The classic concept of the viability thresholds of ischemia differentiates 
between two critical flow rates, the threshold of electrical failure and the 
threshold of membrane failure. These thresholds mark the upper and lower flow 
limits of the ischemic penumbra which is thought to suffer only functional but 
not structural injury. Recent studies of the functional and metabolic 
disturbances suggest a more complex pattern of thresholds. At declining flow 
rates, protein synthesis is inhibited at first (at a threshold of about 0.55 
ml/gm/min), followed by a stimulation of anaerobic glycolysis (at 0.35 
ml/gm/min), the release of neurotransmitters and the beginning disturbance of 
energy metabolism (at about 0.20 ml/min), and finally the anoxic depolarization 
(< 0.15 ml/gm/min). The penumbra, as defined by the classic flow thresholds, 
does not remain viable for extended periods. Since viability of the tissue 
requires maintenance of energy-dependent metabolic processes, penumbra is 
redefined as a region of constrained blood supply in which the energy metabolism 
is preserved. Imaging of the penumbra by combining autoradiographic cerebral 
blood flow measurements with bioluminescent images of adenosine triphosphate 
(ATP) demonstrates a gradual expansion of the infarct core (in which ATP is 
depleted) into the penumbra until, after a few hours, the penumbra has 
disappeared. It is suggested that the limited survival of the penumbra is due to 
periinfarct depolarizations, which result in repeated episodes of tissue 
hypoxia, because the increased metabolic workload is not coupled to an adequate 
increase of collateral blood supply. This explains pharmacological suppression 
of periinfarct depolarizations lowering the threshold of metabolic disturbances 
and reducing the volume of the ischemic infarct.