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A new hypothesis of chronic fatigue syndrome: Co-conditioning theory
Medical Hypotheses 75 (2010) 244–249
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A new hypothesis of chronic fatigue syndrome: Co-conditioning theory Masaaki Tanaka a,*, Yasuyoshi Watanabe a,b a b
Department of Physiology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan RIKEN Center for Molecular Imaging Science, 6-7-3 Minatojima-minamimachi, Chuo-ku, Hyogo 650-0047, Japan
a r t i c l e
i n f o
Article history: Received 18 February 2010 Accepted 25 February 2010
s u m m a r y Chronic fatigue syndrome is an illness characterized by a profound, disabling, and unexplained sensation of fatigue lasting at least 6 months, which severely impairs daily functioning and is accompanied by a combination of non-specific symptoms. Many potential causes of chronic fatigue syndrome have been investigated, including viral infections, immune dysfunctions, abnormal neuroendocrine responses, central nervous system abnormalities, autonomic dysfunctions, impaired exercise capacities, sleep disruptions, genetic backgrounds, psychiatric abnormalities, personality, and abnormal psychological processes. However, no etiology, specific physical signs or laboratory test abnormalities have been found. It is essential to establish a conceptual theory of chronic fatigue syndrome that can explain its pathophysiology in order to identify the clinical entity and to develop effective treatment methods. In this article, a new conceptual hypothesis about the pathophysiology of chronic fatigue syndrome, the co-conditioning theory, is presented: after repetitive overwork and/or stress, alarm signal to rest and fatigue sensation may cause in response to an unconditioned stimulus (impaired homeostasis and function) that has been paired with a conditioned stimulus (overwork and/or stress). In the future, a new treatment strategy for patients with chronic fatigue syndrome, re-co-conditioning therapy, may be developed on the basis of the co-conditioning theory. In addition, this theory will likely contribute to a better understanding of the pathophysiology of chronic fatigue syndrome. Ó 2010 Elsevier Ltd. All rights reserved.
Introduction Chronic fatigue syndrome (CFS) is an illness characterized by a profound, disabling, and unexplained sensation of fatigue lasting at least 6 months, which severely impairs daily functioning and is accompanied by a combination of non-specific symptoms. Sporadic CFS-like cases have been described for at least two centuries [1]. However, after the outbreak of a CFS-like illness at the Royal Free Hospital in 1955 [2], interest in CFS increased. Today, the prevalence of CFS in the general adult population is considered to be 0.007–2.8% [3–9] depending on the diagnostic criteria used. The first formal case definition of CFS was proposed by the United States Centers for Disease Control and Prevention (CDC) in 1988 [10], and then in Australia [11] and United Kingdom [12]. The current international standard case definition was published by the CDC in 1994 [13]. The definition requires at least 6 months of persistent or relapsing fatigue that substantially reduces occupational, social, educational, and personal activities, which is not substantially alleviated by an ordinary rest. In addition, 4 or more of the following symptoms must be present for more than 6 months: impaired memory or concentration, sore throat, tender * Corresponding author. Tel.: +81 6 6645 3711; fax: +81 6 6645 3712. E-mail address: [email protected] (M. Tanaka). 0306-9877/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2010.02.032
cervical or axillary lymph nodes, muscle pain, pain in several joints, new onset headaches, unrefreshing sleep, or malaise after exertion. Medical conditions that are associated with fatigue and many psychiatric disorders were listed among the exclusion criteria. Therefore, CFS is diagnosed based on the symptoms, the presence of disability, and the exclusion of obvious potential causes of fatigue. Despite many researchers’ and clinicians’ efforts, so far, no physical signs or laboratory tests define the disease. Various causes of CFS have so far been investigated, including viral infections, immune dysfunctions, abnormal neuroendocrine responses, central nervous system abnormalities, autonomic dysfunctions, impaired exercise capacities, sleep disruptions, genetic characteristics, psychiatric abnormalities, personality, and abnormal psychological processes. However, no etiology, specific physical signs or laboratory test abnormalities have been found. Therefore, CFS is thought to be a heterogeneous condition having complex and multifactorial etiologies that manifest with similar symptoms [14]. In the absence of underlying common pathophysiology, some researchers, practitioners, and patients have not been able to agree on the name (CFS), case definitions, or even the existence of the illness [15]. Furthermore, the prognosis for patients with CFS is not satisfactory. A systematic review of CFS patient outcomes over a 1–5-year follow-up period noted that the median rate of recovery was 5% (ranging 0–31%), the median proportion
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of patients who improved was 40% (ranging 8–63%), and the proportion of patients who returned to work was 8–30% [16]. It is essential to establish a conceptual theory of CFS that explains its pathophysiology in order to identify the clinical entity of CFS and to development effective treatment methods. In this article, a new conceptual hypothesis of the pathophysiology of CFS is presented, along with a possible new treatment strategy for patients with CFS based on the new theory.
Inactivity
Handicap
Alarm signal to rest & accompanying manifestations Co-conditioning Unconditioned stimuli Conditioned stimuli
Impaired homeostasis & function
Co-conditioning theory (Fig. 1) An organism continuously works to meet internal and external demands while maintaining its homeostasis and functions. Fatigue can be defined as homeostatic and functional impairment caused by overwork and/or stress, while stress can be defined as an internal or external threat to the organism’s homeostasis and functions [17]. In response to acute stress, the internal environment adapts to meet the demand (allostasis) [18]; a number of neurotransmitters, neuropeptides, and hormones are linked to the response. The response to acute stress that promotes survival in the context of a life-threatening situation may be favorable. Conversely, the response may promote fight or flight behavior at the expense of homeostasis and certain functions, which may accelerate perturbation of the homeostasis and these functions, to cause fatigue. Moreover, once the threat has passed, an additional stress response is required to avoid possible overshooting that may produce harmful effects with respect to homeostasis and certain functions. When an organism is fatigued, an alarm signal to take a rest (inhibitory system) may occur in order to avoid further overwork. The organism may recognize that the alarm signal is caused by fatigue, resulting in a sensation of fatigue. After repetitive overwork and/or stress, the organism may express the alarm signal and the fatigue sensation in response to an unconditioned stimulus (impaired homeostasis and function) that has been paired with a conditioned stimulus [overwork and/ or stress (or even expectation of overwork and/or stress)], and the threshold that triggers the alarm signal and the fatigue sensation may be lowered (central sensitization). This classical conditioning may be response-specific. In addition to the fatigue sensation, some of other accompanying manifestations specific to each organism that occur due to overwork and/or stress may be conditioned simultaneously; this conditioning may be preserved even after the homeostatic and functional disturbances have gone. This may occur in patients with CFS, resulting in a long-lasting alarm signal to take a rest and a severe fatigue sensation, which may be a specific feature of the illness. The long persistence of the alarm signal and the severe fatigue sensation may lead to physical and mental inactivity, which can induce further functional impairment [19]. The familial, social, economic, or educational handicaps that can develop due to CFS can induce further stress and inactivity; this may result in patients with CFS giving up many important aspects of their lives. Of course, impaired homeostasis and function may also contribute to the pathophysiology of CFS, although the quality and quantity of these impairments may vary among individuals . There is some evidence that supports the co-conditioning theory. Firstly, there appears to be an inhibitory system to avoid overwork in the central nervous system. During sustained maximal isometric contractions, transcranial magnetic stimulation of human motor cortex showed to cause a larger short-latency motor evoked potential and a longer silent period following a shortlatency motor evoked potential in the contracting muscle, which indicate that physical fatigue is caused not only by increased excitation but also by increased inhibition in the motor cortex [20]. Another study demonstrated that regulation of the excitation and inhibition in the motor cortex, which occurs during physical fatigue, occurs ‘upstream’ of the output of the motor cortex [21].
Overwork
Stress & stress response
Fig. 1. Co-conditioning theory. When an organism is fatigued, an alarm signal to take a rest (inhibitory system) occurs in order to avoid further overwork. The organism recognizes that the alarm signal is caused by fatigue, resulting in a sensation of fatigue. After repetitive overwork and/or stress, the organism expresses the alarm signal and the fatigue sensation in response to an unconditioned stimulus (impaired homeostasis and function) that has been paired with a conditioned stimulus [overwork and/or stress (or even expectation of overwork and/or stress)], and the threshold that triggers the alarm signal and the fatigue sensation is lowered (central sensitization). This classical conditioning is response-specific. In addition to the fatigue sensation, some of other accompanying manifestations specific to each organism that occur due to overwork and/or stress are conditioned simultaneously; this conditioning is preserved even after the homeostatic and functional disturbances have gone. This occurs in patients with chronic fatigue syndrome (CFS), resulting in a long-lasting alarm signal to take a rest and a severe fatigue sensation, which is a specific feature of the illness. The long persistence of the alarm signal and the severe fatigue sensation lead to physical and mental inactivity, which can induce further functional impairment. The familial, social, economic, or educational handicaps that can develop due to CFS can induce further stress and inactivity; this results in patients with CFS giving up many important aspects of their lives.
Moreover, human studies have shown that fatigue during any forms of exercise occurs without any evidence of a catastrophic disruption in the homeostasis of skeletal muscle, and cortical motor unit recruitment reserves are always present at the point of physical exhaustion [22]. It was therefore insisted that, during exercise, physical activity is controlled or inhibited by a central governor in the brain in order to avoid a catastrophic disruption in the homeostasis of skeletal muscle and that the level of skeletal muscle recruitment from the motor cortex is controlled in response to the afferent feedback from the periphery, which is referred to as the central governor model [22]. Furthermore, a human functional magnetic resonance imaging (fMRI) study reported that activated brain areas during a sustained maximum-effort handgrip contraction substantially increased and then decreased in the primary, secondary, and association sensorimotor cortices; however, as the muscle becomes fatigued, the ability to generate force declines, and a stronger central command is needed to recruit additional motor units to maintain the desired motor output [23], which indicates that fatigue-related inhibition occurs in the motor cortices. This finding is supported by the human electroencephalographic [24] and magnetoencephalographic [25] studies. The inhibitory system may work not only through physical fatigue but also through mental fatigue: during a fatigue-inducing mental task, healthy subjects showed reduced fMRI responsiveness of task-related brain regions [26]. Surprisingly, patients with CFS showed reduced responsiveness not only of task-related brain regions but also of task-unrelated regions [26]. In patients with CFS, the inhibitory system that suppresses brain activities may easily be heightened by fatigue loads in all brain regions, and excessive inhibitory responses in the central nervous system may be a characteristic feature of CFS. Secondly, the fatigue sensation can be conditioned: an animal model of classically conditioned fatigue sensation has been developed [27]. In this animal model, rats received paired conditioned
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and unconditioned stimuli. For the conditioned stimulus, sucrose solution feeding was used, and for the unconditioned stimulus, intraperitoneal injection of a synthetic double-stranded RNA, polyriboinosinic:polyribocytidylic acid (polyI:C), was given. The polyI:C injection was related to decreased spontaneous running wheel activity and increased body temperature. After a 4-day training period, the rats conditioned with sucrose solution showed decreased both spontaneous activity and increased body temperature when given only the sucrose solution. Finally, Pavlovian conditioning and central sensitization, which may result from the conditioning, seem to be involved in the acquisition and preservation of chronic pain, which is highly associated with CFS. The role for conditioning in the development and maintenance of chronic pain has been suggested: patients with chronic pain are more easily influenced by conditioning than healthy controls; and this susceptibility may contribute to the persistence of the chronic pain [28]. In addition, central sensitization has been proposed as one of the causes for the chronic pain in patients with CFS [29]. The symptoms of CFS often occur along with other illnesses, such as fibromyalgia, multiple chemical sensitivities, irritable bowel syndrome, and temporomandibular joint dysfunction [30,31]. In particular, the relationship between CFS and fibromyalgia has been studied in detail. Although the two disorders have specific criteria, 20–70% of patients with fibromyalgia meet the criteria for CFS [29,32–34], while 35–70% of those with CFS meet the criteria for fibromyalgia [29,33,35]. The overlap in case definitions, symptoms, laboratory test results, patient characteristics, and treatments has led some researchers to suggest that these conditions are arbitrarily classified and that they should be considered different manifestations of the same pathophysiological processes [36]. Fibromyalgia is characterized by unexplained chronic pain of at least 3 months’ duration [37]. The principal features of fibromyalgia include chronic widespread pain in the presence of multiple tender points throughout the body on physical examination and frequent accompanying symptoms, such as fatigue, impaired concentration or attention, sleep disturbance, and depression. With respect to the pathogenesis, no clear muscle pathology has been found in patients with fibromyalgia [37]. Psychological distress or psychopharmacological factors may play a causal role in fibromyalgia [37,38]. Fibromyalgia can be conceptualized as a stress disorder, in which adverse life experience, stress regulation, and pain processing mechanisms are highly inter-related [14]. Therefore, CFS, a condition that overlaps to a high degree with fibromyalgia, may also be conceptualized as a stress disorder. Why different organisms adopt different behavioral strategies to cope with stress has been explained in evolutionary terms: natural selection maintains a balance of different traits preserving genes for high aggression (Hawks) and low aggression (Doves) within a population [39]. It has also been explained why individuals may differ in their vulnerability to different stress-related diseases and how this relates to the range of personality types, especially aggressive Hawks and non-aggressive Doves, in a population. A conceptual framework has been presented that shows that Hawks, due to inefficient management of mediators of allostasis, are more likely to be violent, to develop CFS, fibromyalgia, impulse control disorders, hypertension, cardiac arrhythmias, sudden death, atypical depression, autoimmune diseases, and inflammation, whereas Doves, due to the greater release of mediators of allostasis, are more susceptible to anxiety disorders, metabolic syndromes, melancholic depression, psychotic states, and infection [39]. Adverse effects on the body occur when the mediators of allostasis, such as hormones, neurotransmitters, and immuno-cytokines, are too often increased or when they are inefficiently managed [18,40]. The cost to the organism’s homeostasis is referred to as the allostatic load, which can be described as cumulative wear and tear [41]. Thus, insuffi-
cient levels of the mediators of allostasis may play a primary causal role in the development of CFS. The neural mechanisms of co-conditioning theory in patients with CFS remain to be clarified. Serotonin (5-HT) activity may be involved in the classical conditioning of the fatigue sensation. In polyI:C-induced fatigued rats, the expression of 5-HT transporter is increased, while the extracellular 5-HT level in the medial prefrontal cortex is decreased; polyI:C-induced fatigue is attenuated by a 5-HT1A receptor agonist but not by 5-HT2, 5-HT3, or dopamine D3 receptor agonists [42]. In addition, the conditioning of polyI:C-induced fatigue was completely blocked by a 5-HT1A receptor agonist [27]. The orbitofrontal cortex may also be related to the co-conditioning, since this brain region has also been associated with stimulus-outcome learning [43] and extinction of Pavlovian conditioning [44]. Moreover, a human fMRI study revealed that activation of the orbitofrontal cortex occurred with physical fatigue [45]. Thus, in patients with CFS, the 5-HT activity and the orbitofrontal cortex may play a role in co-conditioning and even in the extinction of the co-conditioning. Implications for clinical manifestations The main complaint of patients with CFS is a persistent or relapsing severe fatigue sensation, though most patients with CFS have many concomitant symptoms. Some patients with CFS complain about symptoms of impaired memory or concentration, headaches, sore throat, tender glands, pain in muscles or several joints, or gastrointestinal problems [46]. Dizziness, nausea, anorexia, and night sweats have also been reported [47]. In addition to these symptoms, some patients with CFS have immune dysfunctions, abnormal neuroendocrine responses, central nervous system abnormalities, autonomic dysfunctions, impaired exercise capacity, and sleep disruptions [14]. According to the co-conditioning theory, some of these accompanying clinical manifestations may reflect the pathophysiology of CFS co-conditioned in each patient. Thus, information related to the accompanying clinical manifestations would be helpful for the understanding of each CFS patient’s pathophysiology, and would then help to select the most appropriate treatment strategy and to evaluate the effectiveness of the treatment used for each patient. Implications for treatment (Fig. 2) It is useful to distinguish among categories of predisposing, precipitating, and perpetuating factors to understand the etiology and treatment of CFS [15]. With respect to predisposing factors, certain personality characteristics (neuroticism and introversion) and lifestyles are associated with the development of CFS [15]. In addition, family and twin data have shown a familial predisposition to CFS [48–50], and gene polymorphisms related to cytokines [51], estrogen [52], hypothalamus–pituitary–adrenal (HPA) function [53,54], and neurotransmitter systems [54–56] may be related to the development of CFS. This suggests that some genetic backgrounds also predispose individuals to CFS. With respect to precipitating factors, acute physical and psychological stresses, as well as infection, have been found to be risk factors for the development of CFS [57]. Finally, with respect to perpetuating factors, psychological processes, including a strong belief in a physical cause of the illness, a strong focus on body sensations, and a poor sense of control over complaints, have been reported to increase fatigue severity in patients with CFS [58]. Moreover, decreased activity, solicitous behavior [59], and lack of family [60] or social [61] support are perpetuating factors of CFS. Furthermore, in patients with CFS, a sensation of severe fatigue, longer illness duration, and co-morbid psychiatric disorder are risk factors for poor prognosis [16]. Based
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on the identification of the perpetuating factors, cognitive behavior therapy in combination with a graded exercise program (cognitive behavior therapy for CFS always includes a graded activity program) has been developed for the treatment of CFS [62]. Cognitive behavior therapy is used to modify behaviors and beliefs that may maintain the disability and symptoms [63]. This is the only effective common therapy that has been shown to result in beneficial outcomes in patients with CFS [64]; in patients with CFS, successful therapy attenuated not only severe fatigue, but also the co-morbid symptoms and the laboratory test abnormalities [65]. The central components of this therapy for CFS include explanation of the etiological model, motivation for the therapy, challenging and changing of fatigue-related conditions, achievement and maintenance of a basic amount of physical activity, gradual increase in physical activity, and planning work rehabilitation or rehabilitation in other personal activities [15]. This therapy is a general form of psychotherapy directed at changing operant conditioningrelated cognitions and behaviors. In contrast, the effectiveness of pharmacological, supplementary, complementary, or other interventions for patients with CFS has not yet been fully proven [14,15]. However, these interventions may to some extent be useful for attenuating co-morbid symptoms, such as psychiatric symptoms, sleep disruptions, and pain. In addition, individualized pharmacological therapy based on the specific physical signs, laboratory tests, and gene polymorphisms may result in favorable outcomes through the improvement or attenuation of the impaired homeostasis and function in patients with CFS . The aims of cognitive behavior therapy in patients with CFS could be understood from the viewpoint of the co-conditioning theory. This therapy may contribute to a better treatment for overwork, stress, and stress responses, as well as avoidance of inactivity and the attenuation of psychological responses as a result of the familial, social, economical, or educational handicaps that are associated with the development of CFS. However, this therapy may have only modest effects, unless it specifically involves the elimination of the alarm signal to rest that is conditioned in patients with CFS. Therefore, it appears that the direct elimination or reduction of the alarm signal to rest, in combination with cognitive behavior therapy, is more effective for the treatment of CFS. Thus, a new therapy based on the co-conditioning theory is required. Reco-conditioning and central desensitization of the inhibitory alarm signal caused by overwork and/or stress may effectively reduce the
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severe fatigue sensation and improve functional disabilities in patients with CFS (re-co-conditioning therapy). Patients with CFS may try to gradually increase their mental and physical activity levels to cause ‘‘pleasant” fatigue sensation simultaneously in classical re-conditioning-related manner (just like systematic desensitization therapy [66]) to resemble the pre-illness period unless this may cause severe post-exertional fatigue sensation, stress and stress responses, impaired homeostasis or function, or abnormal manifestations; the patients should maintain their optimal activity levels over time and introduce favorable responses to fatigue loads. Given the evolutionary time scale, humans are not well adapted to the modern environment. Systems that have evolved to be robust against various but common perturbations are extremely fragile when faced with unusual, unanticipated perturbations [67,68]; the modern environment may easily cause homeostatic and functional impairment (fatigue). Therefore, re-co-conditioning therapy should be performed under conditions that favor the system’s robustness, such as conditions that would be relatively close to those under which the human beings have been adapted. Of course, such conditions would also be useful for the prevention of CFS and even for the prevention of disease recurrence. Both severe fatigue sensation and some of the accompanying symptoms, physical signs, and laboratory test abnormalities may be conditioned simultaneously. Thus, the re-co-conditioning therapy should also be effective for the treatment of some of the concomitant clinical manifestations in patients with CFS. A variety of factors may contribute to the development of CFS; the illness appears to have a multidimensional nature. Therefore, a comprehensive assessment of each patient is essential to select the most appropriate re-co-conditioning treatment for each particular patient. Of course, it is necessary to evaluate the effectiveness of the treatment at appropriate time intervals and to change the treatment strategies for CFS as needed. Currently, re-co-conditioning therapy is in its conceptual stage, so that actual treatment protocols for patients with CFS need to be developed in the near future. Of note, impaired homeostasis itself would not be alleviated by this therapy alone. However, re-co-conditioning therapy in combination with cognitive behavior program and pharmacological therapy is likely to be effective for treating patients with CFS, and the co-conditioning theory would stand the test of time.
Future studies
Cognitive behavior therapy Inactivity
Handicap
Re-co-conditioning therapy Alarm signal to rest & accompanying manifestations
Pharmacological therapy therapy Impaired homeostasis & function
Overwork
Stress & stress response
Fig. 2. Treatment strategies for patients with chronic fatigue syndrome. Re-coconditioning therapy aims to treat the excessive alarm signal to rest and some of the accompanying manifestations; cognitive behavior therapy deals with stress and stress responses, overwork, inactivity, and the psychological responses as a result of the familial, social, economic, and educational handicaps; and pharmacological therapy tries to treat impaired homeostasis and function.
The reliability and validity of the co-conditioning theory should be confirmed, and the theory must be tested thoroughly. This could be done by further clarifying the mechanisms of CFS and, ultimately, by demonstrating the effectiveness of re-co-conditioning therapy (in combination with a cognitive behavior program and pharmacological therapy) for patients with CFS. However, given the various forms, intensities, and time courses of CFS, in addition to comprehensive information about each patient’s background, more detailed and precise information about CFS, such as its epidemiology, predisposing, precipitating, and perpetuating factors, and prognosis is essential for the selection of the most appropriate treatment strategy for each CFS patient. To obtain these data, well-designed prospective cohort studies involving a large number of subjects in several countries are necessary. Since the 1994 diagnostic criteria for CFS [13], which are now considered the international standard, have conceptual and operational problems in classifying the illness by symptoms and functional disability, guidelines for systematic and uniform case definition and specific instruments for classification have been presented to exclude ambiguities [69]. Nevertheless, new diagnostic criteria need to be developed for researches. In addition, current evaluation methods for CFS [69] are not satisfactory for this angle. The checklist
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individual strength [70], Chalder fatigue scale [71], and Krupp fatigue severity scale [72] have been proposed to evaluate the fatigue level in patients with CFS [69]. However, the validity and suitability of these scales for evaluating fatigue severity in patients with CFS have been questioned [73]. With respect to the questionnaires that measure the functional disability that accompanies the severe fatigue sensation, the Medical Outcomes Survey Short Form-36 [74] and the sickness impact profile [75] have been recommended, and the activity record [76] and actigraphy [77] have been proposed to measure daily activity [69]. However, the reliability and validity of these scales have not been fully confirmed. Overall, new diagnostic criteria and evaluation methods for CFS need to be developed before large-scale research studies. If the reliability and validity of the diagnostic criteria and evaluation methods are not ensured, then the quality of the clinical research would not be promising. Patients who have a severe fatigue sensation due to a medical condition must be treated. For example, fatigue sensation is the most prevalent cancer-related symptom; approximately 60–96% of cancer patients who are undergoing cancer treatment feel fatigue [78], and the fatigue sensation is associated with functional impairment, reduced quality of life, and morbidity. Thus, the effective management of fatigue sensation would reduce the disease burden associated with cancer and its treatment [79]. In such cases, curing the cancer appears to be the most effective way to attenuate or overcome the fatigue sensation. However, 30–40% of patients cured of cancer experience persistent fatigue sensation [80]. These patients can be characterized by severe fatigue sensation with no apparent cause, which is similar to CFS [81]. The pathophysiology of chronic severe fatigue sensation caused by medical conditions may be explained by the co-conditioning theory; thus, the re-co-conditioning strategy in combination with cognitive behavior program and pharmacological therapy may be effective for alleviating these patients’ fatigue sensation and functional disability. Overwork seems to be a primary cause of fatigue. Fatigue from overwork can be characterized by significant fatigue that may or may not be accompanied by a sensation of severe fatigue, whereas CFS can be characterized by a sensation of severe fatigue sensation without significant fatigue or at least without apparent causes of the fatigue sensation. The sensation of severe fatigue that occurs from overwork can be distinguished from that occurring with CFS: the overwork-related sensation of severe fatigue is decreased by ordinary rest, while the sensation of severe fatigue is not relieved by an ordinary rest in patients with CFS. However, it is difficult to evaluate the severity of fatigue, so that, in the case of overwork with little or no sensation of fatigue, a very serious problem may occur: further overwork can result in a homeostatic catastrophe causing death from overwork, which is known in Japanese as ‘karoshi’. Therefore, it is important to further clarify the mechanism of fatigue itself, as well as sensation of fatigue, and to establish objective and quantitative evaluation methods and more effective treatment strategies for fatigue.
Source of funding We declare that the sponsors had no involvement such as the role of sponsors, if any, in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.
Conflicts of interest statement None declared.
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Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
A new hypothesis of chronic fatigue syndrome: Co-conditioning theory Masaaki Tanaka a,*, Yasuyoshi Watanabe a,b a b
Department of Physiology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan RIKEN Center for Molecular Imaging Science, 6-7-3 Minatojima-minamimachi, Chuo-ku, Hyogo 650-0047, Japan
a r t i c l e
i n f o
Article history: Received 18 February 2010 Accepted 25 February 2010
s u m m a r y Chronic fatigue syndrome is an illness characterized by a profound, disabling, and unexplained sensation of fatigue lasting at least 6 months, which severely impairs daily functioning and is accompanied by a combination of non-specific symptoms. Many potential causes of chronic fatigue syndrome have been investigated, including viral infections, immune dysfunctions, abnormal neuroendocrine responses, central nervous system abnormalities, autonomic dysfunctions, impaired exercise capacities, sleep disruptions, genetic backgrounds, psychiatric abnormalities, personality, and abnormal psychological processes. However, no etiology, specific physical signs or laboratory test abnormalities have been found. It is essential to establish a conceptual theory of chronic fatigue syndrome that can explain its pathophysiology in order to identify the clinical entity and to develop effective treatment methods. In this article, a new conceptual hypothesis about the pathophysiology of chronic fatigue syndrome, the co-conditioning theory, is presented: after repetitive overwork and/or stress, alarm signal to rest and fatigue sensation may cause in response to an unconditioned stimulus (impaired homeostasis and function) that has been paired with a conditioned stimulus (overwork and/or stress). In the future, a new treatment strategy for patients with chronic fatigue syndrome, re-co-conditioning therapy, may be developed on the basis of the co-conditioning theory. In addition, this theory will likely contribute to a better understanding of the pathophysiology of chronic fatigue syndrome. Ó 2010 Elsevier Ltd. All rights reserved.
Introduction Chronic fatigue syndrome (CFS) is an illness characterized by a profound, disabling, and unexplained sensation of fatigue lasting at least 6 months, which severely impairs daily functioning and is accompanied by a combination of non-specific symptoms. Sporadic CFS-like cases have been described for at least two centuries [1]. However, after the outbreak of a CFS-like illness at the Royal Free Hospital in 1955 [2], interest in CFS increased. Today, the prevalence of CFS in the general adult population is considered to be 0.007–2.8% [3–9] depending on the diagnostic criteria used. The first formal case definition of CFS was proposed by the United States Centers for Disease Control and Prevention (CDC) in 1988 [10], and then in Australia [11] and United Kingdom [12]. The current international standard case definition was published by the CDC in 1994 [13]. The definition requires at least 6 months of persistent or relapsing fatigue that substantially reduces occupational, social, educational, and personal activities, which is not substantially alleviated by an ordinary rest. In addition, 4 or more of the following symptoms must be present for more than 6 months: impaired memory or concentration, sore throat, tender * Corresponding author. Tel.: +81 6 6645 3711; fax: +81 6 6645 3712. E-mail address: [email protected] (M. Tanaka). 0306-9877/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2010.02.032
cervical or axillary lymph nodes, muscle pain, pain in several joints, new onset headaches, unrefreshing sleep, or malaise after exertion. Medical conditions that are associated with fatigue and many psychiatric disorders were listed among the exclusion criteria. Therefore, CFS is diagnosed based on the symptoms, the presence of disability, and the exclusion of obvious potential causes of fatigue. Despite many researchers’ and clinicians’ efforts, so far, no physical signs or laboratory tests define the disease. Various causes of CFS have so far been investigated, including viral infections, immune dysfunctions, abnormal neuroendocrine responses, central nervous system abnormalities, autonomic dysfunctions, impaired exercise capacities, sleep disruptions, genetic characteristics, psychiatric abnormalities, personality, and abnormal psychological processes. However, no etiology, specific physical signs or laboratory test abnormalities have been found. Therefore, CFS is thought to be a heterogeneous condition having complex and multifactorial etiologies that manifest with similar symptoms [14]. In the absence of underlying common pathophysiology, some researchers, practitioners, and patients have not been able to agree on the name (CFS), case definitions, or even the existence of the illness [15]. Furthermore, the prognosis for patients with CFS is not satisfactory. A systematic review of CFS patient outcomes over a 1–5-year follow-up period noted that the median rate of recovery was 5% (ranging 0–31%), the median proportion
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of patients who improved was 40% (ranging 8–63%), and the proportion of patients who returned to work was 8–30% [16]. It is essential to establish a conceptual theory of CFS that explains its pathophysiology in order to identify the clinical entity of CFS and to development effective treatment methods. In this article, a new conceptual hypothesis of the pathophysiology of CFS is presented, along with a possible new treatment strategy for patients with CFS based on the new theory.
Inactivity
Handicap
Alarm signal to rest & accompanying manifestations Co-conditioning Unconditioned stimuli Conditioned stimuli
Impaired homeostasis & function
Co-conditioning theory (Fig. 1) An organism continuously works to meet internal and external demands while maintaining its homeostasis and functions. Fatigue can be defined as homeostatic and functional impairment caused by overwork and/or stress, while stress can be defined as an internal or external threat to the organism’s homeostasis and functions [17]. In response to acute stress, the internal environment adapts to meet the demand (allostasis) [18]; a number of neurotransmitters, neuropeptides, and hormones are linked to the response. The response to acute stress that promotes survival in the context of a life-threatening situation may be favorable. Conversely, the response may promote fight or flight behavior at the expense of homeostasis and certain functions, which may accelerate perturbation of the homeostasis and these functions, to cause fatigue. Moreover, once the threat has passed, an additional stress response is required to avoid possible overshooting that may produce harmful effects with respect to homeostasis and certain functions. When an organism is fatigued, an alarm signal to take a rest (inhibitory system) may occur in order to avoid further overwork. The organism may recognize that the alarm signal is caused by fatigue, resulting in a sensation of fatigue. After repetitive overwork and/or stress, the organism may express the alarm signal and the fatigue sensation in response to an unconditioned stimulus (impaired homeostasis and function) that has been paired with a conditioned stimulus [overwork and/ or stress (or even expectation of overwork and/or stress)], and the threshold that triggers the alarm signal and the fatigue sensation may be lowered (central sensitization). This classical conditioning may be response-specific. In addition to the fatigue sensation, some of other accompanying manifestations specific to each organism that occur due to overwork and/or stress may be conditioned simultaneously; this conditioning may be preserved even after the homeostatic and functional disturbances have gone. This may occur in patients with CFS, resulting in a long-lasting alarm signal to take a rest and a severe fatigue sensation, which may be a specific feature of the illness. The long persistence of the alarm signal and the severe fatigue sensation may lead to physical and mental inactivity, which can induce further functional impairment [19]. The familial, social, economic, or educational handicaps that can develop due to CFS can induce further stress and inactivity; this may result in patients with CFS giving up many important aspects of their lives. Of course, impaired homeostasis and function may also contribute to the pathophysiology of CFS, although the quality and quantity of these impairments may vary among individuals . There is some evidence that supports the co-conditioning theory. Firstly, there appears to be an inhibitory system to avoid overwork in the central nervous system. During sustained maximal isometric contractions, transcranial magnetic stimulation of human motor cortex showed to cause a larger short-latency motor evoked potential and a longer silent period following a shortlatency motor evoked potential in the contracting muscle, which indicate that physical fatigue is caused not only by increased excitation but also by increased inhibition in the motor cortex [20]. Another study demonstrated that regulation of the excitation and inhibition in the motor cortex, which occurs during physical fatigue, occurs ‘upstream’ of the output of the motor cortex [21].
Overwork
Stress & stress response
Fig. 1. Co-conditioning theory. When an organism is fatigued, an alarm signal to take a rest (inhibitory system) occurs in order to avoid further overwork. The organism recognizes that the alarm signal is caused by fatigue, resulting in a sensation of fatigue. After repetitive overwork and/or stress, the organism expresses the alarm signal and the fatigue sensation in response to an unconditioned stimulus (impaired homeostasis and function) that has been paired with a conditioned stimulus [overwork and/or stress (or even expectation of overwork and/or stress)], and the threshold that triggers the alarm signal and the fatigue sensation is lowered (central sensitization). This classical conditioning is response-specific. In addition to the fatigue sensation, some of other accompanying manifestations specific to each organism that occur due to overwork and/or stress are conditioned simultaneously; this conditioning is preserved even after the homeostatic and functional disturbances have gone. This occurs in patients with chronic fatigue syndrome (CFS), resulting in a long-lasting alarm signal to take a rest and a severe fatigue sensation, which is a specific feature of the illness. The long persistence of the alarm signal and the severe fatigue sensation lead to physical and mental inactivity, which can induce further functional impairment. The familial, social, economic, or educational handicaps that can develop due to CFS can induce further stress and inactivity; this results in patients with CFS giving up many important aspects of their lives.
Moreover, human studies have shown that fatigue during any forms of exercise occurs without any evidence of a catastrophic disruption in the homeostasis of skeletal muscle, and cortical motor unit recruitment reserves are always present at the point of physical exhaustion [22]. It was therefore insisted that, during exercise, physical activity is controlled or inhibited by a central governor in the brain in order to avoid a catastrophic disruption in the homeostasis of skeletal muscle and that the level of skeletal muscle recruitment from the motor cortex is controlled in response to the afferent feedback from the periphery, which is referred to as the central governor model [22]. Furthermore, a human functional magnetic resonance imaging (fMRI) study reported that activated brain areas during a sustained maximum-effort handgrip contraction substantially increased and then decreased in the primary, secondary, and association sensorimotor cortices; however, as the muscle becomes fatigued, the ability to generate force declines, and a stronger central command is needed to recruit additional motor units to maintain the desired motor output [23], which indicates that fatigue-related inhibition occurs in the motor cortices. This finding is supported by the human electroencephalographic [24] and magnetoencephalographic [25] studies. The inhibitory system may work not only through physical fatigue but also through mental fatigue: during a fatigue-inducing mental task, healthy subjects showed reduced fMRI responsiveness of task-related brain regions [26]. Surprisingly, patients with CFS showed reduced responsiveness not only of task-related brain regions but also of task-unrelated regions [26]. In patients with CFS, the inhibitory system that suppresses brain activities may easily be heightened by fatigue loads in all brain regions, and excessive inhibitory responses in the central nervous system may be a characteristic feature of CFS. Secondly, the fatigue sensation can be conditioned: an animal model of classically conditioned fatigue sensation has been developed [27]. In this animal model, rats received paired conditioned
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and unconditioned stimuli. For the conditioned stimulus, sucrose solution feeding was used, and for the unconditioned stimulus, intraperitoneal injection of a synthetic double-stranded RNA, polyriboinosinic:polyribocytidylic acid (polyI:C), was given. The polyI:C injection was related to decreased spontaneous running wheel activity and increased body temperature. After a 4-day training period, the rats conditioned with sucrose solution showed decreased both spontaneous activity and increased body temperature when given only the sucrose solution. Finally, Pavlovian conditioning and central sensitization, which may result from the conditioning, seem to be involved in the acquisition and preservation of chronic pain, which is highly associated with CFS. The role for conditioning in the development and maintenance of chronic pain has been suggested: patients with chronic pain are more easily influenced by conditioning than healthy controls; and this susceptibility may contribute to the persistence of the chronic pain [28]. In addition, central sensitization has been proposed as one of the causes for the chronic pain in patients with CFS [29]. The symptoms of CFS often occur along with other illnesses, such as fibromyalgia, multiple chemical sensitivities, irritable bowel syndrome, and temporomandibular joint dysfunction [30,31]. In particular, the relationship between CFS and fibromyalgia has been studied in detail. Although the two disorders have specific criteria, 20–70% of patients with fibromyalgia meet the criteria for CFS [29,32–34], while 35–70% of those with CFS meet the criteria for fibromyalgia [29,33,35]. The overlap in case definitions, symptoms, laboratory test results, patient characteristics, and treatments has led some researchers to suggest that these conditions are arbitrarily classified and that they should be considered different manifestations of the same pathophysiological processes [36]. Fibromyalgia is characterized by unexplained chronic pain of at least 3 months’ duration [37]. The principal features of fibromyalgia include chronic widespread pain in the presence of multiple tender points throughout the body on physical examination and frequent accompanying symptoms, such as fatigue, impaired concentration or attention, sleep disturbance, and depression. With respect to the pathogenesis, no clear muscle pathology has been found in patients with fibromyalgia [37]. Psychological distress or psychopharmacological factors may play a causal role in fibromyalgia [37,38]. Fibromyalgia can be conceptualized as a stress disorder, in which adverse life experience, stress regulation, and pain processing mechanisms are highly inter-related [14]. Therefore, CFS, a condition that overlaps to a high degree with fibromyalgia, may also be conceptualized as a stress disorder. Why different organisms adopt different behavioral strategies to cope with stress has been explained in evolutionary terms: natural selection maintains a balance of different traits preserving genes for high aggression (Hawks) and low aggression (Doves) within a population [39]. It has also been explained why individuals may differ in their vulnerability to different stress-related diseases and how this relates to the range of personality types, especially aggressive Hawks and non-aggressive Doves, in a population. A conceptual framework has been presented that shows that Hawks, due to inefficient management of mediators of allostasis, are more likely to be violent, to develop CFS, fibromyalgia, impulse control disorders, hypertension, cardiac arrhythmias, sudden death, atypical depression, autoimmune diseases, and inflammation, whereas Doves, due to the greater release of mediators of allostasis, are more susceptible to anxiety disorders, metabolic syndromes, melancholic depression, psychotic states, and infection [39]. Adverse effects on the body occur when the mediators of allostasis, such as hormones, neurotransmitters, and immuno-cytokines, are too often increased or when they are inefficiently managed [18,40]. The cost to the organism’s homeostasis is referred to as the allostatic load, which can be described as cumulative wear and tear [41]. Thus, insuffi-
cient levels of the mediators of allostasis may play a primary causal role in the development of CFS. The neural mechanisms of co-conditioning theory in patients with CFS remain to be clarified. Serotonin (5-HT) activity may be involved in the classical conditioning of the fatigue sensation. In polyI:C-induced fatigued rats, the expression of 5-HT transporter is increased, while the extracellular 5-HT level in the medial prefrontal cortex is decreased; polyI:C-induced fatigue is attenuated by a 5-HT1A receptor agonist but not by 5-HT2, 5-HT3, or dopamine D3 receptor agonists [42]. In addition, the conditioning of polyI:C-induced fatigue was completely blocked by a 5-HT1A receptor agonist [27]. The orbitofrontal cortex may also be related to the co-conditioning, since this brain region has also been associated with stimulus-outcome learning [43] and extinction of Pavlovian conditioning [44]. Moreover, a human fMRI study revealed that activation of the orbitofrontal cortex occurred with physical fatigue [45]. Thus, in patients with CFS, the 5-HT activity and the orbitofrontal cortex may play a role in co-conditioning and even in the extinction of the co-conditioning. Implications for clinical manifestations The main complaint of patients with CFS is a persistent or relapsing severe fatigue sensation, though most patients with CFS have many concomitant symptoms. Some patients with CFS complain about symptoms of impaired memory or concentration, headaches, sore throat, tender glands, pain in muscles or several joints, or gastrointestinal problems [46]. Dizziness, nausea, anorexia, and night sweats have also been reported [47]. In addition to these symptoms, some patients with CFS have immune dysfunctions, abnormal neuroendocrine responses, central nervous system abnormalities, autonomic dysfunctions, impaired exercise capacity, and sleep disruptions [14]. According to the co-conditioning theory, some of these accompanying clinical manifestations may reflect the pathophysiology of CFS co-conditioned in each patient. Thus, information related to the accompanying clinical manifestations would be helpful for the understanding of each CFS patient’s pathophysiology, and would then help to select the most appropriate treatment strategy and to evaluate the effectiveness of the treatment used for each patient. Implications for treatment (Fig. 2) It is useful to distinguish among categories of predisposing, precipitating, and perpetuating factors to understand the etiology and treatment of CFS [15]. With respect to predisposing factors, certain personality characteristics (neuroticism and introversion) and lifestyles are associated with the development of CFS [15]. In addition, family and twin data have shown a familial predisposition to CFS [48–50], and gene polymorphisms related to cytokines [51], estrogen [52], hypothalamus–pituitary–adrenal (HPA) function [53,54], and neurotransmitter systems [54–56] may be related to the development of CFS. This suggests that some genetic backgrounds also predispose individuals to CFS. With respect to precipitating factors, acute physical and psychological stresses, as well as infection, have been found to be risk factors for the development of CFS [57]. Finally, with respect to perpetuating factors, psychological processes, including a strong belief in a physical cause of the illness, a strong focus on body sensations, and a poor sense of control over complaints, have been reported to increase fatigue severity in patients with CFS [58]. Moreover, decreased activity, solicitous behavior [59], and lack of family [60] or social [61] support are perpetuating factors of CFS. Furthermore, in patients with CFS, a sensation of severe fatigue, longer illness duration, and co-morbid psychiatric disorder are risk factors for poor prognosis [16]. Based
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on the identification of the perpetuating factors, cognitive behavior therapy in combination with a graded exercise program (cognitive behavior therapy for CFS always includes a graded activity program) has been developed for the treatment of CFS [62]. Cognitive behavior therapy is used to modify behaviors and beliefs that may maintain the disability and symptoms [63]. This is the only effective common therapy that has been shown to result in beneficial outcomes in patients with CFS [64]; in patients with CFS, successful therapy attenuated not only severe fatigue, but also the co-morbid symptoms and the laboratory test abnormalities [65]. The central components of this therapy for CFS include explanation of the etiological model, motivation for the therapy, challenging and changing of fatigue-related conditions, achievement and maintenance of a basic amount of physical activity, gradual increase in physical activity, and planning work rehabilitation or rehabilitation in other personal activities [15]. This therapy is a general form of psychotherapy directed at changing operant conditioningrelated cognitions and behaviors. In contrast, the effectiveness of pharmacological, supplementary, complementary, or other interventions for patients with CFS has not yet been fully proven [14,15]. However, these interventions may to some extent be useful for attenuating co-morbid symptoms, such as psychiatric symptoms, sleep disruptions, and pain. In addition, individualized pharmacological therapy based on the specific physical signs, laboratory tests, and gene polymorphisms may result in favorable outcomes through the improvement or attenuation of the impaired homeostasis and function in patients with CFS . The aims of cognitive behavior therapy in patients with CFS could be understood from the viewpoint of the co-conditioning theory. This therapy may contribute to a better treatment for overwork, stress, and stress responses, as well as avoidance of inactivity and the attenuation of psychological responses as a result of the familial, social, economical, or educational handicaps that are associated with the development of CFS. However, this therapy may have only modest effects, unless it specifically involves the elimination of the alarm signal to rest that is conditioned in patients with CFS. Therefore, it appears that the direct elimination or reduction of the alarm signal to rest, in combination with cognitive behavior therapy, is more effective for the treatment of CFS. Thus, a new therapy based on the co-conditioning theory is required. Reco-conditioning and central desensitization of the inhibitory alarm signal caused by overwork and/or stress may effectively reduce the
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severe fatigue sensation and improve functional disabilities in patients with CFS (re-co-conditioning therapy). Patients with CFS may try to gradually increase their mental and physical activity levels to cause ‘‘pleasant” fatigue sensation simultaneously in classical re-conditioning-related manner (just like systematic desensitization therapy [66]) to resemble the pre-illness period unless this may cause severe post-exertional fatigue sensation, stress and stress responses, impaired homeostasis or function, or abnormal manifestations; the patients should maintain their optimal activity levels over time and introduce favorable responses to fatigue loads. Given the evolutionary time scale, humans are not well adapted to the modern environment. Systems that have evolved to be robust against various but common perturbations are extremely fragile when faced with unusual, unanticipated perturbations [67,68]; the modern environment may easily cause homeostatic and functional impairment (fatigue). Therefore, re-co-conditioning therapy should be performed under conditions that favor the system’s robustness, such as conditions that would be relatively close to those under which the human beings have been adapted. Of course, such conditions would also be useful for the prevention of CFS and even for the prevention of disease recurrence. Both severe fatigue sensation and some of the accompanying symptoms, physical signs, and laboratory test abnormalities may be conditioned simultaneously. Thus, the re-co-conditioning therapy should also be effective for the treatment of some of the concomitant clinical manifestations in patients with CFS. A variety of factors may contribute to the development of CFS; the illness appears to have a multidimensional nature. Therefore, a comprehensive assessment of each patient is essential to select the most appropriate re-co-conditioning treatment for each particular patient. Of course, it is necessary to evaluate the effectiveness of the treatment at appropriate time intervals and to change the treatment strategies for CFS as needed. Currently, re-co-conditioning therapy is in its conceptual stage, so that actual treatment protocols for patients with CFS need to be developed in the near future. Of note, impaired homeostasis itself would not be alleviated by this therapy alone. However, re-co-conditioning therapy in combination with cognitive behavior program and pharmacological therapy is likely to be effective for treating patients with CFS, and the co-conditioning theory would stand the test of time.
Future studies
Cognitive behavior therapy Inactivity
Handicap
Re-co-conditioning therapy Alarm signal to rest & accompanying manifestations
Pharmacological therapy therapy Impaired homeostasis & function
Overwork
Stress & stress response
Fig. 2. Treatment strategies for patients with chronic fatigue syndrome. Re-coconditioning therapy aims to treat the excessive alarm signal to rest and some of the accompanying manifestations; cognitive behavior therapy deals with stress and stress responses, overwork, inactivity, and the psychological responses as a result of the familial, social, economic, and educational handicaps; and pharmacological therapy tries to treat impaired homeostasis and function.
The reliability and validity of the co-conditioning theory should be confirmed, and the theory must be tested thoroughly. This could be done by further clarifying the mechanisms of CFS and, ultimately, by demonstrating the effectiveness of re-co-conditioning therapy (in combination with a cognitive behavior program and pharmacological therapy) for patients with CFS. However, given the various forms, intensities, and time courses of CFS, in addition to comprehensive information about each patient’s background, more detailed and precise information about CFS, such as its epidemiology, predisposing, precipitating, and perpetuating factors, and prognosis is essential for the selection of the most appropriate treatment strategy for each CFS patient. To obtain these data, well-designed prospective cohort studies involving a large number of subjects in several countries are necessary. Since the 1994 diagnostic criteria for CFS [13], which are now considered the international standard, have conceptual and operational problems in classifying the illness by symptoms and functional disability, guidelines for systematic and uniform case definition and specific instruments for classification have been presented to exclude ambiguities [69]. Nevertheless, new diagnostic criteria need to be developed for researches. In addition, current evaluation methods for CFS [69] are not satisfactory for this angle. The checklist
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individual strength [70], Chalder fatigue scale [71], and Krupp fatigue severity scale [72] have been proposed to evaluate the fatigue level in patients with CFS [69]. However, the validity and suitability of these scales for evaluating fatigue severity in patients with CFS have been questioned [73]. With respect to the questionnaires that measure the functional disability that accompanies the severe fatigue sensation, the Medical Outcomes Survey Short Form-36 [74] and the sickness impact profile [75] have been recommended, and the activity record [76] and actigraphy [77] have been proposed to measure daily activity [69]. However, the reliability and validity of these scales have not been fully confirmed. Overall, new diagnostic criteria and evaluation methods for CFS need to be developed before large-scale research studies. If the reliability and validity of the diagnostic criteria and evaluation methods are not ensured, then the quality of the clinical research would not be promising. Patients who have a severe fatigue sensation due to a medical condition must be treated. For example, fatigue sensation is the most prevalent cancer-related symptom; approximately 60–96% of cancer patients who are undergoing cancer treatment feel fatigue [78], and the fatigue sensation is associated with functional impairment, reduced quality of life, and morbidity. Thus, the effective management of fatigue sensation would reduce the disease burden associated with cancer and its treatment [79]. In such cases, curing the cancer appears to be the most effective way to attenuate or overcome the fatigue sensation. However, 30–40% of patients cured of cancer experience persistent fatigue sensation [80]. These patients can be characterized by severe fatigue sensation with no apparent cause, which is similar to CFS [81]. The pathophysiology of chronic severe fatigue sensation caused by medical conditions may be explained by the co-conditioning theory; thus, the re-co-conditioning strategy in combination with cognitive behavior program and pharmacological therapy may be effective for alleviating these patients’ fatigue sensation and functional disability. Overwork seems to be a primary cause of fatigue. Fatigue from overwork can be characterized by significant fatigue that may or may not be accompanied by a sensation of severe fatigue, whereas CFS can be characterized by a sensation of severe fatigue sensation without significant fatigue or at least without apparent causes of the fatigue sensation. The sensation of severe fatigue that occurs from overwork can be distinguished from that occurring with CFS: the overwork-related sensation of severe fatigue is decreased by ordinary rest, while the sensation of severe fatigue is not relieved by an ordinary rest in patients with CFS. However, it is difficult to evaluate the severity of fatigue, so that, in the case of overwork with little or no sensation of fatigue, a very serious problem may occur: further overwork can result in a homeostatic catastrophe causing death from overwork, which is known in Japanese as ‘karoshi’. Therefore, it is important to further clarify the mechanism of fatigue itself, as well as sensation of fatigue, and to establish objective and quantitative evaluation methods and more effective treatment strategies for fatigue.
Source of funding We declare that the sponsors had no involvement such as the role of sponsors, if any, in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.
Conflicts of interest statement None declared.
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