Bart Roelands

Central Fatigue The Serotonin Hypothesis and Beyond

The original central fatigue hypothesis suggested that an exercise-induced increase in extracellular serotonin concentrations in several brain regions contributed to the development of fatigue during prolonged exercise. Serotonin has been linked to fatigue because of its well known effects on sleep, lethargy and drowsiness and loss of motivation. Several nutritional and pharmacological studies have attempted to manipulate central serotonergic activity during exercise, but this work has yet to provide robust evidence for a significant role of serotonin in the fatigue process. However, it is important to note that brain function is not determined by a single neurotransmitter system and the interaction between brain serotonin and dopamine during prolonged exercise has also been explored as having a regulative role in the development of fatigue. This revised central fatigue hypothesis suggests that an increase in central ratio of serotonin to dopamine is associated with feelings of tiredness and lethargy, accelerating the onset of fatigue, whereas a low ratio favours improved performance through the maintenance of motivation and arousal. Convincing evidence for a role of dopamine in the development of fatigue comes from work investigating the physiological responses to amphetamine use, but other strategies to manipulate central catecholamines have yet to influence exercise capacity during exercise in temperate conditions. Recent findings have, however, provided support for a significant role of dopamine and noradrenaline (norepinephrine) in performance during exercise in the heat. As serotonergic and catecholaminergic projections innervate areas of the hypothalamus, the thermoregulatory centre, a change in the activity of these neurons may be expected to contribute to the control of body temperature whilst at rest and during exercise. Fatigue during prolonged exercise clearly is influenced by a complex interaction between peripheral and central factors.

Acute dopamine/noradrenaline reuptake inhibition enhances human exercise performance in warm, but not temperate conditions

Nine healthy endurance‐trained males were recruited to examine the effect of a dual dopamine/noradrenaline reuptake inhibitor on performance, thermoregulation and the hormonal responses to exercise. Subjects performed four trials, ingesting either a placebo (pla) or 2 × 300 mg bupropion (bup), prior to exercise in temperate (18°C) or warm (30°C) conditions. Trials consisted of 60 min cycle exercise at 55%Wmax immediately followed by a time trial (TT). TT performance in the heat was significantly improved by bupropion (pla: 39.8 ± 3.9 min, bup: 36.4 ± 5.7 min; P= 0.046), but no difference between treatments was apparent in temperate conditions (pla: 30.6 ± 2.2 min, bup: 30.6 ± 1.9 min; P= 0.954). While TT power output was consistently lower in the heat when compared to temperate conditions, this decrement was attenuated by bupropion. At the end of the TT in the heat, both core temperature (pla 39.7 ± 0.3°C, bup 40.0 ± 0.3°C; P= 0.017) and HR (pla 178 ± 7 beats min−1, bup 183 ± 12 beats min−1; P= 0.039), were higher in the bupropion trial than in the placebo. Circulating pituitary and adrenal hormone concentrations increased throughout exercise in all trials. Circulating serum prolactin was elevated above temperate levels during exercise in a warm environment (P < 0.001). These data indicate that performance in warm conditions is enhanced by acute administration of a dual dopamine/noradrenaline reuptake inhibitor. No such effect was apparent under temperate conditions. It appears that bupropion enabled subjects to maintain a greater TT power output in the heat with the same perception of effort and thermal stress reported during the placebo trial, despite the attainment of a higher core temperature.

Intense exercise increases circulating endocannabinoid and BDNF levels in humans—Possible implications for reward and depression

The endocannabinoid system is known to have positive effects on depression partly through its actions on neurotrophins, such as Brain-Derived Neurotrophic Factor (BDNF). As BDNF is also considered the major candidate molecule for exercise-induced brain plasticity, we hypothesized that the endocannabinoid system represents a crucial signaling system mediating the beneficial antidepressant effects of exercise. Here we investigated, in 11 healthy trained male cyclists, the effects of an intense exercise (60 min at 55% followed by 30 min at 75% W(max)) on plasma levels of endocannabinoids (anandamide, AEA and 2-arachidonoylglycerol, 2-AG) and their possible link with serum BDNF. AEA levels increased during exercise and the 15 min recovery (P<0.001), whereas 2-AG concentrations remained stable. BDNF levels increased significantly during exercise and then decreased during the 15 min of recovery (P<0.01). Noteworthy, AEA and BDNF concentrations were positively correlated at the end of exercise and after the 15 min recovery (r>0.66, P<0.05), suggesting that AEA increment during exercise might be one of the factors involved in exercise-induced increase in peripheral BDNF levels and that AEA high levels during recovery might delay the return of BDNF to basal levels. AEA production during exercise might be triggered by cortisol since we found positive correlations between these two compounds and because corticosteroids are known to stimulate endocannabinoid biosynthesis. These findings provide evidence in humans that acute exercise represents a physiological stressor able to increase peripheral levels of AEA and that BDNF might be a mechanism by which AEA influences the neuroplastic and antidepressant effects of exercise.

The effects of acute dopamine reuptake inhibition on performance.

INTRODUCTION Acute bupropion (dopamine/noradrenaline reuptake inhibitor) administration significantly improved time trial performance and increased core temperature in the heat (30 degrees C). PURPOSE The present study was performed to examine the effect of a dopaminergic reuptake inhibitor on exercise capacity and thermoregulation during prolonged exercise in temperate and warm conditions. METHODS Eight healthy well-trained male cyclists participated in this study. Subjects ingested either placebo (PLA; 20 mg) or methylphenidate (MPH; Ritalin; 20 mg) 1 h before the start of exercise in temperate (18 degrees C) or warm (30 degrees C) conditions and cycled for 60 min at 55% Wmax, immediately followed by a time trial (TT; PLA18 and MPH18; PLA30 and MPH30) to measure exercise performance. RESULTS MPH did not influence TT performance at 18 degrees C (P = 0.397). TT was completed 16% faster in MPH30 (38.1 +/- 6.4 min) than in PLA30 (45.4 +/- 7.3 min; P = 0.049). In the heat Tcore was significantly higher at rest (P = 0.009), and throughout the TT in MPH30 (P < 0.018), reaching values above 40 degrees C. Throughout MPH30, heart rates were significantly higher (P < 0.05). CONCLUSIONS These results show that MPH has a clear ergogenic effect that was not apparent in 18 degrees C. The combination of a dopamine reuptake inhibitor and exercise in the heat clearly improved performance and caused hyperthermia without any change in the perception of effort or thermal stress compared with the PLA trial. This response may potentially increase the risk of developing heat illness during exercise in individuals taking drugs of this nature.

Guidelines to Classify Subject Groups in Sport-Science Research

AIM To review current cycling-related sport-science literature to formulate guidelines to classify female subject groups and to compare this classification system for female subject groups with the classification system for male subject groups. METHODS A database of 82 papers that described female subject groups containing information on preexperimental maximal cycle-protocol designs, terminology, biometrical and physiological parameters, and cycling experience was analyzed. Subject groups were divided into performance levels (PLs), according to the nomenclature. Body mass, body-mass index, maximal oxygen consumption (VO2max), peak power output (PPO), and training status were compared between PLs and between female and male PLs. RESULTS Five female PLs were defined, representing untrained, active, trained, well-trained, and professional female subjects. VO2max and PPO significantly increased with PL, except for PL3 and PL4 (P < .01). For each PL, significant differences were observed in absolute and relative VO2max and PPO between male and female subject groups. Relative VO2max is the most cited parameter for female subject groups and is proposed as the principal parameter to classify the groups. CONCLUSION This systematic review shows the large variety in the description of female subject groups in the existing literature. The authors propose a standardized preexperimental testing protocol and guidelines to classify female subject groups into 5 PLs based on relative VO2max, relative PPO, training status, absolute VO2max, and absolute PPO.

Alterations in Central Fatigue by Pharmacological Manipulations of Neurotransmitters in Normal and High Ambient Temperature

The scientific evidence is reviewed for the involvement of the brain monoamines serotonin, dopamine and noradrenaline (norepinephrine) in the onset of fatigue, in both normal and high ambient temperatures. The main focus is the pharmacological manipulations used to explore the central fatigue hypothesis. The original central fatigue hypothesis emphasizes that an exercise-induced increase in serotonin is responsible for the development of fatigue. However, several pharmacological studies attempted and failed to alter exercise capacity through changes in serotonergic neurotransmission in humans, indicating that the role of serotonin is often overrated. Recent studies, investigating the inhibition of the reuptake of both dopamine and noradrenaline, were capable of detecting changes in performance, specifically when ambient temperature was high. Dopamine and noradrenaline are prominent in innervated areas of the hypothalamus, therefore changes in the catecholaminergic concentrations may also be expected to be involved with the regulation of body core temperature during exercise in the heat. Evidence from different studies suggests that it is very unlikely that one neurotransmitter system is responsible for the appearance of central fatigue. The exact mechanism of fatigue is not known; presumably a complex interplay between both peripheral and central factors induces fatigue. Central fatigue will be determined by the collaboration of the different neurotransmitter systems, with the most important role possibly being for the catecholamines dopamine and noradrenaline.

Acute norepinephrine reuptake inhibition decreases performance in normal and high ambient temperature

Combined inhibition of dopamine (DA)/norepinephrine (NE) reuptake improves exercise performance and increases core temperature in the heat. A recent study demonstrated that this effect may primarily be related to increased DA activity. NE reuptake inhibition (NERI), however, has received little attention in humans, certainly in the heat, where central fatigue appears to be a main factor influencing performance. Therefore the present study examines the effect of NERI (reboxetine) on exercise capacity, thermoregulation, and hormonal response in normal and high temperature. Nine healthy well-trained male cyclists participated in this study. Subjects ingested either placebo (Pla; 2 x 8 mg) or reboxetine (Rebox; 2 x 8 mg). Subjects exercised in temperate (18 degrees C) or warm (30 degrees C) conditions and cycled for 60 min at 55% W(max) immediately followed by a time trial (TT; Pla18/Rebox18; Pla30/Rebox30) to measure exercise performance. Acute NERI decreased power output and consequently exercise performance in temperate (P = 0.018) and warm (P = 0.007) conditions. Resting heart rate was significantly elevated by NERI (18 degrees C: P = 0.02; 30 degrees C: P = 0.018). In Rebox18, heart rate was significantly higher than in the Pla18, while in the heat no effect of the drug treatment was reported during exercise. In Rebox30, all hormone concentrations increased during exercise, except for growth hormone (GH), which was significantly lower during exercise. In Rebox18, prolactin (PRL) concentrations were significantly elevated; GH was significantly higher at rest, but significantly lower during exercise. In conclusion, manipulation of the NE system decreases performance and modifies hormone concentrations, thereby indicating a central NE effect of the drug. These findings confirm results from previous studies that predominantly increased DA activity is important in improving performance.

Neurophysiological Determinants of Theoretical Concepts and Mechanisms Involved in Pacing

Fatigue during prolonged exercise is often described as an acute impairment of exercise performance that leads to an inability to produce or maintain a desired power output. In the past few decades, interest in how athletes experience fatigue during competition has grown enormously. Research has evolved from a dominant focus on peripheral causes of fatigue towards a complex interplay between peripheral and central limitations of performance. Apparently, both feedforward and feedback mechanisms, based on the principle of teleoanticipation, regulate power output (e.g. speed) during a performance. This concept is called ‘pacing’ and represents the use of energetic resources during exercise, in a way such that all energy stores are used before finishing a race, but not so far from the end of a race that a meaningful slowdown can occur.It is believed that the pacing selected by athletes is largely dependent on the anticipated exercise duration and on the presence of an experientially developed performance template. Most studies investigating pacing during prolonged exercise in ambient temperatures, have observed a fast start, followed by an even pace strategy in the middle of the event with an end sprint in the final minutes of the race. A reduction in pace observed at commencement of the event is often more evident during exercise in hot environmental conditions. Further, reductions in power output and muscle activation occur before critical core temperatures are reached, indicating that subjects can anticipate the exercise intensity and heat stress they will be exposed to, resulting in a tactical adjustment of the power output. Recent research has shown that not only climatic stress but also pharmacological manipulation of the central nervous system has the ability to cause changes in endurance performance. Subjects seem to adapt their strategy specifically in the early phases of an exercise task. In high-ambient temperatures, dopaminergic manipulations clearly improve performance. The distribution of the power output reveals that after dopamine reuptake inhibition, subjects are able to maintain a higher power output compared with placebo. Manipulations of serotonin and, especially, noradrenaline, have the opposite effect and force subjects to decrease power output early in the time trial. Interestingly, after manipulation of brain serotonin, subjects are often unable to perform an end sprint, indicating an absence of a reserve capacity or motivation to increase power output. Taken together, it appears that many factors, such as ambient conditions and manipulation of brain neurotransmitters, have the potential to influence power output during exercise, and might thus be involved as regulatory mechanisms in the complex skill of pacing.

Effects of different types of acute and chronic (training) exercise on glycaemic control in type 1 diabetes mellitus: a meta-analysis

OBJECTIVE Exercise has been accepted and generally recommended for the management of type 1 diabetes mellitus (T1D) and for improving the overall quality of life in affected individuals. This meta-analysis was conducted to determine the overall effects of exercise (acute bouts of exercise and chronic exercise [or training]) on acute and chronic glycaemic control in patients with T1D, the effects of different types of exercise on glycaemic control and which conditions are required to obtain these positive effects. METHODS PubMed, ISI Web of Knowledge and SPORTDiscus™ were consulted to identify studies on T1D and exercise. Cohens d statistics were used for calculating mean effect sizes (ES) as follows: small d = 0.3, medium d = 0.5 and large d = 0.8. Ninety-five percent confidence intervals (95% CIs) were used to establish the significance of our findings. RESULTS From a total of 937 studies, 33 that met the inclusion criteria were selected. Nine studies were used to calculate the ES of a single bout of aerobic exercise; 13 studies to calculate the ES of aerobic training; 2 studies to calculate the ES of strength training; 4 studies to calculate the ES of combined (aerobic and strength) training and 6 studies to calculate the ES of high-intensity exercise (HIE) and training. ES for exercise on acute glycaemic control were large, while they were small for chronic glycaemic control. Aerobic exercise, resistance exercise, mixed exercise (aerobic combined with resistance training) and HIE acutely decreased blood glucose levels. To prevent late-onset hypoglycaemic episodes, the use of single bouts of sprints into an aerobic exercise can be recommended. This meta-analysis also showed that a regular exercise training programme has a significant effect on acute and chronic glycaemic control, although not all exercise forms showed significant results. Specifically, aerobic training is a favourable tool for decreasing chronic glycaemic control, while resistance training, mixed and HIE did not significantly improve chronic glycaemic control. Although, this meta-analysis showed there was a tendency for improvement in glycaemic control due to resistance training or resistance training combined with endurance training, there were not enough studies and/or subjects to confirm this statistically. CONCLUSIONS Based on this meta-analysis, we can conclude that the addition of brief bouts of high-intensity, sprint-type exercise to aerobic exercise can minimize the risk of sustaining a hypoglycaemic episode. We can also conclude that only regular aerobic training will improve the glycated haemoglobin level of a patient with T1D.

Central fatigue and neurotransmitters, can thermoregulation be manipulated?

Fatigue is a complex phenomenon that can be evoked by peripheral and central factors. Although it is obvious that fatigue has peripheral causes such as glycogen depletion and cardiovascular strain, recent literature also focuses on the central origin of fatigue. It is clear that different brain neurotransmitters – such as serotonin, dopamine and noradrenaline – are implicated in the occurrence of fatigue, but manipulation of these neurotransmitters produced no conclusive results on performance in normal ambient temperature. Exercise in the heat not only adds an extra challenge to the cardiorespiratory system, but also to the brain. This provides a useful tool to investigate the association between exercise‐induced hyperthermia and central fatigue. This review focuses on the effects of pharmacological manipulations on performance and thermoregulation in different ambient temperatures. Dopaminergic reuptake inhibition appears to counteract hyperthermia‐induced fatigue in 30 °C, while noradrenergic neurotransmission shows negative effects on performance in both normal and high temperature, and serotonergic manipulations did not lead to significant changes in performance. It is, however, unlikely that one neurotransmitter system is responsible for the delay or onset of fatigue. Further research is required to determine the exact mechanisms of fatigue in different environmental conditions.