The coupling of cerebral blood flow (CBF) to neuronal activity is well preserved during evolution. Upon changes in the neuronal activity, an incompletely understood coupling mechanism regulates diameter changes of supplying blood vessels, which adjust CBF within seconds. The physiologic brain tissue oxygen content would sustain unimpeded brain function for only 1 second if continuous oxygen supply would suddenly stop. This suggests that the CBF response has evolved to balance oxygen supply and demand. Surprisingly, CBF increases surpass the accompanying increases of cerebral metabolic rate of oxygen (CMRO 2 ). However, a disproportionate CBF increase may be required to increase the concentration gradient from capillary to tissue that drives oxygen delivery. However, the brain tissue oxygen content is not zero, and tissue pO 2 decreases could serve to increase oxygen delivery without a CBF increase. Experimental evidence suggests that CMRO 2 can increase with constant CBF within limits and decreases of baseline CBF were observed with constant CMRO 2 . This conflicting evidence may be viewed as an oxygen paradox of neurovascular coupling. As a possible solution for this paradox, we hypothesize that the CBF response has evolved to safeguard brain function in situations of moderate pathophysiological interference with oxygen supply. Keywords: brain; CMRO 2 ; functional hyperemia; neurovascular coupling; oxygen A quick glance at basic numbers of oxygen and glucose delivery to the brain and cerebral energy metabolism suggests that the most delicate function of cerebral blood flow (CBF) is the delivery of sufficient amounts of oxygen to the tissue where the oxygen reserve is so low that ATP production declines almost immediately once blood flow ceases. Therefore, the intuitive explanation for the rapid and large CBF response to neuronal activation is the supply of the additional oxygen needed. Experimental observations of large CBF responses accompanying small increases of cerebral metabolic rate of oxygen (CMRO 2 ), however, have cast doubt on this intuitive assumption. A number of alternative hypotheses may reconcile the seemingly conflicting findings: (1) A small increase of CMRO 2 may only be possible with a large increase in CBF due to physical limitations of oxygen delivery.
Journal of Cerebral Blood(2) The large CBF response may be necessary to ensure oxygen delivery to the areas most distant from blood supply. (3) The large CBF response may not be necessary in its full extent but may have evolved as a safety mechanism ensuring sufficient oxygen supply in situations where oxygen delivery to the brain is impaired. (4) The large CBF response may be necessary for reasons other than oxygen delivery.In this opinion paper, we discuss studies on brain energy metabolism and neurovascular coupling. Based on the available evidence, we hypothesize that the surprisingly large CBF response to neuronal activation has evolved as a safety mechanism for oxygen delivery. To support this hypothesis, we first review basic facts on ...