What is the point of cerebral blood flow?

Teleological justification – that is, assigning function to phenomena as opposed to describing in purely mechanistic terms – is inescapable in Physiology, due to the explanatory power it brings. Think: the heart pumps blood in order to supply a situation-appropriate cardiac output and properly compensates when called upon. This teleological justification of cardiac function as serving cardiac output is relatively agreeable, and a vast body of literature both supports it and takes it as a tacit premise. Nevertheless, a number of physiologists have presented alternative non-cardiocentric conceptualizations of cardiac function (e.g. Furst & González-Alonso, 2023; Stöhr, 2022). Stöhr (2022) suggested that perhaps cardiac function serves a different, as yet unknown, purpose. Stöhr posits: perhaps the creation of a specific cardiac output is an example of accidental utility rather than purpose. Furst and González-Alonso (2023) extended this: the heart's purpose is to equilibrate arterial and venous forces, but the movement of blood is ‘primed’ by metabolic processes. Perhaps neither explanation is perfectly correct and the answer lies dynamically somewhere amongst the proposed theories. This matter may be discussed heatedly by cardiac physiologists and rightly so; challenges to convention require testing, but can, if found to be the case, generate new directions and questions in the field. In a similar vein, regarding cerebral vascular function rather than cardiac function, in the current issue of The Journal of Physiology, Professor Buxton suggests an extension to the current teleological understanding of the function served by cerebral sensitivity to blood gases (Buxton, 2024). He suggests that the responses of cerebral blood flow (CBF) to neural activation, hypoxia and hypercapnia occur to maintain the ratio of O2 to CO2 in brain tissue, which aids in preserving an appropriate phosphorylation potential, and thus protects cerebral metabolism. Should the brain tissue O2/CO2 ratio fall below a critical threshold, cerebral metabolism will also be compromised. Professor Buxton uses exceptionally comprehensive thermodynamic modelling of O2 and CO2 convective and diffusive transport to estimate the brain tissue O2/CO2 ratio during different physiological states (e.g. neural activation, hypoxia and hypercapnia). Then, these estimates are compared to the O2/CO2 ratio calculated from published data of CBF and blood gases. Buxton's work provides a new perspective for understanding how CBF – through O2 and CO2 transport – aids upkeep of cerebral metabolism (see Fig. 1). Further assessment of brain tissue O2/CO2 by use as an outcome measure during exposure to various environmental and physiological states would aid deliberation of this new teleology's utility and explanatory power. For instance, recent evidence that CM R O 2 ${\mathrm{CM}}{{\mathrm{R}}_{{{\mathrm{O}}_{\mathrm{2}}}}}$ can become reduced during iso-oxic hypercapnia (unpublished observations) could be interpreted through the lens of brain tissue O2/CO2 ratio prioritization. During hypercapnia, elevated tissue P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ cannot be ‘fixed’ by increasing CBF; that is, arterial CO2 increases and, despite continued CO2 washout, tissue CO2 continues to be greater than arterial (aside from during extreme exogenous hypercapnia) due to metabolic production. One could interpret these findings through Buxton's model to indicate that the increase in tissue CO2 during hypercapnia reduces the brain tissue O2/CO2 ratio to a degree that cannot be compensated for via CBF changes, and so cerebral oxidative metabolism is reduced via reduction of the phosphorylation potential. Concerning the contracting heart, Stöhr (2022) argues that principles of cardiac mechanics such as preload and afterload, etc. have been well characterized but in fact should be considered modifying principles rather than teleological explanations which illuminate the purpose of the beating of the heart ‘… because they modify cardiac contraction but they themselves do not explain it, since no clear biological purpose has been established in relation to these principles…’. This change in perspective could be considered akin to Buxton's. They, in essence, argue that the understanding of cerebral vascular physiology concerning (1) reactivity to hypoxia in order to maintain tissue P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ and (2) reactivity to hypo- and hypercapnia to maintain tissue pH merely describe the activity of the modifying principles of CBF control, while the ‘clear biological purpose’ is yet lacking. I believe no-one disagrees that CBF serves cerebral metabolism, via control of O2 delivery and pH regulation/CO2 washout; however, Buxton expands this convention to suggest that protection of metabolism occurs through the maintenance of the brain tissue O2/CO2 ratio. Indeed, the maintenance of such an O2/CO2 ratio is the biological purpose explaining CBF sensitivity. Distinguishing authentic biological function from accidental utility is a challenge that should be embraced. Disputes regarding the teleological purpose of biological functions often receive confused objection from advocates of the established order. Yet, the charge of our calling is to take these challenges and subject them to empirical examination through shrewd study design and careful measurement to tease out the truth, if it exists. The consideration here is thus: (1) Does CBF truly serve tissue P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ and tissue pH during hypoxia and hypo- and hypercapnia, while the maintenance of the conceptual ‘tissue O2/CO2 ratio’ occurs merely by accident? Or (2) does CBF truly serve tissue O2/CO2 due to the ratio's direct ties to the phosphorylation potential, while the conservation of tissue P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ and tissue pH occurs accidently. Disentangling this would somehow require simultaneous measurement (difficult) of all factors during isolated manipulations of each (impossible?). Assuredly, the noumenal reality is likely a combination of these options and more, where cerebral vascular reactivity functions to maintain cerebral metabolism through appropriate responses to the combined ‘pressures’ of all measurable and unmeasurable factors (e.g. heat, pH, P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ , P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ , perfusion pressure, all relevant cations and anions, all endo-, para- and autocrine signals, etc. plus the trans-cerebral gradients of each), and would therefore be best explained by some unifying theory of everything. But, which explanation, among the contemporary options, cuts closest to the truth and is of the greatest utility to us as physiologists? To echo Professor Joyner's (2024) conclusion regarding Furst and González-Alonso (2023), if Buxton's complex ‘brain tissue O2/CO2 ratio’ context proves to hold true in more situations than the arguably simpler alternatives, offers more explanatory power, and offers more useful insights and applications, then it should be taken up. Either way, there is work to be done. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared. Sole author. No funding was received for this work.

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