Rapid hematoma growth triggers spreading depolarizations in experimental intracortical hemorrhage

Abstract

Recurrent waves of spreading depolarization (SD) occur in brain injury and are thought to affect outcomes. What triggers SD in intracerebral hemorrhage is poorly understood. We employed intrinsic optical signaling, laser speckle flowmetry, and electrocorticography to elucidate the mechanisms triggering SD in a collagenase model of intracortical hemorrhage in mice. Hematoma growth, SD occurrence, and cortical blood flow changes were tracked. During early hemorrhage (0–4 h), 17 out of 38 mice developed SDs, which always originated from the hematoma. No SD was detected at late time points (8–52 h). Neither hematoma size, nor peri-hematoma perfusion were associated with SD occurrence. Further, arguing against ischemia as a trigger factor, normobaric hyperoxia did not inhibit SD occurrence. Instead, SDs always occurred during periods of rapid hematoma growth, which was two-fold faster immediately preceding an SD compared with the peak growth rates in animals that did not develop any SDs. Induced hypertension accelerated hematoma growth and resulted in a four-fold increase in SD occurrence compared with normotensive animals. Altogether, our data suggest that spontaneous SDs in this intracortical hemorrhage model are triggered by the mechanical distortion of tissue by rapidly growing hematomas.

Spreading Depolarizations Suppress Hematoma Growth in Hyperacute Intracerebral Hemorrhage in Mice

“…Here, we show that SDs slow hemorrhage growth during acute (0-4 hours) experimental cortical hemorrhage and implicate the vasoconstrictive effect of SDs as the mechanism by which hemorrhage growth is suppressed (Figure 6). Considering that rapid hematoma expansion can lead to secondary hematoma growth via rupture of nearby arterioles, 34 slowing hematoma growth by SD may prevent such secondary growth as well. Clinically, oligemia is commonly observed in the perihematomal tissue, [41][42][43][44] and it is tempting to speculate a causal link to SD occurrence.…”

“…The occurrence of SD during hyperacute intracerebral hemorrhage is well documented in the experimental setting, including gyrencephalic swine. 29,30,33,34 However, clinical, electrophysiological detection of SD has so far been limited to later stages because of the need for a craniectomy for hematoma evacuation to place the recording electrodes. [26][27][28]31,32 Therefore, although highly likely, we do not know with certainty whether SD occurs in hyperacute intracerebral hemorrhage in the human brain.…”

“…General surgical preparation was performed as described previously. 34 Briefly, mice were allowed to breathe spontaneously under isoflurane anesthesia (2.5% induction, 1%-1.25% maintenance in 69% N 2 /30% O 2 ). Blood pressure was continuously monitored via a femoral artery catheter (PowerLab; ADInstruments, Colorado Springs, MO).…”

“…We have recently shown that rapid hematoma growth precedes and precipitates SDs during the hyperacute phase (0-4 hours) of intracerebral hemorrhage in a cortical collagenase model in mice. 34 Here, we examined the impact of those SDs on hematoma growth and volume. Data reveal a previously unrecognized protective effect of SDs limiting hyperacute intracerebral hemorrhage growth in this experimental model.…”

Numerical Simulation of Concussive-generated Cortical Spreading Depolarization to Optimize DC-EEG Electrode Spacing for Non-invasive Visual Detection

“…These issues could be explored for their connection to the mechanism of SD generation by brain deformation. A recent study suggests spontaneous SDs in an “intracortical hemorrhage model are triggered by the mechanical distortion of tissue by rapidly growing hematomas” [82].…”