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J Cereb Blood Flow Metab. 2010 February; 30(2): 255–266.
Published online 2009 October 7. doi:  10.1038/jcbfm.2009.203
PMCID: PMC2855235

Traumatic brain injury: an overview of pathobiology with emphasis on military populations


This review considers the pathobiology of non-impact blast-induced neurotrauma (BINT). The pathobiology of traumatic brain injury (TBI) has been historically studied in experimental models mimicking features seen in the civilian population. These brain injuries are characterized by primary damage to both gray and white matter and subsequent evolution of secondary pathogenic events at the cellular, biochemical, and molecular levels, which collectively mediate widespread neurodegeneration. An emerging field of research addresses brain injuries related to the military, in particular blast-induced brain injuries. What is clear from the effort to date is that the pathobiology of military TBIs, particularly BINT, has characteristics not seen in other types of brain injury, despite similar secondary injury cascades. The pathobiology of primary BINT is extremely complex. It comprises systemic, local, and cerebral responses interacting and often occurring in parallel. Activation of the autonomous nervous system, sudden pressure-increase in vital organs such as lungs and liver, and activation of neuroendocrine-immune system are among the most important mechanisms significantly contributing to molecular changes and cascading injury mechanisms in the brain.

Keywords: blast-induced neurotrauma, blast injury, mechanisms, models, traumatic brain injury


In this review, we focus on blast-induced neurotrauma (BINT), including mechanisms underlying brain damage and challenges imposed by this complex injury from both clinical and experimental perspectives. Whereas we do not consider the broader topic of traumatic brain injuries (TBIs) in the civilian population, there are a number of reviews from the past 5 years that consider this topic in detail, particularly from the perspectives of animal models (Cernak, 2005; Kazanis, 2005; LaPlaca et al, 2007; Manvelyan, 2006; Morales et al, 2005; Potts et al, 2009; Weber, 2007), and the understanding that we have gained from these models with regard to general pathobiology (Bramlett and Dietrich, 2007; Park et al, 2008; Povlishock and Katz, 2005; Werner and Engelhard, 2007), mechanisms of cell injury (Bayir and Kagan, 2008; Mazzeo et al, 2009; Raghupathi, 2004; Robertson, 2004; Sullivan et al, 2005; Yakovlev and Faden, 2004; Zhang et al, 2005), posttraumatic epilepsy (D'Ambrosio and Perucca, 2004; Dichter, 2009; Garga and Lowenstein, 2006; Pitkanen and McIntosh, 2006; Pitkanen et al, 2009; Willmore and Ueda, 2009), axonal injury (Bales et al, 2009; Buki and Povlishock, 2006; Hurley et al, 2004), behavior (Fujimoto et al, 2004; Schallert, 2006), proteomics (Ottens et al, 2007), biomarkers (Kochanek et al, 2008; Kovesdi et al, 2009), and neuroprotection (Bales et al, 2009; Beauchamp et al, 2008; Byrnes et al, 2009; Cook et al, 2009; Dichter, 2009; Dietrich et al, 2009; Forsyth et al, 2006; Gibson et al, 2008; Jain, 2008; Jennings et al, 2008; Kokiko and Hamm, 2007; Mammis et al, 2009; Margulies and Hicks, 2009; Marklund et al, 2006; Mechoulam and Shohami, 2007; Rogers and Wagner, 2006; Schouten, 2007; Schumacher et al, 2007; Stein, 2008; Stoica et al, 2009; Vink and Nimmo, 2009; Wang et al, 2006; Wise et al, 2005; Xiong et al, 2009).

TBIs caused by explosion

Throughout Operation Enduring Freedom and Operation Iraqi Freedom, explosive devices have become more powerful, their detonation systems more creative, and their additives more devastating. According to the Department of Defense ‘Personnel & Procurement Statistics', over 73% of all US military casualties in Operation Enduring Freedom and Operation Iraqi Freedom are caused by explosive weaponry (Defense Manpower Data Center, 2008). As of January 2008 (Congressional Research Service, 2008), the Department of Defense reported that over 5,500 soldiers had suffered traumatic brain injuries. As a continuing threat to our troops, blast injury, especially BINT, has been called the signature wound of the war in Iraq (Elder and Cristian, 2009). Civilians are also frequent victims of explosive devices such as landmines and unexploded ordnance (Bilukha et al, 2008), or explosive weaponry used in terrorist incidents (Center for Terrorism and Intelligence Studies, 2009). Indeed, terrorists increasingly use suicidal–homicidal bombers who deliberately accompany the explosive device, often wearing it, to ensure maximal harm. The bombers drive or walk into buses, subways, residential areas, shopping malls, and government buildings. In both civilian and military environments, exposure to a blast may cause instant death, injuries with immediate manifestation of symptoms, or latent injuries, which may manifest over and/or after an extended period after the initial blast exposure (Ling et al, 2009). Due to the complexity of injurious environment as well as of the resulting injuries, there is a need for prospective, longitudinal studies to confirm reports of long-term effects of exposure to blasts.

Protection from blast injuries presents several challenges. Although body armor protects the torso from shrapnel and projectiles, it may intensify the blast wave effect in two ways (Courtney and Courtney, 2009). First, body armor constitutes an improved contact surface for shock-front–body interaction and energy transfer; second, it may also serve as a reflecting surface that concentrates the power of an explosion as the blast wave resonates internally (Phillips et al, 1988). The improved interceptive properties of body armors have increased the survival rate of soldiers by protecting them from penetrating injuries. In parallel with the increased survival rate, however, the rate of severe, debilitating, long-term consequences has also increased (Martin et al, 2008). There are differing findings and anecdotal information about the influence of body armor on the blast load inside the organism. For example, Phillips et al (1988) reported generally higher intrathoracic pressure in sheep protected with cloth ballistic vests. He hypothesized that the ‘likely mechanisms of injury enhancement include an increase in the target surface area and an alteration of the effective loading function on the thorax'. Conversely, Long reported significant reduction of brain pathology for rats protected with soft ‘body armor' comparable to the cloth ballistic vest protection used by Phillips. There are also opinions that the influence of body armor on the blast energy transfer into the body, thus potential development of blast-induced neurological deficits, depends on the type of the body armor, that is, soft (cloth without interceptive plate) versus hard (with interceptive plate). The lack of sound knowledge of the effects of different types of body armor on non-impact, blast-induced brain damage necessitates well-designed and orchestrated experimental and clinical studies.

Besides being acutely injured, soldiers serving in theater and some military professionals during their daily activity or training are also subjected to repeated low-level blast exposure. The cumulative effects of the exposures could lead to serious short-term and long-term health impairments (Richmond et al, 1981). For those without body armor, the effects of blast are more deadly and the whole spectrum of blast injuries is expected (Champion et al, 2009; Ling et al, 2009). Apart from the injuries caused by blast overpressure (primary blast effects), these soldiers have increased potential for penetrating injuries from shrapnel and other debris (secondary blast effects), and for acceleration and deceleration of the body and head (tertiary blast effects) (Figure 1).

Figure 1
Complex injurious environment because of blast: primary blast effects, that is, effects of the blast wave itself (primary blast injury); secondary blast effects caused by particles propelled by blast-force (secondary, that is, penetrating blast) injury; ...

Basic mechanisms of explosive injuries

A blast wave generated by an explosion starts with a single pulse of increased air pressure that lasts a few milliseconds. The negative pressure or suction of the blast wave follows the positive wave immediately (Owen-Smith, 1981). The duration of the blast wave—that is, the time that an object in the path of the shock wave is subjected to the pressure effects—depends on the type of explosive and the distance from the point of detonation (Clemedson, 1956). The blast wave progresses from the source of the explosion as a sphere of compressed and rapidly expanding gases, which displaces an equal volume of air at high velocity (Rossle, 1950). The velocity of the blast wave in air may be extremely high, depending on the type and amount of explosive used. The blast wave is the main determinant of primary blast injury and consists of the front of high pressure that compresses the surrounding air and falls rapidly to negative pressure. It travels faster than sound and in few milliseconds damages the surrounding structures. The blast wind following the wave is generated by mass displacement of air by expanding gases; it may accelerate to hurricane proportions and is responsible for disintegration, evisceration, and traumatic amputation of body parts. Thus, a person exposed to an explosion will be subjected not only to a blast wave but also to the high-velocity wind traveling directly behind the shock front of the blast wave (Rossle, 1950). Compared with a hurricane-force wind that travels about 200 km/h and exerts an overpressure of only 1.72 kPa (0.25 psi), a lethal blast-induced overpressure of 690 kPa (100 psi) travels at about 2,414 km/h (Owen-Smith, 1981).

The magnitude of damage from the blast wave depends on five factors: (1) the peak of the initial positive-pressure wave (an overpressure of 690 to 1,724 kPa, for example, 100 to 250 psi, is considered potentially lethal) (Champion et al, 2009); (2) the duration of overpressure; (3) the medium of explosion; (4) the distance from the incident blast wave; and (5) the degree of focusing because of a confined area or walls. For example, explosions near or within hard solid surfaces become amplified two to nine times because of shockwave reflection (Rice and Heck, 2000). Moreover, victims positioned between a blast and a building often suffer from injuries two to three times the degree of injury of a person in an open space. Indeed, people exposed to explosion rarely experience the idealized pressure-wave form, known as the Friedländer wave. Even in open-field conditions, the blast wave reflects from the ground, generating reflective waves that interact with the primary wave and, thus, changing its characteristics. In a closed environment (such as a building, an urban setting, or a vehicle), the blast wave interacts with the surrounding structures and creates multiple wave reflections, which, interacting with the primary wave and between each other, generate a complex wave (Ben-Dor et al, 2001; Mainiero and Sapko, 1996). Previous attempts to define the mechanisms of blast injury suggested the involvement of spalling, implosion, and inertial effects as major physical components of the blast–body interaction and later tissue damage (Benzinger, 1950). Spallation is the disruption that occurs at the boundary between two media of different densities; it occurs when a compression wave in the denser medium is reflected at the interface. Implosion occurs when the shockwave compresses a gas bubble in a liquid medium, raising the pressure in the bubble much higher than the shock pressure; as the pressure wave passes, the bubbles can re-expand explosively and damage surrounding tissue (Benzinger, 1950; Chiffelle, 1966; Phillips, 1986). Inertial effects occur at the interface of the different densities: the lighter object will be accelerated more than the heavier one, so there will be a large stress at the boundary. Recent results suggest a frequency dependence of the blast effects: high-frequency (0.5–1.5 kHz) low-amplitude stress waves target mostly organs that contain abrupt density changes from one medium to another (for example, the air–blood interface in the lungs or the blood–parenchyma interface in the brain), and low-frequency (<0.5 kHz) high-amplitude shear waves disrupt tissue by generating local motions that overcome natural tissue elasticity (Cooper et al, 1991; Gorbunov et al, 2004) (for example, at the contact of gray and white brain matter).

Thus, explosions may cause four major patterns of injury: (1) primary blast injury caused by the blast wave itself; (2) secondary injury caused by the fragments of debris propelled by the explosion; (3) tertiary injury because of the acceleration of the body or part of the body by the blast wind; and (4) flash burns because of the transient, but intense, heat of the explosion (Mellor, 1988). Moreover, the current state-of-the-science suggests that the extent and types of primary blast-induced injuries depend not only on the peak of the overpressure but also on other characteristics, such as the number of overpressure peaks, the lag time and shear fronts between overpressure peaks, their frequency resonance, and electromagnetic pulse generated from the blast.

The complexity of BINT

Potential mechanisms by which blasts cause brain injury include: (1) direct interaction with the head through direct passage of the blast wave through the skull and/or causing acceleration and/or rotation of the head and (2) transfer of kinetic energy from the blast wave through large blood vessels in the abdomen and chest to the central nervous system (Courtney and Courtney, 2009); namely, as the front of the blast overpressure interacts with the body surface and compresses the abdomen and chest, it transfers its kinetic energy to the body's fluid phase. The resulting hydraulic interaction initiates oscillating waves that traverse the body at about the speed of sound in water and deliver the kinetic energy of the blast wave to the brain. Once delivered, that kinetic energy causes both morphological and functional damage to distinct brain structures (Cernak et al, 1999). The two potential ways of interaction do not exclude each other (Bauman et al, 2009). Most recent experimental data suggest both the importance of the blast's direct interaction with the head (Saljo et al, 2008), and the role of shockwave-induced vascular load (Long et al, 2009a) in the pathogenesis of BINT.

Due to the complexity of the injurious environment, that is, multiple blast effects that interact with the body parallel, BINT represents a unique clinical entity caused by interwoven mechanisms of systemic, local, and cerebral responses to blast exposure (Cernak et al, 1991; Cernak et al, 1996a; Figure 2). Whereas mild BINT, in general, is induced by primary blast, moderate to severe brain injuries because of blast are part of a polytrauma and caused by simultaneously acting primary, secondary, tertiary, and sometimes even quaternary effects of the blast.

Figure 2
Simultaneous activation of systemic, local, and cerebral responses to blast exposure, and interactive mechanisms causing or contributing to the pathobiology of BINT.

In general, primary blast injuries are characterized by absence of external injuries and potential parenchymal damage, mostly of the lungs (Rossle, 1950; Chiffelle, 1966); thus, internal injuries are often unrecognized and their severity underestimated (Dedushkin et al, 1992). It was hypothesized (Cernak et al, 1996a; Zuckerman, 1940) that blast overpressure may cause sudden hyperinflation of the lungs and subsequent mechanical irritation of juxtacapillary J-receptors located in the alveolar interstitium and innervated by vagal fibers (Paintal, 1969). The stimulation of the J-receptors causes a vago-vagal reflex leading to apnea followed by rapid breathing, bradycardia, and hypotension, which are frequently observed immediate symptoms after blast exposure. Additionally, chemoreceptors located primarily in the left ventricle can be stimulated by hypoxia/ischemia caused by pulmonary vagal reflex, and subsequently trigger a cardiovascular decompressor Bezold–Jarish reflex, which involves marked increase in vagal (parasympathetic) efferent discharge to the heart (Zucker, 1986). This causes reduction of heart rate (bradycardia) and dilatation of the peripheral blood vessels with resulting lowering of the blood pressure, which could further contribute to cerebral hypoxemia (Cernak et al, 1996a). The importance of vagally mediated cerebral effects has been supported by experiments using rabbits (Cernak et al, 1996a) or rats (Irwin et al, 1999) subjected to blast. Bilateral vagotomy has been shown to mitigate bradycardia, hypotension, and apnea (Cernak et al, 1996a; Irwin et al, 1999). It has also been demonstrated that vagotomy prevented excessive metabolic alterations, but did not eliminate other damaging mechanisms (such as oxidative stress, for example) (Cernak et al, 1996a). Clinical experience shows the importance of vagal influence and brainstem involvement in long-term neurological sequels of TBI (Haig et al, 1996; Kox et al, 2008). Conversely, recent studies show beneficial effects of vagus nerve stimulation in reducing TBI-induced cerebral edema (Clough et al, 2007) or improving motor and cognitive function after injury (Smith et al, 2005). Although currently existing knowledge suggests that blast exposure can cause direct brainstem injury/dysfunction, further studies are necessary to identify all underlying mechanisms.

Blast-induced mechanical tissue injury of peripheral soft tissue and/or internal organs because of perforation, stretching, and/or shearing can lead to hemorrhage and synthesis and release of autacoids, which, when released in systemic circulation, activate the neuroendocrine-immune system and contribute to initiation of secondary brain injury mechanisms (Bhattacharjee, 2008; Cernak et al, 1991; Cernak et al, 1996a).

Experimental challenges of BINT

There is limited available scientific knowledge about the pathobiology of BINT. Moreover, the existing literature is often contradictory, with a broad range of experimental animals and models being used. The purpose of experimental models of TBI is to replicate certain pathological components or phases of clinical trauma in experimental animals aiming to address pathology and/or treatment. The design and choice of a specific model should emulate the goal of research (Cernak, 2005). For example, characterization of basic molecular and gene injury mechanisms that are conserved through evolution may use phylogenetically lower species such as lissencephalic rodents, whereas establishing the pathogenesis of impaired higher brain functions would require larger animals with a gyrencephalic brain. Regardless of the research questions to be addressed, clinically and militarily relevant BINT models should satisfy the following criteria: (1) the injurious component of the blast should be clearly identified and reproduced in controlled, reproducible, and quantifiable manner; (2) the inflicted injury should be reproducible, quantifiable, and mimic components of human BINT; (3) the injury outcome established based on morphological, physiological, biochemical, and/or behavioral parameters should be related to the chosen injurious component of the blast; and (4) the mechanical properties (intensity, complexity of blast signature, and/or its duration) of the injurious factor should predict the outcome severity. Unfortunately, because of lack of well-defined criteria for reliable animal models of BINT, the current experimental models used in an attempt to study BINT vary widely, including classical direct impact TBI models such as controlled cortical impact and fluid percussion injury models, air-gun-type compressed air-delivered impact model, shock and blast tube models, and open-field explosion experiments, among others. The lack of understanding of the physics of blast, unfocused rationale of experiments, and the broad variety of methods used to inflict head injury in the context of BINT research makes the comparison of the experimental results extremely challenging.

Experimental studies on primary blast-induced biological effects routinely use either shock tubes (which use compressed air or gas to generate a shockwave) or blast tubes (which use explosive charges to generate a shockwave) (Nishida, 2001; Robey, 2001). Anesthetized animals are fixed individually in special holders designed to prevent any movement of their bodies in response to blast and, thus, to prevent tertiary effects of the shock or blast wave (Wang et al, 1998). Most shock and blast tubes used in current experimental models replicate the ideal blast wave from an open-air explosion, without the capability to generate a non-ideal blast wave with multiple shock and expansion fronts as seen in real-life conditions, thus limiting the extent of comparability of experimental and clinical findings. A small number of studies use open-field exposure of animals to a blast wave generated by detonation of an explosive (Axelsson et al, 2000; Cernak et al, 1991; Richmond, 1991; Saljo and Hamberger, 2004). Although such an experimental setting is more comparable with in-theater conditions, the physical characteristics (such as homogeneity of the blast wave) are less controllable, so a broader range of biologic response should be expected. A wide range of blast overpressure sustained for various durations has been used in single-exposure experimental studies. In most studies, the animals were subjected to a shock or blast wave with a mean peak overpressure of 52–340 kPa (7.54–49.31 psi) on the nearest surface of an animal's body (Cernak et al, 2001a; Chavko et al, 2007; Clemedson et al, 1969; Saljo et al, 2000). Most experiments used rodents (mice and rats) (Cernak et al, 2001a; Long et al, 2009a), but some have subjected rabbits (Cernak et al, 1997), sheep (Cernak et al, 1991), pigs (Bauman et al, 2009), or nonhuman primates to blast (Bogo et al, 1971; Damon et al, 1968; Richmond et al, 1967; Table 1).

Table 1
A summary of major articles and models of BINT

Primary BINT

A number of behavioral, physiological, biochemical, and pathological changes occur as a result of exposure to primary blast in various animal and human studies. Considerable reductions in food intake and exercise performance have been found in rats exposed to low-intensity shockwaves (83 or 1,129 kPa) (Bauman et al, 1997). Similar findings have been reported for sheep (Mundie et al, 2000).

Vasospasm has been identified as a particularly common complication in patients with moderate or severe BINT (Armonda et al, 2006; Ling et al, 2009). The blast-induced vasospasm can develop early, often within 48 h of injury; it can also manifest later, typically between 10 and 14 days after exposure. Interestingly, the emergence of vasospasm has also been demonstrated in experiments with pigs fitted with armor and exposed to a relatively mild-intensity (172.67/25 psi) blast in the blast tube (Bauman et al, 2009).

Rats exposed to different charges of a plastic explosive (pentaerythritol tetranitrate), intended to generate a blast wave of 220 or 350 kPa (32 or 51 psi) in a blast tube, demonstrated significant decreases in amplitude and frequency of the brain's electric activity measured with electroencephalography (EEG) continuously during 30 min after the blast (Risling et al, 2002). Those changes were more profound in rats exposed to 350 kPa (51 psi) or in those exposed repeatedly to 220 kPa (32 psi). Similarly, transient flattening of the EEG was seen in pigs immediately after an explosive blast that generated a free-field waveform with a peak of approximately 241 kPa (35 psi), in contrast to the unchanged baseline EEG in control animals. Momentary depression of cortical activity accompanied by brief apnea indicates a blast-wave-induced effect on the brainstem or on higher controlling center (Axelsson et al, 2000). Disruption of the EEG waveforms have been found in pigs in which the head, but not the whole body, was inserted into an explosive-driven blast tube and exposed to an approximately 413-kPa (60 psi) blast (Bauman et al, 2009). Dose-dependent increase in intracranial pressure and inverse relationship between the level of blast and the time of the intracranial pressure onset have been found in rats exposed to low-intensity (10, 30, or 60 kPa, for example, 1.45, 4.35, or 8.7 psi) blast (Saljo et al, 2008). Increased intraparenchymal pressure in the brain has been also observed in pigs exposed to approximately 413 kPa (60 psi) (Bauman et al, 2009).

Rhesus monkeys exposed to approximately 207 kPa (30 psi), 276 kPa (40 psi), or 345 kPa (50 psi) had significant, albeit transient, memory and performance deficits (Bogo et al, 1971). Considerable and persistent memory deficits have been shown for rats subjected to moderate- and low-intensity blast waves generated in an air-driven shock tube (Cernak et al, 2001a; Long et al, 2009a; Saljo et al, 2008). Neurological dysfunction had been demonstrated also in pigs exposed to open-field blast (Bauman et al, 2009).

Blast exposure has been reported to cause brain edema and considerable metabolic disturbances in the brain: significantly decreased glucose, magnesium, and ATP concentrations; increased lactate concentration and lactate:pyruvate ratio (Cernak et al, 1996a); as well as impaired function of the Na+, K+, ATPase pump (Cernak et al, 1997). Those changes clearly suggest energy failure or imbalance between energy demand and available energy, shift of glucose metabolism from the aerobic toward the anaerobic pathway, and impairment in neuronal cell membrane permeability. Swelling of neurons, an astroglial response, and myelin debris in the hippocampus have been found after moderate blast injury in animals (Cernak et al, 2001a). Immunohistochemical analyses have shown significant damage to the neuronal cytoskeleton in layers II to IV of the temporal cortex, in the cingulate gyrus and the pirifom cortex, in the dentate gyrus, and in the CA1 region of the hippocampus over 7 days after blast exposure (Saljo et al, 2000). White matter fiber degeneration and a broad array of axonal pathology have been found in the cortex and cerebellum of pigs exposed to 379 kPa (55 psi) or 538 kPa (78 psi), respectively (Bauman et al, 2009).

Oxidative stress, changes in antioxidant–enzyme defense systems (Cernak et al, 2001a), and later cognitive deficits (Cernak et al, 2001a) have also been seen. Nitric oxide production in the brain structures of rats exposed to 339 kPa (49 psi) shockwave was determined by measuring the total nitrite/nitrate concentration, and by the expression of inducible nitric oxide synthase mRNA (Cernak et al, 2001b). The results showed significant elevation of total nitrite/nitrate levels comparable with the changes in the expression of inducible nitric oxide synthase and reduction in cognitive performance. Activation of glial fibrillary acidic protein, an indicator of astrocytosis, was evident in the hippocampus of rats 21 days after a single exposure to a 234 kPa (34 psi) burst of overpressure (Saljo et al, 2001). Astrocytosis has also been shown in the cortex and dentate gyrus of pigs exposed to a peak overpressure of 276 kPa (40 psi) (Bauman et al, 2009).

Studies of the effects of repeated low-level (29–62 kPa, for example, 4.2–9 psi) blast exposures demonstrated accumulating pathological alterations involving multiple organs or organ systems (Elsayed and Gorbunov, 2007; Yang et al, 1996), with activation of the hypothalamic–pituitary–adrenal axis and significant biochemical and hormonal changes in the brain (Mazurkiewicz-Kwilecki, 1980). Moreover, repeated exposures to low-intensity (20 kPa, for example, 2.9 psi) blast caused significant motor and cognitive deficits as well as degeneration of cortical neurons in rats (Moochhala et al, 2004).

BINT versus civilian TBIs: parallels and differences

Recently Margulies and co-workers (Margulies and Hicks, 2009) reviewed the early pathobiological events that accompany TBI, based on experimental models that mimic diffuse and focal TBIs. It is clear that many of the features seen in these animal models likewise accompany BINT, including vasospasm and barrier disruption, EEG abnormalities, oxidative stress, and elevated intracranial pressure, metabolic disturbances, and energy failure (Table 2). Although some studies suggest different temporal and spatial profiles or frequency of pathological changes (for example, vasospasm) in BINT compared with TBI induced by injurious factors other than explosion (Armonda et al, 2006; Ling et al, 2009), other reports emphasize the lack of strong evidence that blast is categorically different from other TBI mechanisms, at least with regard to cognitive sequelae (Belanger et al, 2009). Thus, further experimental and clinical studies are required to identify injury mechanisms generalizable for both BINT and civilian TBI, as well as those specific for BINT.

Table 2
A comparison of the general features seen within the first 24 h in experimental models that mimic civilian TBIs, as recently reviewed by Margulies et al (Margulies and Hicks, 2009), relative to what is currently known about blast-induced brain ...


The problem of BINT and related long-term neurological deficits has been gradually increasing with the progress of military warfare, and the pathological experience of returning veterans of Operation Enduring Freedom/Operation Iraqi Freedom has triggered more intensified attention of researchers toward clarifying the vital mechanisms underlying blast-induced brain damage. Nevertheless, because of the lack of understanding of the complex injurious environment generated by an explosion, and deficient knowledge of shockwave physics among medical researchers, the currently available literature is contradictory and often misleading. There is an obvious need for a well-coordinated, multidisciplinary research approach to clarify injury tolerance levels; to develop reliable, militarily, and clinically relevant experimental models; and to define the injury mechanisms underlying acute and chronic consequences of blast exposure(s). These challenging tasks can only be achieved with a unified front of physicists, military scientists, biomedical researchers, and clinicians applying out-of-the-box thinking and novel research approaches.


This work was supported by a contract from the US Department of Veterans Affairs to the National Academy of Sciences, Institute of Medicine, and NIH/NINDS NS050159.


  • Armonda RA, Bell RS, Vo AH, Ling G, DeGraba TJ, Crandall B, Ecklund J, Campbell WW. 2006. Wartime traumatic cerebral vasospasm: recent review of combat casualties Neurosurgery 591215–1225.1225discussion 25. [PubMed]
  • Axelsson H, Hjelmqvist H, Medin A, Persson JK, Suneson A. Physiological changes in pigs exposed to a blast wave from a detonating high-explosive charge. Mil Med. 2000;165:119–126. [PubMed]
  • Bales JW, Wagner AK, Kline AE, Dixon CE. Persistent cognitive dysfunction after traumatic brain injury: A dopamine hypothesis. Neurosci Biobehav Rev. 2009;33:981–1003. [PMC free article] [PubMed]
  • Bauman RA, Elsayed N, Petras JM, Widholm J. Exposure to sublethal blast overpressure reduces the food intake and exercise performance of rats. Toxicology. 1997;121:65–79. [PubMed]
  • Bauman RA, Ling G, Tong L, Januszkiewicz A, Agoston D, Delanerolle N, Kim Y, Ritzel D, Bell R, Ecklund J, Armonda R, Bandak F, Parks S. An introductory characterization of a combat-casualty-care relevant swine model of closed head injury resulting from exposure to explosive blast. J Neurotrauma. 2009;26:841–860. [PubMed]
  • Bayir H, Kagan VE. Bench-to-bedside review: mitochondrial injury, oxidative stress and apoptosis—there is nothing more practical than a good theory. Crit Care. 2008;12:206. [PMC free article] [PubMed]
  • Beauchamp K, Mutlak H, Smith WR, Shohami E, Stahel PF. Pharmacology of traumatic brain injury: where is the ‘golden bullet'. Mol Med. 2008;14:731–740. [PMC free article] [PubMed]
  • Belanger HG, Kretzmer T, Yoash-Gantz R, Pickett T, Tupler LA. Cognitive sequelae of blast-related versus other mechanisms of brain trauma. J Int Neuropsychol Soc. 2009;15:1–8. [PubMed]
  • Ben-Dor C, Igra O, Elperin T. Handbook of Shock Waves. San Diego: Academic Press; 2001.
  • Benzinger T. 1950. Physiological effects of blast in air and water German Aviation Medicine(World War II), Vol. 2Washington, DC: Department of the Air Force; 1225–1229.1229.
  • Bhattacharjee Y. Neuroscience. Shell shock revisited: solving the puzzle of blast trauma. Science. 2008;319:406–408. [PubMed]
  • Bilukha OO, Brennan M, Anderson M. The lasting legacy of war: epidemiology of injuries from landmines and unexploded ordnance in Afghanistan, 2002–2006. Prehosp Disaster Med. 2008;23:493–499. [PubMed]
  • Bogo V, Hutton RA, Bruner A. 1971. The effects of airblast on discriminated avoidance behavior in rhesus monkeys Technical Progress Report on Contract No. DA-49-146-XZ-372)Vol. DASA 2659Washington, DC: Defense Nuclear Agency; 1–32.32.
  • Bramlett HM, Dietrich WD. Progressive damage after brain and spinal cord injury: pathomechanisms and treatment strategies. Prog Brain Res. 2007;161:125–141. [PubMed]
  • Buki A, Povlishock JT. 2006. All roads lead to disconnection?—Traumatic axonal injury revisited Acta Neurochir (Wien) 148181–193.193discussion 93–4. [PubMed]
  • Byrnes KR, Loane DJ, Faden AI. Metabotropic glutamate receptors astargets for multipotential treatment of neurological disorders. Neurotherapeutics. 2009;6:94–107. [PMC free article] [PubMed]
  • Center for Terrorism and Intelligence Studies 2009. Global Terrorism Database, START (accessed on August 16, 2009)
  • Cernak I, Savic J, Stanimirovic D, Djuricic B, Mrsulja BB. The pathogenesis of pulmonary edema in sheep exposed to FAE charge. J Trauma (China) 1990;6 (Suppl:267–271.
  • Cernak I, Ignjatovic D, Andelic G, Savic J. [Metabolic changes aspart of the general response of the body to the effect of blast waves] Vojnosanit Pregl. 1991;48:515–522. [PubMed]
  • Cernak I, Radosevic P, Malicevic Z, Savic J. Experimental magnesium depletion in adult rabbits caused by blast overpressure. Magnes Res. 1995;8:249–259. [PubMed]
  • Cernak I, Savic J, Malicevic Z, Zunic G, Djurdjevic D, Prokic V. The pathogenesis of pulmonary blast injury: our point of view. Chinese J Traumatol. 1996a;12:28–31.
  • Cernak I, Savic J, Malicevic Z, Zunic G, Radosevic P, Ivanovic I, Davidovic L. Involvement of the central nervous system in the general response to pulmonary blast injury. J Trauma. 1996b;40:S100–S104. [PubMed]
  • Cernak I, Malicevic Z, Prokic V, Zunic G, Djurdjevic D, Ilic S, Savic J. Indirect neurotrauma caused by pulmonary blast injury: Development and prognosis. Int Rev Armed Forces Med Services. 1997;52:114–120.
  • Cernak I, Savic J, Ignjatovic D, Jevtic M. 1999. Blast injury from explosive munitions J Trauma 4796–103.103discussion-4. [PubMed]
  • Cernak I, Savic VJ, Kotur J, Prokic V, Veljovic M, Grbovic D. Characterization of plasma magnesium concentration and oxidative stress followinggraded traumatic brain injury in humans. J Neurotrauma. 2000;17:53–68. [PubMed]
  • Cernak I, Wang Z, Jiang J, Bian X, Savic J. Ultrastructural and functional characteristics of blast injury-induced neurotrauma. J Trauma. 2001a;50:695–706. [PubMed]
  • Cernak I, Wang Z, Jiang J, Bian X, Savic J. Cognitive deficits followingblast injury-induced neurotrauma: possible involvement of nitric oxide. Brain Inj. 2001b;15:593–612. [PubMed]
  • Cernak I. Animal models of head trauma. NeuroRx. 2005;2:410–422. [PubMed]
  • Champion HR, Holcomb JB, Young LA. 2009. Injuries from explosions: physics, biophysics, pathology, and required research focus J Trauma 661468–1477.1477discussion 77. [PubMed]
  • Chavko M, Koller WA, Prusaczyk WK, McCarron RM. 2007. Measurement of blast wave by a miniature fiber optic pressure transducer in the rat brain J Neurosci Methods 159277–281.281e-pub 2006 Sep 1. [PubMed]
  • Chiffelle TL. Technical Progress Report DA-49-146-XY-055) Washington, DC: Defense Atomic Support Agency, Department of Defense; 1966. of direct air-blast injury.
  • Clemedson CJ. Blast injury. Physiol Rev. 1956;36:336–354. [PubMed]
  • Clemedson CJ, Frankenberg L, Jonsson A, Pettersson H, Sundqvist AB. Dynamic response of thorax and abdomen of rabbits in partial and whole-body blast exposure. Am J Physiol. 1969;216:615–620. [PubMed]
  • Clough RW, Neese SL, Sherill LK, Tan AA, Duke A, Roosevelt RW, Browning RA, Smith DC. Cortical edema in moderate fluid percussion brain injury is attenuated by vagus nerve stimulation. Neuroscience. 2007;147:286–293. [PubMed]
  • Congressional Research Service 2008. CRS Report for Congress: United States Military Casualty Statistics—Operation Iraqi Freedom and Operation Enduring FreedomRetrived on August 16, 2009 from
  • Cook AM, Whitlow J, Hatton J, Young B. Cyclosporine A for neuroprotection: establishing dosing guidelines for safe and effective use. Expert Opin Drug Saf. 2009;8:411–419. [PubMed]
  • Cooper GJ, Townend DJ, Cater SR, Pearce BP. The role of stress waves in thoracic visceral injury from blast loading: modification of stress transmission by foams and high-density materials. J Biomech. 1991;24:273–285. [PubMed]
  • Courtney AC, Courtney MW. A thoracic mechanism of mild traumatic brain injury due toblast pressure waves. Med Hypotheses. 2009;72:76–83. [PubMed]
  • D'Ambrosio R, Perucca E. Epilepsy after head injury. Curr Opin Neurol. 2004;17:731–735. [PMC free article] [PubMed]
  • Damon EG, Gaylord CS, Yelverton JT, Richmond DR, Bowen IG, Jones RK, White CS. Effects of ambient pressure on tolerance of mammals to air blast. Aerosp Med. 1968;39:1039–1047. [PubMed]
  • Dedushkin VS, Kosachev ID, Tkachenko SS, Shapovalov VM. Rendering medical care and the volume of the treatment of victims with blast injuries (a review of the literature) Voen Med Zh. 1992. pp. 13–8. [PubMed]
  • Defense Manpower Data Center 2008. Global War on Terrorism: Casualties by ReasonRetrieved on 16 August, 2006 from
  • Dichter MA. Posttraumatic epilepsy: the challenge of translating discoveries in the laboratory to pathways to a cure. Epilepsia. 2009;50 (Suppl 2:41–45. [PubMed]
  • Dietrich WD, Atkins CM, Bramlett HM. Protection in animal models of brain and spinal cord injury with mild to moderate hypothermia. J Neurotrauma. 2009;26:301–312. [PMC free article] [PubMed]
  • Elder GA, Cristian A. Blast-related mild traumatic brain injury: mechanisms of injury and impact on clinical care. Mt Sinai J Med. 2009;76:111–118. [PubMed]
  • Elsayed NM, Gorbunov NV. 2007. Pulmonary biochemical and histological alterations after repeated low-level blast overpressure exposures Toxicol Sci 95289–296.296e-pub 2006 Oct 23. [PubMed]
  • Forsyth RJ, Jayamoni B, Paine TC. Monoaminergic agonists for acute traumatic brain injury. Cochrane Database Syst Rev. 2006. p. CD003984. [PubMed]
  • Fujimoto ST, Longhi L, Saatman KE, Conte V, Stocchetti N, McIntosh TK. Motor and cognitive function evaluation followingexperimental traumatic brain injury. Neurosci Biobehav Rev. 2004;28:365–378. [PubMed]
  • Garga N, Lowenstein DH. Posttraumatic epilepsy: a major problem in desperate need of major advances. Epilepsy Curr. 2006;6:1–5. [PMC free article] [PubMed]
  • Gibson CL, Gray LJ, Bath PM, Murphy SP. Progesterone for the treatment of experimental brain injury; a systematic review. Brain. 2008;131:318–328. [PubMed]
  • Gorbunov NV, McFaul SJ, Van Albert S, Morrissette C, Zaucha GM, Nath J. Assessment of inflammatory response and sequestration of blood iron transferrin complexes in a rat model of lung injury resulting from exposure to low-frequency shock waves. Crit Care Med. 2004;32:1028–1034. [PubMed]
  • Haig AJ, Ho KC, Ludwig G. Clinical, physiologic, and pathologic evidence for vagus dysfunction in a caseof traumatic brain injury. J Trauma. 1996;40:441–444. [PubMed]
  • Hurley RA, McGowan JC, Arfanakis K, Taber KH. Traumatic axonal injury: novel insights into evolution and identification. J Neuropsychiatry Clin Neurosci. 2004;16:1–7. [PubMed]
  • Irwin RJ, Lerner MR, Bealer JF, Mantor PC, Brackett DJ, Tuggle DW. Shock after blast wave injury is caused by a vagally mediated reflex. J Trauma. 1999;47:105–110. [PubMed]
  • Jaffin JH, McKinney L, Kinney RC, Cunningham JA, Moritz DM, Kraimer JM, Graeber GM, Moe JB, Salander JM, Harmon JW. A laboratory model for studying blast overpressure injury. J Trauma. 1987;27:349–356. [PubMed]
  • Jain KK. Neuroprotection in traumatic brain injury. Drug Discov Today. 2008;13:1082–1089. [PubMed]
  • Jennings JS, Gerber AM, Vallano ML. Pharmacological strategies for neuroprotection in traumatic brain injury. Mini Rev Med Chem. 2008;8:689–701. [PubMed]
  • Kato K, Fujimura M, Nakagawa A, Saito A, Ohki T, Takayama K, Tominaga T. Pressure-dependent effect of shock waves on rat brain: induction of neuronal apoptosis mediated by a caspase-dependent pathway. J Neurosurg. 2007;106:667–676. [PubMed]
  • Kaur C, Singh J, Lim MK, Ng BL, Yap EP, Ling EA. The response of neurons and microglia to blast injury in the rat brain. Neuropathol Appl Neurobiol. 1995;21:369–377. [PubMed]
  • Kaur C, Singh J, Lim MK, Ng BL, Yap EP, Ling EA. Studies of the choroid plexus and its associated epiplexus cells in the lateral ventricles of rats following an exposure to a single non- penetrative blast. Arch Histol Cytol. 1996;59:239–248. [PubMed]
  • Kaur C, Singh J, Lim MK, Ng BL, Ling EA. Macrophages/microglia as ‘sensors' of injury in the pineal gland of rats followinga non-penetrative blast. Neurosci Res. 1997;27:317–322. [PubMed]
  • Kazanis I. CNS injury research; reviewing the last decade: methodological errors and a proposal for a new strategy. Brain Res Brain Res Rev. 2005;50:377–386. [PubMed]
  • Kochanek PM, Berger RP, Bayr H, Wagner AK, Jenkins LW, Clark RS. Biomarkers of primary and evolving damage in traumatic and ischemic brain injury: diagnosis, prognosis, probing mechanisms, and therapeutic decision making. Curr Opin Crit Care. 2008;14:135–141. [PubMed]
  • Kokiko ON, Hamm RJ. A review of pharmacological treatments used in experimental models of traumatic brain injury. Brain Inj. 2007;21:259–274. [PubMed]
  • Kovesdi E, Luckl J, Bukovics P, Farkas O, Pal J, Czeiter E, Szellar D, Doczi T, Komoly S, Buki A. 2009. Update on protein biomarkers in traumatic brain injury with emphasis on clinical use in adults and pediatrics Acta Neurochir (Wien)advance online publication 4 August 2009; doi: 10.1007/s00701-009-0463-6. [PubMed]
  • Kox M, Pompe JC, Pickkers P, Hoedemaekers CW, van Vugt AB, van der Hoeven JG. Increased vagal tone accounts for the observed immune paralysis in patients with traumatic brain injury. Neurology. 2008;70:480–485. [PubMed]
  • LaPlaca MC, Simon CM, Prado GR, Cullen DK. CNS injury biomechanics and experimental models. Prog Brain Res. 2007;161:13–26. [PubMed]
  • Leung LY, VandeVord PJ, Dal Cengio AL, Bir C, Yang KH, King AI. Blast related neurotrauma: a review of cellular injury. Mol Cell Biomech. 2008;5:155–168. [PubMed]
  • Ling G, Bandak F, Armonda R, Grant G, Ecklund J. Explosive blast neurotrauma. J Neurotrauma. 2009;26:815–825. [PubMed]
  • Long JB, Bentley TL, Wessner KA, Cerone C, Sweeney S, Bauman RA. Blast overpressure in rats: recreating a battlefield injury in the laboratory. J Neurotrauma. 2009a;26:827–840. [PubMed]
  • Long JB, Bentley TL, Wessner KA, Cerone C, Sweeney S, Bauman RA. Blast overpressure in rats: recreating a battlefield injury in the laboratory. J Neurotrauma. 2009b;26:827–840. [PubMed]
  • Mainiero R, Sapko M. Blast and Fire Propagation in Underground Facilities. Alexandria, VA: Defense Nuclear Agency; 1996. pp. 1–36.
  • Mammis A, McIntosh TK, Maniker AH. 2009. Erythropoietin asa neuroprotective agent in traumatic brain injury Review Surg Neurol 71527–531.531discussion 31. [PubMed]
  • Manvelyan H. Contemporary experimental models of traumatic brain injury. Georgian Med News. 2006;140:1306. [PubMed]
  • Margulies S, Hicks R. Combination therapies for traumatic brain injury: prospective considerations. J Neurotrauma. 2009;26:925–939. [PMC free article] [PubMed]
  • Marklund N, Bakshi A, Castelbuono DJ, Conte V, McIntosh TK. Evaluation of pharmacological treatment strategies in traumatic brain injury. Curr Pharm Des. 2006;12:1645–1680. [PubMed]
  • Martin EM, Lu WC, Helmick K, French L, Warden DL. Traumatic brain injuries sustained in the Afghanistan and Iraq wars. Am J Nurs. 2008;108:40–47. [PubMed]
  • Mazurkiewicz-Kwilecki IM. Single and repeated air blast stress and brain histamine. Pharmacol Biochem Behav. 1980;12:35–39. [PubMed]
  • Mazzeo AT, Beat A, Singh A, Bullock MR. The role of mitochondrial transition pore, and its modulation, in traumatic brain injury and delayed neurodegeneration after TBI. Exp Neurol. 2009;218:363–370. [PubMed]
  • Mechoulam R, Shohami E. Endocannabinoids and traumatic brain injury. Mol Neurobiol. 2007;36:68–74. [PubMed]
  • Mellor SG. The pathogenesis of blast injury and its management. Br J Hosp Med. 1988;39:536–539. [PubMed]
  • Moochhala SM, Md S, Lu J, Teng CH, Greengrass C. Neuroprotective role of aminoguanidine in behavioral changes after blast injury. J Trauma. 2004;56:393–403. [PubMed]
  • Morales DM, Marklund N, Lebold D, Thompson HJ, Pitkanen A, Maxwell WL, Longhi L, Laurer H, Maegele M, Neugebauer E, Graham DI, Stocchetti N, McIntosh TK. Experimental models of traumatic brain injury: do we really need to build a better mousetrap. Neuroscience. 2005;136:971–989. [PubMed]
  • Mundie TG, Dodd KT, Lagutchik MS, Morris JR, Martin D. Effects of blast exposure on exercise performance in sheep. J Trauma. 2000;48:1115–1121. [PubMed]
  • Nakagawa A, Fujimura M, Kato K, Okuyama H, Hashimoto T, Takayama K, Tominaga T. Shock wave-induced brain injury in rat: novel traumatic brain injury animal model. Acta Neurochir Suppl. 2008;102:421–424. [PubMed]
  • Nishida M. 2001. Shock tubes and tunnels: facilities, instrumentation, and techniques. Shock tubes Handbook of Shock Waves(Ben-Dor C, Igra O, Elperin T, eds), Vol. 1,San Diego: Academic Press; 553–585.585.
  • Ottens AK, Kobeissy FH, Fuller BF, Liu MC, Oli MW, Hayes RL, Wang KK. Novel neuroproteomic approaches to studying traumatic brain injury. Prog Brain Res. 2007;161:401–418. [PubMed]
  • Owen-Smith MS. Explosive blast injury. Med Bull US Army Eur. 1981;38:36–43.
  • Paintal AS. Mechanism of stimulation of type J pulmonary receptors. J Physiol. 1969;203:511–532. [PubMed]
  • Park E, Bell JD, Baker AJ. Traumatic brain injury: can the consequences be stopped. CMAJ. 2008;178:1163–1170. [PMC free article] [PubMed]
  • Phillips YY. Primary Blast Injuries. Ann Emerg Med. 1986;15:1446–1450. [PubMed]
  • Phillips YY, Mundie TG, Yelverton JT, Richmond DR. Cloth ballistic vest alters response to blast. J Trauma. 1988;28:S149–S152. [PubMed]
  • Pitkanen A, McIntosh TK. Animal models of post-traumatic epilepsy. J Neurotrauma. 2006;23:241–261. [PubMed]
  • Pitkanen A, Immonen RJ, Grohn OH, Kharatishvili I. From traumatic brain injury to posttraumatic epilepsy: what animal models tell us about the process and treatment options. Epilepsia. 2009;50 (Suppl 2:21–29. [PubMed]
  • Potts MB, Adwanikar H, Noble-Haeusslein LJ. Models of traumatic cerebellar injury. Cerebellum. 2009;8:211–221. [PMC free article] [PubMed]
  • Povlishock JT, Katz DI. Update of neuropathology and neurological recovery after traumatic brain injury. J Head Trauma Rehabil. 2005;20:76–94. [PubMed]
  • Raghupathi R. Cell death mechanisms followingtraumatic brain injury. Brain Pathol. 2004;14:215–222. [PubMed]
  • Rice D, Heck J. Terrorist bombings: ballistics, patterns of blast injury and tactical emergency care. Tactical Edge J Summer. 2000. pp. 53–56.
  • Richmond DR, Damon EG, Bowen IG, Fletcher ER, White CS. Air-blast studies with eight species of mammals. Techn Progr Rep DASA 1854. Fission Prod Inhal Proj. 1967. pp. 1–44. [PubMed]
  • Richmond DR, Yelverton JT, Fletcher ER, Phillips YY, Jaeger JJ, Young AJ. The Biological Effects of Repeated Blasts. Washington, DC: Defense Nuclear Agency; 1981. pp. 1–39.
  • Richmond DR. Blast criteria for open spaces and enclosures. Scand Audiol Suppl. 1991;34:49–76. [PubMed]
  • Risling M, Suneson A, Bursell J, Larsson I-L, Persson J. 2002. Evaluation of Diffuse Blastwave Induced Brain Injury using EEG Stockholm: Swedish Defence Research Agency; ISSN 1650-1942; published on December 2002.
  • Robertson CL. Mitochondrial dysfunction contributes to cell death followingtraumatic brain injury in adult and immature animals. J Bioenerg Biomembr. 2004;36:363–368. [PubMed]
  • Robey R. 2001. Shock tubes and tunnels: facilities, instrumentation, and techniques. Blast tubes Handbook of shock waves(Ben-Dor C, Igra O, Elperin T, eds), Vol. 1,San Diego: Academic Press; 623–650.650.
  • Rogers E, Wagner AK. Gender, sex steroids, and neuroprotection followingtraumatic brain injury. J Head Trauma Rehabil. 2006;21:279–281. [PubMed]
  • Rossle R. 1950. Pathology of blast effects German Aviation Medicine(World War II), Vol. 2Washington, DC: Department of the Air Force; 1260–1273.1273.
  • Saljo A, Bao F, Haglid KG, Hansson HA. Blast exposure causes redistribution of phosphorylated neurofilament subunits in neurons of the adult rat brain. J Neurotrauma. 2000;17:719–726. [PubMed]
  • Saljo A, Bao F, Hamberger A, Haglid KG, Hansson HA. Exposure to short-lasting impulse noise causes microglial and astroglial cell activation in the adult rat brain. Pathophysiology. 2001;8:105–111. [PubMed]
  • Saljo A, Bao F, Jingshan S, Hamberger A, Hansson HA, Haglid KG. Exposure to short-lasting impulse noise causes neuronal c-Jun expression and induction of apoptosis in the adult rat brain. J Neurotrauma. 2002a;19:985–991. [PubMed]
  • Saljo A, Bao F, Shi J, Hamberger A, Hansson HA, Haglid KG. Expression of c-Fos and c-Myc and deposition of beta-APP in neurons in the adult rat brain asa result of exposure to short-lasting impulse noise. J Neurotrauma. 2002b;19:379–385. [PubMed]
  • Saljo A, Hamberger A. 7th International Neurotrauma Symposium. Adelaide, Australia: Medimond, Monduzzi Editore; 2004. Intracranial sound pressure levels during impulse noise exposure.
  • Saljo A, Arrhen F, Bolouri H, Mayorga M, Hamberger A. Neuropathology and pressure in the pig brain resulting from low-impulse noise exposure. J Neurotrauma. 2008;25:1397–1406. [PubMed]
  • Saljo A, Svensson B, Mayorga M, Hamberger A, Bolouri H. Low levels of blast raises intracranial pressure and impairs cognitive function in rats. J Neurotrauma. 2009;28:1345–52. [PubMed]
  • Savic J, Tatic V, Ignjatovic D, Mrda V, Erdeljan D, Cernak I, Vujnov S, Simovic M, Andelic G, Duknic M. Pathophysiologic reactions in sheep to blast waves from detonation of aerosol explosives. Vojnosanit Pregl. 1991;48:499–506. [PubMed]
  • Schallert T. Behavioral tests for preclinical intervention assessment. NeuroRx. 2006;3:497–504. [PubMed]
  • Schouten JW. Neuroprotection in traumatic brain injury: a complex struggle against the biology of nature. Curr Opin Crit Care. 2007;13:134–142. [PubMed]
  • Schumacher M, Guennoun R, Stein DG, De Nicola AF. Progesterone: therapeutic opportunities for neuroprotection and myelin repair. Pharmacol Ther. 2007;116:77–106. [PubMed]
  • Smith DC, Modglin AA, Roosevelt RW, Neese SL, Jensen RA, Browning RA, Clough RW. Electrical stimulation of the vagus nerve enhances cognitive and motor recovery following moderate fluid percussion injury in the rat. J Neurotrauma. 2005;22:1485–1502. [PMC free article] [PubMed]
  • Stein DG. Progesterone exerts neuroprotective effects after brain injury. Brain Res Rev. 2008;57:386–397. [PMC free article] [PubMed]
  • Stoica B, Byrnes K, Faden AI. Multifunctional drug treatment in neurotrauma. Neurotherapeutics. 2009;6:14–27. [PMC free article] [PubMed]
  • Sullivan PG, Rabchevsky AG, Waldmeier PC, Springer JE. Mitochondrial permeability transition in CNS trauma: causeor effect of neuronal cell death. J Neurosci Res. 2005;79:231–239. [PubMed]
  • Vink R, Nimmo AJ. Multifunctional drugs for head injury. Neurotherapeutics. 2009;6:28–42. [PubMed]
  • Wang KK, Larner SF, Robinson G, Hayes RL. Neuroprotection targets after traumatic brain injury. Curr Opin Neurol. 2006;19:514–519. [PubMed]
  • Wang Z, Sun L, Yang Z, Leng H, Jiang J, Yu H, Gu J, Li Z. Development of serial bio-shock tubes and their application. Chin Med J (Engl) 1998;111:109–113. [PubMed]
  • Weber JT. Experimental models of repetitive brain injuries. Prog Brain Res. 2007;161:253–261. [PubMed]
  • Werner C, Engelhard K. Pathophysiology of traumatic brain injury. Br J Anaesth. 2007;99:4–9. [PubMed]
  • Willmore LJ, Ueda Y. Posttraumatic epilepsy: hemorrhage, free radicals and the molecular regulation of glutamate. Neurochem Res. 2009;34:688–697. [PubMed]
  • Wise PM, Dubal DB, Rau SW, Brown CM, Suzuki S. Are estrogens protective or risk factors in brain injury and neurodegeneration? Reevaluation after the Women's health initiative. Endocr Rev. 2005;26:308–312. [PubMed]
  • Xiong Y, Mahmood A, Chopp M. Emerging treatments for traumatic brain injury. Expert Opin Emerg Drugs. 2009;14:67–84. [PMC free article] [PubMed]
  • Yakovlev AG, Faden AI. Mechanisms of neural cell death: implications for development of neuroprotective treatment strategies. NeuroRx. 2004;1:5–16. [PubMed]
  • Yang Z, Wang Z, Tang C, Ying Y. Biological effects of weak blast waves and safety limits for internal organ injury in the human body. J Trauma. 1996;40:S81–S84. [PubMed]
  • Zhang X, Chen Y, Jenkins LW, Kochanek PM, Clark RS. Bench-to-bedside review: apoptosis/programmed cell death triggered by traumatic brain injury. Crit Care. 2005;9:66–75. [PMC free article] [PubMed]
  • Zucker IH. Left ventricular receptors: physiological controllers or pathological curiosities. Basic Res Cardiol. 1986;81:539–557. [PubMed]
  • Zuckerman S. Experimental study of blast injuries to the lungs. Lancet II. 1940;236:219–224.

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