The ME Association ME/CFS (& Long Covid) Weekly Research Round-up

July 9, 2021

The weekly research round-up now includes recent publications about ME/CFS and about Long Covid. We highlight several studies that have particularly caught our interest and follow these with the full list of publications together with their abstracts (summaries).

All research relating to ME/CFS can be located in the ME Association: Index of ME/CFS Published Research. It is a free resource and available to anyone.

This extensive library of research is normally updated at the end of each month, but with the change in staff, it will be updated again by 01 August 2021.

The Index provides an A-Z of published research studies, selected key documents and articles, listed by subject matter, on myalgic encephalomyelitis, myalgic encephalopathy, and/or chronic fatigue syndrome (ME/CFS).

You can use it to easily locate and read any research that you might be interested in regard to, e.g., epidemiology, infection, neurology, post-exertional malaise etc.

You can also find the Research Index in the Research section of the website together with a list of Research Summaries that provide more detailed lay explanations of the more interesting work that has been published to date.

ME/CFS Research Published 26 June – 2 July 2021

Seven new research studies on ME/CFS have been published during this period and we have also included ten studies on Long Covid. We highlight two on ME/CFS from the selection below: 

The second paper (2) examined the use of melatonin plus Zinc in ME/CFS as currently no approved drugs are available to treat the condition. This proof-of-concept, 16-week, randomised, placebo-controlled, double-blind trial assessed fatigue, sleep disturbances, anxiety/depression, and health-related quality of life. 

It involved 50 people with ME/CFS (some who had a placebo) and found a significant reduction in the perception of physical fatigue in those who had the melatonin plus Zinc. The findings from the study suggest that treatment for 16 weeks is safe and potentially effective in reducing fatigue and improving quality of life – although no objective outcomes were measured.  

The sixth paper (6) reviewed current knowledge of ME/CFS, confirming that difficulty in ME/CFS management has stemmed from a lack of a concrete understanding of its etiology and pathogenesis

It reviewed the potential association between dysfunction of the autoimmune, neuroendocrine, or autonomic nervous systems and the development of ME/CFS. The authors also examined the treatment options available and conclude that our understanding is still evolving. 

ME/CFS Research References and Abstracts 

1. Bioenergetic and Proteomic Profiling of Immune Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients: An Exploratory Study 

Fernandez-Guerra P, Gonzalez-Ebsen AC, Boonen SE, Courraud J, Gregersen N, Mehlsen J, Palmfeldt J, Olsen RKJ, Brinth LS. Biomolecules. 2021 Jun 29;11(7):961. 


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous, debilitating, and complex disease. Along with disabling fatigue, ME/CFS presents an array of other core symptoms, including autonomic nervous system (ANS) dysfunction, sustained inflammation, altered energy metabolism, and mitochondrial dysfunction.

Here, we evaluated patients' symptomatology and the mitochondrial metabolic parameters in peripheral blood mononuclear cells (PBMCs) and plasma from a clinically well-characterised cohort of six ME/CFS patients compared to age- and gender-matched controls.

We performed a comprehensive cellular assessment using bioenergetics (extracellular flux analysis) and protein profiles (quantitative mass spectrometry-based proteomics) together with self-reported symptom measures of fatigue, ANS dysfunction, and overall physical and mental well-being.

This ME/CFS cohort presented with severe fatigue, which correlated with the severity of ANS dysfunction and overall physical well-being. PBMCs from ME/CFS patients showed significantly lower mitochondrial coupling efficiency. They exhibited proteome alterations, including altered mitochondrial metabolism, centred on pyruvate dehydrogenase and coenzyme A metabolism, leading to a decreased capacity to provide adequate intracellular ATP levels.

Overall, these results indicate that PBMCs from ME/CFS patients have a decreased ability to fulfil their cellular energy demands.  

2. Effect of Melatonin Plus Zinc Supplementation on Fatigue Perception in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial  

Castro-Marrero J, Zaragozá MC, López-Vílchez I, Galmés JL, Cordobilla B, Maurel S, Domingo JC, Alegre-Martín J. Antioxidants (Basel, Switzerland). 2021 Jun 23;10(7):1010. 


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystem, and profoundly debilitating condition, probably of multifactorial etiology. No effective approved drugs are currently available for its treatment.

Several studies have proposed symptomatic treatment with melatonin and zinc supplementation in chronic illnesses; however, little is known about the synergistic effect of this treatment on fatigue-related symptoms in ME/CFS.

The primary endpoint of the study was to assess the effect of oral melatonin plus zinc supplementation on fatigue in ME/CFS. Secondary measures included participants' sleep disturbances, anxiety/depression, and health-related quality of life.

A proof-of-concept, 16-week, randomized, placebo-controlled, double-blind trial was conducted in 50 ME/CFS patients assigned to receive either oral melatonin (1 mg) plus zinc (10 mg) supplementation (n = 24) or matching placebo (n = 26) once daily. Endpoint outcomes were evaluated at baseline, and then reassessed at 8 and 16 weeks of treatment and 4 weeks after treatment cessation, using self-reported outcome measures.

The most relevant results were the significant reduction in the perception of physical fatigue in the Mel-Zinc group at the final treatment follow-up versus placebo (p < 0.05), and the significant improvement in the physical component summary at all follow-up visits in the experimental group.

Urinary 6-sulfatoxymelatonin levels were significantly elevated though the treatment in experimental group vs. placebo (p < 0.0001); however, no significant differences were observed for zinc concentration among participants.

Our findings suggest that oral melatonin plus zinc supplementation for 16 weeks is safe and potentially effective in reducing fatigue and improving the quality of life in ME/CFS.

This clinical study was registered on (NCT03000777).  

3. Subcortical brain segment volumes in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 

Addiego FM, Zajur K, Knack S, Jamieson J, Rayhan RU, Baraniuk JN. Life Sci. 2021 Jun 29:119749. [Epub ahead of print.] 


Aims:There is controversy about brain volumes in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (CFS) and Gulf War Illness (GWI). Subcortical regions were assessed because of significant differences in blood oxygenation level dependent signals in the midbrain between these diseases. 

Materials and method:Magnetization-prepared rapid acquisition with gradient echo (MPRAGE) images from 3 Tesla structural magnetic resonance imaging scans from sedentary control (n = 34), CFS (n = 38) and GWI (n = 90) subjects were segmented in FreeSurfer. Segmented subcortical volumes were regressed against intracranial volume and age, then iteratively analyzed by multivariate general linear modeling with disease status, gender, and demographics as independent co-variates. 

Key findings:The optimal model for all subjects used disease status and gender as fixed factors with independent variables eliminated after iteration. Volumes of anterior and midanterior corpus callosum were significantly larger in GWI than CFS. Gender was a significant variable for many segment volumes, and so female and male subjects were analyzed separately. CFS females had smaller left putamen, right caudate and left cerebellum white matter than control women. CFS males had larger left hippocampus than GWI males. Orthostatic status and posttraumatic distress syndrome were not significant covariates. 

Significance:CFS and GWI were appropriate “illness controls” for each other. The different patterns of adjusted segment volumes suggested that sexual dimorphisms contributed to pathological changes. Previous volumetric studies may need to be re-evaluated to account for gender differences. The findings are framed by comparison to the spectrum of magnetic resonance imaging outcomes in the literature.  

4. Changes in the Allostatic Response to Whole-Body Cryotherapy and Static-Stretching Exercises in Chronic Fatigue Syndrome Patients vs. Healthy Individuals 

Kujawski S, Bach AM, Słomko J, Pheby DFH, Murovska M, Newton JL, Zalewski P.  J Clin Med. 2021 Jun 25;10(13):2795. 


This study represents a comparison of the functional interrelation of fatigue and cognitive, cardiovascular, and autonomic nervous systems in a group of Chronic Fatigue Syndrome (CFS) patients compared with those in healthy individuals at different stages of analysis: at baseline and after changes induced by whole-body cryotherapy (WBC) combined with a static-stretching (SS) program.

The study included 32 patients (Fukuda criteria) and 18 healthy controls. Fatigue, cognitive, cardiovascular, and autonomic function, and arterial stiffness were measured before and after 10 sessions of WBC with SS.

In the patients, a disturbance in homeostasis was observed. The network relationship based on differences before and after intervention showed comparatively higher stress and eccentricity in the CFS group: 50.9 ± 56.1 vs. 6.35 ± 8.72, p = 0.002, r = 0.28; and 4.8 ± 0.7 vs. 2.4 ± 1, p < 0.001, r = 0.46, respectively.

Before and after intervention, in the CFS group increased fatigue was related to baroreceptor function, and baroreceptor function was in turn related to aortic stiffness, but no such relationships were observed in the control group.

Differences in the network structure underlying the interrelation among the four measured criteria were observed in both groups, before the intervention and after ten sessions of whole cryotherapy with a static stretching exercise. 

5. Parent-child discrepancies in health-related quality of life of children and adolescents with myalgic encephalomyelitis/chronic fatigue syndrome 

Ekberg, K.M., Torres, C. & Jason, L.A. Qual Life Res (2021). 


Purpose: Few studies have examined parent-child discrepancies on self-report measures of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptomatology and health-related quality of life (HRQOL). The aim of this study was to investigate parent-child reporting discrepancies between a pediatric sample of diagnosed patients with ME/CFS and controls to better understand the role of children and adolescent reporting. 

Method: Data for this study were drawn from a community-based epidemiological study of pediatric ME/CFS in the Chicagoland area. A total of 147 parent-child dyads (75 pairs with ME/CFS and 72 control pairs) completed measures assessing HRQOL and ME/CFS symptomatology. At the individual level, agreement was assessed using intra-class correlation coefficient (ICC) scores. Agreement was measured at the group level by a comparison of means using paired-sample t-tests. 

Results: Intra-class correlations revealed varied agreement in both parent-child pairs of children who met at least one case definition of ME/CFS and in parent-child pairs in the control group. 

Conclusion:The current study provides support for the existence of discrepancies between parent-child reports of ME/CFS symptomatology and HRQOL measures. Limitations and future directions are discussed.  

6. A Comprehensive Update of the Current Understanding of Chronic Fatigue Syndrome 

Noor N , Urits I, Degueure A , Rando L , Kata V , Cornett EM, Kaye AD, Imani F, Narimani-Zamandabadi M, Varrassi G, Viswanathm O. Anesth Pain Med.11(3):e113629. 


This is a comprehensive literature review of chronic fatigue syndrome (CFS). We provide a description of the background, etiology, pathogenesis, diagnosis, and management regarding CFS. CFS is a multifaceted illness that has many symptoms and a wide array of clinical presentations. As of recent, CFS has been merged with myalgic encephalomyelitis (ME).

Much of the difficulty in its management has stemmed from a lack of a concrete understanding of its etiology and pathogenesis. There is a potential association between dysfunction of the autoimmune, neuroendocrine, or autonomic nervous systems and the development of CFS.

Possible triggering events, such as infections followed by an immune dysregulation resulting have also been proposed. In fact, ME/CFS was first described following Epstein Barr virus (EBV) infections, but it was later determined that it was not always preceded by EBV infection.

Patient diagnosed with CFS have shown a noticeably earlier activation of anaerobic metabolism as a source of energy, which is suggestive of impaired oxygen consumption.

The differential diagnoses range from tick-borne illnesses to psychiatric disorders to thyroid gland dysfunction. Given the many overlapping symptoms of CFS with other illnesses makes diagnosing it far from an easy task. The Centers for Disease Control and Prevention (CDC) considers it a diagnosing of exclusion, stating that self-reported fatigue for at minimum of six months and four of the following symptoms are necessary for a proper diagnosis: memory problems, sore throat, post-exertion malaise, tender cervical or axillary lymph nodes, myalgia, multi-joint pain, headaches, and troubled sleep.

 In turn, management of CFS is just as difficult. Treatment ranges from conservative, such as cognitive behavioral therapy (CBT) and antidepressants, to minimally invasive management. Minimally invasive management involving ranscutaneous electrical acupoint stimulation of target points has demonstrated significant improvement in fatigue and associated symptoms in a 2017 randomized controlled study.

The understanding of CFS is evolving before us as we continue to learn more about it. As further reliable studies are conducted, providing a better grasp of what the syndrome encompasses, we will be able to improve our diagnosis and management of it.  

7. Central Autonomic Network Disturbance in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: A Pilot Study 

Zinn MA, Zinn ML, Jason LA NeuroRegulation, 8(20), &3-86. (2021) 


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease of the central nervous system known to be associated with multiple behavioral symptoms (fatigue, low stamina, dizziness, etc.) combined with autonomic nervous system (ANS) dysfunction, thus implicating the central autonomic network (CAN). 

Post exertional malaise (PEM) is a core feature of ME/CFS, characterized by a pathological reduction in stamina in response to performing minor physical or mental tasks, often lasting at least 24 hours. 

Exact low -resolution electromagnetic tomography (eLORETA) allows non-invasive investigation of cortical regions of interest that may contribute to better understanding of the role of the brain disturbances in behavioral manifestations of PEM.

This pilot study therefore aimed to use eLORETA to characterize changes in current density in cortical structures related to the CAN following submaxima l isometric handgrip exercise in seven patients with ME/CFS and six neurotypical healthy controls (HCs).

Resting EEG was recorded at pre- and post- handgrip, and 24 hours later. Findings showed that significant differences occurred immediately post-test, which were most pronounced after 24 hours, particularly in the low alpha (8 –10 Hz) and low beta (13 –18 Hz) frequency sub bands.

Together, the present findings offer support for EEG source localization techniques to investigate PEM. If confirmed, this study could provide a useful instrument for aiding functional diagnosis and evaluation of treatment outcomes. 

Long-COVID Research References  

  1. Avascular necrosis as a part of ‘long COVID-19' 
  2. Covid-19: Long covid cases are underreported in GP records, research suggests 
  3. Somatic symptom disorders and long COVID: A critical but overlooked topic 
  4. Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation 
  5. Altered Vascular Endothelium-Dependent Responsiveness in Frail Elderly Patients Recovering from COVID-19 Pneumonia: Preliminary Evidence 
  6. Risk factors for long covid in previously hospitalised children using the ISARIC Global follow-up protocol: A prospective cohort study 
  7. The Impact of Post-COVID-19 Syndrome on Self-Reported Physical Activity 
  8. The Neurological Manifestations of Post-Acute Sequelae of SARS-CoV-2 Infection 
  9. The Long COVID: a new challenge for gender-specific medicine? 
  10. Getting to grips with long covid 

Katrina Pears, Research Correspondent, ME Association

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