Distribution of Blood–Brain Barrier Disruption in Primary Blast Injury

Traumatic brain injury (TBI) resulting from explosive-related blast overpressure is a topic at the forefront of neurotrauma research. Compromise of the blood–brain barrier (BBB) and other cerebral blood vessel dysfunction is commonly reported in both experimental and clinical studies on blast injury. This study used a rifle primer-driven shock tube to investigate cerebrovascular injury in rats exposed to low-impulse, pure primary blast at three levels of overpressure (145, 232, and 323 kPa) and with three survival times (acute, 24, and 48 h). BBB disruption was quantified immunohistochemically by measuring immunoglobulin G (IgG) extravasation with image analysis techniques. Pure primary blast generated small lesions scattered throughout the brain. The number and size of lesions increased with peak overpressure level, but no significant difference was seen between survival times. Despite laterally directed blast exposure, equal numbers of lesions were found in each hemisphere of the brain. These observations suggest that cerebrovascular injury due to primary blast is distinct from that associated with conventional TBI.     

Computational modeling of blast induced whole-body injury: a review

Blast injuries affect millions of lives across the globe due to its traumatic after effects on the brain and the whole body. To date, military grade armour materials are designed to mitigate ballistic and shrapnel attacks but are less effective in resisting blast impacts. In order to improve blast absorption characteristics of armours, the first key step is thoroughly understands the effects of blasts on the human body itself. In the last decade, a plethora of experimental and computational work has been carried out to investigate the mechanics and pathophysiology of Traumatic Brain Injury (TBI). However, very few attempts have been made so far to study the effect of blasts on the various other parts of the body such as the sensory organs (eyes and ears), nervous system, thorax, extremities, internal organs (such as the lungs) and the skeletal system. While an experimental evaluation of blast effects on such physiological systems is difficult, developing finite element (FE) models could allow the recreation of realistic blast scenarios on full scale human models and simulate the effects. The current article reviews the state-of-the-art in computational research in blast induced whole-body injury modelling, which would not only help in identifying the areas in which further research is required, but would also be indispensable for understanding body location specific armour design criteria for improved blast injury mitigation.     

Development of a Finite Element Model for Blast Brain Injury and the Effects of CSF Cavitation

Blast-related traumatic brain injury is the most prevalent injury for combat personnel seen in the current conflicts in Iraq and Afghanistan, yet as a research community,we still do not fully understand the detailed etiology and pathology of this injury. Finite element (FE) modeling is well suited for studying the mechanical response of the head and brain to blast loading. This paper details the development of a FE head and brain model for blast simulation by examining both the dilatational and deviatoric response of the brain as potential injury mechanisms. The levels of blast exposure simulated ranged from 50 to 1000 kPa peak incident overpressure and 1–8 ms in positive-phase duration, and were comparable to real-world blast events. The frontal portion of the brain had the highest pressures corresponding to the location of initial impact, and peak pressure attenuated by 40–60% as the wave propagated from the frontal to the occipital lobe. Predicted brain pressures were primarily dependent on the peak overpressure of the impinging blast wave, and the highest predicted brain pressures were 30%less than the reflected pressure at the surface of blast impact. Predicted shear strain was highest at the interface between the brain and the CSF. Strain magnitude was largely dependent on the impulse of the blast, and primarily caused by the radial coupling between the brain and deforming skull.The largest predicted strains were generally less than 10%,and occurred after the shock wave passed through the head.For blasts with high impulses, CSF cavitation had a large role in increasing strain levels in the cerebral cortex and periventricular tissues by decoupling the brain from the skull. Relating the results of this study with recent experimental blast testing suggest that a rate-dependent strain-based tissue injury mechanism is the source primary blast TBI.     

Mild traumatic brain injury and posttraumatic stress disorder in returning veterans: Perspectives from cognitive neuroscience

A significant proportion of military personnel deployed in support of Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) has been exposed to war-zone events potentially associated with traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD). There has been significant controversy regarding healthcare policy for those service members and military veterans who returned from OEF/OIF deployments with both mild TBI and PTSD. There is currently little empirical evidence available to address these controversies. This review uses a cognitive neuroscience framework to address the potential impact of mild TBI on the development, course, and clinical management of PTSD. The field would benefit from research efforts that take into consideration the potential differential impact of mild TBI with versus without persistent cognitive deficits, longitudinal work examining the trajectory of PTSD symptoms when index trauma events involve TBI, randomized clinical trials designed to examine the impact of mild TBI on response to existing PTSD treatment interventions, and development and examination of potential treatment augmentation strategies.     

Altered gene expression in cultured microglia in response to simulated blast overpressure: Possible role of pulse duration

Blast overpressure has long been known to cause barotrauma to air-filled organs such as lung and middle ear. However, experience in Iraq and Afghanistan is revealing that individuals exposed to explosive munitions can also suffer traumatic brain injury (TBI) even in the absence of obvious external injury. The interaction of a blast shock wave with the brain in the intact cranial vault is extremely complex making it difficult to conclude that a blast wave interacts in a direct manner with the brain to cause injury. In an attempt to “isolate” the shock wave and test its primary effects on cells, we exposed cultured microglia to simulated blast overpressure in a barochamber. Overpressures ranging from 15 to 45 psi did not change microglial Cox-2 levels or TNF-α secretion nor did they cause cell damage. Microarray analysis revealed increases in expression of a number of microglial genes relating to immune function and inflammatory responses to include Saa3, Irg1, Fas and CxCl10. All changes in gene expression were dependent on pulse duration and were independent of pressure. These results indicate that microglia are mildly activated by blast overpressure and uncover a heretofore undocumented role for pulse duration in this process.     

Impact of posttraumatic stress disorder and injury severity on recovery in children with traumatic brain injury

The adverse impact on recovery of posttraumatic stress disorder (PTSD) in mild traumatic brain injury (TBI) has been demonstrated in returned veterans. The study assessed this effect in children's health outcomes following TBI and extended previous work by including a full range of TBI severity, and improved assessment of PTSD within a longitudinal design. There were 205 children and adolescents (6 to 15 years of age) who experienced a TBI that were assessed at 2, 3, 6, 12, and 18 months following the TBI. Severity of TBI was classified as mild, moderate, or severe. After controlling for the impact of the severity of TBI, premorbid behavioral and emotional problems and executive function, children with TBI and PTSD did not experience as much psychosocial recovery as those without PTSD. Furthermore the level of psychosocial function was no better than that experienced by children with a severe TBI. In contrast, severe TBI was predictive of a poorer physical recovery in the first 6 months, after which recovery was equivalent across all severity levels.     

Angiopoietins as promising biomarkers and potential therapeutic targets in brain injury

Traumatic brain injury (TBI) and sub-arachnoid hemorrhage (SAH) are major causes of long-term disability, mortality, and enormous economic costs to society. The full spectrum of neurological damage created by TBI or SAH is not usually manifested at the time of injury, but evolves gradually over the course of hours to days (or weeks) following these injuries. Angiopoietins, important regulators of vascular structure and function, are hallmark indicators of vascular injury and may therefore represent promising targets in the treatment of SAH and TBI. In animal models and human tissues, normal intracerebral and pial vessels show strong expression of Angiopoietin-1 (Ang-1), but only minimal expression or presentation of Angiopoietin-2 (Ang-2). After several types of neurotrauma, the ratios of Ang-1 and Ang-2 expression in brain microvessel are disturbed and appear to contribute to the remarkable loss of blood–brain barrier (BBB) in these injuries. Angiopoietins levels, and perhaps more importantly, Angiopoietin ratios (1:2) may have novel and important diagnostic and prognostic uses in TBI and SAH brain injury. Ang-1/2 evaluation in plasma, serum and cerebrospinal fluid may provide new therapeutic modalities which can modify ‘secondary’ forms of brain injury after TBI and SAH.     

Family burden and parental distress following mild traumatic brain injury in children and its relationship to post-concussive symptoms

OBJECTIVE: To examine the relationship of mild traumatic brain injuries (TBI) and post-concussive symptoms (PCS) to post injury family burden and parental distress, using data from a prospective, longitudinal study. METHODS: Participants included 71 children with mild TBI with loss of consciousness (LOC), 110 with mild TBI without LOC, and 97 controls with orthopedic injuries not involving the head (OI), and their parents. Shortly after injury, parents and children completed a PCS interview and questionnaire, and parents rated premorbid family functioning. Parents also rated family burden and parental distress shortly after injury and at 3 months post injury. RESULTS: Mild TBI with LOC was associated with greater family burden at 3 months than OI, independent of socioeconomic status and premorbid family functioning. Higher PCS shortly after injury was related to higher ratings of family burden and distress at 3 months. CONCLUSIONS: Mild TBI are associated with family burden and distress more than mild injuries not involving the head, although PCS may influence post injury family burden and distress more than the injury per se. Clinical implications of the current findings are noted in the Discussion section.     

Sleep disturbances following mild traumatic brain injury in childhood

OBJECTIVE: To examine objective and subjective reports of sleep disturbance in school-aged children who had sustained mild traumatic brain injury (TBI) at least 6 months prior to the study. METHODS: Eighteen children aged 7-12 years with a history of mild TBI (GCS 13-15. LOC < 15 min) were compared to 30 children with orthopedic injuries using actigraphy and parental and self-report sleep questionnaires. RESULTS: Parents reported greater sleep disturbance in the mild TBI group. No significant differences were found in parental ratings of daytime sleepiness, child-reported sleep difficulties, or objective (actigraph) sleep measures. CONCLUSIONS: The finding of greater parental reports of sleep disturbance following mild TBI 6 months after injury requires greater exploration and future research with a larger sample followed from the point of injury would seem appropriate.     

Comprehensive assessment of memory functioning following traumatic brain injury in children

This study examined specific memory functions in 52 children with mild‐moderate or severe traumatic brain injury (TBI) and 29 noninjured controls using the Wide Range Assessment of Memory and Learning (WRAML). Children's recall varied as a function of injury severity and task demands. The participants with severe brain injuries performed worse than controls on global measures of visual memory, learning, and general memory functioning, as well as on specific subtests measuring recall of contextual verbal information. Children with mild‐moderate brain injuries performed similarly to controls except for poorer performance on 2 subtests measuring sound‐symbol learning and recall of geometric designs. Results suggest that the WRAML provides clinically useful information and that specific aspects of memory processing need to be evaluated following childhood TBI.     

Long-Term Executive Functioning Outcomes for Complicated and Uncomplicated Mild Traumatic Brain Injury Sustained in Early Childhood

This study investigated long-term executive functioning following early mild traumatic brain injury (TBI), differentiating between complicated (n = 34) and uncomplicated injuries (n = 18). Children post mild TBI were compared to 33 controls at least 7-years post-injury. The complicated mild TBI group performed significantly worse on divided attention compared to both groups, with younger age at injury and neurological symptoms predictors of outcome. No significant group differences existed on speed of information processing, selective attention, working memory, or goal setting. These findings indicate that specific aspects of executive function are compromised by early complicated mild TBI and argue for a stratified definition of mild TBI.     

冲击波强度与幼年大鼠肺冲击伤程度的量效关系

目的:探索冲击波强度与幼年大鼠肺冲击伤程度的量效关系,为儿童冲击伤研究提供动物模型和基础。方法:选取20天龄幼年健康SD雄鼠40只,随机分为4组:BIG1、BIG2、BIG3和BIG4,每组各10只,采用BST-Ⅰ型生物激波管以4.8~5.8 MPa驱动压致伤,观察各组动物伤后生命体征、肺大体解剖和光镜病理等,并进行肺冲击伤严重程度评分。结果:幼鼠在驱动压致伤后均出现了不同程度的呼吸急促、心率加快的表现,外耳道出血发生率为57.5%（46/80）。肺大体解剖表现为不同程度的肺出血、水肿和肺不张等。光镜下病理主要表现为不同程度的肺出血、渗出、炎症细胞的浸润、肺间质水肿增厚、肺泡内水肿和肺泡壁的断裂等。4.8 MPa驱动压时,动物所受超压峰值为433 kPa,正向冲量14 226.4 kPa[?m,肺器官损伤定级（OIS）集中在Ⅱ、Ⅲ级（40%、30%）,肺冲击伤简明损伤定级（AIS）评分为0.90±0.57,损伤程度为轻度;5.0 MPa驱动压时,超压峰值为447.7 kPa,正向冲量14 463.5 kPa[?m,OIS多集中在Ⅲ级（60%）,AIS评分为1.60±0.69,损伤程度为中度;5.5 MPa驱动压时,超压峰值为484.7 kPa,正向冲量15 017.0 kPa[?m,OIS多集中在Ⅳ级（70%）,AIS评分为3.10±0.56,损伤程度为较重;5.8 MPa驱动压时,超压峰值为506.8 kPa, 正向冲量15 325.5 kPa[?m,OIS集中在Ⅴ级（40%）附近,AIS评分为4.00±0.67,肺损伤程度为重度。各组间损伤严重程度有明显统计学差异（P<0.05）。结论:利用BST-I型生物激波管,采用4.8~5.8 MPa高压段的驱动压可建立稳定的幼年SD鼠轻~重度肺冲击伤模型。幼年大鼠肺组织对冲击波损伤的耐受性强于成年大鼠肺组织,也强于幼年兔肺组织,其机制尚不太清楚,值得进一步深入研究。     

Up-regulation of reactivity and survival genes in astrocytes after exposure to short duration overpressure

Gurdjian et al. proposed decades ago that pressure gradients played a major factor in neuronal injury due to impact. In the late 1950s, their experiments on concussion demonstrated that the principal factor in the production of concussion in animals was the sudden increase of intracranial pressure accompanying head injury. They reported the increase in pressure severity correlated with an increase in 'altered cells' resulting in animal death. More recently, Hardy et al. (2006) demonstrated the presence of transient pressure pulses with impact conditions. These studies indicate that short duration overpressure should be further examined as a mechanism of traumatic brain injury (TBI). In the present study, we designed and fabricated a barochamber that simulated overpressure noted in various head injury studies. We tested the effect of overpressure on astrocytes. Expressions of apoptotic, reactivity and survival genes were examined at 24, 48 and 72 h post-overpressure exposure. At 24 h, we found elevated levels of reactivity and survival gene expression. By 48 h, a decreased expression of apoptotic genes was demonstrated. This study reinforces the hypothesis that transient pressure acts to instigate the cellular response displayed following TBI.     

Diffusion tensor imaging detects axonal injury in a mouse model of repetitive closed-skull traumatic brain injury

Mild traumatic brain injuries (TBI) are common in athletes, military personnel, and the elderly, and increasing evidence indicates that these injuries have long-term health effects. However, the difficulty in detecting these mild injuries in vivo is a significant impediment to understanding the underlying pathology and treating mild TBI. In the following experiments, we present the results of diffusion tensor imaging (DTI) and histological analysis of a model of mild repetitive closed-skull brain injury in mouse. Histological markers used included silver staining and amyloid precursor protein (APP) immunohistochemistry to detect axonal injury, and Iba-1 immunohistochemistry to assess microglial activation. At 24h post-injury, before silver staining or microglial abnormalities were apparent by histology, no significant changes in any of the DTI parameters were observed within white matter. At 7 days post-injury we observed a reduction in axial and mean diffusivity. Relative anisotropy at 7 days correlated strongly with the degree of silver staining. Interestingly, APP was not observed at any timepoint examined. In addition to the white matter alterations, mean diffusivity was elevated in ipsilateral cortex at 24h but returned to sham levels by 7 days. Altogether, this demonstrates that DTI is a sensitive method for detecting axonal injury despite a lack of conventional APP pathology. Further, this reflects a need to better understand the histological basis for DTI signal changes in mild TBI.     

The role of the family for behavioral outcome in children and adolescents following traumatic brain injury

This study assessed the behavioral outcome of 51 children with traumatic brain injury (TBI) up to 2 years following injury. Children with severe injuries, but not those with mild or moderate injuries, were reported by parents to have a greater incidence of behavior problems following TBI. Regression analyses indicated that the presence of a partner for the primary caregiver of the child and the acute emotional reaction of the parent to the injury were both predictive of child behavioral outcome, although not by 2-year follow-up. These findings suggest that parental coping resources may impact on the development of child behavioral sequelae following TBI, emphasizing the role of the family in the child's response and the importance of supportive intervention.     

Pathophysiology of battlefield associated traumatic brain injury

As more data is accumulated from Operation Iraqi Freedom and Operation Enduring Freedom (OEF in Afghanistan), it is becoming increasing evident that traumatic brain injury (TBI) is a serious and highly prevalent battle related injury. Although traditional TBIs such as closed head and penetrating occur in the modern battle space, the most common cause of modern battle related TBI is exposure to explosive blast. Many believe that explosive blast TBI is unique from the other forms of TBI. This is because the physical forces responsible for explosive blast TBI are different than those for closed head TBI and penetrating TBI. The unique force associated with explosive blast is the blast shock pressure wave. This shock wave occurs over a very short period, milliseconds, and has a specific profile known as the Freidlander curve. This pressure–time curve is characterized by an initial very rapid up-rise followed by a longer decay that reaches a negative inflection point before returning to baseline. This is important as the effect of this shock pressure on brain parenchyma is distinct. The diffuse interaction of the pressure wave with the brain leads to a complex cascade of events that affects neurons, axons, glia cells, and vasculature. It is only by properly studying this disease will meaningful therapies be realized.     

Posttraumatic stress disorder and traumatic brain injury: can they co-exist?

The possibility that posttraumatic stress disorder (PTSD) can develop following traumatic brain injury (TBI) has been the subject of considerable debate. The traditional view has held that impaired consciousness that occurs with TBI precludes encoding of the traumatic experience, and this prevents subsequent reexperiencing symptoms. This paper critically reviews available, empirical studies on PTSD in TBI populations and suggests that these two conditions can co-exist. The various mechanisms that may mediate PTSD following TBI are discussed, and special attention is given to issues that recognize the distinctive features of PTSD following TBI. These processes include implicit processing, biologically mediated fear conditioning, and reconstruction of trauma memories. Finally implications for assessment, treatment, and forensic investigation of PTSD in TBI populations are, addressed. This review concludes that TBI populations provide a useful means by which the role of traumatic memories (and impaired memories) in posttraumatic adjustment can be studied.     

Understanding predictors of functional recovery and outcome 30 months following early childhood head injury

Much is known about outcome following traumatic brain injury (TBI) in school-age children; however, recovery in early childhood is less well understood. Some argue that such injuries should lead to good outcome, because of the plasticity of the developing brain. Other purport that the young brain is vulnerable, with injury likely to result in a substantial impairment (H. G. Taylor & J. Alden, 1997). The aim of this study was to examine outcomes following TBI during early childhood, to plot recovery over the 30 months postinjury, and to identify predictors of outcome. The study compared 3 groups of children sustaining mild, moderate, and severe TBI, ages 2.0 to 6.11 years at injury, with healthy controls. Groups were comparable for preinjury adaptive and behavioral function, psychosocial characteristics, age, and gender. Results suggested a strong association between injury severity and outcomes across all domains. Further, 30-month outcome was predicted by injury severity, family factors, and preinjury levels of child function. In conclusion, children with more severe injuries and lower preinjury adaptive abilities, and whose families are coping poorly, are at greatest risk of long-term impairment in day-to-day skills, even several years postinjury.     

Mild Traumatic Brain Injury Predictors Based on Angular Accelerations During Impacts

Although Head Injury Criterion (HIC) is an effective criterion for head injuries caused by linear acceleration such as skull fractures, no criteria for head injuries caused by rotational kinematics has been accepted as effective so far. This study proposed two criteria based on angular accelerations for Traumatic Brain Injury (TBI), which we call Rotational Injury Criterion (RIC) and Power Rotational Head Injury Criterion (PRHIC). Concussive and non-concussive head acceleration data obtained from football head impacts were utilized to develop new injury criteria. A well-validated human brain Finite Element (FE) model was employed to find out effective injury criteria for TBI. Correlation analyses were performed between the proposed criteria and FE-based brain injury predictors such as Cumulative Strain Damage Measure (CSDM), which is defined as the percent volume of the brain that exceeds a specified first principal strain threshold, proposed to predict Diffuse Axonal Injury (DAI) which is one of TBI. The RIC was significantly correlated with the CSDMs with the strain thresholds of less than 15% (R > 0.89), which might predict mild TBI. In addition, PRHIC was also strongly correlated with the CSDMs with the strain thresholds equal to or greater than 20% (R > 0.90), which might predict more severe TBI.