Blast overpressure induces shear-related injuries in the brain of rats exposed to a mild traumatic brain injury
- Miguel A Gama Sosa1, 4, 8Email author,
- Rita De Gasperi2, 4, 8,
- Alejandro J Paulino2, 4,
- Paul E Pricop2, 4,
- Michael C Shaughness9,
- Eric Maudlin-Jeronimo9,
- Aaron A Hall9,
- William G M Janssen5,
- Frank J Yuk5,
- Nathan P Dorr2, 4,
- Dara L Dickstein5, 6, 8,
- Richard M McCarron9,
- Mikulas Chavko9,
- Patrick R Hof5, 6, 8,
- Stephen T Ahlers9 and
- Gregory A Elder3, 4, 7, 8
© Gama Sosa et al.; licensee BioMed Central Ltd. 2013
Received: 2 July 2013
Accepted: 6 August 2013
Published: 14 August 2013
Blast-related traumatic brain injury (TBI) has been a significant cause of injury in the military operations of Iraq and Afghanistan, affecting as many as 10-20% of returning veterans. However, how blast waves affect the brain is poorly understood. To understand their effects, we analyzed the brains of rats exposed to single or multiple (three) 74.5 kPa blast exposures, conditions that mimic a mild TBI.
Rats were sacrificed 24 hours or between 4 and 10 months after exposure. Intraventricular hemorrhages were commonly observed after 24 hrs. A screen for neuropathology did not reveal any generalized histopathology. However, focal lesions resembling rips or tears in the tissue were found in many brains. These lesions disrupted cortical organization resulting in some cases in unusual tissue realignments. The lesions frequently appeared to follow the lines of penetrating cortical vessels and microhemorrhages were found within some but not most acute lesions.
These lesions likely represent a type of shear injury that is unique to blast trauma. The observation that lesions often appeared to follow penetrating cortical vessels suggests a vascular mechanism of injury and that blood vessels may represent the fault lines along which the most damaging effect of the blast pressure is transmitted.
KeywordsBlast overpressure injury Neuropathology Shear injury Traumatic brain injury
Traumatic brain injury (TBI) has been a common cause of mortality and morbidity in the military operations in Iraq and Afghanistan . It is estimated that 10-20% of returning veterans have suffered a TBI . Due to the prominent use of improvised explosive devices (IED) in Iraq and Afghanistan, a characteristic feature of TBI in these conflicts has been its association with blast exposure . Single or multiple blast exposures have been commonly seen in association with chronic neurological and psychiatric sequelae including persistent cognitive impairment, post-traumatic stress disorder (PTSD) and depression . Blast injuries occur through multiple mechanisms that may be related to effects of the primary blast wave, to injuries associated with objects including shrapnel contained within the IED being propelled by the blast wind, or by the individual being knocked down or thrown into solid objects .
How the primary blast wave itself affects the brain is not well understood . Direct tissue damage, bleeding, and diffuse axonal injury (DAI) are the best known pathophysiological mechanisms associated with the type of non-blast TBI most commonly encountered during blunt impact injuries in civilian life [4, 5]. Blast-associated moderate-to-severe TBIs likely result from mechanisms in part similar to those found in non-blast TBI. The degree to which the primary blast wave injures the brain remains controversial [3, 4].
Whereas most attention in the Iraq and Afghanistan conflicts initially focused on the moderate-to-severe end of the TBI spectrum, the type of injuries that would be recognized in the field, it soon became apparent that mild TBIs (mTBI) were much more common and were frequently not being recognized at the time of the initial injury . We had previously established conditions that approximate mTBI exposures experimentally. These studies found that exposures up to 74.5 kPa, while representing a blast level that is transmitted to the brain , led to no persistent neurological impairments or lung damage , although animals subjected to repetitive blast exposure, which has been common in the current conflicts , exhibited a variety of chronic behavioral and biochemical changes [7, 8]. In contrast, animals exposed to 116.7 kPa blast exposures frequently had gross cerebral and subdural hemorrhages as well as contusions and significant lung pathology [5, 6, 9], features that are not consistent with mTBI.
In the present study we explored the pathological effects of blast overpressure shock waves in rats exposed to 74.5 kPa blast exposures. We describe a type of shear injury in the brain that has not been described in non-blast TBI models and appears to be unique to blast-associated brain injury.
All studies were approved by the Institutional Animal Care and Use Committees of the Naval Medical Research Center and the James J. Peters VA Medical Center. Two-month-old male Long Evans Hooded rats (250-350 g; Charles River Laboratories International, Wilmington, MA, USA) were used. Animals were housed at a constant 22°C temperature in rooms on a 12:12 hour light cycle with lights on at 7 AM. All animals were individually housed in standard clear plastic cages equipped with Bed-O’Cobs laboratory animal bedding (The Andersons, Maumee, OH, USA) and EnviroDri nesting paper (Sheppard Specialty Papers, Milford, NJ, USA). Access to food and water was ad libitum.
Blast overpressure exposure
Time harvested (post-blast)
Histopathological and immunohistochemical analyses
Animals were anesthetized with ketamine (65 mg/kg)/xylazine (13 mg/kg)/acepromazine (2 mg/kg) and transcardially perfused with cold 4% paraformaldehyde in phosphate-buffered saline (PBS). Brains were removed and postfixed overnight in the same fixative. To exclude perfusion artifacts in some cases the brain was dissected and immersion fixed in 4% paraformaldehyde in PBS. Coronal sections of 50 μm thickness were prepared with a Leica VT1000 Vibratome (Vienna, Austria) and stored in sterile PBS at 4°C. For general histopathology serial sections were selected at 500 μm intervals, air-dried and stained with hematoxylin and eosin (H&E).
Immunohistochemical staining was performed on free-floating sections. The primary antibodies used were a rabbit polyclonal anti-collagen IV antiserum (1:500; Millipore, Billerica, MA, USA), a rabbit polyclonal anti-ionized calcium-binding adaptor molecule 1 (Iba-1, 1:400; Wako, Richmond, VA, USA), a rabbit polyclonal anti-laminin (1:150; Sigma-Aldrich, St. Louis, MO, USA), a rabbit polyclonal antibody against the neurofilament heavy subunit (NFH, 1:300, Sigma-Aldrich), a mouse monoclonal antibody against phosphorylated neurofilaments (SMI31, 1:500, Covance Research Products, Denver, PA, USA), a mouse monoclonal antibody against the APP-N-terminal region (clone 22C11, 1:150, Millipore), a mouse monoclonal anti-β-III tubulin (Tuj, 1:500; Covance), a mouse monoclonal anti-2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase, 1:200; Millipore), a mouse monoclonal anti-α-smooth muscle actin (α-SMA, 1:500; Sigma), a rat monoclonal anti-glial fibrillary acidic protein (GFAP, 1:500, gift of Dr. Robert Lazzarini), a mouse monoclonal antibody that recognizes tau protein phosphorylated at Ser202 (CP-13, 1:300, gift of Dr. Peter Davies). Sections were blocked with Tris-buffered saline (TBS; 50 mM Tris–HCl, 0.15 M NaCl pH 7.6), and 0.15 M NaCl/0.1% Triton X-100/5% goat serum (TBS-TGS) for 1 hour, and the primary antibody was applied overnight in TBS-TGS at room temperature. Following washing in PBS for 1 hour, immunofluorescence staining was detected by incubation with species-specific AlexaFluor secondary antibody conjugates (1:300; Molecular Probes, Burlingame CA, USA) for 2 hours in TBS-TGS. Nuclei were counterstained with 1 μg/ml 4′,6-diamidino-2-phenylindole (DAPI). Immunoperoxidase staining for collagen IV was performed on pepsin-digested tissue as previously described  and sections were counterstained with 0.5% cresyl violet. Stained sections were photographed on a Zeiss AxioImager microscope using the AxioVision Release 4.3 software program (Zeiss, Thornwood, NY, USA), a Nikon Eclipse E400 connected to a DXC-390 CCD camera (Nikon, Melville, NY, USA) or a Zeiss LSM 710 confocal microscope. Unstained sections of fixed brain were photographed on a Nikon SMZ1500 stereomicroscope equipped with an oblique coherent contrast illumination system and connected to a SPOT RT digital camera (Sterling Heights, MI, USA). Digital images were color balanced using Adobe Photoshop 11.0 (Adobe Systems, San Jose, CA, USA).
For TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling) staining, sections were washed in TBS, permeabilized with 0.1% Triton X-100 in TBS for 1 hr and washed extensively with TBS. End labeling of DNA with fluorescein-dUTP was performed using a commercial kit (Roche, Indianapolis, IN, USA). After several washes with PBS, the sections were blocked and stained with a mouse monoclonal anti-α-smooth muscle actin antibody as described above.
Animals groups and study rationale
We have been examining the acute and chronic effects of blast exposure in the rat focusing on conditions that mimic an mTBI exposure [6–8]. A pressure of 74.5 kPa was chosen based on previous studies suggesting that it best approximates an mTBI exposure [6, 8]. Multiple blast exposures have been common in the conflicts in Iraq and Afghanistan and Hoge et al.  found that more than 50% of soldiers returning from Iraq who reported no injuries still reported at least two episodes in which an IED exploded near the soldier. This figure rose to nearly 90% among soldiers who suffered mTBIs. We therefore included rats that received three 74.5 kPa blast exposures administered on consecutive days. During the course of our prior studies brain tissue was collected at times ranging from 4 to 10 months following blast exposure (3×-chronic exposure). Here we took advantage of the availability of this tissue to examine the histopathological consequences of blast exposure, supplementing it with tissue from rats that received one or three blast exposures and were sacrificed at 24 hours post-blast (1×− and 3×−acute exposure). Table 1 contains a summary of the animals examined. There was no mortality in any of the blast-exposed or control groups.
Screen for neuropathology
We performed a general screen for neuropathology on all the rats listed in Table 1. Following perfusion, brains were cut into 50 μm-thick Vibratome sections and initially imaged by diascopic bright/dark field microscopy for gross abnormalities. H&E staining was performed on every 10th section from each brain. Based on these observations sections were selected for further analysis.
Intraventricular hemorrhages are common following blast exposure
Lack of histopathology in blast-exposed brains
A screen for neuropathology did not reveal any widespread histopathologic alterations in H&E-stained sections in either the acute (1×- and 3×-acute) or chronic (3×-chronic) groups. Immunohistochemical staining for neurofilament proteins or β-III tubulin (Tuj) revealed no general neuronal pathology. No axonal pathology was found by immunostaining for the amyloid precursor protein (APP) whose accumulation in axons is widely used as a marker of axonal injury in humans and experimental animal models of TBI . TUNEL staining did not reveal evidence of generalized apoptosis. CNPase immunostaining was performed as a measure of myelin integrity and was normal. No generalized reactive astrocytosis or microglial activation was detected by staining for GFAP or the activated microglia marker Iba-1. Collagen IV immunostaining revealed no vascular pathology. In contrast to a recent study showing accumulation of hyperphosphorylated tau in both human cases and a mouse models of blast associated brain injury  we did not detect any accumulation of hyperphosphorylated tau in blast-exposed animals by immunostaining with the antibody CP-13, which recognizes phosphorylated tau at Ser202.
Blast induces shear-related injuries in brain
Brain pathology associated with experimental mTBI
1 x 74.5
Tear causing repositioning of part of the caudate-putamen into the insula.
1 x 74.5
Blood in dorsal 3rd and lateral ventricles as well as choroid plexus.
1 x 74.5
Blood in dorsal 3rd and lateral ventricles.
3 x 74.5
Blood in dorsal 3rd ventricle.
3 x 74.5
Blood in aqueduct, dorsal 3rd and lateral ventricles; vascular disruption affecting external capsule and CA1 field; blood in the adjacent parenchymal tissue.
3 x 74.5
Tear spanning the perirhinal cortex, external capsule, hippocampal CA1 region and dentate gyrus resulting in tissue architectural abnormalities.
3 x 74.5
Lesion in the secondary auditory cortex expanding to the perirhinal region.
3 x 74.5
Tear at the surface of the secondary somatosensory cortex extending into the insular cortex; lesion involves repositioning of cortical layers; disruption of piriform cortex by the insertion of olfactory tubercle/lateral olfactory tract tissue.
3 x 74.5
Disruption of layers I, II and III in primary visual cortex; presence of ectopic neurons in layer I; lesion of hippocampal CA1.
3 x 74.5
Tear and repositioning of layers I, II and III in primary somatosensory cortex; ectopic neurons in layer I; disruption of parietal and somatosensory cortex and ventral/intermediate entorhinal cortex by the insertion of ectopic tissue.
3 x 74.5
Lesion in motor cortex altering the cortical architecture.
3 x 74.5
Displacement of amygdalohippocampal and posteromedial cortical amygdaloid nucleus tissue disrupting the ventral hippocampal CA1 field.
Disruption of the upper cortical layers I, II, and III in the primary visual cortex in a 3×-chronic exposure animal is illustrated in Figure 8B. In this example two areas are visible where the cortical layers have been disrupted (compare to a control brain in Figure 8A). In the area on the left of the tear in Figure 8B the cortical layers are misaligned. In the region on the right of the tear in Figure 8B ectopic cells are visible in layer I including a variety of spindle-shaped cells (Figure 8C). These cells were identified as neurons based on their immunostaining for NeuN (Figure 8D and H). In another 3×-chronic exposure animal (Figure 8F, G, J and K) a lesion in the primary somatosensory cortex produced a tear that disrupted layers I to III resulting in a portion of layers II and III being avulsed relative to layer I (arrows in Figure 8F, G, J and K; compare to panel E from control brain). NeuN immunostaining (Figure 8J) demonstrated the neuronal character of these ectopic cells, which also included many spindle-shaped neurons. Figures 9B and C show disruption of the CA1 field of the hippocampus by a tear (compare panel 9B to 9A that shows the same region in a control brain). This tear disrupted the primary visual cortex and severely damaged the hippocampal layers (arrow in panel C).
Behavioral alterations associated with blast-related focal lesions
Blast-related rips and tears frequently follow vascular fault lines
Whether primary blast forces directly damage the brain is still controversial and if they do, the exact mechanisms that mediate injury remain unknown [3, 4, 14]. While it was once thought that the skull forms a protective barrier preventing the blast pressure wave from directly damaging the brain , studies in animal models subsequently showed that the blast pressure wave is transmitted to the brain with little attenuation [5, 13, 15–23].
Here, we analyzed the early (24 hours) and long-term (>4 months) pathological effects in the brains of rats exposed to blast overpressure, using a model that approximates a mild TBI exposure. The earliest and most common pathological finding at 24 hours post-blast was the presence of blood in the choroid plexus, ventricles and cerebral aqueduct, occurring even after a single blast exposure. This pathology seems best explained by direct effects of blast on the choroid plexus leading to vascular rupture and blood leakage into the ventricles. These results are in agreement with a previous study indicating that the choroid plexus is extremely sensitive to the blast wave .
We did not observe any generalized neuropathology or evidence for diffuse axonal injury as judged by APP immunostaining. We also did not observe accumulation of hyperphosphorylated tau as has been reported in another model of blast TBI . Rather, the most prominent effects were what we describe as focal rips or tears in the tissue. These lesions seem best described as shear-related because they result in displacement of adjacent tissue planes causing a realignment of the layers that in some cases led to avulsion and relocation of tissue. Because the lesions are found at 24 hours post-blast exposure, they appear to represent acute lesions. With time these lesions evolve into chronic lesions that exhibit a glial and microglial reaction as well as a neuronal reaction which includes thinning of dendrites in the adjacent tissue. These results are in agreement with a previous study reporting that blast exposure in rats induces microglial activation and hypertrophy in the brain . The spindle-shaped neurons with elongated nuclei that were observed in some lesions have been described in a previous study in which it was suggested that overpressure shock waves cause the long axis of the neurons to align toward the shock wave source .
Interestingly, we found that tears often seemed to follow penetrating cortical vessels suggesting that blood vessels could represent fault lines along which the blast pressure may propagate. Several mechanisms could be envisioned as to how this might occur. In what has been called a thoracic mechanism [3, 27], it has been proposed that a high-pressure blast hitting the body can induce oscillating high-pressure waves that can be transmitted through the systemic circulation to the brain. Blood pressure in the systemic circulation has been shown to rise during passage of the blast pressure wave [28–30]. Because the arterial capacity to expand in response to the sudden increase in blood pressure depends in part on the pressure in the surrounding parenchyma, brain damage might result from pressure differentials between the pressure on the arterial walls and that in the neighboring parenchyma. A lower pressure in the surrounding brain would allow the arterial wall to expand as a consequence of a sudden increase in blood pressure leading to tissue damage at high/low pressure interphases. This situation could occur if the blast-induced brain compression is not uniform or if the head is partially exposed to the blast creating regions of higher and lower pressures. The contribution of a thoracic mechanism could be directly tested in our model by performing shielding experiments that limit the blast exposure to either head or body. Simultaneous monitoring of blood pressure and intracranial pressure with comparisons of the time course of intracranial pressure and blood pressure changes could also help to tease out the relationship between systemic and brain factors.
A vascular mechanism is supported by the finding in some instances of microscopic hemorrhages in vessels within the lesion. In other instances, even when a direct vascular lesion is not visible, it can be speculated that lesions followed a penetrating vessel or were the result of pressure transmitted through a specific vascular territory. For example, the lesion in Figure 7 might have arisen from a high-pressure wave transmitted through the vessels supplying the piriform cortex and the lateral olfactory tract resulting in compression and mechanical disruption of the neighboring tissue and causing a tear through which the lateral olfactory tract was avulsed. Dilated vessels such as those seen in Figure 9 in the hippocampus could have been responsible for rupturing and displacing neighboring tissue to the more dorsal CA1 region. However, despite the fact that isolated vascular pathology was observed, few lesions whether acute or chronic showed any evidence of hemorrhage and most lesions could not be unequivocally associated with a vascular origin. In addition, if pressures were transmitted through the vascular bed it is curious that vessels sufficiently dilated to produce the type of lesions observed would not result in more cases of obvious hemorrhage.
Alternatively, hemorrhages might not occur if the blast pressure were transmitted through the vascular compartment but not intravascularly. This could occur if the main pressure wave was being transmitted through the Virchow-Robin compartment. Several studies have documented that intracranial pressure increases acutely following blast exposure [7, 15, 20–27, 31, 32]. Increased CSF pressure transmitted through the Virchow-Robin compartment could generate local pressure differentials at the interface between the vascular basal lamina and the surrounding tissues. Shearing along this plane would conceptually leave the blood vessel wall intact preventing hemorrhages.
Computer modeling has suggested that blast-associated shear strains should be at their highest at the brain/CSF interface  where cavitation effects could occur which have long been speculated as playing a major role in the deleterious effects of blast exposure [31, 34]. Another study suggested that highest shear strains should occur at the skull/brain interface  consistent with our observation that lesions are found at the cortical surface where the shear wave would move perpendicular to the longitudinal blast wave. Whether propagating as a pressure wave through the ventricular system or generated at the cortical surface such a mechanism could explain expansion of lesions along vascular fault lines without production of hemorrhage.
Here we used the rat to model mTBI resulting from blast overpressure exposure. We describe a new type of shear injury in the brain that has not been described in non-blast TBI models and appears to be unique to blast-associated brain injury. Why they occur in such a focal fashion when the entire brain is presumably subjected to the same blast exposure remains unclear. Yet, the fact that lesions often follow penetrating cortical vessels suggests that blood vessels may represent the fault lines along which the most damaging blast pressure is transmitted.
Functionally, the effects of these lesions remain speculative. In prior studies we have shown that these animals exhibit chronic behavioral and biochemical changes [7, 8]. Focal lesions might be responsible for focal dysfunction in some animals. However, given the low occurrence of the lesions in a given animal, it is unclear whether they can explain the full behavioral and biochemical phenotype. However, the dramatic nature of the lesions, from a neuropathological point of view, suggests that locally constrained but significant parenchymal stress and damage may result in more widespread functional consequences in our model.
Amyloid precursor protein
Glial fibrillary acidic protein
Ionized calcium-binding adapter molecule 1
Improvised explosive devices
Post-traumatic stress disorder
Smooth muscle actin
Traumatic brain injury
Terminal deoxynucleotidyltransferase-mediated dUTP, nick-end labeling.
We thank Bridget Wicinski for expert technical assistance. We thank Drs. Peter Davies, and Robert Lazzarini for gifts of antibodies. This work was supported by grant 1I01RX000179-01 from the Department of Veterans Affairs. MAGS is supported by the General Medical Research Service, James J. Peters VA Medical Center. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense nor the U.S. Government.
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