Exercise challenges the cardiovascular, pulmonary, and musculoskeletal systems and it can have profound metabolic effects. In contrast to our extensive knowledge about the peripheral adaptations to exercise, information about the specific effects of exercise on the central nervous system (CNS) is relatively limited . The inherent complexity of the CNS and the methodologic difficulties in evaluating the in vivo neurochemistry of the human brain and spinal cord have hindered the advancement of knowledge in this area of exercise science. However, recent advances in neuroimaging technology, such as positron emission tomography (PET) and functional MRI (fMRI), and the development of in vivo neurochemical sampling techniques such as microdialysis, have added valuable information to help us better understand the effects of exercise on the CNS.
The CNS can be considered the integrative center for all behavior. It receives and interprets sensory information from both the external word and the internal environment . During exercise, sensory feedback from the periphery results in alterations in the CNS that can have profound effects on subsequent motor activity and psychologic function. A comprehensive review of all the neurobiologic changes induced by exercise and their clinical relevance is beyond the scope of this article. Alternatively, this article focuses on how exercise-induced changes in the CNS contribute to exercise-related fatigue, the overtraining syndrome, and improvements in mood and cognition that can occur with regular physical activity.
Many studies have addressed fatigue mechanisms at the muscular and peripheral neuromuscular level. Much less is known about the role of the CNS, particularly the brain, during exercise-related fatigue . A failure of CNS recruitment of skeletal muscle forms the basis for the “central (nervous system) fatigue” hypothesis. This model maintains that alterations in brain neurotransmitter concentrations influence the density of neural impulses reaching exercising muscles, thus influencing the rate at which fatigue develops during exercise. In fact, several studies have demonstrated a reduction in central neural drive to muscle after fatiguing muscle contractions .
A reduction in CNS drive to motor neurons can result from either a decline in corticospinal (descending) impulses reaching the motorneurons, or an inhibition of motorneuron excitability by neurally mediated afferent feedback from the exercising muscle. It has been proposed that reflex inhibition of motor neuron firing rates may result from sensory feedback from mechanoreceptors or free nerve endings that are sensitive to muscle metabolites that accumulate during fatiguing exercise [5••].
Recent investigation has focused on the role of exercise-induced alterations in neurotransmitter function as a cause for central fatigue during exercise. A central disturbance of amino acid metabolism involving the serotonergic (5-hydroxytryptamine [5-HT]) system has generated the strongest interest. Increases in 5-HT can have a profound influence on several aspects of CNS function that influence level of arousal, sleepiness, and mood. The serotonergic system can also affect the hypothalamic-pituitary axis and some motor function [6•]. Thus, it is easy to hypothesize that brain 5-HT could also have an effect on perception of effort and fatigue during exercise.
Several animal studies have demonstrated increases in brain 5-HT concentrations with prolonged exercise [5••,7••] and results from both animal and human studies suggest that blocking the reuptake of neurally released 5-HT or the administration of a 5-HT agonist before endurance exercise increases perceived effort and decreases endurance time [5••,6•,8]. Unfortunately, cerebral serotonin kinematics cannot be evaluated directly in humans, because of its limited passage across the blood-brain barrier . Alternatively, investigators have attempted to evaluate brain 5-HT activity indirectly by examining nutritional factors that affect the availability of precursors for brain serotonergic activity.
Brain serotonin levels have been shown to be highly dependent upon plasma free tryptophan, which serves as a metabolic precursor of serotonin. Plasma free tryptophan levels increase when the concentration of plasma free fatty acids are elevated. Because endurance exercise increases plasma free fatty acid levels, such activity may enhance the entry of tryptophan into the CNS via the blood-brain barrier, elevating brain serotonin levels. Branched-chain amino acids and tryptophan compete for the same carrier in the membrane that composes the blood-brain barrier. As branched-chain amino acids are utilized as substrate for energy during prolonged exercise, entry of tryptophan across the blood-brain barrier is competitively favored, resulting in increased concentrations of serotonin in the CNS [6•,10••].
Utilizing arterial and jugular venous sampling techniques, Nybo et al.  examined the effects of prolonged exercise on cerebral tryptophan balance. At rest, there was a small net release of tryptophan from the brain. With exercise, the plasma concentration of free tryptophan increased by approximately 50%. There was a positive correlation between the arterial concentration of free tryptophan and its arteriovenous difference across the brain, supporting the hypothesis that serotonin levels in the brain could increase when exercise elevates the plasma concentration of free tryptophan. However, a net uptake of tryptophan by the brain was seen in only 50% of the subjects during the 65-minute exercise protocol carried out at 50% of maximal oxygen uptake. A cerebral release of tryptophan was maintained in the other subjects, although compared with resting values, the level was reduced in magnitude. Because this study involved endurance-trained subjects, it is possible that the duration of exercise was too short or the intensity too low to result in a net uptake of tryptophan in all of the subjects.
Research has also focused on the influence of dopamine in the development of central fatigue, because it is well established that dopamine plays a critical role in motor control. Animal studies have demonstrated an increase in central dopamine levels during exercise. However, at the point of task failure, central dopamine levels decline back toward resting levels . It is unclear whether task failure is a direct result of the declining levels of central dopamine or whether it is a consequence of rising concentrations of central 5-HT that occur as dopamine-induced inhibition of 5-HT synthesis diminishes. Examining the role of dopamine in central fatigue in humans poses many challenges. Exercise may affect dopaminergic activity only in small regions of the brain, and the alterations in dopamine concentrations may be too small to measure using current jugular venous sampling techniques. Additionally, because polar catecholamines do not easily penetrate the blood-brain barrier, increased dopaminergic activity may not be readily detected by measuring concentrations in the jugular blood [7••,9]. Thus, conclusive evidence supporting a causal relationship between exercise-related fatigue and dopamine deficiency in healthy human subjects is currently lacking.
The role of the acetylcholine in the development of central fatigue has also generated interest. Acetylcholine is the most abundant neurotransmitter in the body and it plays a critical role in the generation of muscular force [5••]. Cholinergic neurons transmit signals for motor and preganglionic sympathetic fibers as well as for neurons in the CNS involving memory, awareness, and temperature regulation . Acetylcholine is synthesized from choline obtained from various dietary food sources. Investigators have demonstrated that fatiguing exercise, such as marathon running, can result in marked declines in plasma choline concentrations . However, the effect of reduced plasma choline concentration on central acetylcholine release needs further clarification.
During exercise, several substances external to the CNS have the ability to communicate with the brain. Studies suggest that cytokines are one of the most important messengers in this communication network [12•]. Cytokines are a group of soluble, regulatory proteins produced by a variety of cells such as immune cells, endothelial cells, and fat-storing cells [12•,13]. Cytokines can be broadly categorized according to their structure and function, into interleukins, interferons, tumor necrosis factor, growth factors, and chemokines [12•]. The plasma concentration of several cytokines increases during and after prolonged exercise [7••,13], although levels of interleukin (IL)-6 appear to increase to the greatest extent [13,14•].
Interleukin-6 has a variety of physiologic roles that are relevant to exercise, including having an influence on glucose homeostasis, fatty acid mobilization, muscle soreness, and immune function [7••]. Moreover, increased IL-6 concentrations in the CNS are associated with behavioral changes during both physiologic and psychologic stress [14•]. Because of these known features of IL-6 characteristics, significant attention has focused on this cytokine and its contribution to the effects of exercise on the CNS.
Animal studies have demonstrated that the direct administration of IL-6 into the CNS can result in decreased locomotor activity [14•]. In humans, an overproduction of IL-6 has been implicated in the development of cancer-related fatigue . Additionally, the importance of IL-6 as contributing factor to fatigue is illustrated by the work of Nishimoto et al.  involving patients with Castleman's disease, a lymphoproliferative disorder characterized by either localized or disseminated lymphadenopathy. Dysregulated overproduction of IL-6 from affected lymph nodes is thought to be responsible for the systemic manifestations of the disease, including profound malaise. This group of investigators administered humanized anti-IL-6 receptor antibody (rhPM-1) to patients with Castleman's disease in order to block IL-6 signal transduction. Immediately after administration of the rhPM-1, study participants reported that their malaise had resolved. Additionally, when IL-6 was directly administered to healthy individuals in order to achieve plasma concentrations of IL-6 comparable with those demonstrated following an episode of prolonged exercise, these subjects reported an increased sensation of fatigue .
Because IL-6 is known to cross the blood-brain barrier and can bind to receptors in the CNS, it has been hypothesized that the large release of IL-6 from skeletal muscles during prolonged exercise could act as a feedback mechanism contributing to the development of central fatigue [14•]. By measuring the internal jugular arteriovenous IL-6 difference, Nybo et al.  were able to demonstrate that the brain also releases IL-6 during prolonged exercise. The elevated expression of IL-6 in the brain could further contribute to the sensation of fatigue that develops with extended bouts of exercise .
The extraordinary complexity of the bidirectional communication that occurs between the CNS and peripheral organ systems during exercise creates an enormous challenge to understand definitively the role of the CNS in the development of acute fatigue [7••]. Further investigation is required to help better understand the role of the various factors discussed above in the development of central fatigue. These studies should help to broaden our general understanding of the effects of exercise on the central nervous system and may have important implications related to endurance performance and the treatment of fatigue associated with various chronic medical and psychiatric disorders.
The concept of central fatigue is also important as one tries to understand the fatigue that often plagues athletes suffering from overtraining syndrome (OTS). OTS, often called burnout or staleness, has been variably defined in the medical literature. However, most descriptions of this condition recognize that OTS includes chronic physiologic and psychologic maladaptations and athletic performance decrements that result when prolonged, excessive exercise training stresses are applied in the setting of inadequate recovery [10••]. A detailed discussion of OTS is beyond the scope of this article. Several comprehensive reviews of OTS have recently been published [12•,19,20]. Although the exact biochemical and metabolic changes fundamental to the development of OTS have not been clearly established, changes within the CNS appear to play an important role in the development of chronic fatigue and many of the other common signs and symptoms that are frequently seen in OTS such as disrupted sleep, changes in appetite and weight, irritability, impaired concentration, decreased motivation, and depressed mood [10••].
Many of the same theories regarding acute central fatigue that focus on alterations in brain neurotransmitters and the central effects of peripherally released inflammatory mediators, have also been applied to help explain the mechanisms underlying the development of OTS. In particular, a great deal of attention focuses on the role of the serotonergic system as an etiologic factor in the development of OTS. Serotonin is an attractive neurotransmitter to implicate in the development of OTS because it is extensively involved in various neurovascular, metabolic, and hormonal processes. Similar to what has been discussed previously with regard to increased brain serotonin levels and acute central fatigue, it has been proposed that overtraining can result in chronically diminished concentrations of branched-chain amino acids and increased plasma free tryptophan levels and that these training-provoked alterations in nutrient metabolism may result in persistently elevated levels of serotonin in the brain [10••,18,21]. Although the results of animal studies provide supporting evidence for this hypothesis, conclusive data from human studies remain lacking .
In addition to direct central effects, such as fatigue, altered mood, and decreased ability to concentrate, alterations in brain neurotransmitter concentrations that result from the prolonged application of heavy training loads with inadequate recovery can have profound systemic physiologic effects. In particular, in response to the stress of arduous physical training, the CNS can greatly influence the systemic neuroendocrine environment. The CNS influences the peripheral neuroendocrine milieu through two hormonal axes: the hypothalamic-pituitary-adrenocortical (HPA) axis, and the sympathetic-adrenal medullary (SAM) axis. The primary hormonal end-products of these two systems (adrenaline, noradrenaline, and cortisol) play essential roles in the mobilization and redistribution of energy substrates and serve to enhance the responsiveness of the cardiovascular system [10••]. Changes in systemic levels of catecholamines and glucocorticoids have been implicated in the development of some of the characteristic signs and symptoms of OTS [12•].
Some studies suggest that high-volume training stress can result in hypothalamic and pituitary dysfunction. As a result, overtrained athletes may experience decreased pituitary release of thyroid-stimulating hormone, a reduced pituitary adrenocorticotropic response to corticotropin-releasing hormone, and alterations in growth hormone release, with increased release in the early stages of OTS and decreased release in advanced stages . There is also evidence of reduced intrinsic activity of the sympathetic nervous system in the later stages of OTS. This decline in sympathetic activity may be dependent upon negative feedback from increased concentrations of circulating free catecholamines that are released during prolonged heavy exercise training . Ultimately, it may be changes in noradrenergic, serotonergic, or dopaminergic activity in the hypothalamus and pituitary gland that occur with the prolonged stress of overtraining that lead to alterations in the HPA and SAM axes . Circulating cytokines, released in association with a state of chronic systemic inflammation induced by overtraining, may also bind to receptors in the hypothalamus and further impact the HPA and SAM axes [12•].
Many of the signs and symptoms that characterize OTS are remarkably comparable with the manifestations of clinical depression, and unfavorable changes in global mood, behavior, and cognition are a rather consistent finding in athletes suffering from OTS [12•]. Some of these similar clinical manifestations may result from shared physiologic and biochemical changes that occur in these two disorders [12•]. As a result, differentiating primary depression from OTS can at times be quite difficult. A careful assessment of the athlete's training history, a review of the individual's other life stressors, as well as inquiring about a family history of depression may help to clarify this question . For many athletes, the physical demands of athletic training are not the sole cause of OTS. Psychologic factors such as excessive expectations from a coach or family, competitive stress, and personality type, as well as non–training-related stressors (eg, social, educational, occupational, economical, nutritional, and travel) may also play contributory roles [10••,19,21].
Mood and Cognition
In contrast to the potentially detrimental psychologic effects of chronic exercise for the overtrained athlete, for the general population, exercise in moderation can have extremely positive effects on psychologic wellbeing. Regular physical activity can change a person's perception of his or her physical self and identity in a positive way and it can also be used as a means to reduce stress and anxiety [23,24]. Experimental studies support a positive effect on mood for moderate-intensity exercise  and numerous cross-sectional and longitudinal studies have demonstrated the beneficial effects of regular exercise on the clinical course of several depressive disorders, including major depressive disorder and minor depression .
Several hypotheses have been developed to try to explain the mechanisms by which exercise can exert beneficial effects on depressive disorders. One, in particular, that has received considerable attention is the β-endorphin hypothesis. β-endorphin is an endogenous opioid released by the anterior pituitary [7••]. The mood elevation described by many athletes in response to prolonged exercise, such as the “runner's high” reported by athletes participating in long-distance running, had previously been attributed to the release of endogenous opiates such as β-endorphin . Initial support for the hypothesis that β-endorphin contributes to the antidepressant effects of exercise was derived from studies demonstrating an association between postexercise mood elevations and increases in circulating β-endorphin levels [24,27]. Additionally, improvements in mood that occur with an acute bout of endurance exercise can be reduced when the opioid antagonist naloxone is administered . Despite evidence that exercise-induced increases in β-endorphin levels are associated with short-term mood enhancement, it is not conclusive that these changes result in more sustained effects [7••,27]. Further research may help to clarify the role that endogenous opiates play in the antidepressant effects of exercise.
Several other theories have been suggested to help explain the beneficial effects of exercise on mood. Both biologic and psychologic mechanisms have been proposed (Table 1). However, none of these theories has been confirmed through rigorous scientific study. Given the complexity of the interaction between exercise and psychological function, an integrative biopsychosocial model that incorporates several mechanisms will likely provide the best explanation .
The potentially favorable neurobiologic effects of regular exercise have generated increased interest in the possible role of exercise to help preserve cognitive function in older adults. This is a timely concern, because the number of adults in the United States aged 65 years and older is growing rapidly, and this group is at high risk for developing dementia [30•]. Several prospective studies have demonstrated that physical activity is associated with a reduced risk of cognitive decline in older adults [30•,31•,32,33]. The benefits of exercise on the preservation of cognitive function extend beyond the ability of regular physical activity to reduce the risk of certain medical conditions that are associated with poor cognitive function in older adults, such as cardiovascular disease, cerebrovascular disease, hypertension, and diabetes mellitus . Animal research has demonstrated that exercise can help preserve neuronal tissue, stimulate neurogenesis, and promote brain vascularization. These findings lend support to the concept that exercise has direct effects on the brain that may help to maintain brain function and promote brain plasticity .
Exercise can have profound effects on numerous biologic systems within the human body, including the CNS. Our knowledge regarding many of the specific effects of exercise on the CNS remains incomplete, although new research technologies have allowed investigators to gain a better understanding of the changes that occur in the brain and spinal cord in response to exercise. Recent studies have also provided valuable insight into the bidirectional nature of the communication that occurs between the periphery and the CNS and the neurobiologic mechanisms that allow this interaction to take place.
As our knowledge of the physiologic workings of the CNS has improved, interest in the role that central factors play in mediating fatigue has grown significantly. Although several theories now exist, the exact mechanisms underlying central fatigue remain unknown. It appears that the acute fatigue associated with an episode of prolonged exercise, as well as the chronic fatigue associated with the OTS, are both mediated by alterations in a number of neuromodulators. Alterations in brain neurotransmitters and the central effects of peripherally released inflammatory mediators during the prolonged stress of overtraining have also been implicated in the development of numerous psychologic and peripheral physiologic changes that may occur with the OTS. In addition to fatigue, many of the signs and symptoms that characterize OTS are quite comparable with those seen in clinical depression. It appears that many of the shared clinical manifestations of OTS and depression result from similar neurobiochemical changes in the CNS.
Although prolonged exercise training may have detrimental psychologic consequences for the overtrained athlete, in contrast, exercise in moderation can have a positive impact on psychologic function for most individuals. Numerous studies have now demonstrated the benefits of exercise on mood and psychologic well being, although further research is required to clarify the mechanism by which exercise exerts these effects. The neurobiologic effects of exercise have also been implicated in the potential role of exercise to help preserve cognitive function in older adults. Because mental illness and dementia are both major public health concerns, the role of exercise as a preventative and therapeutic modality needs to be given much stronger consideration.
The author thanks D. Michael Elnicki, MD and E. Ann Clegern, MSW for their helpful comments on drafts of this manuscript.
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