Peri-Infarct Hot-Zones Have Higher Susceptibility to Optogenetic Functional Activation-Induced Spreading Depolarizations

Abstract

Background and Purpose: Spreading depolarizations (SDs) are recurrent and ostensibly spontaneous depolarization waves that may contribute to infarct progression after stroke. Somatosensory activation of the metastable peri-infarct tissue triggers peri-infarct SDs at a high rate. Methods: We directly measured the functional activation threshold to trigger SDs in peri-infarct hot zones using optogenetic stimulation after distal middle cerebral artery occlusion in Thy1-ChR2-YFP mice. Results: Optogenetic activation of peri-infarct tissue triggered SDs at a strikingly high rate (64%) compared with contralateral homotopic cortex (8%; P =0.004). Laser speckle perfusion imaging identified a residual blood flow of 31±2% of baseline marking the metastable tissue with a propensity to develop SDs. Conclusions: Our data reveal a spatially distinct increase in SD susceptibility in peri-infarct tissue where physiological levels of functional activation are capable of triggering SDs. Given the potentially deleterious effects of peri-infarct SDs, the effect of sensory overstimulation in hyperacute stroke should be examined more carefully.

Frequency selective neuronal modulation triggers spreading depolarizations in the rat endothelin-1 model of stroke

“…Our experiments showed that following focal cortical ischemia: i ) SDs appear in the ET-1 injection site and in the peri-injection zone following a drop in local vRBC above 60%; ii ) spontaneous SDs and PIPs present in a robust spatio-temporal pattern, with SDs manifesting at the ET-1 injection site and in the peri-injection zone, and PIPs appearing exclusively in the peri-injection zone and strictly following SDs. The threshold of 60% drop in V RBC necessary to trigger SDs observed here is well in line with the 70% threshold observed in the MCAO model, 62 , 63 and to the 45% observed by Bere and collaborators. 64 In both cases, however, a drop in vRBC by 60–70% may be a conservative estimate as the isoflurane anesthesia used in those studies is vasodilatory and known to reduce the volume of vascular bed affected by ischemia, as demonstrated in the photothrombotic model of stroke.…”

“…Thanks to these measurements, we were able to associate vascular and neuronal phenomena, concluding that SDs were generated only during the initial phase of stroke, when V RBC fell to below 40% of its pre-stroke level. While this number may not be directly translatable to humans due to differences in collateral perfusion between species and the use of anesthetics in our experiment, our and others’ work indicate that resting perfusion is significantly higher than the level necessary for supporting resting brain activity, 62 in support of such large perfusion deficit threshold. The high SDs’ spatial variability observed in this preclinical study and their disappearance following spontaneous reperfusion, undersinjection sites the importance of measuring neuronal state in individual subjects.…”

“…Our findings, in a model of focal cortical ischemia, build upon previous work on large-vessel stroke. 25 , 62 …”

Pericytes: Intrinsic Transportation Engineers of the CNS Microcirculation

“…In a study by Khennouf et al (2018) characterizing the effects of physiological stimuli and cortical spreading depression on penetrating arterioles and capillaries, the authors hypothesized that impaired brain hyperemia after spreading depolarization contributes to prolonged cortical dysfunction in patients and that preventing pericyte constriction could reduce the long-lasting decrease in blood flow after spreading depolarization ( Grubb et al, 2020 ; Figure 3 ). It was further shown that peri-infarct depolarizations are triggered by a transient mismatch in supply and demand in the ischemic brain ( Sugimoto et al, 2020 ). Interestingly, a recent study ( Bornstädt et al, 2015 ) proposed that minimizing sensory stimulation and hypoxic or hypotensive transients in stroke reduced the incidence of spreading depolarization and its adverse outcomes.…”

“…(Grubb et al, 2020;Figure 3). It was further shown that peri-infarct depolarizations are triggered by a transient mismatch in supply and demand in the ischemic brain (Sugimoto et al, 2020). Interestingly, a recent study (Bornstädt et al, 2015) proposed that minimizing sensory stimulation and hypoxic or hypotensive transients in stroke reduced the incidence of spreading depolarization and its adverse outcomes.…”