Distinct Spatiotemporal Patterns of Spreading Depolarizations during Early Infarct Evolution: Evidence from Real-Time Imaging

Abstract

Experimental and clinical studies indicate that waves of cortical spreading depolarization (CSD) appearing in the ischemic penumbra contribute to secondary lesion growth. We used an embolic stroke model that enabled us to investigate inverse coupling of blood flow by laser speckle imaging (CBF LSF ) to CSD as a contributing factor to lesion growth already in the early phase after arterial occlusion. Embolization by macrospheres injected into the left carotid artery of anesthetized rats reduced CBF LSF in the territories of the middle cerebral artery (MCA) (8/14 animals), the posterior cerebral artery (PCA) (2/14) or in less clearly defined regions (4/14). Analysis of MCA occlusions (MCAOs) revealed a first CSD wave starting off during ischemic decline at the emerging core region, propagating concentrically over large portions of left cortex. Subsequent recurrent waves of CSD did not propagate concentrically but preferentially circled around the ischemic core. In the vicinity of the core region, CSDs were coupled to waves of predominantly vasoconstrictive CBF LSF responses, resulting in further decline of CBF in the entire inner penumbra and in expansion of the ischemic core. We conclude that CSDs and corresponding CBF responses follow a defined spatiotemporal order, and contribute to early evolution of ischemic territories.

Neurovascular Coupling During Cortical Spreading Depolarization and –Depression

“…OEF indicates oxygen extraction fraction. Adapted from Kumagai et al 18 with the permission of Macmillan Publishers Ltd. Copyright ©2011, ISCBFM.…”

“…Studies of focal ischemia in both rats and cats confirm that such persisting hypoperfusion after CSD is associated with high risk of tissue injury. [17][18][19] Recent studies have demonstrated that ischemia and oxidative stress are sources of prolonged pericyte constrictions 29,30 ( Figure 1B). By this mechanism, waves of spreading ischemia might hinder (no reflow) or disturb (increase CTH further) the subsequent recovery of tissue perfusion and thereby add to the metabolic derangement of penumbral tissue.…”

“…Figure 6C shows sequential laser speckle contrast images (left) obtained in a rat model of focal ischemia, demonstrating the CBF responses to a CSD propagating from severely ischemic tissue outwards into less affected tissue. 18 The time courses (D, K, Q and V) illustrate the characteristic transition from positive to negative and prolonged CBF responses in relation to CSD passages, according to the postocclusion CBF reduction. 18,19 Note that CBF remains low after the CSD in the most severely ischemic tissue (labeled V and highlighted by a red circle), unlike the pattern in the right panel of Figure 6B.…”

“…18 The time courses (D, K, Q and V) illustrate the characteristic transition from positive to negative and prolonged CBF responses in relation to CSD passages, according to the postocclusion CBF reduction. 18,19 Note that CBF remains low after the CSD in the most severely ischemic tissue (labeled V and highlighted by a red circle), unlike the pattern in the right panel of Figure 6B. The corresponding tissue (within the dashed A B C Figure 6.…”

“…16 In rat and cat models of focal ischemia, CSD-related CBF transients range from monophasic, positive CBF responses in peri-ischemic tissue, over biphasic transients in mildly ischemic tissue, to negative CBF transients in more severe ischemia. [17][18][19] During CSD in animal models, capillary flow patterns become severely disturbed. 10,20,21 The passage of a CSD causes erythrocytes in some capillaries to reduce their speed, whereas other capillaries reveal 4-fold increases in flow or higher.…”