Initiation site of experimentally-evoked spreading depolarizations influence tissue outcomes in a murine stroke model

Spreading depolarization waves (SDs) are implicated in secondary expansion of brain injuries and are the target for initial clinical intervention trials. However, the assumption that SD directly causes neuronal injury has been challenged by recent findings with experimentally-induced SD in stroke models. The current study addressed this controversy by examining whether stroke consequences are confounded by the precise location of experimental SD initiation. Focal ischemic lesions were generated by transient distal middle cerebral artery occlusion in male mice. Clusters of SDs (6 at 10-min intervals) were induced by either focal KCl application or optogenetic stimulation during occlusion. SDs were initiated either in regions close to the infarct core (penumbral-SD; <50% perfusion) or in less compromised tissue in the same hemisphere (remote-SD; >70% perfusion). Despite the fact that all SDs fully invaded stroke expansion areas, the location of experimental SD induction had significant effects on stroke outcomes measured 48 h after reperfusion. Penumbral-SDs resulted in larger infarct expansion than seen in control stroke mice lacking experimentally-imposed SD. Conversely, remote-SDs led to significantly smaller infarcts than stroke alone. Laser speckle contrast imaging of blood flow in injury expansion areas showed enhanced hypoperfusion responses after penumbral-SDs and larger hyperemic responses after remote-SDs, suggesting that differential vascular responses could contribute to stroke outcomes. Overall, this study helps to reconcile different prior reports by showing that experimentally-induced SDs can either exacerbate or reduce stroke-induced injury depending on the SD initiation site and further strengthens evidence for injurious roles of SDs initiating in vulnerable brain tissue.