Connectivity between Salience and Default Mode Networks and subcortical nodes distinguishes between two classes of ME/CFS

Abstract:

Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease with unknown pathophysiology. Functional MRI (fMRI) studies in ME/CFS have reported disparate connectivities for the brain salience (SA) and default mode (DMN) networks.

In this study, we acquired resting state and task fMRI with an advanced scanner for improved subject numbers: 24 healthy controls (HC) and 42 ME/CFS patients, 18 meeting International Consensus Criteria (ICC) and 24 meeting Fukuda criteria. We evaluated mean FC between SA and DMN network hub, and subcortical regions known to be involved in ME/CFS. We tested the hypothesis that ME/CFS connectivity differed from HC and the ICC and Fukuda classes are distinguished by different connectivities with HC for different pairs of SA, DMN or subcortical hubs.

During resting state fMRI only two connections differed from HC, both for Fukuda ME/CFS and both with an SA hub. During task fMRI 10 ME/CFS connections differed from HC, 5 for ICC and 5 for Fukuda. None were common to both classes. Eight of the 10 different connections involved an SA hub, six of 10 were weaker in ME/CFS, 4 stronger.

SA connections to the hippocampus and brainstem reticular activation system (RAS) differed from and were stronger than HC. The SA mediates the relative activity of the DMN and executive networks and imbalance will have functional consequences. The RAS and hippocampus modulate cortical activation. Different regulatory connections are consistent with the impaired cognitive performance and sleep-wake cycle of ME/CFS. Different neuropathology is involved in ICC and Fukuda classes.

Source: Su J, Thapaliya K, Eaton-Fitch N, Marshall-Gradisnik SM, Barnden LR. Connectivity between Salience and Default Mode Networks and subcortical nodes distinguishes between two classes of ME/CFS. Brain Connect. 2022 Nov 9. doi: 10.1089/brain.2022.0049. Epub ahead of print. PMID: 36352819. https://pubmed.ncbi.nlm.nih.gov/36352819/

Long COVID: mechanisms, risk factors and recovery

Abstract:

New findings: What is the topic of this review? The emerging condition of long COVID, its epidemiology, pathophysiological impacts on patients of different backgrounds, physiological mechanisms emerging as explanations of the condition, and treatment strategies being trialled. The review leads from a Physiological Society online conference on this topic. What advances does it highlight? Progress in understanding the pathophysiology and cellular mechanisms underlying Long COVID and potential therapeutic and management strategies.

Abstract: Long COVID, the prolonged illness and fatigue suffered by a small proportion of those infected with SARS-CoV-2, is placing an increasing burden on individuals and society. A Physiological Society virtual meeting in February 2022 brought clinicians and researchers together to discuss the current understanding of long COVID mechanisms, risk factors and recovery.

This review highlights the themes arising from that meeting. It considers the nature of long COVID, exploring its links with other post-viral illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome, and highlights how long COVID research can help us better support those suffering from all post-viral syndromes. Long COVID research started particularly swiftly in populations routinely monitoring their physical performance – namely the military and elite athletes.

The review highlights how the high degree of diagnosis, intervention and monitoring of success in these active populations can suggest management strategies for the wider population. We then consider how a key component of performance monitoring in active populations, cardiopulmonary exercise training, has revealed long COVID-related changes in physiology – including alterations in peripheral muscle function, ventilatory inefficiency and autonomic dysfunction. The nature and impact of dysautonomia are further discussed in relation to postural orthostatic tachycardia syndrome, fatigue and treatment strategies that aim to combat sympathetic overactivation by stimulating the vagus nerve.

We then interrogate the mechanisms that underlie long COVID symptoms, with a focus on impaired oxygen delivery due to micro-clotting and disruption of cellular energy metabolism, before considering treatment strategies that indirectly or directly tackle these mechanisms. These include remote inspiratory muscle training and integrated care pathways that combine rehabilitation and drug interventions with research into long COVID healthcare access across different populations.

Overall, this review showcases how physiological research reveals the changes that occur in long COVID and how different therapeutic strategies are being developed and tested to combat this condition.

Source: Astin R, Banerjee A, Baker MR, Dani M, Ford E, Hull JH, Lim PB, McNarry M, Morten K, O’Sullivan O, Pretorius E, Raman B, Soteropoulos DS, Taquet M, Hall CN. Long COVID: mechanisms, risk factors and recovery. Exp Physiol. 2022 Nov 22. doi: 10.1113/EP090802. Epub ahead of print. PMID: 36412084. https://physoc.onlinelibrary.wiley.com/doi/10.1113/EP090802 (Full text)

Severe myalgic encephalomyelitis/chronic fatigue syndrome in children and young people: a British Paediatric Surveillance Unit study

Abstract:

Objectives: Primary objective: to determine the point prevalence and incidence rate of severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in children aged 5-16 years over 13 months.

Secondary objectives: to describe the demographic features, symptoms, impact on activities of daily living, school attendance and time to diagnosis.

Design: Prospective surveillance study conducted by the British Paediatric Surveillance Unit. Paediatricians was asked if they had assessed a child with severe ME/CFS (screening definition for prevalence and incidence: children (5-16 years) diagnosed with ME/CFS so severe that they are unable to attend school for more than 1 hour a week during the last 6 weeks of the school term).

Participants: Patients 5-16 years of age, seen by paediatricians and two large ME/CFS specialist services across the UK and Ireland.

Outcome measures: Paediatrician-completed questionnaires describing demographics, symptoms, function and treatment, (applying National Institute for Health and Care Excellence (NICE)-recommended criteria to assess severity of ME/CFS). Diagnosis of severe, probable severe or possible severe ME/CFS was made only with evidence of NICE-recommended screening blood tests.

Results: 285 cases were reported, of which of which 33 were severe, 4 probable severe and 55 possible severe. Estimated prevalence was 3.2 per million children (95% CI 2.2 to 4.5). Including possible/probable severe ME/CFS gave 8.9 per million children (95% CI 7.2 to 11). The incidence rate was 0.90 per million children-years (95% CI 0.43 to 1.65) (1.97 per million children-years (95% CI 1.24 to 2.99)). Median age was 13 years and 58% of cases were female. Median time to diagnosis was 0.47 years.

Conclusions: Although the incidence of children presenting with severe ME/CFS is low, all were very disabled. In addition, the majority receive little or no education. Paediatricians need to consider how to provide rehabilitation and education for these disabled young people.

Source: Royston AP, Rai M, Brigden A, Burge S, Segal TY, Crawley EM. Severe myalgic encephalomyelitis/chronic fatigue syndrome in children and young people: a British Paediatric Surveillance Unit study. Arch Dis Child. 2022 Dec 1:archdischild-2022-324319. doi: 10.1136/archdischild-2022-324319. Epub ahead of print. PMID: 36456114. https://adc.bmj.com/content/early/2022/11/30/archdischild-2022-324319 (Full text)

Muscle sodium content in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Muscle fatigue and pain are key symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Although the pathophysiology is not yet fully understood, there is ample evidence for hypoperfusion which may result in electrolyte imbalance and sodium overload in muscles. Therefore, the aim of this study was to assess levels of sodium content in muscles of patients with ME/CFS and to compare these to healthy controls.

Methods: Six female patients with ME/CFS and six age, BMI and sex matched controls underwent 23Na-MRI of the left lower leg using a clinical 3T MR scanner before and after 3 min of plantar flexion exercise. Sodium reference phantoms with solutions of 10, 20, 30 and 40 mmol/L NaCl were used for quantification. Muscle sodium content over 40 min was measured using a dedicated plugin in the open-source DICOM viewer Horos. Handgrip strength was measured and correlated with sodium content.

Results: Baseline tissue sodium content was higher in all 5 lower leg muscle compartments in ME/CFS compared to controls. Within the anterior extensor muscle compartment, the highest difference in baseline muscle sodium content between ME/CFS and controls was found (mean ± SD; 12.20 ± 1.66 mM in ME/CFS versus 9.38 ± 0.71 mM in controls, p = 0.0034). Directly after exercise, tissue sodium content increased in gastrocnemius and triceps surae muscles with + 30% in ME/CFS (p = 0.0005) and + 24% in controls (p = 0.0007) in the medial gastrocnemius muscle but not in the extensor muscles which were not exercised. Compared to baseline, the increase of sodium content in medial gastrocnemius muscle was stronger in ME/CFS than in controls with + 30% versus + 17% to baseline at 12 min (p = 0.0326) and + 29% versus + 16% to baseline at 15 min (p = 0.0265). Patients had reduced average handgrip strength which was associated with increased average muscle tissue sodium content (p = 0.0319, R2 = 0.3832).

Conclusion: Muscle sodium content before and after exercise was higher in ME/CFS than in healthy controls. Furthermore, our findings indicate an inverse correlation between muscle sodium content and handgrip strength. These findings provide evidence that sodium overload may play a role in the pathophysiology of ME/CFS and may allow for potential therapeutic targeting.

Source: Petter E, Scheibenbogen C, Linz P, Stehning C, Wirth K, Kuehne T, Kelm M. Muscle sodium content in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Transl Med. 2022 Dec 9;20(1):580. doi: 10.1186/s12967-022-03616-z. PMID: 36494667. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03616-z (Full text)

Mild SARS-CoV-2 infection results in long-lasting microbiota instability

Abstract:

Viruses targeting mammalian cells can indirectly alter the gut microbiota, potentially compounding their phenotypic effects. Multiple studies have observed a disrupted gut microbiota in severe cases of SARS-CoV-2 infection that require hospitalization. Yet, despite demographic shifts in disease severity resulting in a large and continuing burden of non-hospitalized infections, we still know very little about the impact of mild SARS-CoV-2 infection on the gut microbiota in the outpatient setting. To address this knowledge gap, we longitudinally sampled 14 SARS-CoV-2 positive subjects who remained outpatient and 4 household controls. SARS-CoV-2 cases exhibited a significantly less stable gut microbiota relative to controls, as long as 154 days after their positive test. These results were confirmed and extended in the K18-hACE2 mouse model, which is susceptible to SARS-CoV-2 infection. All of the tested SARS-CoV-2 variants significantly disrupted the mouse gut microbiota, including USA-WA1/2020 (the original variant detected in the United States), Delta, and Omicron. Surprisingly, despite the fact that the Omicron variant caused the least severe symptoms in mice, it destabilized the gut microbiota and led to a significant depletion in Akkermansia muciniphila. Furthermore, exposure of wild-type C57BL/6J mice to SARS-CoV-2 disrupted the gut microbiota in the absence of severe lung pathology.

IMPORTANCE Taken together, our results demonstrate that even mild cases of SARS-CoV-2 can disrupt gut microbial ecology. Our findings in non-hospitalized individuals are consistent with studies of hospitalized patients, in that reproducible shifts in gut microbial taxonomic abundance in response to SARS-CoV-2 have been difficult to identify. Instead, we report a long-lasting instability in the gut microbiota. Surprisingly, our mouse experiments revealed an impact of the Omicron variant, despite producing the least severe symptoms in genetically susceptible mice, suggesting that despite the continued evolution of SARS-CoV-2 it has retained its ability to perturb the intestinal mucosa. These results will hopefully renew efforts to study the mechanisms through which Omicron and future SARS-CoV-2 variants alter gastrointestinal physiology, while also considering the potentially broad consequences of SARS-CoV-2-induced microbiota instability for host health and disease.

Source: Vaibhav Upadhyay, Rahul Suryawanshi, Preston Tasoff, Maria McCavitt-Malvido, G. Renuka Kumar, Victoria Wong Murray, Cecilia Noecker, Jordan E. Bisanz, Yulin Hswen, Connie Ha, Bharat Sreekumar, Irene P. Chen, Susan V Lynch, Melanie Ott, Sulggi Lee, Peter J. Turnbaugh. Mild SARS-CoV-2 infection results in long-lasting microbiota instability. bioRxiv 2022.12.07.519508; doi: https://doi.org/10.1101/2022.12.07.519508  https://www.biorxiv.org/content/10.1101/2022.12.07.519508v1.full (Full text)

Investigating undergraduate medical education on myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background and Objectives: ME/CFS is a poorly understood, highly stigmatised condition which significantly reduces patients’ quality of life. ME/CFS had been identified as a gap in many health professionals’ knowledge, therefore this research aims to explore the understanding of ME/CFS amongst UK medical students.

Methods: An online survey developed using Redcap was distributed to participants who were recruited via social media or via medical societies’ emails. The participants were undergraduate UK medical students.

Results: 94 students completed the survey from more than 16 medical schools. 35% of the students did not know what ME/CFS is and 88% say that the disease has not been covered in their course so far. 89% of participants would like to learn more about ME/CFS, specifically through elearning and videos.

Discussion: Participants were generally unaware of ME/CFS and its symptoms and had not received relevant teaching or exposure to the disease. Education on ME/CFS within undergraduate UK medical schools is currently inadequate and the interest expressed by students in this survey demonstrates a new teaching opportunity for UK medical schools.

Source: Victoria Alice Reid and Nina Muirhead.Investigating undergraduate medical education on myalgic encephalomyelitis/chronic fatigue syndrome. The British Student Doctor Journal (BSDJ), Cardiff University Press, Year: 2022, Volume: 6 Issue: 1, Page/Article: 35-40. https://thebsdj.cardiffuniversitypress.org/articles/308 (Full text available as PDF file)

Brain fog of post-COVID-19 condition and Chronic Fatigue Syndrome, same medical disorder?

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is characterized by persistent physical and mental fatigue. The post-COVID-19 condition patients refer physical fatigue and cognitive impairment sequelae. Given the similarity between both conditions, could it be the same pathology with a different precipitating factor?

Objective: To describe the cognitive impairment, neuropsychiatric symptoms, and general symptomatology in both groups, to find out if it is the same pathology. As well as verify if the affectation of smell is related to cognitive deterioration in patients with post-COVID-19 condition.

Methods: The sample included 42 ME/CFS and 73 post-COVID-19 condition patients. Fatigue, sleep quality, anxiety and depressive symptoms, the frequency and severity of different symptoms, olfactory function and a wide range of cognitive domains were evaluated.

Results: Both syndromes are characterized by excessive physical fatigue, sleep problems and myalgia. Sustained attention and processing speed were impaired in 83.3% and 52.4% of ME/CFS patients while in post-COVID-19 condition were impaired in 56.2% and 41.4% of patients, respectively. Statistically significant differences were found in sustained attention and visuospatial ability, being the ME/CFS group who presented the worst performance. Physical problems and mood issues were the main variables correlating with cognitive performance in post-COVID-19 patients, while in ME/CFS it was anxiety symptoms and physical fatigue.

Conclusions: The symptomatology and cognitive patterns were similar in both groups, with greater impairment in ME/CFS. This disease is characterized by greater physical and neuropsychiatric problems compared to post-COVID-19 condition. Likewise, we also propose the relevance of prolonged hyposmia as a possible marker of cognitive deterioration in patients with post-COVID-19.

Source: Azcue N, Gómez-Esteban JC, Acera M, Tijero B, Fernandez T, Ayo-Mentxakatorre N, Pérez-Concha T, Murueta-Goyena A, Lafuente JV, Prada Á, López de Munain A, Ruiz-Irastorza G, Ribacoba L, Gabilondo I, Del Pino R. Brain fog of post-COVID-19 condition and Chronic Fatigue Syndrome, same medical disorder? J Transl Med. 2022 Dec 6;20(1):569. doi: 10.1186/s12967-022-03764-2. PMID: 36474290. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03764-2 (Full text)

Impaired pulmonary and muscle function during moderate exercise in female patients recovered from SARS-CoV-2

Abstract:

This study aimed to assess pulmonary and muscle dysfunction by analyzing the slow component of oxygen uptake (VO2SC), and mechanical and ventilatory efficiency in adult women recovered from the severe acute respiratory syndrome coronavirus type II (SARS-CoV-2) during a constant load test. 32 women (N = 17 patients with SARS-CoV-2; N = 15 control group) performed two cardiopulmonary exercise tests (CPX) on a cycle ergometer.

In the first test, the participants performed incremental CPX until extenuation. In the second test the participants performed a 10-min CPX at a constant load intensity (watts) corresponding to the first ventilatory threshold. There was a 48-72 h rest period between the two tests. There was a significant increase in the VO2SC in the patients recovered from SARS-CoV-2 (160.4 ± 60 mL min-1) in comparison with the healthy participants (59.6 ± 65 mL min-1) (P < 0.001).

Mechanical efficiency significantly decreased in patients recovered from SARS-CoV-2 compared to the control group (P = 0.04). Ventilatory inefficiency significantly increased in the patients recovered from SARS-CoV-2 compared with the control group (P < 0.001). Adult women recovered from SARS-CoV-2 infection have important pulmonary and muscular dysfunction and fatigue which contributes to increasing the VO2SC and reducing mechanical and ventilatory efficiency during mild-moderate exercise at a constant load.

Source: Pleguezuelos E, Del Carmen A, Moreno E, Ortega P, Robles A, Serra-Prat M, Miravitlles M, Yebenes JC, Garnacho-Castaño MV. Impaired pulmonary and muscle function during moderate exercise in female patients recovered from SARS-CoV-2. Sci Rep. 2022 Dec 4;12(1):20943. doi: 10.1038/s41598-022-24941-9. PMID: 36464697.  https://www.nature.com/articles/s41598-022-24941-9 (Full text)

Tissue specific signature of HHV-6 infection in ME/CFS

Abstract:

First exposure to various human herpesviruses (HHVs) including HHV-6, HCMV and EBV does not cause a life-threatening disease. In fact, most individuals are frequently unaware of their first exposure to such pathogens. These herpesviruses acquire lifelong latency in the human body where they show minimal genomic activity required for their survival. We hypothesized that it is not the latency itself but a timely, regionally restricted viral reactivation in a sub-set of host cells that plays a key role in disease development.

HHV-6 (HHV-6A and HHV-6B) and HHV-7 are unique HHVs that acquire latency by integration of the viral genome into sub-telomeric region of human chromosomes. HHV-6 reactivation has been linked to Alzheimer’s Disease, Chronic Fatigue Syndrome, and many other diseases. However, lack of viral activity in commonly tested biological materials including blood or serum strongly suggests tissue specific localization of active HHV-6 genome.

Here in this paper, we attempted to analyze active HHV-6 transcripts in postmortem tissue biopsies from a small cohort of ME/CFS patients and matched controls by fluorescence in situ hybridization using a probe against HHV-6 microRNA (miRNA), miR-aU14. Our results show abundant viral miRNA in various regions of the human brain and associated neuronal tissues including the spinal cord that is only detected in ME/CFS patients and not in controls.

Our findings provide evidence of tissue-specific active HHV-6 and EBV infection in ME/CFS, which along with recent work demonstrating a possible relationship between herpesvirus infection and ME/CFS, provide grounds for renewed discussion on the role of herpesviruses in ME/CFS.

Source: Prusty, Bhupesh K.; Kasimir, Francesca; Toomey, Danny; Liu, Zheng; Agnes Kaiping and Ariza, Maria Eugenia. Tissue specific signature of HHV-6 infection in ME/CFS. Front. Mol. Biosci. Sec. Molecular Diagnostics and Therapeutics. doi: 10.3389/fmolb.2022.1044964 https://www.frontiersin.org/articles/10.3389/fmolb.2022.1044964/abstract

Molecular and cellular similarities in the brain of SARS-CoV-2 and Alzheimer’s disease individuals

Abstract:

Infection with the etiological agent of COVID-19, SARS-CoV-2, appears capable of impacting cognition, which some patients with Post-acute Sequelae of SARS-CoV-2 (PASC). To evaluate neuro-pathophysiological consequences of SARS-CoV-2 infection, we examine transcriptional and cellular signatures in the Broadman area 9 (BA9) of the frontal cortex and the hippocampal formation (HF) in SARS-CoV-2, Alzheimer’s disease (AD) and SARS-CoV-2 infected AD individuals, compared to age- and gender-matched neurological cases. Here we show similar alterations of neuroinflammation and blood-brain barrier integrity in SARS-CoV-2, AD, and SARS-CoV-2 infected AD individuals. ‘

Distribution of microglial changes reflected by the increase of Iba-1 reveal nodular morphological alterations in SARS-CoV-2 infected AD individuals. Similarly, HIF-1α is significantly upregulated in the context of SARS-CoV-2 infection in the same brain regions regardless of AD status. The finding may help to inform decision-making regarding therapeutic treatments in patients with neuro-PASC, especially those at increased risk of developing AD.

Source: Griggs E, Trageser K, Naughton S, Yang EJ, Mathew B, Van Hyfte G, Hellmers L, Jette N, Estill M, Shen L, Fischer T, Pasinetti GM. Molecular and cellular similarities in the brain of SARS-CoV-2 and Alzheimer’s disease individuals. bioRxiv [Preprint]. 2022 Nov 23:2022.11.23.517706. doi: 10.1101/2022.11.23.517706. PMID: 36451886; PMCID: PMC9709800. https://www.biorxiv.org/content/10.1101/2022.11.23.517706v1.full (Full text)