Fatigue of voluntary muscular effort is a complex and multifaceted phenomenon. Traditionally, investigators have primarily focused on factors that result in dysfunction of the contraction process within the muscle itself (peripheral fatigue) with little consideration for the important role of the central nervous system (CNS fatigue). Peripheral fatigue has been well studied and can involve impairments in neuromuscular transmission and propagation down the sarcolemma, dysfunction within the sarcoplasmic reticulum involving calcium release and uptake, availability of metabolic substrates and accumulation of metabolites, and actin-myosin crossbridge interactions(10,36,44,46).
Much less effort has been focused on CNS fatigue even though it has been documented for over a century that “psychological factors” can affect exercise performance and that a dysfunction at any step in the continuum from the brain to the contractile machinery will result in muscular fatigue (3,61). Experimental support for a specific role of CNS fatigue is limited primarily because of a lack of objective measures. Indeed, CNS fatigue is often accepted only by default when the experimental findings do not support the hypothesis of a muscle dysfunction. Even then, it is often dismissed as reflecting a lack of motivation or an unfamiliarity with the experimental situation. Investigators then design future experiments to minimize this possibility (16). In addition, most investigations that support a CNS role in fatigue are limited since they generally fail to provide plausible biological mechanisms and thereby relegate such a role to a “black box” phenomenon which is hard to defend.
An understanding of the workings of the CNS has grown exponentially over the past several decades. Accordingly, it is becoming increasingly evident that virtually all behaviors and perceptions have a biological basis. This concept has sparked renewed interest in the development of hypotheses, which can be tested in a systematic fashion, that may help to explain the role of the CNS in fatigue during prolonged exercise. Hypotheses have been developed that implicate the neurotransmitters serotonin (5-HT), dopamine (DA), and acetylcholine (Ach), as well as known neuromodulators like ammonia and various cytokines (substances secreted from immune cells). This article will provide a brief summary of the scientific evidence regarding a specific role of the CNS in fatigue during exercise, as well as the possibility that this effect is mediated by exercise-induced changes in various neurotransmitters and neuromodulators.
DEFINITION OF CNS FATIGUE
One of the many difficulties with reviewing the scientific literature on fatigue is the diversity of definitions of central and peripheral fatigue. We define fatigue in general as an acute impairment of exercise performance that includes both an increase in the perceived effort necessary to exert a desired force or power output and the eventual inability to produce that force or power output. A specific definition of CNS fatigue is even more elusive. It has been defined as a negative central influence that exists despite the subject's full motivation or, more objectively, as a force generated by voluntary muscular effort that is less than that produced by electrical stimulation. Our working definition is that CNS fatigue is a subset of fatigue(failure to maintain the required or expected force or power output) associated with specific alterations in CNS function that cannot reasonably be explained by dysfunction within the muscle itself. This definition is considerably broader to allow the likelihood that “psychological” factors like motivation and perception are important factors in fatigue. In fact, the unwillingness to generate and maintain adequate CNS drive to the working muscle is the most likely explanation of fatigue in most people during normal activities. In addition, the etiology of the often debilitating fatigue that accompanies infections and other diseases, recovery from injury or surgery, chronic fatigue syndrome, and various mental disorders almost certainly has nothing to do with the muscle itself and therefore probably lies within the CNS.
Evidence for CNS Fatigue during Voluntary Muscular Effort
The technique routinely used to identify the role of central versus peripheral factors in fatigue is one in which the muscular force that a subject can elicit voluntarily is compared to that elicited by supramaximal electrical stimulations (Twitch Interpolation Technique). Using this technique investigators determine whether the force exerted voluntarily by a subject can be enhanced by a single or brief train of electrical shocks applied to the nerve supplying the muscle or the muscle itself (52).
Many studies using this technique have found that the force of maximal voluntary contractions and those elicited by electrical shocks typically decline in parallel during repeated muscular contractions(17,19,44). Consequently, it is often concluded that reduction in CNS drive is not a factor in muscular fatigue. However, there are at least four exceptions to this notion(44). First, maintaining maximal CNS motor drive is very difficult and unpleasant and requires a very well-practiced individual to accomplish it, and under most circumstances most people do “let off” centrally. Second, it is sometimes not possible even in highly motivated, well-practiced individuals to maintain a maximal central drive for some muscles, including the soleus and diaphragm(14,18). Third, it is more difficult to activate all motor units innervating a muscle during repeated maximal concentric as compared with eccentric contractions (81,88). Finally, it has been reported that subjects are unable to generate a maximal drive during sustained maximal voluntary contractions while at high altitude(49).
Other evidence for reduced CNS drive comes from experiments that are often dismissed because of methodological problems associated with inadequate practice of the task or because the effect is thought to represent alterations in “psychological factors” like attention, motivation, and perceptions involving effort and pain. For example, it has been shown that force generation and electromyographic (EMG) activity during repeated maximal voluntary contractions may be enhanced by encouragement(73,77) and that fatigue is more pronounced in subjects who are concentrating on their performance and is reduced when they are disturbed (5,77). This is also true when tasks are performed with closed versus open eyes(4,76,77). Rube and Sechar(73) also observed that the sum of the maximal voluntary force elicited by maximal contractions of each of two legs was substantially more than that elicited by contractions in which both legs are used together. Interestingly, when subjects trained with two legs together they became less fatigued with the two-legged task but not when each leg was tested separately and vice versa. They concluded that the central motor commands involving in one-leg and two-leg exercise are significantly different and that training-induced decreases in fatigue involve adaptations within the CNS as well as the muscle.
Evidence from animal studies also illustrates the importance of central motor drive during prolonged tread-mill running to fatigue. We completed a series of studies (27-29) in which activation of a reward system in the brain was used to motivate rats to run on a treadmill. In one of the experiments, we compared the run time to fatigue in rats that were motivated to run by either electrical stimulation of the ventral tegmental area (VTA) of the brain, the origin of rewarding dopaminergic mesolimbic projections, or by an electric shock grid placed at the back of the treadmill lane. We found that untrained rats ran significantly longer on a motorized treadmill (25 m·min-1, 5% grade) while receiving the positive brain stimulation (63 ± 10 min) than when they received the electric shocks (42 ± 10 min) (27). It is not known why the brain stimulation was a more powerful stimulus in delaying fatigue than the electric shocks, but it was subsequently determined that it was not likely related to stress hormone-mediated influences on cardiovascular or metabolic function since both conditions are known to produce very large increases in these hormones (29).
Neurobiological Mechanisms of CNS Fatigue
The possibility that there are specific neurobiological mechanisms that can affect the magnitude of descending motor drive has received the least experimental attention as a possible factor in muscular fatigue. This is the case even though few would argue that willingness/motivation to adequately maintain central motor drive is the most likely explanation of fatigue in most people during normal activities and even in many experimental situations. Interestingly, the first hint that a muscle is not able to maintain a contraction is not an inability to exert the necessary force but, rather, a perception that it is necessary to increase the effort associated with the task (30,49,56,65). Therefore, because impaired motor performance is usually associated with increased perceived effort, as well as a failure to produce the necessary force, the“psychological/physiological” processes that contribute to either of these factors should be included as possible fatigue mechanisms(44).
It is generally thought that a reduction in CNS drive to the motor neuron can be a result of either 1) a reduction in the corticospinal (descending) impulses reaching the motoneurons and/or 2) an inhibition of motoneuron excitability by neurally mediated afferent feedback from the muscle. A majority of the evidence supports feedback inhibition at the level of the spinal cord. For example, it is common to observe a concurrent decline in force, relaxation rate, and motor neuron discharge rate during both maximal voluntary contractions and imposed electrical contractions. This led to the proposal by Bigland-Ritchie (19) that inhibition of motor neuron firing rates may result from a reflex involving feedback from mechanoreceptors or perhaps group III or IV free nerve endings, which are known to be sensitive to muscle metabolites that accumulate during fatigue. It was suggested that this may be an example of CNS's attempt to optimize the maximal force that can be produced by fatiguing muscle so that the most safe and economical pattern of muscle activation can occur. These and other aspects of feedback regulation are generally referred to as the sensory feedback hypothesis (44). Although the majority of this research assumes that sensory feedback inhibits motor unit discharge rates at the level of the motor neuron in the spinal cord, an important contribution from a reduction in central drive at or above the level of the corticospinal tract certainly cannot be excluded.
In fact, there is direct evidence of decreases in central motor drive during fatiguing contractions. For example, data from monkeys show that the discharge rates of neurons in the primary motor cortex often decrease from the first to the twentieth repetition of an isometric elbow-flexion(66). However, the most convincing evidence comes from a study in human subjects in which a relatively new technique involving transcranial magnetic stimulation (TMS) was used. This technique can be used to assess central nervous system excitability from the motor cortex to the alpha-motoneuron (26). In this study, the magnitude of the motor responses elicited in the muscle by transcranial magnetic stimulation was transiently decreased after fatiguing exercise. Although there are several possible explanations for this effect, the authors suggested that decreased central drive likely involved the accumulation and depletion of neurotransmitters in CNS pathways located upstream from the corticospinal neurons.
It is also interesting that some individuals with “effort syndromes,” such as chronic fatigue syndrome (CFS) in which the major symptom is chronic debilitating fatigue, show little or no impairment of the ability to exert force if they are highly motivated(13,51,57,58,79). A very high degree of motivation will usually allow these patients to produce maximal CNS drive, although this is not true for all subjects. For example, Lloyd et al.(58) studied the decrease in maximal force-generating capacity, the degree of central activation of the muscle, and the subjective perception of effort during prolonged submaximal isometric exercise in 12 male patients and 13 naive, healthy male subjects. They showed that isolated muscle function (arm curls) was normal in these patients who generally rate the level of perceived exertion as much higher than expected and complain of protracted fatigue after an exercise bout. The results of a recent study by Kent-Braun et al. (57) using tibialis anterior muscle confirmed that CFS patients appeared to have normal fatigability and metabolism and normal muscle membrane function and excitation-contraction coupling but had an inability to fully activate skeletal muscle during intense, sustained exercise.
Data on the effects of whole body/large muscle group exercise in CFS patients are also beginning to appear. Studies generally show that CFS patients have a relatively normal cardiovascular response to graded exercise tests (at least in comparison with very deconditioned individuals) but have higher perceived exertion ratings in relation to heart rate during exercise and tend to stop early, well before the normal physiological limit is reached(51,71,79). These studies are consistent in that no defect of neuromuscular function was found and that some patients have a significant impairment of voluntary activation of muscle. It appears that this is related to an abnormality in the perception of effort that translates into an inability/unwillingness to reach and/or maintain the level of effort(central drive) necessary to achieve maximal performance during heavy work involving whole body or large muscle groups. Therefore, it appears that there is a significant central component of muscle fatigue in CFS, although it is still too early to determine at which level of the central nervous system such a defect lies (i.e., at or above the level of the corticospinal tract).
The mechanism(s) underlying alterations in central nervous system fatigue in normal individuals or in patients with effort syndromes is not known, but in both cases it is likely related to CNS processes occurring at the highest levels. There is good evidence that the sense of effort is strongly influenced by the magnitude of the corollary discharge from the motor cortex (motor command) that projects to the primary somatosensory cortex(44,67). For example, when the force that a muscle can exert is experimentally reduced (e.g., by fatigue or with curarization), the perceived effort for that task increases in association with the more substantial motor command that the subject must generate to achieve the target force. Whether or not these higher centers are modified by neural input from other brain centers, afferent feedback from the working muscle and/or changes in neurotransmitter metabolism subsequent to the passage of blood-borne substances across the blood-brain barrier is not well studied but is the topic of a great deal of recent interest. Indeed, there is recent evidence that CFS patients demonstrate a significant reduction in 24-h basal plasma levels of the norepinephrine metabolite, MHPG, and an elevation in the mean basal plasma level of the serotonin metabolite, 5-HIAA, when compared with normal individuals (43). A possible upregulation of hypothalamic 5-HT receptors in these patients has also been reported(9).
Possible Role of Neurotransmitters in Exercise Fatigue
Much interest has recently been focused on the possible exercise-induced alterations in neurotransmitter function during exercise as an explanation for CNS fatigue during exercise. New hypotheses that involve serotonin (5-HT), acetylcholine, and dopamine, and studies that evaluate the merits of each of them are beginning to appear.
Brain serotonin and CNS fatigue. Of the many proposed causes of CNS fatigue, the role of brain serotonin has generated the most interest. Serotonin (5-hydroxytryptamine, (5-HT)) was first proposed to be a potential mediator of CNS fatigue by Newsholme et al. (69). Increases in brain 5-HT can have important effects on arousal, lethargy, sleepiness, and mood that could be linked to altered perceptions of effort and muscular fatigue (92). While 5-HT is probably not the neurotransmitter involved in CNS fatigue during prolonged exercise, review of the mechanisms involved in the control of brain serotonin synthesis and turnover make it a particularly attractive candidate as a mediator of CNS fatigue during prolonged exercise.
The Central Fatigue Hypothesis suggests that increased concentrations of brain 5-HT can impair CNS function during prolonged exercise and thereby cause a deterioration in sport and exercise performance (69). Increased brain 5-HT synthesis occurs in response to an increased delivery to the brain of blood-borne tryptophan (TRP), an amino acid precursor to 5-HT. This occurs because none of the enzymes involved in 5-HT synthesis is saturated under physiological conditions (69). Most of the TRP in blood plasma circulates loosely bound to albumin, but the free tryptophan (f-TRP) is transported across the blood/brain barrier(32). This transport occurs via a specific mechanism that TRP shares with other large neutral amino acids, most notably the branched-chain amino acids (BCAAs)-leucine, isoleucine, and valine(35,90). Thus, brain 5-HT synthesis will increase when there is an increase in the concentration ratio of f-TRP to BCAA, that is, when f-TRP/BCAAs rises (31,33,34). It was proposed that this would occur during prolonged exercise as 1) BCAAs are taken up from the blood and oxidized for energy in contracting skeletal muscles and 2) plasma free fatty acids (FFAs) increase in the blood, causing a parallel increase in plasm f-TRP because FFAs displace TRP from its usual binding sites on plasma albumin molecules (40)(Fig. 1). Investigators have begun to test the validity of this hypothesis in experiments involving the effects of exercise on brain 5-HT synthesis and turnover, the effects of 5-HT agonist and antagonist drugs on exercise fatigue, and the influence of nutritional strategies that alter the plasma f-TRP/BCAA ratio.
Association between increased brain 5-HT and fatigue. Barchas and Freedman (12) were the first investigators to examine changes in whole brain 5-HT following prolonged exercise in the rat. They reported that 3 h of low intensity swimming resulted in small but significant increases in brain 5-HT concentrations. Romanowski and Graiec(72) also reported two-fold increases in whole brain 5-HT following 90 min of treadmill running. However, the most extensive series of investigations into the effects of acute exercise on the brain serotonergic system in rats have been performed by Chaouloff et al.(31-35). They primarily studied the relationships among prolonged exercise and the concentrations of f-TRP and BCAA in plasma, and f-TRP, 5-HT, and its major metabolite 5-hydroxy-indole-acetic acid (5-HIAA) in specific brain regions. Their first experiment showed that 1 h of treadmill running at 20 m·min-1 resulted in a marked increase in brain TRP concentration. This increase was paralleled by a small but significant increase in 5-hydroxyindoleacetic acid(5-HIAA) that indicated that treadmill running increased 5-HT synthesis and turnover (32). Subsequently, Chaouloff et al.(33) documented similar increases in TRP and 5-HIAA in cerebrospinal fluid (CSF) following a similar exercise bout. Concentrations of TRP and 5-HIAA returned to normal by 1 h after cessation of exercise.
Chaouloff et al. (35) also examined regional differences in brain 5-HT and 5-HIAA during exercise. They found increases in 5-HT and 5-HIAA in the midbrain, hippocampus, and striatum following exercise(90 min of treadmill running at 20 m·min-1). Blomstrand et al.(25) also found that increases in plasma f-TRP (but not total TRP) and regional brain TRP, 5-HT, and 5-HIAA concentrations immediately after treadmill runs to exhaustion in both trained (≈ 180 min of exercise) and untrained (≈ 72 min of exercise) rats. When considered together, these data suggest that prolonged moderate and exhaustive exercise in rats increases 5-HT synthesis and turnover in various brain regions and that this is likely a result of increases in plasma f-TRP.
We have extended those observations to include a study of the effects of both moderate and fatiguing exercise on 5-HT and dopamine (DA) in various regions of the rat brain (8)(Fig. 2). Measurements of 5-HT and DA and their principle metabolites 5-HIAA and DOPAC were made in the midbrain, striatum, hypothalamus, and hippocampus of rats sacrificed at rest after 1 h of exercise at a pace set to elicit approximately 60-65% ˙VO2max, and at fatigue (approximately 3 h). The concentrations of 5-HT and 5-HIAA were higher in all brain regions at 1 h except for the hippocampus where only 5-HIAA was elevated. At fatigue 5-HT remained elevated, whereas 5-HIAA increased even further in the midbrain and striatum. Dopamine and DOPAC increased in most brain regions after 1 h of exercise but then decreased at fatigue. These data show a good association between increased brain 5-HT and fatigue during prolonged exercise. Alternatively, brain DA, which has been linked with increased arousal, motivation, muscular coordination, and increased endurance performance(31,35,55), actually decreased towards the end of prolonged exercise as fatigue developed. The significance of this apparent inverse relationship between brain 5-HT and DA as fatigue develops requires further investigation. Interestingly, Chaouloff et al.(34) have shown that the increase in 5-HT and 5-HIAA during 90 min of exercise could be attenuated by prior administration of amphetamine, suggesting that the exercise-induced increases in brain 5-HT may be attenuated by increases in dopaminergic/noradrenergic activity. This also seems to fit with the suggestions of Chaouloff et al.(34) that the magnitude of the increase in 5-HT and 5-HIAA in the hippocampus and striatum during this moderate level of exercise was not as great as expected from the increased availability of TRP.
Drug-induced alterations in brain 5-HT and fatigue. While the results of these investigations describe a good relationship between increased brain 5-HT (and perhaps decreased DA) and exercise fatigue, they are not sufficient to prove a causal link. Bailey et al.(6-8) completed a series of experiments to better approach the question of cause and effect by testing the effects of specific drug-induced alterations in brain 5-HT activity on fatigue in rats. In their initial experiment (7), they found that administration of a specific 5-HT1c agonist (m-chlorophenyl piprazine) reduced endurance performance in a dose response manner. Subsequently, they(6) observed that a more general 5-HT agonist (quipazine dimaleate) caused early fatigue, whereas administration of the 5-HT antagonist(LY-53,857) actually delayed fatigue (Fig. 3). The supposition that these drug-induced effects resulted from specific alterations in brain 5-HT activity is supported by the observation that fatigue could not be explained by alterations in body temperature, blood glucose, muscle and liver glycogen, or various stress hormones(6-8).
These results, using a pharmacological approach in a rat model, have been confirmed in human subjects who were given paroxetine (a 5-HT re-uptake blocker that acts as a 5-HT agonist upon acute administration)(87). When paroxetine was administered prior to prolonged running to fatigue at 70% ˙VO2max, exercise time was reduced(87) compared with the placebo trial. There were no reports of strange side-effects and no differences were found among various markers of cardiovascular, thermoregulatory, and metabolic function.
The aforementioned studies in both rats and humans appear to provide good evidence that brain 5-HT activity increases during prolonged exercise and that this may cause CNS fatigue. However, the strength of these findings will continue to be questioned until methods are available to measure more directly CNS fatigue during dynamic exercise in humans and until more is known about the specific physiological mechanisms for such an effect.
Potential mechanisms of fatigue owing to increased brain 5-HT activity. Investigators are beginning to explore the possible physiological mechanisms underlying a possible effect of elevated brain 5-HT on CNS fatigue. The serotonergic system is associated with numerous brain functions that could positively or negatively affect endurance performance. Increased serotonergic activity may induce fatigue through inhibition of the dopaminergic system(8,34) and/or by reducing arousal and motivation to perform (92). Furthermore, serotonergic activity can affect the hypothalamic-pituitary-adrenal axis, thermoregulation, pain, and mood, depending on the specific situation and the species studied(1,2,45,92). Based on our observations that fatigue during prolonged exercise in rats is associated with increased brain 5-HT and reduced brain dopamine (6,8), our working hypothesis is that a low ratio of 5-HT/DA in the brain favors improved performance (i.e., increased arousal, motivation, and optimal neuromuscular coordination), whereas a high 5-HT/DA ratio favors decreased performance(i.e., decreased motivation, lethargy, sleepiness, and loss of motor coordination). The latter would constitute CNS fatigue.
Nutritional Effects on Markers of Altered Brain 5-HT and CNS Fatigue
For obvious ethical reasons, investigators have used the rat model to study the effects of fatigue on regional brain concentrations of 5-HT and metabolites. Investigations in humans have focused primarily on nutritional factors that affect TRP availability to the brain (i.e., proposed markers of CNS fatigue).
Blomstrand et al. (22) were the first to approach the problem in humans. They initially studied 22 subjects before and after a marathon race and found that plasma f-TRP was ≈2.4 times higher and branched chain amino acids (BCAA) were slightly lower (≈19%) after the race. They also reported similar responses after a soccer match (45% increase in f-TRP; 29% decrease in BCAA) and prolonged cross country skiing (28% decrease in BCAA; f-TRP not reported in this study)(23,24). The drop in f-TRP/BCAA following exercise in these studies was consistent with their hypothesis that TRP availability to the brain is increased by prolonged exercise and that increased brain 5-HT activity and CNS fatigue may occur as a result. These data also provided the basis for their hypotheses involving possible nutritional strategies that may help to delay CNS fatigue during prolonged exercise.
The theoretical possibility that CNS fatigue could be delayed by nutritional strategies designed to alter the plasma f-TRP/BCAA ratio is centered around two primary strategies involving BCAA and/or carbohydrate supplementation during exercise. Both of these would theoretically decrease the f-TRP/BCAA ratio and thereby decrease the availability of f-TRP to the brain for 5-HT synthesis.
Blomstrand et al. (23,24) were also the first to focus on the administration of BCAA as a way to delay CNS fatigue. They reported that the administration of 7.5 to 21 g of BCAA prior to and during a marathon race, a cross-country ski race, or a soccer match was associated with small improvements in some subjects in both physical (marathon running and cross-country skiing) and mental performance(23,24). However, it should be noted that while field studies such as these are designed to mimic real world situations, they are often limited in scientific value. For example, subjects are often not appropriately matched prior to dividing them into control and experimental groups to prevent inherent differences in the performance capacity of the groups. In addition, studies of this nature often do not (or cannot)“blind” subjects to the experimental treatments to prevent bias on the part of the subjects toward the treatment they believe to be the better one. Finally, these studies often fail to control important variables such as exercise intensity and food and water intake across the treatments. These limitations and others increase the likelihood that benefits ascribed to a particular nutritional supplement may have actually resulted from inherent differences in the groups of subjects, subject bias, and/or one or more of the uncontrolled variables.
Skepticism about the results of these early field studies is also heightened by the observations in recent wellcontrolled laboratory experiments that show no beneficial effects of BCAA supplementation during exercise. Varnier et al. (82) infused approximately 20 g BCAA or saline over 70 min prior to exercise using a double-blinded, cross-over design and found no differences in performance of a graded incremental exercise test to fatigue. Verger et al. (83) also reported that ingestion of BCAA in rats actually caused early fatigue during treadmill running as compared with rats fed either water or glucose. We performed a double-blinded, cross-over study in the laboratory to determine the effects of a smaller, more palatable, supplement of BCAA (approximately 0.5 g × h-1 BCAA consumed in a carbohydrate-electrolyte drink) during cycling exercise at 70% ˙VO2max to fatigue (42). This low dose of BCAA was chosen to replace the calculated maximum amount of BCAA uptake and metabolism by muscle that would occur under these conditions and to decrease the likelihood that the BCAA supplements would impair water absorption rates in the gut, produce gastrointestinal (G-I) distress, or otherwise be unpalatable. The results of this study showed that the low dose BCAA supplement was palatable when added to a carbohydrate-electrolyte drink, didn't cause G-I distress, and prevented the slight drop in plasma BCAA concentration that occurred during prolonged cycling. However, the supplements did not affect ride times to fatigue, perceived exertion, or various measures of cardiovascular and metabolic function. Finally, it is interesting that Blomstrand et al. (21) did not find any benefit of BCAA supplements on endurance performance in their most recent controlled laboratory study. In this study, subjects performed exhaustive exercise on a cycle ergometer at a work rate corresponding to 75% ˙VO2max while consuming in random order either a 6% carbohydrate solution (CHO), a 6% carbohydrate solution containing 7 g·l-1 of BCAAs (CHO + BCAA), or a flavored water placebo. As expected, both carbohydrate groups performed longer before fatigue as compared with the water placebo group. However, there were no differences in performance between the CHO and CHO + BCAA treatments.
It is also important that the administration of large amounts of BCAA required to produce physiologically relevant alterations in plasma f-TRP/BCAA during exercise is likely to increase plasma ammonia, which can be toxic to the brain and may also negatively affect muscle metabolism(11,62,63,85). Acute ammonia toxicity, although transient and reversible, may be severe enough in critical regions of the central nervous system to impair performance (coordination, motor control) and/or produce severe symptoms of CNS fatigue (11). The buffering of ammonia could also cause fatigue in the muscle by depleting glycolytically-derived carbon skeletons (pyruvate) and by draining intermediates of the tricarboxylic acid cycle which are coupled to glutamine production by transamination reactions (84,85). This could conceivably impair oxidative metabolism in the muscle and lead to early fatigue.
We reasoned that carbohydrate feedings may be a more appropriate strategy for delaying CNS fatigue because very large attenuations in f-TRP and f-TRP/BCAA would likely be achieved during exercise without the potential negative consequences of administering large doses of BCAA. This is because of the well-established suppressive effects of carbohydrate feedings on mobilization of free acids (FFA) (69) which compete with f-TRP for binding sites on plasma albumin molecules. This would thereby reduce concentrations of f-TRP and f-TRP/BCAA, which is likely to suppress the production of 5-HT in the brain and minimize CNS fatigue(42). These effects might occur in addition to the well known benefits of carbohydrate supplements on peripheral mechanisms of fatigue(36).
This hypothesis was tested in a double-blinded, placebo controlled study in the laboratory in which subjects drank either a water placebo, a 6% carbohydrate-electrolyte drink, or a 12% carbohydrate-electrolyte drink during prolonged cycling at 70% ˙VO2max to fatigue(42). When subjects consumed the water placebo, plasma f-TRP increased by ≈ 7-fold (in direct proportion to plasma free fatty acids), while total-TRP and BCAAs changed very little during the ride. When subjects consumed either the 6% or 12% carbohydrate-electrolyte solution (5 ml·kg-1·30 min-1), the increases in plasma f-TRP were greatly reduced and fatigue was delayed by approximately 1 h. The carbohydrate feedings caused a slight reduction in plasma BCAAs (≈19% and 31% in the 6% and 12% CHO groups, respectively), but this decrease was probably inconsequential with respect to the very large attenuation (5-7 fold) of plasma f-TRP (Fig. 4). Although it was not possible to distinguish between the beneficial effects of carbohydrate feedings on central versus peripheral mechanisms of fatigue in this study, the substantial delay in fatigue could not be explained by typical markers of peripheral muscle fatigue involving cardiovascular, thermoregulatory, and metabolic function.
Brain Dopamine and CNS Fatigue
Dopamine (DA) was the first neurotransmitter to be investigated for its potential role in determining CNS fatigue. This was probably the case because of the previously established role of DA in controlling movement (summarized below) and the prior use of amphetamine by athletes to improve performance. Increases in whole brain DA metabolism following running activity were first documented by Bliss and Ailion (20).
These results have most recently been confirmed by Chaouloff et al.(33) and Bailey et al. (8). Regional analyses indicate that DA metabolism is enhanced during exercise in the midbrain, hippocampus, striatum, and hypothalamus(34,54). In the circling rat, changes in DA synthesis and metabolism in the caudate nucleus and nucleus accumbens have been associated with changes in posture and direction, respectively(47).
From these investigations it is obvious that increased brain dopaminergic activity is necessary during physical activity and may affect endurance performance. Indeed, several authors have found endurance performance to be improved following increased dopaminergic activation by amphetamine. Bhagat and Wheeler (15) found swimming endurance in the rat to be improved following administration of amphetamine in doses ranging from 10 to 20 mg·kg-1. In comparison, Gerald (50) found that endurance performance in rats running at 18.8 m·min-1 was increased from 45.5 to 76.0 min (67%) following injection of 2.5 mg·kg-1 of amphetamine (Fig. 5). Administration of doses greater that 2.5 mg·kg-1 resulted in a reduction of endurance performance (50). Endurance performance is also impaired following destruction of dopaminergic neurons by 6-hydroxydopamine (6-OHDA) (54).
Bailey et al. (8) have demonstrated the importance of increased brain DA synthesis and metabolism during exercise. They found that fatigue in the rat is associated with a reduction of dopamine synthesis and metabolism in the brain stem and midbrain. Furthermore, when brain DA synthesis and metabolism is maintained, fatigue is delayed(8).
While it is clear that amphetamine administration can improve endurance performance, the mechanisms underlying this effect remain unexamined. From some of the results provided by Chaouloff et al.(34,35) it appears reasonable to hypothesize that increased brain dopaminergic activity may be beneficial owing to its ability to inhibit brain 5-HT synthesis and metabolism. It is also possible that when dopaminergic activity is reduced during prolonged exercise fatigue is precipitated by a loss of coordination (i.e., reduced efficiency) and/or a reduction in motivation. With development of more specific pharmacological agents (for example, dor-peridone, a peripheral DA antagonist) and in vitro measurement and induction techniques (i.e., brain dialysis and push-pull cannulation) it appears that this area is ready for more mechanistic research.
Choline/Acetylcholine and CNS Fatigue
Acetylcholine is the most ubiquitous neurotransmitter in the body. Synthesis, release, and reuptake of acetylcholine are essential for the generation of muscular force. Acetylcholine is also an important neurotransmitter employed by preganglionic sympathetic fibers and neurons within the central nervous system. Within the central nervous system, acetylcholine has been associated with memory, awareness, and temperature regulation. As with 5-HT, the rate of synthesis of acetylcholine is determined by the availability of its precursor, choline. It has recently been hypothesized that fatigue during prolonged exercise may be initiated by a reduction in cholinergic activity subsequent to depletions in availability of choline (37,38,75,89).
Support for this concept has been provided by Wurtman and colleagues at the Massachusetts Institute of Technology (37). In the first of two preliminary experiments, they found that plasma choline levels were reduced approximately 40% in runners following completion of the Boston Marathon. Similar reductions in plasma choline, as a result of consumption of a cholinefree diet, have been associated with a reduced speed of transmission of the contraction-generating impulse in skeletal muscle(91). In a follow-up investigation, performance during a 20-mile run was improved when plasma choline was maintained or elevated by consumption of a beverage supplemented with choline citrate.
The results of the only laboratory investigation on the effects of choline supplementation on exercise performance (78) were not consistent with those described above. In this study choline supplementation(2.43 g, 1 h before exercise) did not improve exercise time to exhaustion during prolonged (70% of ˙VO2max) or intense (150% of˙VO2max) cycling (78). Furthermore, serum choline levels were not depleted by either of these exercise conditions(78).
Cytokines and CNS Fatigue
Even though little is known about the neurophysiological/psychological basis of CNS fatigue, it is likely that the sense of effort and its relationship with the willingness to start and continue to perform at maximal levels can be influenced by alterations in neurotransmitters and/or humoral factors in circulation (neuromodulators) that may directly or indirectly alter neurotransmitter activity. For example, fatigue associated with infections like the influenza virus and Epstein-Barr virus (mononucleosis) or the newly characterized disease known as chronic fatigue syndrome (CFS) may be a result of one or more of a variety of soluble substances released from immune cells(cytokines) that affect on fatigue at the level of the central nervous system(53,64). Increased interferon production is expected in CFS patients because abnormalities in cell-mediated immunity is a prominent diagnostic criteria for CFS (60,80). Given that cytokines such as alpha interferon are capable of producing“fatigue” and other neuropsychiatric symptoms(64,86), it is hypothesized that immunological disturbances are relevant to the pathogenesis of chronic fatigue in these patients (58).
Enhanced cytokine release is also a likely explanation for the abnormal response to exercise in subjects with acute viral or bacterial infections(59,60). During ongoing acute infection, as well as in the convalescent phase, exercise tolerance is reduced(41,48). Again, the exact mechanisms behind the decreased performance capacity that occurs under these conditions are not known, but depleted fuel stores, lack of available metabolic substrates, or lactic acidosis do not appear to be the limiting factors(13,57).
Ammonia and CNS Fatigue
Another substance released into the blood by muscle during exercise and known to be toxic to the brain is ammonia (11). Increased ammonia can alter CNS function either by acting directly on selected brain centers (70), by altering the brain membrane permeability to selected amino acids that are precursors to various neurotransmitters, and possibly by altering reactions involving a-ketoglutarate, glutamate, and glutamine, and their subsequent impact on the metabolism of various neurotransmitters (11).
Elevated blood ammonia, which accumulates quickly in the brain, is found during brief intense exercise as well as prolonged moderate exercise,(11) and it is thought to arise principally from stimulation of the purine nucleotide cycle in muscle, in particular the fast twitch (FT) fibers (68). This is a consequence of an increase in myokinase activity, which converts two ADP molecules into an ATP and an AMP molecule. Ammonia is a byproduct of the subsequent conversion of AMP to inosine monophosphate (IMP). However, there is increasing evidence that substantial increases in ammonia can result from branched chain amino acid catabolism. This is especially true when glycogen stores are low at the beginning of exercise, during the latter stages of prolonged exercise when carbohydrate stores are depleted, or when branched chain amino acids are given as supplements during exercise (84,85). Carbohydrate loading abolished the increase in branched-chain amino acid oxidation and substantially blunted the increase in plasma ammonia during 2 h of cycling at 70-75% ˙VO2max(84), whereas branched chain amino acid supplementation during exercise substantially increased plasma ammonia during prolonged exercise(85).
Regardless of the precise mechanism of elevated ammonia during exercise, it has been proposed that exhaustive exercise can induce a state of acute ammonia toxicity which, although transient and reversible, may be severe enough in critical regions of the central nervous system to impair performance(coordination, motor control) and/or fatigue (11). It should be noted, however, that ammonia buffering could cause fatigue in the muscle by depleting glycolytically-derived carbon skeletons (pyruvate) and by draining intermediates of the tricarboxylic acid cycle which are coupled to glutamine production by transamination reactions(84,85). This could conceivably impair oxidative metabolism in the muscle and lead to early fatigue.
SUMMARY AND CONCLUSIONS
Fatigue during prolonged exercise has traditionally been associated with mechanisms that result in dysfunction of the contractile process. More recently, however, interest in CNS mechanisms of fatigue has grown as our understanding of the physiological workings of the CNS has improved. CNS fatigue is a form of fatigue associated with specific alterations in CNS function that cannot be reasonably accounted for by peripheral dysfunction within the muscle itself. It is likely that the CNS plays an important role in mediating fatigue since changes in motivational level have a profound effect on endurance performance and since the first indication that fatigue may be imminent is an increased perception of effort at the same absolute workload. Reduction is CNS drive to the muscle may be mediated by afferent feedback from the muscle or a reduction in corticospinal impulses reaching the motorneurons. Changes in afferent feedback from the muscle may be the result of changes in muscle metabolites during exercise and an attempt to produce the most safe and efficient level of muscle activation.
A reduction in corticospinal impulses reaching motorneurons could be the result of alterations in neurotransmitter function in the brain. Neurotransmitters potentially involved in fatigue during prolonged exercise include serotonin, acetylcholine, and dopamine. Of these, serotonin (5-HT) has received most of the recent attention because 5-HT synthesis is increased during prolonged exercise, and increases in brain 5-HT have been associated with lethargy and loss of motor drive. Nutritional and pharmacological manipulations have been used to investigate the possible role of 5-HT in mediating fatigue. In general, when brain 5-HT activity or TRP availability to the brain is increased, fatigue during prolonged exercise is hastened. Preliminary evidence indicates that this may be the result of changes in brain dopamine synthesis and metabolism. Furthermore, hastened fatigue as a result of increased brain 5-HT activity is not associated with altered HPA axis activity, energy substrate utilization, or thermoregulatory ability.
In comparison, brain dopamine synthesis is essential to any movement and an increase in brain dopaminergic activity in various brain regions increases endurance performance. An increase in brain dopaminergic activity may delay fatigue by inhibiting brain 5-HT synthesis and by directly activating motor pathways. Changes in cholinergic activity in the CNS are likely to be important in maintaining activity; however, the effects of manipulation of this system on fatigue during prolonged exercise remain unclear. Release of ammonia into the blood during exercise could also alter CNS function by acting directly on selected brain centers or by altering the permeability of the blood brain barrier to amino acids involved in neurotransmission.
Fatigue during prolonged exercise obviously is influenced by CNS as well as peripheral factors. Elucidation of how the CNS influences fatigue during prolonged exercise is relevant to endurance performance and several fatigue related disorders such as chronic fatigue syndrome and depression.
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