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BRAIN NEUROTRAUMA
MOLECULAR,
NEUROPSYCHOLOGICAL,
and
REHABILITATION ASPECTS
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45
CONTENTS
45.1 Introduction...................................................................................................................................................................... 631
45.2 Blast-Body and Blast-Brain Interactions.......................................................................................................................... 632
45.3 Modifying Potential of Systemic Changes Caused by Blast............................................................................................ 633
45.3.1 Air Emboli............................................................................................................................................................ 633
45.3.2 Activation of the Autonomous Nervous System................................................................................................... 634
45.3.3 Vascular Mechanisms........................................................................................................................................... 635
45.3.4 Systemic Inflammation......................................................................................................................................... 636
45.4 Requirements for Blast-Induced Injury Models............................................................................................................... 636
45.5 Choice of Models.............................................................................................................................................................. 636
45.5.1 Experimental Environment Generating Blast...................................................................................................... 638
45.6 Blast-Induced Neurotrauma.............................................................................................................................................. 640
45.6.1 Animal Models of BINT...................................................................................................................................... 640
45.7 Conclusion........................................................................................................................................................................ 641
References.................................................................................................................................................................................. 641
45.1INTRODUCTION
Explosions are physical phenomena that result in the sudden
release of energy; they may be chemical, nuclear, or mechanical. This process results in a near-instantaneous pressure
rise above atmospheric pressure. The positive pressure rise
(overpressure) compresses the surrounding medium (air
or water) and results in the propagation of a blast wave,
which extends outward from the explosion in a radial fashion. As the front or leading edge of the blast wave expands,
the positive phase is followed by a decrease in pressure and
the development of a negative wave (underpressure) before
subsequently returning to baseline. Figure 45.1 shows an idealized form of a shock wave (Friedlnder wave) (Friedlander,
1955) generated by a spherical, uncased explosive in the air
in free field conditions. The extent of damage from the blast
wave mainly depends on five factors: (1) the peak of the initial positive-pressure wave (an overpressure of 6901,724
kPa, for example, 100250 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. Intensity of an explosion pressure wave declines with the cubed root of the distance from
the explosion. Thus, a person 3 m (10 ft) from an explosion
experiences nine times more overpressure than a person 6
m (20 ft) away. Additionally, explosions near or within hard
solid surfaces can be amplified two to nine times because of
shock wave reflection (Rice and Heck, 2000). Indeed, it was
observed that victims positioned between a blast and a building often suffer injuries two to three times the degree of the
injury of a person in an open space. People exposed to explosion rarely experience the idealized pressure-wave form.
Even in open-field conditions, the blast wave reflects from
the ground, generating reflective waves that interact with the
primary wave, 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).
Blast injuries are characterized by interwoven mechanisms
of systemic, local, and cerebral responses to blast exposure
(Cernak, 2010). When a blast generated by explosion strikes
631
632
PSO
Pressure
Positive impulse, is
PS(t)
Ambient
tA + tO
tA
PO
Negative
impulse IS
tA + tO + tO
P SO
PS (t)
Positive
phase
tA
t=0
Negative phase
Duration
tO
Duration
tO
FIGURE 45.1 The Friedlnder wave describing an ideal blast from a spherical source in an open environment. t0 is the time at which
the pressure began to rise above ambient pressure. Positive magnitude is the difference between peak pressure and ambient pressure.
Positive duration is the time between t0 and when the pressure goes below ambient pressure. Positive impulse is the integral of the
pressure-time trace during the positive phase. Negative magnitude is the difference between ambient and peak negative pressure. (From
Ngo, T. et al., EJSE Special Issue: Loading on Structures, 7691, 2007.)
effects caused by post-detonation environmental contaminants, such as bacteria and radiation from dirty bombs,
and tissue reactions to fuel and metal residues, among others (Kluger et al., 2007). Often, especially in the case of
moderate-to-severe blast injuries, the multiple blast effects
interact with the body simultaneously. In some literature
sources, such an injurious environment and related injuries
are referred to as blast plus scenarios (Moss et al., 2009).
When a shock wave generated by detonating a highenergy explosive strikes a living body, several physical events
take place: a fraction of the shock wave is reflected, whereas
another fraction of the shock wave energy is absorbed and
propagates through the body as a tissue-transmitted shock
wave (Clemedson and Criborn, 1955). Different organ and
body structures differ in their reaction. Nevertheless, tissues typically respond (1) either on the impulse of the shock
wavethis response is of longer durationor (2) on the
pressure variations of the shock wave, and this response is in
a form of oscillations or pressure deflections of shorter duration (Clemedson and Pettersson, 1956). For example, basic
experiments showed that tissues in the abdomen and costal
interspaces react with typical impulse response, whereas the
rib and the hind leg responded with a more or less pure maximum pressure type curve (Clemedson and Granstom, 1950;
Clemedson et al., 1956, 1969).
The energy of the primary blast shock wave is either
absorbed or transformed into the kinetic energy of a
medium,which could be solid, liquid, gas, or plasma, when
the interaction between them occurs (Clemedson and Jonsson,
1961). The transferred kinetic energy, then, moves and
633
Secondary blast-induced
neurotrauma
(penetrating head injury)
Site of impact
coup
FIGURE 45.2 Complex injurious environment resulting from blast. Primary blast effects are caused by the blast wave itself (excludes penetrating and blunt force injury); secondary blast effects are caused by particles propelled by the blast (penetrating or blunt force injury); tertiary
blast effects are caused by acceleration and deceleration of the body and its impact with other objects (penetrating or blunt force [including
coup-contrecoup] injury). (From Cernak I. and L.J. Noble-Haeusslein. J Cereb Blood Flow Metab. 30:25566. 2010. With permission.)
634
Blast
Local responce
Systemic response
Mechanical
tissue injury
Vascular
loading
Cerebral response
ANS
activation
Perforation
Stretching
Shearing
Hemorrhage
Cardio-respiratory
dysfunction
Synthesis/release
of autacoids
Initiation of
secondary injury
mechanisms
Hypoxia
SNS: Stress
response
Increased NE
and E synthesis
and release
PNS: Vago-vagal
reflexes
BezoldJarish
reflex
Efferent reflex to
juxtacapilary Jreceptor stimulation
Impaired
homeostasis
Body weight
Cardiovascular function
Respiratory function
Sleep
BBB &
vascular
alterations
Increased
permeability &
brain edema
Vasospasm
Compromised CBF
Inflammation
Glial activation
Macrophage
infiltration
FIGURE 45.3 Simultaneous activation of systemic, local, and cerebral responses to blast exposure and interactive mechanisms causing or contributing to the pathobiology of BINT. ANS, autonomous nervous system; BBB, bloodbrain barrier; CBF, cerebral blood flow;
E, epinephrine; NE, norepinephrine; SNS, sympathetic nervous system; PNS, parasympathetic nervous system. (From Cernak, I. Front Neurol.
1:151, 2010.)
635
(CVP). Hypoxia caused by alveolar damage and subsequently reduced surface area for gas exchange, impaired
ventilation/perfusion caused by J-receptor activation, or
decreased cardiac output from activation of BezoldJarish
reflex, among others, increases pulmonary arterial resistance, which might also increase ThorP (Gelman, 2008).
The elevated ThorP further amplifies the increase in central
venous pressure.
Having a high density of 1- and 2-adrenergic receptors and hence high sensitivity to adrenergic stimulation, the
venoconstriction and mobilization of blood volume mainly
depend on splanchnic circulation (Pang, 2001; Rutlen etal.,
1979). Thus, it is highly feasible that the initial sudden
drop in systemic arterial pressure initiates a compensatory
increase in sympathetic outflow through vagovagal reflexes
with reduction in the inhibitory influences of the baroreceptors of the carotid sinus and aortic area on the vasomotor center. Consequently, the increased sympathetic stimuli induced
by blast constrict venous smooth musculature and lead to
mobilization of splanchnic blood toward the heart (Rutlen
et al., 1979).
Cerebrovascular vasospasm has been found frequently in
casualties with moderate or severe blast-induced traumatic
brain injury (TBI), more often than in patients with TBI of
other origins (i.e., impact, fall, or acceleration/deceleration)
(Armonda et al., 2006; Ling et al., 2009). Vasospasm can
develop early, often within 48 hours of injury, and can also
manifest later, typically between 1014 days postexposure.
It is noteworthy that although cerebral vasospasm is usually prompted by subarachnoid hemorrhage, subarachnoid
45.3.3Vascular Mechanisms
Bearing in mind the previously described mechanisms of
blast effects, it becomes obvious that one of the most important media for the shock wave's energy transfer is blood.
Veins contain approximately 70% of total blood volume.
From this, the splanchnic system receives approximately
25% of cardiac output (translating into approximately 20%
of total blood volume) compared with 18% in arteries and
only 3% in terminal arteries and arterioles (Gelman, 2008).
In general, veins are 30 times more compliant than the
arteries, and splanchnic and cutaneous veins represent the
most compliant venous vessels of all. Thus, these venous
systems form the largest blood volume reservoirs in the
human body. Figure 45.4 shows a simplified schematic representation of the consequences of blast-induced pressure
changes and their extremely complex interactions, which
form several interconnected loops. The shock wave's energy
transferred to the body leads not only to a sudden increase
in both abdominal and thoracic pressures (ThorP), but
also causes increase in intramural central venous pressure
Abdomen
Abdominal pressure
Thorax
Thoracic pressure
Heart
Liver
Hepatic venous
pressure
Right atrial
pressure
Left ventricular
pressure
Liver infarct
(hermorrhagic or
ischemic)
Liver
oxygen
supply
Lungs
Bezold
Jarish reflex
activation
(Intramural)
Central
venous
pressure
Liver blood
flow
Cardiac
output
Hypoxia
Impaired
ventilation/
perfusion
Lung
pressure
J-receptors
activation
Gas
exchange
Alveolar
distention/
damage
Shock wave propagation
FIGURE 45.4 Simplified overview of vascular mechanisms activated by shock wave propagation through the body leading to alterations
in functions of multiple organs and organ systems, which significantly influence the brain's response to blast. (Created by Ibolja Cernak for
the Committee on Gulf War and Health: Long-Term Effects of Blast Exposures, Institute of Medicine, U.S. National Academies, Copyright
2014.)
636
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 blast injuries; (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 (Cernak and Noble-Haeusslein,
2010). The mechanistic factors underlying blast injuries are
extremely complex as compared with the injuries caused
by an impact or acceleration/deceleration force. Hence, an
appropriate and clinically relevant blast injury model should
be based on sufficient knowledge of shock wave physics, the
characteristics of the injurious environment generated by an
explosion, and clinical manifestations of resultant injuries.
45.3.4Systemic Inflammation
Blast exposure can activate multiple inflammatory mechanisms (Cernak, 2010). Tissue disruption stimulates synthesis
and release of autacoids (i.e., biological factors acting like
local hormones near the site of their synthesis with a brief
duration of action). Indeed, increased concentrations of various prostaglandins, leukotrienes, and cytokines have been
found in the blood of blast casualties (Cernak et al., 1999a,
1999b; Surbatovic et al., 2007). These autacoids directly affect
a number of stages of cellular and humoral immunity, and
also act as feedback modifiers connecting the early and late
phases of the immune response (Melmon et al., 1981). Indeed,
they can stimulate selected migration of cells to the injury
site, and directly or indirectly modify the turnover of T- and
B-lymphocytes, the production or release of lymphokines,
and the activity of T helper or T-suppressor cells (Khan and
Melmon, 1985; Melmon et al., 1981). It has been suggested that
inflammatory cells of systemic origin that have been induced
by shock wave propagation through the body significantly contribute to blast-induced inflammation in the brain and related
neurodegeneration (Cernak, 2010), which was supported by
additional experimental data (Valiyaveettil et al., 2013).
Blast exposures have been reported to cause significant
alterations in neuroendocrine system involving multiple hypothalamopituitary end axes (Baxter et al., 2013; Cernak et al.,
1999c; Wilkinson et al., 2012). The importance of the immunoneuroendocrine network in injury response and inflammation control is well established (Besedovsky and del Rey,
1996, 2002; Chrousos, 1995). Thus, it is highly likely that blast
exposure, through multiple interwoven mechanisms, causes a
massive stimulation of the central nervous system (CNS) with
broad consequences on all aspects of vital functions.
637
In silico
Biological models
Surrogate /
physical
In vitro
Ex vivo
In vivo
Anatomic correctness
Physiological correctness
Phylogenetic maturity
Size
Biofidelity
Complexity
Blast loading conditions
Geometry
Gender
Age
Position
Choice of blast environment
Field explosion
Open field
(no obstacles)
Partially/fully
confined space
(obstacles)
Laboratory conditions
Shock tube
(compressed air/gas)
Blast tube
(explosive charge)
FIGURE 45.5 Factors influencing the choice of blast injury and BINT models. (Created by Ibolja Cernak for the Committee on Gulf War
and Health: Long-Term Effects of Blast Exposures Institute of Medicine, U.S. National Academies, Copyright 2014.)
638
monkey, cat, and dog, is only about half of the lung density
of smaller species (e.g., rodents), whereas lung volumes normalized to body mass are three times bigger in large species
than in smaller animals (White et al., 1965). Also, there are
significant interspecies differences in body geometry that
influence the blast-body blast-head interactions (Bass etal.,
2012). The body position of the animal in the shock tube also
has an important impact on blast injury severity. Animals
facing the incoming shock wave front with their chest and
abdomen (i.e., supine position) provide the best conditions
for the shock wave's energy transfer; consequently, they have
the highest mortality rate and most severe injuries (Cernak
et al., 2011). Furthermore, in blast injury modeling, especially when acceleration is included as one of the mechanistic
factors, scaling laws should be taken into careful consideration (Bass et al., 2008, 2012). Taking a blast-head scenario
as an example, for a given blast, when calculating the net
loading scales for cross-sectional area of the skull, even if
other parameters would be identical, a specimen 20-fold the
size would experience 20-fold less acceleration for the same
blast. Nevertheless, other anatomical differences between
the human and animal heads, such as bone volume fraction,
trabecular separation and number, and connectivity density,
among others (Holzer et al., 2012; Pietschmann et al., 2010),
should also be considered. Evolutionary and developmental changes in the structure and arrangement of blood vessels (Vries, 1904) are also important factors that should be
taken into account when choosing models for reproducing
blast injury. For example, the internal carotid artery is the
main blood supply both in humans/nonhuman primates and
rodents (rats and mice). Nevertheless, although in lower vertebrates the internal carotid artery directs the blood to the
brain parenchyma through the posterior branch without contribution from the basilar artery, in higher vertebrates, there
are the two posterior branches that stem from a single and
central branch turning into the branch of the basilar artery
(Casals et al., 2011). These anatomical differences could significantly influence the shock wave propagation through the
cerebrovasculature.
Previously, it has been shown that the level of phylogenetic maturity has a decisive role in brain's response to a
high-pressure environment (Brauer et al., 1979), a factor
that should be taken into account in planning blast-induced
neurotrauma (BINT) experiments. Because basic molecular
and gene injury-response mechanisms are conserved through
evolution, phylogenetically lower species such as rodents can
be used for studies studying blast-induced changes at cellular
and subcellular levels. However, establishing the pathogenesis of impaired higher brain functions would require larger
animals with a gyrencephalic brain.
639
the findings with animal models about the subsonic jet wind
effects (Desmoulin and Dionne, 2009). Interestingly, a recent
article argues that the environment inside a shock/blast tube
induces artificially enhanced injuries because of reflected
shock waves and rarefaction waves; thus, exposure of animals to shock waves in a shock/blast tube will cause severe,
rare, and complex blast injuries, which are not comparable
to injuries acquired in real-life, open-field blast conditions
(Chen and Constantini, 2013).
Prone position with head and body oriented along the direction of shock wave propagation (perpendicular to the shock
front) is the most commonly used orientation in current rodent
model studies with shock tubes (Dal Cengio Leonardi et al.,
2012; Saljo et al., 2010; Vandevord et al., 2012; Zhu et al.,
2010). However, although this position is natural for quadrupeds, it does not reproduce the most frequent human scenario
when the soldiers are in upright position and facing with torso
toward the front of an incoming shock wave. It has been shown
that both the pattern and severity of organ damage caused by
blast depend on the orientation of the body toward the shock
wave front (Cernak et al., 2011). The lung seems to be the most
vulnerable organ to the effects of blast across injury severity and in both prone and supine body positions. Similarly,
blast severity seemed to be positively correlated with lesion
frequency and severity in both prone and supine positions
(Koliatsos et al., 2011). As in the lung, supine position was
associated with more severe findings in the heart such as dilation of ventricles and atria, right more than left. In contrast
to lung injuries, prone disposition caused more severe liver
pathology such as congestion, mottling, and white discoloration adjacent to apparently hemorrhagic sites, compared with
supine positioning. In the prone, but not the supine position,
there was some association between blast severity and liver
infarct rate (Koliatsos et al., 2011). The prone position was
also linked to more damage in kidneys and spleen. Recently,
Ahlers and associates showed that low-intensity blast exposure
produced an impairment of spatial memory that was specific
to the orientation of the animal (Ahlers et al., 2012).
The choice of the animal holder is another important component in shock/blast tube experiments. Namely, if the animal is fixed on a solid platform, the waves reflecting from it
will amplify the primary shock wave and increase the complexity and severity of blast injuries. Furthermore, a bulky
animal holder when placed inside the tube could obstruct the
central flow of the shock wave propagating along the driver
and contribute to nonhomogeneous field conditions.
When choosing the system for generating blast, besides
the physics, the physiological effects of the driver conditions
also should be taken into account. Namely, when compressed
helium was used to generate a shock wave, the oxygen content was reduced by approximately 75% in the driven section
(Reneer et al., 2011). The oxygen content in the driven section
was moderately reduced and the carbon monoxide content
very high after oxyhydrogen-driven blasts. The carbon monoxide content was above the acceptable levels in the driver of
an explosive-generated blast tube as a result of combustion
(Reneer et al., 2011).
640
to those seen in impact TBIs rather than to structural alterations seen in soldiers exposed to blast and with diagnosed
BINT. There are also models where the animals are exposed
to whole body blast and their body protected aiming to prevent any blast-induced systemic effects. The utilization of
different materials such as cardboard (Chavko et al., 2011)
or Kevlar fabric without interceptive plate (Long et al., 2009;
Reneer et al., 2011) further complicates the comparison of
experimental findings.
Taken together, 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 are significantly reducing the reliability
of the published literature and slowing down the progress of
this research field. Hence, there is a dire need for a well-coordinated, multidisciplinary research approach to clarify injury
tolerance levels for animal models relevant for military experience and to define the injury mechanisms underlying acute
and chronic consequences of blast exposure(s).
45.7CONCLUSION
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. The long-term health problems manifesting
in growing number of veterans have triggered intensified
research efforts aiming to clarify the vital mechanisms underlying blast injuries and blast-induced brain damage. This is
an extremely challenging task, which requires a unified front
of physicists, military scientists, biomedical researchers,
and clinicians applying out-of-the-box thinking and novel
research approaches. Clear guidelines about experimental
models that are acceptable for blast injury research should be
established and strict adherence to those guidelines enforced.
Without such consensus among blast researchers and close
cooperation between the researchers and those with military
operational experience, this research field will remain contradictory and misleading, and the soldiers with blast injuries
and/or BINT left without improvement in their treatment.
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