Experimental Physiology

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1 Exp Physiol 11.9 (216) pp Symposium Report Symposium Report Does cerebral hypoxia facilitate central fatigue? Christoph Siebenmann 1 and Peter Rasmussen 2,3 1 Department of Environmental Physiology, School of Technology and Health, Royal Institute of Technology, Solna, Sweden 2 H. Lundbeck A/S, Valby, Denmark 3 Department of Neuroscience and Pharmacology, University of Copenhagen, Denmark Experimental Physiology New Findings What is the topic of this review? This review addresses whether a mismatch between cerebral O 2 demand and delivery accelerates the development of central fatigue during endurance-type exercise. What advances does it highlight? ThedifficultywithstudyingtheimportanceofcerebralO 2 availabilityforexerciseperformance is to manipulate cerebral O 2 availability independently of muscular O 2 availability. The different approaches to overcome this limitation indicate that cerebral oxygenation is not a major limiting factor in normoxia, but may limit performance in submaximal exercise tasks in hypoxia. Central fatigue originates within the central nervous system and is characterized by a decrease in voluntary muscle activation. Reduced systemic O 2 availability can facilitate central fatigue by enhancing the afferent input of the chemosensitive nerves that play a pivotal role in development of central fatigue. There is accumulating evidence that, in some situations, inadequate O 2 availability to the brain itself promotes central fatigue. This short review presents some of the recent findings supporting a direct effect of inadequate cerebral O 2 availability on central fatigue and addresses the persisting limitations. (Received 27 November 215; accepted after revision 16 February 216; first published online 18 February 216) Corresponding author P. Rasmussen: Department of Neuroscience and Pharmacology, University of Copenhagen, Blegdamsvej 3, DK 22, Copenhagen, Denmark. peter@prec.dk In this brief review, we expand on the pivotal role that the CNS plays as the ultimate site where exercise starts and ends. Our focal point is whether exercise can be limited by insufficient O 2 availability to the brain per se. The loss of muscle contractive force during exhaustive exercise is often the combined result of mechanisms originating within the muscle itself (peripheral fatigue), within the cardiovascular and respiratory systems and within the CNS (central fatigue). Peripheral fatigue reduces the contractive force generated in response to activation of a given motor neuron, whereas the failure to perform or sustain a muscular task because of a decrease in voluntary muscle activation characterizes This Report is a summary of a presentation that took place at the Physiology 215 Meeting during a symposium on The brain in hypoxia; curiosity, cause and consequence. central fatigue. In normoxia, central fatigue seems to occur primarily as a reflex response to the stimulation of group III/IV afferents by agents/metabolites accumulating within working muscles (Gandevia et al. 199). It may serve as a protective mechanism that prevents peripheral fatigue from exceeding a critical threshold (Amann et al. 29). However, such a critical threshold would be likely to vary depending on mental factors, the environment and the exercise mode, duration and intensity, so that the final balance between peripheral and central fatigue is context and task specific (Thomas et al. 215). A factor that can play a critical role in the development of central fatigue is O 2 availability. A reduced O 2 supply to exercising muscles accelerates the formation of the fatigue metabolites that stimulate type III/IV nerve fibres. This effect may be aided by a direct impact of hypoxia on the nerve fibres themselves, which induces an increase DOI: /EP8564

2 1174 C. Siebenmann and P. Rasmussen Exp Physiol 11.9 (216) pp MCA V mean (cm s 1 ) Rest Exercise P a CO 2 (kpa) Figure 1. The sensitivity of cerebral blood flow to arterial CO 2 tension at rest and during exercise In six healthy men, arterial CO 2 tension (P aco2 ) was increased by inspiratory CO 2 supplementation or reduced by voluntary hyperventilation. Cerebral blood flow was estimated from mean blood flow velocity in the middle cerebral artery (MCA V mean ) as determined by Doppler ultrasound sonography. During resting measurements, the subjects were sitting still on a bicycle ergometer, whereas measurements during exercise were conducted at a workload corresponding to 67% of maximal exercise capacity. A linear relationship between P aco2 and MCA V mean was observed at rest, whereas the relationship was curvilinear and steeper (P <.5) with exercise. Modified from Rasmussen et al. (26). in resting discharge rate (Hill et al. 1992). A more controversial question, however, is whether inadequate O 2 availability to the brain per se promotes central fatigue. Muscular exercise is associated with increased metabolic demand in activated brain areas (Ide & Secher, 2). During mild to moderate whole-body exercise, this is met by a proportional increase in blood flow to these areas. As the exercise intensity exceeds the ventilatory threshold, a disproportional increase in pulmonary ventilation reduces arterial CO 2 tension (P aco2 ). Carbon dioxide is a powerful dilator of cerebral resistance vessels, and exercise enhances this effect (Fig. 1). The decrease in P aco2 that occurs above the ventilatory threshold consequently counteracts the increase in blood flow to the activated brain areas, so that cerebral blood flow plateaus or declines as exercise intensity increases (Hellström et al. 1996). This uncoupling of cerebral O 2 supply from consumption leads to a 5 1 mmhg decrease in mitochondrial P O2 during maximal exercise (Fig. 2; Rasmussen et al. 21a). When a similar decrease in mitochondrial P O2 was provoked in resting subjects by hypoxic breathing or voluntary hyperventilation, maximal isometric hand-grip strength declined (Rasmussen et al. 27). Given that the short duration of the contractions was unlikely to tax aerobic ATP recovery, reduced muscular O 2 availability does not explain this observation, pointing towards central fatigue instead. Nevertheless, as an adverse effect of hypoxia on maximal voluntary strength production of rested muscles is not a common finding (Perrey & Rupp, 29), these results need to be interpreted with caution. 15 Rowing time trial Incremental cycling ΔP Mito O 2 (mmhg) Δ P Mito O 2 (mmhg) Rest m 5 m m 15 m Post Rest 44 % 81% % Distance covered Workload (% of max) Figure 2. Cerebral mitochondrial O 2 tension during time trial and incremental exercise The left panel illustrats measurements obtained during a 2 km ergometer rowing time trail in six highly trained men. The right panel presents results measured in 16 normal men performing ergometer cycling exercise at two submaximal exercise intensities and at maximal intensity. The cerebral mitochondrial O 2 tension ( P MitoO2 ) was calculated from arterial O 2 content and saturation, jugular venous O 2 content, the arterial O 2 tension required for 5% oxyhaemoglobin saturation and cerebral metabolic rate; see Rasmussen et al. (21a,b) for detail. P <.5 versus rest. Data from Rasmussen et al. (21a,b).

3 Exp Physiol 11.9 (216) pp Cerebral hypoxia and central fatigue 11 In another study, reductions in cerebral mitochondrial P O2 were provoked by high-intensity cycling exercise in normoxia and hypoxia (Rasmussen et al. 21a). The reductionincerebralmitochondrialp O2 was accompanied by a proportional decrease in maximal voluntary contraction force of the elbow flexor. Transcranial magnetic stimulation of the motor cortex indicated that the decrease in maximal voluntary contraction was related to reduced voluntary cortical activation (Fig. 3). These two studies support the concept that the decreases in cerebral mitochondrial P O2 that occur with strenuous whole-body endurance exercise can facilitate central fatigue during strength tasks involving rested muscle groups, although this is not a universal finding (Goodall et al. 21). Nevertheless, in normoxia and even in mild hypoxia the contribution of inadequate cerebral O 2 availability to central fatigue development is small compared with that of type III/IV fibre afferents (Goodall et al. 21, 212). The balance between peripheral and central fatigue, however, progressively shifts centrally as the severity of hypoxia increases, supporting the idea that pronounced reductions in cerebral oxygenation play a more appreciable role in central fatigue (Goodall et al. 21). The challenge of experimentally demonstrating a link between cerebral hypoxia and central fatigue is to isolate theeffectoflowcerebralo 2 availability from that of low muscular O 2 availability. Different approaches have been used, all with their respective limitations. In one approach, subjects performed high-intensity, constant-load cycling exercise in normoxia as well as in mild and severe hypoxia (Amann et al. 27). Immediately before exhaustion, subjects were switched to breathing a hyperoxic gas. This rapidly increased cerebral oxygenation and allowed the continuation of exercise in severe hypoxia but not in normoxia or mild hypoxia. Interestingly, the magnitude of peripheral fatigue was similar at exhaustion in normoxia and mild hypoxia, whereas exhaustion in severe hypoxia was associated with lower peripheral fatigue (if subjects were not switched to hyperoxic breathing). Although no direct markers of central fatigue were assessed, these results support the contention that type III/IV afferents dominate the development of central fatigue in normoxia, whereas the contribution of reduced cerebral oxygenation increases with hypoxia (Goodall et al. 21). The limitation of the reoxygenation approach is that hyperoxic breathing increases O 2 availability in the skeletal and respiratory muscles, which may allow the continuation of exercise independent of the restoration of cerebral oxygenation. In another approach, CO 2 was added to the inspired air to increase cerebral blood flow during incremental cycling exercise in hypoxia (Subudhi et al. 211; Siebenmann et al. 213). Although this mitigated the exercise-induced decrease in cerebral oxygenation, it did not enhance maximal exercise performance (Fig. 4), thus not supporting the hypothesis that cerebral deoxygenation promotes central fatigue. The limitation of this approach is that CO 2 supplementation aggravates exercise-induced acidosis, which could have overridden an ergogenic effect of the improved cerebral oxygenation. Furthermore, exhaustion during incremental exercise occurs when muscular O 2 demand exceeds the capacity of the MVC (% of rest) Voluntary activation (%) r =.35 P <.1 r =.35 P < Δ P Mito O 2 (mmhg) Figure 3. Correlation between cerebral mitochondrial O 2 tension and arm flexor voluntary activation and force generation Maximal isometric elbow flexing was performed during cycle exercise in normoxia and hypoxia. Data are individual values (filled circles) and mean values (open symbols) for 16 subjects. The four colours illustrate exercise in normoxia at 124 (black), 226 (green) and 279 W (red) and in hypoxia at 124 W (blue). The regression lines are computed according to the mean values. The cerebral mitochondrial O 2 tension ( P MitoO2 )was calculated from the arterial O 2 content and saturation, jugular venous O 2 content, the arterial O 2 tension required for 5% oxyhaemoglobin saturation and cerebral metabolic rate; see Rasmussen et al. (21a) for detail. Voluntary activation was assessed by transcranial magnetic stimulation of the motor areal during a maximal voluntary contraction manoeuvre. MVC, force generated during maximal isometric elbow flexor contraction. Modified from Rasmussen et al. (21a).

4 1176 C. Siebenmann and P. Rasmussen Exp Physiol 11.9 (216) pp cardiorespiratory system for O 2 delivery (Levine, 28), so that central fatigue may not play a role. Nevertheless, the increase in cerebral oxygenation resulting from inspiratory CO 2 supplementation also failed to improve performance during submaximal exercise in hypoxia, namely intermittent, constant-load, isometric knee extension to exhaustion (Rupp et al. 215). Transcranial magnetic stimulation and electrical stimulation of the peripheral motor nerve, however, indicated that the improved cerebral oxygenation shifted the origin of muscle fatigue from primarily central to peripheral, which supports the contention that reduced cerebral oxygenation facilitates central fatigue. A third approach to manipulate cerebral oxygenation independently of muscular O 2 supply is vascular occlusion of the exercising muscle. Millet et al. (212) observed that the oxygenation of the occluded muscle decreased with exercise to the same extent in normoxia and hypoxia, whereas cerebral oxygenation decreased in hypoxia only. The exercise duration to fatigue was reduced in hypoxia compared with normoxia, again, supporting the idea that low cerebral oxygenation promotes central fatigue. The interpretation was, however, complicated by the observation that peripheral fatigue was similar after exhaustion in both environments. If cerebral hypoxia had accelerated the development of central fatigue in hypoxia, 16 Hypocapnia Isocapnia 35 MCA V mean (% of rest) Frontal lobe oxygenation (change, %) Maximal workload (W) Workload (% of max) Hypocapnia Isocapnia Figure 4. Inspiratory CO 2 supplementation during incremental exercise in hypoxia Eight healthy humans (four men and four women) performed incremental cycling exercise to exhaustion at 3454 m altitude, with (isocapnia) and without (hypocapnia) inspiratory CO 2 supplementation regulated to clamp the end-tidal CO 2 tension at 4 mmhg. The top left panel illustrates the mean blood flow velocity in the middle cerebral artery (MCA V mean ) as determined by ultrasound Doppler sonography throughout the exercise test; the bottom left panel illustrates frontal lobe oxygenation as determined by near-infrared spectroscopy. The right panel includes the individual maximal workloads that were reached in the hypocapnic and isocapnic trials, respectively. Modified from Siebenmann et al. (213).

5 Exp Physiol 11.9 (216) pp Cerebral hypoxia and central fatigue 1177 less peripheral fatigue would have been expected. Another factor that needs consideration is the hypoxia-induced increase in the resting discharge rate of type III/IV fibres that may accelerate the development of central fatigue independent of cerebral oxygenation (Hill et al. 1992). In summary, the role of decreases in cerebral oxygenation in the development of central fatigue is small during whole-body exercise in normoxia but seems to increase with the severity of hypoxia. It has to be emphasized that, despite the elegant approaches used, the problem of separating the O 2 supply to the brain and the muscles persists. Therefore, a contribution of mechanisms other than inadequate cerebral O 2 supply, particularly of simultaneous reductions in muscle O 2 supply, cannot be excluded. References Amann M, Proctor LT, Sebranek JJ, Pegelow DF & Dempsey JA (29). Opioid-mediated muscle afferents inhibit central motor drive and limit peripheral muscle fatigue development in humans. JPhysiol587, Amann M, Romer LM, Subudhi AW, Pegelow DF & Dempsey JA (27). Severity of arterial hypoxaemia affects the relative contributions of peripheral muscle fatigue to exercise performance in healthy humans. JPhysiol581, Gandevia SC, Macefield G, Burke D & McKenzie DK (199). Voluntary activation of human motor axons in the absence of muscle afferent feedback. The control of the deafferented hand. Brain 113, Goodall S, González-Alonso J, Ali L, Ross EZ & Romer LM (212). Supraspinal fatigue after normoxic and hypoxic exercise in humans. JPhysiol59, Goodall S, Ross EZ & Romer LM (21). Effect of graded hypoxia on supraspinal contributions to fatigue with unilateral knee-extensor contractions. JApplPhysiol19, Hellström G, Fischer-Colbrie W, Wahlgren NG & Jogestrand T (1996). Carotid artery blood flow and middle cerebral artery blood flow velocity during physical exercise. JApplPhysiol 81, Hill JM, Pickar JG, Parrish MD & Kaufman MP (1992). Effects of hypoxia on the discharge of group III and IV muscle afferents in cats. JApplPhysiol73, Ide K & Secher NH (2). Cerebral blood flow and metabolism during exercise. Prog Neurobiol 61, Levine BD (28). V O2 max: what do we know, and what do we still need to know? JPhysiol586, Millet GY, Muthalib M, Jubeau M, Laursen PB & Nosaka K (212). Severe hypoxia affects exercise performance independently of afferent feedback and peripheral fatigue. JApplPhysiol112, Perrey S & Rupp T (29). Altitude-induced changes in muscle contractile properties. High Alt Med Biol 1, Rasmussen P, Dawson EA, Nybo L, van Lieshout JJ, Secher NH & Gjedde A (27). Capillary-oxygenation-level-dependent near-infrared spectrometry in frontal lobe of humans. J Cereb Blood Flow Metab 27, Rasmussen P, Nielsen J, Overgaard M, Krogh-Madsen R, Gjedde A, Secher NH & Petersen NC (21a). Reduced muscle activation during exercise related to brain oxygenation and metabolism in humans. JPhysiol588, Rasmussen P, Overgaard A, Bjerre AF, Bjarrum M, Carlsson C, Petersen N, Nielsen HB, Volianitis S, Gjedde A & Secher NH (21b). The effects of normoxia, hypoxia, and hyperoxia on cerebral haemoglobin saturation using near infrared spectroscopy during maximal exercise. Int J Ind Ergonom 4, Rasmussen P, Stie H, Nielsen B & Nybo L (26). Enhanced cerebral CO2 reactivity during strenuous exercise in man. Eur J Appl Physiol 96, Rupp T, Le Roux Mallouf T, Perrey S, Wuyam B, Millet GY & Verges S (215). CO 2 clamping, peripheral and central fatigue during hypoxic knee extensions in men. Med Sci Sports Exerc 47, Siebenmann C, Sørensen H, Jacobs RA, Haider T, Rasmussen P & Lundby C (213). Hypocapnia during hypoxic exercise and its impact on cerebral oxygenation, ventilation and maximal whole body O 2 uptake. Respir Physiol Neurobiol 185, Subudhi AW, Olin JT, Dimmen AC, Polaner DM, Kayser B & Roach RC (211). Does cerebral oxygen delivery limit incremental exercise performance? JApplPhysiol111, Thomas K, Goodall S, Stone M, Howatson G, St Clair Gibson A & Ansley L (215). Central and peripheral fatigue in male cyclists after 4-, 2-, and 4-km time trials. Med Sci Sports Exerc 47, Additional information Competing interests None declared. Author contributions Conception of the work; acquisition, analysis or interpretation of data; and drafting the work or revising it critically for important intellectual content: C.S. and P.R. Both authors approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Both persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. Funding None. Acknowledgements We acknowledge all collaborators who have contributed to our understanding of central fatigue.