Neurovascular coupling is optimized to compensate for the increase in proton production from nonoxidative glycolysis and glycogenolysis during brain activation and maintain homeostasis of pH, pCO2, and pO2

During transient brain activation cerebral blood flow (CBF) increases substantially more than cerebral metabolic rate of oxygen consumption (CMRO2) resulting in blood hyperoxygenation, the basis of BOLD-fMRI contrast. Explanations for the high CBF versus CMRO2 slope, termed neurovascular coupling (NVC) constant, focused on maintenance of tissue oxygenation to support mitochondrial ATP production. However, paradoxically the brain has a 3-fold lower oxygen extraction fraction (OEF) than other organs with high energy requirements, like heart and muscle during exercise. Here, we hypothesize that the NVC constant and the capillary oxygen mass transfer coefficient (which in combination determine OEF) are co-regulated during activation to maintain simultaneous homeostasis of pH and partial pressure of CO2 and O-2 (pCO(2) and pO(2)). To test our hypothesis, we developed an arteriovenous flux balance model for calculating blood and brain pH, pCO(2), and pO(2) as a function of baseline OEF (OEF0), CBF, CMRO2, and proton production by nonoxidative metabolism coupled to ATP hydrolysis. Our model was validated against published brain arteriovenous difference studies and then used to calculate pH, pCO(2), and pO(2) in activated human cortex from published calibrated fMRI and PET measurements. In agreement with our hypothesis, calculated pH, pCO(2), and pO(2) remained close to constant independently of CMRO2 in correspondence to experimental measurements of NVC and OEF0. We also found that the optimum values of the NVC constant and OEF0 that ensure simultaneous homeostasis of pH, pCO(2), and pO(2) were remarkably similar to their experimental values. Thus, the high NVC constant is overall determined by proton removal by CBF due to increases in nonoxidative glycolysis and glycogenolysis. These findings resolve the paradox of the brain's high CBF yet low OEF during activation, and may contribute to explaining the vulnerability of brain function to reductions in blood flow and capillary density with aging and neurovascular disease.

Automated summary

During brain activation, cerebral blood flow increases more than cerebral metabolic rate of oxygen consumption, resulting in blood hyperoxygenation. The high neurovascular coupling constant in the brain is maintained to support mitochondrial ATP production and maintain homeostasis of pH, pCO2, and pO2. The optimal values of the neurovascular coupling constant and oxygen extraction fraction (OEF) are remarkably similar to their experimental values.