Penetrating ballistic-like brain injury in the rat: differential time courses of hemorrhage, cell death, inflammation, and remote degeneration.

Acute and delayed cerebral injury was assessed in a recently developed rat model of a penetrating ballistic-like brain injury (PBBI). A unilateral right frontal PBBI trajectory was used to induce survivable injuries to the frontal cortex and striatum. Three distinct phases of injury progression were observed. Phase I (primary injury, 0-6 h) began with immediate (<5 min) intracerebral hemorrhage (ICH) that reached maximal volumetric size at 6 h (27.0 +/- 2.9 mm(3)). During Phase II (secondary injury, 6-72 h), a core lesion of degenerate neurons surrounding the injury track expanded into peri-lesional areas to reach a maximal volume of 69.9 +/- 6.1 mm(3) at 24 h. The core lesion consisted of predominately necrotic cell death and included marked infiltration of both neutrophils (24 h) and macrophages (72 h). Phase III (delayed degeneration, 3-7 days) involved the degeneration of neurons and fiber tracts remote from the core lesion including the thalamus, internal capsule, external capsule, and cerebral peduncle. Overall, different time courses of hemorrhage, lesion evolution, and inflammation were consistent with complementary roles in injury development and repair, providing key information about these mediators of primary, secondary, and delayed brain injury development. The similarities/differences of PBBI to other focal brain injury models are discussed.

AC electrocorticographic correlates of peri-infarct depolarizations during transient focal ischemia and reperfusion.

Several studies have highlighted a delayed secondary pathology developing after reperfusion in animals subjected to prolonged cerebral ischemia, and recently we have shown that peri-infarct depolarizations (PIDs) occur not only during ischemia, but also in this delayed period of infarct maturation. Here we study the electrocorticographic (ECoG) manifestations of PIDs as signatures of developing secondary pathology. DC- and traditional AC-ECoG signals were recorded continuously from epidural, nonpolarizable electrodes during 2 h of middle cerebral artery occlusion (MCAo) and 22 h of reperfusion in freely behaving rats. During MCAo, seizures and PIDs recurred frequently and their incidence was significantly correlated. After reperfusion, seizures and PIDs ceased, and for the next several hours delta wave abnormalities dominated the ECoG with progressively increasing amplitude. After a variable period (5 to 15 h), the ECoG amplitude decremented with the onset of a prolonged repetitive series of PIDs. Initial PIDs in this delayed phase produced transient depressions of the high amplitude ECoG signal, but thereafter the ECoG was persistently attenuated, with no transient depressions during subsequent PIDs. The time of onset of postreperfusion PIDs, and hence measures of ECoG attenuation, correlated with 24 h infarct volumes. PIDs could always be detected in baseline shifts of the AC-ECoG signal with a low high-pass cutoff setting. These results suggest that delayed PIDs after reperfusion contribute to a complex secondary pathology involving delayed edema, intracranial hypertension, and hypoperfusion. The manifestation of PIDs in ECoG/electroencephalography recordings may enable continuous real-time monitoring of infarct progression.

Characterization of a new rat model of penetrating ballistic brain injury.

Penetrating brain injury (PBI) is a leading cause of mortality and morbidity in modern warfare and accounts for a significant number of traumatic brain injuries worldwide. Here we characterize the pathophysiology of a new rat model of PBI that simulates the large temporary cavity caused by energy dissipation from a penetrating bullet round. Male Sprague-Dawley rats (250-300 g) were subjected to a simulated ballistic wound to the right frontal hemisphere implemented by an inflatable penetrating probe. Three levels of injury severity were compared to control animals. Neurological and physiological outcome was assessed over a 3-day recovery period and brain tissue collected at 72 h for histopathological evaluation. Brain-injured regions included the ipsilateral frontal cortex and striatum with volumetric increases in intracranial hemorrhage (5-18 mm3) and lesion size (9-86 mm3) related to severity. Similarly, hemispheric swelling increased (3-14%) following PBI, associated with a significant rise in intracranial pressure. Astrogliosis was present in regions adjacent to the core-injury along with microglial and leukocyte infiltration. Injury remote to the lesion was observed in the cerebral peduncle that may have accounted, in part, for observed neurological deficits. Neurological and balance beam testing revealed sensorimotor deficits that persisted through 72 h. Severe electroencephalographic disturbances included the occurrence of cortical spreading depression, slow-waves, and brain seizure activity. In conclusion, this rat PBI model replicates diverse, salient features of clinical PBI pathology, generates reproducible and quantifiable measures of outcome, and is scalable by injury severity, rendering it an attractive vehicle for experimental brain trauma research.

Delayed secondary phase of peri-infarct depolarizations after focal cerebral ischemia: relation to infarct growth and neuroprotection.

In focal cerebral ischemia, peri-infarct depolarizations (PIDs) cause an expansion of core-infarcted tissue into adjacent penumbral regions of reversible injury and have been shown to occur through 6 hr after injury. However, infarct maturation proceeds through 24 hr. Therefore, we studied PID occurrence through 72 hr after both transient and permanent middle cerebral artery occlusion (MCAo) via continuous DC recordings in nonanesthetized rats. PIDs occurred an average 13 times before reperfusion at 2 hr and then ceased for an average approximately 8 hr. After this quiescent period, PID activity re-emerged in a secondary phase, which reached peak incidence at 13 hr and consisted of a mean 52 PIDs over 2-24 hr. This phase corresponded to the period of infarct maturation; rates of infarct growth through 24 hr coincided with changes in PID frequency and peaked at 13 hr. In permanent MCAo, PIDs also occurred in a biphasic pattern with a mean of 78 events over 2-24 hr. Parameters of secondary phase PID incidence correlated with infarct volumes in transient and permanent ischemia models. The role of secondary phase PIDs in infarct development was further investigated in transient MCAo by treating rats with a high-affinity NMDA receptor antagonist at 8 hr after injury, which reduced post-treatment PID incidence by 57% and provided 37% neuroprotection. Topographic mapping with multielectrode recordings revealed multiple sources of PID initiation and patterns of propagation. These results suggest that PIDs contribute to the recruitment of penumbral tissue into the infarct core even after the restoration of blood flow and throughout the period of infarct maturation.