Spreading Depolarization

Spreading depolarization (SD) is the generic term for all waves of abrupt, near-complete breakdown of the neuronal transmembrane ion gradients that cause cytotoxic edema and propagate at about 3 mm/min in cerebral gray matter. The SD continuum describes the spectrum from short-lasting SDs in metabolically intact tissue to SDs of intermediate duration to terminal SD in severely ischemic tissue. Accordingly, SDs occur in human diseases; from the harmless migraine aura to stroke to circulatory arrest. This means that there are overlaps but also large variations in mechanistic aspects along the continuum. For example, SD induces either transient hyperperfusion variably followed by mild oligemia in normal tissue (normal neurovascular response) or severe hypoperfusion (inverse neurovascular response = spreading ischemia) variably followed by hyperemia in tissue at risk for progressive injury.1

We discovered the phenomenon of inverse neurovascular coupling by coincidence in a rat model mimicking the conditions present at the boundary zone between subarachnoid blood and cortical surface after aneurysmal subarachnoid hemorrhage (aSAH).3 In this model, spreading ischemia resulted from topical application of artificial cerebrospinal fluid (ACSF) containing an elevated K+ concentration ([K+]ACSF) in combination with either the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine (L-NNA) or the NO scavenger hemoglobin to the brain cortex (= NO↓/K+↑-model). Notably, the SD-induced spreading ischemia could be the sole cause of widespread cortical infarcts.2 An NO donor caused spreading ischemia to revert to a normal neurovascular response to SD 5. A decade later, we observed spreading ischemia in aSAH patients for the first time.4 In our recent clinical follow-up study, spreading ischemia occurred in the same time window in which serial neuroimaging-proven brain infarcts developed at the recording site.7 This confirmed our original translational hypothesis that spreading ischemia is involved in the pathogenesis of delayed ischemic stroke after aSAH.3
CSD final

Following the recent concept of translational medicine by Marc Fisher 6, this development not only included classic translation from bench to bedside but also reverse and lateral translation. Lateral translation occurs when a proven clinical therapy or technology stimulates basic and/or clinical researchers to enhance these proven modalities. Reverse translation occurs when clinical advances encourage basic science researchers to understand more about the mechanisms underlying clinical observations, technologies or therapies. For example, driven by our clinical findings, we have continued to elucidate the mechanism underlying spreading ischemia in rodent experiments.

One of our recent experimental studies has recently suggested that prolonged elevation of the baseline extracellular K+ concentration ([K+]o) causes rundown of the α2 Na+/K+-ATPase, located in a microdomain above the endoplasmic reticulum.8 This may result in increased Ca2+ uptake by internal stores of astrocytes, vascular myocytes and pericytes since Ca2+ outflux via plasmalemmal Na+/Ca2+-exchanger declines. Augmented Ca2+ mobilization from internal stores during SD could then enhance vasoconstriction, thereby contributing to spreading ischemia. However, augmented Ca2+ mobilization activates constitutive NOS, thereby antagonizing vasoconstriction. This could explain why spreading ischemia in the NO↓/K+↑-model requires reduced NO availability in addition to elevated baseline [K+]o. Further insight into the mechanisms underlying inverse neurovascular coupling could help us to find novel treatment strategies in the clinic following the tenet espoused by Max Planck that ‘insight must precede application’.
Recommended product: PSI HR

Case example: Center for Stroke Research Berlin, Charité University Medicine Berlin

Prof. Dr. med. Jens P. Dreier Charité University Medicine Berlin, Germany Center for Stroke Research Berlin

The inverse neurovascular response to SD is observed as a spreading perfusion deficit causing prolongation of SD (Dreier 2011). Laser Speckle Contrast Analysis (LASCA or LSCI) is an ideal tool to differentiate the normal (fig. 1) from the inverse neurovascular response to SD (fig. 2) because it visualizes the perfusion changes in space and time, and is easily combined with various electrophysiological methods to measure, for example, SD or additional variables such as tissue partial pressure of oxygen.

Figure 1

Figure 1

Figure 2

Figure 2

Open cranial window experiments in rats. Using Perimed’s PeriCam PSI laser speckle contrast analysis imager, two-dimensional maps of cortical cerebral blood flow are obtained with very high spatial and temporal resolution. Regions of interest can be defined (circles) in which cerebral blood flow is quantified over time. Figure 1 shows typical perfusion changes of an SD-induced spreading hyperemia and figure 2 of an SD-induced spreading ischemia. The left panels give consecutive images and the right panels the time courses of cerebral blood flow in the regions of interest. See the full videos here:

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  • Dreier, J. P. (2011). "The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease." Nat. Med 17(4): 439-447.    
  • Dreier, J. P., N. Ebert, J. Priller, D. Megow, U. Lindauer, R. Klee, U. Reuter, Y. Imai, K. M. Einhaupl, I. Victorov and U. Dirnagl (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(4): 658-666.    
  • Dreier, J. P., K. Korner, N. Ebert, A. Gorner, I. Rubin, T. Back, U. Lindauer, T. Wolf, A. Villringer, K. M. Einhaupl, M. Lauritzen and U. Dirnagl (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(9): 978-990.    
  • Dreier, J. P., S. Major, A. Manning, J. Woitzik, C. Drenckhahn, J. Steinbrink, C. Tolias, A. I. Oliveira-Ferreira, M. Fabricius, J. A. Hartings, P. Vajkoczy, M. Lauritzen, U. Dirnagl, G. Bohner and A. J. Strong (2009). "Cortical spreading ischaemia is a novel process involved in ischaemic damage in patients with aneurysmal subarachnoid haemorrhage." Brain 132(Pt 7): 1866-1881.    
  • Dreier, J. P., G. Petzold, K. Tille, U. Lindauer, G. Arnold, U. Heinemann, K. M. Einhaupl and U. Dirnagl (2001). "Ischaemia triggered by spreading neuronal activation is inhibited by vasodilators in rats." J Physiol 531(Pt 2): 515-526.    
  • Fisher, M. (2013). "The spectrum of translational stroke research." Neurol Res 35(5): 443-447.    
  • Luckl, J., C. L. Lemale, V. Kola, V. Horst, U. Khojasteh, A. I. Oliveira-Ferreira, S. Major, M. K. L. Winkler, E. J. Kang, K. Schoknecht, P. Martus, J. A. Hartings, J. Woitzik and J. P. Dreier (2018). "The negative ultraslow potential, electrophysiological correlate of infarction in the human cortex." Brain 141(6): 1734-1752.    
  • Major, S., G. C. Petzold, C. Reiffurth, O. Windmuller, M. Foddis, U. Lindauer, E. J. Kang and J. P. Dreier (2017). "A role of the sodium pump in spreading ischemia in rats." J Cereb Blood Flow Metab 37(5): 1687-1705.    
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