) has not been evaluated in vivo. We tested the hypothesis that prolonged inhalation of 70% or 79% argon for 24h after closed-head injury (CHI) improves neurologic outcome and overall recovery at 36days post-injury. We also compared effects of the 30% or 21% residual oxygen on argon's potential neuroprotective capacity. Adult male C57/black mice (n = 240) were subjected to closed-head traumatic brain injury, followed by inhalation of 70% argon or nitrogen (30% oxygen), or 79% argon or nitrogen (21% oxygen) for 24h. Neurologic outcome (rotarod, neuroscore, and Morris water maze) was evaluated for up to 36days post-injury. Histologic parameters of neurologic degeneration (Fluoro-Jade staining) and inflammation (F4/80 microglia immunostaining) were assessed in subgroups at 24h and on post-injury day 7. Our CHI protocol consistently resulted in significant brain injury. After argon inhalation for 24h at either concentration, mice did not show significant improvement with regard to neuroscores, rotarod performance, Morris water maze performance, or overall recovery (body weight), compared to nitrogen controls, up to 36days. At 7days post-injury, histologic markers of neurodegeneration and inflammation, particularly in the hippocampus, consistently demonstrated significant injury. Notably, recovery was reduced in mice treated with the higher oxygen concentration (30%) after CHI compared to 21%. Prolonged argon treatment did not improve neurologic outcome, overall recovery (weight), nor markers of neurodegeneration or neuroinflammation after significant CHI compared to nitrogen. While neuroprotective in predominately ischemic injury, argon did not provide protection after TBI in this model, highlighting the crucial importance of assessing argon's strengths and weaknesses in preclinical models to fully understand its organ protective potential in different pathologies and gas mixtures.

MRI Volumetric Quantification in Persons with a History of Traumatic Brain Injury and Cognitive Impairment.

While traumatic brain injury (TBI) is recognized as a risk factor for dementia, there is lack of clinical tools to identify brain changes that may confer such vulnerability. Brain MRI volumetric quantification can sensitively identify brain atrophy. To characterize regional brain volume loss in persons with TBI presenting with cognitive impairment. IRB approved review of medical records in patients with cognitive decline focused on those who had documented TBI histories and brain MRI scans after TBI (n = 40, 67.7±14.5 years) with volumetric quantification by applying an FDA cleared software program. TBI documentation included head trauma mechanism. Brain volumes were compared to a normative database to determine the extent of atrophy. Correlations between these regions and global tests of cognition (MMSE in n = 17, MoCA in n = 27, n = 14 in both) were performed. Multiple regions demonstrated volume loss in TBI, particularly ventral diencephalon, putamen, and pallidum with smaller magnitude of atrophy in temporal lobes and brainstem. Lobar structures showed strongest correlations between atrophy and lower scores on MMSE and MoCA. The hippocampus, while correlated to tests of cognitive function, was the least atrophic region as a function of TBI history. Persons with TBI history exhibit show regional brain atrophy. Several of these areas, such as thalamus and temporal lobes, also correlate with cognitive function. Alzheimer's disease atrophy was less likely given relative sparing of the hippocampi. Volumetric quantification of brain MRI in TBI warrants further investigation to further determine its clinical potential in TBI and differentiating causes of cognitive impairment.

193 Does Stem Cell Therapy Hold Promise In The Management Of Traumatic Brain Injuries? A Literature Review of Animal Studies

Abstract INTRODUCTION There are no neuroprotective and neuroregenerative treatments available for Traumatic Brain Injury (TBI). Clinical trials investigating potential treatments such as therapeutic hypothermia and progesterone have failed. Pre-clinical studies indicate there may be a role of stem-cells in promoting neuroprotection/neuroregeneration in-vivo in animal models of TBI. We aim to provide a pre-clinical literature review into stem-cells as a potential therapeutic option in TBI-animal models. METHODS Using the terms “traumatic brain injury”, “stem-cell”, “preclinical”, and “animal studies”, a literature search was conducted on Pubmed and Google Scholar. Studies were included if there was an in-vivo animal model of TBI with either intravenous or intra-cortical stem-cell transplantation, along-with a control group, and investigated either motor or behavioral outcomes, or a combination. RESULTS >Twenty-seven studies (n = 1184 animals) satisfied the criteria. 774/1184 (65.4%) animals were investigated for outcomes. 17 studies harvested stem-cells from human-source, whereas 10 harvested stem-cells from animal-source. Bone-marrow stromal-cells (BMSC) were used in 17 studies, neural stem-cells (NSC) in 7, and miscellaneous in 3. 450/774 (58.1%) animals received any stem-cell transplantation, whereas 324 were controls. Of animals receiving stem-cell transplantation (450), 339 (75.3%) showed significantly better outcomes relative to control animals in each individual study, with exception of one study. Amongst transplanted animals, functional outcomes did not differ significantly when grouped by stem-cell type (P = 0.553), transplantation route (P = 0.054), and source (P = 0.784). Animals were followed-up until 1 week (n = 5 studies), 2 weeks (n = 10), 4 weeks (n = 5), or >4-weeks (n = 7). CONCLUSION This pre-clinical data demonstrates that stem-cell transplantation may have treatment potential in TBI as shown by improvement in functional outcome in as many as three-quarters of all animals that were treated with stem-cells. This data provides a foundation for the design of clinical translational studies.

Peptide Pharmacological Approaches to Treating Traumatic Brain Injury: a Case for Arginine-Rich Peptides.

Traumatic brain injury (TBI) has a devastating effect on victims and their families, and has profound negative societal and economic impacts, a situation that is further compounded by the lack of effective treatments to minimise injury after TBI. The current strategy for managing TBI is partly through preventative measures and partly through surgical and rehabilitative interventions. Secondary brain damage remains the principal focus for the development of a neuroprotective therapeutic. However, the complexity of TBI pathophysiology has meant that single-action pharmacological agents have been largely unsuccessful in combatting the associated brain injury cascades, while combination therapies to date have proved equally ineffective. Peptides have recently emerged as promising lead agents for the treatment of TBI, especially those rich in the cationic amino acid, arginine. Having been shown to lessen the impact of ischaemic stroke in animal models, there are reasonable grounds to believe that arginine-rich peptides may have neuroprotective therapeutic potential in TBI. Here, we review a range of peptides previously examined as therapeutic agents for TBI. In particular, we focus on cationic arginine-rich peptides -- a new class of agents that growing evidence suggests acts through multiple neuroprotective mechanisms.

Neurogenic plasticity of mesenchymal stem cell, an alluring cellular replacement for traumatic brain injury.

Traumatic brain injury (TBI) imposes horrendous neurophysiological alterations leading to most devastating forms of neuro-disability. Which includes impaired cognition, distorted locomotors activity and psychosomatic disability in both youths and adults. Emerging evidence from recent studies has identified mesenchymal stem cells (MSCs) as one of the promising category of stem cells having excellent neuroregenerative capability in TBI victims. Some of the clinical and animal studies reported that MSCs transplantation could cure neuronal damage as well as improve cognitive and locomotors behaviors in TBI. However, mechanism behind their broad spectrum neuroregenerative potential in TBI has not been reviewed yet. Therefore, in the present article, we present a comprehensive data on the important attributes of MSCs, such as neurotransdifferentiation, neuroprotection, axonal repair and plasticity, maintenance of blood-brain integrity, reduction of reactive oxygen species (ROS) and immunomodulation. We have reviewed in detail the crucial neurogenic capabilities of MSCs in vivo and provided consolidated knowledge regarding their cellular remodeling in TBI for future therapeutic implications.

Neurorestoration after traumatic brain injury through angiotensin II receptor blockage.

See Moon (doi:10.1093/awv239) for a scientific commentary on this article.Traumatic brain injury frequently leads to long-term cognitive problems and physical disability yet remains without effective therapeutics. Traumatic brain injury results in neuronal injury and death, acute and prolonged inflammation and decreased blood flow. Drugs that block angiotensin II type 1 receptors (AT1R, encoded by AGTR1) (ARBs or sartans) are strongly neuroprotective, neurorestorative and anti-inflammatory. To test whether these drugs may be effective in treating traumatic brain injury, we selected two sartans, candesartan and telmisartan, of proven therapeutic efficacy in animal models of brain inflammation, neurodegenerative disorders and stroke. Using a validated mouse model of controlled cortical impact injury, we determined effective doses for candesartan and telmisartan, their therapeutic window, mechanisms of action and effect on cognition and motor performance. Both candesartan and telmisartan ameliorated controlled cortical impact-induced injury with a therapeutic window up to 6 h at doses that did not affect blood pressure. Both drugs decreased lesion volume, neuronal injury and apoptosis, astrogliosis, microglial activation, pro-inflammatory signalling, and protected cerebral blood flow, when determined 1 to 3 days post-injury. Controlled cortical impact-induced cognitive impairment was ameliorated 30 days after injury only by candesartan. The neurorestorative effects of candesartan and telmisartan were reduced by concomitant administration of the peroxisome proliferator-activated receptor gamma (PPARγ, encoded by PPARG) antagonist T0070907, showing the importance of PPARγ activation for the neurorestorative effect of these sartans. AT1R knockout mice were less vulnerable to controlled cortical impact-induced injury suggesting that the sartan's blockade of the AT1R also contributes to their efficacy. This study strongly suggests that sartans with dual AT1R blocking and PPARγ activating properties have therapeutic potential for traumatic brain injury.

Expression and Cell Distribution of SENP3 in Brain Tissue After Traumatic Brain Injury in Mice: A Pilot Study.

SUMO-specific proteases 3 (SENP3) is a member of the small ubiquitin-like modifier-specific protease family and deconjugates SUMO2/3 from protein substrates. To date, the expression and function of SENP3 in traumatic brain injury (TBI) are unclear. The present study examined dynamic changes in SENP3 expression in the cerebral cortex and in its cellular localization, using an acute TBI model in adult mice. SENP3 expression was examined at 3, 6, 12, 24 h, 3, and 5 days after TBI using Western Blot analysis and quantitative real-time PCR. Immunohistochemistry and immunofluorescence were examined to detect SENP3 localization. Western Blot indicated that SENP3 protein levels gradually increased from 3 h after TBI and peaked at 24 h. Quantitative real-time PCR demonstrated a gradual increase in SENP3 expression, which peaked 12 h after TBI and declined subsequently. Immunohistochemical staining demonstrated that SENP3-positive cells were observed in both the sham and 24 h post-TBI groups. However, robust expression of SENP3 was seldom observed in the sham group, while it was notably enhanced after TBI. Furthermore, immunofluorescence results revealed that the expression of SENP3 increased more significantly in neurons at day 1 after TBI compared with sham group and less significantly in astrocytes and microglia. Moreover, the SENP3-positive cells that were co-expressed with NeuN also expressed caspase-3, indicating a potential correlation between SENP3 and apoptosis after TBI. Collectively, our results showed obvious up-regulation of SENP3 expression in the brain after TBI, especially in the neurons. However, the full role of SENP3 and its therapeutic potential in TBI needs further investigation.

Transplanted hUCB-MSCs migrated to the damaged area by SDF-1/CXCR4 signaling to promote functional recovery after traumatic brain injury in rats

Transplanted human umbilical cord mesenchymal stem cells (hUC-MSCs) have exhibited considerable therapeutic potential for traumatic brain injury (TBI). However, how hUC-MSCs migrating to the injury region and the mechanism of hUC-MSCs promoting functional recovery after TBI are still unclear. In this study, we investigated whether stromal cell-derived factor-1 (SDF-1) was involved in the hUC-MSCs migration and the possible mechanisms that might be involved in the beneficial effect on functional recovery. In vitro experiments demonstrated that SDF-1 induces a concentration-dependent migration of hUC-MSCs. Furthermore, pre-treatment with the CXCR4-specific antagonist AMD3100 significantly prevented the migration of hUC-MSCs in vitro. We found that the expression of SDF-1 increased significantly around the damaged area. Transplanted hUC-MSCs were localized to regions where SDF-1 was highly expressed. Additionally, our results showed that hUC-MSCs-treated animals showed significantly improved functional recovery compared with controls. In hUC-MSCs-transplanted group, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells were decreased and BrdU-positive cells were significantly increased compared with control group, more of BrdU-positive cells co-localized with GFAP. These suggest that SDF-1 plays an important role in the migration of hUC-MSCs to the damaged area and hUC-MSCs are beneficial for functional recovery after TBI.

Neural Stem-Like Cells Derived from Human Amnion Tissue are Effective in Treating Traumatic Brain Injury in Rat

Although human amnion derived mesenchymal stem cells (AMSC) are a promising source of stem cells, their therapeutic potential for traumatic brain injury (TBI) has not been widely investigated. In this study, we evaluated the therapeutic potential of AMSC using a rat TBI model. AMSC were isolated from human amniotic membrane and characterized by flow cytometry. After induction, AMSC differentiated in vitro into neural stem-like cells (AM-NSC) that expressed higher levels of the neural stem cell markers, nestin, sox2 and musashi, in comparison to undifferentiated AMSC. Interestingly, the neurotrophic factors, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT-3), glial cell derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) were markedly upregulated after neural stem cell induction. Following transplantation in a rat TBI model, significant improvements in neurological function, brain tissue morphology, and higher levels of BDNF, NGF, NT-3, GDNF and CNTF, were observed in the AM-NSC group compared with the AMSC and Matrigel groups. However, few grafted cells survived with minimal differentiation into neural-like cells. Together, our results suggest that transplantation of AM-NSC promotes functional rehabilitation of rats with TBI, with enhanced expression of neurotrophic factors a likely mechanistic pathway.

Evaluation of late cognitive impairment and anxiety states following traumatic brain injury in mice: The effect of minocycline

Comorbidity of cognitive and stress disorders is a common clinical sequel of traumatic brain injury (TBI) that is essentially determined by the site and severity of the insult, but also by the extent of the ensuing neuroinflammatory response. The present study sought to examine the late effects of closed-head TBI on memory function and anxiety in mice, in order to further examine the potential efficacy of an acute anti-inflammatory treatment with minocycline. The mouse model of closed-head injury by mechanical percussion was applied on anesthetized Swiss mice. The treatment protocol included three injections of minocycline (i.p.) at 5min (90mg/kg), 3h and 9h (45mg/kg) post-TBI. The Novel Object Recognition Test as well as the Elevated Plus Maze (EPM) and Elevated Zero Maze (EZM) tasks were employed to assess post-TBI memory and anxiety respectively. Our results revealed a recognition memory deficit that was significant up to at least 13 weeks post-TBI. However, neither EPM nor EZM revealed any alteration in post-TBI anxiety levels albeit some mild disinhibition. Most importantly, minocycline was able to attenuate the memory impairment in an effective and lasting manner, highlighting its therapeutic potential in TBI.

Effects of posttraumatic carbamylated erythropoietin therapy on reducing lesion volume and hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome in rats following traumatic brain injury

Carbamylated erythropoietin (CEPO) is a modified erythropoietin molecule that does not affect hematocrit. In this study, the authors compared the efficacy of a single dose with a triple dose of CEPO treatment for traumatic brain injury (TBI) in rats. Traumatic brain injury was induced by controlled cortical impact over the left parietal cortex. Carbamylated erythropoietin (50 μg/kg) was administered intraperitoneally in rats with TBI at 6 hours (CEPO × 1) or at 6, 24, and 48 hours (CEPO × 3) postinjury. Neurological function was assessed using a modified neurological severity score and foot fault and Morris water maze tests. Animals were killed 35 days after injury, and brain sections were stained for immunohistochemical analysis to assess lesion volume, cell loss, cell proliferation, angiogenesis, and neurogenesis after CEPO treatment. Compared with the vehicle treatment, single treatment of CEPO (6 hours) significantly reduced lesion volume and hippocampal cell loss, enhanced angiogenesis and neurogenesis in the injured cortex and hippocampus, and significantly improved sensorimotor functional recovery and spatial learning in rats after TBI. Importantly, triple dosing of CEPO (6, 24, and 48 hours) further reduced lesion volume and improved functional recovery and neurogenesis compared with the CEPO × 1 group. The authors' results indicate that CEPO has considerable therapeutic potential in TBI and related pathologies and furthermore that repeated dosing in the subacute phase might have important pharmacological relevance.

Test-retest Reliability of Event-related Potentials in Traumatic Brain Injury and Healthy

Test-retest Reliability of Event-related Potentials in Traumatic Brain Injury and Healthy

Update of Neuropathology and Neurological Recovery After Traumatic Brain Injury

This review focuses on the potential for traumatic brain injury to evoke both focal and diffuse changes within the brain parenchyma, while considering the cellular constituents involved and the subcellular perturbations that contribute to their dysfunction. New insight is provided on the pathobiology of traumatically induced cell body injury and diffuse axonal damage. The consequences of axonal damage in terms of subsequent deafferentation and any potential retrograde cell death and atrophy are addressed. The regional and global metabolic sequelae are also considered. This detailed presentation of the neuropathological consequences of traumatic brain injury is used to set the stage for better appreciating the neurological recovery occurring after traumatic injury. Although the pathological and clinical effects of focal and diffuse damage are usually intermingled, the different clinical manifestations of recovery patterns associated with focal versus diffuse injuries are presented. The recognizable patterns of recovery, involving unconsciousness, posttraumatic confusion/amnesia, and postconfusional restoration, that typically occur across the full spectrum of diffuse injury are described, recognizing that the patient's long-term recovery may involve more idiosyncratic combinations of dysfunction. The review highlights the relationship of focal lesions to localizing syndromes that may be embedded in the evolving natural history of diffuse pathology. It is noted that injuries with primarily focal pathology do not necessarily follow a comparable pattern of recovery with distinct phases. Potential linkages of these recovery patterns to the known neuropathological sequelae of injury and various reparative mechanisms are considered and it is proposed that potential biological markers and newer imaging technologies will better define these linkages.