Downloaded by [University of Alberta], [Ibolja Cernak] at 08:46 05 March 2015

BRAIN NEUROTRAUMA
MOLECULAR,
NEUROPSYCHOLOGICAL,
and
REHABILITATION ASPECTS
Edited by

Firas H. Kobeissy, PhD
Psychoproteomics and Nanotechnology Research Center
Department of Psychiatry
University of Florida
Gainsville, Florida, USA

Boca Raton London New York

CRC Press is an imprint of the
Taylor & Francis Group, an informa business

Downloaded by [University of Alberta], [Ibolja Cernak] at 08:46 05 March 2015

Cover art designed by Alexdrina Chong, M.S., graphic designer.

CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
© 2015 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
Version Date: 20141223
International Standard Book Number-13: 978-1-4665-6599-9 (eBook - PDF)
This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable
data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made.
The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors are personal to them
and do not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is intended for use by medical,
scientific or health-care professionals and is provided strictly as a supplement to the medical or other professional’s own judgement, their knowledge of
the patient’s medical history, relevant manufacturer’s instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures or diagnoses should be independently verified. The reader is strongly urged to consult the
relevant national drug formulary and the drug companies’ printed instructions, and their websites, before administering any of the drugs recommended
in this book. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole
responsibility of the medical professional to make his or her own professional judgements, so as to advise and treat patients appropriately. The authors
and publishers have also attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if
permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may
rectify in any future reprint.
Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic,
mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or
retrieval system, without written permission from the publishers.
For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact
the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides
licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment
has been arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation
without intent to infringe.
Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com
and the CRC Press Web site at
http://www.crcpress.com

45

Blast Injuries and Blast-Induced
Neurotrauma
Overview of Pathophysiology and
Experimental Knowledge Models and Findings
Ibolja Cernak

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

45.1 INTRODUCTION
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 (Friedländer 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 690–1,724
kPa, for example, 100–250 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. 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

Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects

PSO

Pressure

Positive impulse, is

PS(t)
Ambient

tA + tO

tA

PO

Downloaded by [University of Alberta], [Ibolja Cernak] at 09:21 05 March 2015

Negative
impulse IS

tA + tO + tO

P SO
PS (t)

Positive
phase
tA
t=0

Negative phase

Duration
tO

Duration
tO

Time after explosion

FIGURE 45.1  The Friedländer 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, 76–91, 2007.)

a living body, part of the shock wave is reflected and another
fraction is absorbed becoming a tissue-transmitted shock wave.
The transferred kinetic energy causes low-frequency stress
waves that accelerate a medium from its resting state, leading
to rapid physical movement, displacement, deformation, or rupture of the medium (Clemedson, 1956; Clemedson and Criborn,
1955). Thus, a militarily relevant blast injury model should be
able to capture and measure these phenomena based on sufficient knowledge of shock wave physics, the characteristics of
the injurious environment generated by an explosion, and the
clinical manifestations and sequelae of the injuries. The purpose of this chapter is to outline the pathophysiology of blastbody/blast-brain interactions and to summarize the scientific
evidence to date for the selection of appropriate experimental
models for characterizing and understanding these interactions.

45.2 BLAST-BODY AND BLAST-BRAIN
INTERACTIONS
Conceptually, explosive blast may have five distinct effects
on the body (Figure 45.2): (1) primary blast effects causing
injuries as sole consequences of the shock wave–body interaction; (2) secondary blast effects from the fragments of
debris propelled by the explosion and connecting with the
body, causing penetrating and/or blunt trauma; (3) tertiary
blast effects from acceleration/deceleration of the body or
part of the body (Richmond et al., 1961); (4) quaternary
blast effects caused by the transient but intense heat of the
explosion (flash burns) (Mellor, 1988); and (5) quinary blast

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
wave—this response is of longer duration—or (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

Blast Injuries and Blast-Induced Neurotrauma

Secondary blast-induced
neurotrauma
(penetrating head injury)

Primary blast-induced neurotrauma
(without a direct blow to the head)
Kinetic energy transfer to the CNS
Lung injury-induced hypoxia/ischemia
Hemorrhage-induced hypoxia/ischemia
Hormones released from injured tissue

Downloaded by [University of Alberta], [Ibolja Cernak] at 09:21 05 March 2015

Tertiary blast mechanisms
(i.e., effect of the impacts
with other objects)

Site of impact
“coup”

Injury to the brain
opposite the site
of impact
“contrecoup”

Secondary blast mechanisms
(i.e., effect of the missiles
being propelled by
blast force)

Primary blast mechanisms
(i.e., effects of the blast wave itself )

Tertiary blast-induced neurotrauma
(coup-contrecoup)

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. 30:255–66. 2010. With permission.)

accelerates elements of the medium from their resting state
with a speed that depends on the density of the medium; this
leads to the medium's rapid physical movement, displacement,
deformation, or rupture (Clemedson and Pettersson, 1956).
As a result, the main physical mechanisms of the blast-body
interaction and subsequent tissue damage include spalling,
implosion, and inertia (Benzinger, 1950). Spallation occurs at
the boundary between two media of different densities when
a compression wave in the denser medium is reflected at the
interface. Implosion happens in a liquid medium containing
a dissolved gas. Because the shock wave penetrates such a
medium, it compresses the gas bubbles, raising the pressure in
the bubbles much higher than the initial shock pressure; after
the pressure wave passes, the bubbles can rebound explosively
and damage surrounding tissue. Inertial effects also occur at
the interface of the different densities; the lighter object will
be accelerated more than the heavier one, creating a large
stress at the boundary (Sanborn et al., 2012)
Recent results suggest a frequency dependence of the
primary blast effects. High-frequency (0.5–1.5 kHz) lowamplitude stress waves have been observed to 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). On the
other hand, low-frequency (<0.5 kHz), high-amplitude shear
waves show a tendency to disrupt a tissue by generating local

motions that overcome natural tissue elasticity (for example,
at the contact of gray and white brain matter) (Cooper et al.,
1991; Gorbunov et al., 2004).

45.3 MODIFYING POTENTIAL OF SYSTEMIC
CHANGES CAUSED BY BLAST
Because of the complexity of the injurious environment (i.e.,
multiple blast effects that may interact with the body in parallel), blast injuries involve interwoven mechanisms of systemic, local, and cerebral responses to blast exposure (Cernak
et al., 1991, 1996b) (Figure 45.3). Even when the multiorgan
responses are mild, systemic changes significantly extend the
original organ damage and influence their severity and functional outcome. Air emboli, activation of the autonomous
nervous system, vascular mechanisms, and systemic inflammation are among the most important deleterious systemic
alterations that could modify the initial injuries due to blast.

45.3.1  Air Emboli
Air emboli develop as a consequence of the shock wave passing through the body and organs containing media of different
densities and constituent states, that is, gas–air, fluid–blood,
and solid–parenchyma (Clemedson and Hultman, 1954). Using

634

Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects

Blast

Local responce

Systemic response

Mechanical
tissue injury

Vascular
loading

Cerebral response

ANS
activation

Perforation
Stretching

Change in vascular tonus

Downloaded by [University of Alberta], [Ibolja Cernak] at 09:21 05 March 2015

Shearing
Hemorrhage

Cardio-respiratory
dysfunction

Synthesis/release
of autacoids

Alterations in blood cells
& generation and
migration of blood-born
immune cells

Initiation of
secondary injury
mechanisms

Activation of neuroendocrine-immune system

Hypoxia

SNS: Stress
response
Increased NE
and E synthesis
and release
PNS: Vago-vagal
reflexes
Bezold–Jarish
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, blood–brain 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.)

an ultrasonic Doppler blood-flow detector, Nevison, Mason,
and colleagues have clearly shown air emboli passing through
the carotid artery in dogs subjected to blast in a shock tube
(Mason et al., 1971; Nevison et al., 1971). Interestingly, the
dynamics of the air emboli release as recorded by the embolus
detector showed a cyclic pattern, initially occurring over the
first 10 seconds and again about 2 and 12 minutes after the
blast. It is noteworthy that the air emboli release occurred parallel with a dramatic decrease in blood flow velocity and tissue
convulsion likely from hypoxia/anoxia. Similar experimental findings have been described by others (Chu et al., 2005;
Clemedson and Hultman, 1954; Kirkman and Watts, 2011) and
supported by clinical studies (Freund et al., 1980; Tsokos et al.,
2003a, 2003b). Indeed, a massive compressed-air embolism
of the aorta and multiple air spaces in the interstitium, compressing the collecting tubules in the kidneys (Freund et al.,
1980) and venous air embolism in the lungs (Tsokos et al.,
2003a), have been reported in victims of severe blast injury. It
is expected that the rate of the air emboli release is dependent
on the intensity of blast, and the subsequent changes in blood
flow and oxygenation level are also graded.

45.3.2 Activation of the Autonomous
Nervous System
When the incident overpressure wave is transmitted through
the body, it increases the pressure inside organs (Clemedson

and Pettersson, 1956). The subsequent sudden hyperinflation
of the lungs (Cernak et al., 1996b; Zuckerman, 1940) stimulates the juxtacapillary J receptors located in the alveolar
interstitium and innervated by vagal fibers (Paintal, 1969).
The resulting vagovagal reflex leads to apnea followed by
tachypnea, bradycardia, and hypotension (i.e., symptoms
frequently observed immediately after blast exposure).
Moreover, hypoxia/ischemia due to damaged alveoli, air
emboli, or triggered pulmonary vagal reflex can activate a
cardiovascular decompressor Bezold–Jarish reflex, which
markedly increases vagal (parasympathetic) efferent discharge to the heart (Zucker, 1986). This reflex slows the heart
rate and dilates the peripheral blood vessels that precipitates a drop in blood pressure and could potentiate cerebral
hypoxia (Cernak et al., 1996a, 1996b). Indeed, Axelsson and
colleagues in their experimental study using pigs showed that
the blast-induced short-lasting apnea correlated to diminished electrical activity of the brain (Axelsson et al., 2000).
A substantial number of experimental studies further demonstrated the importance of vagally mediated cerebral effects
of blast (Cernak et al., 1996b; Irwin et al., 1999; Ohnishi
et al., 2001).
The explosive environment is a dramatic one, and may initiate endocrine mechanisms known as the classical “flightor-fight” stress response (Selye, 1976). This is demonstrated
in a recent experimental study (Tumer et al., 2013) showing
increased expression of the catecholamine-biosynthesizing

635

Blast Injuries and Blast-Induced Neurotrauma

enzymes, tyrosine hydroxylase and dopamine hydroxylase,
in the rat adrenal medulla, along with elevated plasma levels
of norepinephrine at 6 hours after blast injury. Thus, accumulating experimental and clinical evidence suggests the following sequence of blast-induced alterations in autonomous
nervous system activity: instantaneous triggering of parasympathetic reflexes followed by neuroendocrine changes
from sympathetic nervous system activation.

(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 Bezold–Jarish
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 α 1- and α 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 et al.,
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 10–14 days postexposure.
It is noteworthy that although cerebral vasospasm is usually prompted by subarachnoid hemorrhage, subarachnoid

Downloaded by [University of Alberta], [Ibolja Cernak] at 09:21 05 March 2015

45.3.3 Vascular 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.)

Downloaded by [University of Alberta], [Ibolja Cernak] at 09:21 05 March 2015

636

Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects

hemorrhage is not required for vasospasm in blast-induced
TBI (Magnuson et  al., 2012). A recent experimental study
using theoretical and in vitro models demonstrated that a single rapid mechanical insult is capable of inducing vascular
hypercontractility and remodeling, indicative of vasospasm
initiation. Furthermore, the results implied that the prolonged hypercontraction is linked to switching of the vascular smooth muscle phenotype in tissues exposed to simulated
blast (Alford et al., 2011). These findings suggest a hypothetical scenario that when the shock wave passes through the
vasculature, it interacts with cellular elements of vascular
wall such as endothelium and vascular smooth muscle. As
a consequence of this interaction, various mediators and
modulators are released, which cause hypercontraction and
subsequent genetic switch that potentiates vascular remodeling and cerebral vasospasm (Hald and Alford, 2013).

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.

45.3.4 Systemic 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.

45.4 REQUIREMENTS FOR BLAST-INDUCED
INJURY MODELS
Regardless of the research questions to be addressed, clinically and militarily relevant blast injury models should
satisfy all of the following four criteria: (1) the injurious

45.5  CHOICE OF MODELS
The purpose of experimental models of CNS damage such
as TBI is to replicate certain pathological components or
phases of clinical trauma in experimental animals, aiming
to address pathology and/or treatment. The goal of research
specifies the design and choice of the experimental model
(Cernak, 2005; Risling and Davidsson, 2012). The extremely
complex nature of blast injuries requires full understanding
of blast physics, and a model reproducing multiple aspects
of blast injuries should be defined with particular scientific
fidelity to conditions observed in theater. Otherwise, a model
will lack military and clinical relevance and the obtained
results might be dangerously misleading. Because of the
widely varying experimental conditions the currently existing models use, the results across studies are very difficult to
compare or summarize (Panzer et al., 2012).
There are several decision-making steps in the process
of choosing a model for blast research (Figure 45.5). Most
importantly, the researcher should identify which of the blast
effects should be reproduced. If the choice is primary blast,
the experimenter should ensure the animals are restrained so
that there will be no blast-induced acceleration of the body/
head during the exposure. Namely, in a situation where the
body/head is allowed to move, the injury mechanisms would
involve both primary and tertiary blast effects; this would
make the interpretation of the results difficult. Next, a decision should be made about the biological complexity of the
research study. This factor will dictate the choice of the biological surrogate used to reproduce blast-induced pathologies seen in humans (e.g., cell culture, tissue, small or large
experimental animals, nonhuman primates); positioning of
the biological surrogates; means of generating a shock wave
(open field, shock or blast tubes); and length of the experiment, among others. Thus, based on the research question
and the scale of complexity, a choice is made between nonbiological models and biological models.
Nonbiological models such as in silico and surrogate physical models provide an experimental platform for analyzing

637

Blast Injuries and Blast-Induced Neurotrauma

Choice of the experimental subject
Nonbiological models

Downloaded by [University of Alberta], [Ibolja Cernak] at 09:21 05 March 2015

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.)

interactions between blast loading and different types of
materials; the obtained information then is extrapolated to
biological materials at different levels of scaling. The biofidelic computer (i.e., in silico) models provide spatially and
temporally resolved descriptions of stress, strain, and acceleration that blast generates; as such, they are helpful tools in
characterizing the physics of the blast-induced mechanical
changes in the brain tissue (Chafi et al., 2010; Nyein et al.,
2010; Zhu et al., 2010). The physical surrogate models use
a human surrogate torso or head, which are made from synthetic materials (such as glass/epoxy or polyurethane) with
biofidelic properties and incorporate multiple displacement
and pressure sensors molded into the organs’ material to
record the biomechanical parameters such as linear/angular
acceleration, velocity, displacement, force, torque, and pressure (Desmoulin and Dionne, 2009; Ganpule et al., 2012;
Roberts et al., 2012).
The nonbiological models can be valuable in identifying
blast-induced biomechanical alterations and suggest potential consequences in biological systems. Nevertheless, they
are unable to give explanations for functional and physiological changes in a living system caused by blast exposure. Hence the need for biological (in vitro, ex vivo, and
in vivo) models, which use biological systems of differing
complexity. The in vitro models use cell cultures and can
be helpful in characterizing the cell-response mechanisms
to blast loading in a highly controlled experimental environment (Effgen et al., 2012; Panzer et al., 2012). The ex
vivo models use an organ or a segment of a specific tissue
such as brain or spinal cord, taken outside the organism into
an artificial environment, which is more controlled than is

possible with in vivo experiments. As for all blast injury
models, applying operationally relevant loading histories is
critical for the in vitro and ex vivo models. Namely, mechanisms of the energy transfer to the tissue and the resultant
biological response can be reliably analyzed only when
blast-loading conditions are realistic and would happen at
the cellular or tissue level of an individual who had been
exposed to and survived a militarily relevant blast environment (Effgen et al., 2012).
The success of a research study using biological models,
especially at the whole-animal level, depends on rigorous
selection of animal species used as experimental models.
Rodents are the most frequently used experimental animals
in trauma research. The relatively small size and low cost
of rodents permit repetitive measurements of morphological, biochemical, cellular, and behavioral parameters that
require relatively large numbers of animals; this, because of
ethical, technical, and/or financial limitations, is less achievable in phylogenetically higher species (Cernak, 2005).
Nevertheless, the anatomical and physiological differences
between humans and rodents, especially in circulatory and
nervous systems, limit the utilization of small experimental
animals in blast-injury research.
Extensive studies conducted in Albuquerque, New
Mexico, confirmed by German, Swedish, and British findings, demonstrated significant interspecies differences in
blast tolerance among 15 mammals (Bowen et al., 1967;
Richmond et al., 1967, 1968, 2005). The size-dependent
differences in blast tolerance have been explained by reference to variation of interspecies lung densities and volumes.
Namely, lung density in larger species, including man and

Downloaded by [University of Alberta], [Ibolja Cernak] at 09:21 05 March 2015

638

Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects

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 et al.,
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.

45.5.1  Experimental Environment Generating Blast
Experimental studies on primary blast-induced biological
responses are performed either in an open environment or laboratory conditions. The open field exposure studies use animals exposed to a blast wave that is generated by detonation

of an explosive (Axelsson et al., 2000; Bauman et al., 2009;
Lu et al., 2012; Richmond, 1991; Saljo and Hamberger, 2004;
Savic et al., 1991). 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.
Experiments performed in laboratory conditions use
either shock tubes (which use compressed air or gas to generate a shock wave) or blast tubes (which use explosive charges)
(Nishida, 2001; Robey, 2001). Both of these tubes focus the
blast wave energy in a linear direction from the source to
the subject, maximizing the amount of blast energy (Reneer
et al., 2011) without the exponential decay of the shock wave's
velocity and pressure seen in free-field explosions (Celander
et  al., 1955). The induction system routinely used in blast
exposure models consists of a cylindrical metal tube divided
by a plastic or metal diaphragm into two main, driver and
driven, sections. The anesthetized animals are fixed individually in special holders designed to prevent any movement of
their body in response to the blast. The high pressure in the
driver section is generated by either explosive charge or compressed gas, which ruptures the diaphragm when reaching the
material's tolerance to pressure. After the diaphragm ruptures,
the resultant shock wave travels along the driven section with
supersonic velocity, and interacts with the animal positioned
inside the driven section. The duration of the overpressure
can be varied by changing the length and/or diameter of the
high-pressure chamber (Celander et al., 1955).
In the case of shock tubes, either compressed atmospheric
air or another gas is used. The compressed air fails to expand
as quickly as would an ideal gas when the membrane is
ruptured and also generates a broad range of overpressure
peaks. Use of a lighter gas, such as helium, improves the performance of shock tubes because of the increased speed of
sound within a helium environment (Celander et al., 1955).
Although shock/blast tubes are convenient means of generating shock waves, they lack the ability to generate the acoustic, thermal, optical, and electromagnetic components found
in actual blast environments (Ling et al., 2009). Moreover,
although the positive phase of free-field explosive blast can
be reproduced by careful adjustment of the driver's length,
driver's gas, and the specimen location, the negative phase
and recompression shock are often artifacts of the rarefaction from the open end of the tube; thus, the simulated blast
wave is incorrect when compared with the signature of the
militarily relevant blast (Ritzel et al., 2012). Because of this,
it is recommended that shock tubes be fitted with a reflectioneliminator at their end to eliminate the waves reverberating
the length of the tube.
In the case of blast tubes, combustion of an explosive generates high pressures and volumes in the driver section without
a diaphragm. Blast tubes use high-energy explosives placed
within a heavy-walled, small-diameter driver section (often
a gun barrel), expanding into the wider diameter driven (i.e.,
test) section (Ritzel et al., 2012). The cons for using a blast
tube include (1) dispersion of the combustion products and

Downloaded by [University of Alberta], [Ibolja Cernak] at 09:21 05 March 2015

Blast Injuries and Blast-Induced Neurotrauma

residue in the test section; (2) generation of strong transverse
waves either within the driver or in the wider test section,
caused by the charge and charge and driver configuration;
and (3) introduction of additional operating costs and more
complex environmental control for safe handling, setting,
and firing of the charges.
A wide range of blast overpressure sustained for various
durations has been used in single-exposure experimental
studies. In most studies, the animals are 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., 2001b; Chavko et al., 2007; Clemedson et al.,
1969; Saljo et al., 2000). Most experiments have used rodents
(mice and rats) (Cernak et al., 2001a; Long et al., 2009), but
some have subjected rabbits (Cernak et al., 1997), sheep
(Savic et al., 1991), pigs (Bauman et al., 2009), or nonhuman
primates to blast (Bogo et al., 1971; Damon et al., 1968; Lu
et al., 2012; Richmond et al., 1967).
Special consideration should be given to positioning of the
specimen in the shock/blast tubes, and its orientation in relation to the incident shock wave. There is an ongoing debate
about whether the specimen should be positioned inside
or outside shock/blast tubes. Namely, the biomechanical
response of the animal significantly depends on the placement location in the tube (Sundaramurthy et al., 2012) as well
as on the orientation of the specimen as compared with the
propagating incident shock wave (Cernak et al., 2011; Varas
et al., 2011). The majority of the currently existing literature
supports the need of placing the specimen inside the shock/
blast tube (Sundaramurthy et al., 2012; Varas et  al., 2011).
Experimental studies have shown that when the animal is
positioned inside the shock tube, it is subjected to a load that
is due to the pure blast wave comparable to the shock wave
generated in free-field conditions (near-optimal, so-called
Friedlander-type shock wave). When the animal was positioned at the exit, there was a sharp decay in pressure after
the initial shock front, which was caused by the expansion
wave from the exit of the shock tube eliminating the exponentially decaying blast wave (Sundaramurthy et al., 2012).
This phenomenon led to significant decrease of the positive
blast impulse (Figure 45.4) and conversion of most of the
blast energy from supersonic blast wave to subsonic jet wind
(Haselbacher et al., 2007), which has effects that are significantly different from those generated by a blast wave. Namely,
because of the jet wind, the restrained animal experiences
more severe compression of the head and neck and the thoracic cavity is exposed to higher pressure of longer positivephase duration. The importance of animal's positioning in
relation to the shock tube (inside versus outside) was further
demonstrated by Svetlov and colleagues (Svetlov et al., 2010,
2012) who exposed the rats to blast loading by placing the
rats 50 mm outside the shock tube. Their results suggested
that the subsonic jet wind represented the bulk of the blast
impulse, and the injuries were caused by the combination of
blast wave and subsonic jet wind, as opposed to a pure blast
wave injury. Experiments with surrogate physical models
(dummy heads) placed at the exit of the shock tube supported

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

Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects

Taken together, when deciding which system to use to
generate blast conditions, the blast and shock wave physics
and the pros and cons of engineering solutions should be
carefully weighed, especially when considering ultrasound
or laser as a source for a shock wave (Takeuchi et al., 2013).
The basic tenets of physics should always be remembered:
that shock waves are single, mainly positive pressure pulses
that are followed by comparatively small tensile wave components and their effects are mainly from forward-directed
energy (i.e., in the direction of the shock wave propagation).

Downloaded by [University of Alberta], [Ibolja Cernak] at 09:21 05 March 2015

45.6  Blast-Induced Neurotrauma
Blast can interact with the brain by means of a (1) direct
interaction with the head via direct passage of the blast wave
through the skull (primary blast), causing acceleration and/
or rotation of the head (tertiary blast), or through impacting
particles accelerated by the energy released during explosion (secondary blast) (Goldstein et al., 2012; Mellor, 1988),
and (2) kinetic energy transfer of the primary blast wave to
organs and organ systems, including fluid medium (blood) in
large blood vessels in the abdomen and chest, and the CNS
(Cernak and Noble-Haeusslein, 2010; Cernak et al., 2001b).
Namely, during the interaction with the body surface, the
shock wave compresses the abdomen and chest and transfers
its kinetic energy to the body's internal structures, including
the blood as fluid medium. The resulting oscillating waves
traverse the body at about the speed of sound in water and
deliver the shock wave's energy to the brain. Clemedson,
based on his extensive experimental work on shock wave
propagation through the body (Clemedson and Jonsson,
1961), was among the first scientists to suggest the possibility
of shock wave transmission to the CNS (Clemedson, 1956).
These two potential avenues of interaction do not exclude
each other (Cernak and Noble-Haeusslein, 2010). Most recent
experimental data suggest both the importance of the blast's
direct interaction with the head (Moss et al., 2009) and the
role of shock wave–induced vascular load (Cernak, 2010) in
the pathogenesis of BINT.

45.6.1  Animal Models of BINT
The majority of currently used experimental models of
BINT use rodents exposed to a shock wave generated in
laboratory conditions using a compressed gas–driven
shock tube (Baalman et al., 2013; Cernak et al., 2011;
Goldstein et al., 2012; Kamnaksh et al., 2011; Pun et al.,
2011; Readnower et  al., 2010; Reneer et al., 2011; Svetlov
et al., 2012; Valiyaveettil et  al., 2012a; Vandevord et al.,
2012). Experiments with larger animals mainly involve pigs
(Ahmed et al., 2012; Bauman et  al., 2009) or nonhuman
primates (Bogo et al., 1971; Lu et al., 2012).
Accumulating evidence suggests that primary blast
causes significant behavioral impairments and cognitive
deficits in multiple animal models (Bogo et al., 1971; Cernak
et al., 2001a; Lu et al., 2012). These deficits show a dosedependence from primary blast intensity as well as related

to degenerative processes in the brain. The wide range of
molecular changes starts early with metabolic impairments,
including altered glucose metabolism shifting from aerobic toward anaerobic pathway measured as elevated lactate
concentration and increased lactate/pyruvate ration (Cernak
et al., 1996b), decline in energy reserve (Cernak et al., 1995,
1996b), and increased oxidative stress (Readnower et al.,
2010) in parallel with ultrastructural changes in brainstem
and hippocampus (Cernak et al., 2001b; Saljo et al., 2000),
and activation of early immediate genes (Saljo et al., 2002).
Later, the mechanisms include inflammation (Cernak et al.,
2011; Kaur et al., 1997, 1995; Kwon et al., 2011; Readnower
et al., 2010; Saljo et al., 2001), diffuse axonal injury (Garman
et al., 2011; Risling et al., 2011), and apoptotic and nonapoptotic cascades leading to neurodegeneration (Svetlov et al.,
2010; Vandevord et al., 2012; Wang et al., 2010). Emerging
evidence suggests that certain brain structures might have a
more pronounced sensitivity toward blast effects either from
anatomical features and localization or functional properties of neuronal pathways and/or cells (Koliatsos et al., 2004;
Valiyaveettil et al., 2012a, 2012b). Indeed, higher sensitivity
of the cerebellum/brainstem, the corticospinal system, and
the optic tract has been found (Koliatsos et al., 2011) based
on the extent of multifocal axonal and neuronal cell degeneration. Additionally, based on regional specific alterations
in the activity of acetylcholinesterase, the vulnerability of
the frontal cortex and medulla has been observed in mice
exposed to blast overpressure (Valiyaveettil et al., 2012a,
2012b). These changes showed a tendency toward chronicity.
The mechanisms involved in the pathobiology of BINT
show some similarities with blunt TBI, although with earlier onset of brain edema and later onset of cerebral vasospasm (Agoston et al., 2009). Using a pig model of blast
exposure, Ahmed and colleagues have shown that protein
biomarker levels in cerebrospinal fluid can provide insight
into the pathobiology of BINT (Ahmed et al., 2012). Their
findings implicated neuronal and glial cell damage, compromised vascular permeability, and inflammation induced
by blast. The early-phase biomarker included claudin-5, vascular endothelial growth factor, and von Willebrand factor,
whereas neurofilament-heavy chain, neuron-specific enolase,
vascular endothelial growth factor, and glial fibrillary acidic
protein levels remained significantly elevated compared to
baseline at 2 weeks postinjury.
Despite the progressively growing experimental data on
BINT, it is very difficult to compare the results and consolidate the findings into one comprehensive pool of knowledge.
Namely, because of the lack of well-defined criteria for reliable animal models of BINT, the current experimental models used in an attempt to study BINT vary widely, and include
classical direct impact TBI models such as controlled cortical
impact and fluid percussion injury models, air gun–type compressed air-delivered impact models, shock and blast tube
models, and open-field explosion experiments, among others.
Some experimental models expose only the head of the animal to an extremely focused overpressure field (Kuehn et al.,
2011; Prima et al., 2013) causing brain damage comparable

Downloaded by [University of Alberta], [Ibolja Cernak] at 09:21 05 March 2015

Blast Injuries and Blast-Induced Neurotrauma

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).

45.7 CONCLUSION
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.

REFERENCES
Agoston, D.V., A. Gyorgy, O. Eidelman, and H.B. Pollard. 2009.
Proteomic biomarkers for blast neurotrauma: targeting cerebral edema, inflammation, and neuronal death cascades.
J Neurotrauma. 26:901–11.
Ahlers, S.T., E. Vasserman-Stokes, M.C. Shaughness, A.A. Hall,
D.A. Shear, M. Chavko et al. 2012. Assessment of the
effects of acute and repeated exposure to blast overpressure
in rodents: toward a greater understanding of blast and the
potential ramifications for injury in humans exposed to blast.
Front Neurol. 3:32.
Ahmed, F., A. Gyorgy, A. Kamnaksh, G. Ling, L. Tong, S. Parks
et al. 2012. Time-dependent changes of protein biomarker levels in the cerebrospinal fluid after blast traumatic brain injury.
Electrophoresis. 33:3705–11.

641
Alford, P.W., B.E. Dabiri, J.A. Goss, M.A. Hemphill, M.D.
Brigham, and K.K. Parker. 2011. Blast-induced phenotypic
switching in cerebral vasospasm. Proc Natl Acad Sci U S A.
108:12705–10.
Armonda, R.A., R.S. Bell, A.H. Vo, G. Ling, T.J. DeGraba, B.
Crandall et al. 2006. Wartime traumatic cerebral vasospasm:
recent review of combat casualties. Neurosurgery. 59:1215–25;
discussion 1225.
Axelsson, H., H. Hjelmqvist, A. Medin, J.K. Persson, and A.
Suneson. 2000. Physiological changes in pigs exposed to a
blast wave from a detonating high-explosive charge. Mil Med.
165:119–26.
Baalman, K.L., R.J. Cotton, S.N. Rasband, and M.N. Rasband.
2013. Blast wave exposure impairs memory and decreases
axon initial segment length. J Neurotrauma. 30:741–51.
Bass, C.R., M.B. Panzer, K.A. Rafaels, G. Wood, J. Shridharani,
and B. Capehart. 2012. Brain injuries from blast. Ann Biomed
Eng. 40:185–202.
Bass, C.R., K.A. Rafaels, and R.S. Salzar. 2008. Pulmonary
injury risk assessment for short-duration blasts. J Trauma.
65:604–15.
Bauman, R.A., G. Ling, L. Tong, A. Januszkiewicz, D. Agoston,
N. Delanerolle et al. 2009. An introductory characterization
of a combat-casualty-care relevant swine model of closed
head injury resulting from exposure to explosive blast. J
Neurotrauma. 26:841–60.
Baxter, D., D.J. Sharp, C. Feeney, D. Papadopoulou, T.E. Ham, S.
Jilka et al. 2013. Pituitary dysfunction after blast traumatic
brain injury: the UK BIOSAP study. Ann Neurol. 74:527–36.
Ben-Dor, C., O. Igra, and T. Elperin. 2001. Handbook of Shock
Waves. Academic Press, San Diego, CA.
Benzinger, T. 1950. Physiological effects of blast in air and water. In
German Aviation Medicine, World War II. Vol. 2. Department
of the Air Force, Washington, DC. pp. 1225–1229.
Besedovsky, H.O., and A. del Rey. 2002. Introduction: immuneneuroendocrine network. Front Horm Res. 29:1–14.
Besedovsky, H.O., and A. del Rey. 1996. Immune-neuroendocrine interactions: facts and hypotheses. Endocr Rev.
17:64–102.
Bogo, V., R.A. Hutton, and A. Bruner. 1971. The effects of airblast on discriminated avoidance behavior in rhesus monkeys. In Technical Progress Report on Contract No.
DA-49-146-XZ-372. Vol. DASA 2659. Defense Nuclear
Agency, Washington DC. pp. 1–32.
Bowen, I.G., E.R. Fletcher, D.R. Richmond, F.G. Hirsch, and C.S.
White. 1967. Biophysical mechanisms and scaling procedures
applicable in assessing responses of the thorax energized
by air-blast overpressures or by non-penetrating missiles.
Technical Progress Report DASA 1857. Fission Prod Inhal
Proj. 1–46.
Brauer, R.W., W.M. Mansfield, Jr., R.W. Beaver, and H.W. Gillen.
1979. Stages in development of high-pressure neurological
syndrome in the mouse. J Appl Physiol Respir Environ Exerc
Physiol. 46:756–65.
Casals, J.B., N.C. Pieri, M.L. Feitosa, A.C. Ercolin, K.C. Roballo,
R.S. Barreto et al. 2011. The use of animal models for stroke
research: a review. Comp Med. 61:305–13.
Celander, H., C.J. Clemedson, U.A. Ericsson, and H.I. Hultman.
1955. A study on the relation between the duration of a shock
wave and the severity of the blast injury produced by it. Acta
Physiol Scand. 33:14–8.
Cernak, I. 2005. Animal models of head trauma. NeuroRx. 2:410–22.
Cernak, I. 2010. The importance of systemic response in the pathobiology of blast-induced neurotrauma. Front Neurol. 1(151):1–9.

Downloaded by [University of Alberta], [Ibolja Cernak] at 09:21 05 March 2015

642

Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects

Cernak, I., D. Ignjatovic, G. Andelic, and J. Savic. 1991. [Metabolic
changes as part of the general response of the body to the
effect of blast waves]. Vojnosanit Pregl. 48:515–22.
Cernak, I., Z. Malicevic, V. Prokic, G. Zunic, D. Djurdjevic, S. Ilic,
and J. Savic. 1997. Indirect neurotrauma caused by pulmonary blast injury: Development and prognosis. Int Rev. Armed
Forces Med Serv. 52:114–120.
Cernak, I., A.C. Merkle, V.E. Koliatsos, J.M. Bilik, Q.T. Luong,
T.M. Mahota, L. Xu, N. Slack, D. Windle, and F.A. Ahmed.
2011. The pathobiology of blast injuries and blast-induced
neurotrauma as identified using a new experimental model of
injury in mice. Neurobiol Dis. 41:538–51.
Cernak, I., and L.J. Noble-Haeusslein. 2010. Traumatic brain injury:
an overview of pathobiology with emphasis on military populations. J Cereb Blood Flow Metab. 30:255–66.
Cernak, I., P. Radosevic, Z. Malicevic, and J. Savic. 1995.
Experimental magnesium depletion in adult rabbits caused by
blast overpressure. Magnes Res. 8:249–59.
Cernak, I., J. Savic, D. Ignjatovic, and M. Jevtic. 1999a. Blast injury from
explosive munitions. J Trauma. 47:96–103; discussion 103–4.
Cernak, I., J. Savic, Z. Malicevic, G. Zunic, D. Djurdjevic, and V.
Prokic. 1996a. The pathogenesis of pulmonary blast injury:
our point of view. Chin J Traumatol. 12:28–31.
Cernak, I., J. Savic, Z. Malicevic, G. Zunic, P. Radosevic, I. Ivanovic
et al. 1996b. Involvement of the central nervous system in
the general response to pulmonary blast injury. J Trauma.
40:S100–4.
Cernak, I., J. Savic, G. Zunic, N. Pejnovic, O. Jovanikic, and V.
Stepic. 1999b. Recognizing, scoring, and predicting blast
injuries. World J Surg. 23:44–53.
Cernak, I., V.J. Savic, A. Lazarov, M. Joksimovic, and S. Markovic.
1999c. Neuroendocrine responses following graded traumatic
brain injury in male adults. Brain Inj. 13:1005–15.
Cernak, I., Z. Wang, J. Jiang, X. Bian, and J. Savic. 2001a. Cognitive
deficits following blast injury-induced neurotrauma: possible
involvement of nitric oxide. Brain Inj. 15:593–612.
Cernak, I., Z. Wang, J. Jiang, X. Bian, and J. Savic. 2001b.
Ultrastructural and functional characteristics of blast injuryinduced neurotrauma. J Trauma. 50:695–706.
Chafi, M.S., G. Karami, and M. Ziejewski. 2010. Biomechanical
assessment of brain dynamic responses due to blast pressure
waves. Ann Biomed Eng. 38:490–504.
Champion, H.R., J.B. Holcomb, and L.A. Young. 2009. Injuries
from explosions: physics, biophysics, pathology, and required
research focus. J Trauma. 66:1468–77; discussion 1477.
Chavko, M., W.A. Koller, W.K. Prusaczyk, and R.M. McCarron.
2007. Measurement of blast wave by a miniature fiber optic
pressure transducer in the rat brain. J Neurosci Methods.
159:277–81.
Chavko, M., T. Watanabe, S. Adeeb, J. Lankasky, S.T. Ahlers, and
R.M. McCarron. 2011. Relationship between orientation to
a blast and pressure wave propagation inside the rat brain. J
Neurosci Methods. 195:61–6.
Chen, Y., and S. Constantini. 2013. Caveats for using shock tube in blastinduced traumatic brain injury research. Front Neurol. 4:117.
Chrousos, G.P. 1995. The hypothalamic-pituitary-adrenal axis and
immune-mediated inflammation. N Engl J Med. 332:1351–62.
Chu, S.J., T.Y. Lee, H.C. Yan, S.H. Lin, and M.H. Li. 2005.
L-Arginine prevents air embolism-induced acute lung injury
in rats. Crit Care Med. 33:2056–60.
Clemedson, C.J. 1956. Shock wave transmission to the central nervous system. Acta Physiol Scand. 37:204–14.
Clemedson, C.J., and C.O. Criborn. 1955. Mechanical response of
different parts of a living body to a high explosive shock wave
impact. Am J Physiol. 181:471–6.

Clemedson, C.J., L. Frankenberg, A. Jonsson, H. Pettersson, and
A.B. Sundqvist. 1969. Dynamic response of thorax and abdomen of rabbits in partial and whole-body blast exposure. Am
J Physiol. 216:615–20.
Clemedson, C.J., and S.A. Granstom. 1950. Studies on the genesis
of "rib markings" in lung blast injury. Acta Physiol Scand.
21:131–44.
Clemedson, C.J., and H.I. Hultman. 1954. Air embolism and the
cause of death in blast injury. Mil Surg. 114:424–37.
Clemedson, C.J., and A. Jonsson. 1961. Transmission of elastic disturbances caused by air shock waves in a living body. J Appl
Physiol. 16:426–30.
Clemedson, C.J., A. Jonsson, and H. Pettersson. 1956. Propagation
of an air-transmitted shock wave in muscular tissue. Nature.
177:380–1.
Clemedson, C.J., and H. Pettersson. 1956. Propagation of a high
explosive air shock wave through different parts of an animal
body. Am J Physiol. 184:119–26.
Cooper, G.J., D.J. Townend, S.R. Cater, and B.P. Pearce. 1991. The
role of stress waves in thoracic visceral injury from blast loading: modification of stress transmission by foams and highdensity materials. J Biomech. 24:273–85.
Dal Cengio Leonardi, A., N.J. Keane, C.A. Bir, A.G. Ryan, L. Xu,
and P.J. Vandevord. 2012. Head orientation affects the intracranial pressure response resulting from shock wave loading
in the rat. J Biomech. 45:2595–602.
Damon, E.G., C.S. Gaylord, J.T. Yelverton, D.R. Richmond, I.G.
Bowen, R.K. Jones et al. 1968. Effects of ambient pressure on tolerance of mammals to air blast. Aerosp Med.
39:1039–47.
Desmoulin, G.T., and J.P. Dionne. 2009. Blast-induced neurotrauma:
surrogate use, loading mechanisms, and cellular responses.
J Trauma. 67:1113–22.
Effgen, G.B., C.D. Hue, E. Vogel, 3rd, M.B. Panzer, D.F. Meaney,
C.R. Bass et al. 2012. A multiscale approach to blast neurotrauma modeling: part II: methodology for inducing blast
injury to in vitro models. Front Neurol. 3:23.
Freund, U., J. Kopolovic, and A.L. Durst. 1980. Compressed air
emboli of the aorta and renal artery in blast injury. Injury.
12:37–8.
Friedlander, F.G. 1955. Propagation of a Pulse in an Inhomogeneous
Medium. Ulan Press.
Ganpule, S., A. Alai, E. Plougonven, and N. Chandra. 2012.
Mechanics of blast loading on the head models in the study of
traumatic brain injury using experimental and computational
approaches. Biomech Model Mechanobiol
Garman, R.H., L.W. Jenkins, R.C. Switzer, 3rd, R.A. Bauman, L.C.
Tong, P.V. Swauger et al. 2011. Blast exposure in rats with
body shielding is characterized primarily by diffuse axonal
injury. J Neurotrauma. 28:947–59.
Gelman, S. 2008. Venous function and central venous pressure:
a physiologic story. Anesthesiology. 108:735–48.
Goldstein, L.E., A.M. Fisher, C.A. Tagge, X.L. Zhang, L. Velisek,
J.A. Sullivan et al. 2012. Chronic traumatic encephalopathy
in blast-exposed military veterans and a blast neurotrauma
mouse model. Sci Transl Med. 4:134ra60.
Gorbunov, N.V., S.J. McFaul, S. Van Albert, C. Morrissette,
G.M. Zaucha, and J. Nath. 2004. 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.
32:1028–34.
Hald, E.S., and P.W. Alford. 2013. Smooth muscle phenotype
switching in blast traumatic brain injury-induced cerebral
vasospasm. Transl Stroke Res. 5:385–93.

Downloaded by [University of Alberta], [Ibolja Cernak] at 09:21 05 March 2015

Blast Injuries and Blast-Induced Neurotrauma
Haselbacher, A., S. Balachandar, and S.W. Kieffer. 2007. Openended shock tube flows: Influence of pressure ration and diaphragm position. AIAAA J. 45:1917–1929.
Holzer, A., M.F. Pietschmann, C. Rosl, M. Hentschel, O. Betz, M.
Matsuura et al. 2012. The interrelation of trabecular microstructural parameters of the greater tubercle measured for different species. J Orthop Res. 30:429–34.
Irwin, R.J., M.R. Lerner, J.F. Bealer, P.C. Mantor, D.J. Brackett, and
D.W. Tuggle. 1999. Shock after blast wave injury is caused by
a vagally mediated reflex. J Trauma. 47:105–10.
Kamnaksh, A., E. Kovesdi, S.K. Kwon, D. Wingo, F. Ahmed, N.E.
Grunberg et al. 2011. Factors affecting blast traumatic brain
injury. J Neurotrauma. 28:2145–53.
Kaur, C., J. Singh, M.K. Lim, B.L. Ng, and E.A. Ling. 1997.
Macrophages/microglia as 'sensors' of injury in the pineal
gland of rats following a non-penetrative blast. Neurosci Res.
27:317–22.
Kaur, C., J. Singh, M.K. Lim, B.L. Ng, E.P. Yap, and E.A. Ling.
1995. The response of neurons and microglia to blast injury in
the rat brain. Neuropathol Appl Neurobiol. 21:369–77.
Khan, M.M., and K.L. Melmon. 1985. Are autacoids more than theoretic modulators of immunity? Clin Immunol Rev. 4:1–30.
Kirkman, E., and S. Watts. 2011. Characterization of the response
to primary blast injury. Philos Trans R Soc Lond B Biol Sci.
366:286–90.
Kluger, Y., A. Nimrod, P. Biderman, A. Mayo, and P. Sorkin. 2007.
The quinary pattern of blast injury. Am J Disaster Med.
2:21–5.
Koliatsos, V.E., I. Cernak, L. Xu, Y. Song, A. Savonenko, B.J. Crain
et al. 2011. A mouse model of blast injury to brain: initial
pathological, neuropathological, and behavioral characterization. J Neuropathol Exp Neurol. 70:399–416.
Koliatsos, V.E., T.M. Dawson, A. Kecojevic, Y. Zhou, Y.F. Wang,
and K.X. Huang. 2004. Cortical interneurons become activated by deafferentation and instruct the apoptosis of pyramidal neurons. Proc Natl Acad Sci U S A. 101:14264–9. Epub
2004 Sep 20.
Kuehn, R., P.F. Simard, I. Driscoll, K. Keledjian, S. Ivanova, C.
Tosun et al. 2011. Rodent model of direct cranial blast injury.
J Neurotrauma. 28:2155–69.
Kwon, S.-K.C., E. Kovesdi, A.B. Gyorgy, D. Wingo, A. Kamnaksh,
J. Walker, J.B. Long, and D.V. Agoston. 2011. Stress and traumatic brain injury; a behavioral, proteomics and histological
study. Front Neurol. 2.
Ling, G., F. Bandak, R. Armonda, G. Grant, and J. Ecklund. 2009.
Explosive blast neurotrauma. J Neurotrauma. 26:815–25.
Long, J.B., T.L. Bentley, K.A. Wessner, C. Cerone, S. Sweeney,
and R.A. Bauman. 2009. Blast overpressure in rats: recreating a battlefield injury in the laboratory. J Neurotrauma.
26:827–40.
Lu, J., K.C. Ng, G. Ling, J. Wu, D.J. Poon, E.M. Kan et al. 2012.
Effect of blast exposure on the brain structure and cognition in
Macaca fascicularis. J Neurotrauma. 29:1434–54.
Magnuson, J., F. Leonessa, and G.S. Ling. 2012. Neuropathology of
explosive blast traumatic brain injury. Curr Neurol Neurosci
Rep. 12:570–9.
Mainiero, R., and M. Sapko. 1996. Blast and fire propagation in
underground facilities, from http://www.dtic.mil/get-tr-doc/
pdf?AD=ADA314855, Defense Nuclear Agency, Alexandria,
VA.
Mason, W., T.G. Damon, A.R. Dickinson, and T.O. Nevison, Jr.
1971. Arterial gas emboli after blast injury. Proc Soc Exp Biol
Med. 136:1253–5.
Mellor, S.G. 1988. The pathogenesis of blast injury and its management. Br J Hosp Med. 39:536–9.

643
Melmon, K.L., R.E. Rocklin, and R.P. Rosenkranz. 1981. Autacoids
as modulators of the inflammatory and immune response. Am
J Med. 71:100–6.
Moss, W.C., M.J. King, and E.G. Blackman. 2009. Skull flexure
from blast waves: a mechanism for brain injury with implications for helmet design. Phys Rev Lett. 103:108702.
Nevison, T.O., W.V. Mason, and A.R. Dickinson. 1971.
Measurement of blood velocity and detection of emboli by
ultrasonic Doppler technique. In 11th Annual Symposium on
Experimental Mechanics. University of New Mexico Press,
Albuquerque, NM. Pp. 63–68.
Ngo, T., P. Mendis, A. Gupta, J. Ramsay. 2007. Blast loading and
blast effects on structures—An overview. EJSE Special Issue:
Loading on Structures, 76–91.
Nishida, M. 2001. Shock tubes and tunnels: facilities, instrumentation, and techniques. Shock tubes. In C. Ben-Dor, O. Igra, and
T. Elperin, eds. Handbook of Shock Waves. Vol. 1. Academic
Press, San Diego, CA. pp. 553–585.
Nyein, M.K., A.M. Jason, L. Yu, C.M. Pita, J.D. Joannopoulos, D.F.
Moore et al. 2010. In silico investigation of intracranial blast
mitigation with relevance to military traumatic brain injury.
Proc Natl Acad Sci U S A. 107:20703–8.
Ohnishi, M., E. Kirkman, R.J. Guy, and P.E. Watkins. 2001. Reflex
nature of the cardiorespiratory response to primary thoracic
blast injury in the anaesthetised rat. Exp Physiol. 86:357–64.
Paintal, A.S. 1969. Mechanism of stimulation of type J pulmonary
receptors. J Physiol. 203:511–32.
Pang, C.C. 2001. Autonomic control of the venous system in
health and disease: effects of drugs. Pharmacol Ther.
90:179–230.
Panzer, M.B., K.A. Matthews, A.W. Yu, B. Morrison, 3rd, D.F.
Meaney, and C.R. Bass. 2012. A multiscale approach to
blast neurotrauma modeling: part I - development of novel
test devices for in vivo and in vitro blast injury models. Front
Neurol. 3:46.
Pietschmann, M.F., A. Holzer, C. Rosl, A. Scharpf, T. Niethammer,
V. Jansson, and P.E. Muller. 2010. What humeri are suitable
for comparative testing of suture anchors? An ultrastructural
bone analysis and biomechanical study of ovine, bovine and
human humeri and four different anchor types. J Biomech.
43:1125–30.
Prima, V., V.L. Serebruany, A. Svetlov, R.L. Hayes, and S.I. Svetlov.
2013. Impact of moderate blast exposures on thrombin biomarkers assessed by calibrated automated thrombography in
rats. J Neurotrauma. 30:1881–7.
Pun, P.B., E.M. Kan, A. Salim, Z. Li, K.C. Ng, S.M. Moochhala
et  al. 2011. Low level primary blast injury in rodent brain.
Front Neurol. 2:19.
Readnower, R.D., M. Chavko, S. Adeeb, M.D. Conroy, J.R. Pauly,
R.M. McCarron et al. 2010. Increase in blood-brain barrier
permeability, oxidative stress, and activated microglia in a rat
model of blast-induced traumatic brain injury. J Neurosci Res.
88:3530–9.
Reneer, D.V., R.D. Hisel, J.M. Hoffman, R.J. Kryscio, B.T. Lusk,
and J.W. Geddes. 2011. A multi-mode shock tube for investigation of blast-induced traumatic brain injury. J Neurotrauma.
28:95–104.
Rice, D., and J. Heck. 2000. Terrorist bombings: ballistics, patterns
of blast injury and tactical emergency care. Tactical Edge J.
Summer:53–55.
Richmond, D.R. 1991. Blast criteria for open spaces and enclosures.
Scand Audiol Suppl. 34:49–76.
Richmond, D.R., I.G. Bowen, and C.S. White. 1961. Tertiary blast
effects. Effects of impact on mice, rats, guinea pigs and rabbits. Aerosp Med. 32:789–805.

Downloaded by [University of Alberta], [Ibolja Cernak] at 09:21 05 March 2015

644

Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects

Richmond, D.R., E.G. Damon, I.G. Bowen, E.R. Fletcher, and C.S.
White. 1967. Air-blast studies with eight species of mammals.
Techn Progr Rep DASA 1854. Fission Prod Inhal Proj:1–44.
Richmond, D.R., E.G. Damon, E.R. Fletcher, I.G. Bowen, and C.S.
White. 1968. The relationship between selected blast-wave
parameters and the response of mammals exposed to air blast.
Ann N Y Acad Sci. 152:103–21.
Risling, M., and J. Davidsson. 2012. Experimental animal models
for studies on the mechanisms of blast-induced neurotrauma.
Front Neurol. 3:30.
Risling, M., S. Plantman, M. Angeria, E. Rostami, B.M. Bellander,
M. Kirkegaard et al. 2011. Mechanisms of blast induced brain
injuries, experimental studies in rats. Neuroimage. 54 Suppl
1:S89–97.
Ritzel, D.V., S.A. Parks, J. Roseveare, G. Rude, and T.W. Sawyer.
2012. Experimental blast simulation for injury studies. RTOMP-HFM-207, Halifax, Canada. 1–20.
Roberts, J.C., T.P. Harrigan, E.E. Ward, T.M. Taylor, M.S. Annett,
and A.C. Merkle. 2012. Human head-neck computational
model for assessing blast injury. J Biomech. 45:2899–906.
Robey, R. 2001. Shock tubes and tunnels: facilities, instrumentation, and techniques. Blast tubes. In C. Ben-Dor, O. Igra, and
T. Elperin, eds. Handbook of Shock Waves. Vol. 1. Academic
Press, San Diego, CA. pp. 623–650.
Rutlen, D.L., E.W. Supple, and W.J. Powell, Jr. 1979. The role of the
liver in the adrenergic regulation of blood flow from the splanchnic to the central circulation. Yale J Biol Med. 52:99–106.
Saljo, A., F. Bao, K.G. Haglid, and H.A. Hansson. 2000. Blast exposure causes redistribution of phosphorylated neurofilament
subunits in neurons of the adult rat brain. J Neurotrauma.
17:719–26.
Saljo, A., F. Bao, A. Hamberger, K.G. Haglid, and H.A. Hansson.
2001. Exposure to short-lasting impulse noise causes microglial and astroglial cell activation in the adult rat brain.
Pathophysiology. 8:105–111.
Saljo, A., F. Bao, J. Shi, A. Hamberger, H.A. Hansson, and K.G.
Haglid. 2002. Expression of c-Fos and c-Myc and deposition
of beta-APP in neurons in the adult rat brain as a result of exposure to short-lasting impulse noise. J Neurotrauma. 19:379–85.
Saljo, A., H. Bolouri, M. Mayorga, B. Svensson, and A. Hamberger.
2010. Low-level blast raises intracranial pressure and impairs
cognitive function in rats: prophylaxis with processed cereal
feed. J Neurotrauma. 27:383–9.
Saljo, A., and A. Hamberger. 2004. Intracranial sound pressure
levels during impulse noise exposure In 7th International
Neurotrauma Symposium. Vol. CD E912. Medimond,
Monduzzi Editore, Adelaide, Australia.
Sanborn, B., X. Nie, W. Chen, and T. Weerasooriya. 2012. Inertia
effects on characterization of dynamic response of brain tissue. J Biomech. 45:434–9.
Savic, J., V. Tatic, D. Ignjatovic, V. Mrda, D. Erdeljan, I. Cernak
et  al. 1991. [Pathophysiologic reactions in sheep to blast
waves from detonation of aerosol explosives]. Vojnosanit
Pregl. 48:499–506.
Selye, H. 1976. Forty years of stress research: principal remaining
problems and misconceptions. Can Med Assoc J. 115:53–6.
Sundaramurthy, A., A. Alai, S. Ganpule, A. Holmberg, E. Plougonven,
and N. Chandra. 2012. Blast-induced biomechanical loading
of the rat: an experimental and anatomically accurate computational blast injury model. J Neurotrauma. 29:2352–64.
Surbatovic, M., N. Filipovic, S. Radakovic, N. Stankovic, and Z.
Slavkovic. 2007. Immune cytokine response in combat casualties: blast or explosive trauma with or without secondary
sepsis. Mil Med. 172:190–5.

Svetlov, S.I., V. Prima, O. Glushakova, A. Svetlov, D. Kirk, H.
Gutierrez et al. 2012. Neuro-glial and systemic mechanisms
of pathological responses in rat models of primary blast
overpressure compared to “composite“ blast. Front Neurol.
3:15.
Svetlov, S.I., V. Prima, D.R. Kirk, H. Gutierrez, K.C. Curley, R.L.
Hayes et al. 2010. Morphologic and biochemical characterization of brain injury in a model of controlled blast overpressure exposure. J Trauma. 69:795–804.
Takeuchi, S., H. Nawashiro, S. Sato, S. Kawauchi, K. Nagatani, H.
Kobayashi et al. 2013. A better mild traumatic brain injury
model in the rat. Acta Neurochir Suppl. 118:99–101.
Tsokos, M., F. Paulsen, S. Petri, B. Madea, K. Puschel, and E.E.
Turk. 2003a. Histologic, immunohistochemical, and ultrastructural findings in human blast lung injury. Am J Respir
Crit Care Med. 168:549–55.
Tsokos, M., E.E. Turk, B. Madea, E. Koops, F. Longauer, M. Szabo
et al. 2003b. Pathologic features of suicidal deaths caused by
explosives. Am J Forensic Med Pathol. 24:55–63.
Tumer, N., S. Svetlov, M. Whidden, N. Kirichenko, V. Prima, B.
Erdos et al. 2013. Overpressure blast-wave induced brain
injury elevates oxidative stress in the hypothalamus and catecholamine biosynthesis in the rat adrenal medulla. Neurosci
Lett. 544:62–7.
Valiyaveettil, M., Y. Alamneh, Y. Wang, P. Arun, S. Oguntayo, Y.
Wei et al. 2013. Contribution of systemic factors in the pathophysiology of repeated blast-induced neurotrauma. Neurosci
Lett. 539:1–6.
Valiyaveettil, M., Y. Alamneh, S. Oguntayo, Y. Wei, Y. Wang, P.
Arun et al. 2012a. Regional specific alterations in brain acetylcholinesterase activity after repeated blast exposures in
mice. Neurosci Lett. 506:141–5.
Valiyaveettil, M., Y.A. Alamneh, S.A. Miller, R. Hammamieh, P.
Arun, Y. Wang et al. 2012b. Modulation of cholinergic pathways and inflammatory mediators in blast-induced traumatic
brain injury. Chem Biol Interact. 203:371–5.
Vandevord, P.J., R. Bolander, V.S. Sajja, K. Hay, and C.A. Bir.
2012. Mild neurotrauma indicates a range-specific pressure
response to low level shock wave exposure. Ann Biomed Eng.
40:227–36.
Varas, J.M., M. Phillipens, S.R. Meijer, A. van den Berg, C., P.C.
Sibma, van Bree, J.L.M., and D.V.W.M. de Vries. 2011.
Physics of IED blast shock tube simulations for mTBI
research. Front Neurol. 2:1–14.
Vries, H.D. 1904. The evidence of evolution. Science. 20:395–401.
Wang, Y., Z. Ye, X. Hu, J. Huang, and Z. Luo. 2010. Morphological
changes of the neural cells after blast injury of spinal cord and
neuroprotective effects of sodium beta-aescinate in rabbits.
Injury. 41:707–16.
White, C.S., I.G. Bowen, and D.R. Richmond. 1965. Biological tolerance to air blast and related biomedical criteria. CEX-65.4.
CEX Rep Civ Eff Exerc. 1–239.
Wilkinson, C.W., K.F. Pagulayan, E.C. Petrie, C.L. Mayer, E.A.
Colasurdo, J.B. Shofer et al. 2012. High prevalence of chronic
pituitary and target-organ hormone abnormalities after blastrelated mild traumatic brain injury. Front Neurol. 3:11.
Zhu, F., H. Mao, A. Dal Cengio Leonardi, C. Wagner, C. Chou,
X. Jin et al. 2010. Development of an FE model of the rat
head subjected to air shock loading. Stapp Car Crash J.
54:211–25.
Zucker, I.H. 1986. Left ventricular receptors: physiological controllers or pathological curiosities? Basic Res Cardiol. 81:539–57.
Zuckerman, S. 1940. Experimental study of blast injuries to the
lungs. Lancet. 236:219–24.

Sign up to vote on this title
UsefulNot useful