Spreading depolarizations are not only electrochemical waves, but also elicit profound changes in cerebral blood flow. These changes can help brain tissue recover, or in pathologic conditions, may worsen injury through a process known as spreading ischemia.
In otherwise healthy cortex, spreading depolarization (SD) acts as a potent stimulus to increase regional cerebral blood flow (rCBF) (= spreading hyperemia) in order to meet the increased energy demand and to clear the extracellular space from metabolites. A shallow initial hypoperfusion sometimes precedes the hyperemia, and a very prolonged, moderate hypoperfusion (= oligemia) follows it (Lauritzen 1994). This sequence of rCBF changes applies to naïve cortex of almost all properly investigated mammals (Santos et al 2014). With sufficient temporal resolution, traces of the blood-oxygen-level dependent (BOLD) signal from a functional magnetic resonance imaging (MRI) study in migraineurs with aura suggested that the rCBF response to SD in otherwise healthy human cortex follows the same pattern (Hadjikhani et al 2001).
By contrast, SD can cause severe vasoconstriction instead of vasodilatation by inverse neurovascular coupling under pathological conditions (see movie-1) (Dreier et al 1998). This causes severe hypo- instead of hyperperfusion, which runs together with the depolarization wave in the tissue (= spreading ischemia). In contrast to the physiological oligemia (cf. above), spreading ischemia starts during the massive disturbance of ion homeostasis and delays its recovery. Key process underlying spreading ischemia is a vicious circle between vasoconstrictors released by neurons/astrocytes and vasoconstriction-induced perpetuation of neuronal/astrocytic depolarization (Dreier 2011). Interestingly, vasodilators such as the L-type calcium antagonist nimodipine or the NO-donor S-nitroso-N-acetylpenicillamine caused pharmacologically induced spreading ischemia to revert to almost normal spreading hyperemia (Dreier et al 1998; Dreier et al 2001).
When cortex was selectively exposed to erythrocyte products in rats, spreading ischemias by themselves, i.e. without preceding ischemia, were sufficient to cause widespread cortical necrosis (Dreier et al 2000). When spreading ischemias occurred as a consequence of middle cerebral artery occlusion (MCAO), they expanded the ischemic core (see movie-2) (Shin et al 2006; Strong et al 2007). Spreading ischemia was moreover observed in rats during incomplete global forebrain ischemia (Bere et al 2014). In clinical studies, spreading ischemia was recorded in patients with aneurysmal subarachnoid hemorrhage (aSAH) (Dreier et al 2009), malignant hemispheric stroke (Woitzik et al 2013) and traumatic brain injury (Hinzman et al 2014) with durations of more than two hours after aSAH. Spreading ischemia is a promising target for novel therapeutic strategies.
- Bere Z, Obrenovitch TP, Bari F, Farkas E (2014) Ischemia-induced depolarizations and associated hemodynamic responses in incomplete global forebrain ischemia in rats. Neuroscience 260:217-26
- Dreier JP, Korner K, Ebert N, Gorner A, Rubin I, Back T, Lindauer U, Wolf T, Villringer A, Einhaupl KM, Lauritzen M, Dirnagl U (1998) Nitric oxide scavenging by hemoglobin or nitric oxide synthase inhibition by N-nitro-L-arginine induces cortical spreading ischemia when K+ is increased in the subarachnoid space. J Cereb Blood Flow Metab 18:978-90
- Dreier JP, Ebert N, Priller J, Megow D, Lindauer U, Klee R, Reuter U, Imai Y, Einhaupl KM, Victorov I, Dirnagl U (2000) Products of hemolysis in the subarachnoid space inducing spreading ischemia in the cortex and focal necrosis in rats: a model for delayed ischemic neurological deficits after subarachnoid hemorrhage? J Neurosurg 93:658-66
- Dreier JP, Petzold G, Tille K, Lindauer U, Arnold G, Heinemann U, Einhaupl KM, Dirnagl U (2001) Ischaemia triggered by spreading neuronal activation is inhibited by vasodilators in rats. J Physiol 531:515-26
- Dreier JP, Major S, Manning A, Woitzik J, Drenckhahn C, Steinbrink J, Tolias C, Oliveira-Ferreira AI, Fabricius M, Hartings JA, Vajkoczy P, Lauritzen M, Dirnagl U, Bohner G, Strong AJ (2009) Cortical spreading ischaemia is a novel process involved in ischaemic damage in patients with aneurysmal subarachnoid haemorrhage. Brain 132:1866-81
- Dreier JP (2011) The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med 17:439-47
- Hadjikhani N, Sanchez Del Rio M, Wu O, Schwartz D, Bakker D, Fischl B, Kwong KK, Cutrer FM, Rosen BR, Tootell RB, Sorensen AG, Moskowitz MA (2001) Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A 98:4687-92
- Hinzman JM, Andaluz N, Shutter LA, Okonkwo DO, Pahl C, Strong AJ, Dreier JP, Hartings JA (2014) Inverse neurovascular coupling to cortical spreading depolarizations in severe brain trauma. Brain 137:2960-72
- Lauritzen M (1994) Pathophysiology of the migraine aura. The spreading depression theory. Brain 117 ( Pt 1):199-210
- Santos E, Scholl M, Sanchez-Porras R, Dahlem MA, Silos H, Unterberg A, Dickhaus H, Sakowitz OW (2014) Radial, spiral and reverberating waves of spreading depolarization occur in the gyrencephalic brain. Neuroimage 99:244-55
- Shin HK, Dunn AK, Jones PB, Boas DA, Moskowitz MA, Ayata C (2006) Vasoconstrictive neurovascular coupling during focal ischemic depolarizations. J Cereb Blood Flow Metab 26:1018-30
- Strong AJ, Anderson PJ, Watts HR, Virley DJ, Lloyd A, Irving EA, Nagafuji T, Ninomiya M, Nakamura H, Dunn AK, Graf R (2007) Peri-infarct depolarizations lead to loss of perfusion in ischaemic gyrencephalic cerebral cortex. Brain 130:995-1008
- Woitzik J, Hecht N, Pinczolits A, Sandow N, Major S, Winkler MK, Weber-Carstens S, Dohmen C, Graf R, Strong AJ, Dreier JP, Vajkoczy P (2013) Propagation of cortical spreading depolarization in the human cortex after malignant stroke. Neurology 80:1095-102