homeostatic failure – American ME and CFS Society

Chronic inflammation, neuroglial dysfunction, and plasmalogen deficiency as a new pathobiological hypothesis addressing the overlap between post-COVID-19 symptoms and myalgic encephalomyelitis/chronic fatigue syndrome

Highlights:

Plasmalogens (Pls) are lipids containing a vinyl-ether bond in their glycerol backbone.
Pls have antioxidant properties and are important for curved membrane assemblies.
Post-COVID-19 symptoms are highly prevalent and share several features with ME/CFS.
Pls depletion is a shared biological hallmark of ME/CFS and acute COVID-19 syndrome.
Pls replacement is a promising tool against neuroinflammation in these two conditions.

Abstract:

After five waves of coronavirus disease 2019 (COVID-19) outbreaks, it has been recognized that a significant portion of the affected individuals developed long-term debilitating symptoms marked by chronic fatigue, cognitive difficulties (“brain fog”), post-exertional malaise, and autonomic dysfunction. The onset, progression, and clinical presentation of this condition, generically named post-COVID-19 syndrome, overlap significantly with another enigmatic condition, referred to as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Several pathobiological mechanisms have been proposed for ME/CFS, including redox imbalance, systemic and central nervous system inflammation, and mitochondrial dysfunction. Chronic inflammation and glial pathological reactivity are common hallmarks of several neurodegenerative and neuropsychiatric disorders and have been consistently associated with reduced central and peripheral levels of plasmalogens, one of the major phospholipid components of cell membranes with several homeostatic functions.

Of great interest, recent evidence revealed a significant reduction of plasmalogen contents, biosynthesis, and metabolism in ME/CFS and acute COVID-19, with a strong association to symptom severity and other relevant clinical outcomes. These bioactive lipids have increasingly attracted attention due to their reduced levels representing a common pathophysiological manifestation between several disorders associated with aging and chronic inflammation. However, alterations in plasmalogen levels or their lipidic metabolism have not yet been examined in individuals suffering from post-COVID-19 symptoms.

Here, we proposed a pathobiological model for post-COVID-19 and ME/CFS based on their common inflammation and dysfunctional glial reactivity, and highlighted the emerging implications of plasmalogen deficiency in the underlying mechanisms. Along with the promising outcomes of plasmalogen replacement therapy (PRT) for various neurodegenerative/neuropsychiatric disorders, we sought to propose PRT as a simple, effective, and safe strategy for the potential relief of the debilitating symptoms associated with ME/CFS and post-COVID-19 syndrome.

Source: Adriano Maia Chaves-Filho, Olivia Braniff, Angelina Angelova, Yuru Deng, Marie-Ève Tremblay. Chronic inflammation, neuroglial dysfunction, and plasmalogen deficiency as a new pathobiological hypothesis addressing the overlap between post-COVID-19 symptoms and myalgic encephalomyelitis/chronic fatigue syndrome. Brain Research Bulletin, Volume 201, September 2023, 110702. https://www.sciencedirect.com/science/article/pii/S0361923023001272 (Full text)

Converging Evidence of Similar Symptomatology of ME/CFS and PASC Indicating Multisystemic Dyshomeostasis

Abstract:

The purpose of this article is to review the evidence of similar symptomatology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute sequelae of SARS-CoV-2 infection (PASC).

Reanalysis of data from a study by Jason comparing symptom reports from two groups of ME/CFS and PASC patients shows a notably similar symptomatology. Symptom scores of the PASC group and the ME/CFS group correlated 0.902 (p < 0.0001) across items. The hypothesis is presented that ME/CFS and PASC are caused by a chronic state of multisystemic disequilibrium including endocrinological, immunological, and/or metabolic changes.

The hypothesis holds that a changed set point persistently pushes the organism towards a pathological dysfunctional state which fails to reset. To use an analogy of a thermostat, if the ‘off switch’ of a thermostat intermittently stops working, for periods the house would become warmer and warmer without limit. The hypothesis draws on recent investigations of the Central Homeostasis Network showing multiple interconnections between the autonomic system, central nervous system, and brain stem.

The hypothesis helps to explain the shared symptomatology of ME/CFS and PASC and the unpredictable, intermittent, and fluctuating pattern of symptoms of ME/CFS and PASC. The current theoretical approach remains speculative and requires in-depth investigation before any definite conclusions can be drawn.

Source: Marks DF. Converging Evidence of Similar Symptomatology of ME/CFS and PASC Indicating Multisystemic Dyshomeostasis. Biomedicines. 2023; 11(1):180. https://doi.org/10.3390/biomedicines11010180 https://www.mdpi.com/2227-9059/11/1/180 (Full text)

Lessons From Heat Stroke for Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Introduction:

We here provide an overview of the pathophysiological mechanisms during heat stroke and describe similar mechanisms found in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Both conditions are characterized by disturbed homeostasis in which inflammatory pathways play a central role. Splanchnic vasoconstriction, increased gut permeability, gut-related endotoxemia, systemic inflammatory response, central nervous system dysfunction, blood coagulation disorder, endothelial-cell injury, and mitochondrial dysfunction underlie heat stroke. These mechanisms have also been documented in ME/CFS.

Moreover, initial transcriptomic studies suggest that similar gene expressions are altered in both heat stroke and ME/CFS. Finally, some predisposing factors for heat stroke, such as pre-existing inflammation or infection, overlap with those for ME/CFS. Notwithstanding important differences – and despite heat stroke being an acute condition – the overlaps between heat stroke and ME/CFS suggest common pathways in the physiological responses to very different forms of stressors, which are manifested in different clinical outcomes. The human studies and animal models of heat stroke provide an explanation for the self-perpetuation of homeostatic imbalance centered around intestinal wall injury, which could also inform the understanding of ME/CFS. Moreover, the studies of novel therapeutics for heat stroke might provide new avenues for the treatment of ME/CFS. Future research should be conducted to investigate the similarities between heat stroke and ME/CFS to help identify the potential treatments for ME/CFS.

Source: Dominic Stanculescu, Nuno Sepúlveda, Chin Leong Lim and Jonas Bergquist. Lessons From Heat Stroke for Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front. Neurol., 13 December 2021 | https://doi.org/10.3389/fneur.2021.789784 https://www.frontiersin.org/articles/10.3389/fneur.2021.789784/full (Full text)

Cortical autonomic network connectivity predicts symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis and chronic fatigue syndrome (ME/CFS) represents a significant public health challenge given the presence of many unexplained patient symptoms. Research has shown that many features in ME/CFS may result from a dysfunctional autonomic nervous system (ANS). We explored the role of the cortical autonomic network (CAN) involved in higher-order control of ANS functioning in 34 patients with ME/CFS and 34 healthy controls under task-free conditions.

All participants underwent resting-state quantitative electroencephalographic (qEEG) scalp recordings during an eyes-closed condition. Source analysis was performed using exact low-resolution electromagnetic tomography (eLORETA), and lagged coherence was used to estimate intrinsic functional connectivity between each node across 7 frequency bands: delta (1-3 Hz), theta (4-7 Hz), alpha-1 (8-10 Hz), alpha-2 (10-12 Hz), beta-1 (13-18 Hz), beta-2 (19-21 Hz), and beta-3 (22-30 Hz). Symptom ratings were measured using the DePaul Symptom Questionnaire and the Short Form (SF-36) health survey. Graph theoretical analysis of weighted, undirected connections revealed significant group differences in baseline CAN organization.

Regression results showed that cognitive, affective, and somatomotor symptom cluster ratings were associated with alteration to CAN topology in patients, depending on the frequency band. These findings provide evidence for reduced higher-order homeostatic regulation and adaptability in ME/CFS. If confirmed, these findings address the CAN as a potential therapeutic target for managing patient symptoms.

Source: Zinn MA, Jason LA. Cortical autonomic network connectivity predicts symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Int J Psychophysiol. 2021 Oct 15:S0167-8760(21)00900-4. doi: 10.1016/j.ijpsycho.2021.10.004. Epub ahead of print. PMID: 34662673. https://pubmed.ncbi.nlm.nih.gov/34662673/

Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-symptom disease with widespread evidence of disrupted systems. The authors hypothesize that it is caused by the upregulation of the corticotropin-releasing factor receptor type 2 (CRFR2) in the raphé nuclei and limbic system, which impairs the ability to maintain homeostasis. The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2.

Materials and Methods: This open-label trial tested the safety, tolerability and efficacy of an acute dose of CT38s (a short-lived, CRFR2-selective agonist, with no known off-target activity) in 14 ME/CFS patients. CT38s was subcutaneously-infused at one of four dose-levels (i.e., infusion rates of 0.01, 0.03, 0.06, and 0.20 μg/kg/h), for a maximum of 10.5 h. Effect was measured as the pre-/post-treatment change in the mean 28-day total daily symptom score (TDSS), which aggregated 13 individual patient-reported symptoms.

Results: ME/CFS patients were significantly more sensitive to the transient hemodynamic effects of CRFR2 stimulation than healthy subjects in a prior trial, supporting the hypothesized CRFR2 upregulation. Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a CRFR2 role in the disease. The acute dose of CT38s was associated with an improvement in mean TDSS that was sustained (over at least 28 days post-treatment) and correlated with both total exposure and pre-treatment symptom severity. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by −7.5 ± 1.9 (or −25.7%, p = 0.009), with all monitored symptoms improving.

Conclusion: The trial supports the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism may be a viable treatment approach warranting further study.

Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03613129.

Source: Gerard Pereira, Hunter Gillies, Sanjay Chanda, Michael Corbett, Suzanne D. Vernon, Tina Milani and Lucinda Bateman. Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front. Syst. Neurosci., 01 September 2021. https://doi.org/10.3389/fnsys.2021.69824 https://www.frontiersin.org/articles/10.3389/fnsys.2021.698240/full (Full text)

Homeostatic disturbance of thermoregulatory functions in rats with chronic fatigue

Abstract:

Chronic fatigue syndrome (CFS) is characterized by long-lasting fatigue, and a range of symptoms, and is involved in homeostasis disruption. CFS patients frequently complain of low grade fever or chill even under normal body temperature indicating that thermosensory or thermoregulatory functions might be disturbed in CFS. However, little is known about the detailed mechanisms. To elucidate whether and how thermoregulatory function was altered during the development of chronic fatigue, we investigated temporal changes in body temperature with advance of fatigue accumulation in a chronic fatigue rat model using a wireless transponder.

Our findings demonstrated that the body temperature was adaptively increased in response to fatigue loading in the early phase, but unable to retain in the late phase. The tail heat dissipation was often observed and the frequency of tail heat dissipation gradually increased initially, then decreased. In the late phase of fatigue loading, the body temperature for the tail heat dissipation phase decreased to a value lower than that for the non-dissipation phase. These results suggest that adaptive changes in thermoregulatory function occurred with fatigue progression, but this system might be disrupted by long-lasting fatigue, which may underlie the mechanism of fatigue chronification.

Source: Li D, Hu D, Shigeta M, Ochi Y, Watanabe Y, Li F, Cui Y. Homeostatic disturbance of thermoregulatory functions in rats with chronic fatigue. Neurosci Res. 2020 Apr 30. pii: S0168-0102(20)30157-7. doi: 10.1016/j.neures.2020.04.005. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/32361157

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis?

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease characterized by debilitating fatigue, lasting for at least 6 months, with severe impairment of daily functioning and associated symptoms. A significant percentage of ME/CFS patients remains undiagnosed, mainly due to the complexity of the disease and the lack of reliable objective biomarkers. ME/CFS patients display decreased metabolism and the severity of symptoms appears to be directly correlated to the degree of metabolic reduction that may be unique to each individual patient. However, the precise pathogenesis is still unknown preventing the development of effective treatments. The ME/CFS phenotype has been associated with abnormalities in energy metabolism, mostly with mitochondrial dysfunction, resulting in reduced oxidative metabolism. Mitochondrial dysfunction may be further contributing to the ME/CSF symptomatology by extracellular secretion of mitochondrial DNA, which could create an “innate” inflammatory state in the hypothalamus, thus disrupting normal homeostasis. We propose that stimulation of hypothalamic mast cells activates microglia leading to focal inflammation in the brain and disturbed homeostasis.

Source: Hatziagelaki E, Adamaki M, Tsilioni I, Dimitriadis G, Theoharides TC. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis? J Pharmacol Exp Ther. 2018 Aug 3. pii: jpet.118.250845. doi: 10.1124/jpet.118.250845. [Epub ahead of print] http://jpet.aspetjournals.org/content/early/2018/08/03/jpet.118.250845.long (Full article)

Slow wave sleep in the chronically fatigued: Power spectra distribution patterns in chronic fatigue syndrome and primary insomnia

Abstract:

OBJECTIVES: To investigate slow wave sleep (SWS) spectral power proportions in distinct clinical conditions sharing non-restorative sleep and fatigue complaints without excessive daytime sleepiness (EDS), namely the chronic fatigue syndrome (CFS) and primary insomnia (PI). Impaired sleep homeostasis has been suspected in both CFS and PI.

METHODS: We compared perceived sleep quality, fatigue and sleepiness symptom-intensities, polysomnography (PSG) and SWS spectral power distributions of drug-free CFS and PI patients without comorbid sleep or mental disorders, with a good sleeper control group.

RESULTS: Higher fatigue without EDS and impaired perceived sleep quality were confirmed in both patient groups. PSG mainly differed in sleep fragmentation and SWS durations. Spectral analysis revealed a similar decrease in central ultra slow power (0.3-0.79Hz) proportion during SWS for both CFS and PI and an increase in frontal power proportions of faster frequencies during SWS in PI only. The latter was correlated to affective symptoms whereas lower central ultra slow power proportions were related to fatigue severity and sleep quality impairment.

CONCLUSIONS: In combination with normal (PI) or even increased SWS durations (CFS), we found consistent evidence for lower proportions of slow oscillations during SWS in PI and CFS.

SIGNIFICANCE: Observing normal or increased SWS durations but lower proportions of ultra slow power, our findings suggest a possible quantitative compensation of altered homeostatic regulation.

Source: Neu D, Mairesse O, Verbanck P, Le Bon O. Slow wave sleep in the chronically fatigued: Power spectra distribution patterns in chronic fatigue syndrome and primary insomnia. Clin Neurophysiol. 2015 Oct;126(10):1926-33. doi: 10.1016/j.clinph.2014.12.016. Epub 2015 Jan 10. https://www.ncbi.nlm.nih.gov/pubmed/25620040

Non-REM sleep EEG power distribution in fatigue and sleepiness

Abstract:

OBJECTIVES: The aim of this study is to contribute to the sleep-related differentiation between daytime fatigue and sleepiness.

METHODS: 135 subjects presenting with sleep apnea-hypopnea syndrome (SAHS, n=58) or chronic fatigue syndrome (CFS, n=52) with respective sleepiness or fatigue complaints and a control group (n=25) underwent polysomnography and psychometric assessments for fatigue, sleepiness, affective symptoms and perceived sleep quality. Sleep EEG spectral analysis for ultra slow, delta, theta, alpha, sigma and beta power bands was performed on frontal, central and occipital derivations.

RESULTS: Patient groups presented with impaired subjective sleep quality and higher affective symptom intensity. CFS patients presented with highest fatigue and SAHS patients with highest sleepiness levels. All groups showed similar total sleep time. Subject groups mainly differed in sleep efficiency, wake after sleep onset, duration of light sleep (N1, N2) and slow wave sleep, as well as in sleep fragmentation and respiratory disturbance. Relative non-REM sleep power spectra distributions suggest a pattern of power exchange in higher frequency bands at the expense of central ultra slow power in CFS patients during all non-REM stages. In SAHS patients, however, we found an opposite pattern at occipital sites during N1 and N2.

CONCLUSIONS: Slow wave activity presents as a crossroad of fatigue and sleepiness with, however, different spectral power band distributions during non-REM sleep. The homeostatic function of sleep might be compromised in CFS patients and could explain why, in contrast to sleepiness, fatigue does not resolve with sleep in these patients. The present findings thus contribute to the differentiation of both phenomena.

Source: Neu D, Mairesse O, Verbanck P, Linkowski P, Le Bon O. Non-REM sleep EEG power distribution in fatigue and sleepiness. J Psychosom Res. 2014 Apr;76(4):286-91. doi: 10.1016/j.jpsychores.2014.02.002. Epub 2014 Feb 17. https://www.ncbi.nlm.nih.gov/pubmed/24630178

A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis

Abstract:

To explore brain involvement in chronic fatigue syndrome (CFS), the statistical parametric mapping of brain MR images has been extended to voxel-based regressions against clinical scores.

Using SPM5 we performed voxel-based morphometry (VBM) and analysed T(1) – and T(2) -weighted spin-echo MR signal levels in 25 CFS subjects and 25 normal controls (NC). Clinical scores included CFS fatigue duration, a score based on the 10 most common CFS symptoms, the Bell score, the hospital anxiety and depression scale (HADS) anxiety and depression, and hemodynamic parameters from 24-h blood pressure monitoring. We also performed group × hemodynamic score interaction regressions to detect locations where MR regressions were opposite for CFS and NC, thereby indicating abnormality in the CFS group.

In the midbrain, white matter volume was observed to decrease with increasing fatigue duration. For T(1) -weighted MR and white matter volume, group × hemodynamic score interactions were detected in the brainstem [strongest in midbrain grey matter (GM)], deep prefrontal white matter (WM), the caudal basal pons and hypothalamus. A strong correlation in CFS between brainstem GM volume and pulse pressure suggested impaired cerebrovascular autoregulation.

It can be argued that at least some of these changes could arise from astrocyte dysfunction. These results are consistent with an insult to the midbrain at fatigue onset that affects multiple feedback control loops to suppress cerebral motor and cognitive activity and disrupt local CNS homeostasis, including resetting of some elements of the autonomic nervous system (ANS).

Source: Barnden LR, Crouch B, Kwiatek R, Burnet R, Mernone A, Chryssidis S, Scroop G, Del Fante P. A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis. NMR Biomed. 2011 Dec;24(10):1302-12. doi: 10.1002/nbm.1692. Epub 2011 May 11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369126/ (Full article)