Central Nervous System (CNS) fatigue is a topic so unexplored by the scientists of today that we still do not know the specific mechanism that causes it . CNS fatigue, also referred to as neuromuscular fatigue, is a subjective state in which one feels tired or exhausted and in which the capacity for normal work or activity is reduced . Muscle fatigue, the decline in voluntary force during sustained maximal efforts, is caused by both central and peripheral mechanisms . It is widely known that much of the fatigue arises from processes occurring within the muscle such as disturbances in the excitation-contraction coupling, depletion of muscle glycogen and accumulation of metabolites . Hence, It is believed that fatigue onsets at some point during the chain of events between the CNS and the stimulation of the muscle fiber . There has been much speculation on whether central nervous system fatigue is a disease, such as chronic fatigue syndrome, or is it caused by a lack of energy and build up of waste product.
Distinguishing between peripheral and central fatigue, peripheral fatigue refers to events occurring within the motor unit . Central fatigue involves events occurring in the brain and spinal cord .
Fatigue occurs at the neuromuscular junction when an action potential fails to cross from the motor neuron to the muscle fiber . The neuromuscular junction, or motor endplate, is the interface between the end of unmyelinated and myelinated motor neurons and a muscle fiber . Its main function is to transmit the nerve impulse and to initiate muscle action .
The purpose of this paper is to examine whether or not central nervous system fatigue can be delayed during exercise; as well as the potential causes for CNS fatigue, ultimately leading to its definition. We will accomplish this by first examining the excitation contraction – coupling process to revisit the basic process of motor unit stimulation. Following, we will move on to observe several studies going in depth on the effects of nutritional supplementations. The focal point of nutritional supplementations will be on Branched-Chain Amino Acids, Carbohydrate, and Caffeine.
Neurotransmitters will be the next focal point, in which the functions of Acetylcholine at the motor endplate will be examined closely. Along with acetylcholine, serotonin and its mood regulating qualities will be examined closely. Furthering the discussion of serotonin we will analyze several studies involving the 5-HT/Dopamine ratio which has shown profound effects on CNS fatigue during exercise . Along with neurotransmitters, neuromodulators are also attributable to CNS fatigue. The most significant neuromodulators, Cytokines and Ammonia will be the ones examined.
This will lead us to the discussion of the possibility that central nervous system fatigue could be caused by a disease. Chronic Fatigue syndrome is a disorder associated with persistent physical and mental fatigue . Lastly, an examination of the Central Governor Model  will give insight to the approach of CNS fatigue as a sensation or emotion, not a peripheral mechanism.
THE EXCITATION-CONTRACTION COUPLING PROCESS
In order to understand central nervous system fatigue one must take a step back and understand of how a muscle fiber twitch is stimulated. This is explained in the excitation-coupling process . The excitation and contraction process that occurs at the neuromuscular junction leading to the ultimate goal of a muscle fiber twitch is a long and complicated process . Essentially it begins with the stimulation of a motor neuron and the generation of an action potential that travels down the axon causing the release of Ca++ in the process . The resultant influx of Ca++ into the nerve terminal leads to the exocytosis of vesicles containing Acetylcholine (Ach) . The Ach then crosses the synapse, binding to receptors on the endplate region of the sarcolemma and generating an endplate potential causing an influx of Na+ . This increase in Na+ results in a depolarization of the endplate . The action potential generated then travels down the sarcolemma by way of the t-tubular network . The voltage sensors bound to the t-tubule membrane are then stimulated and undergo a conformational change as a result of the action potential . This leads to the opening of the Ca++ channels in the sarcoplasmic reticulum, causing an efflux of Ca++ . With the present increase in cycstolic Ca++ concentration increase, Ca++ binds to Tropin C, causing a conformational change of tropomyosin . The active site of actin is then exposed allowing the actin-myosin cross-bridge formation to occur and a muscle fiber twitch is stimulated .
It is believed that at some point during this excitation and contraction process a mechanism causes the onset of fatigue. Where and when is still unknown but several scientists believe that nutritional supplementation can delay the onset of CNS fatigue [2,3,4,5,10,12,13,14,20,21,22,23,24,25,27].
EFFECT OF BRANCHED-CHAIN AMINO ACIDS
Branched-chain amino acids are one supplement that has been researched extensively in endurance runners . Prolonged exercise increases the plasma-concentration ratio of free tryptophan/Branched-chain amino acids (BCAAs), as well as the uptake of tryptophan by the brain . The supplementation and intake of BCAAs may reduce the uptake of tryptophan by the brain and 5-HT synthesis, hence delaying fatigue [4,22]. Hassmen et al.  reported that 30-km cross country runners supplied with a mixed BCAA and carbohydrate solution during the 30-km race exhibited an increase in cognitive performance measured via the use of the Stroop Colour-Word Test. The Colour-Word test involves assessing words with variations of different colors, color words and regular words [5,13]. This increase was compared to a placebo group who performed the same exercise and showed no differences in the beverage they consumed . Therefore, BCAA supplementation had a noticeable effect on more complex tasks . Blomstrand et al.  demonstrated similar results in terms of the placebo group v. experimental group, in a study consisting of seven male endurance-trained cyclists performing exhaustive exercise on a cycle ergometer. During 60 minute exercise at a given work rate the subjects’ ratings of perceived exertion when they were given BCAAs were 7% lower, and their ratings of mental fatigue were 15% lower than when they were given placebo .
Carbohydrate is the main energy source for athletic performance . To fully understand the effect on mental fatigue, we must review its peripheral effects . High levels of blood glucose and glycogen stores located in the muscles and liver before any endurance exercise will lengthen time to exhaustion while delaying the onset of peripheral fatigue . Carbohydrates have been demonstrated to increase performance while consumed during the actual exercise . Muscles constantly require glucose, the end product of carbohydrates, for contractions of the muscles to produce a force .
When there is a decrease of blood glucose and an insufficient amount of glycogen stores in the muscle and liver to produce more, the muscles must seek elsewhere for an energy substrate . A decline in blood glucose, hypoglycemia, during prolonged exercise will decrease exercise time to exhaustion and impair work output, thus causing fatigue .
Understanding the affects of carbohydrates on exercise in general, it must be known that nutritional status can alter brain neurochemistry . Carbohydrate consumption before and during exercise inflicts a decrease in 5-HT concentration through a decrease in free tryptophan and tryptophan to the brain . The decrease in 5-HT concentration represents a delay in fatigue and will be discussed later in this article . Davis et al.  reported that cyclists who cycled for 225 minutes at 68% of their VO2max that received a 6 or 12% carbohydrate drink delayed the onset of fatigue. The placebo group in this study who received a water beverage during exercise exhibited a decrease in glucose and insulin levels, as well as a seven-fold decrease in the plasma-concentration ratio of free tryptophan/Branched-chain amino acids [8,20,21,23].
Caffeine is the most commonly consumed drug in the world, and athletes frequently use it as an ergogenic aid [12,24]. Caffeine improves concentration, reduces fatigue, and enhances alertness . It is believed that caffeine enhances neuromuscular transmission and improves skeletal muscle contractility. However, acute caffeine ingestion does not seem to increase maximal voluntary contractions or maximal power output nor delay fatigue . Using caffeine as a supplement can also be detrimental to those who become dependent on it. In this case withdrawal of caffeine can increase fatigue as well as irritability, headaches, and mood swings .
Kalmar et al.  found that caffeine may increase the descending drive from the motor cortex by blocking the inhibitory effects of adenosine, which then increased a subject’s ability to excite a motor unit pool. Adenosine is a nucleoside comprised of adenine and ribose that is the structural component of nucleic acids and the major molecular component AMP, ADP, ATP . The excitation of the motor unit pool could increase synaptic input to the cell body of the alpha-motorneuron by increasing its excitability, bringing the motorneuron closer to threshold, and facilitating maximal activation . An increase in activation of spinal or supraspinal mechanisms may represent an increase in motor unit recruitment or an increase in the discharge rates . It was also stated that caffeine may exert its effect on the neuromuscular system peripherally, by altering excitation-contraction coupling . However, more research is needed to ultimately determine the effects of caffeine on the central nervous system.
NEUROTRANSMITTER FUNCTION AND CNS FATIGUE
Acetylcholine (Ach) is the primary neurotransmitter involved in the autonomic nervous system, especially at the motor endplate . In regards to the motor endplate, in low quantity acetylcholine elicits a muscular contraction and in large quantity acetylcholine can actually inhibit the muscular contractions resulting from the stimulation of the nerve . Within the neuromuscular junction there are approximately 50 to 70 vesicles containing Ach per um2 of nerve terminal area with a diameter of 30 to 50 nm [9,28]. These vesicles are strategically placed within the neuromuscular junction so that the clusters of Ach can be directly across from their postsynaptic receptors .
During fatigue it is speculated that Ach is increased at the NMJ and therefore causes inhibition of the nerve stimulation at the NMJ . Different modalities of exercise elicit different response of Ach at the NMJ. Training at high-intensity has resulted in a greater dispersion of Ach receptor and vesicle clusters within the overall nerve terminal and endplate areas, thus resulting in a decrease in stimulation and ultimately greater fatigability .
Wilson and Deschenes  also noted that endurance exercise increased the nerve terminal area and pre- and post- synaptic areas, where as resistance exercise increase the postsynaptic area. The pre-synaptic area is the nerve terminal containing the Ach vesicles lying close to but do not come in contact with the sarcolemma . The postsynaptic area on the other hand is a component of the sarcolemma located adjacent to the synaptic cleft .
Increases in hypertrophy due to resistance training have also shown to increase Ach at the NMJ . With hypertrophy, the increase in muscle size elicits an increase in the size of the NMJ which in turn will require a proportionate increase in Ach to elicit adequate stimulation of the greater muscle fiber, thus delaying fatigue .
Serotonin is another neurotransmitter playing a large role in the determination of CNS fatigability. In brief, serotonin plays a large role in the regulation of mood in the brain and is widely considered the main argument of CNS fatigue [18,19]. Serotonin has been linked to fatigue because of its well known effects on sleep, lethargy and drowsiness, and loss of motivation [18,19]. However, serotonin itself cannot be attributed to fatigue alone, it is more effective when associated with dopamine.
The serotonin/dopamine ratio or 5-HT/dopamine ratio can be directly associated to fatigue [11,22]. If 5-HT production is high and dopamine production is low, this causes an imbalance in the 5-HT/dopamine ratio, which in turn elicits reduced exercise performance . Conversely, if 5-HT production is low and dopamine production is high then this imbalance should cause an increase in performance, thus delaying fatigue .
Decreased 5-HT production results in less 5-HT turnover in the brain and thus there would be a less subjective feeling of fatigue . As a result the tryptophan/BCAA ratio should be balanced in this case . Likewise, increased dopamine production would cause an increase in mood state, which would not result in fatigue but result in more motivation, concentration and enhanced performance .
NEUROMODULATORS AND CNS FATIGUE
Neuromodulators are released by neurons and immune cells to convey information to adjacent or distant neurons, either enhancing or inhibiting their activities . The neuromodulators that are most influential CNS fatigue are Cytokines and Ammonia . Increases in cytokine levels have been associated with reduced exercise tolerance associated with acute viral or bacterial infection . Along with the findings of Davis et al. , Katafuchi et al.  found that cytokines play a large role in hypothalamo-pituitary and sympathetic activation, as well as immunosuppression. Ammonia on the other hand, has been observed to negatively affect the CNS function due to the accumulations of ammonia in the blood and brain during exercise . However, further research is needed to clarify the actual effects of these two neuromodulators.
CHRONIC FATIGUE SYNDROME
Could the cause of central nervous system fatigue be a disease? This has been debated amongst scientists for years to date. Chronic fatigue syndrome (CFS) is a disorder associated with persistent, often debilitating, physical and mental fatigue that cane be aggravated by even modest degrees of physical activity [11,16,29]. CFS can onset suddenly or gradually. The majority of CFS cases onset suddenly, with the beginning of another disease, such as the flu or another illness [11,29]. Other sudden onsets of CFS can occur during a period of significant physical or emotional stress . The gradual arrival of CFS begins with mild symptoms that slowly increase over time . Usually these patients are negligent that anything is wrong for awhile and attribute symptoms to other illnesses or stress .
Some of the symptoms experienced by individuals with CFS along with fatigue include disturbances to the autonomic nervous system, psychological disturbances, sleep patterns, poor temperature control, hypersensitivity, cognitive problems, and pain [11,29].
Georgiades et al.  examined the acute exercise related responses of circulating amino acids that have influenced the central 5-hydroxytryptamine (5-HT; Serotoninergic) system and dopamine function relative to subjects with similar physical activity histories.
In using the cycle ergometer test, the subjects with CFS exhibited a higher rate of perceived exertion (RPE) than the subjects without, which could lead to the indication that CFS leads to altered perception of work output . RPE is the individual’s perception of how hard they are working based on a scale ranging from 6-17 and very, very light to very, very hard . The RPE exhibited by the CFS individuals most likely attributed to the lower peak VO2max rather than a true maximum .
In CFS patients, 5-HT levels have been deemed the most significant difference in subjects with the disease and those without . The increase in brain 5-HT concentration can be linked to the lower RPE due to higher turnover rate of 5-HT in the brain . The high rate of 5-HT turnover is linked to an imbalance of the plasma-concentration ratio of free tryptophan/Branched-chain amino acids [11,21,22]. Tryptophan is an essential amino acid and a precursor for serotonin . The imbalance of the plasma-concentration ratio of free tryptophan/Branched-chain amino acids is most likely due to an increase in free tryptophan, hence the high turnover exhibited by 5-HT in the brain [11,22].
Along with the 5-HT system, the dopaminergic system has also been implicated in central fatigue during exercise . Dopamine is a chemical naturally produced by the hypothalamus and is commonly referred to as a “reward” neurotransmitter . If there are high levels of arousal, motivation, and physical performance, dopamine is usually present . Tyrosine, an essential amino acid and precursor to dopamine, had very low levels in the CFS at all time points including rest, therefore a mechanism must be limiting its production .
Analyzing the findings on 5-HT and Dopamine with CFS patients, it can be determined that if 5-HT production is high and dopamine production is low, then the 5-HT/Dopamine ratio is unbalanced, which in turn elicits reduced exercise performance . In addition, the free tryptophan/tyrosine ratio implicates fatigue due to high effort perception via the RPE (Borg) Scale .
The cause of CFS however cannot be entirely attributed to CNS factors. Other factors must be taken into consideration, such as the individual’s heterogeneous nature and the fact that this disease is a multistage disease . At different stages in this disease different values of 5-HT and dopamine as well as their precursors must be examined carefully for they could have different implications [11,16,25].
These considerations can be accomplished by through assessment and treatment modalities. Some treatments suggest drug therapy intervention to reestablish the chemical levels in the brain but this has not been proven scientifically [11,25]. The best way to approach therapy in CFS is cognitive-behavioral therapy, which helps identify and exclude factors contributing and maintaining chronic fatigue .
CENTRAL GOVERNOR MODEL
One of the more recent propositions on CNS fatigue is the Central Governor Model (CGM). The CGM “proposes that exercise performance is regulated by the central nervous system specifically to ensure that catastrophic physiological failure does not occur during normal exercise .” In essence, the main focal point of this model is to stress that peripheral fatigue cannot be used as a primary and direct influence on performance, rather fatigue should be considered a sensation or emotion, not connected to a physical manifestation .
The CGM offers a unique perspective on the bodily response to the tasks such as the Wingate test. The Wingate test is a high intensity cycling test that measures anaerobic exercise capacity and is typically performed for 30 seconds . Contrary to the popular belief that fatigue during the Wingate test is caused by an accumulation of Pi and ADP, the CGM states that fatigue is cause by a reduced rate of motor unit recruitment by the CNS .
Assessed through an Electromyographic (EMG) response from the rectus femoris, Weir et al.  reported that findings have actually been contradictory to the CGM. According to the CGM, the EMG amplitude should decline as the brain decreases motor unit recruitment to avoid rigor . Analyzing the results from the EMG in the Wingate test, it suggested that the central neural drive remains unchanged during the test, so peripheral mechanisms must explain the power output reduction . However, this is not consistent when examining events that require a pacing strategy.
Events requiring a pacing strategy such as the 100m dash and 400m dash offer results that directly contradict the findings in the Wingate test . In examining high intensity, short duration exercise, the bodily decisions to adopt a pacing strategy is not contingent metabolic events because a metabolic steady state is not achieved so expeditiously . Can a dramatic increase in pace during the last 5-10% of a race, such as a 400m dash, be attributed to peripheral mechanisms when fatigue is assumed to be at its highest? According to Weir et al.  it cannot be associated to peripheral mechanisms. Weir et al.  responded further by proposing that the CNS regulates motor unit recruitment so that ATP consumption and production are matched, preventing rigor. Therefore it is safe to predict that fatigue occurs faster where ATP demand is the greatest .
Taking into consideration the physiological factors, as well as the nutritional and neuromuscular adaptations in CNS fatigue we must ask ourselves again, is it possible to delay CNS fatigue during exercise?
It has been shown through few nutritional factors that fatigue may perhaps be delayed [2,3,4,5,10,12,13,14,20,21,22,23,24,25,27]. But there is still much to debate on how much of that is attributed to peripheral fatigue. Certainly the supplementation of carbohydrates will delay fatigue . After all carbohydrates are the main energy sources for athletic performance . Carbohydrate consumption before and during exercise was demonstrated to inflict a decrease in 5-HT concentration through a decrease in free tryptophan and tryptophan to the brain .
Caffeine could either delay fatigue or begin the onset of fatigue sooner than it has had in the past [12,14,24,27]. The variable in this is the individual. Whether the individual uses caffeine in the right and controlled manner in respect to their body composition will determine its overall effect on delaying CNS fatigue . Caffeine after all is classified as an ergogenic aid by most and a waste by others . It was shown through several studies that caffeine had no acute effects on maximal voluntary contractions or maximal power output nor delaying fatigue . So perhaps the effect of caffeine can be seen as a “placebo effect,” in that by taking caffeine, individuals would function under the assumption that this ergogenic aid is giving them “new life” while exercising . If the literature states that caffeine has no acute effects on maximal voluntary contractions and maximal power output, is it safe to assume that perhaps it does chronically? It may be for individuals dependent on the substance, but in all reality it most likely does not.
BCAAs on the other hand, I believe do have a significant effect on CNS fatigue, especially when combined with carbohydrates as exhibited in the study by Hassmen et al . The use of the Stroops Colour-Word Test showed uncompromisable results that cognitive performanced by the five to seven fold [5,13]. Blomstrand et al.  reported that the supplementation and intake of BCAAs may reduce the uptake of tryptophan by the brain and 5-HT synthesis and was exhibited vividly cycling study. Given the subjects’ ratings of perceived exertion when they were given BCAAs was 7% lower and their ratings of mental fatigue was 15% lower than the placebo group, there is no doubt that BCAAs are effective in delaying CNS fatigue .
The correlation between BCAAs and 5-HT synthesis has implied that 5-HT could delay CNS fatigue . Serotonin plays a large role in the regulation of mood in the brain and when coupled with dopamine in the 5-HT/dopamine ratio, there is reason to believe that it does indeed elicit an effect on CNS fatigue [11,22]. The imbalance of the 5-HT/dopamine ratio, favoring an increase in 5-HT synthesis and a decrease in dopamine secretion is the most practical way to approach the effect of the two neurotransmitters . Due to their physiological defined characteristics; serotonin related to mood and dopamine as a “reward” hormone, it was assumed that their imbalance would lead to CNS fatigue, and possible a chronic case of fatigue .
The most influential neurotransmitter, Acetylcholine, I believe cannot be attributed to CNS fatigue other than its physiological factors. Deschenes et al.  demonstrated in low quantity, acetylcholine elicits a muscular contraction and in large quantity acetylcholine can actually inhibit the muscular contractions resulting from the stimulation of the nerve. Under only the previous conditions alone can Ach be attributed with fatigue because otherwise it does not appear to have any other affect [9,17]. With hypertrophy Ach increases in the number of Ach containing vesicles but that is only primarily due to the increase in size of the neuromuscular junction in order to keep pace with the hypertrophic demands of the body . Hence it is still undetermined whether Ach plays more of a role in CNS fatigue and the possibility of Ach delaying CNS fatigue.
Revisiting the question posed earlier, is CNS fatigue the result of a disease or the build up of waste product? The conclusion must be that both are attributable to CNS fatigue albeit a build up of waste product is more in the peripheral area of fatigue. Chronic Fatigue Syndrome was examined extensively and proved to make valid statements in discussing the 5-HT/dopamine ratio . Although other factors must be taken into consideration when attributing CNS fatigue to CFS, it is hard to overlook the fact that perhaps right now we could be at a different stage of CFS, just not exhibiting a majority of the symptoms . Our values of 5-HT and dopamine as well as their precursors could be imbalanced [11,16]. The use of the RPE scale in CFS patients as opposed to non-CFS patients as reported by Georgiades et al.  proposes valid points about CFS patients’ interpretations of their work outputs, but this alone cannot be the determinant of whether CFS is the cause of CNS fatigue.
The Central Governor Model poses one of the most interesting perspectives on fatigue. The proposition states that fatigue is due to a sensation or emotion experienced by the brain and not by a peripheral mechanism . Specifically, it proposes that the subconscious bran determines the metabolic cost that is required to perform a given task . The task that is interpreted by the brain is regulated to the extent that if motor unit recruitment is to high, the brain will decrease recruitment in order to avoid a terminal metabolic crisis and catastrophe via production and retention of Pi and ADP .
After extensively researching and forming opinions about the possible factors causing CNS fatigue, it is more than apparent that much more experimentation is needed to fully grasp this concept. Much speculation has been proposed about neurotransmitters and neuromodulators but there is no “gold standard” to measure the effectiveness of each. The same applies as to whether CNS fatigue is caused by a disease or not. We simply are not at the technological point we need to be at in order to effectively determine fact from speculation.
The studies examined throughout this paper have contradicted each other to numerous degrees. The various theories and explanations surveyed through this study all posed valid points, however the degree to which they contradict unfortunately is enough to note that the true definition of CNS fatigue is not feasible at this point. Essentially what we accomplished through this paper was form a definition of what does not delay, cause, or is responsible for CNS fatigue. The true effects of the internal and external variables in relation to CNS fatigue require much further research and experimentation.
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Ryan Donahue, CSCS, Is an Assistant Strength & Conditioning Coach at Northeastern University, Boston MA, where he is also currently working to complete a Doctorate in Physical Therapy. Ryan received his B.S. from the University of Connecticut where he also worked with many of the university’s athletic programs, including football. Ryan can be reached at firstname.lastname@example.org.