Myalgia and Fatigue: Translation from Mouse Sensory Neurons to Fibromyalgia and Chronic Fatigue Syndromes

Excerpt:

Muscle fatigue and pain are among the most common complaints at emergency rooms and clinics across the country. Fatigue and pain are often acute, remitting spontaneously or appearing to be attenuated by a variety of drugs and treatment modalities.

In spite of these remissions, popular magazines (e.g., Time) estimate that each year Americans spend over $30 billion on herbal remedies and $50 billion on alternative therapies to treat symptoms that include muscle pain and fatigue. These statistics indicate that even acute muscle pain and fatigue are serious health problems that are not adequately addressed by current medical practice. Occasionally, muscle pain and fatigue take on a chronic nature, leading to syndromes including chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS)—devastating conditions characterized by continuing, debilitating fatigue, which is made worse by even mild exercise in the case of CFS and by chronic widespread pain (CWP) with a particular emphasis in the muscles, which can prevent most or all activities in the case of FMS.

Both of these conditions are frequently associated with each other and with a variety of other illnesses, such as temporomandibular disorder (TMD), irritable bowel syndrome (IBS), and multiple chemical sensitivity. These syndromes destroy lives, respond poorly to current treatment strategies, and can lead to exhaustion of the financial resources of afflicted patients. Together, these disorders affect 7 to 20 million people in the United States each year, as reported by various authorities (Reeves et al. 2007). Clearly, patients with these syndromes deserve a concerted research effort to understand, treat, and eventually cure these illnesses. In contrast to cutaneous pain, which has been thoroughly studied and is comparatively well understood, the molecular mechanisms for muscle pain are still unknown.

Even more enigmatic is the symptom of debilitating fatigue. Mosso, in his compendious volume on the subject a century ago, remarked that all cultures seem to have just one word for fatigue (Mosso 1904). Yet fatigue describes many conditions, including failure of muscle fibers to shorten normally, deficient motor command signals, feelings of tiredness, heaviness, pressure, and weakness from muscles, and a feeling of mental fatigue that impedes concentration and performance of conceptual tasks.

The subject of most physiological investigations of fatigue has been voluntary muscle contraction. Decreased function causing failure of voluntary muscle contraction can occur at all levels of the neuromuscular system, including the motor cortex, signaling to motoneurons, motoneuron signals to the muscle, excitation-contraction coupling in the muscle, and actin-myosin filament interactions. However, the most common failure is a decrease in the motor command signal from the motor cortex (see recent reports and reviews by Bellinger et al. 2008; Gibson et al. 2003; Noakes et al. 2005; St Clair and Noakes 2004).

A recent review suggests that failures in voluntary muscle contraction are most often caused by a central comparator that integrates homeostatic inputs from many physiological systems and shuts down motor commands when energy resources are threatened (Noakes 2007). One of the homeostatic inputs is suggested to “originate from a difference between subconscious representations of baseline physiological homeostatic state and the state of physiological activity induced by physical activity, which creates a second order representation which is perceived by consciousnessproducing structures as the sensation of fatigue” (Gibson et al. 2003, page 174).

We suggest that there is a simpler sensation of fatigue that is triggered by inputs from specific receptors that are sensitive to metabolites produced by muscle contraction. We further propose that this elementary sensation is transduced, conducted, and perceived within a unique sensory system with properties analogous to other sensory modalities such as pain. We call it the “sensation of muscle fatigue.”

Copyright © 2010 by Taylor and Francis Group, LLC.

 

Source: Light AR, Vierck CJ, Light KC. Myalgia and Fatigue: Translation from Mouse Sensory Neurons to Fibromyalgia and Chronic Fatigue Syndromes. In: Kruger L, Light AR, editors. Translational Pain Research: From Mouse to Man. Boca Raton, FL: CRC Press/Taylor & Francis; 2010. Chapter 11. Frontiers in Neuroscience. https://www.ncbi.nlm.nih.gov/books/NBK57253/ (Full chapter)

 

Fatigue, depressive symptoms, and anxiety from adolescence up to young adulthood: a longitudinal study

Abstract:

Fatigue is a common complaint among adolescents. We investigated the course of fatigue in females during the transition from adolescence to young adulthood and examined psychological, immunological, and life style risk factors for development of fatigue and chronic fatigue syndrome (CFS)-related symptoms.

Six hundred and thirty-three healthy females (age 14.63±1.37 years) filled out questionnaires measuring fatigue severity, depressive symptoms, anxiety, chronic fatigue syndrome (CFS)-related symptoms, sleep features, and life style characteristics at baseline and 4½ years thereafter.

Of 64 participants LPS- and CD2CD28-induced cytokine data at baseline were available. The best predictor of fatigue in young adulthood was previous fatigue severity. In participants who were non-fatigued during adolescence and who experienced a notable increase in fatigue, fatigue development was preceded by emotional problems and CFS-related complaints during adolescence. Increases as well as decreases in fatigue severity were accompanied by respectively increase and decrease in depressive symptoms and anxiety, suggesting that these symptoms cluster and co-vary over time.

Higher interferon (IFN)-γ, higher IFN-γ/interleukin (IL)-4 ratio, lower tumor necrosis factor-α and lower IL-10 at baseline were related to fatigue severity at follow up. The rise in total number of CFS-related symptoms at follow up was predicted by anxiety and decreased physical activity during adolescence. Sleep and substance use were associated with fatigue severity and anxiety and depression.

In conclusion, vulnerability to develop fatigue and associated symptoms in young adulthood can to a certain extent be identified already years before the manifestation of complaints.

Copyright © 2011 Elsevier Inc. All rights reserved.

 

Source: ter Wolbeek M, van Doornen LJ, Kavelaars A, Tersteeg-Kamperman MD, Heijnen CJ. Fatigue, depressive symptoms, and anxiety from adolescence up to young adulthood: a longitudinal study. Brain Behav Immun. 2011 Aug;25(6):1249-55. doi: 10.1016/j.bbi.2011.04.015. Epub 2011 Apr 28. https://www.ncbi.nlm.nih.gov/pubmed/21549830

 

Does a decrease in avoidance behavior and focusing on fatigue mediate the effect of cognitive behavior therapy for chronic fatigue syndrome?

Abstract:

OBJECTIVE: Cognitive behavior therapy (CBT) leads to a significant reduction in fatigue severity and impairment in patients with chronic fatigue syndrome (CFS). The purpose of the present study was to determine whether the effect of CBT for CFS on fatigue and impairment is mediated by a decrease in avoidance behavior and focusing on fatigue.

METHODS: For this purpose, we reanalyzed a randomized controlled trial which was previously conducted to test the efficacy of CBT for CFS. Two hundred nineteen patients completed assessment prior and subsequent to treatment or a control group period.

RESULTS: Mediation analysis revealed that a decrease in focusing on fatigue mediated the effect of CBT for CFS on fatigue and impairment. Avoidance of activity and avoidance of aversive stimuli were not significantly changed by treatment and were therefore excluded from mediation analysis.

CONCLUSION: A decrease in the focus on fatigue seems to contribute to the treatment effect of CBT for CFS.

Copyright © 2011 Elsevier Inc. All rights reserved.

 

Source: Wiborg JF, Knoop H, Prins JB, Bleijenberg G. Does a decrease in avoidance behavior and focusing on fatigue mediate the effect of cognitive behavior therapy for chronic fatigue syndrome? J Psychosom Res. 2011 Apr;70(4):306-10. doi: 10.1016/j.jpsychores.2010.12.011. Epub 2011 Feb 12. https://www.ncbi.nlm.nih.gov/pubmed/21414449

 

The Newcastle NHS Chronic Fatigue Syndrome Service: not all fatigue is the same

Abstract:

In England the Department of Health has funded specialist clinical services aimed at diagnosing and managing the symptoms of chronic fatigue syndrome (CFS). These services are not available to those who do not fulfil the diagnostic criteria for CFS. This service evaluation examined the proportion of those referred to a specialist CFS service fulfilling the Fukuda diagnostic criteria for CFS and the alternative fatigue-associated diagnoses. The CFS database was interrogated to include every patient referred to the Newcastle service from November 2008 to December 2009. All medical notes were reviewed and the diagnosis, sex and age recorded. Data were compared to a previous service evaluation (2005-07).

In 2008-09, 260 subjects were referred: 19 referrals per month (260/14), compared with 17 referrals per month in 2005-07 (375/24). The proportion of patients diagnosed with CFS increased significantly compared with 2007 (36% [20/56] vs 60% [157/260]; p < 0.0001). Of the 40% of patients subsequently found not to have CFS the most common diagnosis was fatigue associated with a chronic disease (47% of all alternative diagnoses); 20% had primary sleep disorders, 15% psychological/psychiatric illnesses and 4% a cardiovascular disorder. Thirteen per cent remained unexplained (5.2% of the total referrals).

This study found a significant increase in the proportion of patients referred to National Health Service (NHS) CFS services diagnosed with CFS. A large proportion of patients presenting with fatigue are not eligible for referral to the Department of Health specialist fatigue services, which represents an unmet need in terms of symptom management in current NHS services.

 

Source: Newton JL, Mabillard H, Scott A, Hoad A, Spickett G. The Newcastle NHS Chronic Fatigue Syndrome Service: not all fatigue is the same. J R Coll Physicians Edinb. 2010 Dec;40(4):304-7. doi: 10.4997/JRCPE.2010.404. https://www.ncbi.nlm.nih.gov/pubmed/21132135

 

Fatigue severity remains stable over time and independently associated with orthostatic symptoms in chronic fatigue syndrome: a longitudinal study

Abstract:

OBJECTIVES: to examine fatigue variability over time in chronic fatigue syndrome (CFS) and the effect of other symptoms on its predictability.

DESIGN: longitudinal cohort study of patients with CFS (Fukuda criteria).

SETTING: specialist CFS clinical service.

SUBJECTS: phase 1: 100 patients who participated in a study of CFS symptoms in 2005 were revisited in 2009. Phase 2: 25 patients completed fatigue diaries to address intra- and inter-day variability in perceived fatigue.

MAIN OUTCOME MEASURES: phase 1: subjects completed fatigue impact scale (FIS), Epworth sleepiness scale (ESS), orthostatic grading scale (OGS) and hospital anxiety and depression scale (HADS). Changes in variables represented the differences between 2005 and 2009. Phase 2: subjects rated fatigue on a scale of 0 (no fatigue) to 10 (severe fatigue) four times a day for 5 weeks.

RESULTS: symptom assessment tools were available in both 2005 and 2009 for 74% of patients. FIS and HADS depression (HAD-D) and anxiety (HAD-A) scores significantly improved during follow-up whereas ESS and OGS remained stable. FIS improved in 29/74 (39%) subjects, and by ≥ 10 points in 19 (26%). FIS worsened by ≥ 10 points in 33/74 (45%) subjects. On multivariate analysis, independent predictors of current fatigue (FIS in 2009) were FIS in 2005, HAD-D in 2009, OGS in 2009 and change in HAD-A. Reported fatigue was stable from week to week and from day to day. Patients reported higher fatigue in the morning (mean ± SD; 6.4 ± 2), becoming significantly lower at lunchtime (6.2 ± 2; P < 0.05) and increasing again to 7 ± 2 at bedtime.

CONCLUSIONS: current fatigue is independently associated with current autonomic symptom burden, current depression and change in anxiety during follow-up. These findings have implications for targeted symptom management in CFS.

 

Source: Jones DE, Gray J, Frith J, Newton JL. Fatigue severity remains stable over time and independently associated with orthostatic symptoms in chronic fatigue syndrome: a longitudinal study. J Intern Med. 2011 Feb;269(2):182-8. doi: 10.1111/j.1365-2796.2010.02306.x. Epub 2010 Nov 14. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2010.02306.x/full (Full article)

 

The genetics and epigenetics of fatigue

Abstract:

Fatigue is a common symptom and includes both physical and mental components. It can be associated with a variety of different syndromes and diseases, but in many cases is not associated with other comorbid conditions. Most humans have experienced acute fatigue in relation to different stressors. Acute fatigue typically decreases as the effect of the triggering factor is reduced and a normal homeostatic balance is restored. Fatigue that persists for 6 months or more is termed chronic fatigue. Chronic fatigue (CF) in combination with a minimum of 4 of 8 symptoms and the absence of diseases that could explain these symptoms, constitute the case definition for chronic fatigue syndrome. In spite of its prevalence, the biology of fatigue is relatively poorly understood and biological markers have not yet been identified.

This literature search was performed in PubMed to identify research on the genetics and epigenetics of fatigue. Publications were included if fatigue was a major topic and the topic was combined with genetic and/or epigenetic measurements in adult humans. A total of 40 publications were identified.

Although altered functioning in the hypothalamic-pituitary-adrenal axis, the serotonergic system, and associations with infectious agents have been identified, the search for genetic or epigenetic markers of fatigue, either in the context of CF or chronic fatigue syndrome (CFS) has been relatively unproductive or, in the case of epigenetics, nonexistent. Although several studies, both hypothesis-testing and hypothesis-generating, have been performed to search for biomarkers, they have mostly been underpowered, restricted by the heterogeneity of the phenotype, or limited by an unsystematic study design.

To be able to confirm the hypothesis that risk for, or levels of, fatigue are influenced by the genetic or epigenetic background of an individual, studies need to be based on larger sample sizes with a more clearly defined phenotype. Studies need to focus not only on the influence of a single aspect such as single nucleotide polymorphisms (SNPs) or differential gene expression on disease risk or state, but also on the systems biology behind the disease in combination with information on environmental influences and validation of findings in functional studies.

Copyright (c) 2010 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

 

Source: Landmark-Høyvik H, Reinertsen KV, Loge JH, Kristensen VN, Dumeaux V, Fosså SD, Børresen-Dale AL, Edvardsen H. The genetics and epigenetics of fatigue. PM R. 2010 May;2(5):456-65. doi: 10.1016/j.pmrj.2010.04.003. https://www.ncbi.nlm.nih.gov/pubmed/20656628

 

Perspectives on fatigue from the study of chronic fatigue syndrome and related conditions

Abstract:

Fatigue is a symptom whose causes are protean and whose phenotype includes physical, mood, and behavioral components. Chronic fatigue syndrome (CFS) is an illness that has strong biological underpinnings and no definite etiology. Diagnostic criteria established by the Centers for Disease Control and Prevention have helped classify CFS as an overlap of mood, behavioral, and biological components. These include the presence of fatigue for more than 6 months associated with a diminution of functional activity and somatic symptoms, and pain not attributable to a specific diagnosis or disease. Four of the following criteria need to be present: sore throat, impaired memory or cognition, unrefreshing sleep, postexertional fatigue, tender glands, aching stiff muscles, joint pain, and headaches.

Many researchers have observed that CFS shares features in common with other somatic syndromes, including irritable bowel syndrome, fibromyalgia, and temporomandibular joint dysfunction. Correlations between inflammation and infection, augmented sensory processing, abnormalities of neurotransmitters, nerve growth factors, low levels of serotonin and norepinephrine, abnormalities of homeostasis of the stress system, and autonomic dysfunction may be hallmarks of CFS. The relative contributions of each of these abnormalities to the profound fatigue associated with CFS need to be explored further to better evaluate and treat the syndrome.

Copyright (c) 2010 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

 

Source: Clauw DJ. Perspectives on fatigue from the study of chronic fatigue syndrome and related conditions. PM R. 2010 May;2(5):414-30. doi: 10.1016/j.pmrj.2010.04.010. https://www.ncbi.nlm.nih.gov/pubmed/20656623

 

Neuroendocrine and immune contributors to fatigue

Abstract:

Central fatigue, a persistent and subjective sense of tiredness, generally correlates poorly with traditional markers of disease. It is frequently associated with psychosocial factors, such as depression, sleep disorder, anxiety, and coping style, which suggest that dysregulation of the body’s stress systems may serve as an underlying mechanism in the maintenance of chronic fatigue (CF).

This article addresses the endocrine, neural, and immune factors that contribute to fatigue and describes research regarding the role of these factors in chronic fatigue syndrome as a model for addressing the biology of CF. In general, hypoactivity of the hypothalamic-pituitary-adrenal axis, autonomic nervous system alterations characterized by sympathetic overactivity and low vagal tone, as well as immune abnormalities, may contribute to the expression of CF. Noninvasive methods for evaluating endocrine, neural, and immune function are also discussed.

Simultaneous evaluation of neuroendocrine and immune systems with noninvasive techniques will help elucidate the underlying interactions of these systems, their role in disease susceptibility, and progression of stress-related disorders.

Copyright (c) 2010 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

 

Source: Silverman MN, Heim CM, Nater UM, Marques AH, Sternberg EM. Neuroendocrine and immune contributors to fatigue. PM R. 2010 May;2(5):338-46. doi: 10.1016/j.pmrj.2010.04.008. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933136/ (Full article)

 

What is fatigue? Pathological and nonpathological fatigue

Abstract:

Aid in understanding issues surrounding the construct validity of fatigue including the distinction between pathological versus nonpathological fatigue. Fatigue is a universal symptom reported by individuals in the general population as well as by those suffering from different medical and psychological illnesses, including cancer, multiple sclerosis, chronic fatigue syndrome, depression, and anxiety. Chronic fatigue is a significant problem in many primary care settings, and the debilitating and prolonged nature of fatigue can pose significant economic consequences for society. Researchers have struggled to better assess and understand the etiology and classification of fatigue within different illness groups.

Copyright (c) 2010 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

 

Source: Jason LA, Evans M, Brown M, Porter N. What is fatigue? Pathological and nonpathological fatigue. PM R. 2010 May;2(5):327-31. doi: 10.1016/j.pmrj.2010.03.028. https://www.ncbi.nlm.nih.gov/pubmed/20656613

 

Measuring fatigue in clinical and community settings

Abstract:

OBJECTIVE: The Chalder Fatigue Scale (CFQ) is a widely used instrument to assess fatigue in both clinical and nonclinical settings. Psychometric properties of the scale and discriminative abilities were examined.

METHODS: A total of 361 patients with CFS and 1615 individuals in the community were assessed with the CFQ. Principal component analysis (PCA) was used to explore the structure of the scale. Receiver-operating characteristic curve (ROC) was used to investigate the discriminative properties.

RESULTS: Two components, physical and mental fatigue, were identified in the CFS patient group and in the general population samples. Area under the curve for ROC was .91. The fatigue scale effectively discriminates, at high scores, between CFS patients and the general population.

CONCLUSION: Physical and mental fatigue are clearly separable components of fatigue. The CFQ can discriminate reliably between clinical and nonclinical conditions.

Copyright (c) 2010 Elsevier Inc. All rights reserved.

 

Source: Cella M, Chalder T. Measuring fatigue in clinical and community settings. J Psychosom Res. 2010 Jul;69(1):17-22. doi: 10.1016/j.jpsychores.2009.10.007. Epub 2009 Dec 11. https://www.ncbi.nlm.nih.gov/pubmed/20630259