Longitudinal Biochemical and Behavioral Alterations in a Gyrencephalic Model of Blast-Related Mild Traumatic Brain Injury.

Blast-related traumatic brain injury (bTBI) is a major cause of neurological disorders in the U.S. military that can adversely impact some civilian populations as well and can lead to lifelong deficits and diminished quality of life. Among these types of injuries, the long-term sequelae are poorly understood because of variability in intensity and number of the blast exposure, as well as the range of subsequent symptoms that can overlap with those resulting from other traumatic events (e.g., post-traumatic stress disorder). Despite the valuable insights that rodent models have provided, there is a growing interest in using injury models using species with neuroanatomical features that more closely resemble the human brain. With this purpose, we established a gyrencephalic model of blast injury in ferrets, which underwent blast exposure applying conditions that closely mimic those associated with primary blast injuries to warfighters. In this study, we evaluated brain biochemical, microstructural, and behavioral profiles after blast exposure using in vivo longitudinal magnetic resonance imaging, histology, and behavioral assessments. In ferrets subjected to blast, the following alterations were found: 1) heightened impulsivity in decision making associated with pre-frontal cortex/amygdalar axis dysfunction; 2) transiently increased glutamate levels that are consistent with earlier findings during subacute stages post-TBI and may be involved in concomitant behavioral deficits; 3) abnormally high brain N-acetylaspartate levels that potentially reveal disrupted lipid synthesis and/or energy metabolism; and 4) dysfunction of pre-frontal cortex/auditory cortex signaling cascades that may reflect similar perturbations underlying secondary psychiatric disorders observed in warfighters after blast exposure.

Twenty Years of Blast-Induced Neurotrauma: Current State of Knowledge.

Blast-induced neurotrauma (BINT) is an important injury paradigm of neurotrauma research. This short communication summarizes the current knowledge of BINT. We divide the BINT research into several broad categories-blast wave generation in laboratory, biomechanics, pathology, behavioral outcomes, repetitive blast in animal models, and clinical and neuroimaging investigations in humans. Publications from 2000 to 2023 in each subdomain were considered. The analysis of the literature has brought out salient aspects. Primary blast waves can be simulated reasonably in a laboratory using carefully designed shock tubes. Various biomechanics-based theories of BINT have been proposed; each of these theories may contribute to BINT by generating a unique biomechanical signature. The injury thresholds for BINT are in the nascent stages. Thresholds for rodents are reasonably established, but such thresholds (guided by primary blast data) are unavailable in humans. Single blast exposure animal studies suggest dose-dependent neuronal pathologies predominantly initiated by blood-brain barrier permeability and oxidative stress. The pathologies were typically reversible, with dose-dependent recovery times. Behavioral changes in animals include anxiety, auditory and recognition memory deficits, and fear conditioning. The repetitive blast exposure manifests similar pathologies in animals, however, at lower blast overpressures. White matter irregularities and cortical volume and thickness alterations have been observed in neuroimaging investigations of military personnel exposed to blast. Behavioral changes in human cohorts include sleep disorders, poor motor skills, cognitive dysfunction, depression, and anxiety. Overall, this article provides a concise synopsis of current understanding, consensus, controversies, and potential future directions.

Human lung simulants subjected to underwater explosions - An experimental investigation.

An experimental investigation was performed on human lung simulants to evaluate their response to an underwater explosive blast. The artificial lungs were instrumented with sensors to record changes in the internal pressure and strains for a specimen with and without a surrounding ribcage. The lungs were to-scale models representative of a 50th-percentile male. The experiments were performed using 65.5 mg of explosive charge placed 0.5 m from the lungs in an 8,200-liter water tank. The tank was instrumented with blast transducers and high-speed cameras to measure the pressure from the explosive charge and record the lung deformation history through high-speed images and digital image correlation. Results showed a significantly delayed response to the underwater blast due to the lungs' inertia. In addition, the lung response was indifferent to its orientation relative to the shock direction. The lungs initially contracted after the underwater shock and then expanded, showing a 50% change in relative volume, from minimum to maximum volume, over a 7 ms duration. Results and observations qualitatively relate to the types of injuries observed during preexisting case studies.

Thoracoabdominal injuries after a bomb explosion: blast injuries and their clinical effects.

PURPOSE: To report the types and effects of injuries to the thoracoabdominal region caused by blast and emphasize the importance of the early detection of primary blast injuries. METHODS: Of the 98 patients injured as a result of a bomb explosion, 31 with thoracoabdominal injuries were included in the study. The demographic and laboratory data, operations performed, and radiological findings were obtained from the electronic records of the patients. The injuries caused by the explosion were divided into four categories as primary, secondary, tertiary, and quaternary. The patients with a new injury severity score (NISS) of ≥ 16 were considered to have critical injuries. RESULTS: While mortality developed in 16 (51.6%) of 31 patients included in the study, 15 (48.4%) were discharged after treatment. The mean ages of the patients in the mortality and survivor groups were 29.6 ± 4.5 and 31.1 ± 10.7 years, respectively (p > 0.005). When the two groups were examined, the rate of hypovolemic shock and NISS score were significantly higher in the mortality group (p = 0.001 and p < 0.001, respectively) and the pH of the patients in the mortality group was more acidic (7.18 ± 0.13 vs. 7.34 ± 0.13, p = 0.002). One patient in the survivor group required surgery after the explosion due to missed primary blast injuries. CONCLUSIONS: To make the best use of resources in terrorist attacks and mass casualties that place a huge burden on health systems, it is important to evaluate patients with the highest index of suspicion for concealed blast injuries in terms of hospitalization and observation. In addition, health systems need to develop a cost-effective strategy considering the possibility of delayed-onset blast injuries.

Pre-hospital continuous positive airway pressure after blast lung injury and hypovolaemic shock: a modelling study.

BACKGROUND: In non-traumatic respiratory failure, pre-hospital application of CPAP reduces the need for intubation. Primary blast lung injury (PBLI) accompanied by haemorrhagic shock is common after mass casualty incidents. We hypothesised that pre-hospital CPAP is also beneficial after PBLI accompanied by haemorrhagic shock. METHODS: We performed a computer-based simulation of the cardiopulmonary response to PBLI followed by haemorrhage, calibrated from published controlled porcine experiments exploring blast injury and haemorrhagic shock. The effect of different CPAP levels was simulated in three in silico patients who had sustained mild, moderate, or severe PBLI (10%, 25%, 50% contusion of the total lung) plus haemorrhagic shock. The primary outcome was arterial partial pressure of oxygen (Pao2) at the end of each simulation. RESULTS: In mild blast lung injury, 5 cm H2O ambient-air CPAP increased Pao2 from 10.6 to 12.6 kPa. Higher CPAP did not further improve Pao2. In moderate blast lung injury, 10 cm H2O CPAP produced a larger increase in Pao2 (from 8.5 to 11.1 kPa), but 15 cm H2O CPAP produced no further benefit. In severe blast lung injury, 5 cm H2O CPAP inceased Pao2 from 4.06 to 8.39 kPa. Further increasing CPAP to 10-15 cm H2O reduced Pao2 (7.99 and 7.90 kPa, respectively) as a result of haemodynamic impairment resulting from increased intrathoracic pressures. CONCLUSIONS: Our modelling study suggests that ambient air 5 cm H2O CPAP may benefit casualties suffering from blast lung injury, even with severe haemorrhagic shock. However, higher CPAP levels beyond 10 cm H2O after severe lung injury reduced oxygen delivery as a result of haemodynamic impairment.

Defining blast loading 'zones of relevance' for primary blast injury research: A consensus of injury criteria for idealised explosive scenarios.

Blast injuries remain a serious threat to defence and civilian populations around the world. 'Primary' blast injuries (PBIs) are caused by direct blast wave interaction with the human body, particularly affecting air-containing organs. Work to define blast loading conditions for injury research has received relatively little attention, though with a continued experimental focus on PBIs and idealised explosion assumptions, meaningful test outcomes and subsequent clinical applications, rely on appropriate simulated conditions. This paper critically evaluates and combines existing PBI criteria (grouped into those affecting the auditory system, pulmonary injuries and brain trauma) as a function of idealised blast wave parameters. For clinical blast injury researchers, analysis of the multi-injury criteria indicates zones of appropriate loading conditions for human-scale test items and demonstrates the importance of simulating blast conditions that are both realistic and relevant to the injury type. For certain explosive scenarios, spatial interpretation of the 'zones of relevance' could support emergency response and hazard preparedness by informing triage, patient management and resource allocation, thus leading to improved health outcomes. This work will prove useful to clinical blast injury researchers, blast protection engineers and clinical practitioners involved in the triage, diagnosis, and treatment of PBIs.

Damage-Associated Molecular Patterns and Their Signaling Pathways in Primary Blast Lung Injury: New Research Progress and Future Directions.

Primary blast lung injury (PBLI) is a common cause of casualties in wars, terrorist attacks, and explosions. It can exist in the absence of any other outward signs of trauma, and further develop into acute lung injury (ALI) or a more severe acute respiratory distress syndrome (ARDS). The pathogenesis of PBLI at the cellular and molecular level has not been clear. Damage-associated molecular pattern (DAMP) is a general term for endogenous danger signals released by the body after injury, including intracellular protein molecules (HMGB1, histones, s100s, heat shock proteins, eCIRP, etc.), secretory protein factors (IL-1ß, IL-6, IL-10, TNF-α, VEGF, complements, etc.), purines and pyrimidines and their derived degradation products (nucleic acids, ATP, ADP, UDPG, uric acid, etc.), and extracellular matrix components (hyaluronic acid, fibronectin, heparin sulfate, biglycan, etc.). DAMPs can be detected by multiple receptors including pattern recognition receptors (PRRs). The study of DAMPs and their related signaling pathways, such as the mtDNA-triggered cGAS-YAP pathway, contributes to revealing the molecular mechanism of PBLI, and provides new therapeutic targets for controlling inflammatory diseases and alleviating their symptoms. In this review, we focus on the recent progress of research on DAMPs and their signaling pathways, as well as the potential therapeutic targets and future research directions in PBLI.

Exposure to blast shock waves via the ear canal induces deficits in vestibular afferent function in rats.

The ears are air-filled structures that are directly impacted during blast exposure. In addition to hearing loss and tinnitus, blast victims often complain of vertigo, dizziness and unsteady posture, suggesting that blast exposure induces damage to the vestibular end organs in the inner ear. However, the underlying mechanisms remain to be elucidated. In this report, single vestibular afferent activity and the vestibulo-ocular reflex (VOR) were investigated before and after exposure to blast shock waves (∼20 PSI) delivered into the left external ear canals of anesthetized rats. Single vestibular afferent activity was recorded from the superior branch of the left vestibular nerves of the blast-treated and control rats one day after blast exposure. Blast exposure reduced the spontaneous discharge rates of the otolith and canal afferents. Blast exposure also reduced the sensitivity of irregular canal afferents to sinusoidal head rotation at 0.5-2Hz. Blast exposure, however, resulted in few changes in the VOR responses to sinusoidal head rotation and translation. To the best of our knowledge, this is the first study that reports blast exposure-induced damage to vestibular afferents in an animal model. These results provide insights that may be helpful in developing biomarkers for early diagnosis of blast-induced vestibular deficits in military and civilian populations.

Assessment of necroptosis in the retina in a repeated primary ocular blast injury mouse model.

Primary blast injury (caused by the initial rapid increase in pressure following an explosive blast) to the retina and optic nerve (ON) causes progressive visual loss and neurodegeneration. Military personnel are exposed to multiple low-overpressure blast waves, which may be in quick succession, such as during breacher training or in combat. We investigated the necroptotic cell death pathway in the retina in a mouse repeated primary ocular blast injury (rPBI) model using immunohistochemistry. We further evaluated whether intravitreal injections of a potent necroptosis inhibitor, Necrostatin-1s (Nec-1s), protects the retina and ON axons by retinal ganglion cells (RGC) counts, ON axonal counting and optical coherence tomography (OCT) analysis of vitreous haze. Receptor interacting protein kinase (RIPK) 3, increased in the inner plexiform layer 2 days post injury (dpi) and persisted until 14 dpi, whilst RIPK1 protein expression did not change after injury. The number of degenerating ON axons was increased at 28 dpi but there was no evidence of a reduction in the number of intact ON axons or RNA-binding protein with multiple splicing (RBPMS)+ RGC in the retina by 28 dpi in animals not receiving any intravitreal injections. But, when intravitreal injections (vehicle or Nec-1s) were given there was a significant reduction in RBPMS+ RGC numbers, suggesting that rPBI with intraocular injections is damaging to RGC. There were fewer RGC lost after Nec-1s than vehicle injection, but there was no effect of Nec-1s or vehicle treatment on the number of degenerating axons. OCT analysis demonstrated no effect of rPBI on vitreous haze, but intravitreal injection combined with rPBI increased vitreous haze (P = 0.004). Whilst necroptosis may be an active cell death signalling pathway after rPBI, its inhibition did not prevent cell death, and intravitreal injections in combination with rPBI increased vitreous inflammation and reduced RBPMS+ RGC numbers, implying intravitreal injection is not an ideal method for drug delivery after rPBI.

Management of primary blast lung injury: a comparison of airway pressure release versus low tidal volume ventilation.

BACKGROUND: Primary blast lung injury (PBLI) presents as a syndrome of respiratory distress and haemoptysis resulting from explosive shock wave exposure and is a frequent cause of mortality and morbidity in both military conflicts and terrorist attacks. The optimal mode of mechanical ventilation for managing PBLI is not currently known, and clinical trials in humans are impossible due to the sporadic and violent nature of the disease. METHODS: A high-fidelity multi-organ computational simulator of PBLI pathophysiology was configured to replicate data from 14 PBLI casualties from the conflict in Afghanistan. Adaptive and responsive ventilatory protocols implementing low tidal volume (LTV) ventilation and airway pressure release ventilation (APRV) were applied to each simulated patient for 24 h, allowing direct quantitative comparison of their effects on gas exchange, ventilatory parameters, haemodynamics, extravascular lung water and indices of ventilator-induced lung injury. RESULTS: The simulated patients responded well to both ventilation strategies. Post 24-h investigation period, the APRV arm had similar PF ratios (137 mmHg vs 157 mmHg), lower sub-injury threshold levels of mechanical power (11.9 J/min vs 20.7 J/min) and lower levels of extravascular lung water (501 ml vs 600 ml) compared to conventional LTV. Driving pressure was higher in the APRV group (11.9 cmH2O vs 8.6 cmH2O), but still significantly less than levels associated with increased mortality. CONCLUSIONS: Appropriate use of APRV may offer casualties with PBLI important mortality-related benefits and should be considered for management of this challenging patient group.

Using Gas-Driven Shock Tubes to Produce Blast Wave Signatures.

The increased incidence of improvised explosives in military conflicts has brought about an increase in the number of traumatic brain injuries (TBIs) observed. Although physical injuries are caused by shrapnel and the immediate blast, encountering the blast wave associated with improvised explosive devices (IEDs) may be the cause of traumatic brain injuries experienced by warfighters. Assessment of the effectiveness of personal protective equipment (PPE) to mitigate TBI requires understanding the interaction between blast waves and human bodies and the ability to replicate the pressure signatures caused by blast waves. Prior research has validated compression-driven shock tube designs as a laboratory method of generating representative pressure signatures, or Friedlander-shaped blast profiles; however, shock tubes can vary depending on their design parameters and not all shock tube designs generate acceptable pressure signatures. This paper presents a comprehensive numerical study of the effects of driver gas, driver (breech) length, and membrane burst pressure of a constant-area shock tube. Discrete locations in the shock tube were probed, and the blast wave evolution in time at these points was analyzed to determine the effect of location on the pressure signature. The results of these simulations are used as a basis for suggesting guidelines for obtaining desired blast profiles.

Remote ischemic conditioning improves outcome independent of anesthetic effects following shockwave-induced traumatic brain injury.

Traumatic brain injury due to primary blast exposure is a major cause of ongoing neurological and psychological impairment in soldiers and civilians. Animal and human evidence suggests that low-level blast exposure is capable of inducing white matter injury and behavioural deficits. There are currently no effective therapies to treat the underlying suspected pathophysiology of low-level primary blast or concussion. Remote ischemic conditioning (RIC) has been shown to have cardiac, renal and neuro-protective effects in response to brief cycles of ischemia. Here we examined the effects of RIC in two models of blast injury. We used a model of low-level primary blast in rats to evaluate the effects of RIC neurofilament expression. We subsequently used a model of traumatic brain injury in adult zebrafish using pulsed high intensity focused ultrasound (pHIFU) to evaluate the effects of RIC on behavioural outcome and apoptosis in a post-traumatic setting. In blast exposed rats, RIC pretreatment modulated NF200 expression suggesting an innate biological buffering effect. In zebrafish, behavioural deficits and apoptosis due to pHIFU-induced brain injury were reduced following administration of serum derived from RIC rats. The results in the zebrafish model demonstrate the humoral effects of RIC independent of anesthetic effects that were observed in the rat model of injury. Our results indicate that RIC is effective in improving outcome following modeled brain trauma in pre- and post-injury paradigms. The results suggest a potential role for innate biological systems in the protection against pathophysiological processes associated with impairment following shockwave induced trauma.

CD28 deficiency attenuates primary blast-induced renal injury in mice via the PI3K/Akt signalling pathway.

INTRODUCTION: Primary blast affects the kidneys due to direct shock wave damage and the production of proinflammatory cytokines without effective treatment. CD28 has been reported to be involved in regulating T cell activation and secretion of inflammatory cytokines. The aim of this study was to investigate the influence of primary blast on the kidney and the effect of CD28 in mice. METHODS: A mouse model of primary blast-induced kidney injury was established using a custom-made explosive device. The severity of kidney injury was investigated by H&E staining. ELISA was applied to study serum inflammation factors' expression. Western blot assays were used to analyse the primary blast-induced inflammatory factors' expression in the kidney. Immunofluorescence analysis was used to examine the PI3K/Akt signalling pathway. RESULTS: Histological examination demonstrated that compared with the primary blast group, CD28 deficiency caused a significant decrease in the severity of the primary blast-induced renal injury. Moreover, ELISA and western blotting revealed that CD28 deficiency significantly reduced the levels of interleukin (IL)-1ß, IL-4 and IL-6, and increased the IL-10 level (p<0.05). Finally, immunofluorescence analysis indicated that PI3K/Akt expression also changed. CONCLUSIONS: CD28 deficiency had protective effects on primary blast-induced kidney injury via the PI3K/Akt signalling pathway. These findings improve the knowledge on primary blast injury and provide theoretical basis for primary blast injury treatment.

Indirect Traumatic Optic Neuropathy Induced by Primary Blast: A Fluid-Structure Interaction Study.

Current knowledge of traumatic ocular injury is still limited as most studies have focused on the ocular injuries that happened at the anterior part of the eye, whereas the damage to the optic nerve known as traumatic optic neuropathy (TON) is poorly understood. The goal of this study is to understand the mechanism of the TON following the primary blast through a fluid-structure interaction model. An axisymmetric three-dimensional (3D) eye model with detailed orbital components was developed to capture the dynamics of the eye under the blast wave. Our numerical results demonstrated a transient pressure elevation in both vitreous and cerebrospinal fluid (CSF). A high strain rate over 100 s-1 was observed throughout the optic nerve during the blast with the most vulnerable part located at the intracanalicular region. The optic nerve deforming at such a high strain rate may account for the axonal damage and vision loss in patients subjected to the primary blast. The results from this work would enhance the understanding of indirect TON and provide guidance in the design of protective eyewear against such injury.

Computational Modeling of Primary Blast Lung Injury: Implications for Ventilator Management.

Primary blast lung injury (PBLI) caused by exposure to high-intensity pressure waves is associated with parenchymal tissue injury and severe ventilation-perfusion mismatch. Although supportive ventilation is often required in patients with PBLI, maldistribution of gas flow in mechanically heterogeneous lungs may lead to further injury due to increased parenchymal strain and strain rate, which are difficult to predict in vivo. In this study, we developed a computational lung model with mechanical properties consistent with healthy and PBLI conditions. PBLI conditions were simulated with bilateral derecruitment and increased perihilar tissue stiffness. As a result of these tissue abnormalities, airway flow was heterogeneously distributed in the model under PBLI conditions, during both conventional mechanical ventilation (CMV) and high-frequency oscillatory ventilation. PBLI conditions resulted in over three-fold higher parenchymal strains compared to the healthy condition during CMV, with flow distributed according to regional tissue stiffness. During high-frequency oscillatory ventilation, flow distribution became increasingly heterogeneous and frequency-dependent. We conclude that the distribution and rate of parenchymal distension during mechanical ventilation depend on PBLI severity as well as ventilatory modality. These simulations may allow realistic assessment of the risks associated with ventilator-induced lung injury following PBLI, and facilitate the development of alternative lung-protective ventilation modalities.

Co-existence of t(9;22) and t(8;21) in primary blast phase of chronic myelogenous leukemia: clinical experience and literature review.

Rare chronic myelogenous leukemia (CML) patients manifested as the primary blast phase without a chronic and accelerated phase. The occurrence of a t(8;21) translocation in secondary blast phase of CML or Philadelphia chromosome positive acute myelogenous leukemia (Ph+ AML) has been reported previously. No case of primary blast phase of chronic myelogenous leukemia (CML-BP) bearing one clone with t(9;22) and t(8;21) simultaneously has been reported. One Chinese patient presenting with extensive spontaneous ecchymosis and enlarged spleen diagnosed as acute myelogenous leukemia (AML) by smear and immunophenotype was given chemotherapy including daunorubicin 3 days and cytarabine 7 days without a tyrosine kinase inhibitor (TKI) drug at the beginning. Fresh frozen plasma and 4-factor prothrombin complex concentrate was also transfused for coagulation disorder. However, fusion genes BCR/ABL p210 and AML1/ETO were both positive and karyotype analysis showed the abnormalities of t(9;22) and t(8;21) in the same clones. Bone marrow aspirate on 7th day of chemotherapy indicated hypocellularity with 45% blasts remaining. Cytarabine was prolonged to nine days combined with imatinib 600 mg per day. His bone marrow aspirate after complete remission revealed t(8;21) clones disappearing, especially FISH of bone marrow smear detecting the BCR/ABL fusion signals in the basophilic erythroblasts, which confirmed his diagnosis as primary blast phase of CML rather than Ph+ AML. Thus, we report for the first time one patient diagnosed as primary blast phase of CML presenting with t(9;22) and t(8;21) simultaneously.

Nanometer ultrastructural brain damage following low intensity primary blast wave exposure.

Blast-induced mild traumatic brain injury (mTBI) is of particular concern among military personnel due to exposure to blast energy during military training and combat. The impact of primary low-intensity blast mediated pathophysiology upon later neurobehavioral disorders has been controversial. Developing a military preclinical blast model to simulate the pathophysiology of human blast injury is an important first step. This article provides an overview of primary blast effects and perspectives of our recent studies demonstrating ultrastructural changes in the brain and behavioral disorders resulting from open-field blast exposures up to 46.6 kPa using a murine model. The model is scalable and permits exposure to varying magnitudes of primary blast injuries by placing animals at different distances from the blast center or by changing the amount of C4 charge. We here review the implications and future applications and directions of using this animal model to uncover the underlying mechanisms related to primary blast injury. Overall, these studies offer the prospect of enhanced understanding of the pathogenesis of primary low-intensity blast-induced TBI and insights for prevention, diagnosis and treatment of blast induced TBI, particularly mTBI/concussion related to current combat exposures.

Xenon Protects against Blast-Induced Traumatic Brain Injury in an In Vitro Model.

The aim of this study was to evaluate the neuroprotective efficacy of the inert gas xenon as a treatment for patients with blast-induced traumatic brain injury in an in vitro laboratory model. We developed a novel blast traumatic brain injury model using C57BL/6N mouse organotypic hippocampal brain-slice cultures exposed to a single shockwave, with the resulting injury quantified using propidium iodide fluorescence. A shock tube blast generator was used to simulate open field explosive blast shockwaves, modeled by the Friedlander waveform. Exposure to blast shockwave resulted in significant (p < 0.01) injury that increased with peak-overpressure and impulse of the shockwave, and which exhibited a secondary injury development up to 72 h after trauma. Blast-induced propidium iodide fluorescence overlapped with cleaved caspase-3 immunofluorescence, indicating that shock-wave-induced cell death involves apoptosis. Xenon (50% atm) applied 1 h after blast exposure reduced injury 24 h (p < 0.01), 48 h (p < 0.05), and 72 h (p < 0.001) later, compared with untreated control injury. Xenon-treated injured slices were not significantly different from uninjured sham slices at 24 h and 72 h. We demonstrate for the first time that xenon treatment after blast traumatic brain injury reduces initial injury and prevents subsequent injury development in vitro. Our findings support the idea that xenon may be a potential first-line treatment for those with blast-induced traumatic brain injury.

Effects of Mild Blast Traumatic Brain Injury on Cerebral Vascular, Histopathological, and Behavioral Outcomes in Rats.

To determine the effects of mild blast-induced traumatic brain injury (bTBI), several groups of rats were subjected to blast injury or sham injury in a compressed air-driven shock tube. The effects of bTBI on relative cerebral perfusion (laser Doppler flowmetry [LDF]), and mean arterial blood pressure (MAP) cerebral vascular resistance were measured for 2 h post-bTBI. Dilator responses to reduced intravascular pressure were measured in isolated middle cerebral arterial (MCA) segments, ex vivo, 30 and 60 min post-bTBI. Neuronal injury was assessed (Fluoro-Jade C [FJC]) 24 and 48 h post-bTBI. Neurological outcomes (beam balance and walking tests) and working memory (Morris water maze [MWM]) were assessed 2 weeks post-bTBI. Because impact TBI (i.e., non-blast TBI) is often associated with reduced cerebral perfusion and impaired cerebrovascular function in part because of the generation of reactive oxygen and nitrogen species such as peroxynitrite (ONOO-), the effects of the administration of the ONOO- scavenger, penicillamine methyl ester (PenME), on cerebral perfusion and cerebral vascular resistance were measured for 2 h post-bTBI. Mild bTBI resulted in reduced relative cerebral perfusion and MCA dilator responses to reduced intravascular pressure, increases in cerebral vascular resistance and in the numbers of FJC-positive cells in the brain, and significantly impaired working memory. PenME administration resulted in significant reductions in cerebral vascular resistance and a trend toward increased cerebral perfusion, suggesting that ONOO- may contribute to blast-induced cerebral vascular dysfunction.

Primary Blast Causes Delayed Effects without Cell Death in Shell-Encased Brain Cell Aggregates.

Previous work in this laboratory used underwater explosive exposures to isolate the effects of shock-induced principle stress without shear on rat brain aggregate cultures. The current study has utilized simulated air blast to expose aggregates in suspension and enclosed within a spherical shell, enabling the examination of a much more complex biomechanical insult. Culture medium-filled spheres were exposed to single pulse overpressures of 15-30 psi (∼6-7 msec duration) and measurements within the sphere at defined sites showed complex and spatially dependent pressure changes. When brain aggregates were exposed to similar conditions, no cell death was observed and no changes in several commonly used biomarkers of traumatic brain injury (TBI) were noted. However, similarly to underwater blast, immediate and transient increases in the protein kinase B signaling pathway were observed at early time-points (3 days). In contrast, the oligodendrocyte marker 2',3'-cyclic nucleotide 3'-phosphodiesterase, as well as vascular endothelial growth factor, both displayed markedly delayed (14-28 days) and pressure-dependent responses. The imposition of a spherical shell between the single pulse shock wave and the target brain tissue introduces greatly increased complexity to the insult. This work shows that brain tissue can not only discriminate the nature of the pressure changes it experiences, but that a portion of its response is significantly delayed. These results have mechanistic implications for the study of primary blast-induced TBI and also highlight the importance of rigorously characterizing the actual pressure variations experienced by target tissue in primary blast studies.