The ME Association ME/CFS Research Round-up

November 16, 2020

Emma Northwood, Research Correspondent, ME Association

We show below brief summaries of the research studies about ME/CFS that have recently been published, followed by the abstracts from those studies.

All research relating to ME/CFS can be located in the ME Association: Index of ME/CFS Published Research.

This extensive library of research is updated at the end of each month and is correct to 02 November 2020. It is a free resource and available to anyone.

The Index provides an A-Z of published research studies and 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 in a particular area that you might be interested in, 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 lay explanations of the more important and interesting work that has been published to date.

ME/CFS Research Published 30 Oct – 07 Nov 2020

Eight new research studies were published, and we highlight two of them:

Biomedical understanding

A research group from New Zealand investigated epigenetic patterns distinct to 10 ME/CFS patients compared to 10 age-/sex- matched healthy controls (1).

Despite the small number of participants, and variations in investigative processes to assess the DNA molecules, their results revealed epigenetic changes to 59% of the same genes as other studies.

Genetics and exposure to environmental factors can influence the likelihood of getting ME/CFS.

Behaviours and environmental factors, such viral infection, toxins/chemicals, stressful life events, can affect how your genes work and this is called epigenetics.

Unlike genetic changes, epigenetic changes are reversible and do not change your DNA sequence, but they can change how your body reads DNA sequences.

In particular, differences were found relating to the immune system and mitochondrial functional pathways in the ME/CFS group. Differences in the neurological system – the brain, spinal cord and nerves – were also observed.

“Mitochondria generate most of the chemical energy needed to power the cell’s biochemical reactions.”

The results show strong validation to the importance of different functional pathways in the ME/CFS disease. Many of the specific targets that were identified here can now become the focus in other studies to understand and improve the effects of ME/CFS.


Included in this past week’s published research is a study (2) which has provided more evidence that post-exertional malaise – the worsening of symptoms following even minor physical or mental exertion – should be considered as a top symptom of diagnostic importance for ME/CFS.

By statistically analysing results from several studies (called a meta-analysis) they estimated that ME/CFS sufferers were over 10 times more likely to be affected by post-exertional malaise than healthy controls.

Other research

Also included are several studies on fibromyalgia and a review on ME/CFS immunological and environmental factors. 

A study also brings to light that suicide by ME/CFS sufferers may not be depression-led but due to feeling trapped by the lack of treatments and a loss of self.

ME/CFS Research References and Abstracts

1. Helliwell AM, Sweetman EC, Stockwell PA, Edgar CD, Chatterjee A, Tate WP.
Changes in DNA methylation profiles of myalgic encephalomyelitis /chronic fatigue syndrome patients reflect systemic dysfunctions.
Clinical Epigenetics. 2020 Nov 4;12(1):167

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a lifelong debilitating disease with a complex pathology not yet clearly defined.

Susceptibility to ME/CFS involves genetic predisposition and exposure to environmental factors, suggesting an epigenetic association. Epigenetic studies with other ME/CFS cohorts have used array-based technology to identify differentially methylated individual sites.

Changes in RNA quantities and protein abundance have been documented in our previous investigations with the same ME/CFS cohort used for this study.

Results: DNA from a well-characterised New Zealand cohort of 10 ME/CFS patients and 10 age-/sex-matched healthy controls was isolated from peripheral blood mononuclear (PBMC) cells, and used to generate reduced genome-scale DNA methylation maps using reduced representation bisulphite sequencing (RRBS).

The sequencing data were analysed utilising the DMAP analysis pipeline to identify differentially methylated fragments, and the MethylKit pipeline was used to quantify methylation differences at individual CpG sites. DMAP identified 76 differentially methylated fragments and Methylkit identified 394 differentially methylated cytosines that included both hyper- and hypo-methylation.

Four clusters were identified where differentially methylated DNA fragments overlapped with or were within close proximity to multiple differentially methylated individual cytosines. These clusters identified regulatory regions for 17 protein encoding genes related to metabolic and immune activity.

Analysis of differentially methylated gene bodies (exons/introns) identified 122 unique genes. Comparison with other studies on PBMCs from ME/CFS patients and controls with array technology showed 59% of the genes identified in this study were also found in one or more of these studies.

Functional pathway enrichment analysis identified 30 associated pathways. These included immune, metabolic and neurological-related functions differentially regulated in ME/CFS patients compared to the matched healthy controls.

Conclusions: Major differences were identified in the DNA methylation patterns of ME/CFS patients that clearly distinguished them from the healthy controls.

Over half found in gene bodies with RRBS in this study had been identified in other ME/CFS studies using the same cells but with array technology.

Within the enriched functional immune, metabolic and neurological pathways, a number of enriched neurotransmitter and neuropeptide reactome pathways highlighted a disturbed neurological pathophysiology within the patient group.

2. Brown A, Jason LA.
Meta-analysis investigating post-exertional malaise between patients and controls.
Journal of Health Psychology. 2020 Nov-Dec;25(13-14):2053-2071.

Post-exertional malaise is either required or included in many previously proposed case definitions of myalgic encephalomyelitis/chronic fatigue syndrome.

A meta-analysis of odds ratios (ORs; association between patient status and post-exertional malaise status) and a number of potential moderators (i.e. study-level characteristics) of effect size were conducted.

Post-exertional malaise was found to be 10.4 times more likely to be associated with a myalgic encephalomyelitis/chronic fatigue syndrome diagnosis than with control status. Significant moderators of effect size included patient recruitment strategy and control selection.

These findings suggest that post-exertional malaise should be considered a cardinal symptom of myalgic encephalomyelitis/chronic fatigue syndrome.

3. Devendorf AR, McManimen SL, Jason LA.
Suicidal ideation in non-depressed individuals: The effects of a chronic, misunderstood illness.
Journal of Health Psychology. 2020 Nov-Dec;25(13-14):2106-2117.

Chronic illness is a risk factor for suicide but is often explained with depression. Research has shown an increased suicide rate in patients with myalgic encephalomyelitis and chronic fatigue syndrome, but specific risk factors have been unexplored.

We qualitatively analyzed responses from 29 patients who endorsed suicidal ideation but did not meet depression criteria. Two themes were developed: (1) feeling trapped and (2) loss of self, loss of others, stigma and conflict.

Myalgic encephalomyelitis and chronic fatigue syndrome caused patients severe disability, restructured their lives, and inflicted serious pain.

Participants emphasized that they were not depressed, but felt trapped by the lack of treatments available.

4. Bjørklund G, Dadar M, Pivina L, Doşa MD, Semenova Y, Maes M.
A Review: Environmental, Neuro-immune, and Neuro-oxidative Stress Interactions in Chronic Fatigue Syndrome.
Molecular Neurobiology. 2020 Nov;57(11):4598-4607

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS) is a complex, multisystem disease that is characterized by long-term fatigue, exhaustion, disabilities, pain, neurocognitive impairments, gastrointestinal symptoms, and post-exertional malaise, as well as lowered occupational, educational, and social functions.

The clinical and biomarker diagnosis of this disorder is hampered by the lack of validated diagnostic criteria and laboratory tests with adequate figures of merit, although there are now many disease biomarkers indicating the pathophysiology of CFS.

Here, we review multiple factors, such as immunological and environmental factors, which are associated with CFS and evaluate current concepts on the involvement of immune and environmental factors in the pathophysiology of CFS.

The most frequently reported immune dysregulations in CFS are modifications in immunoglobulin contents, changes in B and T cell phenotypes and cytokine profiles, and decreased cytotoxicity of natural killer cells.

Some of these immune aberrations display a moderate diagnostic performance to externally validate the clinical diagnosis of CFS, including the expression of activation markers and protein kinase R (PKR) activity.

Associated with the immune aberrations are activated nitro-oxidative pathways, which may explain the key symptoms of CFS.

This review shows that viral and bacterial infections, as well as nutritional deficiencies, may further aggravate the immune-oxidative pathophysiology of CFS.

Targeted treatments with antioxidants and lipid replacement treatments may have some clinical efficacy in CFS.

We conclude that complex interactions between immune and nitro-oxidative pathways, infectious agents, environmental factors, and nutritional deficiencies play a role in the pathophysiology of CFS.

5. Pednekar DD, Amin MR, Azgomi HF, Aschbacher K, Crofford LJ, Faghih RT.
Characterization of Cortisol Dysregulation in Fibromyalgia and Chronic Fatigue Syndromes: A State-Space Approach.
IEEE Transactions of Biomedical Engineering. 2020 Nov;67(11):3163-3172.

Objective: Fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS) are complicated medical disorders, with little known etiologies.

The purpose of this research is to characterize FMS and CFS by studying the variations in cortisol secretion patterns, timings, amplitudes, the number of underlying pulses, as well as infusion and clearance rates of cortisol.

Methods: Using a physiological state-space model with plausible constraints, we estimate the hormonal secretory events and the physiological system parameters (i.e., infusion and clearance rates).

Results: Our results show that the clearance rate of cortisol is lower in FMS patients as compared to their matched healthy individuals based on a simplified cortisol secretion model.

Moreover, the number, magnitude, and energy of hormonal secretory events are lower in FMS patients.

During early morning hours, the magnitude and energy of the hormonal secretory events are higher in CFS patients.

Conclusion: Due to lower cortisol clearance rate, there is a higher accumulation of cortisol in FMS patients as compared to their matched healthy subjects.

As the FMS patient accumulates higher cortisol residues, internal inhibitory feedback regulates the hormonal secretory events. Therefore, the FMS patients show a lower number, magnitude, and energy of hormonal secretory events.

Though CFS patients have the same number of secretory events, they secrete lower quantities during early morning hours. When we compare the results for CFS patients against FMS patients, we observe different cortisol alteration patterns.

Significance: Characterizing CFS and FMS based on the cortisol alteration will help us to develop novel methods for treating these disorders.

6. Aakre CA.
Fibromyalgia screening in patients with unexplained chronic fatigue.
Menopause. 2020 Nov 2.

Women often complain of symptoms of fatigue and generalized aches and pains around menopause. Even though fibromyalgia is more prevalent in midlife women, not all women presenting with aches and pain and disrupted sleep meet diagnostic criteria for fibromyalgia.

This Practice Pearl addresses the distinction between chronic fatigue syndrome and fibromyalgia and the management of fibromyalgia in perimenopausal and postmenopausal women.

7. Falaguera-Vera FJ, Garcia-Escudero M, Bonastre-Férez J, Zacarés M, Oltra E.
Pressure Point Thresholds and ME/CFS Comorbidity as Indicators of Patient's Response to Manual Physiotherapy in Fibromyalgia.
International Journal of Environmental Research and Public Health. 2020 Oct 31;17(21):E8044.

Current pharmacological treatments of Fibromyalgia (FM) are merely symptom palliative, as clinical trials have so far failed to provide overall benefits without associated harms.

Polypharmacy often leads to patient's health deterioration and chronic drug use to an eventual lack of patient's response. Emerging evidence supports that physiotherapy treatments based on mechanical triggers improve FM symptoms and therefore could be used for therapeutic purposes by themselves or in combination with current pharmacological treatments, as part of integrative medicine programs.

However, a paucity of studies rigorously and systematically evaluating this possibility exists.

This study uses scores from validated standardized questionnaires, algometer pressure point threshold (PPT) readings and responses from a custom self-developed questionnaire to determine the impact of a pressure-controlled custom manual protocol on FM hyperalgesia/allodynia, fatigue and patient's quality of life.

The results show that patient's baseline sensitivity to pain inversely correlates with treatment response in FM. Moreover, post-stratification analysis unexpectedly reveals that patients presenting comorbid ME/CFS do not seem to respond to the applied therapy as those presenting FM only.

Therefore, pre-treatment PPTs and ME/CFS comorbidity may serve as indicators to predict patient's response to physiotherapy programs based on mechanical triggers.

Further exploration of these findings is granted. In addition, the study of gene expression profiles in the blood collection generated by this study should help unveil the molecular mechanisms behind patient's differential response to manual therapy.

8. Sarzi-Puttini P, Giorgi V, Marotto D, Atzeni F.
Fibromyalgia: an update on clinical characteristics, aetiopathogenesis and treatment.
Nature Reviews Rheumatology. 2020 Nov;16(11):645-660.

Fibromyalgia is characterized by chronic widespread pain, fatigue, sleep disturbances and functional symptoms. The etiopathogenesis, diagnostic criteria and classification criteria of fibromyalgia are still debated and, consequently, so are the strategies for treating this condition.

Fibromyalgia is the third most frequent musculoskeletal condition, and its prevalence increases with age. However, although diagnosis has improved with the evolution of more accurate diagnostic criteria, a considerable proportion of physicians still fail to recognize the syndrome.

Many factors contribute to the development of fibromyalgia in a unique manner: genetic predisposition, personal experiences, emotional-cognitive factors, the mind-body relationship and a biopsychological ability to cope with stress.

The multiple components of the pathogenesis and maintenance of the condition necessitate a multi-modal treatment approach. Individually tailored treatment is an important consideration, with the increasing recognition that different fibromyalgia subgroups exist with different clinical characteristics.

Consequently, although an evidence-based approach to fibromyalgia management is always desirable, the approach of physicians is inevitably empirical, and must have the aim of creating a strong alliance with the patient and formulating shared, realistic treatment goals.

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