Central nervous system fatigue

Short description: Associated with concentration changes in synaptic neurotransmitters in the CNS

Central nervous system fatigue, or central fatigue, is a form of fatigue that is associated with changes in the synaptic concentration of neurotransmitters within the central nervous system (CNS; including the brain and spinal cord) which affects exercise performance and muscle function and cannot be explained by peripheral factors that affect muscle function.[1][2][3][4] In healthy individuals, central fatigue can occur from prolonged exercise and is associated with neurochemical changes in the brain, involving (but not limited to) serotonin (5-HT), noradrenaline, and dopamine.[2][3][4] The roles of dopamine, noradrenaline, and serotonin in CNS fatigue are unclear, as pharmacological manipulation of these systems has yielded mixed results.[5][6] Central fatigue plays an important role in endurance sports and also highlights the importance of proper nutrition in endurance athletes.

## Contents

* 1 Neurochemical mechanisms
* 1.1 Noradrenaline
* 1.2 Serotonin
* 1.3 Dopamine
* 1.4 Acetylcholine
* 1.5 Cytokines
* 1.6 Ammonia
* 2 Manipulation
* 2.1 Dopamine reuptake and release agents
* 2.2 Caffeine
* 2.3 Carbohydrates
* 2.4 Branched-chain amino acids
* 3 Role
* 4 Possible connection with Chronic fatigue syndrome
* 5 Loud Noise Exposure Damage
* 6 References

## Neurochemical mechanisms

Existing experimental methods have provided enough evidence to suggest that variations in synaptic serotonin, noradrenaline, and dopamine are significant drivers of central nervous system fatigue.[2][3][4] An increased synaptic dopamine concentration in the CNS is strongly ergogenic (promotes exercise performance).[2][3][4] Paradoxically, however, direct dopamine agonists such as bromocriptine and pramipexole have caused opposite, pro-fatigue effects in healthy humans.[5]

### Noradrenaline

Manipulation of norepinephrine suggests it may actually play a role in creating a feeling of fatigue. Reboxetine, an NRI, decreased time to fatigue and increased subjective feelings of fatigue.[7][8] This may be explained by a paradoxical decrease in adrenergic activity led by feedback mechanisms.

### Serotonin

In the brain, serotonin is a neurotransmitter and regulates arousal, behavior, sleep, and mood, among other things.[9] During prolonged exercise where central nervous system fatigue is present, serotonin levels in the brain are higher than normal physiological conditions; these higher levels can increase perceptions of effort and peripheral muscle fatigue.[9] The increased synthesis of brain serotonin occurs because of a higher proportion of tryptophan, the serotonin precursor, in the blood and which results in larger amounts of tryptophan crossing the blood–brain barrier. An important factor of serotonin synthesis is the transport mechanism of tryptophan across the blood–brain barrier. The transport mechanism for tryptophan is shared with the branched chain amino acids (BCAAs), leucine, isoleucine, and valine. During extended exercise, BCAAs are consumed for skeletal muscle contraction, allowing for greater transport of tryptophan across the blood–brain barrier. None of the components of the serotonin synthesis reaction are saturated under normal physiological conditions,[10] allowing for the increased production of the neurotransmitter. However the failure of BCAAs to decrease time to fatigue consistently limit this hypothesis. This may be due to a counter-acting mechanism: BCAAs also limit the uptake of tyrosine, another aromatic amino acid, like tryptophan. Tyrosine is a precursor to catecholamine, which enhances performance drive.[11]

### Dopamine

Dopamine is a neurotransmitter that regulates arousal, motivation, muscular coordination, and endurance performance, among other things.[12] Dopamine levels have been found to be lower after prolonged exercise.[13] A decrease in dopamine can decrease athletic performance as well as mental motivation. Dopamine itself cannot cross the blood brain barrier and must be synthesized within the brain. In rats bred for running, increased activity of the ventral tegmental area have been observed, and VTA activity correlates with voluntary wheel running. As the VTA is an area dense in dopaminergic neurons that project to many areas of the brain, this suggests that dopaminergic neurotransmission drives physical performance. Further supporting this theory is the fact that dopamine reuptake inhibitors as well as norepinephrine dopamine reuptake inhibitors are able to increase exercise performance, especially in the heat.[8]

### Acetylcholine

Acetylcholine is required for the generation of muscular force. In the central nervous system, acetylcholine modulates arousal and temperature regulation. It also may play a role in central fatigue. During exercise, levels of acetylcholine drop.[14] This is due to a decrease in plasma choline levels. However, there have been conflicting results in studies about the effect of acetylcholine on fatigue. One study found that plasma choline levels had dropped 40% after the subjects ran the Boston Marathon.[14] Another study found that choline supplementation did not improve time to exhaustion.[15] This study also found that plasma choline levels had not changed in either the placebo or the choline supplemented groups. More research is needed to investigate acetylcholine's effects on fatigue.

### Cytokines

Cytokines can manipulate neurotransmissions creating sickness behavior, characterized by malaise and fatigue. In animal models, IL-1b stimulates serotonin release and increases activity of GABA. Lipopolysaccharide challenges also inhibit activity of histaminergic and dopaminergic neurons.[16]

### Ammonia

Increased circulating levels of ammonia may alter brain function and result in fatigue.[17] One hypothesized reason that BCAAs fail to increase exercise performance is due to increased oxidation of BCAAs in supplementation that results in increased fatigue, canceling out the effects on serotonin receptors.[citation needed]

## Manipulation

Controlling central nervous system fatigue can help scientists develop a deeper understanding of fatigue as a whole. Numerous approaches have been taken to manipulate neurochemical levels and behavior. In sports, nutrition plays a large role in athletic performance. In addition to fuel, many athletes consume performance-enhancing drugs including stimulants in order to boost their abilities.

### Dopamine reuptake and release agents

Amphetamine is a stimulant that has been found to improve both physical and cognitive performance. Amphetamine blocks the reuptake of dopamine and norepinephrine, which delays the onset of fatigue by increasing the amount of dopamine, despite the concurrent increase in norepinephrine, in the central nervous system.[2][18][19] Amphetamine is a widely used substance among collegiate athletes for its performance enhancing qualities,[20] as it can improve muscle strength, reaction time, acceleration, anaerobic exercise performance, power output at fixed levels of perceived exertion, and endurance.[3][19][18]

Methylphenidate has also been shown to increase exercise performance in time to fatigue and time trial studies.[21]

### Caffeine

Caffeine is the most widely consumed stimulant in North America. Caffeine causes the release of epinephrine from the adrenal medulla. In small doses, caffeine can improve endurance.[22] It has also been shown to delay the onset of fatigue in exercise. The most probable mechanism for the delay of fatigue is through the obstruction of adenosine receptors in the central nervous system.[23] Adenosine is a neurotransmitter that decreases arousal and increases sleepiness. By preventing adenosine from acting, caffeine removes a factor that promotes rest, and delays fatigue.

### Carbohydrates

Carbohydrates are the main source of energy in organisms for metabolism. They are an important source of fuel in exercise. A study conducted by the Institute of Food, Nutrition, and Human Health at Massey University investigated the effect of consuming a carbohydrate and electrolyte solution on muscle glycogen use and running capacity on subjects that were on a high carbohydrate diet.[24] The group that consumed the carbohydrate and electrolyte solution before and during exercise experienced greater endurance capacity. This could not be explained by the varying levels of muscle glycogen; however, higher plasma glucose concentration may have led to this result. Dr. Stephen Bailey posits that the central nervous system can sense the influx of carbohydrates and reduces the perceived effort of the exercise, allowing for greater endurance capacity.[25]

### Branched-chain amino acids

Several studies have attempted to decrease the synthesis of serotonin by administering branched-chain amino acids and inhibiting the transport of tryptophan across the blood brain barrier.[26] The studies performed resulted in little or no change in performance between increased BCAA intake and placebo groups. One study in particular administered a carbohydrate solution and a carbohydrate + BCAA solution.[27] Both of the groups were able to run for longer before fatigue compared to the water placebo group. However, both the carbohydrate and the carbohydrate + BCAA groups had no differences in their performance. Branch-chained amino acid supplementation has proven to have little to no effect on performance. There has been little success utilizing neurotransmitter precursors to control central nervous system fatigue.

One review hypothesized that the inconsistency with BCAA administration was the result of ammonia accumulation as a result of increased BCAA oxidation.[7]

## Role

Central nervous system fatigue is a key component in preventing peripheral muscle injury.[28] The brain has numerous receptors, such as osmoreceptors, to track dehydration, nutrition, and body temperature. With that information as well as peripheral muscle fatigue information, the brain can reduce the quantity of motor commands sent from the central nervous system. This is crucial in order to protect the homeostasis of the body and to keep it in a proper physiological state capable of full recovery. The reduction of motor commands sent from the brain increases the amount of perceived effort an individual experiences. By forcing the body through a higher perceived intensity, the individual becomes more likely to cease exercise by means of exhaustion. Perceived effort is greatly influenced by the intensity of corollary discharge from the motor cortex that affects the primary somatosensory cortex.[29] Endurance athletes learn to listen to their body. Protecting organs from potentially dangerous core temperatures and nutritional lows is an important brain function. Central nervous system fatigue alerts the athlete when physiological conditions are not optimal so either rest or refueling can occur. It is important to avoid hyperthermia and dehydration, as they are detrimental to athletic performance and can be fatal.[30]

## Possible connection with Chronic fatigue syndrome

Chronic fatigue syndrome is a name for a group of diseases that are dominated by persistent fatigue. The fatigue is not due to exercise and is not relieved by rest.[31]

Through numerous studies, it has been shown that people with chronic fatigue syndrome have an integral central fatigue component.[1] In one study, the subjects' skeletal muscles were checked to ensure they had no defects that prevented their total use. It was found that the muscles functioned normally on a local level, but they failed to function to their full extent as a whole. The subjects were unable to consistently activate their muscles during sustained use, despite having normal muscle tissue.[32] In another study, the subjects experienced higher perceived effort in relation to heart rate as compared to the control during a graded exercise test.[33] The chronic fatigue subjects would stop before any sort of limit on the body was reached. Both studies proved that peripheral muscle fatigue was not causing the subjects with chronic fatigue syndrome to cease exercising. It is possible that the higher perception of effort required to use the muscles results in great difficulty in accomplishing consistent exercise.[1]

The main cause of fatigue in chronic fatigue syndrome most likely lies in the central nervous system. A defect in one of its components could cause a greater requirement of input to result in sustained force. It has been shown that with very high motivation, subjects with chronic fatigue can exert force effectively.[34] Further investigation into central nervous system fatigue may result in medical applications.

## Loud Noise Exposure Damage

Exposure to loud noise is a major environmental threat to public health. Loud noise exposure, apart from affecting the inner ear, is deleterious for cardiovascular, endocrine and nervous systems and it is associated with neuropsychiatric disorders. A study indicates that loud noise exposure represents a detrimental stimulus for specific brain areas. This consists mostly on decreased catecholamine innervation which involves multiple brain regions. These data lend substance to clinical findings showing impaired memory, mood alterations and other behavioral alterations induced by prolonged noise exposure. The occurrence of nigrostriatal dopamine innervation further strengthens this association. Similarly, in Parkinson’s disease a loss of auditory function occurs, which is compatible with the loss of cochlear dopamine innervation, which in turn protects from the effects of loud noise. Thus, a vicious circle may occur, where the excitotoxic effects of loud noise may destroy dopamine nerve endings producing a loss of dopamine in their terminal fields, including the efferent synapses with cochlear hair cells, where dopamine exerts a gating control. In this way, the transmission of loud noise would no longer be hampered despite a loss in the detection of pure tones. Altogether the findings provide a bridge between environmental exposure to loud noise and the onset of neuropsychiatric alterations such as: cognitive impairment, depressive symptoms, behavioral abnormalities, movement disorders, as recently documented in general populations. Since environmental noise exposure represents an increasing worldwide polluting agent,[35] loud noise exposure deserve particular attention in the light of their potential impact on public health.[36]

## References

1. ↑ 1.0 1.1 1.2 Davis J. M., Bailey S. P. (1997). "Possible mechanisms of central nervous system fatigue during exercise". Medicine & Science in Sports & Exercise 29 (1): 45–57. doi:10.1097/00005768-199701000-00008. PMID 9000155.
2. ↑ 2.0 2.1 2.2 2.3 2.4 "Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing". Sports Med. 43 (5): 301–311. May 2013. doi:10.1007/s40279-013-0030-4. PMID 23456493. "It is very unlikely that a single neurotransmitter system is responsible for the appearance of central fatigue [3]. ... Serotonin, the only neurotransmitter implicated in the original central fatigue hypothesis, has not yielded conclusive results in human studies [3]. ... 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. ... 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. ... Dopaminergic drugs appear to override a safety switch and allow athletes to use a reserve capacity that is ‘off-limits’ in a normal (placebo) situation.".
3. ↑ 3.0 3.1 3.2 3.3 3.4 "Is it time to turn our attention toward central mechanisms for post-exertional recovery strategies and performance?". Front. Physiol. 6: 79. March 2015. doi:10.3389/fphys.2015.00079. PMID 25852568. "Central fatigue is accepted as a contributor to overall athletic performance ... Post-exercise recovery has largely focused on peripheral mechanisms of fatigue, but there is growing acceptance that fatigue is also contributed to through central mechanisms which demands that attention should be paid to optimizing recovery of the brain. ... Aside from accounting for the reduced performance of mentally fatigued participants, this model rationalizes the reduced RPE and hence improved cycling time trial performance of athletes using a glucose mouthwash (Chambers et al., 2009) and the greater power output during a RPE matched cycling time trial following amphetamine ingestion (Swart, 2009). ... Dopamine stimulating drugs are known to enhance aspects of exercise performance (Roelands et al., 2008)".
4. ↑ 4.0 4.1 4.2 4.3 "Neurophysiological effects of exercise in the heat". Scand. J. Med. Sci. Sports 25 Suppl 1: 65–78. June 2015. doi:10.1111/sms.12350. PMID 25943657. "Physical fatigue has classically been attributed to peripheral factors within the muscle (Fitts, 1996), the depletion of muscle glycogen (Bergstrom & Hultman, 1967) or increased cardiovascular, metabolic, and thermoregulatory strain (Abbiss & Laursen, 2005; Meeusen et al., 2006b). In recent decennia however, it became clear that the central nervous system plays an important role in the onset of fatigue during prolonged exercise (Klass et al., 2008), certainly when ambient temperature is increased (Bruck & Olschewski, 1987; Nielsen et al., 1990; Nybo & Nielsen, 2001a). It was suggested that central fatigue could be related to a change in the synthesis and metabolism of brain monoamines, such as serotonin (5-HT), dopamine (DA), and noradrenaline (NA; Meeusen &Roelands, 2010). ... 5-HT, DA, and NA have all been implicated in the control of thermoregulation and are thought to mediate thermoregulatory responses, certainly since their neurons innervate the hypothalamus (Roelands & Meeusen, 2010). ... This suggests that NA contributes to the development of supraspinal fatigue during prolonged exercise. More studies on the plausible mechanism of this strong performance deterioration are needed. ... Strikingly, both the ratings of perceived exertion and the thermal sensation were not different to the placebo trial. This indicates that subjects did not feel they were producing more power and consequently more heat. ... Taken together, these data indicate strong ergogenic effects of an increased DA concentration in the brain, without any change in the perception of effort. ... The combined effects of DA and NA on performance in the heat were studied by our research group on a number of occasions. ... the administration of bupropion (DA/NA reuptake inhibitor) significantly improved performance. Coinciding with this ergogenic effect, the authors observed core temperatures that were much higher compared with the placebo situation. Interestingly, this occurred without any change in the subjective feelings of thermal sensation or perceived exertion. Similar to the methylphenidate study (Roelands et al., 2008b), bupropion may dampen or override inhibitory signals arising from the central nervous system to cease exercise because of hyperthermia, and enable an individual to continue maintaining a high power output".
5. ↑ 5.0 5.1 Micallef, Joëlle; Rey, Marc; Eusebio, Alexandre; Audebert, Christine; Rouby, Frank; Jouve, Elisabeth; Tardieu, Sophie; Blin, Oliver (March 2009). "Antiparkinsonian drug-induced sleepiness: a double-blind placebo-controlled study of L-dopa, bromocriptine and pramipexole in healthy subjects" (in en). British Journal of Clinical Pharmacology 67 (3): 333–340. doi:10.1111/j.1365-2125.2008.03310.x. PMID 19220275. PMC 2675044. https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.2008.03310.x.
6. ↑ Roelands, Bart; de Koning, Jos; Foster, Carl; Hettinga, Floor; Meeusen, Romain (2013-05-01). "Neurophysiological Determinants of Theoretical Concepts and Mechanisms Involved in Pacing" (in en). Sports Medicine 43 (5): 301–311. doi:10.1007/s40279-013-0030-4. ISSN 1179-2035. https://doi.org/10.1007/s40279-013-0030-4.
7. ↑ 7.0 7.1 Meeusen, Romain; Watson, Philip; Hasegawa, Hiroshi; Roelands, Bart; Piacentini, Maria F. (1 January 2006). "Central fatigue: the serotonin hypothesis and beyond". Sports Medicine 36 (10): 881–909. doi:10.2165/00007256-200636100-00006. ISSN 0112-1642. PMID 17004850.
8. ↑ 8.0 8.1 Roelands, Bart; Meeusen, Romain (1 March 2010). "Alterations in Central Fatigue by Pharmacological Manipulations of Neurotransmitters in Normal and High Ambient Temperature". Sports Medicine 40 (3): 229–246. doi:10.2165/11533670-000000000-00000. ISSN 0112-1642. PMID 20199121. https://www.researchgate.net/publication/41720970.
9. ↑ 9.0 9.1 Young, S. N. The clinical psychopharmacology of tryptophan. In: Nutrition and the Brain. Vol. 7, R. J. Wurtman and J. J. Wurtman, (Eds.). New York: Raven, 1986, pp. 49–88
10. ↑ Newsholme, E. A., I. N. Acworth, and E. Bloomstrand. Amino acids, brain neurotransmitters and a functional link between muscle and brain that is important in sustained exercise. In: Advances in Myochemistry, G. Benzi (Ed.). London: John Libbey Eurotext Ltd., 1987
11. ↑ Choi, Sujean; Disilvio, Briana; Fernstrom, Madelyn H.; Fernstrom, John D. (November 2013). "Oral branched-chain amino acid supplements that reduce brain serotonin during exercise in rats also lower brain catecholamines". Amino Acids 45 (5): 1133–42. doi:10.1007/s00726-013-1566-1. PMID 23904096. https://epublications.marquette.edu/biomedsci_fac/21.
12. ↑ Chaouloff, F., D. Laude, and J. L. Elghozi. Physical exercise: evidence for differential consequences of tryptophan on 5-HT synthesis and metabolism in central serotonergic cell bodies and terminals.J. Neural Transm. 78:121–130, 1989.
13. ↑ Bailey, S. P., J. M. Davis and E. N. Ahlborn. Neuroendocrine and substrate responses to altered brain 5-HT activity during prolonged exercise to fatigue. J. Appl. Physiol. 74:3006–3012, 1993
14. ↑ 14.0 14.1 Conlay, L. A., Sabournjian, L. A., and Wurtman, R. J. Exercise and neuromodulators: choline and acetylcholine in marathon runners.Int. J. Sports Med. 13(Suppl. 1):S141-142, 1992
15. ↑ Spector, S. A., M. R. Jackman, L. A. Sabounjian, C. Sakkas, D. M. Landers, and W. T. Willis. Effects of choline supplementation on fatigue in trained cyclists. Med. Sci. Sports Exerc. 27:668–673, 1995
16. ↑ Harrington, Mary E. (7 December 2016). "Neurobiological studies of fatigue". Progress in Neurobiology 99 (2): 93–105. doi:10.1016/j.pneurobio.2012.07.004. ISSN 0301-0082. PMID 22841649.
17. ↑ Wilkinson, Daniel J.; Smeeton, Nicholas J.; Watt, Peter W. (1 July 2010). "Ammonia metabolism, the brain and fatigue; revisiting the link". Progress in Neurobiology 91 (3): 200–219. doi:10.1016/j.pneurobio.2010.01.012. ISSN 1873-5118. PMID 20138956.
18. ↑ 18.0 18.1 Parr JW (July 2011). "Attention-deficit hyperactivity disorder and the athlete: new advances and understanding". Clin. Sports Med. 30 (3): 591–610. doi:10.1016/j.csm.2011.03.007. PMID 21658550. "In 1980, Chandler and Blair47 showed significant increases in knee extension strength, acceleration, anaerobic capacity, time to exhaustion during exercise, pre-exercise and maximum heart rates, and time to exhaustion during maximal oxygen consumption (VO2 max) testing after administration of 15 mg of dextroamphetamine versus placebo. Most of the information to answer this question has been obtained in the past decade through studies of fatigue rather than an attempt to systematically investigate the effect of ADHD drugs on exercise. ... In 2008, Roelands and colleagues53 studied the effect of reboxetine, a pure NE reuptake inhibitor, similar to atomoxetine, in 9 healthy, well-trained cyclists. They too exercised in both temperate and warm environments. They showed decreased power output and exercise performance at both 18°C and 30°C. Their conclusion was that DA reuptake inhibition was the cause of the increased exercise performance seen with drugs that affect both DA and NE (MPH, amphetamine, and bupropion).".
19. ↑ 19.0 19.1 "Nutritional supplements and ergogenic AIDS". Prim. Care 40 (2): 487–505. June 2013. doi:10.1016/j.pop.2013.02.009. PMID 23668655. "Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training ...
Physiologic and performance effects
• Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
• Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
• Improved reaction time
• Increased muscle strength and delayed muscle fatigue
• Increased acceleration
• Increased alertness and attention to task".
20. ↑ Bracken NM (January 2012). "National Study of Substance Use Trends Among NCAA College Student-Athletes". NCAA Publications. National Collegiate Athletic Association. Retrieved 8 October 2013.
21. ↑ Roelands, Bart; Meeusen, Romain (1 March 2010). "Alterations in Central Fatigue by Pharmacological Manipulations of Neurotransmitters in Normal and High Ambient Temperature". Sports Medicine 40 (3): 229–246. doi:10.2165/11533670-000000000-00000. ISSN 0112-1642. PMID 20199121. https://www.researchgate.net/publication/41720970.
22. ↑ "Does caffeine added to carbohydrate provide additional ergogenic benefit for endurance?". Int J Sport Nutr Exerc Metab 21 (1): 71–84. February 2011. doi:10.1123/ijsnem.21.1.71. PMID 21411838.
23. ↑ Central nervous system effects of caffeine and adenosine on fatigue. J. Mark Davis, Zuowei Zhao, Howard S. Stock, Kristen A. Mehl, James Buggy, Gregory A. Hand. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology Published 1 February 2003 Vol. 284 no. R399-R404DOI: 10.1152/ajpregu.00386.2002
24. ↑ Foskett A.; Williams C.; Boobis L.; Tsintzas K. (2008). "Carbohydrate availability and muscle energy metabolism during intermittent running". Med Sci Sports Exerc 40 (1): 96–103. doi:10.1249/mss.0b013e3181586b2c. PMID 18091017.
25. ↑ DAVIS J. MARK; BAILEY STEPHEN P. (1997). "Possible mechanisms of central nervous system fatigue during exercise". Medicine & Science in Sports & Exercise 29 (1): 45–57. doi:10.1097/00005768-199701000-00008. PMID 9000155.
26. ↑ Meeusen, R., & Watson, P. (2007). Amino acids and the brain: do they play a role in "central fatigue"? Int J Sport Nutr Exerc Metab, 17 Suppl, S37-46
27. ↑ Blomstrand, E., S. Andersson, P. Hassmen, B. Ekblom, and E. A. Newsholme. Effect of branched-chain amino acid and carbohydrate supplementation on the exercise-induced change in plasma and muscle concentration of amino acids in human subjects. Acta Phys. Scand. 153:87–96, 1995
28. ↑ Fatigue is a Brain-Derived Emotion that Regulates the Exercise Behavior to Ensure the Protection of Whole Body Homeostasis. Timothy David Noakes. Front Physiol. 2012; 3: 82. Prepublished online 2012 January 9. Published online 2012 April 11. doi: 10.3389/fphys.2012.00082.
29. ↑ Enoka, R. M. and D.G. Stuart. Neurobiology of muscle fatigue. J. Appl. Physiol. 72:1631–1648, 1992.
30. ↑ Murray R. Dehydration, hyperthermia, and athletes: science and practice. J Athl Train. 1996;31(3):248–252.
31. ↑ Evangard B; Schacterie R.S.; Komaroff A. L. (1999). "Chronic fatigue syndrome: new insights and old ignorance". Journal of Internal Medicine 246 (5): 455–469. doi:10.1046/j.1365-2796.1999.00513.x. PMID 10583715.
32. ↑ Kent-Braun, J. A., K. R. Sharma, M. W. Weiner, B. Massie, and R. G. Miller. Central basis of muscle fatigue in chronic fatigue syndrome. Neurology 43:125–131, 1993
33. ↑ Riley, M. S., C. J. O'Brien, D. R. McCluskey, N. P. Bell, and D. P. Nicholls. Aerobic work capacity in patients with chronic fatigue syndrome. Br. Med. J. 301:953–956, 1990
34. ↑ Stokes, M. J., R. G. Cooper, and R. H. Edwards. Normal muscle strength and fatigability in patients with effort syndromes. Br. Med. J. 297:1014–1017, 1988.
35. ↑ "Data and statistics" (in en). 2011. https://www.euro.who.int/en/health-topics/environment-and-health/noise/data-and-statistics.
36. ↑ Frenzilli, Giada; Ryskalin, Larisa; Ferrucci, Michela; Cantafora, Emanuela; Chelazzi, Silvia; Giorgi, Filippo S.; Lenzi, Paola; Scarcelli, Vittoria et al. (2017-06-26). "Loud Noise Exposure Produces DNA, Neurotransmitter and Morphological Damage within Specific Brain Areas". Frontiers in Neuroanatomy 11: 49. doi:10.3389/fnana.2017.00049. ISSN 1662-5129. PMID 28694773.

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