Thermodynamic limitations on brain oxygen metabolism: physiological implications

Abstract

A recent hypothesis is that maintaining the brain tissue ratio of O2 to CO2 is critical for preserving the entropy increase available from oxidative metabolism of glucose, with a fall of that available entropy leading to a reduction of the phosphorylation potential and impairment of brain energy metabolism. The hypothesis suggests that physiological responses under different conditions can be understood as preserving tissue O2/CO2. To test this idea, a mathematical model of O2 and CO2 transport was used to calculate how well different physiological responses maintain tissue O2/CO2, showing good agreement with reported experimental measurements for increased neural activity, hypercapnia and hypoxia. The results highlight the importance of thinking about brain blood flow as a way to modulate tissue O2/CO2, rather than simply in terms of O2 delivery to the capillary bed. The hypoxia modeling focused on humans at high altitude, including acclimatized lowlanders and adapted populations, with a primary finding that decreasing CO2 by increasing ventilation rate is much more effective for preserving tissue O2/CO2 than increasing blood hemoglobin content. The modeling provides a new framework and perspective for understanding how blood flow and other physiological factors support energy metabolism in the brain under a wide range of conditions.

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

“…We assessed whether this criterion alone could predict the experimental values of NVC coupling and OEF 0 . As shown in Figure S6A, and in agreement with Buxton (2021Buxton ( , 2023, the value of pO T 2 /pCO T 2 during activation is highly dependent on the NVC constant being close to uniform at the experimental value of n = 2.28 when OEF 0 is also at its experimental mean value of 0.42. However, as shown in Figure S6B,C, when n = 2.28, the pO T 2 /pCO T 2 ratio as a function of CMRO 2 ′ is close to constant regardless of large variations in OEF 0 and R glyc .…”

“…Using Monte Carlo and sensitivity analysis we found that optimization of n and OEF 0 with the objective of minimizing deviations in the levels of pH, pCO 2 , and pO 2 resulted in a narrow range of values similar to those measured in vivo. In contrast to previous work, in which variations in pO 2 or pO T 2 ∕ pCO T 2 were minimized (Buxton, 2010(Buxton, , 2021Buxton, 2023;Gjedde, 2005), OEF 0 did not have to be assumed.…”

“…Using Monte Carlo and sensitivity analysis we found that optimization of and with the objective of minimizing deviations in the levels of , , and resulted in a narrow range of values similar to those measured in vivo. In contrast to previous work, in which variations in or were minimized (Buxton, 2010, 2021; Buxton, 2023; Gjedde, 2005), did not have to be assumed. Implications of these findings for the decline in brain function with aging and neurovascular disease, as well as for the evolution of brain size and energy metabolism are discussed.…”

“…Another potential mechanism by which brain function is sensitive to is a shift in the tissue ratio, which based on theoretical calculations could reduce the efficiency of mitochondrial production if it dropped below 50% of preactivation values (Buxton, 2021, 2023). Buxton (2021, 2023) calculated that maintenance of a constant ratio accurately predicts in vivo measurements of NVC during activation and other conditions independent of nonoxidative glycolysis. We assessed whether this criterion alone could predict the experimental values of NVC coupling and .…”

Two distinct modes of hemodynamic responses in the human brain

“…Early studies using positron emission tomography (PET) have demonstrated that a modest increase in CMRO2 is accompanied by a much larger increase in CBF (Fox et al, 1988;Fox & Raichle, 1986), resul ng in a ∆CBF/∆CMRO2 ra o (n-ra o) of approximately 2-4 and, consequently, a posi ve BOLD response (Ances et al, 2008;Buxton, 2010;Uludağ et al, 2004). Although the regulatory mechanisms of this hemodynamic response are s ll subject to debate (A. D. Ekstrom, 2021;Hillman, 2014), this overcompensa ng CBF likely maintains the par al pressure of oxygen in capillaries to allow diffusion into brain ssue (Buxton, 2020(Buxton, , 2023DiNuzzo et al, 2023).…”