circadian rhythm – American ME and CFS Society

Sleep and circadian rhythm alterations in myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID fatigue syndrome and its association with cardiovascular risk factors: A prospective cohort study

Abstract:

This study aimed to investigate circadian rhythm manifestations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients (including a subpopulation of long-COVID patients) and matched healthy controls while also exploring their association with cardiovascular health variables.

Thirty-one ME/CFS patients (75% females), 23 individuals diagnosed with post-COVID ME/CFS (56% females) and 31 matched healthy controls (68% females) were enrolled in this study. Demographic and clinical characteristics were assessed using validated self-reported outcome measures. Actigraphy data, collected over one week, were used to analyze the 24-h profiles of wrist temperature, motor activity, and sleep circadian variables in the study participants. Associations between lipid profile with endothelial dysfunction biomarkers (such as endothelin-1, ICAM-1 and VCAM-1) and with sleep and circadian variables were also studied.

No differences were found in these variables between the two group of patients. Patients showed lower activity and worse sleep quality than matched healthy controls, together with a worse lipid profile than controls, that was associated with disturbances in the circadian temperature rhythm. ICAM-1 levels were associated with plasma lipids in healthy controls, but not in patients, who showed higher levels of endothelin-1 and VCAM-1.

These findings suggest that lipid profiles in ME/CFS are linked to disrupted circadian rhythms and sleep patterns, likely due to endothelial dysfunction. Furthermore, they highlight the intricate relationship between sleep, circadian rhythms, and cardiovascular health in this condition.

Source: Zerón-Rugerio MF, Zaragozá MC, Domingo JC, Sanmartín-Sentañes R, Alegre-Martin J, Castro-Marrero J, Cambras T. Sleep and circadian rhythm alterations in myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID fatigue syndrome and its association with cardiovascular risk factors: A prospective cohort study. Chronobiol Int. 2024 Jul 22:1-12. doi: 10.1080/07420528.2024.2380020. Epub ahead of print. PMID: 39037125. https://pubmed.ncbi.nlm.nih.gov/39037125/

Nutrition and Chronobiology as Key Components of Multidisciplinary Therapeutic Interventions for Fibromyalgia and Associated Chronic Fatigue Syndrome: A Narrative and Critical Review

Abstract:

Fibromyalgia (FM) is often accompanied by chronic fatigue syndrome (CFS). It is a poorly understood disorder that mainly affects women and leads to chronic pain, fatigue, and insomnia, among other symptoms, which decrease quality of life. Due to the inefficiency of current pharmacological treatments, increasing interest is being directed towards non-pharmacological multicomponent therapies. However, nutrition and chronobiology are often overlooked when developing multicomponent therapies.

This narrative and critical review explore the relevance of nutritional and chronobiological strategies in the therapeutic management of FM and the often-associated CFS. Reviewed literature offers scientific evidence for the association of dietary habits, nutrient levels, body composition, gut microbiota imbalance, chronobiological alterations, and their interrelation with the development and severity of symptoms. This review highlights the key role of nutrition and chronobiology as relevant and indispensable components in a multidisciplinary approach to FM and CFS.

Source: Carrasco-Querol N, Cabricano-Canga L, Bueno Hernández N, Gonçalves AQ, Caballol Angelats R, Pozo Ariza M, Martín-Borràs C, Montesó-Curto P, Castro Blanco E, Dalmau Llorca MR, et al. Nutrition and Chronobiology as Key Components of Multidisciplinary Therapeutic Interventions for Fibromyalgia and Associated Chronic Fatigue Syndrome: A Narrative and Critical Review. Nutrients. 2024; 16(2):182. https://doi.org/10.3390/nu16020182 https://www.mdpi.com/2072-6643/16/2/182 (Full text)

Serum from Myalgic encephalomyelitis/chronic fatigue syndrome patients causes loss of coherence in cellular circadian rhythms

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling disorder characterized by disrupted daily patterns of activity, sleep, and physiology. Past studies in ME/CFS patients have examined circadian rhythms, suggested that desynchronization between central and peripheral rhythms may be an important pathological feature, and identified associated changes in post-inflammatory cytokines such as transforming growth factor beta (TGFB). However, no previous studies have examined circadian rhythms in ME/CFS using cellular models or studied the role of cytokines on circadian rhythms.

In this study, we used serum samples previously collected from ME/CFS patients (n = 20) selected for the presence of insomnia symptoms and matched controls (n = 20) to determine the effects of serum factors and TGFB on circadian rhythms in NIH3T3 mouse immortalized fibroblasts stably transfected with the Per2-luc bioluminescent circadian reporter.

Compared to control serum, ME/CFS serum caused a significant loss of rhythm robustness (decreased goodness of fit) and nominally increased the rate of damping of cellular rhythms. Damping rate was associated with insomnia severity in ME/CFS patients using the Pittsburgh Sleep Quality Index (PSQI). Recombinant TGFB1 peptide applied to cells reduced rhythm amplitude, caused phase delay and decreased robustness of rhythms.

However, there was no difference in TGFB1 levels between ME/CFS and control serum indicating the effects of serum on cellular rhythms cannot be explained by levels of this cytokine. Future studies will be required to identify additional serum factors in ME/CFS patients that alter circadian rhythms in cells.

Source: Heather Wei, Zoe Adelsheim, Rita Fischer, Michael J. McCarthy. Serum from Myalgic encephalomyelitis/chronic fatigue syndrome patients causes loss of coherence in cellular circadian rhythms. Journal of Neuroimmunology. Available online 24 June 2023, 578142. https://doi.org/10.1016/j.jneuroim.2023.578142 https://www.sciencedirect.com/science/article/abs/pii/S0165572823001285

Circadian skin temperature rhythm and dysautonomia in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the role of endothelin-1 in the vascular dysregulation

Abstract:

Purpose: There is accumulating evidence of autonomic dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); however, little is known about its association with circadian rhythms and endothelial dysfunction. This study aimed to explore the relationship between autonomic responses using an orthostatic test, skin temperature circadian variations, and circulating endothelial biomarkers in ME/CFS.

Methods: Sixty-seven adult female ME/CFS patients and 48 matched healthy controls were enrolled. Demographic and clinical characteristics suggestive of autonomic disturbances were assessed using validated self-reported outcome measures. Postural changes in blood pressure [BP], heart rate [HR], and wrist temperature (WT) were recorded during the orthostatic test. Actigraphy during one week was used to determine the 24-hour profile of peripheral temperature and motor activity. Circulating endothelial biomarkers were also measured as indicators of endothelial functioning.

Results: ME/CFS patients showed higher BP and HR values than healthy controls at rest (p < 0.05 for both), and also higher amplitude of the circadian activity rhythm (p < 0.01). Circulating levels of endothelin-1 (ET-1) and vascular cell adhesion molecule-1 (VCAM-1) were significantly higher in ME/CFS (p < 0.05). In ME/CFS, ET-1 levels were associated with the stability and amplitude of the temperature rhythm, (p < 0.01), and also with the self-reported questionnaires (p < 0.001).

Conclusions: ME/CFS patients exhibited alterations in circadian rhythms and hemodynamic measures that are associated with endothelial dysfunction, supporting previous evidence of dysautonomia in ME/CFS. Future investigation in this area is needed to assess vascular tone abnormalities and dysautonomia which may provide therapeutic targets for ME/CFS.

Source: Trinitat Cambras, Maria Fernanda Zerón-Rugerio, Antoni Díez-Noguera et al. Circadian skin temperature rhythm and dysautonomia in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the role of endothelin-1 in the vascular dysregulation, 21 September 2022, PREPRINT (Version 1) available at Research Square https://doi.org/10.21203/rs.3.rs-2044838/v1 (Full text)

Circadian rhythm disruption in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Implications for the post-acute sequelae of COVID-19

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.

Source: Michael J. McCarthy. Circadian rhythm disruption in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Implications for the post-acute sequelae of COVID-19. Brain, Behavior, & Immunity – Health, Volume 20, 2022, 100412, ISSN 2666-3546, https://doi.org/10.1016/j.bbih.2022.100412. (Full text)

Disturbances in sleep, circadian rhythms and daytime functioning in relation to coronavirus infection and Long-COVID – A multinational ICOSS study

Abstract:

This protocol paper describes the second survey produced by the International Covid Sleep Study (ICOSS) group with the aim to examine the associations between SARS-CoV-2 infection and sleep, sleepiness, and circadian problems as potential predisposing factors for more severe COVID-19 disease profile and for development of Long-COVID in the general population. The survey consists of 47 questions on sleep, daytime sleepiness, circadian rhythm, health, mental wellbeing, life habits, and socioeconomic situation before and during the pandemic, and conditional questions to those reporting having had coronavirus infection, being vaccinated, or suffering from particular sleep symptoms or sleep disorders. Surveys will be administered online between May and November 2021 in Austria, Brazil, Bulgaria, Canada, China, Croatia, Finland, France, Germany, Israel, Italy, Japan, Norway, Portugal, Sweden and USA. Data collected by the survey will give valuable information on the open questions regarding COVID-19 disease risk factors, symptomatology and evolution of Long-COVID, and on other long-term consequences related to the pandemic.

Source: Merikanto I, Dauvilliers Y, Chung F, Holzinger B, De Gennaro L, Wing YK, Korman M, Partinen M; 2nd ICOSS members. Disturbances in sleep, circadian rhythms and daytime functioning in relation to coronavirus infection and Long-COVID – A multinational ICOSS study. J Sleep Res. 2021 Dec 28:e13542. doi: 10.1111/jsr.13542. Epub ahead of print. PMID: 34964184. https://pubmed.ncbi.nlm.nih.gov/34964184/

Mitochondria and Immunity in Chronic Fatigue Syndrome

Abstract:

It is widely accepted that the pathophysiology and treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) could be considerably improved. The heterogeneity of ME/CFS and the confusion over its classification have undoubtedly contributed to this, although this would seem a consequence of the complexity of the array of ME/CFS presentations and high levels of diverse comorbidities.

This article reviews the biological underpinnings of ME/CFS presentations, including the interacting roles of the gut microbiome/permeability, endogenous opioidergic system, immune cell mitochondria, autonomic nervous system, microRNA-155, viral infection/re-awakening and leptin as well as melatonin and the circadian rhythm. This details not only relevant pathophysiological processes and treatment options, but also highlights future research directions.

Due to the complexity of interacting systems in ME/CFS pathophysiology, clarification as to its biological underpinnings is likely to considerably contribute to the understanding and treatment of other complex and poorly managed conditions, including fibromyalgia, depression, migraine, and dementia. The gut and immune cell mitochondria are proposed to be two important hubs that interact with the circadian rhythm in driving ME/CFS pathophysiology.

Source: Anderson G, Maes M. Mitochondria and immunity in chronic fatigue syndrome [published online ahead of print, 2020 May 26]. Prog Neuropsychopharmacol Biol Psychiatry. 2020;109976. doi:10.1016/j.pnpbp.2020.109976 https://pubmed.ncbi.nlm.nih.gov/32470498/

Circadian rhythm abnormalities and autonomic dysfunction in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract:

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients frequently show autonomic symptoms which may be associated with a hypothalamic dysfunction. This study aimed to explore circadian rhythm patterns in rest and activity and distal skin temperature (DST) and their association with self-reported outcome measures, in CFS/ME patients and healthy controls at two different times of year.

Ten women who met both the 1994 CDC/Fukuda definition and 2003 Canadian criteria for CFS/ME were included in the study, along with ten healthy controls matched for age, sex and body mass index. Self-reported measures were used to assess fatigue, sleep quality, anxiety and depression, autonomic function and health-related quality of life. The ActTrust actigraph was used to record activity, DST and light intensity, with data intervals of one minute over seven consecutive days. Sleep variables were obtained through actigraphic analysis and from subjective sleep diary. The circadian variables and the spectral analysis of the rhythms were calculated. Linear regression analysis was used to evaluate the relationship between the rhythmic variables and clinical features. Recordings were taken in the same subjects in winter and summer.

Results showed no differences in rhythm stability, sleep latency or number of awakenings between groups as measured with the actigraph. However, daily activity, the relative amplitude and the stability of the activity rhythm were lower in CFS/ME patients than in controls. DST was sensitive to environmental temperature and showed lower nocturnal values in CFS/ME patients than controls only in winter. A spectral analysis showed no differences in phase or amplitude of the 24h rhythm, but the power of the second harmonic (12h), revealed differences between groups (controls showed a post-lunch dip in activity and peak in DST, while CFS/ME patients did not) and correlated with clinical features. These findings suggest that circadian regulation and skin vasodilator responses may play a role in CFS/ME.

Source: Cambras T, Castro-Marrero J, Zaragoza MC, Díez-Noguera A, Alegre J. Circadian rhythm abnormalities and autonomic dysfunction in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. PLoS One. 2018 Jun 6;13(6):e0198106. doi: 10.1371/journal.pone.0198106. eCollection 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991397/ (Full article)

The putative role of oxidative stress and inflammation in the pathophysiology of sleep dysfunction across neuropsychiatric disorders: Focus on chronic fatigue syndrome, bipolar disorder and multiple sclerosis

Abstract:

Sleep and circadian abnormalities are prevalent and burdensome manifestations of diverse neuro-immune diseases, and may aggravate the course of several neuropsychiatric disorders. The underlying pathophysiology of sleep abnormalities across neuropsychiatric disorders remains unclear, and may involve the inter-play of several clinical variables and mechanistic pathways.

In this review, we propose a heuristic framework in which reciprocal interactions of immune, oxidative and nitrosative stress, and mitochondrial pathways may drive sleep abnormalities across potentially neuroprogressive disorders. Specifically, it is proposed that systemic inflammation may activate microglial cells and astrocytes in brain regions involved in sleep and circadian regulation. Activated glial cells may secrete pro-inflammatory cytokines (for example, interleukin-1 beta and tumour necrosis factor alpha), nitric oxide and gliotransmitters, which may influence the expression of key circadian regulators (e.g., the Circadian Locomotor Output Cycles Kaput (CLOCK) gene). Furthermore, sleep disruption may further aggravate oxidative and nitrosative, peripheral immune activation, and (neuro) inflammation across these disorders in a vicious pathophysiological loop.

This review will focus on chronic fatigue syndrome, bipolar disorder, and multiple sclerosis as exemplars of neuro-immune disorders. We conclude that novel therapeutic targets exploring immune and oxidative & nitrosative pathways (p.e. melatonin and molecular hydrogen) hold promise in alleviating sleep and circadian dysfunction in these disorders.

Source: Morris G, Stubbs B, Köhler CA, Walder K, Slyepchenko A, Berk M, Carvalho AF. The putative role of oxidative stress and inflammation in the pathophysiology of sleep dysfunction across neuropsychiatric disorders: Focus on chronic fatigue syndrome, bipolar disorder and multiple sclerosis. Sleep Med Rev. 2018 Apr 4. pii: S1087-0792(17)30152-1. doi: 10.1016/j.smrv.2018.03.007. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29759891

Modeling diurnal hormone profiles by hierarchical state space models

Abstract:

Adrenocorticotropic hormone (ACTH) diurnal patterns contain both smooth circadian rhythms and pulsatile activities. How to evaluate and compare them between different groups is a challenging statistical task. In particular, we are interested in testing (1) whether the smooth ACTH circadian rhythms in chronic fatigue syndrome and fibromyalgia patients differ from those in healthy controls and (2) whether the patterns of pulsatile activities are different. In this paper, a hierarchical state space model is proposed to extract these signals from noisy observations. The smooth circadian rhythms shared by a group of subjects are modeled by periodic smoothing splines. The subject level pulsatile activities are modeled by autoregressive processes. A functional random effect is adopted at the pair level to account for the matched pair design. Parameters are estimated by maximizing the marginal likelihood. Signals are extracted as posterior means. Computationally efficient Kalman filter algorithms are adopted for implementation. Application of the proposed model reveals that the smooth circadian rhythms are similar in the two groups but the pulsatile activities in patients are weaker than those in the healthy controls.

Source: Liu Z, Guo W. Modeling diurnal hormone profiles by hierarchical state space models. Stat Med. 2015 Oct 30;34(24):3223-34. doi: 10.1002/sim.6579. Epub 2015 Jul 7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592415/ (Full article)