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Yang Z, Black K, Ohman-Strickland P, Graber JM, Kipen H, Fang M, Zarbl H. Disruption of central and peripheral circadian clocks and circadian controlled estrogen receptor rhythms in night shift nurses in working environments. FASEB J 2024; 38:e23719. [PMID: 38837828 PMCID: PMC11884403 DOI: 10.1096/fj.202302261rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 05/13/2024] [Accepted: 05/21/2024] [Indexed: 06/07/2024]
Abstract
Chronic disruption of circadian rhythms by night shift work is associated with an increased breast cancer risk. However, little is known about the impact of night shift on peripheral circadian genes (CGs) and circadian-controlled genes (CCGs) associated with breast cancer. Hence, we assessed central clock markers (melatonin and cortisol) in plasma, and peripheral CGs (PER1, PER2, PER3, and BMAL1) and CCGs (ESR1 and ESR2) in peripheral blood mononuclear cells (PBMCs). In day shift nurses (n = 12), 24-h rhythms of cortisol and melatonin were aligned with day shift-oriented light/dark schedules. The mRNA expression of PER2, PER3, BMAL1, and ESR2 showed 24-h rhythms with peak values in the morning. In contrast, night shift nurses (n = 10) lost 24-h rhythmicity of cortisol with a suppressed morning surge but retained normal rhythmic patterns of melatonin, leading to misalignment between cortisol and melatonin. Moreover, night shift nurses showed disruption of rhythmic expressions of PER2, PER3, BMAL1, and ESR2 genes, resulting in an impaired inverse correlation between PER2 and BMAL1 compared to day shift nurses. The observed trends of disrupted circadian markers were recapitulated in additional day (n = 20) and night (n = 19) shift nurses by measurement at early night and midnight time points. Taken together, this study demonstrated the misalignment of cortisol and melatonin, associated disruption of PER2 and ESR2 circadian expressions, and internal misalignment in peripheral circadian network in night shift nurses. Morning plasma cortisol and PER2, BMAL1, and ESR2 expressions in PBMCs may therefore be useful biomarkers of circadian disruption in shift workers.
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Affiliation(s)
- Zhenning Yang
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA
- Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA
| | - Kathleen Black
- Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA
| | - Pamela Ohman-Strickland
- Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA
- Department of Biostatistics and Epidemiology, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA
| | - Judith M Graber
- Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA
- Department of Biostatistics and Epidemiology, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA
| | - Howard Kipen
- Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA
- Department of Environmental and Occupational Health and Justice, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA
| | - Mingzhu Fang
- Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA
- Department of Environmental and Occupational Health and Justice, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA
- Current affiliation: Research and Early Development, Nonclinical Safety, Bristol Myers Squibb, New Brunswick, New Jersey, 08901, USA
| | - Helmut Zarbl
- Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA
- Department of Environmental and Occupational Health and Justice, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA
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Zhang YD, Wang LN. Research progress in the treatment of chronic fatigue syndrome through interventions targeting the hypothalamus-pituitary-adrenal axis. Front Endocrinol (Lausanne) 2024; 15:1373748. [PMID: 38660512 PMCID: PMC11039924 DOI: 10.3389/fendo.2024.1373748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 03/28/2024] [Indexed: 04/26/2024] Open
Abstract
Chronic fatigue syndrome (CFS) causes great harm to individuals and society. Elucidating the pathogenesis of CFS and developing safe and effective treatments are urgently needed. This paper reviews the functional changes in the hypothalamus-pituitary-adrenal (HPA) axis in patients with CFS and the associated neuroendocrine mechanisms. Despite some controversy, the current mainstream research evidence indicates that CFS patients have mild hypocortisolism, weakened daily variation in cortisol, a weakened response to the HPA axis, and an increase in negative feedback of the HPA axis. The relationship between dysfunction of the HPA axis and the typical symptoms of CFS are discussed, and the current treatment methods are reviewed.
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Affiliation(s)
- Yi-Dan Zhang
- College of Basic Medicine, Naval Medical University, Shanghai, China
| | - Li-Na Wang
- Department of Traditional Chinese Medicine, Naval Medical University, Shanghai, China
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McCarthy MJ. Circadian rhythm disruption in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Implications for the post-acute sequelae of COVID-19. Brain Behav Immun Health 2022; 20:100412. [PMID: 35465246 PMCID: PMC9019698 DOI: 10.1016/j.bbih.2022.100412] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 01/07/2022] [Indexed: 02/06/2023] Open
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a common and disabling disorder primarily characterized by persistent fatigue and exercise intolerance, with associated sleep disturbances, autonomic dysfunction, and cognitive problems. The causes of ME/CFS are not well understood but may coincide with immune and inflammatory responses following viral infections. During the current SARS-CoV2 coronavirus pandemic, ME/CFS has been increasingly reported to overlap with persistent “long COVID” symptoms, also called the post-acute sequelae of COVID-19 (PASC). Given the prominence of activity and sleep problems in ME/CFS, circadian rhythm disruption has been examined as a contributing factor in ME/CFS. While these studies of circadian rhythms have been pursued for decades, evidence linking circadian rhythms to ME/CFS remains inconclusive. A major limitation of older chronobiology studies of ME/CFS was the unavailability of modern molecular methods to study circadian rhythms and incomplete understanding of circadian rhythms outside the brain in peripheral organ systems. Major methodological and conceptual advancements in chronobiology have since been made. Over the same time, biomarker research in ME/CFS has progressed. Together, these new developments may justify renewed interest in circadian rhythm research in ME/CFS. Presently, we review ME/CFS from the perspective of circadian rhythms, covering both older and newer studies that make use of modern molecular methods. We focus on transforming growth factor beta (TGFB), a cytokine that has been previously associated with ME/CFS and has an important role in circadian rhythms, especially in peripheral cells. We propose that disrupted TGFB signaling in ME/CFS may play a role in disrupting physiological rhythms in sleep, activity, and cognition, leading to the insomnia, energy disturbances, cognition problems, depression, and autonomic dysfunction associated with ME/CFS. Since SARS-like coronavirus infections cause persistent changes in TGFB and previous coronavirus outbreaks have caused ME/CFS-like syndromes, chronobiological considerations may have immediate implications for understanding ME/CFS in the context of the COVID-19 pandemic and possibly suggest new avenues for therapeutic interventions.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is characterized by disrupted sleep and activity implicating circadian clocks. The incidence of ME/CFS is expected to increase as a result of the post-acute sequelae of COVID-19. Biomarker studies in ME/CFS patients implicate Transforming Growth Factor B (TGFB). TGFB has roles in synchronizing circadian rhythms in peripheral cells. Identification of biomarkers and new methodologies may facilitate progress in the chronobiological basis of ME/CFS.
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Affiliation(s)
- Michael J McCarthy
- UC San Diego Department of Psychiatry and Center for Circadian Biology, 9500 Gilman Dr, La Jolla CA 92093, USA.,VA San Diego Medical Center, San Diego CA, 3350 La Jolla Village Dr MC 116A, San Diego CA, 92161, USA
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Ding M, Zhao C, Li Y, Liu X, Wang X, Liu F, Wang J, Xiong N, Song Y, Xu Y. Changes in the levels of IL-1β, cortisol and chromogranin A in saliva of subjects with occupational fatigue. Exp Ther Med 2020; 20:1782-1788. [PMID: 32742409 DOI: 10.3892/etm.2020.8799] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 04/06/2020] [Indexed: 11/06/2022] Open
Abstract
Changes in the levels of interleukin-1β (IL-1β), cortisol and chromogranin A (CgA) in saliva of subjects with occupational fatigue were investigated. Doctors in the Emergency Department were selected as research subjects. Saliva was collected before work (after full rest) and after work (≥24 h). Electroencephalogram (EEG) was performed. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of IL-1β, cortisol and CgA in saliva. In order to obtain permission for human specimens, the study was approved by the Ethics Committee of the Affiliated Hospital of Hebei University of Engineering and registered for clinical trials (registration no. ChiC-TR-DCD-14005746). As there were only 4 subjects in this study without fatigue waves in EEG, and the number of these subjects was not sufficient to constitute a control group, the comparison of the contents of IL-1β, cortisol and CgA of all subjects before and after working for 18 h was just a confirmation of the statistical results of 43 cases with fatigue waves in the EEG. According to the results, there was no change in the contents of IL-1β and cortisol in the saliva of subjects with occupational fatigue before and after fatigue, whereas, there was a significant change in the content of CgA before and after fatigue. However, there was no correlation between the content of CgA and fatigue. The results of the present study revealed that IL-1β, cortisol and CgA indicators are not suitable diagnostic markers for occupational fatigue.
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Affiliation(s)
- Min Ding
- Central Laboratory, Medical College, Hebei University of Engineering, Handan, Hebei 056038, P.R. China
| | - Chaoxian Zhao
- Department of Biochemistry, Medical College, Hebei University of Engineering, Handan, Hebei 056002, P.R. China
| | - Yan Li
- Emergency Department, Affiliated Hospital of Hebei University of Engineering, Handan, Hebei 056002, P.R. China
| | - Xiaoxia Liu
- Department of Biochemistry, Medical College, Hebei University of Engineering, Handan, Hebei 056002, P.R. China
| | - Xueling Wang
- Central Laboratory, Medical College, Hebei University of Engineering, Handan, Hebei 056038, P.R. China
| | - Fengli Liu
- Department of Epidemiology, Medical College, Hebei University of Engineering, Handan, Hebei 056038, P.R. China
| | - Jian Wang
- Department of Biochemistry, Medical College, Hebei University of Engineering, Handan, Hebei 056002, P.R. China
| | - Nanyan Xiong
- Department of Biochemistry, Medical College, Hebei University of Engineering, Handan, Hebei 056002, P.R. China
| | - Yonghong Song
- Department of Biochemistry, Medical College, Hebei University of Engineering, Handan, Hebei 056002, P.R. China
| | - Yanli Xu
- Department of Epidemiology, Medical College, Hebei University of Engineering, Handan, Hebei 056038, P.R. China
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Torrente-Rodríguez RM, Tu J, Yang Y, Min J, Wang M, Song Y, Yu Y, Xu C, Ye C, IsHak WW, Gao W. Investigation of cortisol dynamics in human sweat using a graphene-based wireless mHealth system. MATTER 2020; 2:921-937. [PMID: 32266329 PMCID: PMC7138219 DOI: 10.1016/j.matt.2020.01.021] [Citation(s) in RCA: 215] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
Understanding and assessing endocrine response to stress is crucial to human performance analysis, stress-related disorder diagnosis, and mental health monitoring. Current approaches for stress monitoring are largely based on questionnaires, which could be very subjective. To avoid stress-inducing blood sampling and to realize continuous, non-invasive, and real-time stress analysis at the molecular levels, we investigate the dynamics of a stress hormone, cortisol, in human sweat using an integrated wireless sensing device. Highly sensitive, selective, and efficient cortisol sensing is enabled by a flexible sensor array that exploits the exceptional performance of laser-induced graphene for electrochemical sensing. Herein, we report the first cortisol diurnal cycle and the dynamic stress response profile constructed from human sweat. Our pilot study demonstrates a strong empirical correlation between serum and sweat cortisol, revealing exciting opportunities offered by sweat analysis toward non-invasive dynamic stress monitoring via wearable and portable sensing platforms.
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Affiliation(s)
- Rebeca M. Torrente-Rodríguez
- Department of Medical Engineering, Division of Engineering and Applied Science, California Institute of Technology, Pasadena, California, 91125, USA
- These authors contributed equally to this work
| | - Jiaobing Tu
- Department of Medical Engineering, Division of Engineering and Applied Science, California Institute of Technology, Pasadena, California, 91125, USA
- These authors contributed equally to this work
| | - Yiran Yang
- Department of Medical Engineering, Division of Engineering and Applied Science, California Institute of Technology, Pasadena, California, 91125, USA
| | - Jihong Min
- Department of Medical Engineering, Division of Engineering and Applied Science, California Institute of Technology, Pasadena, California, 91125, USA
| | - Minqiang Wang
- Department of Medical Engineering, Division of Engineering and Applied Science, California Institute of Technology, Pasadena, California, 91125, USA
| | - Yu Song
- Department of Medical Engineering, Division of Engineering and Applied Science, California Institute of Technology, Pasadena, California, 91125, USA
| | - You Yu
- Department of Medical Engineering, Division of Engineering and Applied Science, California Institute of Technology, Pasadena, California, 91125, USA
| | - Changhao Xu
- Department of Medical Engineering, Division of Engineering and Applied Science, California Institute of Technology, Pasadena, California, 91125, USA
| | - Cui Ye
- Department of Medical Engineering, Division of Engineering and Applied Science, California Institute of Technology, Pasadena, California, 91125, USA
| | - Waguih William IsHak
- Department of Psychiatry and Behavioral Neurosciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Wei Gao
- Department of Medical Engineering, Division of Engineering and Applied Science, California Institute of Technology, Pasadena, California, 91125, USA
- Lead Contact
- Correspondence:
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Li KD, Yan K, Wang QS, Tian JS, Xu D, Zhang WY, Cui YL. Antidepressant-like effects of dietary gardenia blue pigment derived from genipin and tyrosine. Food Funct 2019; 10:4533-4545. [PMID: 31264676 DOI: 10.1039/c9fo00480g] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Gardenia blue pigments derived from genipin reacting with amino acids have been used as natural food colorants for nearly 30 years in East Asia. However, their pharmacological effects, especially antidepressant-like effects, have not been reported so far. In this study, one of the gardenia blue pigments, was obtained from the reaction of genipin with tyrosine (genipin-tyrosine derivant (GTD)), and its antidepressant-like effects were investigated in lipopolysaccharide (LPS) or chronic unpredictable mild stress (CUMS) models. The results showed that GTD could attenuate depressive-like behaviors in both animal models. GTD reversed the LPS-induced cytokine increase of TNF-α, IL-6, and corticosterone (CORT) in mice plasma and hippocampus. In CUMS rats, GTD treatment significantly reduced hypothalamic-pituitary-adrenal (HPA) axis-related stress hormone levels in plasma including those of CORT, adrenocorticotropic hormone (ACTH), and corticotropin-releasing hormone (CRH). Besides, GTD increased plasma testosterone and hippocampal brain-derived neurotrophic factor (BDNF) levels in CUMS rats. GTD increased serotonin (5-HT), dopamine (DA), and norepinephrine (NE) in rat hippocampus and corpus striatum. Consistently, hippocampal metabolomic analysis demonstrated that GTD restored monoamine neurotransmitter metabolism, mitochondrial oxidative function, and membrane structural integrity. Our data suggested that GTD produced antidepressant-like activity through the restoration of the HPA axis hormone balance and the regulation of neurotransmitter release.
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Affiliation(s)
- Kuang-Dai Li
- Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, PR China.
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Ferrero K, Silver M, Cocchetto A, Masliah E, Langford D. CNS findings in chronic fatigue syndrome and a neuropathological case report. J Investig Med 2017; 65:974-983. [PMID: 28386034 DOI: 10.1136/jim-2016-000390] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2017] [Indexed: 11/04/2022]
Abstract
Chronic fatigue syndrome (CFS) is characterized as a persistent, debilitating complex disorder of unknown etiology, whereby patients suffer from extreme fatigue, which often presents with symptoms that include chronic pain, depression, weakness, mood disturbances, and neuropsychological impairment. In this mini review and case report, we address central nervous system (CNS) involvement of CFS and present neuropathological autopsy findings from a patient who died with a prior diagnosis of CFS. Among the most remarkable pathological features of the case are focal areas of white matter loss, neurite beading, and neuritic pathology of axons in the white matter with axonal spheroids. Atypical neurons displaying aberrant sprouting processes in response to injury are observed throughout cortical gray and white matter. Abundant amyloid deposits identical to AD plaques with accompanying intracellular granular structures are observed as well. Neurofibrillary tangles are also present in the white matter of the frontal cortex, thalamus and basal ganglia. Taken together, these neuropathological findings warrant further studies into CNS disease associated with CFS.
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Affiliation(s)
- Kimberly Ferrero
- Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Mitchell Silver
- Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Alan Cocchetto
- State University of New York at Alfred, Engineering Technologies, Alfred, New York, USA
| | - Eliezer Masliah
- University of California San Diego, La Jolla, California, USA
| | - Dianne Langford
- Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
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Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways. Mol Neurobiol 2016; 54:6806-6819. [PMID: 27766535 DOI: 10.1007/s12035-016-0170-2] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 09/27/2016] [Indexed: 12/19/2022]
Abstract
There is evidence that immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways play a role in the pathophysiology of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). There is also evidence that these neuroimmune diseases are accompanied by hypothalamic-pituitary-adrenal (HPA) axis hypoactivity as indicated by lowered baseline glucocorticoid levels. This paper aims to review the bidirectional communications between immune-inflammatory and O&NS pathways and HPA axis hypoactivity in ME/CFS, considering two possibilities: (a) Activation of immune-inflammatory pathways is secondary to HPA axis hypofunction via attenuated negative feedback mechanisms, or (b) chronic activated immune-inflammatory and O&NS pathways play a causative role in HPA axis hypoactivity. Electronic databases, i.e., PUBMED, Scopus, and Google Scholar, were used as sources for this narrative review by using keywords CFS, ME, cortisol, ACTH, CRH, HPA axis, glucocorticoid receptor, cytokines, immune, immunity, inflammation, and O&NS. Findings show that activation of immune-inflammatory and O&NS pathways in ME/CFS are probably not secondary to HPA axis hypoactivity and that activation of these pathways may underpin HPA axis hypofunction in ME/CFS. Mechanistic explanations comprise increased levels of tumor necrosis factor-α, T regulatory responses with elevated levels of interleukin-10 and transforming growth factor-β, elevated levels of nitric oxide, and viral/bacterial-mediated mechanisms. HPA axis hypoactivity in ME/CFS is most likely a consequence and not a cause of a wide variety of activated immune-inflammatory and O&NS pathways in that illness.
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Kim JS. Post-stroke Mood and Emotional Disturbances: Pharmacological Therapy Based on Mechanisms. J Stroke 2016; 18:244-255. [PMID: 27733031 PMCID: PMC5066431 DOI: 10.5853/jos.2016.01144] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 09/07/2016] [Accepted: 09/08/2016] [Indexed: 11/11/2022] Open
Abstract
Post-stroke mood and emotional disturbances are frequent and diverse in their manifestations. Out of the many post-stroke disturbances, post-stroke depression, post-stroke anxiety, post-stroke emotional incontinence, post-stroke anger proneness, and post-stroke fatigue are frequent and important symptoms. These symptoms are distressing for both the patients and their caregivers, and negatively influence the patient's quality of life. Unfortunately, these emotional disturbances are not apparent and are therefore often unnoticed by busy clinicians. Their phenomenology, predicting factors, and pathophysiology have been under-studied, and are under-recognized. In addition, well-designed clinical trials regarding these symptoms are rare. Fortunately, these mood and emotional disturbances may be treated or prevented by various methods, including pharmacological therapy. To administer the appropriate therapy, we have to understand the phenomenology and the similarities and differences in the pathophysiological mechanisms associated with these emotional symptoms. This narrative review will describe some of the most common or relevant post-stroke mood and emotional disturbances. The phenomenology, factors or predictors, and relevant lesion locations will be described, and pharmacological treatment of these emotional disturbances will be discussed based on presumable pathophysiological mechanisms.
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Affiliation(s)
- Jong S. Kim
- Department of Neurology, University of Ulsan, Asan Medical Center, Seoul, Korea
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Twisk FNM. Accurate diagnosis of myalgic encephalomyelitis and chronic fatigue syndrome based upon objective test methods for characteristic symptoms. World J Methodol 2015; 5:68-87. [PMID: 26140274 PMCID: PMC4482824 DOI: 10.5662/wjm.v5.i2.68] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Revised: 02/10/2015] [Accepted: 05/27/2015] [Indexed: 02/06/2023] Open
Abstract
Although myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are considered to be synonymous, the definitional criteria for ME and CFS define two distinct, partially overlapping, clinical entities. ME, whether defined by the original criteria or by the recently proposed criteria, is not equivalent to CFS, let alone a severe variant of incapacitating chronic fatigue. Distinctive features of ME are: muscle weakness and easy muscle fatigability, cognitive impairment, circulatory deficits, a marked variability of the symptoms in presence and severity, but above all, post-exertional “malaise”: a (delayed) prolonged aggravation of symptoms after a minor exertion. In contrast, CFS is primarily defined by (unexplained) chronic fatigue, which should be accompanied by four out of a list of 8 symptoms, e.g., headaches. Due to the subjective nature of several symptoms of ME and CFS, researchers and clinicians have questioned the physiological origin of these symptoms and qualified ME and CFS as functional somatic syndromes. However, various characteristic symptoms, e.g., post-exertional “malaise” and muscle weakness, can be assessed objectively using well-accepted methods, e.g., cardiopulmonary exercise tests and cognitive tests. The objective measures acquired by these methods should be used to accurately diagnose patients, to evaluate the severity and impact of the illness objectively and to assess the positive and negative effects of proposed therapies impartially.
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Fischer DB, William AH, Strauss AC, Unger ER, Jason L, Marshall GD, Dimitrakoff JD. Chronic Fatigue Syndrome: The Current Status and Future Potentials of Emerging Biomarkers. FATIGUE-BIOMEDICINE HEALTH AND BEHAVIOR 2014; 2:93-109. [PMID: 24932428 DOI: 10.1080/21641846.2014.906066] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Chronic fatigue syndrome (CFS) remains an incompletely characterized illness, in part due to controversy regarding its definition, biological basis and diagnosis. Biomarkers are objective measures that may lead to improvements in our understanding of CFS by providing a more coherent and consistent approach to study, diagnosis and treatment of the illness. Such metrics may allow us to distinguish between CFS subtypes - each defined by characteristic biomarkers - currently conflated under the single, heterogeneous condition of CFS. These delineations, in turn, may guide more granular, focused, and targeted treatment strategies based on more precise characterizations of the illness. Here, we review potential CFS biomarkers related to neurological and immunological components of the illness, and discuss how these biomarkers may be used to move the field of CFS forward, emphasizing clinical utility and potential routes of future research.
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Affiliation(s)
| | | | - Adam Campbell Strauss
- Harvard Medical School, 25 Shattuck Street, Boston, MA, USA 02115 ; Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03766
| | | | | | | | - Jordan D Dimitrakoff
- Harvard Medical School, 25 Shattuck Street, Boston, MA, USA 02115 ; Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 ; Johns Hopkins University School of Medicine, Baltimore, MD
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12
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Twisk FNM. The status of and future research into Myalgic Encephalomyelitis and Chronic Fatigue Syndrome: the need of accurate diagnosis, objective assessment, and acknowledging biological and clinical subgroups. Front Physiol 2014; 5:109. [PMID: 24734022 PMCID: PMC3974331 DOI: 10.3389/fphys.2014.00109] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 03/04/2014] [Indexed: 12/26/2022] Open
Abstract
Although Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS) are used interchangeably, the diagnostic criteria define two distinct clinical entities. Cognitive impairment, (muscle) weakness, circulatory disturbances, marked variability of symptoms, and, above all, post-exertional malaise: a long-lasting increase of symptoms after a minor exertion, are distinctive symptoms of ME. This latter phenomenon separates ME, a neuro-immune illness, from chronic fatigue (syndrome), other disorders and deconditioning. The introduction of the label, but more importantly the diagnostic criteria for CFS have generated much confusion, mostly because chronic fatigue is a subjective and ambiguous notion. CFS was redefined in 1994 into unexplained (persistent or relapsing) chronic fatigue, accompanied by at least four out of eight symptoms, e.g., headaches and unrefreshing sleep. Most of the research into ME and/or CFS in the last decades was based upon the multivalent CFS criteria, which define a heterogeneous patient group. Due to the fact that fatigue and other symptoms are non-discriminative, subjective experiences, research has been hampered. Various authors have questioned the physiological nature of the symptoms and qualified ME/CFS as somatization. However, various typical symptoms can be assessed objectively using standardized methods. Despite subjective and unclear criteria and measures, research has observed specific abnormalities in ME/CFS repetitively, e.g., immunological abnormalities, oxidative and nitrosative stress, neurological anomalies, circulatory deficits and mitochondrial dysfunction. However, to improve future research standards and patient care, it is crucial that patients with post-exertional malaise (ME) and patients without this odd phenomenon are acknowledged as separate clinical entities that the diagnosis of ME and CFS in research and clinical practice is based upon accurate criteria and an objective assessment of characteristic symptoms, as much as possible that well-defined clinical and biological subgroups of ME and CFS patients are investigated in more detail, and that patients are monitored before, during and after interventions with objective measures and biomarkers.
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Disturbances in the Voluntary Control of Emotional Expression After Stroke. NEUROPSYCHIATRIC SYMPTOMS OF NEUROLOGICAL DISEASE 2013. [DOI: 10.1007/978-1-4471-2428-3_7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Martino D, Macerollo A, Leckman JF. Neuroendocrine aspects of Tourette syndrome. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2013; 112:239-79. [PMID: 24295624 DOI: 10.1016/b978-0-12-411546-0.00009-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
There is sparse evidence suggesting the participation of neuroendocrine mechanisms, mainly involving sex and stress steroid hormones, to the pathophysiology of neurodevelopmental disorders such as Tourette syndrome (TS) and obsessive-compulsive disorder (OCD). Patients with TS exhibit a sex-specific variability in gender distribution (male/female ratio=3-4/1) and in its natural history, with a severity peak in the period around puberty. The administration of exogenous androgens may worsen tics in males with TS, whereas drugs counteracting the action of testosterone might show some antitic efficacy. This suggests a higher susceptibility of patients with TS to androgen steroids. There are insufficient data on the regulation of the hypothalamic-pituitary-gonadal (HPG) axis in TS. However, preliminary evidence suggests that a subgroup of women with TS might be more sensitive to the premenstrual trough of estrogen levels. Patients with TS exhibit differences in a number of behavioral, cognitive, and anatomical traits that appear to be sex related. There is a body of evidence supporting, albeit indirectly, the hypothesis of an increased exposure to androgenic steroids during the very early phases of neural development. Animal models in rodents suggest a complex role of gonadal hormones upon the modulation of anxiety-related and stereotyped behaviors during adult life. Patients with TS exhibit an enhanced reactivity of the hypothalamic-pituitary-adrenal axis to external stressors, despite a preserved diurnal cortisol rhythm and a normal restoration of the baseline activity of the axis following the acute stress response. Preliminary evidence suggests the possible implication of oxytocin (OT) in disorders related to the TS spectrum, especially non-tic-related OCD. The injection of OT in the amygdala of rodents was shown to be able to induce hypergrooming, suggesting the possible involvement of this neuropeptide in the pathophysiology of complex, stereotyped behaviors. In contrast, there is anecdotal clinical evidence that tics improve following periods of affectionate touch and sexual intercourse.
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Affiliation(s)
- Davide Martino
- Queen Elizabeth Hospital, Woolwich, London, United Kingdom; Centre for Neuroscience and Trauma, Queen Mary University of London, London, United Kingdom; King's College Hospital, London, United Kingdom.
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15
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16
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Nater UM, Heim CM, Raison C. Chronic fatigue syndrome. NEUROBIOLOGY OF PSYCHIATRIC DISORDERS 2012; 106:573-87. [DOI: 10.1016/b978-0-444-52002-9.00034-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
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Activity Limitations and Participation Restrictions in Patients with Chronic Fatigue Syndrom—Construction of a Disease Specific Questionnaire. ACTA ACUST UNITED AC 2011. [DOI: 10.1300/j092v10n03_02] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Scherling C, Collins B, MacKenzie J, Bielajew C, Smith A. Pre-chemotherapy differences in visuospatial working memory in breast cancer patients compared to controls: an FMRI study. Front Hum Neurosci 2011; 5:122. [PMID: 22053153 PMCID: PMC3205481 DOI: 10.3389/fnhum.2011.00122] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2011] [Accepted: 10/10/2011] [Indexed: 11/13/2022] Open
Abstract
INTRODUCTION Cognitive deficits are a side-effect of chemotherapy, however pre-treatment research is limited. This study examines neurofunctional differences during working memory between breast cancer (BC) patients and controls, prior to chemotherapy. METHODS Early stage BC females (23), scanned after surgery but before chemotherapy, were individually matched to non-cancer controls. Participants underwent functional magnetic resonance imaging (fMRI) while performing a Visuospatial N-back task and data was analyzed by multiple group comparisons. fMRI task performance, neuropsychological tests, hospital records, and salivary biomarkers were also collected. RESULTS There were no significant group differences on neuropsychological tests, estrogen, or cortisol. Patients made significantly fewer commission errors but had less overall correct responses and were slower than controls during the task. Significant group differences were observed for the fMRI data, yet results depended on the type of analysis. BC patients presented with increased activations during working memory compared to controls in areas such as the inferior frontal gyrus, insula, thalamus, and midbrain. Individual group regressions revealed a reverse relationship between brain activity and commission errors. CONCLUSION This is the first fMRI investigation to reveal neurophysiological differences during visuospatial working memory between BC patients pre-chemotherapy and controls. These results also increase the knowledge about the effects of BC and related factors on the working memory network. SIGNIFICANCE This highlights the need to better understand the pre-chemotherapy BC patient and the effects of associated confounding variables.
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Affiliation(s)
| | - Barbara Collins
- School of Psychology, University of OttawaOttawa, ON, Canada
- Ottawa HospitalOttawa, ON, Canada
| | | | | | - Andra Smith
- School of Psychology, University of OttawaOttawa, ON, Canada
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Son GH, Chung S, Kim K. The adrenal peripheral clock: glucocorticoid and the circadian timing system. Front Neuroendocrinol 2011; 32:451-65. [PMID: 21802440 DOI: 10.1016/j.yfrne.2011.07.003] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2010] [Revised: 04/25/2011] [Accepted: 07/06/2011] [Indexed: 12/27/2022]
Abstract
The mammalian circadian timing system is organized in a hierarchy, with the master clock residing in the suprachiasmatic nucleus (SCN) of the hypothalamus and subsidiary peripheral clocks in other brain regions as well as peripheral tissues. Since the local oscillators in most cells contain a similar molecular makeup to that in the central pacemaker, determining the role of the peripheral clocks in the regulation of rhythmic physiology and behavior is an important issue. Glucocorticoids (GCs) are a class of multi-functional adrenal steroid hormones, which exhibit a robust circadian rhythm, with a peak linked with the onset of the daily activity phase. It has long been believed that the production and secretion of GC is primarily governed through the hypothalamus-pituitary-adrenal (HPA) neuroendocrine axis in mammals. Growing evidence, however, strongly supports the notion that the periodicity of GC involves the integrated activity of multiple regulatory mechanisms related to circadian timing system along with the classical HPA neuroendocrine regulation. The adrenal-intrinsic oscillator as well as the central pacemaker plays a pivotal role in its rhythmicity. GC influences numerous biological processes, such as metabolic, cardiovascular, immune and even higher brain functions, and also acts as a resetting signal for the ubiquitous peripheral clocks, suggesting its importance in harmonizing circadian physiology and behavior. In this review, we will therefore focus on the recent advances in our understanding of the circadian regulation of adrenal GC and its functional relevance.
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Affiliation(s)
- Gi Hoon Son
- Department of Biological Sciences, Seoul National University, Brain Research Center for the 21st Century Frontier Program in Neuroscience, Seoul 151-742, Republic of Korea
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Rahman K, Burton A, Galbraith S, Lloyd A, Vollmer-Conna U. Sleep-wake behavior in chronic fatigue syndrome. Sleep 2011; 34:671-8. [PMID: 21532961 DOI: 10.1093/sleep/34.5.671] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
STUDY OBJECTIVES Disturbances of the internal biological clock manifest as fatigue, poor concentration, and sleep disturbances-symptoms reminiscent of chronic fatigue syndrome (CFS) and suggestive of a role for circadian rhythm disturbance in CFS. We examined circadian patterns of activity, sleep, and cortisol secretion in patients with CFS. DESIGN Case-control study, 5-day behavioral observation. SETTING Natural setting/home environment PARTICIPANTS 15 patients with CFS and 15 healthy subjects of similar age, sex, body mass index (BMI), and activity levels. INTERVENTIONS N/A. MEASUREMENTS Self-report questionnaires were used to obtain medical history and demographic information and to assess health behaviors, somatic and psychological symptoms, and sleep quality. An actiwatch accelerometer recorded activity and sleep patterns over 5 days with concurrent activity and symptom logs. Diurnal salivary cortisol secretion was measured. Additionally, overnight heart rate monitoring and pain sensitivity assessment was undertaken. RESULTS Ratings of symptoms, disability, sleep disturbance, and pain sensitivity were greater in patients with CFS. No between-group differences were found in the pattern or amount of sleep, activity, or cortisol secretion. Afternoon activity levels significantly increased evening fatigue in patients but not control subjects. Low nocturnal heart rate variability was identified as a biological correlate of unrefreshing sleep. CONCLUSIONS We found no evidence of circadian rhythm disturbance in CFS. However, the role of autonomic activity in the experience of unrefreshing sleep warrants further assessment. The activity symptom-relationship modelled here is of clinical significance in the approach to activity and symptom management in the treatment of CFS.
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Chung S, Son GH, Kim K. Circadian rhythm of adrenal glucocorticoid: Its regulation and clinical implications. Biochim Biophys Acta Mol Basis Dis 2011; 1812:581-91. [DOI: 10.1016/j.bbadis.2011.02.003] [Citation(s) in RCA: 154] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2010] [Revised: 01/31/2011] [Accepted: 02/07/2011] [Indexed: 10/18/2022]
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Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders. Biol Psychol 2011; 87:183-94. [PMID: 21315796 DOI: 10.1016/j.biopsycho.2011.02.002] [Citation(s) in RCA: 157] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2010] [Revised: 12/08/2010] [Accepted: 02/03/2011] [Indexed: 01/14/2023]
Abstract
Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is the most investigated biological risk marker in functional somatic disorders (FSDs), such as chronic fatigue syndrome (CFS), fibromyalgia (FM), and irritable bowel syndrome (IBS). Our aim was to assess whether there is an association between basal hypocortisolism and FSD and to identify potential moderators of this association. Meta-analysis on 85 studies revealed that although basal cortisol levels were generally lower in FSD subjects compared to controls, this association did not reach statistical significance (SMD -0.07, 95% CI -0.17 to 0.04, p=0.241). However, when the three FSD were assessed separately, statistically significant basal hypocortisolism was observed in CFS subjects compared to controls (SMD -0.14, 95% CI -0.28 to 0.00, p=0.047), but not in FM or IBS. When all potential moderators were entered into a meta-regression analysis, only type of FSD and female gender were significant independent predictors of basal hypocortisolism. In conclusion, we did not find evidence to consider all three main FSD as hypocortisolemic disorders, as significant reduction in basal cortisol compared to healthy controls was only found in CFS and in females with FM, but not in IBS.
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Silverman MN, Heim CM, Nater UM, Marques AH, Sternberg EM. Neuroendocrine and immune contributors to fatigue. PM R 2010; 2:338-46. [PMID: 20656615 DOI: 10.1016/j.pmrj.2010.04.008] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2010] [Accepted: 04/09/2010] [Indexed: 01/24/2023]
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.
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Affiliation(s)
- Marni N Silverman
- Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, National Institutes of Health, Rockville, MD(dagger)
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Alterations in diurnal salivary cortisol rhythm in a population-based sample of cases with chronic fatigue syndrome. Psychosom Med 2008; 70:298-305. [PMID: 18378875 DOI: 10.1097/psy.0b013e3181651025] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVE To examine diurnal salivary cortisol rhythms and plasma IL-6 concentrations in persons with chronic fatigue syndrome (CFS), persons not fulfilling a diagnosis of CFS (we term them cases with insufficient symptoms or fatigue, ISF) and nonfatigued controls (NF). Previous studies of CFS patients have implicated the hypothalamic-pituitary-adrenal axis and the immune system in the pathophysiology of CFS, although results have been equivocal. METHODS Twenty-eight people with CFS, 35 persons with ISF, and 39 NF identified from the general population of Wichita, Kansas, were admitted to a research ward for 2 days. Saliva was collected immediately on awakening (6:30 AM), at 08:00 AM, 12 noon, 4:00 PM, 8:00 PM and at bedtime (10:00 PM) and plasma was obtained at 7:30 AM. Salivary cortisol concentrations were assessed using radioimmunoassay, and plasma IL-6 was measured using sandwich enzyme-linked immunosorbent assay. RESULTS People with CFS demonstrated lower salivary cortisol concentrations in the morning and higher salivary cortisol concentrations in the evening compared with both ISF and NF groups indicating a flattening of the diurnal cortisol profile. Mean plasma IL-6 concentrations were highest in CFS compared with the other groups, although these differences were no longer significant after controlling for BMI. Attenuated decline of salivary cortisol concentrations across the day and IL-6 concentration were associated with fatigue symptoms in CFS. CONCLUSIONS These results suggest an altered diurnal cortisol rhythm and IL-6 concentrations in CFS cases identified from a population-based sample.
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Adam EK, Hawkley LC, Kudielka BM, Cacioppo JT. Day-to-day dynamics of experience--cortisol associations in a population-based sample of older adults. Proc Natl Acad Sci U S A 2006; 103:17058-63. [PMID: 17075058 PMCID: PMC1636578 DOI: 10.1073/pnas.0605053103] [Citation(s) in RCA: 574] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
In 156 older adults, day-to-day variations in cortisol diurnal rhythms were predicted from both prior-day and same-day experiences, to examine the temporal ordering of experience-cortisol associations in naturalistic environments. Diary reports of daily psychosocial, emotional, and physical states were completed at bedtime on each of three consecutive days. Salivary cortisol levels were measured at wakeup, 30 min after awakening, and at bedtime each day. Multilevel growth curve modeling was used to estimate diurnal cortisol profiles for each person each day. The parameters defining those profiles (wakeup level, diurnal slope, and cortisol awakening response) were predicted simultaneously from day-before and same-day experiences. Prior-day feelings of loneliness, sadness, threat, and lack of control were associated with a higher cortisol awakening response the next day, but morning awakening responses did not predict experiences of these states later the same day. Same-day, but not prior-day, feelings of tension and anger were associated with flatter diurnal cortisol rhythms, primarily because of their association with higher same-day evening cortisol levels. Although wakeup cortisol levels were not predicted by prior-day levels of fatigue and physical symptoms, low wakeup cortisol predicted higher levels of fatigue and physical symptoms later that day. Results are consistent with a dynamic and transactional function of cortisol as both a transducer of psychosocial and emotional experience into physiological activation and an influence on feelings of energy and physical well-being.
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Affiliation(s)
- Emma K Adam
- School of Education and Social Policy and Cells to Society Center, Institute for Policy Research, Northwestern University, Evanston, IL 60208, USA.
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Sjögren E, Leanderson P, Kristenson M. Diurnal saliva cortisol levels and relations to psychosocial factors in a population sample of middle-aged swedish men and women. Int J Behav Med 2006; 13:193-200. [PMID: 17078769 DOI: 10.1207/s15327558ijbm1303_2] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Whereas psychosocial risk factors increase the risk for disease, psychosocial resources reduce this risk. To examine a possible pathway for these effects, the relations between saliva cortisol levels and psychosocial factors were studied in a random sample of 257 men and women aged 30 to 64 years. Saliva samples were collected at home on waking, 30 min after waking, and in the evening. A flatter diurnal rhythm of cortisol, that is, lower deviations between awakening and evening cortisol levels, was related to high levels of psychosocial risk factors (cynicism, depression, and vital exhaustion), whereas a steeper diurnal rhythm was related to psychosocial resources (social support and coping), general health, and well-being (all p < .05). Our results support earlier suggestions that the capacity of the hypothalamic-pituitary-adrenal-axis to dynamically respond to stress is 1 pathway for observed effects of psychosocial factors regarding risk for disease development.
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Affiliation(s)
- Elaine Sjögren
- Department of Health and Society, Linköping University, Linköping, Sweden.
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Jerjes WK, Taylor NF, Peters TJ, Wessely S, Cleare AJ. Urinary cortisol and cortisol metabolite excretion in chronic fatigue syndrome. Psychosom Med 2006; 68:578-82. [PMID: 16868267 DOI: 10.1097/01.psy.0000222358.01096.54] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Reduced basal hypothalamic-pituitary-adrenal (HPA) axis output in chronic fatigue syndrome (CFS) has been inferred from low cortisol levels in blood, saliva, and urine in some studies. Because > 95% of cortisol is metabolized before excretion, we assessed cortisol output by assay of both cortisol metabolites and free cortisol in 24-hour urine collections and also investigated sex differences in these between CFS and control groups. METHOD We calculated total urinary cortisol metabolites (TCM) and cortisol metabolite ratios from individual steroid data in 40 patients (20 males and 20 females) with CFS who were free of medication or comorbid psychiatric disorder likely to influence the HPA axis. Results were compared with those of 40 healthy volunteers (20 males and 20 females) well matched for age and body mass index. Data for free cortisol was obtained on 28 of the patients and 27 of the controls. RESULTS The mean of TCM and cortisol metabolite ratios was not significantly different between patients and controls for either sex (p > .05 for all parameters). Previously established sex differences were confirmed in our controls and were found to be similar in CFS for TCM and the ratios 11OH/11OXO, 5alpha/5beta THF, and 20OH/20OXO (see text) (p < .005, p < .05, p < .05, and p < .005, respectively). Urinary free cortisol values were numerically (but not statistically) lower in patients with CFS than controls, and correlated inversely with fatigue levels in patients. CONCLUSION The finding of normal urinary cortisol metabolite excretion in patients with CFS is at variance with earlier reports that CFS is a hypocortisolemic state. If serum and saliva cortisol levels are lower in CFS, this would suggest that metabolic clearance of cortisol is faster in patients with CFS than controls. This study also demonstrates that sex differences must be taken into account when interpreting results in patients with CFS.
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Affiliation(s)
- Walid K Jerjes
- Department of Clinical Biochemistry, Guy's, King's and St. Thomas' School of Medicine, King's College London, UK.
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Abstract
OBJECTIVE A systematic review of the literature about chronic fatigue syndrome (CFS). METHODS A search of the Medline database (via Ovid and PubMed) with the key words chronic fatigue syndrome, diagnosis, classification, epidemiology, etiology, physiopathology, metabolism, microbiology, immunology, virology, psychology, drug therapy, rehabilitation, and therapy. The reference lists of each article were examined for additional related articles. RESULTS CFS was defined in 1988 by the US Centes for Disease Control and Prevention. The prevalence of chronic fatigue syndrome has ranged from 0.2% to 0.7% in the general population. In 1994, the definition of CFS was revised by Fukuda et al. Despite various research in several topics (e.g. infection, immune systems, neuroendocrinology, autonomic activity, neuromuscular involvement), the pathophysiology remains unknown. CONCLUSION CFS, with its various major clinical and functional impacts, should be associated with a "biopsychosocial model". Progressive muscular rehabilitation, combined with behavioral and cognitive treatment, is an essential part of therapy.
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Affiliation(s)
- D Maquet
- Département des Sciences de la Motricité, Unité de Médecine Physique et Kinésithérapie-Réadaptation, Université de Liège, CHU Sart-Tilman, ISEPK, Belgique.
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Jerjes WK, Peters TJ, Taylor NF, Wood PJ, Wessely S, Cleare AJ. Diurnal excretion of urinary cortisol, cortisone, and cortisol metabolites in chronic fatigue syndrome. J Psychosom Res 2006; 60:145-53. [PMID: 16439267 DOI: 10.1016/j.jpsychores.2005.07.008] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2005] [Revised: 07/05/2005] [Accepted: 07/19/2005] [Indexed: 11/18/2022]
Abstract
OBJECTIVE The aim of this study was to obtain comprehensive information on basal hypothalamic-pituitary-adrenal (HPA) axis activity in chronic fatigue syndrome (CFS) patients who were not affected by medication or comorbid psychiatric disorder likely to influence the HPA axis. METHOD Steroid analysis of urine collections from 0600 to 2100 h at 3-h intervals in CFS patients and in controls. RESULTS Urinary free cortisol and cortisone concentrations showed a significant normal diurnal rhythm, but levels were lower across the cycle in CFS. In contrast, while urinary cortisol metabolites also showed a normal diurnal rhythm, levels were not significantly different between the CFS and controls at any time. Derived metabolite ratios were similar in both groups. CONCLUSION This study provides further evidence for reduced basal HPA axis function in patients with CFS, based on lower free cortisol and cortisone levels, but this is not corroborated by cortisol metabolite data. The difference between these measures cannot be explained by an altered timing of the diurnal rhythm.
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Affiliation(s)
- Walid K Jerjes
- Department of Clinical Biochemistry, Guy's, King's and St Thomas' School of Medicine, Bessemer Road, SE5 9RS London, UK.
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Nijs J, Vaes P, De Meirleir K. The Chronic Fatigue Syndrome Activities and Participation Questionnaire (CFS-APQ): An overview. Occup Ther Int 2006; 12:107-21. [PMID: 16136868 DOI: 10.1002/oti.19] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Chronic fatigue syndrome (CFS) is characterized by severe fatigue and a reduction in activity levels. The purpose of this study was to provide an overview of design, reliability, and validity of the CFS Activities and Participation Questionnaire (CFS-APQ). The CFS-APQ was constructed based on a retrospective analysis of the Karnofsky Performance Status Questionnaire and the Activities of Daily Living Questionnaire (n = 141). In a reliability study of 34 participants the test-retest reliability coefficient of the CFS-APQ was 0.95. In two different studies, the Cronbach alpha coefficient for internal consistency varied between 0.87 (n = 88) and 0.94 (n = 47). The CFS-APQ was administered to 47 patients who listed 183 activities that had become difficult due to their chronic symptoms, and 157 (85.8%) answers matched the content of the CFS-APQ. The outcome of a cross-sectional study (n = 88) studying the correlations between the Medical Outcomes Short Form 36 Health Status Survey subscale scores and the CFS-APQ supported the validity of the CFS-APQ. The CFS-APQ scores correlated with a behavioural assessment of the patients' performance of activities encompassed by the questionnaire (r = 0.29-0.55; n = 63), and correlated with exercise capacity parameters (r = 0.26-0.39; n = 77) obtained during a maximal exercise capacity stress test. Finally, the CFS-APQ correlated with visual analogue scales for pain (r = 0.51) and fatigue (r = 0.50; n = 47). It is concluded that the CFS-APQ generates reliable and valid data, and can be used as a clinical measure of disease severity in patients with CFS. Future studies should aim at examining the sensitivity of the CFS-APQ.
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Affiliation(s)
- Jo Nijs
- Department of Physiology, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
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Jerjes WK, Cleare AJ, Wessely S, Wood PJ, Taylor NF. Diurnal patterns of salivary cortisol and cortisone output in chronic fatigue syndrome. J Affect Disord 2005; 87:299-304. [PMID: 15922454 DOI: 10.1016/j.jad.2005.03.013] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2004] [Revised: 03/21/2005] [Accepted: 03/22/2005] [Indexed: 12/20/2022]
Abstract
BACKGROUND The aim of the present study was to obtain a naturalistic measure of diurnal hypothalamic-pituitary-adrenal (HPA) axis output in CFS patients unaffected by medication or comorbid psychiatric disorder likely to influence the axis. METHOD Cortisol and cortisone levels were measured in saliva samples collected from 0600 h to 2100 h at 3-h intervals in CFS patients and healthy controls. RESULTS Mean cortisol and cortisone concentrations were significantly lower in patients than controls across the whole day, as were levels at each individual time point except 2100 h. Cosinor analysis showed a significant diurnal rhythm of cortisol and cortisone that was not phase-shifted in CFS compared to controls. However, there was a lower rhythm-adjusted mean and a lower amplitude in CFS patients. The cortisol/cortisone ratio showed no diurnal rhythm and did not differ between CFS subjects and controls. LIMITATIONS The sample size was relatively small, and drawn from specialist referral patients who had been ill for some time; generalisation of these results to other populations is therefore unwarranted. CONCLUSION The main findings of this study are to provide further evidence for reduced basal HPA axis function in at least some patients with CFS and to show for the first time that salivary cortisone is also reduced in CFS and has a diurnal rhythm similar to that of cortisol. We have also demonstrated that the cortisol/cortisone ratio remains unchanged in CFS, suggesting that increased conversion of cortisol to cortisone cannot account for the observed lowering of salivary cortisol.
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Affiliation(s)
- W K Jerjes
- Department of Clinical Biochemistry, King's College Hospital, Denmark Hill, London SE5 9RX, United Kingdom.
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Abstract
OBJECTIVES The aim of the present study was to examine the free salivary cortisol response to awakening in men and women reporting low, moderate, and high levels of burnout. METHODS Twenty-two patients on sick leave due to burnout were compared with 22 working participants with low and 20 working participants with intermediate scores on the Shirom-Melamed Burnout Questionnaire (SMBQ), with regard to the free salivary cortisol response to awakening. Saliva samples were collected upon awakening and at +15, +30, and +60 min thereafter. RESULTS Female burnout patients had higher cortisol levels than did the females with low burnout at awakening and at +15, +30, and +60 min after awakening. They also had a greater area under the curve (AUC) for salivary cortisol than did the female participants with low burnout. Male participants with moderate levels of burnout had higher cortisol levels at +60 min after awakening compared with males with low burnout. CONCLUSIONS The results of the present study indicate a dysregulation in hypothalamic-pituitary-adrenocortical axis (HPA axis) activity, characterised by elevated morning salivary cortisol levels, among female burnout patients. Among males, increased cortisol levels were observed among participants with moderate levels of burnout, but not among patients or healthy controls.
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Affiliation(s)
- Giorgio Grossi
- The Stress Clinic, National Institute for Psychosocial Factors and Health, Stockholm, Sweden
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Sánchez Rodríguez A, González Maroño C, Sánchez Ledesma M. [Chronic fatigue syndrome: a syndrome in search of definition]. Rev Clin Esp 2005; 205:70-4. [PMID: 15766479 DOI: 10.1157/13072499] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Affiliation(s)
- A Sánchez Rodríguez
- Servicio de Medicina Interna 1, Hospital Universitario de Salamanca, Salamanca
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Abstract
OBJECTIVES Disturbances of neuroendocrine function, particularly the hypothalamo-pituitary-adrenal (HPA) axis, have been implicated in the pathophysiology of chronic fatigue syndrome (CFS). However, few studies have attempted to measure blood levels of pituitary or adrenal hormones across a whole 24-hour period in CFS, and those that did so have used infrequent sampling periods. Our aim was to assess 24-hour pituitary and adrenal function using frequent blood sampling. METHODS We recruited 15 medication-free patients with CFS without comorbid psychiatric disorder and 10 healthy control subjects. Blood samples were collected over 24 hours and assayed for cortisol, corticotropin (ACTH), growth hormone (GH), and prolactin (PRL) levels on an hourly basis during daytime hours (10 am to 10 pm) and every 15 minutes thereafter (10 pm to 10 am). RESULTS Repeated-measures analyses of variance were undertaken using hormone levels averaged over 2-hour blocks to smooth curves by reducing the influence of sample timing relative to secretory burst. For ACTH, there was both a main effect of group, suggesting reduced mean ACTH secretion in patients with CFS over the whole monitoring period, and a group-by-time interaction, suggesting a differential pattern of ACTH release. Post hoc analysis showed reduced ACTH levels in CFS during the 8 am to 10 am period. In contrast, there were no significant abnormalities in the levels of cortisol, GH, and PRL in patients with CFS over the full cycle compared with control subjects. Cosinor analysis found no differences in the cortisol circadian rhythm parameters, but the ACTH rhythm did differ, patients with CFS showing an earlier acrophase. CONCLUSIONS Patients with CFS demonstrated subtle alterations in HPA axis activity characterized by reduced ACTH over a full circadian cycle and reduced levels during the usual morning physiological peak ACTH secretion. This provides further evidence of subtle dysregulation of the HPA axis in CFS. Whether this dysregulation is a primary feature of the illness or instead represents a biologic effect secondary to having the illness itself remains unclear.
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Affiliation(s)
- Annabella Di Giorgio
- Department of Neurological and Psychiatric Services, University of Bari, Bari, Italy
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36
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Segal TY, Hindmarsh PC, Viner RM. Disturbed adrenal function in adolescents with chronic fatigue syndrome. J Pediatr Endocrinol Metab 2005; 18:295-301. [PMID: 15813608 DOI: 10.1515/jpem.2005.18.3.295] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE To investigate adrenal function in children and adolescents with chronic fatigue syndrome (CFS) compared with age-matched controls. METHODS Case-control study of low dose (500 ng/m2) synacthen tests (LDST) in 23 adolescents with CFS and 17 age-matched controls. Serum cortisol concentrations were measured at 5-min intervals from 10 to 45 minutes. Peak serum cortisol concentration, time to peak, rise in cortisol and area under the curve (AUC) were derived. RESULTS Patients with CFS had significantly lower mean cortisol levels during the LDST (p <0.001), lower peak cortisol (p <0.025), reduced cortisol AUC (p <0.005) and longer time to peak cortisol (p <0.05). Abnormalities were seen in both sexes but were more pronounced in females. Unstimulated adrenal androgen and 17-hydroxyprogesterone concentrations were normal. CONCLUSIONS Adolescents with CFS have subtle alterations in adrenal function suggesting a reduction in central stimulation of the adrenal glands. The more pronounced effects in females may reflect differential central effects of stress on hypothalamic-pituitary-adrenal axis regulation between the sexes.
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Affiliation(s)
- T Y Segal
- University College London Hospitals, UK
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37
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Bower JE, Ganz PA, Dickerson SS, Petersen L, Aziz N, Fahey JL. Diurnal cortisol rhythm and fatigue in breast cancer survivors. Psychoneuroendocrinology 2005; 30:92-100. [PMID: 15358446 DOI: 10.1016/j.psyneuen.2004.06.003] [Citation(s) in RCA: 214] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2003] [Revised: 03/29/2004] [Accepted: 06/09/2004] [Indexed: 11/29/2022]
Abstract
Approximately 30% of breast cancer survivors report persistent fatigue of unknown origin. We have previously shown that cancer-related fatigue is associated with alterations in immunological parameters and serum cortisol levels in breast cancer survivors. The current study examined the diurnal rhythm of salivary cortisol in fatigued and non-fatigued breast cancer survivors. Salivary cortisol measures were obtained from breast cancer survivors with persistent fatigue (n=13) and a control group of non-fatigued survivors (n=16). Participants collected saliva samples upon awakening and at 1200, 1700, and 2200 h on two consecutive days. Diurnal cortisol slope for each day was determined by linear regression of log-transformed cortisol values on collection time and analyzed using multi-level modeling. Fatigued breast cancer survivors had a significantly flatter cortisol slope than non-fatigued survivors, with a less rapid decline in cortisol levels in the evening hours. At the individual patient level, survivors who reported the highest levels of fatigue also had the flattest cortisol slopes. Group differences remained significant in analyses controlling for demographic and medical factors, daily health behaviors, and other potential confounds (e.g. depressed mood, body mass index). Results suggest a subtle dysregulation in hypothalamic-pituitary-adrenal axis functioning in breast cancer survivors with persistent fatigue.
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Affiliation(s)
- Julienne E Bower
- Cousins Center for Psychoneuroimmunology, UCLA Neuropsychiatric Institute, Los Angeles, CA, USA.
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38
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Abstract
Fatigue is a common problem; when chronic and disabling, subjects can be categorized as having chronic fatigue syndrome (CFS). Whilst it is most likely a multifactorial condition of biopsychosocial origin, the nature of the pathophysiological component remains unclear. There has been a wealth of interest in the possible hypothalamo-pituitary-adrenal (HPA) axis dysfunction in CFS, and whether such changes may mediate fatigue. On balance, there appears to be reduced cortisol output in a proportion of patients, together with heightened negative feedback and glucocorticoid receptor function. There is evidence for impaired adrenocorticotropic hormone (ACTH) and cortisol responses to a variety of challenges. However, there is no evidence for a specific or uniform dysfunction of the HPA axis. Evidence that these changes may be related to symptom production comes from randomized controlled trials of glucocorticoid replacement therapy, which have shown improvements in fatigue and disability. Given the many factors that may impinge on the HPA axis in CFS, such as inactivity, sleep disturbance, psychiatric comorbidity, medication and ongoing stress, it seems likely that there is not a single or specific change to the HPA axis in CFS and that the observed HPA axis disturbances are of multifactorial etiology. This is further supported by a comparison of neuroendocrine findings in other conditions in which fatigue is prominent, showing both similarities and differences with the pattern in CFS.
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Affiliation(s)
- A J Cleare
- 1Section of Neurobiology of Mood Disorders, Division of Psychological Medicine, The Institute of Psychiatry, London, UK and Affective Disorders Unit, Maudsley Hospital, London, UK
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39
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Abstract
Chronic fatigue syndrome (CFS) is a common and disabling problem; although most likely of biopsychosocial origin, the nature of the pathophysiological components remains unclear. There has been a wealth of interest in the endocrinology of this condition, which will be reviewed in this article. Most studied has been the hypothalamic-pituitary-adrenal (HPA) axis; although the quality of many studies is poor, the overall balance of evidence points to reduced cortisol output in at least some patients, with some evidence that this is linked to symptom production or persistence. There is evidence for heightened negative feedback and glucocorticoid receptor function and for impaired ACTH and cortisol responses to a variety of challenges. However, there is no evidence for a specific or uniform dysfunction of the HPA axis. Given the many factors that may impinge on the HPA axis in CFS, such as inactivity, sleep disturbance, psychiatric comorbidity, medication, and ongoing stress, it seems likely that HPA axis disturbance is heterogeneous and of multifactorial etiology in CFS. Studies assessing GH, dehydroepiandrostenedione and its sulfate, melatonin, leptin, and neuroendocrine-monoamine interactions are also reviewed. There is some evidence from these studies to suggest alterations of dehydroepiandrostenedione sulfate function and abnormal serotonin function in CFS, but whether these changes are of functional importance remains unclear. To obtain a clearer assessment of the etiological and pathophysiological relevance of endocrine changes in CFS, it is suggested that more prospective cohort studies be undertaken in groups at high risk for CFS, that patients with CFS are followed up into recovery, and that multidimensional assessments are undertaken to unravel the influence of the various confounding factors on the observed endocrine changes in CFS.
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Affiliation(s)
- Anthony J Cleare
- Section of Neurobiology of Mood Disorders, Division of Psychological Medicine, The Institute of Psychiatry, London SE5 8AZ, United Kingdom.
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Edwards S, Hucklebridge F, Clow A, Evans P. Components of the diurnal cortisol cycle in relation to upper respiratory symptoms and perceived stress. Psychosom Med 2003; 65:320-7. [PMID: 12652001 DOI: 10.1097/01.psy.0000033123.70631.8e] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE The purpose of this study was to investigate the relationship between the diurnal pattern of salivary free cortisol to perceived stress and susceptibility to symptoms of upper respiratory illness (URI). METHODS Salivary free cortisol concentration was determined in 34 healthy participants (students) at eight time points, synchronized to awakening, on 2 consecutive days. Participants completed a standard questionnaire to assess perceived stress and subsequently kept a daily record of social proximity and symptoms of upper respiratory illness for 2 weeks. RESULTS Participants characterized by consistently larger awakening responses went on to report significantly more URI symptoms. Participants with less pronounced diurnal decline (flatter profiles) reported fewer URI symptoms. The two cortisol components were themselves related and interacted such that participants high on an interactive vector reported approximately three times more URI symptoms than other participants. The URI-associated cortisol components (dynamic changes) were not related to perceived stress, but underlying cortisol secretory activity (overall levels) in the first 45 minutes after awakening was. Dynamic components were, however, related to a social proximity measure, which in turn was related to URI symptoms. Proximity and the interactive cortisol vector together explained a substantial (28%) percentage of the variance in URI symptom reports. The cortisol vector independently and significantly explained 12% of the variation; the proximity measure independently and nonsignificantly contributed 6% of the variation. CONCLUSIONS URI symptoms were associated with two related dynamic components of the cortisol cycle as determined by synchronization to awakening, whereas stress was related to a measure of overall secretory activity.
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Affiliation(s)
- Sue Edwards
- Psychophysiology and Stress Research Group, University of Westminster, London, United Kingdom
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41
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Hick CB, Tharpe AM. Listening effort and fatigue in school-age children with and without hearing loss. JOURNAL OF SPEECH, LANGUAGE, AND HEARING RESEARCH : JSLHR 2002; 45:573-584. [PMID: 12069009 DOI: 10.1044/1092-4388(2002/046)] [Citation(s) in RCA: 251] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
Parents, audiologists, and educators have long speculated that children with hearing loss must expend more effort and, therefore, fatigue more easily than their peers with normal hearing when listening in adverse acoustic conditions. Until now, however, very few studies have been conducted to substantiate these speculations. Two experiments were conducted with school-age children with mild-to-moderate hearing loss and with normal hearing. In the first experiment, salivary cortisol levels and a self-rating measure were used to measure fatigue. Neither cortisol measurements nor self-rated measures of fatigue revealed significant differences between children with hearing loss and their normal-hearing peers. In the second experiment, however, a dual-task paradigm used to study listening effort indicated that children with hearing loss expend more effort in listening than children with normal hearing. Results are discussed in terms of clinical application and future research needs.
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Affiliation(s)
- Candace Bourland Hick
- Vanderbilt Bill Wilkerson Center for Otolaryngology and Communication Sciences, Nashville, TN, USA.
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Buskila D, Press J. Neuroendocrine mechanisms in fibromyalgia-chronic fatigue. Best Pract Res Clin Rheumatol 2001; 15:747-58. [PMID: 11812019 DOI: 10.1053/berh.2001.0191] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Fibromyalgia and chronic fatigue syndrome are poorly understood disorders that share similar demographic and clinical characteristics. Because of the clinical similarities between both disorders it was suggested that they share a common pathophysiological mechanism, namely, central nervous system dysfunction. This chapter presents data demonstrating neurohormonal abnormalities, abnormal pain processing and autonomic nervous system dysfunction in fibromyalgia and chronic fatigue syndrome. The possible contribution of the central nervous system dysfunction to the development and symptomatology of these conditions is discussed. The chapter concludes by reviewing the effect of current treatments and emerging therapeutic modalities in fibromyalgia and chronic fatigue syndrome.
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Affiliation(s)
- D Buskila
- Rheumatic Disease Unit and Department of Medicine 'B', Soroka Medical Centre and Ben-Gurion University, Beer-Sheva, 84101, Israel
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44
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Abstract
The chronic fatigue syndrome is characterised by a fatigue that is disproportionate to the intensity of effort that is undertaken, has persisted for 6 months or longer, and has no obvious cause. Unless there has been a long period of patient- or physician-imposed inactivity, objective data may show little reduction in muscle strength or peak aerobic power, but the affected individual avoids heavy activity. The study of aetiology and treatment has been hampered by the low disease prevalence (probably <0.1% of the general population), and (until recently) by a lack of clear and standardised diagnostic criteria. It is unclear how far the aetiology is similar for athletes and nonathletes. It appears that in top competitors, overtraining and/or a negative energy balance can be precipitating factors. A wide variety of other possible causes and/or precipitating factors have been cited in the general population, including psychological stress, disorders of personality and affect, dysfunction of the hypothalamic-pituitary-adrenal axis, hormonal imbalance, nutritional deficits, immune suppression or activation and chronic infection. However, none of these factors have been observed consistently. The prognosis is poor; often disability and impairment of athletic performance are prolonged. Prevention of overtraining by careful monitoring seems the most effective approach in athletes. In those where the condition is established, treatment should aim at breaking the vicious cycle of effort avoidance, deterioration in physical condition and an increase in fatigue through a combination of encouragement and a progressive exercise programme.
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Affiliation(s)
- R J Shephard
- Defence & Civil Institute of Environmental Medicine, and Faculty of Physical Education & Health, University of Toronto, Ontario, Canada.
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45
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Hamilos DL, Nutter D, Gershtenson J, Ikle D, Hamilos SS, Redmond DP, Di Clementi JD, Schmaling KB, Jones JF. Circadian rhythm of core body temperature in subjects with chronic fatigue syndrome. CLINICAL PHYSIOLOGY (OXFORD, ENGLAND) 2001; 21:184-95. [PMID: 11318826 DOI: 10.1046/j.1365-2281.2001.00321.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The pathophysiological basis for chronic fatigue syndrome (CFS) remains poorly understood. Certain symptoms of CFS, namely fatigue, neurocognitive symptoms and sleep disturbance, are similar to those of acute jet lag and shift work syndromes thus raising the possibility that CFS might be a condition associated with disturbances in endogenous circadian rhythms. In this study, we tested this hypothesis by examining the circadian rhythm of core body temperature (CBT) in CFS and control subjects. Continuous recordings of CBT were obtained every 5 min over 48 h in a group of 10 subjects who met the Center for Disease Control (CDC) definition of CFS and 10 normal control subjects. Subjects in the two groups were age, sex and weight-matched and were known to have normal basal metabolic rates and thyroid function. CBT recordings were performed under ambulatory conditions in a clinical research centre with the use of an ingestible radio frequency transmitter pill and a belt-worn receiver-logger. CBT time series were analysed by a cosinor analysis and by a harmonic-regression-plus-correlated-noise model to estimate the mean, amplitude and phase angle of the rhythm. The goodness of fit of each model was also compared using the Akaike Information Criterion (AIC) and sigma2. Average parameters for each group were compared by Student's t-test. By cosinor analysis, the only significant difference between CFS and control groups was in the phase angle of the third harmonic (P=0.02). The optimal harmonic-regression-plus-correlated-noise models selected were ARMA(1,1): control 7, CFS 6; ARMA(2,0): control 1, CFS 4; and ARMA(2,1): control 2 subjects. The optimal fit ARMA model contained two harmonics in eight of 10 control subjects but was more variable in the CFS subjects (1 harmonic: 5 subjects; 2 harmonics: 1 subject; 3 harmonics: 4 subjects). The goodness of fit measures for the optimal ARMA model were also better in the control than the CFS group, but the differences were not statistically significant. We conclude that, measured under ambulatory conditions, the circadian rhythm of CBT in CFS is nearly indistinguishable from that of normal control subjects although there was a tendency for greater variability in the rhythm. Hence, it is unlikely that the symptoms of CFS are because of disturbance in the circadian rhythm of CBT.
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Affiliation(s)
- D L Hamilos
- Washington University School of Medicine, Division of Allergy and Immunology, Euclid Avenue, St Louis, Missouri, USA.
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47
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Cleare A. A reply. Clin Endocrinol (Oxf) 2000; 52:798-799. [PMID: 28796350 DOI: 10.1046/j.1365-2265.2000.0970f.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Affiliation(s)
- Anthony Cleare
- Department of Psychological Medicine, Guy's, King's and St Thomas' School of Medicine and The Institute of Psychiatry, London, UK
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48
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Abstract
Fibromyalgia and widespread pain were common in Gulf War veterans with unexplained illness referred to a rheumatology clinic. Increased tenderness was demonstrated in the postmenstrual phase of the cycle compared with the intermenstrual phase in normally cycling women but not in users of oral contraceptives. Patients with fibromyalgia had high levels of symptoms that have been used to define silicone implant-associated syndrome. Tender points were found to be a common transient finding associated with acute infectious mononucleosis, but fibromyalgia was an unusual long-term outcome. The common association of fibromyalgia with other rheumatic and systemic illnesses was further explored. A preliminary study revealed a possible linkage of fibromyalgia to the HLA region. Patients with fibromyalgia were found to have an impaired ability to activate the hypothalamic pituitary portion of the hypothalamic pituitary adrenal axis as well as the sympathoadrenal system, leading to reduced corticotropin and epinephrine response to hypoglycemia. Much interest has been expressed in the literature on the possible role of autonomic dysfunction in the development or exacerbation of fatigue and other symptoms in chronic fatigue syndrome. Mycoplasma genus and mycoplasma fermentans were detected by polymerase chain reaction in patients with chronic fatigue syndrome. It was reported that myofascial temporomandibular disorder does not run in families. No major therapeutic trials in fibromyalgia, chronic fatigue syndrome, or myofascial pain syndrome were reported over the past year. The effectiveness of cognitive behavioral therapy and behavior therapy for chronic pain in adults was emphasized. A favorable outcome of fibromyalgia and chronic fatigue syndrome in children and adolescents was reported.
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Affiliation(s)
- D Buskila
- Ben Gurion University of the Negev, Faculty of Health Sciences, Soroka Medical Center, Beer Sheva, Israel
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49
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Abstract
OBJECTIVE Many studies suggest mild hypocortisolism in chronic fatigue syndrome (CFS), usually assumed to be due to reduced suprahypothalamic drive to the hypothalamo-pituitary-adrenal (HPA) axis. We wished to explore further the state of the HPA axis in CFS using the 1 microg low dose short Synacthen test. DESIGN Subjects received an intravenous bolus of 1 microg Synacthen; samples for cortisol estimation were taken at baseline and 2, 10, 20, 30, 40 and 60 minutes after injection. PATIENTS We tested 20 subjects suffering from CFS according to the criteria of the Center for Diseases Control without psychiatric comorbidity and 20 matched healthy controls. All subjects were drug free for at least 1 month. MEASUREMENTS We calculated the cortisol responses to the test as the maximum cortisol attained, the incremental rise in cortisol over baseline (Deltavalue) and as the integrated area under the curve. RESULTS There were no significant differences in baseline cortisol or cortisol responses between patients and controls. However, responses generally were low, and many subjects' peak responses were prior to the standard 30 minute sampling time., CONCLUSIONS These results do not lend support to the theory that patients with chronic fatigue syndrome have a low adrenal reserve. However, results from studies assessing the HPA axis are proving to be inconsistent. We suggest that many other factors may be contributing to HPA axis alterations in chronic fatigue syndrome, including sleep disturbance, inactivity, altered circadian rhythmicity, illness chronicity, concomitant medication and comorbid psychiatric disturbance. These sources of heterogeneity need to be considered in future studies, and may explain the inconsistent findings to date.
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Affiliation(s)
- M Hudson
- Department of Psychological Medicine, Guy's King's and St Thomas' School of Medicine and the Institute of Psychiatry, London, UK
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