exercise – Page 6 – American ME and CFS Society

The Interplay between Oxidative Stress, Exercise, and Pain in Health and Disease: Potential Role of Autonomic Regulation and Epigenetic Mechanisms

Abstract:

Oxidative stress can be induced by various stimuli and altered in certain conditions, including exercise and pain. Although many studies have investigated oxidative stress in relation to either exercise or pain, the literature presents conflicting results. Therefore, this review critically discusses existing literature about this topic, aiming to provide a clear overview of known interactions between oxidative stress, exercise, and pain in healthy people as well as in people with chronic pain, and to highlight possible confounding factors to keep in mind when reflecting on these interactions. In addition, autonomic regulation and epigenetic mechanisms are proposed as potential mechanisms of action underlying the interplay between oxidative stress, exercise, and pain.

This review highlights that the relation between oxidative stress, exercise, and pain is poorly understood and not straightforward, as it is dependent on the characteristics of exercise, but also on which population is investigated. To be able to compare studies on this topic, strict guidelines should be developed to limit the effect of several confounding factors. This way, the true interplay between oxidative stress, exercise, and pain, and the underlying mechanisms of action can be revealed and validated via independent studies.

Source: Hendrix J, Nijs J, Ickmans K, Godderis L, Ghosh M, Polli A. The Interplay between Oxidative Stress, Exercise, and Pain in Health and Disease: Potential Role of Autonomic Regulation and Epigenetic Mechanisms. Antioxidants (Basel). 2020 Nov 23;9(11):1166. doi: 10.3390/antiox9111166. PMID: 33238564; PMCID: PMC7700330. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700330/ (Full text)

Profile of circulating microRNAs in myalgic encephalomyelitis and their relation to symptom severity, and disease pathophysiology

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic disease, rooted in multi-system dysfunctions characterized by unexplained debilitating fatigue. Post-exertional malaise (PEM), defined as the exacerbation of the patient’s symptoms following minimal physical or mental stress, is a hallmark of ME/CFS. While multiple case definitions exist, there is currently no well-established biomarkers or laboratory tests to diagnose ME/CFS. Our study aimed to investigate circulating microRNA expression in severely ill ME/CFS patients before and after an innovative stress challenge that stimulates PEM. Our findings highlight the differential expression of eleven microRNAs associated with a physiological response to PEM. The present study uncovers specific microRNA expression signatures associated with ME/CFS in response to PEM induction and reports microRNA expression patterns associated to specific symptom severities. The identification of distinctive microRNA expression signatures for ME/CFS through a provocation challenge is essential for the elucidation of the ME/CFS pathophysiology, and lead to accurate diagnoses, prevention measures, and effective treatment options.

Source: Nepotchatykh, E., Elremaly, W., Caraus, I. et al. Profile of circulating microRNAs in myalgic encephalomyelitis and their relation to symptom severity, and disease pathophysiology. Sci Rep 10, 19620 (2020). https://doi.org/10.1038/s41598-020-76438-y https://www.nature.com/articles/s41598-020-76438-y (Full text)

Effect of disease duration in a randomized Phase III trial of rintatolimod, an immune modulator for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Rintatolimod is a selective TLR3 agonist, which has demonstrated clinical activity for ME/CFS in Phase II and Phase III double-blind, placebo-controlled, randomized, multi-site clinical trials.

Methods and findings: A hypothesis-based post-hoc analysis of the Intent to Treat (ITT) population diagnosed with ME/CFS from 12 independent clinical sites of a Phase III trial was performed to evaluate the effect of rintatolimod therapy based on disease duration. The clinical activity of rintatolimod was evaluated by exercise treadmill tolerance (ETT) using a modified Bruce protocol. The ITT population (n = 208) was divided into two subsets of symptom duration. Patients with symptom duration of 2-8 years were identified as the Target Subset (n = 75); the remainder (<2 year plus >8 year) were identified as the Non-Target Subset (n = 133). Placebo-adjusted percentage improvements in exercise duration and the vertical rise for the Target Subset (n = 75) were more than twice that of the ITT population. The Non-Target Subset (n = 133) failed to show any clinically significant ETT response to rintatolimod when compared to placebo. Within the Target Subset, 51.2% of rintatolimod-treated patients improved their exercise duration by ≥25% (p = 0.003) despite reduced statistical power from division of the original ITT population into two subsets.

Conclusion/significance: Analysis of ETT from a Phase III trial has identified within the ITT population, a subset of ME/CFS patients with ≥2 fold increased exercise response to rintatolimod. Substantial improvement in physical performance was seen for the majority (51.2%) of these severely debilitated patients who improved exercise duration by ≥25%. This magnitude of exercise improvement was associated with clinically significant enhancements in quality of life. The data indicate that ME/CFS patients have a relatively short disease duration window (<8 years) to expect a significant response to rintatolimod under the dosing conditions utilized in this Phase III clinical trial. These results may have direct relevance to the cognitive impairment and fatigue being experienced by patients clinically recovered from COVID-19 and free of detectable SARS-CoV-2.

Source: Strayer DR, Young D, Mitchell WM. Effect of disease duration in a randomized Phase III trial of rintatolimod, an immune modulator for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. PLoS One. 2020 Oct 29;15(10):e0240403. doi: 10.1371/journal.pone.0240403. PMID: 33119613. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240403 (Full text)

Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Gulf War Illness affects 25–30% of American veterans deployed to the 1990–91 Persian Gulf War and is characterized by cognitive post-exertional malaise following physical effort. Gulf War Illness remains controversial since cognitive post-exertional malaise is also present in the more common Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An objective dissociation between neural substrates for cognitive post-exertional malaise in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome would represent a biological basis for diagnostically distinguishing these two illnesses.

Here, we used functional magnetic resonance imaging to measure neural activity in healthy controls and patients with Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome during an N-back working memory task both before and after exercise. Whole brain activation during working memory (2-Back > 0-Back) was equal between groups prior to exercise. Exercise had no effect on neural activity in healthy controls yet caused deactivation within dorsal midbrain and cerebellar vermis in Gulf War Illness relative to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients.

Further, exercise caused increased activation among Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients within the dorsal midbrain, left operculo-insular cortex (Rolandic operculum) and right middle insula. These regions-of-interest underlie threat assessment, pain, interoception, negative emotion and vigilant attention. As they only emerge post-exercise, these regional differences likely represent neural substrates of cognitive post-exertional malaise useful for developing distinct diagnostic criteria for Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Source: Stuart D Washington, Rakib U Rayhan, Richard Garner, Destie Provenzano, Kristina Zajur, Florencia Martinez Addiego, John W VanMeter, James N Baraniuk, Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Brain Communications, Volume 2, Issue 2, 2020, fcaa070, https://doi.org/10.1093/braincomms/fcaa070 https://academic.oup.com/braincomms/article/2/2/fcaa070/5885074 (Full text)

Machine Learning Detects Pattern of Differences in Functional Magnetic Resonance Imaging (fMRI) Data between Chronic Fatigue Syndrome (CFS) and Gulf War Illness (GWI)

Abstract:

Background: Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS) are two debilitating disorders that share similar symptoms of chronic pain, fatigue, and exertional exhaustion after exercise. Many physicians continue to believe that both are psychosomatic disorders and to date no underlying etiology has been discovered. As such, uncovering objective biomarkers is important to lend credibility to criteria for diagnosis and to help differentiate the two disorders.

Methods: We assessed cognitive differences in 80 subjects with GWI and 38 with CFS by comparing corresponding fMRI scans during 2-back working memory tasks before and after exercise to model brain activation during normal activity and after exertional exhaustion, respectively. Voxels were grouped by the count of total activity into the Automated Anatomical Labeling (AAL) atlas and used in an “ensemble” series of machine learning algorithms to assess if a multi-regional pattern of differences in the fMRI scans could be detected.

Results: A K-Nearest Neighbor (70%/81%), Linear Support Vector Machine (SVM) (70%/77%), Decision Tree (82%/82%), Random Forest (77%/78%), AdaBoost (69%/81%), Naïve Bayes (74%/78%), Quadratic Discriminant Analysis (QDA) (73%/75%), Logistic Regression model (82%/82%), and Neural Net (76%/77%) were able to differentiate CFS from GWI before and after exercise with an average of 75% accuracy in predictions across all models before exercise and 79% after exercise. An iterative feature selection and removal process based on Recursive Feature Elimination (RFE) and Random Forest importance selected 30 regions before exercise and 33 regions after exercise that differentiated CFS from GWI across all models, and produced the ultimate best accuracies of 82% before exercise and 82% after exercise by Logistic Regression or Decision Tree by a single model, and 100% before and after exercise when selected by any six or more models. Differential activation on both days included the right anterior insula, left putamen, and bilateral orbital frontal, ventrolateral prefrontal cortex, superior, inferior, and precuneus (medial) parietal, and lateral temporal regions. Day 2 had the cerebellum, left supplementary motor area and bilateral pre- and post-central gyri. Changes between days included the right Rolandic operculum switching to the left on Day 2, and the bilateral midcingulum switching to the left anterior cingulum.

Conclusion: We concluded that CFS and GWI are significantly differentiable using a pattern of fMRI activity based on an ensemble machine learning model.

Source: Provenzano D, Washington SD, Rao YJ, Loew M, Baraniuk J. Machine Learning Detects Pattern of Differences in Functional Magnetic Resonance Imaging (fMRI) Data between Chronic Fatigue Syndrome (CFS) and Gulf War Illness (GWI). Brain Sci. 2020;10(7):E456. Published 2020 Jul 17. doi:10.3390/brainsci10070456 https://www.mdpi.com/2076-3425/10/7/456 (Full text)

Post-exertional Symptoms Distinguish Myalgic encephalomyelitis/chronic Fatigue Syndrome Subjects From Healthy Controls

Abstract:

Background: Post-exertional malaise (PEM) is an exacerbation of symptoms that leads to a reduction in functionality. Recognition of PEM is important for the diagnosis and treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Objective: Symptoms following cardiopulmonary exercise testing were compared between ME/CFS patients and healthy controls.

Methods: Open-ended questionnaires were provided to subjects following two maximal exercise tests, 24 hours apart. Subjects evaluated how they felt at five time points. Responses were classified into 19 symptom categories.

Results: ME/CFS subjects (n = 49) reported an average of 14±7 symptoms compared to 4±3 by controls (n = 10). During the seven days afterwards, ME/CFS subjects reported 4±3 symptoms. None were reported by controls. Fatigue, cognitive dysfunction, and sleep problems were reported with the greatest frequency. ME/CFS patients reported more symptom categories at higher frequencies than controls. The largest differences were observed in cognitive dysfunction, decrease in function, and positive feelings.

Conclusions: A standardized exertional stimulus produced prolonged, diverse symptoms in ME/CFS subjects. This provides clues to the underlying pathophysiology of ME/CFS, leading to improved diagnosis and treatment.

Source: Mateo LJ, Chu L, Stevens S, et al. Post-exertional symptoms distinguish myalgic encephalomyelitis/chronic fatigue syndrome subjects from healthy controls [published online ahead of print, 2020 Jun 16]. Work. 2020;10.3233/WOR-203168. doi:10.3233/WOR-203168 https://pubmed.ncbi.nlm.nih.gov/32568143/

Physical Activity Measures in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Correlations Between Peak Oxygen Consumption, the Physical Functioning Scale of the SF-36 Questionnaire, and the Number of Steps From an Activity Meter

Abstract:

Background: Most studies to assess effort intolerance in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have used questionnaires. Few studies have compared questionnaires with objective measures like an actometer or an exercise test. This study compared three measures of physical activity in ME/CFS patients: the physical functioning scale (PFS) of the SF-36, the number of steps/day (Steps) using an actometer, and the %peak VO2 of a cardiopulmonary stress test.

Methods: Female ME/CFS patients were selected from a clinical database if the three types of measurements were available, and the interval between measurements was ≤ 3 months. Data from the three measures were compared by linear regression.

Results: In 99 female patients the three different measures were linearly, significantly, and positively correlated (PFS vs Steps, PFS vs %peak VO2 and Steps vs %peak VO2: all P < 0.001). Subgroup analysis showed that the relations between the three measures were not different in patients with versus without fibromyalgia and with versus without a maximal exercise effort (RER ≥ 1.1). In 20 patients re-evaluated for symptom worsening, the mean of all three measures was significantly lower (P < 0.0001), strengthening the observation of the relations between them. Despite the close correlation, we observed a large variation between the three measures in individual patients.

Conclusions: Given the large variation in ME/CFS patients, the use of only one type of measurement is inadequate. Integrating the three modalities may be useful for patient care by detecting overt discrepancies in activity and may inform studies that compare methods of improving exercise capacity.

Source: van Campen CMC, Rowe PC, Verheugt FWA, Visser FC. Physical activity measures in patients with myalgic encephalomyelitis/chronic fatigue syndrome: correlations between peak oxygen consumption, the physical functioning scale of the SF-36 questionnaire, and the number of steps from an activity meter. J Transl Med. 2020;18(1):228. Published 2020 Jun 8. doi:10.1186/s12967-020-02397-7 https://pubmed.ncbi.nlm.nih.gov/32513266/

Altered muscle membrane potential and redox status differentiates two subgroups of patients with chronic fatigue syndrome

Abstract:

BACKGROUND: In myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), altered membrane excitability often occurs in exercising muscles demonstrating muscle dysfunction regardless of any psychiatric disorder. Increased oxidative stress is also present in many ME/CFS patients and could affect the membrane excitability of resting muscles.

METHODS: Seventy-two patients were examined at rest, during an incremental cycling exercise and during a 10-min post-exercise recovery period. All patients had at least four criteria leading to a diagnosis of ME/CFS. To explore muscle membrane excitability, M-waves were recorded during exercise (rectus femoris (RF) muscle) and at rest (flexor digitorum longus (FDL) muscle). Two plasma markers of oxidative stress (thiobarbituric acid reactive substance (TBARS) and oxidation-reduction potential (ORP)) were measured. Plasma potassium (K+) concentration was also measured at rest and at the end of exercise to explore K+ outflow.

RESULTS: Thirty-nine patients had marked M-wave alterations in both the RF and FDL muscles during and after exercise while the resting values of plasma TBARS and ORP were increased and exercise-induced K+ outflow was decreased. In contrast, 33 other patients with a diagnosis of ME/CFS had no M-wave alterations and had lower baseline levels of TBARS and ORP. M-wave changes were inversely proportional to TBARS and ORP levels.

CONCLUSIONS: Resting muscles of ME/CFS patients have altered muscle membrane excitability. However, our data reveal heterogeneity in some major biomarkers in ME/CFS patients. Measurement of ORP may help to improve the diagnosis of ME/CFS.

Trial registration Ethics Committee “Ouest II” of Angers (May 17, 2019) RCB ID: number 2019-A00611-56.

Source: Jammes Y, Adjriou N, Kipson N, Criado C, Charpin C, Rebaudet S, Stavris C, Guieu R, Fenouillet E, Retornaz F. Altered muscle membrane potential and redox status differentiates two subgroups of patients with chronic fatigue syndrome. J Transl Med. 2020 Apr 19;18(1):173. doi: 10.1186/s12967-020-02341-9. https://www.ncbi.nlm.nih.gov/pubmed/32306967

Unravelling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Gender-specific changes in the microRNA expression profiling in ME/CFS

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem illness characterized by medically unexplained debilitating fatigue with suggested altered immunological state. Our study aimed to explore peripheral blood mononuclear cells (PBMCs) for microRNAs (miRNAs) expression in ME/CFS subjects under an exercise challenge. The findings highlight the immune response and inflammation links to differential miRNA expression in ME/CFS.

The present study is particularly important in being the first to uncover the differences that exist in miRNA expression patterns in males and females with ME/CFS in response to exercise. This provides new evidence for the understanding of differential miRNA expression patterns and post-exertional malaise in ME/CFS.

We also report miRNA expression pattern differences associating with the nutritional status in individuals with ME/CFS, highlighting the effect of subjects’ metabolic state on molecular changes to be considered in clinical research within the NINDS/CDC ME/CFS Common Data Elements.

The identification of gender-based miRNAs importantly provides new insights into gender-specific ME/CFS susceptibility and demands exploration of sex-suited ME/CFS therapeutics.

Source: Cheema AK, Sarria L, Bekheit M, Collado F, Almenar-Pérez E, Martín-Martínez E, Alegre J, Castro-Marrero J, Fletcher MA, Klimas NG, Oltra E, Nathanson L. Unravelling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Gender-specific changes in the microRNA expression profiling in ME/CFS. J Cell Mol Med. 2020 Apr 14. doi: 10.1111/jcmm.15260. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/32291908

Connectivity differences between Gulf War Illness (GWI) phenotypes during a test of attention

Abstract:

One quarter of veterans returning from the 1990–1991 Persian Gulf War have developed Gulf War Illness (GWI) with chronic pain, fatigue, cognitive and gastrointestinal dysfunction. Exertion leads to characteristic, delayed onset exacerbations that are not relieved by sleep. We have modeled exertional exhaustion by comparing magnetic resonance images from before and after submaximal exercise.

One third of the 27 GWI participants had brain stem atrophy and developed postural tachycardia after exercise (START: Stress Test Activated Reversible Tachycardia). The remainder activated basal ganglia and anterior insulae during a cognitive task (STOPP: Stress Test Originated Phantom Perception). Here, the role of attention in cognitive dysfunction was assessed by seed region correlations during a simple 0-back stimulus matching task (“see a letter, push a button”) performed before exercise. Analysis was analogous to resting state, but different from psychophysiological interactions (PPI).

The patterns of correlations between nodes in task and default networks were significantly different for START (n = 9), STOPP (n = 18) and control (n = 8) subjects. Edges shared by the 3 groups may represent co-activation caused by the 0-back task. Controls had a task network of right dorsolateral and left ventrolateral prefrontal cortex, dorsal anterior cingulate cortex, posterior insulae and frontal eye fields (dorsal attention network). START had a large task module centered on the dorsal anterior cingulate cortex with direct links to basal ganglia, anterior insulae, and right dorsolateral prefrontal cortex nodes, and through dorsal attention network (intraparietal sulci and frontal eye fields) nodes to a default module. STOPP had 2 task submodules of basal ganglia–anterior insulae, and dorsolateral prefrontal executive control regions. Dorsal attention and posterior insulae nodes were embedded in the default module and were distant from the task networks.

These three unique connectivity patterns during an attention task support the concept of Gulf War Disease with recognizable, objective patterns of cognitive dysfunction.

Source: Clarke T, Jamieson JD, Malone P, Rayhan RU, Washington S, VanMeter JW, et al. (2019) Connectivity differences between Gulf War Illness (GWI) phenotypes during a test of attention. PLoS ONE 14(12): e0226481. https://doi.org/10.1371/journal.pone.0226481 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226481 (Full text)