Intracranial Pressure following Penetrating Ballistic-Like Brain Injury in Rats

Abstract

Penetrating ballistic brain injury involves a leading shockwave producing a temporary cavity causing substantial secondary injury. In response to the prevalence of this type of brain trauma in the military, a rat model of penetrating ballistic-like brain injury (PBBI) was established. This study focuses on cerebral physiological responses resulting from a PBBI, specifically the immediate and delayed changes in intracranial pressure (ICP) and cerebral perfusion pressure (CPP). ICP/CPP was measured continuously in rats subjected to PBBI, probe insertion alone, or sham injury. Immediately following the PBBI, a transient (<0.1 sec) and dramatic elevation of ICP reaching 280.0 ± 86.0 mm Hg occurred, accompanied by a profound decrease in CPP to −180.2 ± 90.1 mm Hg. This emergent ICP/CPP response resolved spontaneously within seconds, but was followed by a slowly-developing and sustained secondary phase, which peaked at 24 h post-injury, reaching 37.2 ± 10.4 mm Hg, and remained elevated until 72 h post-injury. The measured decrease in CPP reached 85.3 ± 17.2 mm Hg at 3 h post-injury. By comparison, probe insertion alone did not produce the immediate ICP crisis (28.6 ± 9.1 mm Hg), and only a mild and sustained increase in ICP (13.5 ± 2.1 mm Hg) was observed in the following 3 h post-injury. Injury severity, as measured by lesion volume, brain swelling, and neurological deficits at 1, 3, and 7 days post-injury, also reflected the distinctive differences between the dynamics of the PBBI versus controls. These results not only reinforced the severe nature of this model in mimicking the ballistic effect of PBBI, but also established cerebral pathophysiological targets for neuroprotective therapies.

Introduction

P enetrating ballistic brain injury is one of the most prevalent types of traumatic brain injury (TBI) in military conflicts, as well as in urban civilian populations (Barach et al., 1986; Bell et al., 2009; Carey et al., 1989). Caused by bullets or shrapnel that penetrate the brain with high energy, this type of TBI is vastly different from the brain injury caused by low-energy projectiles such as a stab wound. Although both types of injury produce a defined track of tissue damage, the transmission of projectiles with high kinetic energy and leading shockwave produce a temporary cavity in the brain, which can be many times the size of the projectile itself (Barach et al., 1986; Carey et al., 1989). The rapid intracranial deformation causes a shearing force in the brain tissue, exacerbating the initial injury induced by the projectile penetration alone, and setting off a cascade of secondary injury processes (Carey et al., 1989; Koszyca et al., 1998; Soblosky et al., 1992).

For many years, experimental research on penetrating injuries has focused largely on the low-energy induced TBI (i.e., the stab wound), whereas studies on TBI caused by ballistic events were limited due to the lack of socially acceptable and/or appropriate animal models. Since the ballistic brain injury carries significant military importance, a rat model simulating key features of the ballistic injury (i.e., cerebral penetration and formation of an intracerebral temporary cavity) was established. Pivotal to the dynamics of this penetrating ballistic-like brain injury (PBBI) model is that it can replicate the injury tract and kinetics of the temporary cavity caused by different caliber ballistics entering the brain, without firing a projectile (Williams et al., 2005a).

The histopathological changes and functional deficits of the rat PBBI model have been well defined (Williams et al., 2005a), and the model has also been successfully used to study neuroprotective therapies (Chen et al., 2009; Lu et al., 2009; Shear et al., 2009; Wei et al., 2009). However, PBBI-induced intracranial pressure (ICP) and cerebral perfusion pressure (CPP) changes, and their roles associated with secondary brain injury, have not been systematically evaluated. As elevation in ICP and reduction in CPP have been correlated with post-traumatic complications and unfavorable outcomes (Marmarou, 1992), they remain important clinical indices of injury severity. Therefore, the purpose of this study was to characterize the immediate and sub-acute physiological responses, mainly with regard to ICP and CPP, and the associated secondary injuries (i.e., brain swelling and functional deficits), in a rat model of PBBI.

Methods

Experiments were conducted using male Sprague-Dawley rats (275–325 g; Charles River Laboratories, Raleigh, VA). During surgical procedures, the rats were anesthetized with isoflurane (∼ 5% for induction; 1.5% for maintenance) delivered in a mixture of 30% oxygen and 70% air. All experiments were approved by the Institutional Animal Care and Use Committee of Walter Reed Army Institute of Research, and were conducted in compliance with the Animal Welfare Act and Guide for the Care and Use of Laboratory Animals (National Research Council).

The surgical procedures of PBBI have been described in detail previously (Williams et al., 2005a). Briefly, the head of the anesthetized rat was secured in a stereotaxic frame, a midline scalp incision was made, and a cranial window (∼ 4 mm diameter) was created on the dorsal surface of the skull (4.5 mm anterior and 2.0 mm lateral to the bregma), to expose the right frontal pole. A specially-designed PBBI probe was manually advanced through the cranial window along the axis (angled 50° from the vertical axis and 25° counter-clockwise from the midline), penetrating the right frontal hemisphere to a distance of 1.2 cm (from the dura). The probe was connected to a pressure pulse generator that was activated by a computer to rapidly (<40 msec) inflate/deflate the elastic tubing on the probe into an ellipsoid-shaped and water-filled balloon. The diameter of the balloon was calibrated to be 6.33 mm, creating a temporary cavity equal to 10% of the total brain volume. Following the PBBI event, the probe was manually removed, the cranial window was sealed with sterile bone wax, and the incision was closed with wound clips. In control animals, the probe was inserted into the brain following the same procedure as the PBBI animals, but the balloon was not inflated. Sham animals received only craniotomy without probe penetration.

ICP was measured by inserting a micro-sensor (Codman and Shurtleff, Raynham, MA) into the left posterior hemisphere, contralateral to the site of PBBI, to avoid the direct impact from the balloon expansion. The ICP probe was connected to an ICP monitor (Codman and Shurtleff), and was immobilized with sterile bone wax. On the study day, ICP was measured continuously in the anesthetized rat for 10 min prior to the injury to collect baseline values, and for 3 h continuously after the injury. Over the following 7 days, the ICP was measured daily (5 min each day) in the re-anesthetized animals. Mean arterial blood pressure (MABP) was monitored in parallel via a femoral artery catheter connected to a pressure transducer (Harvard Apparatus, Holliston, MA). The blood gases were also measured prior to PBBI and at 3 h post-injury from the blood collected via the femoral artery catheter. The digitized signals of ICP and MABP were recorded by the Power Lab data acquisition system for PC recording (AD Instruments, Inc., Colorado Springs, CO). CPP, calculated by MABP minus ICP, was recorded simultaneously.

The brain lesion volume, brain swelling, and neurological deficits were measured at 1, 3, and 7 days post-injury. Lesion volume and brain edema were examined as described previously (Martins et al., 2003; Williams et al., 2005b). The injured area, defined as the regions of neuropil pallor, rarefaction, neuronal necrosis, disruption of neuropil architecture, and gross intracerebral hemorrhage (ICH), was quantified from 11 H&E-stained brain sections (at 1-mm intervals from 4.0 mm anterior to 7.0 mm posterior to the bregma), using a computer-assisted image analysis system (Loats Associates, Westminster, MD). Brain swelling was calculated as the change in volume in the ipsilateral hemisphere compared to the contralateral hemisphere ([ipsilateral − contralateral]/contralateral). Neurological deficit was evaluated using a 12-point weighted scale of four neurological measures (Tortella et al., 1999; Williams et al., 2005a).

Statistical analysis

The Student's t-test was used for comparing the difference between the PBBI (n = 12) and probe insertion alone (n = 12) or sham (n = 11) groups, and a p value < 0.05 was considered statistically significant. All data in this study are presented as mean ± SD.

Results

In general, the PBBI caused a biphasic change in ICP seen as an immediate and dramatic, but transient, increase in ICP upon formation of the temporary cavity (i.e., balloon expansion), that was resolved within seconds. This was followed by a steady elevation in ICP measured throughout the ensuing days. Consistent with the ICP responses, decreases were recorded in the corresponding CPP in both phases. The PBBI did not influence MABP, except for causing a transient decrease in MABP at the time of balloon inflation/deflation, nor did it alter the blood gases, as pH, PaO₂, and PaCO₂ remained unchanged during the initial 3 h of injury (p > 0.05 for all groups; Table 1).

Table 1.

Measurement of Arterial Blood Gas Pre-injury and 3 h Post-injury (mean ± SD)

	Group	Pre-injury	3 h post-injury
pH	Sham	7.41 ± 0.05	7.39 ± 0.05
	Probe	7.39 ± 0.03	7.40 ± 0.02
	PBBI	7.39 ± 0.03	7.40 ± 0.02
PaCO₂	Sham	44.7 ± 2.8	43.4 ± 2.8
(mm Hg)	Probe	43.9 ± 5.4	45.8 ± 3.3
	PBBI	45.6 ± 4.6	45.6 ± 3.0
PaO₂	Sham	122.1 ± 9.4	126.2 ± 9.8
(mm Hg)	Probe	128.1 ± 12.3	127.8 ± 12.3
	PBBI	131.2 ± 13.3	130.0 ± 10.2

PaCO₂, partial arterial pressure of carbon dioxide; PaO₂, partial arterial pressure of oxygen; SD, standard deviation; PBBI, penetrating ballistic-like brain injury.

Figure 1 shows the representative, real-time recordings of ICP, CPP, and MABP pre-injury and immediately post-PBBI. Compared with the pre-PBBI baseline level of ICP (7.2 ±2.2 mm Hg; Table 2), penetration of the brain by the probe alone caused a moderate fourfold increase (28.6 ± 9.1 mm Hg; Table 2) in ICP. Formation of the temporary cavity by inflation of the PBBI balloon produced an instantaneous spike in ICP, to 280.0 ± 86.0 mm Hg (>40 × baseline; Table 2). This immediate spike persisted for less than 0.1 sec (Fig. 1B), and its peak was on the order of milliseconds. Concomitantly the changes in CPP inversely mirrored the pattern of the ICP change, with a moderate decrease (∼ 1.5-fold; Table 2) after probe insertion, and a further significant reduction to −180.2 ± 90.1 mm Hg (a negative spike) upon balloon inflation (Fig. 1 and Table 2). The effects of probe insertion and balloon inflation on the MABP were similar to those of CPP (Fig. 1A and Table 2).

FIG. 1.

Representative changes in ICP, CPP, and MABP during and immediately following (<5 min) PBBI in rats. (A) PBBI probe insertion caused an increase in ICP, but a decrease in CPP and MABP. Ballistic-like impact, produced by balloon inflation/deflation, caused an additional dramatic increase in ICP (a positive spike), and a decrease in CPP (a negative spike) and MABP. (B) Compressed time scale (seconds) showing that the ICP and CPP spikes reached peak values as high as +280 mm Hg, and as low as ∼ −180 mm Hg, respectively. The duration of each spike was ∼ 0.1 sec; the peak lasted less than a few milliseconds, as shown in the circle (ICP, intracranial pressure; CPP, cerebral perfusion pressure; MABP, mean arterial blood pressure; PBBI, penetrating ballistic-like brain injury).

Table 2.

Profiles of ICP, CPP, and MABP Pre-, During, and 3 h Post-injury (mean ± SD)

	Group	Pre-injury	During injury	3 h post-injury
ICP	Sham	7.2 ± 2.2	6.7 ± 3.5	6.7 ± 2.9
(mm Hg)	Probe	7.5 ± 1.6	28.6 ± 9.1^#	9.2 ± 1.6^#
	PBBI	7.8 ± 1.7	280.0 ± 86.0^*	18.0 ± 5.1^*
CPP	Sham	99.4 ± 13.5	96.5 ± 16.2	103.3 ± 18.0
(mm Hg)	Probe	94.1 ± 5.9	67.6 ± 12.6^#	94.0 ± 18.1
	PBBI	97.8 ± 12.7	−180.2 ± 90.1^*	85.3 ± 17.2^*
MABP	Sham	105.6 ± 12.8	99.5 ± 9.5	111.1 ± 17.1
(mm Hg)	Probe	101.7 ± 5.2	94.1 ± 14.4	101.5 ± 15.0
	PBBI	105.8 ± 9.8	77.0 ± 16.1^*	104.4 ± 16.0

p < 0.05, PBBI versus probe insertion alone or sham; ^# p < 0.05, probe insertion alone versus sham injury.

ICP, intracranial pressure; CPP, cerebral perfusion pressure; MABP, mean arterial blood pressure; PBBI, penetrating ballistic-like brain injury; SD, standard deviation.

Although the instantaneous spiking of ICP resolved immediately after deflation of the PBBI balloon, continuous monitoring revealed that there was a second, sustained phase of increased ICP in the following hours to days post-injury. As shown in Table 2 and Figure 2A, ICP in the PBBI group was almost threefold elevated compared to the sham group (p < 0.05) by the end of the 3-h recording period. It continued to rise and peaked 24 h post-injury at a very severe level, approaching 37.2 ± 10.4 mm Hg, compared to the probe alone or sham groups (p < 0.05; probe alone: 13.5 ± 2.1 and sham: 9.5 ± 2.9 mm Hg; Fig. 3A). The significantly elevated ICP level persisted for 3 days, returning to baseline levels between days 3 and 4 post-injury (Fig. 3A). The probe insertion alone also caused a second-phase ICP event, that was significantly higher compared to the sham group, but relatively minor compared to the PBBI group, that resolved within 2–3 days post-injury (Fig. 3A).

FIG. 2.

Real-time comparison of ICP, CPP, and MABP during the initial 3 h following injury. (A) Elevation of ICP following probe insertion alone or PBBI. (B) Reduction of CPP. (C) A significant reduction in MABP after balloon inflation was seen in PBBI rats (Pre, pre-injury; P, probe penetration; B, balloon inflation/deflation; mean ± standard deviation; *p < 0.05 PBBI versus probe insertion alone or sham injury; #p < 0.05 probe insertion alone versus sham injury; ICP, intracranial pressure; CPP, cerebral perfusion pressure; MABP, mean arterial blood pressure; PBBI, penetrating ballistic-like brain injury).

FIG. 3.

ICP, brain swelling, lesion volume, and neurological deficits seen in rats measured at 1–7 days following PBBI. (A) ICP. (B) Brain swelling. (C) Lesion size. (D) Neurological deficits. All reached their maximum on day 1 following PBBI. These changes were significantly higher in PBBI rats than in rats subjected to probe insertion alone (mean ± standard deviation; *p < 0.05 PBBI versus probe insertion alone or sham injury; #p < 0.05 probe insertion alone versus sham injury; ICP, intracranial pressure; PBBI, penetrating ballistic-like brain injury).

As shown in Table 2 and Figure 2B, the corresponding decrease in CPP was more severe in the PBBI group than in the probe-alone group, whereas the MABP, except during balloon inflation, was not significantly altered in any group after PBBI (Fig. 2C and Table 2).

The brain swelling, lesion volumes, and neurological deficits were significantly worse in the PBBI group than in the probe-alone group (p < 0.05) as measured at 1, 3, or 7 days post-injury (Fig. 3B, C, and D). Spontaneous recovery of neurological deficits (Fig. 3D), and resolution of the brain swelling (Fig. 3B), were observed at 24 h post-injury, yet remained significantly different from those seen in the probe-alone or sham groups (p < 0.05; Fig. 3B, C, and D).

Discussion

Penetrating brain injury caused by high-energy ballistic impact is mechanically and dynamically different from a stab wound brain injury (Pintar et al., 2001). In the rat model of PBBI, manual insertion of the PBBI probe into the brain creates a defined injury tract mimicking a low-energy stab wound, whereas the rapid inflation/deflation of the PBBI balloon mimics the ballistic shockwave caused by the energy dissipation from a bullet passing through the cerebrum, collectively resulting in a temporary cavity (Williams et al., 2005a). In this study, we demonstrated a unique biphasic pattern of ICP change, in which the initial transient ICP spike (up to 280 mm Hg) resulted from the rapid balloon inflation/deflation (i.e., mimicked the shockwave), whereas the subsequent and sustained increase in ICP that persisted for 3 days post-injury was most likely associated with the evolution of a secondary brain injury resulting from the formation of the temporary cavity. This increase in ICP was accompanied by a reduction in CPP, and the ensuing pathological consequences (i.e., brain swelling, lesion development, and neurological deficits).

Measurement of the pressure following penetration by ballistic projectiles has been conducted in the past, in both brain-simulating material and animal models (Yoganandan et al., 1997; Zhang et al., 2005, 2007). Several studies using brain-simulating materials revealed that the magnitude and duration of the pressure were largely dependent on the type of ballistic projectile, the nature of the brain-simulating material, and the locations of measurement (Yoganandan et al., 1997; Zhang et al., 2005, 2007). As reported by Zhang and associates, the positive pressure inside their brain-simulating material (Sylgard^® gel) produced by a 25-caliber projectile was approximately 50–72 kPa (∼ 350–500 mm Hg), with a duration of ∼ 0.16–4.90 msec (Zhang et al., 2005). Limited studies have also been carried out to measure the intracranial/intracerebral pressure following a simulated gunshot in animal models. For example, an experimental missile wound model using cats produced a biphasic change in ICP similar to that observed in our study (i.e., an abrupt transient rise contralateral to the injury site immediately following the injury that was resolved within minutes, followed by a steady elevation that lasted at least 6 h). The levels of ICP elevation seen during and following injury were proportional to the energy of the projectile (Carey et al., 1989).

In our PBBI model, the parameters for the size and shape of the temporary cavity were calculated based on the cavitation produced in the human brain by a NATO 7.6 mm round. The size of the probe and the volume of the expanded balloon were scaled to the rat brain (Williams et al., 2005a). In this study, we demonstrated that immediately following a 10% PBBI, the magnitude and duration of the ICP spike produced by the balloon inflation were comparable to the pressures recorded in the brain-simulating material (Zhang et al., 2005), or in the brains of the larger animals injured by handgun projectiles (Carey et al., 1989), supporting the relevance of the PBBI pre-clinical model for studying military-type ballistic wounds of the human brain. More importantly, the second phase of the ICP elevation, although far less dramatic than the first spike, reached a clinically severe level comparable to that seen in other experimental models of closed-head TBI (Prins et al., 1996; Rooker et al., 2003), and consistent with clinical ICP measurements in TBI patients (Abadal-Centellas et al., 2007; Olivecrona et al., 2007). Collectively, our results support the rationale of the use of this rat PBBI model to study military-type penetrating brain injury, and identified the ICP:CPP ratio as a valid pathophysiological marker, as well as a therapeutic target of clinical significance (Carey et al., 1989; Kroppenstedt et al., 1998; Prins et al., 1996).

As mentioned earlier, the second phase of sustained ICP elevation was likely the result of secondary injury. The major underlying causes of the persistent and steady elevation of ICP seen after PBBI may include, but are not limited to, ICH and brain swelling. Many clinical and pre-clinical studies have demonstrated that high ICP may cause cerebral hypoxia/ischemia, and consequently exacerbate brain swelling, which in turn further increases the ICP (Ito et al., 1996; Marmarou, 2003; Williams et al., 2005a). Here we demonstrated that a PBBI not only produced a severe increase in ICP, but also caused associated pathological outcomes, including large lesion volumes, significant brain swelling, and neurological deficits. Importantly, probe insertion alone caused far less injury, demonstrating that the balloon inflation simulated the shockwave, and that the resultant cavity exacerbated the brain injury beyond the effects of the mechanical shearing along the injury tract.

Clinically, elevation of ICP represents the leading cause of morbidity and mortality in patients suffering from severe TBI (Marmarou, 1992). Guidelines established by The Brain Trauma Foundation (https://www.braintrauma.org/) suggests that an ICP > 20 mm Hg and a CPP < 70 mm Hg should be treated immediately, and strategies targeting reductions in ICP have shown favorable outcomes and lower mortality (Olivecrona et al., 2007). Furthermore, a recent retrospective review confirms that penetrating brain injury remains the predominant type of severe brain injury seen in military-associated TBI, making up 56% of all severe brain trauma casualties (Martins et al., 2003; Volgas et al., 2005). Consequently, our pre-clinical results showing a severe increase in ICP accompanied by a reduction in CPP, and the ensuing associated pathological consequences, support the potential value of these results as pre-clinical research targets for therapeutic interventional studies using the PBBI model.

In summary, we have characterized immediate and sub-acute (out to 7 days) changes in ICP in a rat model of PBBI, supporting the uniqueness and relevance of this model for mimicking ballistic-type penetrating injury. In addition, by comparing the pathological outcomes of PBBI versus probe insertion alone, we demonstrated that the temporary cavity caused by a ballistic shockwave plays a key role in the development of secondary brain injury.

Footnotes

Author Disclosure Statement

This research was conducted in compliance with the Animal Welfare Act, and other federal statutes and regulations relating to animal experimentation, and adhered to the principles stated in the Guide for the Care and Use of Laboratory Animals (National Institutes of Health publication 85-23). This material has been reviewed by the Walter Reed Army Institute of Research, and there is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors, and are not to be construed as official, or as reflecting the views of the Department of the Army or the Department of Defense.

References

Abadal-Centellas

J.M.

, Llompart-Pou

J.A.

, Homar-Ramirez

, Perez-Barcena

, Rossello-Ferrer

, Ibanez-Juve

2007. Neurologic outcome of posttraumatic refractory intracranial hypertension treated with external lumbar drainage. J. Trauma, 62:282–286discussion 286.

Barach

, Tomlanovich

, Nowak

1986. Ballistics: a pathophysiologic examination of the wounding mechanisms of firearms: Part I. J. Trauma, 26:225–235.

Bell

R.S.

, Vo

A.H.

, Neal

C.J.

, Tigno

, Roberts

, Mossop

, Dunne

J.R.

, Armonda

R.A.

2009. Military traumatic brain and spinal column injury: a 5-year study of the impact blast and other military grade weaponry on the central nervous system. J. Trauma, 66:S104–S111.

Carey

M.E.

, Sarna

G.S.

, Farrell

J.B.

, Happel

L.T.

1989. Experimental missile wound to the brain. J. Neurosurg., 71:754–764.

Chen

, Tortella

F.C.

, Dave

J.R.

, Marshall

V.S.

, Clarke

D.L.

, Sing

, Du

, Lu

X.C.

2009. Human amnion-derived multipotent progenitor cell treatment alleviates traumatic brain injury-induced axonal degeneration. J. Neurotrauma, 26:1987–1997.

Ito

, Marmarou

, Barzo

, Fatouros

, Corwin

1996. Characterization of edema by diffusion-weighted imaging in experimental traumatic brain injury. J. Neurosurg., 84:97–103.

Koszyca

, Blumbergs

P.C.

, Manavis

, Wainwright

, James

, Gilbert

, Jones

, Reilly

P.L.

1998. Widespread axonal injury in gunshot wounds to the head using amyloid precursor protein as a marker. J. Neurotrauma, 15:675–683.

Kroppenstedt

S.N.

, Schneider

G.H.

, Thomale

U.W.

, Unterberg

A.W.

1998. Protective effects of aptiganel HCl (Cerestat) following controlled cortical impact injury in the rat. J. Neurotrauma, 15:191–197.

X.C.

, Si

, Williams

A.J.

, Hartings

J.A.

, Gryder

, Tortella

F.C.

2009. NNZ-2566, a glypromate analog, attenuates brain ischemia-induced non-convulsive seizures in rats. J. Cereb. Blood Flow Metab., 29:1924–1932.

10.

Marmarou

1992. Increased intracranial pressure in head injury and influence of blood volume. J. Neurotrauma, 9,Suppl. 1:S327–S332.

11.

Marmarou

2003. Pathophysiology of traumatic brain edema: current concepts. Acta Neurochir. Suppl., 86:7–10.

12.

Martins

R.S.

, Siqueira

M.G.

, Santos

M.T.

, Zanon-Collange

, Moraes

O.J.

2003. Prognostic factors and treatment of penetrating gunshot wounds to the head. Surg. Neurol., 60:98–104; discussion 104.

13.

Olivecrona

, Rodling-Wahlstrom

, Naredi

, Koskinen

L.O.

2007. Effective ICP reduction by decompressive craniectomy in patients with severe traumatic brain injury treated by an ICP-targeted therapy. J. Neurotrauma, 24:927–935.

14.

Pintar

F.A.

, Kumaresan

, Yoganandan

, Yang

, Stemper

, Gennarelli

T.A.

2001. Biomechanical modeling of penetrating traumatic head injuries: a finite element approach. Biomed. Sci. Instrum., 37:429–434.

15.

Prins

M.L.

, Lee

S.M.

, Cheng

C.L.

, Becker

D.P.

, Hovda

D.A.

1996. Fluid percussion brain injury in the developing and adult rat: a comparative study of mortality, morphology, intracranial pressure and mean arterial blood pressure. Brain Res. Dev. Brain Res., 95:272–282.

16.

Rooker

, Jorens

P.G.

, Van Reempts

, Borgers

, Verlooy

2003. Continuous measurement of intracranial pressure in awake rats after experimental closed head injury. J. Neurosci. Methods, 131:75–81.

17.

Shear

D.A.

, Williams

A.J.

, Sharrow

, Lu

X.C.

, Tortella

F.C.

2009. Neuroprotective profile of dextromethorphan in an experimental model of penetrating ballistic-like brain injury. Pharmacol. Biochem. Behav., 94:56–62.

18.

Soblosky

J.S.

, Rogers

N.L.

, Adams

J.A.

, Farrell

J.B.

, Davidson

J.F.

, Carey

M.E.

1992. Central and peripheral biogenic amine effects of brain missile wounding and increased intracranial pressure. J. Neurosurg., 76:119–126.

19.

Tortella

F.C.

, Britton

, Williams

, Lu

X.C.

, Newman

A.H.

1999. Neuroprotection (focal ischemia) and neurotoxicity (electroencephalographic) studies in rats with AHN649, a 3-amino analog of dextromethorphan and low-affinity N-methyl-D-aspartate antagonist. J. Pharmacol. Exp. Ther., 291:399–408.

20.

Volgas

D.A.

, Stannard

J.P.

, Alonso

J.E.

2005. Current orthopaedic treatment of ballistic injuries. Injury, 36:380–386.

21.

Wei

H.H.

, Lu

X.C.

, Shear

D.A.

, Waghray

, Yao

, Tortella

F.C.

, Dave

J.R.

2009. NNZ-2566 treatment inhibits neuroinflammation and pro-inflammatory cytokine expression induced by experimental penetrating ballistic-like brain injury in rats. J. Neuroinflammation, 6:19.

22.

Williams

A.J.

, Hartings

J.A.

, Lu

X.C.

, Rolli

M.L.

, Dave

J.R.

, Tortella

F.C.

2005a. Characterization of a new rat model of penetrating ballistic brain injury. J. Neurotrauma, 22:313–331.

23.

Williams

A.J.

, Myers

T.M.

, Cohn

S.I.

, Sharrow

K.M.

, Lu

X.C.

, Tortella

F.C.

2005b. Recovery from ischemic brain injury in the rat following a 10 h delayed injection with MLN519. Pharmacol. Biochem. Behav., 81:182–189.

24.

Yoganandan

, Pintar

F.A.

, Kumaresan

, Maiman

D.J.

, Hargarten

S.W.

1997. Dynamic analysis of penetrating trauma. J. Trauma, 42:266–272.

25.

Zhang

, Yoganandan

, Pintar

F.A.

, Gennarelli

T.A.

2005. Temporal cavity and pressure distribution in a brain simulant following ballistic penetration. J. Neurotrauma, 22:1335–1347.

26.

Zhang

, Yoganandan

, Pintar

F.A.

, Guan

, Gennarelli

T.A.

2007. Experimental model for civilian ballistic brain injury biomechanics quantification. J. Biomech., 40:2341–2346.