Inadequate Cerebral Oxygen Delivery and Central Fatigue during Strenuous
Under resting conditions, the brain is protected against hypoxia because cerebral blood flow increases when the arterial oxygen tension becomes low. However, during strenuous exercise, hyperventilation lowers the arterial carbon dioxide tension and blunts the increase in cerebral blood flow, which can lead to an inadequate oxygen delivery to the brain and contribute to the development of fatigue.

Fatigue emerges during exercise as increased difficulty in retaining a required power or as impairment in the ability to produce force and power. The development of fatigue is complex and determined by an intricate interplay between psychological and physiological factors. Even in well-motivated subjects, the relative importance of muscular/peripheral and central factors seems to vary markedly depending on the mode, intensity, and duration of the exercise, besides the nutritional status of the subjects and the environmental setting. Some physiological factors may relate directly or indirectly to homeostatic disturbances in the skeletal muscles, whereas other factors may directly affect the central nervous system (CNS) and its ability to activate the skeletal muscles via the alpha motor neurons.

Previously, the "central fatigue hypothesis" has focused mainly on changes in extracellular neurotransmitter levels or exercise-induced alterations in the activity of different neurotransmitter systems, with the serotonin, dopamine, and ammonia-glutamate-glutamine "hypotheses" as the most dominant. The present review discusses the possibility that, during some exercise conditions, fatigue can be provoked or modulated by inadequate oxygen delivery to the brain and subsequently low cerebral capillary and mitochondrial oxygen tension (PO₂). In turn, this could influence the function of neurons and astrocytes and thereby the ability to maintain motor activation. Although it is recognized that this impairment can occur during exercise at high altitude, it may also arise as a consequence of exercise-induced arterial hypoxemia (EIAH) or exercise conditions where hyperventilation-induced hypocapnia lowers cerebral blood flow (CBF). Hypocapnia may be provoked by exercise at intensities above the ventilatory threshold and, especially, exercise with hyperthermia, which may lower the cerebral perfusion by 20%-30%.

At rest, the brain is protected against hypoxia-induced reductions in arterial oxygen delivery because CBF increases when the arterial oxygen tension becomes low. When exercise and hypoxemia are combined, however, hyperventilation-induced reductions of the arterial carbon dioxide tension (PaCO₂) may become so pronounced that it blunts the increase in CBF, and therefore, increased perfusion fails to compensate for the lower arterial oxygen content. Anecdotes from athletes experiencing blackout or fainting immediately after completing maximal exercise support the idea that oxygen delivery to the brain may become critically low, and studies of maximal rowing in subjects with EIAH show that the cerebral oxygenation falls during such exercise. Although athletes rarely faint during exercise studies in the laboratory, studies with different combinations of strenuous exercise and impaired oxygen delivery to the brain indicate that the CNS function may be compromised and that mitochondrial oxygen tension (P_mito) in the brain may become critically low. At rest and during moderate exercise, the brain is well perfused, and moderate reductions in CBF/cerebral oxygen delivery may be compensated for by increased extraction. However, a relatively high capillary oxygen tension is required to maintain the mitochondrial PO₂ at an adequate level. The main questions raised in the present review are the following: 1) How large reduction in cerebral oxygen delivery and subsequent lowering of the mitochondrial PO₂ can the brain tolerate before it begins to influence motor performance and contribute to the development of so-called central fatigue? 2) Which exercise conditions cause such reductions, and how can we monitor and evaluate whether cerebral oxygenation levels are sufficient?