Cerebral perturbations provoked by prolonged exercise

Abstract

This review addresses cerebral metabolic and neurohumoral alterations during prolonged exercise in humans with special focus on associations with fatigue. Global energy turnover in the brain is unaltered by the transition from rest to moderately intense exercise, apparently because exercise-induced activation of some brain regions including cortical motor areas is compensated for by reduced activity in other regions of the brain. However, strenuous exercise is associated with cerebral metabolic and neurohumoral alterations that may relate to central fatigue. Fatigue should be acknowledged as a complex phenomenon influenced by both peripheral and central factors. However, failure to drive the motorneurons adequately as a consequence of neurophysiological alterations seems to play a dominant role under some circumstances. During exercise with hyperthermia excessive accumulation of heat in the brain due to impeded heat removal by the cerebral circulation may elevate the brain temperature to >40 °C and impair the ability to sustain maximal motor activation. Also, when prolonged exercise results in hypoglycaemia, perceived exertion increases at the same time as the cerebral glucose uptake becomes low, and centrally mediated fatigue appears to arise as the cerebral energy turnover becomes restricted by the availability of substrates for the brain. Changes in serotonergic activity, inhibitory feed-back from the exercising muscles, elevated ammonia levels, and alterations in regional dopaminergic activity may also contribute to the impaired voluntary activation of the motorneurons after prolonged and strenuous exercise. Furthermore, central fatigue may involve depletion of cerebral glycogen stores, as signified by the observation that following exhaustive exercise the cerebral glucose uptake increases out of proportion to that of oxygen. In summary, prolonged exercise may induce homeostatic disturbances within the central nervous system (CNS) that subsequently attenuates motor activation. Therefore, strenuous exercise is a challenge not only to the cardiorespiratory and locomotive systems but also to the brain.

Introduction

Humans have been fascinated by prolonged exercise performances since Antiquity and numerous physiological and psychological experiments have addressed what limits endurance, i.e. what causes fatigue. Physiological investigations have focussed mainly on the relationship between exercise endurance and circulatory, metabolic, muscular, nutritional, and thermoregulatory factors as reviewed in a vast number of recent articles (e.g. Kreider et al., 1993, Tarnopolsky, 1994, Ekblom, 1997, Coyle, 1998, Hargreaves and Febbraio, 1998, Noakes, 1998, Burke and Hawley, 1999, Ivy, 1999, Jones and Carter, 2000, Noakes, 2000, Wagner, 2000, Bassett and Howley, 2000, Bergh and Ekblom, 2000, Febbraio, 2000, Coyle and Gonzalez-Alonso, 2001). Collectively, it appears that many parameters affect the capacity for prolonged exercise, and that the relative importance of the different factors varies depending on the duration of the exercise, its intensity, the exercise mode and not least the environmental setting (Bannister, 1966, Borg et al., 1987, Coyle, 1999, Febbraio, 2000, Nybo and Nielsen, 2001a).

It was recognised already by Mosso (1904) that “mental fatigue” may affect muscular performance, and several studies have provided further evidence to support that the central nervous system (CNS) sometimes fails to drive the motorneurons adequately (Bigland-Ritchie et al., 1978, Kent-Braun, 1999, Taylor et al., 2000, Lepers et al., 2000, Nybo and Nielsen, 2001a, Millet et al., 2002, Nybo, 2003). However, compared to the numerous investigations with focus on a peripheral origin of fatigue, the influence of central fatigue, and especially its relation to neurophysiological changes, have received little scientific attention. Theories involving accumulation or depletion of different substances in the brain have been proposed to explain central fatigue (Newsholme et al., 1987, Conlay et al., 1992, Davis et al., 1992, Davis et al., 2000, Abdelmalki et al., 1997, Guezennec et al., 1998, Blomstrand, 2001), but such hypotheses are based most on results from animals (Blomstrand et al., 1989, Newsholme and Blomstrand, 1995, Meeusen and De Meirleir, 1995, Guezennec et al., 1998, Blomstrand, 2001) or on circumstantial evidence, such as changed levels of substrates, amino acids, neuromodulators, or pituitary hormones in systemic plasma samples from exercising humans (Davis and Bailey, 1997, Struder et al., 1997, Struder et al., 1998, Blomstrand et al., 1997, Marvin et al., 1997, Chinevere et al., 2002). The influence of exercise on the cerebral metabolic rate of oxygen (CMR_oxygen) was evaluated in the 1950’s by Scheinberg and co-workers (1953, 1954) and the cerebral perfusion and metabolism during light to moderate intensity exercise have since then been determined with a variety of techniques (Thomas et al., 1987; Jørgensen et al., 1992a, Jørgensen et al., 1992b; Madsen et al., 1993, Linkis et al., 1995, Poulin et al., 1999, Williamson et al., 1999, Serrador et al., 2000, Christensen et al., 2000). However, only a limited number of investigations have evaluated the cerebral metabolism and neurohumoral responses during fatiguing exercise (Ide et al., 2000b; Nybo and Nielsen, 2001a, Nybo and Nielsen, 2001c; Dalsgaard et al., 2002, Dalsgaard et al., 2003; Nybo et al., 2002a, Nybo et al., 2002b, Nybo et al., 2003a, Nybo et al., 2003b).

Declining isometric strength is one characteristic of skeletal muscle fatigue and it is obvious that such deterioration of contractile force involves factors located in the skeletal muscles, as demonstrated both by stimulation of isolated muscles in vitro and electrically evoked activation of skeletal muscles in vivo (Merton, 1954, West et al., 1996, Westerblad et al., 1998). Muscle fatigue has been ascribed to depletion of substrates (e.g. reduced muscle glycogen concentration, low ATP and CrP levels), accumulation of metabolites, ionic changes, and inadequate oxygen delivery (Bergstrom et al., 1967, Juel, 1997, Chin and Allen, 1997, Sahlin et al., 1998, Coyle, 1999, Nielsen et al., 2001b, Fowles et al., 2002). Analogously it may be considered that metabolic, circulatory, neurotransmitter, thermodynamic changes, or other disturbances of the cerebral homeostasis could lead to central fatigue. Therefore, this review focuses on neurohumoral and cerebral metabolic responses during prolonged exercise with special attention to possible connections to fatigue. Emphasis is on recent work involving human subjects, whereas animal studies and pathological observations are included only if it helps interpreting results obtained from healthy humans. Although, exercise and the aetiology of fatigue are considered from a cerebral point of view, it should be acknowledged that fatigue is a complex phenomenon influenced by peripheral factors as well as psychological aspects such as motivation and the will to succeed.