1.1. 'Normal' and 'inverse' neurovascular coupling to CSD
The term 'cortical spreading depolarization' (CSD) describes the loss of function in the brain's gray matter that is triggered when passive cation influx across the cellular membranes exceeds ATP-dependent Na+ and Ca2+ pump activity. Depolarization of neurons and astrocytes results, followed by cellular swelling and cessation of neuronal function. This mass tissue depolarization propagates through gray matter as a wave, or 'brain tsunami', at ~3 mm/min, and is measured as a slow negative shift, 10-20 mV in amplitude, of the extracellular direct current (DC) potential - the largest extracellular signal generated by the brain.
CSD is a passive process, driven by electrical and diffusion forces. Subsequent repolarization, however, increases energy consumption because additional Na+ and Ca2+ pumps are recruited to correct their harmful intracellular surge. Thus, even in healthy tissue where full repolarization of cellular membranes is achieved within 1-2 min, ATP falls ~50%. To increase oxygen and glucose availability, CSD induces dilation of resistance vessels in healthy tissue. Hence, regional cerebral blood flow (rCBF) increases in response to CSD resulting in cortical spreading hyperemia (CSH), a process which is termed 'normal' neurovascular coupling.
The opposite of the 'normal' neurovascular response, termed 'inverse' neurovascular coupling, occurs when there is local dysfunction of the microvasculature. With 'inverse' coupling, severe microvascular spasm instead of vasodilation is coupled to CSD, resulting in CSI. The perfusion deficit of CSI in turn prolongs the neuronal depolarization since the oxygen-/glucose deprivation further reduces ATP availability (Dreier et al., 1998; Dreier et al., 2000; Windmüller et al., 2005). This is reflected by a prolongation of both the negative DC potential shift and the silencing of neuronal activity. Pharmacologically induced CSI was sufficient to produce widespread focal necrosis in absence of a preceding significant perfusion deficit in rats.2 This suggested that 'inverse' neurovascular coupling is (i) a sufficient condition for CSD to induce cell death, and, thus (ii) a promising target for therapeutic intervention.
1.2. Lesion progression in acute brain injury
The concept of lesion progression originates with the discovery of the ischemic penumbra, the region bordering a core cerebral infarct with rCBF reductions sufficient to depress synaptic activity, but adequate to initially maintain membrane polarization. The penumbra is progressively recruited into the core infarction over time, as shown in clinical imaging studies, and is therefore the target for tissue salvage through early restoration of blood flow or neuroprotective drugs. Without intervention, terminal depolarization in the core gives rise to spontaneous depolarization waves (CSD) that propagate through the penumbra and beyond, causing progressive step-wise expansion of the ischemic core. This effect of CSD is proven to be causal. Accordingly, pharmacological treatments which inhibit CSD also reduce infarct volumes. Unfortunately, however, CSDs become increasingly pharmacoresistant with energy depletion. Recently it has been found that CSDs in the ischemic penumbra of both cats and mice are associated with CSI. This result, together with the finding that CSI alone is sufficient to cause cortical pannecrosis, suggests that the vascular response manifested in CSI, rather than the electrochemical phenomenon of CSD itself, is the critical mechanism of lesion progression.
Lesion progression is also a well-defined clinical entity in aneurysmal subarachnoid hemorrhage (aSAH). Delayed ischemic neurologic deficits (DIND) occur in 33-38% of patients with a peak occurrence around day 7, and 10-13% develop delayed computed tomography (CT)-proven infarcts. The assumed mechanism of DIND is proximal vasospasm resulting from subarachnoid breakdown products of erythrocytes, although the positive predictive value of digital subtraction angiography for the development of DIND is only between 30-50%. A complementary explanation for DIND is the occurrence of CSD, which in the presence of erythrocyte breakdown products, exhibits 'inverse' neurovascular coupling with microarterial spasm arresting microcirculation for minutes to hours (Dreier et al., 1998, 2000, 2006, 2009; Windmüller et al., 2005). Importantly, aSAH is a model disease for the study of lesion progression, since patients can be monitored prior to and throughout the whole period of delayed infarct development.