On the limits of cerebral oxygen extraction

There are over 60 peer-reviewed reports of cerebral blood flow (CBF) changes during exercise. A recurrent finding is that CBF increases by 10–30% from rest to ∼60% of peak oxygen uptake, and thereafter decreases towards, or even below, baseline as exercise intensity progresses. The reduction in CBF at later stages of exercise occurs despite progressive increases in neuronal activity and cerebral perfusion pressure, which normally act to elevate CBF. These CBF dynamics are best explained by a hyperventilation-induced hypocapnia. Heat stress-induced hyperventilation, both at rest and during exercise, is also known to further exacerbate cerebral vasoconstriction and hence reduce CBF. How exercise, in combination with heat stress and/or dehydration, may influence cerebral substrate delivery and metabolism is poorly established. In this issue of The Journal of Physiology is a meritorious study by Trangmar et al. (2014), where ultrasound measurements were made of blood flow through the internal (ICA) and common carotid arteries, middle cerebral artery velocity, brain arterial-to-internal jugular venous differences, and temperature, in 10 trained males during incremental cycling to exhaustion in control, dehydrated (3.1 ± 0.3% reduction in body mass) and rehydrated states. With this insightful and novel experimental design the authors demonstrated that dehydration appeared to accelerate the decline in CBF and oxygen delivery (albeit not significantly between conditions), mediated via reductions in the partial pressure of arterial CO2 () and increased vasoconstrictor activity (as reflected by the relationship between elevations in noradrenaline (NA) with cerebrovascular conductance). However, despite the tendency for reductions in CBF and oxygen delivery, the circulatory strain on the human brain during maximal exercise in the dehydrated state did not compromise the cerebral metabolic rate of O2 (CMRO2) because of a significant compensatory increase in O2 extraction. In view of these novel findings, and in the context of the past literature, a number of topical discussion points arise. Flow, metabolism and extraction. Attributed to increased neuronal activity, some report an elevated CMRO2 with incremental exercise (e.g. Fisher et al., 2013). In Trangmar et al., CMRO2 was well maintained from rest to exercise, in both dehydrated and hydrated states. Why CMRO2 was not increased with exercise might relate to differences in measurement technique between studies. Nonetheless a clear and noteworthy finding in the Trangmar study was the maintenance of CMRO2 in the dehydrated condition, despite greater reductions in CBF and oxygen delivery. This was credited to a proportional increase in O2 extraction. As illustrated in Fig. ​Fig.1,1, the brain has a remarkable capacity to cope with reductions in CBF and O2 delivery by increasing O2 extraction. It is intriguing to note that extraction was only increased from 34% to 39% at maximal exercise, but the capacity is much larger (e.g. 70–80%), as reported in early clinical studies (McHenry et al. 1961). Thus, the brain is probably well able to cope with extremes of exercise and temperature stress. The quantifiable limit of the brain to extract oxygen and protect CMRO2 in conditions of combined and extreme environmental stress (e.g. that of greater dehydration, heat stress, high altitude etc.) is unknown. Figure 1 Cerebral haemodynamics during dehydrated and euhydrated exercise Influence of temperature. According to the Q10 temperature coefficient, CMRO2 should increase by ∼5% per degree increase in core temperature from a resting 37°C. In humans, CMRO2 is elevated by ∼8% during exhaustive exercise at ∼39.5°C compared to ∼37.8°C core temperature (Rasmussen et al. 2010). In Trangmar et al. (2014) jugular venous temperature was ∼1.0°C higher (absolute temperature of 38.2 ± 0.1°C) during the latter stages of dehydrated compared to euhydrated exhaustive exercise; yet CMRO2 was unchanged. Had exercise been prolonged, and core temperature been increased to a greater extent (i.e. >39.0°C) in the dehydrated condition, would CMRO2 be increased, and therefore demand a greater O2 use in accordance with the Q10 temperature coefficient? Role of sympathetic nervous activity in regulating CBF. An additional novel finding in the study by Trangmar and colleagues was that, irrespective of hydration status, the decline in cerebral vascular conductance was associated with a large increase in jugular venous NA and hence may explain some of the decline in CBF over that of the hyperventilation-induced hypocapnia. Because there was no release of NA from the brain, it is likely that this relationship reflects the systemic contribution of NA in cerebrovascular regulation. Regardless, the contribution of both sympathetic nervous activity (SNA) and to reducing CBF seems to be a physiological consequence of operating above the anaerobic threshold, rather than a cause of cerebrovascular dysfunction. Contribution of regional CBF differences during exercise. As the authors acknowledge, there are early reports of a greater percent flow increase in posterior cerebral circulation (as indexed by blood flow in the vertebral artery (VA)) with exercise intensity in contrast to the anterior circulation (as indexed in the ICA) (Sato et al. 2011). Do such regional differences – if they persist with dehydration – alter the findings by Trangmar et al.? It is known that VA flow contributes ∼30% of global CBF at rest. It can be estimated that VA flow might contribute 35–40% of global CBF during exercise, at least at 80% of peak O2 uptake (Sato et al. 2011). Thus, it would seem plausible that compensatory increases in posterior flow might compensate for 5–10% of the reduction in anterior flow. How (and if) such regional differences manifest remains unknown. Naturally many future questions arise, including the consideration of independent manipulations of CBF via , temperature and dehydration, with the measurement of cerebral SNA outflow. The work by Trangmar and colleagues provides clear direction for these future studies.