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Objective: To identify sex-specific predictors of inpatient rehabilitation outcomes among patients with a traumatic brain injury (TBI) from a population-based perspective., Design: Retrospective cohort study., Setting: Inpatient rehabilitation., Participants: Patients in inpatient rehabilitation for a TBI within 1 year of acute care discharge between 2008/2009 and 2011/2012 (N=1730, 70% men, 30% women)., Interventions: None., Main Outcome Measures: Inpatient rehabilitation length of stay, total FIM score, and motor and cognitive FIM ratings at discharge., Results: Sex, as a covariate in multivariable linear regression models, was not a significant predictor of rehabilitation outcomes. Although many of the predictors examined were similar across men and women, sex-specific multivariable models identified some predictors of rehabilitation outcome that are specific for men and women; mechanism of injury (P<.0001) was a significant predictor of functional outcome only among women, whereas comorbidities (P<.0001) was a significant predictor for men only., Conclusions: Predictors of outcomes after inpatient rehabilitation differed by sex, providing evidence for a sex-specific approach in planning and resource allocation for inpatient rehabilitation services for patients with TBI., (Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate possible electroencephalography (EEG) correlates of epileptogenesis after traumatic brain injury (TBI) using the fluid percussion model., Methods: Experiments were conducted on adult 2- to 4-month-old male Sprague-Dawley rats. Two groups of animals were studied: (1) the TBI group with depth and screw electrodes implanted immediately after the fluid percussion injury (FPI) procedure, and (2) a naive age-matched control group with the same electrode implantation montage. Pairs of tungsten microelectrodes (50 μm outer diameter) and screw electrodes were implanted in neocortex inside the TBI core, areas adjacent to TBI, and remote areas. EEG activity, recorded on the day of FPI, and continuously for 2 weeks, was analyzed for possible electrographic biomarkers of epileptogenesis. Video-EEG monitoring was also performed continuously in the TBI group to capture electrographic and behavioral seizures until the caps came off (28-189 days), and for 1 week, at 2, 3, and 6 months of age, in the control group., Results: Pathologic high-frequency oscillations (pHFOs) with a central frequency between 100 and 600 Hz, were recorded from microelectrodes, beginning during the first two post-FPI weeks, in 7 of 12 animals in the TBI group (58%) and never in the controls. pHFOs only occurred in cortical areas within or adjacent to the TBI core. These were associated with synchronous multiunit discharges and popSpikes, duration 15-40 msec. Repetitive pHFOs and EEG spikes (rHFOSs) formed paroxysmal activity, with a unique arcuate pattern, in the frequency band 10-16 Hz in the same areas as isolated pHFOs, and these events were also recorded by screw electrodes. Although loss of caps prevented long-term recordings from all rats, pHFOs and rHFOSs occurred during the first 2 weeks in all four animals that later developed seizures, and none of the rats without these events developed late seizures., Significance: pHFOs, similar to those associated with epileptogenesis in the status rat model of epilepsy, may also reflect epileptogenesis after FPI. rHFOSs could be noninvasive biomarkers of epileptogenesis., Competing Interests: None of the authors has any conflicts of interests to disclosure. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Background: National Football League (NFL) players are exposed to multiple head collisions during their careers. Increasing awareness of the adverse long-term effects of repetitive head trauma has raised substantial concern among players, medical professionals, and the general public., Objective: To determine whether low perfusion in specific brain regions on neuroimaging can accurately separate professional football players from healthy controls., Method: A cohort of retired and current NFL players (n = 161) were recruited in a longitudinal study starting in 2009 with ongoing interval follow up. A healthy control group (n = 124) was separately recruited for comparison. Assessments included medical examinations, neuropsychological tests, and perfusion neuroimaging with single photon emission computed tomography (SPECT). Perfusion estimates of each scan were quantified using a standard atlas. We hypothesized that hypoperfusion particularly in the orbital frontal, anterior cingulate, anterior temporal, hippocampal, amygdala, insular, caudate, superior/mid occipital, and cerebellar sub-regions alone would reliably separate controls from NFL players. Cerebral perfusion differences were calculated using a one-way ANOVA and diagnostic separation was determined with discriminant and automatic linear regression predictive models., Results: NFL players showed lower cerebral perfusion on average (p < 0.01) in 36 brain regions. The discriminant analysis subsequently distinguished NFL players from controls with 90% sensitivity, 86% specificity, and 94% accuracy (95% CI 95-99). Automatic linear modeling achieved similar results. Inclusion of age and clinical co-morbidities did not improve diagnostic classification., Conclusion: Specific brain regions commonly damaged in traumatic brain injury show abnormally low perfusion on SPECT in professional NFL players. These same regions alone can distinguish this group from healthy subjects with high diagnostic accuracy. This study carries implications for the neurological safety of NFL players.

Purpose: Major depression and related mood disorders are the most common long-term outcomes associated with traumatic brain injury (TBI). Given the potentially debilitating consequences of depression, and the fact that TBI patients are frequently refractory to antidepressant drugs, new therapies are clearly needed. We hypothesized that human bone marrow-derived mesenchymal stem cells (hMSC), delivered intravenously, can effectively treat TBI-induced depression and other behavioral deficits associated with TBI., Methods: Rats (n = 8 per group) were subjected to experimental TBI or control sham operation. Six hours post TBI, rats were treated with 1×106 hMSC or vehicle control. Immediately after TBI and prior to hMSC or control treatment, rats were subjected to either targeted precision x-ray irradiation to eliminate subventricular zone (SVZ) proliferation or sham irradiation. One week after TBI, SVZ irradiation, and hMSC treatment, rats were evaluated for the depression-like behavior, anhedonia, using the two-bottle saccharin preference paradigm; and for working memory using the novel object recognition test., Results: TBI resulted in a 54% (p≤0.05) decrease in saccharin preference scores while treatment of TBI with hMSC fully prevented this anhedonic behavior. TBI was also found to produce a 73% (p≤0.05) decrease in novel object interaction time, indicating impaired working memory, and was similarly improved by treatment with hMSC. The ability of hMSC to prevent TBI-associated depression and working memory impairment was eliminated when SVZ proliferation was inhibited by irradiation., Conclusions: This work has identified a possible role for hMSC in the treatment of TBI-induced depression and other behaviors and suggests a mechanistic role for proliferative cells of the SVZ proliferation in hMSC efficacy.

Purpose: Traumatic brain injury (TBI) is an important cause of epilepsy and has also been associated with psychogenic nonepileptic seizures (PNES). We designed a brief questionnaire assessing patient beliefs regarding TBI as the cause of their seizures (Patient Seizure Etiology Questionnaire; PSEQ). This study reports content validity for the PSEQ., Methods: Ninety Veterans undergoing comprehensive evaluation at 3 VA epilepsy centers completed the PSEQ, a series of questions regarding possible causes for their seizures, including TBI. The PSEQ was scored as YES vs. NO for TBI as the proposed cause of seizures. For each patient, two expert reviewers independently completed a structured chart review to determine whether TBI was the proposed cause of seizures (n=180 reviews). Kappa statistic was used to assess agreement between the PSEQ and each chart review and between the PSEQ and combined chart reviews where both reviewers agreed on a TBI seizure etiology., Results: The PSEQ scored higher overall rates for a TBI seizure etiology than did expert chart reviews (40% vs. 28%; p<0.001). The PSEQ agreed with 82% of 180 independent chart reviews (sensitivity 88%; specificity 79%). Kappa statistic for agreement was 0.60. The two reviewers agreed on a probable TBI seizure etiology for 83% of chart reviews. The PSEQ sensitivity increased to 100% when both reviewers were in agreement., Conclusion: The PSEQ provides a direct, standardized measure of patient beliefs regarding TBI as the cause of their seizures and has moderate-substantial agreement with expert chart reviews., (Published by Elsevier Inc.)

Background: Given the recent interest in blast injury spurred by returning soldiers from overseas conflicts, we sought to research the early historical descriptions of blast injuries and their treatments. Consideration was given to specific descriptions of survivors of closed head injury and their treatment., Methods: A review of the medical and nonmedical literature was undertaken, with particular emphasis on pre-1800 descriptions of volcanic eruptions and mining accidents. Compilations of accounts of the Etna eruptions dating from 126 BC were translated into English, and early mining texts from the 1600s and 1700s were reviewed., Results: Accumulations of flammable gases were recorded in many medieval sources and this knowledge of toxic gas which could lead to blast injury was known in the mining community by 1316. No direct attribution of injuries to blast forces was present in the historical record examined before the 1300s, although mining accounts in the 1600s detail deaths due to blast. No specific descriptions of survivors of a closed head injury were found in the mining and volcanic eruption literature., Conclusions: Descriptions and warnings of blast forces were commonly written about in the medieval and Renaissance mining communities. Personal narratives as early as 1316 recognize the traumatic effects of blast injury. No mining or volcanic blast descriptions before 1800 detailed severe closed head injury survivors, suggesting greater mortality than morbidity from blast injury in the premodern era. This review also uncovered that there was no historical treatment or remedy recommended to survivors of blast injury. Blast explosions resulting in injury or death were frequently described, although in simplistic terminology.

Objective: To evaluate epidemiological patterns and lifetime costs of traumatic brain injury (TBI) identified in the emergency department (ED) within a publicly insured population in Ontario, Canada, in 2009., Methods: A nationally representative, population-based database was used to identify TBI cases presenting to Ontario EDs between April 2009 and March 2010. We calculated unit costs for medical treatment and productivity loss, and multiplied these by corresponding incidence estimates to determine the lifetime costs of identified TBI cases across age group, sex, and mechanism of injury., Results: In 2009, there were more than 133,000 ED visits for TBI in Ontario, resulting in a conservative estimate of $945 million in lifetime costs. Lifetime cost estimates ranged from $279 million to $1.22 billion depending on the diagnostic criteria used to define TBI. Peak rates of TBI occurred among young children (ages 0-4 year) and the elderly (ages 85+ years). Males experienced a 53% greater rate of TBI and incurred two-fold higher costs compared with females. Falls, sports/bicyclist-related injuries, and motor vehicle crashes represented 47%, 12%, and 10% of TBI presenting to ED, respectively, and accounted for a significant proportion of costs., Conclusions: This study revealed an enormous health and economic burden associated with TBI identified in the ED setting. Our findings underscore the importance of ongoing surveillance and prevention efforts targeted to vulnerable populations. More research is needed to fully appreciate the burden of TBI across a variety of health care settings.

Objectives: Traumatic brain injury (TBI) is a well-known cause of symptomatic epilepsy. In animal models of post-traumatic epilepsy (PTE), progression of trauma to epilepsy takes several weeks to months. Although this long process is similar to clinical PTE, it is costly and laborious. We used a combination of TBI and kindling as an accelerated animal model to develop epilepsy in much shorter period compared to that occurring in PTE., Methods: Traumatic brain injury was exerted to parieto-temporal cortex of anaesthetised rats by controlled cortical impact (CCI, 5 mm round tip, 4.5 mm/seconds velocity and 150 ms duration). Chemical kindling started 24 hours after CCI by intraperitoneal injection of 30 mg/kg pentylenetetrazole (PTZ) every other day until manifestation of three consecutive generalised seizures. Rapid electrical kindling of the amygdala began 1 week after TBI by exertion of 12 daily threshold stimuli (50 Hz mono-phasic square-wave stimulus of 1 ms per wave for 3 seconds) with 5 minutes interval between each stimulation until the rats became kindled., Results: Controlled cortical impact injury accelerated rate of both chemical and electrical kindling. Number of PTZ injections required for acquisition of generalised seizures decreased from 13.1 ± 1.6 in sham-operated animals to 7.1 ± 0.3 in traumatic rats (p < 0.05). The required number of stimuli to elicit electrically kindled focal and generalised seizures decreased from 24.0 ± 3.9 and 80 ± 6.5 in sham-operated animals to 6.6 ± 0.9 and 53 ± 6.5 in traumatic rats (p < 0.01), respectively., Limitations: Unlike the animal models of PTE in which recurrent seizures occur spontaneously after TBI, in our study, epilepsy is elicited by kindling stimulations., Discussion: Traumatic brain injury facilitates acquisition of epilepsy in both chemical and electrical kindling models. Combination of trauma and kindling can be considered as an inexpensive and time-saving animal model in PTE studies.

Objectives: One out of 50 injury-related presentations to an ED is a transport-related cycling injury. Detailed information about the most frequent mechanism of cycling injuries, sustained injuries and patterns are under-reported. The objective of this research was to examine the pattern of injuries sustained by cyclists at a level 1 trauma centre., Methods: A retrospective review of data of injured cyclists admitted and treated at a level 1 trauma centre between 2011 and 2012 evaluated demographic data, mechanism of injury, injury pattern, economic costs and outcome., Results: Data of 261 patients (mean age of 39 years) were reviewed, of which 88% was male patients with an average age of 38 years. Non-collision cycling injuries were reported in 55% of cases followed by collisions with other motor vehicles in 25.6% of cases. The mean injury severity score (ISS) was 9, but an ISS ≥ 12 was documented in 24%. Predominantly upper limb injuries (24.8%) were found, followed by injuries to the head and lower limb (each with 16.8%). Traumatic brain and chest injuries were equally seen in 8%. The overall length of stay was 4 days, and survival rate was 98%., Conclusion: This current data review reveals that non-collision traffic crashes accounted for the majority of injuries in cyclists treated in this facility, and the upper limb has replaced the head as the most injured body part. With a growing number of cyclists, this information contributes to considerations to improve road safety and trauma management., (© 2015 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine.)

Background: Equestrian activities can be undertaken for competition or leisure. Accidents can lead to bodily injuries. In particular, traumatic brain injury (TBI) can be devastating. Limited data exist regarding the pediatric population with respect to patterns of injury and related neurosurgical intervention., Methods: We retrospectively reviewed data for all pediatric patients diagnosed with equestrian-related injuries with neurological injuries from 2005 through June 2015., Results: Nine patients (1 male and 8 females) had neurological injuries. Their mean age was 10.4 years (range 2.9-16.8 years). Intracranial pathologies ranged from small punctate hemorrhages to large surgical extra-axial hematomas. Five patients also had concurrent skull fractures; 2 exhibited open lesions. Two patients required a decompressive craniotomy with placement of an external ventricular drain. Three patients exhibited other minor injuries; none had thoracic/abdominal/pelvic injuries. At discharge, all had good recovery; 1 patient who had a craniotomy did have a persistent right third-nerve palsy., Conclusion: Equestrian activities can present with dangerous and unpredictable situations, which can lead to profound neurological injury. Caution should be observed for all involved members, as both riders and nonriders are susceptible to harm. Protective gear (such as helmets), adequate training, and extensive experience are encouraged., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

Animal models play a critical role in understanding the biomechanical, pathophysiological, and behavioral consequences of traumatic brain injury (TBI). In preclinical studies, cognitive impairment induced by TBI is often assessed using the Morris water maze (MWM). Frequently described as a hippocampally dependent spatial navigation task, the MWM is a highly integrative behavioral task that requires intact functioning in numerous brain regions and involves an interdependent set of mnemonic and non-mnemonic processes. In this chapter, we review the special considerations involved in using the MWM in animal models of TBI, with an emphasis on maximizing the degree of information extracted from performance data. We include a theoretical framework for examining deficits in discrete stages of cognitive function and offer suggestions for how to make inferences regarding the specific nature of TBI-induced cognitive impairment. The ultimate goal is more precise modeling of the animal equivalents of the cognitive deficits seen in human TBI.

Traumatic brain injury (TBI) has been named the most complex disease in the most complex organ of the body. It is the most common cause of death and disability in the Western world in people <40 years old and survivors commonly suffer from persisting cognitive deficits, impaired motor function, depression and personality changes. TBI may vary in severity from uniformly fatal to mild injuries with rapidly resolving symptoms and without doubt, it is a markedly heterogeneous disease. Its different subtypes differs in their pathophysiology, treatment options and long-term consequences and to date, there are no pharmacological treatments with proven clinical benefit available to TBI patients. To enable development of novel treatment options for TBI, clinically relevant animal models are needed. Due to their availability and low costs, numerous rodent models have been developed which have substantially contributed to our current understanding of the pathophysiology of TBI. The most common animal models used in laboratories worldwide are likely the controlled cortical impact (CCI) model, the central and lateral fluid percussion injury (FPI) models, and weight drop/impact acceleration (I/A) models. Each of these models has inherent advantages and disadvantages; these need to be thoroughly considered when selecting the rodent TBI model according to the hypothesis and design of the study. Since TBI is not one disease, refined animal models must take into account the clinical features and complexity of human TBI. To enhance the possibility of establishing preclinical efficacy of a novel treatment, the preclinical use of several different experimental models is encouraged as well as varying the species, gender, and age of the animal. In this chapter, the methods, limitations, and challenges of the CCI and FPI models of TBI used in rodents are described.

The impact acceleration (I/A) model of traumatic brain injury (TBI) was developed to reliably induce diffuse traumatic axonal injury in rats in the absence of skull fractures and parenchymal focal lesions. This model replicates a pathophysiology that is commonly observed in humans with diffuse axonal injury (DAI) caused by acceleration-deceleration forces. Such injuries are typical consequences of motor vehicle accidents and falls, which do not necessarily require a direct impact to the closed skull. There are several desirable characteristics of the I/A model, including the extensive axonal injury produced in the absence of a focal contusion, the suitability for secondary insult modeling, and the adaptability for mild/moderate injury through alteration of height and/or weight. Furthermore, the trauma device is inexpensive and readily manufactured in any laboratory, and the induction of injury is rapid (~45 min per animal from weighing to post-injury recovery) allowing multiple animal experiments per day. In this chapter, we describe in detail the methodology and materials required to produce the rat model of I/A in the laboratory. We also review current adaptations to the model to alter injury severity, discuss frequent complications and technical issues encountered using this model, and provide recommendations to ensure technically sound injury induction.

Traumatic brain injury (TBI) is the leading cause of death in young adults in industrialized nations and in the developing world the WHO considers TBI a silent epidemic caused by an increasing number of traffic accidents. Despite the major improvement of TBI outcome in the acute setting in the past 20 years, the assessment, therapeutic interventions, and prevention of long-term complications remain a challenge. In order to get a deeper insight into the pathology of TBI and advancement of medical understanding and clinical progress experimental animal models are an essential requirement. This chapter provides an overview of most commonly used experimental animal TBI models and the pathobiological findings based on current data. In addition, limitations and advantages of each TBI model are mentioned. This will hopefully give an insight into the possibilities of each model and be of value in choosing one when designing a study.

Weight drop models in rodents have been used for several decades to advance our understanding of the pathophysiology of traumatic brain injury. Weight drop models have been used to replicate focal cerebral contusion as well as diffuse brain injury characterized by axonal damage. More recently, closed head injury models with free head rotation have been developed to model sports concussions, which feature functional disturbances in the absence of overt brain damage assessed by conventional imaging techniques. Here, we describe the history of development of closed head injury models in the first part of the chapter. In the second part, we describe the development of our own weight drop closed head injury model that features impact plus rapid downward head rotation, no structural brain injury, and long-term cognitive deficits in the case of multiple injuries. This rodent model was developed to reproduce key aspects of sports concussion so that a mechanistic understanding of how long-term cognitive deficits might develop will eventually follow. Such knowledge is hoped to impact athletes and war fighters and others who suffer concussive head injuries by leading to targeted therapies aimed at preventing cognitive and other neurological sequelae in these high-risk groups.

Animal models of traumatic brain injury (TBI) provide important tools for studying the pathobiology of brain trauma and for evaluating therapeutic or diagnostic targets. Incorporation of additional insults such as hemorrhagic shock (HS) and/or hypoxemia (HX) into these models more closely recreates clinical scenarios as TBI often occurs in conjunction with these systemic insults (i.e., polytrauma). We have developed a rat model of polytrauma that combines penetrating TBI, HS and HX. Following brain trauma, HX was induced by reducing the inspired oxygen while HS was induced by withdrawing blood to lower the mean arterial pressure. The physiological, histological, and behavioral aspects of this animal model have been characterized and have demonstrated exacerbating effects of systemic insults on penetrating TBI. As such, this model may facilitate the use of simultaneous assessments of multiple mechanisms and provide a platform for testing novel diagnostic and therapeutic targets.

The central nervous system (CNS) is protected by blood-brain barrier (BBB) and blood-cerebrospinal-fluid (CSF) barrier that limit toxic agents and most molecules from penetrating the brain and spinal cord. However, these barriers also prevent most pharmaceuticals from entering into the CNS. Drug delivery to the CNS following neurotrauma is complicated. Although studies have shown BBB permeability increases in various TBI models, it remains as the key mitigating factor for delivering drugs into the CNS. The commonly used methods for drug delivery in preclinical neurotrauma studies include intraperitoneal, subcutaneous, intravenous, and intracerebroventricular delivery. It should be noted that for a drug to be successfully translated into the clinic, it needs to be administered preclinically as it would be anticipated to be administered to patients. And this likely leads to better dose selection of the drug, as well as recognition of any possible side effects, prior to transition into a clinical trial. Additionally, novel approach that is noninvasive and yet circumvents BBB, such as drug delivery through nerve pathways innervating the nasal passages, needs to be investigated in animal models, as it may provide a viable drug delivery method for patients who sustain mild CNS injury or require chronic treatments. Therefore, the focus of this chapter is to present rationales and methods for delivering drugs by IV infusion via the jugular vein, and intranasally in preclinical studies.

Physical trauma in the central nervous system (CNS) is usually the result of a number of forces in different directions and dimensions. A large number of experimental models have been developed to improve the possibilities to understand the outcome of CNS trauma. In this chapter, we will describe the need for a variety of experimental models for research on traumatic brain injury (TBI) and spinal cord injury (SCI). Models can serve different needs, such as: to test new treatments for injuries, to reveal thresholds for injuries, to provide a better understanding of injury mechanisms, or to test tools and methods for translation between experiments and clinical data. In this chapter, we will discuss on the validation of models and translation between experimental and clinical studies.

The inability of central nervous system (CNS) neurons to regenerate damaged axons and dendrites following traumatic brain injury (TBI) creates a substantial obstacle for functional recovery. Apoptotic cell death, deposition of scar tissue, and growth-repressive molecules produced by glia further complicate the problem and make it challenging for re-growing axons to extend across injury sites. To date, there are no approved drugs for the treatment of TBI, accentuating the need for relevant leads. Cell-based and organotypic bioassays can better mimic outcomes within the native CNS microenvironment than target-based screening methods and thus should speed the discovery of therapeutic agents that induce axon or dendrite regeneration. Additionally, when used to screen focused chemical libraries such as small-molecule protein kinase inhibitors, these assays can help elucidate molecular mechanisms involved in neurite outgrowth and regeneration as well as identify novel drug targets. Here, we describe a phenotypic cellular (high content) screening assay that utilizes brain-derived primary neurons for screening small-molecule chemical libraries.

The goals of this chapter are to provide an introduction into the variety of animal models available for studying traumatic brain injury (TBI) and to provide a concise systematic review of the general materials and methods involved in each model. Materials and methods were obtained from a literature search of relevant peer-reviewed articles. Strengths and weaknesses of each animal choice were presented to include relative cost, anatomical and physiological features, and mechanism of injury desired. Further, a variety of homologous, isomorphic/induced, and predictive animal models were defined, described, and compared with respect to their relative ease of use, characteristics, range, adjustability (e.g., amplitude, duration, mass/size, velocity, and pressure), and rough order of magnitude cost. Just as the primary mechanism of action of TBI is limitless, so are the animal models available to study TBI. With such a wide variety of available animals, types of injury models, along with the research needs, there exists no single "gold standard" model of TBI rendering cross-comparison of data extremely difficult. Therefore, this chapter reflects a representative sampling of the TBI animal models available and is not an exhaustive comparison of every possible model and associated parameters. Throughout this chapter, special considerations for animal choice and TBI animal model classification are discussed. Criteria central to choosing appropriate animal models of TBI include ethics, funding, complexity (ease of use, safety, and controlled access requirements), type of model, model characteristics, and range of control (scope).

Traumatic brain injury (TBI), ranging from mild to severe, almost always elicits an array of behavioral deficits in injured subjects. Some of these TBI-induced behavioral deficits include cognitive and vestibulomotor deficits as well as anxiety and other consequences. Rodent models of TBI have been (and still are) fundamental in establishing many of the pathophysiological mechanisms of TBI. Animal models are also utilized in screening and testing pharmacological effects of potential therapeutic agents for brain injury treatment. This chapter details validated protocols for each of these behavioral deficits post traumatic brain injury in Sprague-Dawley male rats. The elevated plus maze (EPM) protocol is described for assessing anxiety-like behavior; the Morris water maze protocol for assessing cognitive deficits in learning memory and spatial working memory and the rotarod test for assessing vestibulomotor deficits.

Traumatic brain injury (TBI) is one of the leading causes of death and disabilities worldwide. It affects approximately 1.5 million people each year and is associated with severe post-TBI symptoms such as sensory and motor deficits. Several neuro-therapeutic approaches ranging from cell therapy interventions such as the use of neural stem cells (NSCs) to drug-based therapies have been proposed for TBI management. Successful cell-based therapies are tightly dependent on reproducible preclinical animal models to ensure safety and optimal therapeutic benefits. In this chapter, we describe the isolation of NSCs from neonatal mouse brain using the neurosphere assay in culture. Subsequently, dissociated neurosphere-derived cells are used for transplantation into the ipsilateral cortex of a controlled cortical impact (CCI) TBI model in C57BL/6 mice. Following intra-cardiac perfusion and brain removal, the success of NSC transplantation is then evaluated using immunofluorescence in order to assess neurogenesis along with gliosis in the ipsilateral coronal brain sections. Behavioral tests including rotarod and pole climbing are conducted to evaluate the motor activity post-treatment intervention.

The brain has different responses to traumatic injury as a function of its developmental stage. As a model of injury to the immature brain, the piglet shares numerous similarities in regards to morphology and neurodevelopmental sequence compared to humans. This chapter describes a piglet scaled focal contusion model of traumatic brain injury that accounts for the changes in mass and morphology of the brain as it matures, facilitating the study of age-dependent differences in response to a comparable mechanical trauma.

Fluid percussion was first conceptualized in the 1940s and has evolved into one of the leading laboratory methods for studying experimental traumatic brain injury (TBI). Over the decades, fluid percussion has been used in numerous species and today is predominantly applied to the rat. The fluid percussion technique rapidly injects a small volume of fluid, such as isotonic saline, through a circular craniotomy onto the intact dura overlying the brain cortex. In brief, the methods involve surgical production of a circular craniotomy, attachment of a fluid-filled conduit between the dura overlying the cortex and the outlet port of the fluid percussion device. A fluid pulse is then generated by the free-fall of a pendulum striking a piston on the fluid-filled cylinder of the device. The fluid enters the cranium, producing a compression and displacement of the brain parenchyma resulting in a sharp, high magnitude elevation of intracranial pressure that is propagated diffusely through the brain. This results in an immediate and transient period of traumatic unconsciousness as well as a combination of focal and diffuse damage to the brain, which is evident upon histological and behavioral analysis. Numerous studies have demonstrated that the rat fluid percussion model reproduces a wide range of pathological features associated with human TBI.

Traumatic brain injury (TBI) is one of the most common causes of death and disability, and cerebral hypoxia is a frequently occurring harmful secondary event in TBI patients. The hypoxic conditions that occur on the scene of accident, where the airways are often obstructed or breathing is in other ways impaired, could be reproduced using animal TBI models where oxygen delivery is strictly controlled throughout the entire experimental procedure. Monitoring physiological parameters of the animal is of utmost importance in order to maintain an adequate quality of the experiment. Peripheral oxygen saturation, O2 pressure (pO2) in the blood, or fraction of inhaled O2 (FiO2) could be used as goals to validate the hypoxic conditions. Different models of traumatic brain injury could be used to inflict desired injury type, whereas effects then could be studied using radiological, physiological and functional tests. In order to confirm that the brain has been affected by a hypoxic injury, appropriate substances in the affected cerebral tissue, cerebrospinal fluid, or serum should be analyzed.

The Morris water maze (MWM) task is one of the most widely used and versatile tools in behavioral neuroscience for evaluating spatial learning and memory. With regard to detecting cognitive deficits following central nervous system (CNS) injuries, MWM has been commonly utilized in various animal models of neurotrauma, such as fluid percussion injury (FPI), cortical controlled impact (CCI) injury, weight-drop impact injury, and penetrating ballistic-like brain injury (PBBI). More importantly, it serves as a therapeutic index for assessing the efficacy of treatment interventions on cognitive performance following neurotrauma. Thus, it is critical to design an MWM testing paradigm that is sensitive yet discriminating for the purpose of evaluating potential therapeutic interventions. In this chapter, we discuss how multiple test manipulations, including the size of platform, numbers of trials per day, the frequency of retesting intervals, and the texture of platform surface, impact MWM's ability to detect cognitive deficits using a rat model of PBBI.

Objectives: The aim of this study was to describe the demography and epidemiology of Finnish patients with TBI and to analyse the representativeness of a study sample., Materials and Methods: This prospective multi-centre study was conducted as part of an international collaboration within the EU-funded TBIcare project. The study group was recruited from patients attending the regional emergency department (ED) of the Turku University Hospital, Finland. Pre-defined exclusion criteria included age < 18 years, more than 2 weeks from the injury and uncertain diagnosis of TBI. To be included, a need for an acute head CT (NICE-criteria) was required., Results: Of the 620 patients with TBI or suspected TBI, 203 patients were recruited to the study. Falls were the most common injury mechanism. The study group included more males than the total eligible population (p = 0.011), but no other statistical differences were found. The most common cause for being excluded was lack of information available to the research group before discharge (34%)., Conclusion: This study supports previous findings that falls are the most common injury mechanism in the Western countries. Uncertainty about the diagnosis of TBI, lack of representativeness without continuous recruitment and poor information transfer about the ED attendees are major challenges for prospective TBI studies.

Despite prodigious advances in TBI neurobiology research and a broad arsenal of animal models mimicking different aspects of human brain injury, this field has repeatedly experienced collective failures to translate from animals to humans, particularly in the area of therapeutics. This lack of success stems from variability and inconsistent standardization across models and laboratories, as well as insufficient objective and quantifiable diagnostic measures (biomarkers, high-resolution imaging), understanding of the vast clinical heterogeneity, and clinically centered conception of the TBI animal models. Significant progress has been made by establishing well-defined standards for reporting animal studies with "preclinical common data elements" (CDE), and for the reliability and reproducibility in preclinical TBI therapeutic research with the Operation Brain Trauma Therapy (OBTT) consortium. However, to break the chain of failures and achieve a therapeutic breakthrough in TBI will probably require the use of higher species models, specific mechanism-based injury models by which to theranostically targeted treatment portfolios are tested, more creative concepts of therapy intervention including combination therapy and regeneration neurobiology strategies, and the adoption of dosing regimens based upon pharmacokinetic-pharmacodynamic (PK-PD) studies and guided by the injury severity and TBI recovery process.

The application of systems biology tools in analyzing heterogeneous data from multiple sources has become a necessity, especially in biomarker discovery. Such tools were developed with several approaches to address different types of research questions and hypotheses. In the field of neurotrauma and traumatic brain injury (TBI), three distinct approaches have been used so far as systems biology tools, namely functional group categorization, pathway analysis, and protein-protein interaction (PPI) networks. The databases allow for query of the system to identify candidate targets which can be further studied to elucidate potential downstream biomarkers indicative of disease progression, severity, and improvement. The various systems biology tools, databases, and strategies that can be implemented on available TBI data in neuroproteomic studies are discussed in this chapter.

As a result of the wartime urgency to understand, prevent, and treat patients with traumatic brain injury (TBI) during World War II (WWII), clinicians and basic scientists in Great Britain collaborated on research projects that included accident investigations, epidemiologic studies, and development of animal and physical models. Very quickly, investigators from different disciplines shared information and ideas that not only led to new insights into the mechanisms of TBI but also provided very practical approaches for preventing or ameliorating at least some forms of TBI. Neurosurgeon Hugh Cairns (1896-1952) conducted a series of influential studies on the prevention and treatment of head injuries that led to recognition of a high rate of fatal TBI among motorcycle riders and subsequently to demonstrations of the utility of helmets in lowering head injury incidence and case fatality. Neurologists Derek Denny-Brown (1901-1981) and (William) Ritchie Russell (1903-1980) developed an animal model of TBI that demonstrated the fundamental importance of sudden acceleration (i.e., jerking) of the head in causing concussion and forced a distinction between head injury associated with sudden acceleration/deceleration and that associated with crush or compression. Physicist A.H.S. Holbourn (1907-1962) used theoretical arguments and simple physical models to illustrate the importance of shear stress in TBI. The work of these British neurological clinicians and scientists during WWII had a strong influence on subsequent clinical and experimental studies of TBI and also eventually resulted in effective (albeit controversial) public health campaigns and legislation in several countries to prevent head injuries among motorcycle riders and others through the use of protective helmets. Collectively, these studies accelerated our understanding of TBI and had subsequent important implications for both military and civilian populations. As a result of the wartime urgency to understand, prevent, and treat patients with TBI during WWII, clinicians and basic scientists collaborated on research projects that none of them would likely have pursued without these unique circumstances. Very quickly, there was a sharing of information and ideas that not only led to new insights into the mechanisms of TBI but also provided very practical approaches for preventing or ameliorating at least some forms of TBI. Investigators in Great Britain, in particular, pioneered accident investigations, performed epidemiologic studies, and developed animal and physical models that accelerated our understanding of TBI and had subsequent important implications for both military and civilian populations., (© 2016 S. Karger AG, Basel.)

Unique from other brain disorders, traumatic brain injury (TBI) generally results from a discrete biomechanical event that induces rapid head movement. The large size and high organization of the human brain makes it particularly vulnerable to traumatic injury from rotational accelerations that can cause dynamic deformation of the brain tissue. Therefore, replicating the injury biomechanics of human TBI in animal models presents a substantial challenge, particularly with regard to addressing brain size and injury parameters. Here we present the historical development and use of a porcine model of head rotational acceleration. By scaling up the rotational forces to account for difference in brain mass between swine and humans, this model has been shown to produce the same tissue deformations and identical neuropathologies found in human TBI. The parameters of scaled rapid angular accelerations applied for the model reproduce inertial forces generated when the human head suddenly accelerates or decelerates in falls, collisions, or blunt impacts. The model uses custom-built linkage assemblies and a powerful linear actuator designed to produce purely impulsive non-impact head rotation in different angular planes at controlled rotational acceleration levels. Through a range of head rotational kinematics, this model can produce functional and neuropathological changes across the spectrum from concussion to severe TBI. Notably, however, the model is very difficult to employ, requiring a highly skilled team for medical management, biomechanics, neurological recovery, and specialized outcome measures including neuromonitoring, neurophysiology, neuroimaging, and neuropathology. Nonetheless, while challenging, this clinically relevant model has proven valuable for identifying mechanisms of acute and progressive neuropathologies as well as for the evaluation of noninvasive diagnostic techniques and potential neuroprotective treatments following TBI.

Traumatic brain injury (TBI) is a leading cause of death and disability in the USA. Common causes of TBI include falls, violence, injuries from wars, and vehicular and sporting accidents. The initial direct mechanical damage in TBI is followed by progressive secondary injuries such as brain swelling, perturbed cerebral blood flow (CBF), abnormal cerebrovascular reactivity (CR), metabolic dysfunction, blood-brain-barrier disruption, inflammation, oxidative stress, and excitotoxicity, among others. Magnetic resonance imaging (MRI) offers the means to noninvasively probe many of these secondary injuries. MRI has been used to image anatomical, physiological, and functional changes associated with TBI in a longitudinal manner. This chapter describes controlled cortical impact (CCI) TBI surgical procedures, a few common MRI protocols used in TBI imaging, and, finally, image analysis pertaining to experimental TBI imaging in rats.

Successful therapy for TBI disabilities awaits refinement in the understanding of TBI neurobiology, quantitative measurement of treatment-induced incremental changes in recovery trajectories, and effective translation to human TBI using quantitative methods and protocols that were effective to monitor recovery in preclinical models. Details of the specific neurobiology that underlies these injuries and effective quantitation of treatment-induced changes are beginning to emerge utilizing a variety of preclinical and clinical models (for reviews see (Morales et al., Neuroscience 136:971-989, 2005; Fujimoto et al., Neurosci Biobehav Rev 28:365-378, 2004; Cernak, NeuroRx 2:410-422, 2005; Smith et al., J Neurotrauma 22:1485-1502, 2005; Bose et al., J Neurotrauma 30:1177-1191, 2013; Xiong et al., Nat Rev Neurosci 14:128-142, 2013; Xiong et al., Expert Opin Emerg Drugs 14:67-84, 2009; Johnson et al., Handb Clin Neurol 127:115-128, 2015; Bose et al., Brain neurotrauma: molecular, neuropsychological, and rehabilitation aspects, CRC Press/Taylor & Francis, Boca Raton, 2015)). Preclinical models of TBI, essential for the efficient study of TBI neurobiology, benefit from the setting of controlled injury and optimal opportunities for biometric quantitation of injury and treatment-induced changes in the trajectories of disability. Several preclinical models are currently used, and each offer opportunities for study of different aspects of TBI primary and secondary injuries (for review see (Morales et al., Neuroscience 136:971-989, 2005; Xiong et al., Nat Rev Neurosci 14:128-142, 2013; Xiong et al., Expert Opin Emerg Drugs 14:67-84, 2009; Johnson et al., Handb Clin Neurol 127:115-128, 2015; Dixon et al., J Neurotrauma 5:91-104, 1988)). The closed-head, impact-acceleration model of TBI designed by Marmarou et al., 1994 (J Neurosurg 80:291-300, 1994), when used to produce mild to moderate TBI, produces diffuse axonal injuries without significant additional focal injuries of the brain (Morales et al., Neuroscience 136:971-989, 2005; Foda and Marmarou, J Neurosurg 80:301-313, 1994; Kallakuri et al., Exp Brain Res 148:419-424, 2003). Accordingly, use of this preclinical model offers an opportunity for (a) gaining a greater understanding of the relationships of TBI induced diffuse axonal injuries and associated long term disabilities, and (b) to provide a platform for quantitative assessment of treatment interactions upon the trajectories of TBI-induced disabilities. Using the impact acceleration closed head TBI model to induce mild/moderate injuries in the rat, we have observed and quantitated multiple morbidities commonly observed following TBI in humans (Bose et al., J Neurotrauma 30:1177-1191, 2013). This chapter describes methods and protocols used for TBI-induced multiple morbidity involving cognitive dysfunction, balance instability, spasticity and gait, and anxiety-like disorder.

Purpose Primary blast-induced traumatic brain injury (bTBI) is the least understood of the four phases of blast injury. Distant injury induced by the blast wave, on the opposite side from the wave entry, is not well understood. This study investigated the mechanism of distant injury in bTBI. Materials and Methods Eight 8-week-old male Sprague-Dawley rats were divided into two groups: group 1 served as the control group and did not receive any shock wave (SW) exposure; group 2 was exposed to SWs (12.5 ± 2.5 MPa). Propagation of SWs within a brain phantom was evaluated by visualization, pressure measurement, and numerical simulation. Results Intracerebral hemorrhage near the ignition site and elongation of the distant nucleus were observed, despite no apparent damage between the two locations in the animal experiment. Visualization, pressure measurement, and numerical simulation indicated the presence of complex wave dynamics accompanying a sudden increase in pressure, followed by negative pressure in the phantom experiment. Conclusion A local increase in pressure above the threshold caused by interference of reflection and rarefaction waves in the vicinity of the brain-skull surface may cause distant injury in bTBI.

Research models of traumatic brain injury (TBI) hold significant validity towards the human condition, with each model replicating a subset of clinical features and symptoms. After 30 years of characterization and implementation, fluid percussion injury (FPI) is firmly recognized as a clinically relevant model of TBI, encompassing concussion through severe injury. The midline variation of FPI may best represent mild and diffuse clinical brain injury, because of the acute behavioral deficits, the late onset of subtle behavioral morbidities, and the absence of gross histopathology. This chapter outlines the procedures for midline (diffuse) FPI in adult male rats and mice. With these procedures, it becomes possible to generate brain-injured laboratory animals for studies of injury-induced pathophysiology and behavioral deficits, for which rational therapeutic interventions can be implemented.

Due to a high incidence of traumatic brain injury (TBI) in children and adolescents, age-specific studies are necessary to fully understand the long-term consequences of injuries to the immature brain. Preclinical and translational research can help elucidate the vulnerabilities of the developing brain to insult, and provide model systems to formulate and evaluate potential treatments aimed at minimizing the adverse effects of TBI. Several experimental TBI models have therefore been scaled down from adult rodents for use in juvenile animals. The following chapter discusses these adapted models for pediatric TBI, and the importance of age equivalence across species during model development and interpretation. Many neurodevelopmental processes are ongoing throughout childhood and adolescence, such that neuropathological mechanisms secondary to a brain insult, including oxidative stress, metabolic dysfunction and inflammation, may be influenced by the age at the time of insult. The long-term evaluation of clinically relevant functional outcomes is imperative to better understand the persistence and evolution of behavioral deficits over time after injury to the developing brain. Strategies to modify or protect against the chronic consequences of pediatric TBI, by supporting the trajectory of normal brain development, have the potential to improve quality of life for brain-injured children.

Controlled cortical impact (CCI) is a commonly used and highly regarded model of brain trauma that uses a pneumatically or electromagnetically controlled piston to induce reproducible and well-controlled injury. The CCI model was originally used in ferrets and it has since been scaled for use in many other species. This chapter will describe the historical development of the CCI model, compare and contrast the pneumatic and electromagnetic models, and summarize key short- and long-term consequences of TBI that have been gleaned using this model. In accordance with the recent efforts to promote high-quality evidence through the reporting of common data elements (CDEs), relevant study details-that should be reported in CCI studies-will be noted.

Sirtuin3 (SIRT3) is an important protein deacetylase which predominantly presents in mitochondria and exhibits broad bioactivities including regulating energy metabolism and counteracting inflammatory effect. Since inflammatory cascade was proved to be critical for pathological damage following subarachnoid hemorrhage (SAH), we investigated the overall expression and cell-specific distribution of SIRT3 in the cerebral cortex of Sprague-Dawley rats with experimental SAH induced by internal carotid perforation. Results suggested that SIRT3 was expressed abundantly in neurons and endothelia but rarely in gliocytes in normal cerebral cortex. After experimental SAH, mRNA and protein expressions of SIRT3 decreased significantly as early as 8 hours and dropped to the minimum value at 24 h after SAH. By contrast, SOD2 expression increased slowly as early as 12 hours after experimental SAH, rose up sharply at the following 12 hours, and then was maintained at a higher level. In conclusion, attenuated SIRT3 expression in cortical neurons was associated closely with enhanced reactive oxygen species generation and cellular apoptosis, implying that SIRT3 might play an important neuroprotective role during early brain injury following SAH., Competing Interests: The authors declare that they have no competing interests.

Traumatic brain injury (TBI) is the leading cause of death and disability for people under 45 years of age. Clinical TBI is often the result of disparate forces resulting in heterogeneous injuries. Preclinical modeling of TBI is a vital tool for studying the complex cascade of metabolic, cellular, and molecular post-TBI events collectively termed secondary injury. Preclinical models also provide an important platform for studying therapeutic interventions. However, modeling TBI in the preclinical setting is challenging, and most models replicate only certain aspects of clinical TBI. This chapter details the most widely used models of preclinical TBI, including the controlled cortical impact, fluid percussion, blast, and closed head models. Each of these models replicates particular critical aspects of clinical TBI. Prior to selecting a preclinical TBI model, it is important to address what aspect of human TBI is being sought to evaluate.

What is in the best interests of a child, and could that ever include interventions that we might regard as prima facie detrimental to a child's physical well-being? This question is raised a fortiori by growth attenuation treatments in children with severe neurological disorders causing extreme developmental delay. I argue that two principles that provide guidance in generating a conception of best interests for each individual child yield the right results in such cases. The principles are as follows: the potentiality principle, whereby every child should be able to develop its potential and is entitled to receive certain help in doing so, and the principle of psychosomatic harmony, whereby every human being is entitled to treatment that is appropriate to or enables a life in which mind and body are in tune with each other. These principles indicate a certain response to what we can call Ashley-type cases and admit certain caveats.

Objective: The physical events of the first 15 milliseconds of a traumatic brain injury are reviewed from computer simulations using finite element calculations and applied to observed pathology., Methods: The impact creates two shock waves; one through the brain, another through the skull, both injure the brain separately. Two accelerations, anteroposterior and rotary, distort or stretch the brain, because of inertia. The two shockwaves are reflected many times within in the brain, from boundaries where the density or elasticity changes., Results: Overlapping waves form powerful positive or negative pressure nodes. Negative waves are more damaging to neurones and blood vessels, so a random pattern of scattered neural and capillary necroses develop all over the brain. The skull shockwave expands the skull opposite the blow, so creating a damaging negative pressure injury to the brain, contre coup contusion. Acceleration (or deceleration) follows impact, beginning later and lasting longer. Inertia strains the tissue, where the brain is free to move, inflicting characteristic white matter injuries., Conclusions: In the antero-posterior plane, acceleration and inertia stretch and tear long tracts to the spine and blood vessels running from the brain to the dura. Rotatory accelerations stress the inter-hemispheric connections of the brain, especially the corpus callosum, between the hemispheres.

Patients with severe traumatic brain injury (TBI) frequently present with concomitant injuries that may cause secondary brain injury and impact outcomes. Animal models have been developed that combine contemporary models of TBI with a secondary neurologic insult such as hypoxia, shock, long bone fracture, and radiation exposure. Combined injury models may be particularly useful when modeling treatment strategies and in efforts to map basic research to a heterogeneous patient population. Here, we review these models and their collective contribution to the literature on TBI. In addition, we provide protocols and notes for two well-characterized models of TBI plus hemorrhagic shock.

Traumatic brain injury (TBI) in humans causes a broad range of structural damage and functional deficits due to both primary and secondary injury mechanisms. Over the past three decades, animal models have been established to replicate the diverse changes of human TBI, to study the underlying pathophysiology and to develop new therapeutic strategies. However, drugs that were identified as neuroprotective in animal brain injury models were not successful in clinical trials phase II or phase III. Repetitive transcranial magnetic stimulation (rTMS) is a powerful noninvasive approach to excite cortical neurons in humans and animals, widely applied for therapeutic purpose in patients with brain diseases. In addition, recent animal studies showed rTMS as a strong neuroprotective tool. In this chapter, we discuss the rationale and mechanisms related to rTMS as well as therapeutic applications and putative molecular mechanisms. Furthermore, relevant biochemical studies and neuroprotective effect in animal models and possible application of rTMS as a novel treatment for rodent brain injury models are discussed.

Objective: To identify factors that people with a traumatic brain injury and their families perceived as helping to improve their quality of life., Methods: Three focus groups and five interviews were conducted with a total of 37 participants: 14 persons with traumatic brain injury and 23 caregivers. A content analysis was conducted. The constant comparative method was applied., Results: We detected five factors that improved the quality of life of persons with a traumatic brain and their families: 1) Informal support (family and friends); 2) formal support (counseling, employment, built and bureaucratic environment); 3) type of clinical characteristics; 4) social participation, and 5) social visibility., Conclusions: The needs expressed by our participants primarily focused on social and emotional factors. For persons with severe traumatic brain injury attempting to achieve the best possible community integration, a new semiology is required, not limited to medical care, but also involving social and psychological care tailored to the needs of each individual and family and their environment., (Copyright © 2014 SESPAS. Published by Elsevier Espana. All rights reserved.)

This hypothesis-generating research describes the characteristics of traumatic brain injuries (TBIs) sustained among 229 Veterans seeking homeless services. Nearly all participants (83%) had sustained at least one TBI prior to their first episode of homelessness. Among participants with a TBI, assaults, transportation-related accidents, and falls were the most common causes of these injuries. Thirty percent of individuals sustained injuries with severity levels that would be expected to be associated with ongoing TBI-related deficits. Forty-three percent of the Veterans sustained at least one brain injury following their first episode of homelessness. Median lifetime number of TBIs was three. The severity of TBIs was similar among Veterans who sustained injuries before or after their first incident of homelessness. Findings suggest that future research should directly examine the potential bi-directional relationship between TBI and homelessness, as well as the impact of TBI-related deficits on Veterans' ability to benefit from homeless services and/or maintain stable housing.

Primary blast-induced traumatic brain injury (bTBI) has been observed at the boundary of brain tissue and cerebrospinal fluid (CSF). Such injury can hardly be explained by using the theory of compressive wave propagation, since both the solid and fuid materials have similar compressibility and thus the intracranial pressure (ICP) has a continuous distribution across the boundary. Since they have completely different shear properties, it is hypothesized the injury at the interface is caused by shear wave. In the present study, a preliminary combined numerical and theoretical analysis was conducted based on the theory of shear wave propagation/reflection. Simulation results show that higher lateral acceleration of brain tissue particles is concentrated in the boundary region. Based on this fnding, a new biomechanical vector, termed as strain gradient, was suggested for primary bTBI. The subsequent simple theoretical analysis reveals that this parameter is proportional to the value of lateral acceleration. At the boundary of lateral ventricles, high spatial strain gradient implies that the brain tissue in this area (where neuron cells may be contained) undergo significantly different strains and large velocity discontinuity, which may result in mechanical damage of the neuron cells.

With the increasing incidence of blast injury, the research on its mechanisms and protective measures draws more and more attention. Blast injury has many characteristics different from general war injuries or trauma. For example, soldiers often have various degrees of visceral injury without significant surface damage, combined injuries and arterial air embolism. Researchers in China began to investigate blast injury later than the United States and Sweden, but the development is so fast that lots of achievements have been gained, including the development of biological shock tube, the mechanisms and characteristics of blast injury in various organs, as well as protective measures under special environments. This article reviews the past and current situation of blast injury research in China.

Purpose: We once reported blast-induced traumatic brain injury (bTBI) in confined space. Here, bTBI was studied again on goats in the open air using 3.0 kg trinitrotoluene., Methods: The goats were placed at 2, 4, 6 and 8 m far from explosion center. Trinitrotoluene (TNT) was used as the source of the blast wave and the pressure at each distance was recorded. The systemic physiology, electroencephalogram, serum level of S-100 beta, and neuron specific enolase (NSE) were determined pre and post the exposure. Neuroanatomy and neuropathology were observed 4 h after the exposure., Results: Simple blast waveforms were recorded with parameters of 702.8 kPa-0.442 ms, 148.4 kPa-2.503 ms, 73.9 kPa-3.233 ms, and 41.9 kPa-5.898 ms at 2, 4, 6 and 8 m respectively. Encephalic blast overpressure was on the first time recorded in the literature by us at 104.2 kPa-0.60 ms at 2 m, where mortality and burn rate were 44% and 44%. Gross examination showed that bTBI was mainly manifested as congestive expansion of blood vessels and subarachnoid hemorrhage, which had a total incidence of 25% and 19% in 36 goats. Microscopical observation found that the main pathohistological changes were enlarged perivascular space (21/36, 58%), small hemorrhages (9/36, 25%), vascular dilatation and congestion (8/36, 22%), and less subarachnoid hemorrhage (2/36, 6%). After explosion, serum levels of S-100b and NSE were elevated, and EEG changed into slow frequency with declined amplitude. The results indicated that severity and incidence of bTBI is related to the intensity of blast overpressure., Conclusion: Blast wave can pass through the skull to directly injure brain tissue.