Low-intensity Blast Wave Model for Preclinical Assessment of Closed-head Mild Traumatic Brain Injury in Rodents.

Traumatic brain injury (TBI) is a large-scale public health problem. Mild TBI is the most prevalent form of neurotrauma and accounts for a large number of medical visits in the United States. There are currently no FDA-approved treatments available for TBI. The increased incidence of military-related, blast-induced TBI further accentuates the urgent need for effective TBI treatments. Therefore, new preclinical TBI animal models that recapitulate aspects of human blast-related TBI will greatly advance the research efforts into the neurobiological and pathophysiological processes underlying mild to moderate TBI as well as the development of novel therapeutic strategies for TBI. Here we present a reliable, reproducible model for the investigation of the molecular, cellular, and behavioral effects of mild to moderate blast-induced TBI. We describe a step-by-step protocol for closed-head, blast-induced mild TBI in rodents using a bench-top setup consisting of a gas-driven shock tube equipped with piezoelectric pressure sensors to ensure consistent test conditions. The benefits of the setup that we have established are its relative low-cost, ease of installation, ease of use and high-throughput capacity. Further advantages of this non-invasive TBI model include the scalability of the blast peak overpressure and the generation of controlled reproducible outcomes. The reproducibility and relevance of this TBI model has been evaluated in a number of downstream applications, including neurobiological, neuropathological, neurophysiological and behavioral analyses, supporting the use of this model for the characterization of processes underlying the etiology of mild to moderate TBI.

Venous Manometry as an Adjunct for Diagnosis and Multimodal Management of Intracranial Hypertension due to Meningioma Compressing Sigmoid Sinus.

Intracranial venous hypertension is a rare presentation of meningiomas in the transverse-sigmoid sinus region. We describe a case of a young patient presenting with intracranial hypertension due to a meningioma causing compression of the dominant sigmoid sinus. We were able to document the cerebral venous pressure gradient across the lesion confirming our hypothesis that compression of the sigmoid sinus from the meningioma was the cause of intracranial hypertension. The patient is a 17-year-old male who presented with intracranial hypertension due to meningioma at the right dominant sigmoid sinus, which was treated by a Simpson grade IV surgical resection followed by stereotactic radiosurgery. Following treatment, his papilledema resolved and he remains symptom-free at 18 months. In conclusion, venous manometry is a useful adjunct to diagnose intracranial hypertension in non-idiopathic causes of intracranial hypertension. A multimodal management approach of intracranial hypertension due to outflow obstruction from the dominant sinus led to an excellent recovery on follow up.

Post-partum posterior reversible encephalopathy syndrome requiring decompressive craniectomy: case report and review of the literature.

Posterior reversible encephalopathy syndrome (PRES) is an uncommon but potentially devastating syndrome if not recognized and treated appropriately. As the name implies, recognition of the condition and proper management may reverse the clinical and radiological findings. However, diagnosis is not always straightforward. We present the case of a 24-year-old female who was 4 days post-partum and presented with headache, neck pain, and new-onset seizures. She had undergone epidural anesthesia during labor, and initial imaging was suggestive of intracranial hypotension versus pachymeningitis. Despite initial conservative therapy including anti-epileptic drugs, magnesium therapy, empiric antibiotics, and Trendelenburg positioning, the patient continued to deteriorate. Follow-up imaging was suggestive of PRES with signs of intracranial hypertension. The patient underwent a decompressive suboccipital craniectomy for refractory and severe PRES and later fully recovered. This case highlights the sometimes difficult diagnosis of PRES, possible association with pregnancy, eclampsia/preeclampsia and/or cerebrospinal fluid drainage, and the rare but life-saving need for decompression in severe cases.

Exposure to mild blast forces induces neuropathological effects, neurophysiological deficits and biochemical changes.

Direct or indirect exposure to an explosion can induce traumatic brain injury (TBI) of various severity levels. Primary TBI from blast exposure is commonly characterized by internal injuries, such as vascular damage, neuronal injury, and contusion, without external injuries. Current animal models of blast-induced TBI (bTBI) have helped to understand the deleterious effects of moderate to severe blast forces. However, the neurological effects of mild blast forces remain poorly characterized. Here, we investigated the effects caused by mild blast forces combining neuropathological, histological, biochemical and neurophysiological analysis. For this purpose, we employed a rodent blast TBI model with blast forces below the level that causes macroscopic neuropathological changes. We found that mild blast forces induced neuroinflammation in cerebral cortex, striatum and hippocampus. Moreover, mild blast triggered microvascular damage and axonal injury. Furthermore, mild blast caused deficits in hippocampal short-term plasticity and synaptic excitability, but no impairments in long-term potentiation. Finally, mild blast exposure induced proteolytic cleavage of spectrin and the cyclin-dependent kinase 5 activator, p35 in hippocampus. Together, these findings show that mild blast forces can cause aberrant neurological changes that critically impact neuronal functions. These results are consistent with the idea that mild blast forces may induce subclinical pathophysiological changes that may contribute to neurological and psychiatric disorders.

The potential dangers of neck manipulation & risk for dissection and devastating stroke: An illustrative case & review of the literature.

Chiropractic cervical manipulation is a common practice utilized around the world. Most patients are never cleared medically for manipulation, which can be devastating for those few who are at increased risk for dissections. The high velocity thrust used in cervical manipulation can produce significant strain on carotid and vertebral vessels. Once a dissection has occurred, the risk of thrombus formation, ischemic stroke, paralysis, and even death is drastically increased. In this case report, we highlight a case of a 32-year-old woman who underwent chiropractic manipulation and had vertebral artery dissection with subsequent brainstem infarct. She quickly deteriorated and passed away shortly after arrival to the hospital. Although rare, one in 48 chiropractors have experienced such an event. We utilize this case to highlight the risk associated with cervical manipulation and urge open dialogue between chiropractors and physicians. Receiving medical clearance prior to cervical manipulation in potential at risk patients would drastically reduce morbidity and mortality.

Supplements, nutrition, and alternative therapies for the treatment of traumatic brain injury.

Studies using traditional treatment strategies for mild traumatic brain injury (TBI) have produced limited clinical success. Interest in treatment for mild TBI is at an all time high due to its association with the development of chronic traumatic encephalopathy and other neurodegenerative diseases, yet therapeutic options remain limited. Traditional pharmaceutical interventions have failed to transition to the clinic for the treatment of mild TBI. As such, many pre-clinical studies are now implementing non-pharmaceutical therapies for TBI. These studies have demonstrated promise, particularly those that modulate secondary injury cascades activated after injury. Because no TBI therapy has been discovered for mild injury, researchers now look to pharmaceutical supplementation in an attempt to foster success in human clinical trials. Non-traditional therapies, such as acupuncture and even music therapy are being considered to combat the neuropsychiatric symptoms of TBI. In this review, we highlight alternative approaches that have been studied in clinical and pre-clinical studies of TBI, and other related forms of neural injury. The purpose of this review is to stimulate further investigation into novel and innovative approaches that can be used to treat the mechanisms and symptoms of mild TBI.

A Pivotal Randomized Clinical Trial Evaluating the Safety and Effectiveness of a Novel Hydrogel Dural Sealant as an Adjunct to Dural Repair.

BACKGROUND: A watertight dural repair is critical to minimizing the risk of postoperative complications secondary to cerebrospinal fluid (CSF) leaks. OBJECTIVE: To evaluate the safety and efficacy of a novel hydrogel, Adherus Dural Sealant, when compared with control, DuraSeal Dural Sealant System, as an adjunct to standard methods of dural repair. METHODS: In this 17-center, prospective, randomized clinical trial designed as a noninferiority, single-blinded study, 124 patients received Adherus Dural Sealant (test sealant) and 126 received DuraSeal (control). The primary composite endpoint was the proportion of patients who were free of any intraoperative CSF leakage during Valsalva maneuver after dural repair, CSF leak/pseudomeningocele, and unplanned retreatment of the surgical site. Each component was then analyzed individually as a secondary endpoint. Patients were followed for 4 mo after surgery. RESULTS: The primary composite endpoint at the 120-d follow-up was achieved in 91.2% of the test sealant group compared with 90.6% of the control, thus showing that the test sealant was statistically significantly noninferior to DuraSeal ( P = .0049). Post hoc analysis of the primary composite endpoint at 14 d demonstrated superiority of the test sealant over the control ( P = .030). Primary endpoint failures in the control group tended to occur early in follow-up period, while a majority of test dural sealant failures were identified through protocol-required radiographic imaging at the 120-d follow-up visit. CONCLUSION: The test sealant, Adherus Dural Sealant, is a practical, safe, and effective adjunct to achieving a watertight dural closure after primary dural closure in cranial procedures.

A mouse Model of Focal Vascular Injury Induces Astrocyte Reactivity, Tau Oligomers, and Aberrant Behavior.

Neuropsychiatric symptom development has become more prevalent with 270,000 blast exposures occurring in the past 10 years in the United States. How blast injury leads to neuropsychiatric symptomology is currently unknown. Preclinical models of blast-induced traumatic brain injury have been used to demonstrate blood-brain barrier disruption, degenerative pathophysiology, and behavioral deficits. Vascular injury is a primary effect of neurotrauma that can trigger secondary injury cascades and neurodegeneration. Here we present data from a novel scaled and clinically relevant mouse blast model that was specifically developed to assess the outcome of vascular injury. We look at the biochemical effects and behavioral changes associated with blast injury in young-adult male BALB/c mice. We report that blast exposure causes focal vascular injury in the Somatosensory Barrel Field cortex, which leads to perivascular astrocyte reactivity, as well as acute aberrant behavior. Biochemical analysis revealed that mild blast exposure also invokes tauopathy, neuroinflammation, and oxidative stress. Overall, we propose our model to be used to evaluate focal blood-brain barrier disruption and to discover novel therapies for human neuropsychiatric symptoms.

More Learning in Less Time: Optimizing the Resident Educational Experience with Limited Clinical and Educational Work Hours.

OBJECTIVE: Resident education in the United States and elsewhere has undergone significant changes in recent years owing to work hour restrictions, requiring didactics to fit within a limited schedule, while being increasingly effective at accomplishing educational goals. METHODS: A single small program experience in improving the didactic experience of residents is described. RESULTS: Focused mentorship, curricula for intangibles, asynchronous education, and independent curricula all are useful tools in resident education. CONCLUSIONS: Residents can be exposed to both clinical material and specialty-specific mores using focused and intentional educational techniques.

Blast Scaling Parameters: Transitioning from Lung to Skull Base Metrics.

Neurotrauma from blast exposure is one of the single most characteristic injuries of modern warfare. Understanding blast traumatic brain injury is critical for developing new treatment options for warfighters and civilians exposed to improvised explosive devices. Unfortunately, the pre-clinical models that are widely utilized to investigate blast exposure are based on archaic lung based parameters developed in the early 20th century. Improvised explosive devices produce a different type of injury paradigm than the typical mortar explosion. Protective equipment for the chest cavity has also improved over the past 100 years. In order to improve treatments, it is imperative to develop models that are based more on skull-based parameters. In this mini-review, we discuss the important anatomical and biochemical features necessary to develop a skull-based model.

An improved finite element modeling of the cerebrospinal fluid layer in the head impact analysis.

The finite element (FE) method has been widely used to investigate the mechanism of traumatic brain injuries (TBIs), because it is technically difficult to quantify the responses of the brain tissues to the impact in experiments. One of technical challenges to build a FE model of a human head is the modeling of the cerebrospinal fluid (CSF) of the brain. In the current study, we propose to use membrane elements to construct the CSF layer. Using the proposed approach, we demonstrate that a head model can be built by using existing meshes available in commercial databases, without using any advanced meshing software tool, and with the sole use of native functions of the FE package Abaqus. The calculated time histories of the intracranial pressures at frontal, posterior fossa, parietal, and occipital positions agree well with the experimental data and the simulations in the literature, indicating that the physical effects of the CSF layer have been accounted for in the proposed modeling approach. The proposed modeling approach would be useful for bioengineers to solve practical problems.

Single low-dose lipopolysaccharide preconditioning: neuroprotective against axonal injury and modulates glial cells.

AIM: Over 7 million traumatic brain injuries (TBI) are reported each year in the United States. However, treatments and neuroprotection following TBI are limited because secondary injury cascades are poorly understood. Lipopolysaccharide (LPS) administration before controlled cortical impact can contribute to neuroprotection. However, the underlying mechanisms and whether LPS preconditioning confers neuroprotection against closed-head injuries remains unclear. METHODS: The authors hypothesized that preconditioning with a low dose of LPS (0.2 mg/kg) would regulate glial reactivity and protect against diffuse axonal injury induced by weight drop. LPS was administered 7 days prior to TBI. LPS administration reduced locomotion, which recovered completely by time of injury. RESULTS: LPS preconditioning significantly reduced the post-injury gliosis response near the corpus callosum, possibly by downregulating the oncostatin M receptor. These novel findings demonstrate a protective role of LPS preconditioning against diffuse axonal injury. LPS preconditioning successfully prevented neurodegeneration near the corpus callosum, as measured by fluorojade B. CONCLUSION: Further work is required to elucidate whether LPS preconditioning confers long-term protection against behavioral deficits and to elucidate the biochemical mechanisms responsible for LPS-induced neuroprotective effects.

Finite element simulations of the head-brain responses to the top impacts of a construction helmet: Effects of the neck and body mass.

Traumatic brain injuries are among the most common severely disabling injuries in the United States. Construction helmets are considered essential personal protective equipment for reducing traumatic brain injury risks at work sites. In this study, we proposed a practical finite element modeling approach that would be suitable for engineers to optimize construction helmet design. The finite element model includes all essential anatomical structures of a human head (i.e. skin, scalp, skull, cerebrospinal fluid, brain, medulla, spinal cord, cervical vertebrae, and discs) and all major engineering components of a construction helmet (i.e. shell and suspension system). The head finite element model has been calibrated using the experimental data in the literature. It is technically difficult to precisely account for the effects of the neck and body mass on the dynamic responses, because the finite element model does not include the entire human body. An approximation approach has been developed to account for the effects of the neck and body mass on the dynamic responses of the head-brain. Using the proposed model, we have calculated the responses of the head-brain during a top impact when wearing a construction helmet. The proposed modeling approach would provide a tool to improve the helmet design on a biomechanical basis.

Endoplasmic Reticulum Stress Modulation as a Target for Ameliorating Effects of Blast Induced Traumatic Brain Injury.

Blast traumatic brain injury (bTBI) has been shown to contribute to progressive neurodegenerative disease. Recent evidence suggests that endoplasmic reticulum (ER) stress is a mechanistic link between acute neurotrauma and progressive tauopathy. We propose that ER stress contributes to extensive behavioral changes associated with a chronic traumatic encephalopathy (CTE)-like phenotype. Targeting ER stress is a promising option for the treatment of neurotrauma-related neurodegeneration, which warrants investigation. Utilizing our validated and clinically relevant Sprague-Dawley blast model, we investigated a time course of mechanistic changes that occur following bTBI (50 psi) including: ER stress activation, iron-mediated toxicity, and tauopathy via Western blot and immunohistochemistry. These changes were associated with behavioral alterations measured by the Elevated Plus Maze (EPM), Forced Swim Test (FST), and Morris Water Maze (MWM). Following characterization, salubrinal, an ER stress modulator, was given at a concentration of 1 mg/kg post-blast, and its mechanism of action was determined in vitro. bTBI significantly increased markers of injury in the cortex of the left hemisphere: p-PERK and p-eIF2α at 30 min, p-T205 tau at 6 h, and iron at 24 h. bTBI animals spent more time immobile on the FST at 72 h and more time in the open arm of the EPM at 7 days. Further, bTBI caused a significant learning disruption measured with MWM at 21 days post-blast, with persistent tau changes. Salubrinal successfully reduced ER stress markers in vivo and in vitro while significantly improving performance on the EPM. bTBI causes robust biochemical changes that contribute to neurodegeneration, but these changes may be targeted with ER stress modulators.

Reduction of Endothelial Nitric Oxide Increases the Adhesiveness of Constitutive Endothelial Membrane ICAM-1 through Src-Mediated Phosphorylation.

Nitric oxide (NO) is a known anti-adhesive molecule that prevents platelet aggregation and leukocyte adhesion to endothelial cells (ECs). The mechanism has been attributed to its role in the regulation of adhesion molecules on leukocytes and the adhesive properties of platelets. Our previous study conducted in rat venules found that reduction of EC basal NO synthesis caused EC ICAM-1-mediated firm adhesion of leukocytes within 10-30 min. This quick response occurred in the absence of alterations of adhesion molecules on leukocytes and also opposes the classical pattern of ICAM-1-mediated leukocyte adhesion that requires protein synthesis and occurs hours after stimulation. The objective of this study is to investigate the underlying mechanisms of reduced basal NO-induced EC-mediated rapid leukocyte adhesion observed in intact microvessels. The relative levels of ICAM-1 at different cell regions and their activation status were determined with cellular fractionation and western blot using cultured human umbilical vein ECs. ICAM-1 adhesiveness was determined by immunoprecipitation in non-denatured proteins to assess the changes in ICAM-1 binding to its inhibitory antibody, mAb1A29, and antibody against total ICAM-1 with and without NO reduction. The adhesion strength of EC ICAM-1 was assessed by atomic force microscopy (AFM) on live cells. Results showed that reduction of EC basal NO caused by the application of caveolin-1 scaffolding domain (AP-CAV) or NOS inhibitor, L-NMMA, for 30 min significantly increased phosphorylated ICAM-1 and its binding to mAb1A29 in the absence of altered ICAM-1 expression and its distribution at subcellular regions. The Src inhibitor, PP1, inhibited NO reduction-induced increases in ICAM-1 phosphorylation and adhesive binding. AFM detected significant increases in the binding force between AP-CAV-treated ECs and mAb1A29-coated probes. These results demonstrated that reduced EC basal NO lead to a rapid increase in ICAM-1 adhesive binding via Src-mediated phosphorylation without de novo protein synthesis and translocation. This study suggests that a NO-dependent conformational change of constitutive EC membrane ICAM-1 might be the mechanism of rapid ICAM-1 dependent leukocyte adhesion observed in vivo. This new mechanistic insight provides a better understanding of EC/leukocyte interaction-mediated vascular inflammation under many disease conditions that encounter reduced basal NO in the circulation system.

Elucidating the role of compression waves and impact duration for generating mild traumatic brain injury in rats.

BACKGROUND: In total, 3.8 million concussions occur each year in the US leading to acute functional deficits, but the underlying histopathologic changes that occur are relatively unknown. In order to improve understanding of acute injury mechanisms, appropriately designed pre-clinical models must be utilized. METHODS: The clinical relevance of compression wave injury models revolves around the ability to produce consistent histopathologic deficits. Mild traumatic brain injuries activate similar neuroinflammatory cascades, cell death markers and increases in amyloid precursor protein in both humans and rodents. Humans, however, infrequently succumb to mild traumatic brain injuries and, therefore, the intensity and magnitude of impacts must be inferred. Understanding compression wave properties and mechanical loading could help link the histopathologic deficits seen in rodents to what might be happening in human brains following concussions. RESULTS: While the concept of linking duration and intensity of impact to subsequent histopathologic deficits makes sense, numerical modelling of compression waves has not been performed in this context. In this interdisciplinary work, numerical simulations were performed to study the creation of compression waves in an experimental model. CONCLUSION: This work was conducted in conjunction with a repetitive compression wave injury paradigm in rats in order to better understand how the wave generation correlates with histopathologic deficits.

Salubrinal reduces oxidative stress, neuroinflammation and impulsive-like behavior in a rodent model of traumatic brain injury.

Traumatic brain injury (TBI) is the leading cause of trauma related morbidity in the developed world. TBI has been shown to trigger secondary injury cascades including endoplasmic reticulum (ER) stress, oxidative stress, and neuroinflammation. The link between secondary injury cascades and behavioral outcome following TBI is poorly understood warranting further investigation. Using our validated rodent blast TBI model, we examined the interaction of secondary injury cascades following single injury and how these interactions may contribute to impulsive-like behavior after a clinically relevant repetitive TBI paradigm. We targeted these secondary pathways acutely following single injury with the cellular stress modulator, salubrinal (SAL). We examined the neuroprotective effects of SAL administration on significantly reducing ER stress: janus-N-terminal kinase (JNK) phosphorylation and C/EBP homology protein (CHOP), oxidative stress: superoxide and carbonyls, and neuroinflammation: nuclear factor kappa beta (NFκB) activity, inducible nitric oxide synthase (iNOS) protein expression, and pro-inflammatory cytokines at 24h post-TBI. We then used the more clinically relevant repeat injury paradigm and observed elevated NFκB and iNOS activity. These injury cascades were associated with impulsive-like behavior measured on the elevated plus maze. SAL administration attenuated secondary iNOS activity at 72h following repetitive TBI, and most importantly prevented impulsive-like behavior. Overall, these results suggest a link between secondary injury cascades and impulsive-like behavior that can be modulated by SAL administration.

Does Modern Management of Malignant Extracranial Disease Prolong Survival in Patients with ≥3 Brain Metastases?

OBJECTIVE: To assess if modern management of extracranial malignant diseases has prolonged the survival times for patients with more than 2 brain metastases (BM). METHODS: Data from 2385 patients treated with Gamma Knife surgery (GKS) for ≥3 BM between 1982 and 2011 were retrospectively analyzed. The patients were divided into 6 groups based on the treatment year and the median and 10% survival times were compared with the median and mean treatment dates in each group. RESULTS: The later the treatment date, the longer the median as well as the 10% survival times. The relation between the median treatment date and both the 10% and median survival times could be accurately expressed by a linear as well as an exponential curve fit. The median and 10% survival times increased by around 80% and 150%, respectively, between 1990 and 2010. CONCLUSIONS: Both the median and 10% survival times have increased in recent years among patients with more than 2 BM treated with GKS. Both linear and exponential regressions accurately expressed the increase in both median and 10% survival times during the years 1990-2010. Findings from other published data support the observation of longer survival times among patients treated more recently, independent of the patients being treated with GKS or with whole-brain radiation therapy with or without radiosurgery. Thus, earlier findings of short survival times for patients with multiple BM are no longer valid, at least not for patients deemed suitable for radiosurgery. Aggressive management is thus warranted for these patients.

Aneurysmal Subarachnoid Hemorrhage and Neuroinflammation: A Comprehensive Review.

Aneurysmal subarachnoid hemorrhage (SAH) can lead to devastating outcomes including vasospasm, cognitive decline, and even death. Currently, treatment options are limited for this potentially life threatening injury. Recent evidence suggests that neuroinflammation plays a critical role in injury expansion and brain damage. Red blood cell breakdown products can lead to the release of inflammatory cytokines that trigger vasospasm and tissue injury. Preclinical models have been used successfully to improve understanding about neuroinflammation following aneurysmal rupture. The focus of this review is to provide an overview of how neuroinflammation relates to secondary outcomes such as vasospasm after aneurysmal rupture and to critically discuss pharmaceutical agents that warrant further investigation for the treatment of subarachnoid hemorrhage. We provide a concise overview of the neuroinflammatory pathways that are upregulated following aneurysmal rupture and how these pathways correlate to long-term outcomes. Treatment of aneurysm rupture is limited and few pharmaceutical drugs are available. Through improved understanding of biochemical mechanisms of injury, novel treatment solutions are being developed that target neuroinflammation. In the final sections of this review, we highlight a few of these novel treatment approaches and emphasize why targeting neuroinflammation following aneurysmal subarachnoid hemorrhage may improve patient care. We encourage ongoing research into the pathophysiology of aneurysmal subarachnoid hemorrhage, especially in regards to neuroinflammatory cascades and the translation to randomized clinical trials.