When a cerebral infarction occurs, surrounding the core of dying tissue there 
usually is an ischemic penumbra of nonfunctional but still viable tissue. One 
current but controversial hypothesis is that this penumbra tissue often 
eventually dies because of the metabolic stress imposed by multiple cortical 
spreading depression (CSD) waves, that is, by ischemic depolarizations. We 
describe here a computational model of CSD developed to study the implications 
of this hypothesis. After simulated infarction, the model displays the linear 
relation between final infarct size and the number of CSD waves traversing the 
penumbra that has been reported experimentally, although damage with each 
individual wave progresses nonlinearly with time. It successfully reproduces the 
experimental dependency of final infarct size on midpenumbra cerebral blood flow 
and potassium reuptake rates, and predicts a critical penumbra blood flow rate 
beyond which damage does not occur. The model reproduces the dependency of CSD 
wave propagation on N-methyl-D-aspartate activation. It also makes testable 
predictions about the number, velocity, and duration of ischemic CSD waves and 
predicts a positive correlation between the duration of elevated potassium in 
the infarct core and the number of CSD waves. These findings support the 
hypothesis that CSD waves play an important causal role in the death of ischemic 
penumbra tissue.