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Research Digest 04/09/20

Welcome to the 54th Emerge Australia Research Digest, where you will find summaries of some of the latest research and information about ME/CFS, with links to the complete articles.

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Brain Responses in CFS and TMD to Autonomic Challenges: An Exploratory fMRI Study

Authors: Vuong QC, Allison JR, Finkelmeyer A, Newton J, Durham J

Despite the complexity of ME/CFS, most patients have associated autonomic nervous system (ANS) dysfunction which may contribute to pain and fatigue. The purpose of this exploratory study was to test whether patients with ME/CFS with or without temporomandibular disorder (TMD) show differences in brain responses to autonomic challenges.

This study included 52 participants: ME/CFS patients (diagnosed according to the Fukuda criteria) who were classified as either screening positive (CFS+, n=26), or negative (CFS-, n=16) for TMD, and healthy age-matched controls (n=10). Participants were assessed by exploratory functional magnetic resonance imaging (fMRI) to determine brain responses to the Valsalva manoeuvre, a breathing technique used to assess autonomic functioning. 

For all three groups, there was increased brain activation during the manoeuvre in the superior and inferior frontal gyri, the left and right putamen and thalamus, and the insular cortex. CFS+ participants showed greater activity in the left insular cortex as compared with CFS- participants. There were no clusters in which CFS- participants had a larger response than CFS+ participants. CFS+ participants also had greater activity in the left caudate nucleus compared with controls.

The authors conclude that the increased activity in the cortical and subcortical regions observed during autonomic challenges may be modulated by fatigue and pain, and ANS dysfunction may be a contributing factor to these findings. Autonomic dysfunction may play a role in the pathophysiology of both ME/CFS and TMD, explain some of the apparent comorbidity between them and offer avenues to help with treatment.

Autoantibodies to Beta-Adrenergic and Muscarinic cholinergic receptors in Myalgic Encephalomyelitis (ME) patients – a validation study in plasma and cerebrospinal fluid from two Swedish cohorts

Authors: Bynke A, Julin P, Gottfries C, Heidecke H, Scheibenbogen C, Bergquist J

This study aimed to replicate previous findings by the same authors of increased autoantibodies to adrenergic and muscarinic receptors in ME/CFS. The authors also aimed to examine if elevated autoantibodies are present in cerebrospinal fluid (CSF) and to explore if there is a relationship between autoantibody levels and illness severity. 
The study included 48 ME/CFS patients (who met the Canadian Consensus Criteria, International Consensus Criteria and Institute of Medicine criteria) from two Swedish clinics (24 ME/CFS patients from each clinic), and 24 age and gender matched controls. Blood and CSF samples were taken from each patient, and autoantibodies for Alpha- (α1 and α2) and Beta- (β1, β2, β3) adrenergic receptors and muscarinic (M1-5) receptors measured. 

Significant increases in autoantibody levels in ME/CFS patients compared to healthy controls were found for M3 and M4 receptors in both cohorts, and β1, β2, M3 and M4 receptors in one cohort. These results support these authors’ previous findings of elevated autoantibodies to adrenergic and muscarinic receptors in ME/CFS patients. 

However, no significant correlations were detected between autoantibody levels and disease severity, and no significant levels of autoantibodies were detected in the CSF samples.

The authors conclude that there is a general pattern of increased autoantibodies of adrenergic and muscarinic receptors for ME/CFS patients but whether these autoantibodies play a role in the pathogenesis of ME/CFS requires more research.

Review of case definitions for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Authors: Lim E, Son C

This literature review summarised the history, developments and differential symptoms in the case definitions of ME/CFS, and provided a summary of key similarities and differences between different definitions of ME/CFS.
Since 1986, 25 different definitions of ME/CFS have been developed. Of these, the review identified the eight most prominent definitions: (in descending order): Fukuda, Holmes, Oxford, Canadian Consensus Criteria (CCC), International Consensus Criteria (ICC), Australian, Ramsay, and systemic and exertion intolerance disorder (SEID). The researchers divided these definitions into four main categories: ME (ICC, Ramsay), ME/CFS (CCC), CFS (Australian, Oxford, Fukuda, and Holmes), and SEID.

Each case definition is generally comprised of three categories: required conditions, inclusions, and exclusionary symptoms/disorders.

The eight prominent definitions share four core symptoms: orthostatic intolerance, post-exertional malaise, cognitive impairment, and sleep disturbance. However there were also differences between the definitions. CFS and SEID definitions focused on fatigue and cognitive impairment, while ME and ME/CFS also emphasised muscle weakness and neurological symptoms.

Figure 1. Scope of ME/CFS symptoms by case definitions. CFS, chronic fatigue syndrome, IOM, Institute of Medicine. SEID, systemic exertion intolerance disorder. ME myalgic encephalitis, CCC Canadian Consensus Criteria, ICC International Consensus Criteria, GI gastro-intestinal, GU genito-urinary symptoms.

Cognitive Function Declines Following Orthostatic Stress in Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Authors: van Campen CLMC, Rowe PC, Verheugt FWA, Visser FC

Cognitive impairment and orthostatic intolerance (OI) are common symptoms in people with ME/CFS. This study aimed to study cognitive function in people with ME/CFS after the completion of a head-up tilt test (HUT) which induces OI.

128 ME/CFS patients participated in the study. Participants were included if they met both the Fukuda criteria and International Consensus Criteria (ICC) and undertook a HUT to screen for OI. The severity of disease ranged from mild (n=49, 38%) to moderate (n=55, 43%) and severe (24, 19%), as defined by the ICC. Cognitive function was assessed using the N-Back test which measures working memory and relies on information processing speed, commonly reported to be slowed in ME/CFS. The test measures speed and accuracy of responses to visual stimuli. Participants were assessed on the N-Back test before and after they underwent the HUT. 

There was a significant deterioration in cognitive function following orthostatic stress testing, as evidenced by a reduction in accuracy and increased reaction time on the N-Back test following the HUT. There was no significant difference in N-back results based on disease severity.

The authors conclude that orthostatic stress impairs working memory in adults with ME/CFS and also suggest that post-exertional malaise may start immediately after orthostatic stress.

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