Systematic Examination of Gene Expression and Proteomic Evidence Across Tissues Supports the Role of Mitochondrial Dysregulation in ME/CFS

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, multisystem disease characterized by post-exertional malaise and persistent fatigue. The cause of ME/CFS is not well understood, and there are no established biomarkers or FDA-approved pharmacotherapies. The clinical heterogeneity of ME/CFS presents challenges to diagnosis and treatment and necessitates collaborative efforts to generate robust findings. This study leveraged gene and protein expression data from the mapMECFS data repository and the DecodeME Genome-Wide Association Study (GWAS) to assess consistent gene signatures across studies.

The mitochondrial genes MT-RNR1 and MT-RNR2 exhibited lower expression in ME/CFS cases in two studies. Combining this with increased expression of mitochondrial genes in platelets from another study, this supports mitochondrial dysregulation as having a role in ME/CFS.

Furthermore, ME/CFS-associated genes were mapped to compounds in drug databases as possible treatments for further investigation. In muscle gene expression data, 107 approved compounds target 26 genes with functions relevant to mitochondrial support and immunomodulators. From the DecodeME GWAS, 83 approved compounds target 24 genes with functions related to energy metabolism and mitochondrial function.

Though little consistency in specific genes was observed across studies, which highlights the need for larger studies, mitochondrial dysfunction in ME/CFS cases was evident across studies.

Source: Keele GR, Enger M, Barnette Q, Ruiz-Esparza R, Alvarado M, Mathur R, Stratford JK, Giamberardino SN, Brown LM, Webb BT, Carnes MU. Systematic Examination of Gene Expression and Proteomic Evidence Across Tissues Supports the Role of Mitochondrial Dysregulation in ME/CFS. Int J Mol Sci. 2026 Feb 19;27(4):1997. doi: 10.3390/ijms27041997. PMID: 41752134. https://www.mdpi.com/1422-0067/27/4/1997 (Full text)

ICD-10 Diagnoses prior to ME/CFS diagnosis in children and young people suggest potential early diagnostic indicators

Abstract:

To identify ICD-10-GM codes recorded in the year preceding a Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) diagnosis, we conducted a 1:5 matched case–control study using statutory health insurance data of 6–27-year-olds with ME/CFS (ICD-10-GM: G93.3, 2020–2022). Cases (n = 6,077) were matched 1:5 to controls by birth year, sex, and postal code. ICD-10-GM codes from the preceding year were analyzed using multivariable conditional logistic regression, reporting odds ratios (OR) and 95% confidence intervals. Most cases were female and aged 18–27 years.

Forty-four ICD-10-GM code classes were associated with increased and four with decreased odds, spanning 13 diagnostic chapters. Most associations were in chapters F (mental/behavioral disorders), R (respiratory diseases), and M (musculoskeletal disorders). Frequent conditions included fatigue, depression, pain disorders, and somatoform disorders (≥ 10% in cases; ORs 1.11–2.19. Rare diagnoses (≤ 1% prevalence), such as fibromyalgia (OR 2.08, 95% CI: 1.20–3.59) and mild cognitive impairment (2.93, 1.21–7.10), were strongly associated. Four COVID-19 or vaccination-related code classes were identified, with post-COVID-19 condition showing the highest OR (3.84, 2.97–4.98). Several ICD-10-GM codes, including COVID-19 related codes, were associated with later ME/CFS diagnoses.

Prospective studies should clarify timing relative to ME/CFS onset, and distinguish between pre-existing conditions, comorbidities, early manifestations, or misdiagnoses.

Source:Wirth M, Haastert B, Linnenkamp U, Andrich S, Icks A, Pricoco R, Behrends U, De Bock F. ICD-10 Diagnoses prior to ME/CFS diagnosis in children and young people suggest potential early diagnostic indicators. Sci Rep. 2026 Feb 26. doi: 10.1038/s41598-026-40848-1. Epub ahead of print. PMID: 41741569. https://www.nature.com/articles/s41598-026-40848-1 (Full text)

Assessment of dynamic cerebral blood flow changes during cognitive tasks in patients with post-COVID-19 syndrome

Abstract:

The objective of this study was to quantify the variability of cortical blood flow during cognitive load as an indicator of disease-related changes in cerebral capillary blood flow intermittency in patients with post-COVID-19 syndrome. The regulation of cerebral blood flow in the dorsolateral prefrontal cortex under cognitive load was examined using high-resolution functional near-infrared spectroscopy in 36 subjects including 12 patients with post-COVID-19 syndrome and two control groups [12 coronary artery disease patients matched for age and 12 young healthy individuals (CTRL)].

To induce cognitive load, a Flanker task and an N-back task were employed. The structure of temporal variability of local blood flow regulation was assessed using sample entropy at 17 channels spanning both brain hemispheres. The spatial variability of the regional blood flow pattern was evaluated using the coefficient of variation (CV) from sample entropies across all channels.

Results revealed a notable discrepancy in that patients with post-COVID-19 syndrome exhibited reduced temporal variability (lower sample entropy) but elevated spatial variability (higher CV) in comparison to coronary artery disease patients during cognitive load (P = 0.02). In the N-back task, the spatial variability increased from healthy individuals to coronary artery disease patients to patients with post-COVID-19 syndrome and was associated with longer reaction time and with lower accuracy.

The results confirmed that dynamic cerebral blood flow is altered in patients with post-COVID-19 syndrome, which may be related to fatigue during cognitive tasks. Sample entropy and CV values represent different aspects of blood flow regulation fluctuation. Their simultaneous analysis enabled a meaningful distinction between groups suggesting disease-related changes in brain haemodynamic. The presented method is therefore suitable for describing current states of cortical blood flow regulation and for documenting intervention results in patients with post-COVID-19 syndrome or patients with similar symptoms (e.g. myalgic encephalomyelitis/chronic fatigue syndrome).

Source: Kutz DF, Garbsch R, Mooren FC, Schmitz B, Voelcker-Rehage C. Assessment of dynamic cerebral blood flow changes during cognitive tasks in patients with post-COVID-19 syndrome. Brain Commun. 2026 Feb 10;8(1):fcag036. doi: 10.1093/braincomms/fcag036. PMID: 41728261; PMCID: PMC12917544. https://pmc.ncbi.nlm.nih.gov/articles/PMC12917544/ (Full text)

A Continuous Oral Regimen of High-Dose Cromolyn Sodium Is Effective for Some Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients With Mast Cell Activation Syndrome

Abstract:

Our clinical experience in the last four years using oral cromolyn in patients with mast cell activation syndrome (MCAS) suggests that a continuous oral regimen of high-dose cromolyn may enhance compliance with the medication. The five patients described in this retrospective case series were given instructions to take oral cromolyn using a continuous dosing regimen, placing the entire day’s dose in an opaque bottle that is then filled with water, and sipping the solution throughout the day. If a conventional maximum dose of eight vials daily (800 mg) was tolerated but ineffective after a week, the patients were instructed to increase to 1600-2400 mg daily until reaching an optimal effect.

We report that a cromolyn dose of 1600-2400 mg daily, administered using the continuous oral dosing regimen during the day, was effective in controlling signs and symptoms of mast cell activation. All five patients benefitted from a dose of cromolyn that is higher than usual and customary recommendations, but within the safety guidelines of the original Food and Drug Administration (FDA) application. The continuous oral regimen has some theoretical advantages over four discrete doses per day, though further study is needed.

Source: Christoforou ME, van Campen LC, Visser FC, Lee CK, Lemmon SL, Rowe PC, Azola AM. A Continuous Oral Regimen of High-Dose Cromolyn Sodium Is Effective for Some Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients With Mast Cell Activation Syndrome. Cureus. 2026 Jan 22;18(1):e102064. doi: 10.7759/cureus.102064. PMID: 41728426; PMCID: PMC12924640. https://pmc.ncbi.nlm.nih.gov/articles/PMC12924640/ (Full text)

Seeing is Believing: Identifying the “Ideal Manifestation of Hidden Disability” in Ontario’s and Quebec’s Social Benefits Tribunals

Abstract:

The phenomenon of disability skepticism, especially in relation to “hidden” disabilities like chronic fatigue syndrome (CFS), has fostered a culture of doubt among medical, legal, and public entities. This paper explores the intersection of such skepticism with the social benefits adjudication processes in Ontario and Quebec. In drawing parallels to feminist critiques of the “ideal victim” in sexual assault cases, it argues that the tribunals’ biased framework for believability is based on a claimant’s conformity to stereotypical expectations of what an “ideal” claimant with a hidden disability looks like.

By comparatively examining 10 years worth of Ontario and Quebec tribunal decisions featuring claimants with CFS, this study highlights how those with hidden disabilities are evaluated based on visible manifestations of their disability/emotion, medical/expert evidence, and the apparent credibility of themselves or others as witnesses. This research not only addresses a significant gap in the literature but also calls for reforms in the legal treatment of hidden disabilities, advocating for a shift away from entrenched stereotypes towards a more inclusive and equitable system.

Source: Pascale Malenfant, “Seeing is Believing: Identifying the ‘Ideal Manifestation of Hidden Disability’ in Ontario’s and Quebec’s Social Benefits Tribunals” (2026) 48:2 Dal LJ 753. https://digitalcommons.schulichlaw.dal.ca/dlj/vol48/iss2/1/ (Full text available as PDF file)

Myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia – overlap, differences, and emerging insights

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are debilitating chronic illnesses with considerable symptom overlap. Their symptoms include profound fatigue, widespread pain, post-exertional deterioration, sleep disturbance, dysautonomia, and cognitive impairment. These illnesses frequently co-occur; ME/CFS often develops first, particularly after infection. This overlap creates a diagnostic grey area and contributes to severe reductions in quality of life. Despite these shared features, key distinctions remain essential. ME/CFS is characterised by post-exertional neuroimmune exhaustion (PENE)/post-exertional malaise (PEM), a hallmark of post-exertional worsening and multisystem involvement. Contrastingly, FM centres on chronic widespread pain and symptom variability. It is not characterised by PEM/PENE or the same extent of system dysfunction as ME/CFS. Both disorders lack a definitive biomarker as of 2025. Thus, diagnosis remains clinical and supported by objective tests where available.

Main body: Although immune dysregulation is common in patients with each condition, distinct immune signatures have been observed. ME/CFS is characterised by fluctuating pro- and anti-inflammatory cytokine levels and a frequent reduction in natural killer (NK) cell function; this is consistent with immune exhaustion. Patients with FM exhibit elevated IL-6, IL-17 A, and IL-4 levels, and a broader immune imbalance linked to pain amplification rather than immune collapse. Viral infections do not directly cause either condition, but commonly act as triggers. Shared mechanisms, such as spinal reflex arc activation and microglial sensitisation, suggest a common pathway mediated by proprioceptor-induced microglial activation for chronic pain. ME/CFS causes autoimmunity-like processes, whereas evidence of autoimmune drivers for FM is limited. Gut microbiome studies have revealed reduced microbial diversity in patients with ME/CFS. Moreover, the two disorders are characterised by shared, yet distinct, microbial alterations.

Conclusion: Given the chronic and debilitating nature of ME/CFS and FM, prevention and early intervention remain crucial, but understudied. Health education, workplace adaptations, and early diagnostic pathways may substantially reduce the disease burden. Many patients are outside formal healthcare systems. Therefore, digital tools such as symptom-tracking apps, biosensors, remote testing, and assistive technologies are becoming central to disease management and monitoring. These approaches support a transdiagnostic, patient-centred model capable of addressing both conditions and reaching populations that remain underserved.

Source: Murovska M, Krumina A, Araja D, Kujawski S, Zalewski P, Nora-Krukle Z, Berkis U. Myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia – overlap, differences, and emerging insights. J Transl Med. 2026 Feb 20. doi: 10.1186/s12967-026-07889-6. Epub ahead of print. PMID: 41715182. https://link.springer.com/article/10.1186/s12967-026-07889-6 (Full text available as PDF file)

Effects of Cacao Flavonoids in Long COVID-19 Patients with Chronic Fatigue: FLALOC, a Placebo-Controlled Randomized Clinical Trial

Abstract:

Background: In the context of long COVID, persistent fatigue is among the most prevalent symptoms that can develop after SARS-CoV-2 infection. Mitochondrial myopathy and endothelial dysfunction, which are triggers of inflammation, have emerged as prominent causes of long COVID-induced fatigue. Interestingly, the intake of flavanols, particularly (−)-epicatechin (EC), has been associated with the positive modulation of endothelial and mitochondrial structure and function.
Methods: In this work, we conducted a randomized, double-blind, placebo-controlled clinical trial to determine whether an EC-enriched supplement (ECES) improves plasma markers of inflammation, endothelial structure, and fatigue-related endpoints in patients with long COVID-19.
Results: The study included 46 subjects (mean age 52 years) who were instructed to consume two capsules/day for 90 days of either ECES (n = 23) or placebo (n = 23). Endpoints assessed included mean changes in plasma inflammatory markers (IL-1β, IL-6, and TNF-α) and endothelial dysfunction markers (syndecan-1), handgrip strength, fatigue scale, and quality of life (QoL). The results showed significant improvements in the ECES group for inflammatory markers, syndecan-1, and fatigue compared with the placebo group.
Conclusions: The results yield intriguing positive findings for EC and open a new avenue for treating long COVID.
Source: Munguía L, Silva S, Villarreal F, Nájera N, Ceballos G. Effects of Cacao Flavonoids in Long COVID-19 Patients with Chronic Fatigue: FLALOC, a Placebo-Controlled Randomized Clinical Trial. Journal of Clinical Medicine. 2026; 15(4):1468. https://doi.org/10.3390/jcm15041468 https://www.mdpi.com/2077-0383/15/4/1468 (Full text)

The potential causes of myasthenia and fasciculations in severely ill ME/CFS patients: the role of disturbed electrophysiology

Abstract:

Patients with severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are bedridden and suffer from hypersensitivities to light and noise, severe orthostatic intolerance reducing cerebral blood flow, and skeletal muscle symptoms, including loss of force, fatigue, pain, fasciculations, and cramps. Because neurological investigations exclude neuronal causes of myasthenia, we hypothesize a muscular pathomechanism.

In previous articles, we considered insufficient activity of the Na+/K+-ATPase to be the main cause of mitochondrial damage via high intracellular sodium that reverses the transport mode of the sodium-calcium-exchanger to import calcium, causing calcium overload. Low Na+/K+-ATPase activity also causes sarcolemmal depolarization, leading to less effective action potential propagation and loss of force. Depolarization brings the membrane potential closer to the threshold potential, causing hyperexcitability that explains fasciculations and cramps. These increase sodium influx during excitation to further increase the workload of Na+/K+-ATPase. Thereby, depolarization causes further depolarization.

Higher intracellular sodium favors calcium overload and mitochondrial damage, which lowers the energy supply of Na+/K+-ATPase and increases the reactive oxygen species, further inhibiting Na+/K+-ATPase. The muscle is in a state of depolarization even at rest. Depolarization and mitochondrial damage reinforce each other. Thus, dysfunction of Na+/K+-ATPase as a single mechanism can explain the different skeletal muscle symptoms of severely ill ME/CFS patients, comprising loss of force, fatigue, and fasciculations.

Source: Wirth KJ, Steinacker JM. The potential causes of myasthenia and fasciculations in severely ill ME/CFS patients: the role of disturbed electrophysiology. Front Physiol. 2026 Feb 2;16:1693589. doi: 10.3389/fphys.2025.1693589. PMID: 41705124; PMCID: PMC12907180. https://pmc.ncbi.nlm.nih.gov/articles/PMC12907180/ (Full text)

Use of artificial intelligence and machine learning for the management of fibromyalgia: a scoping review

Abstract:

Background: Fibromyalgia (FM) is a complex and multifactorial syndrome characterized by widespread pain, fatigue, cognitive impairment, and other systemic symptoms. The absence of specific biomarkers and the heterogeneous clinical presentation pose significant diagnostic challenges.

Objective: This scoping review aims to explore the current applications of artificial intelligence (AI) and machine learning (ML) in the diagnosis and clinical management of FM.

Methods: A systematic search was conducted in PubMed, EMBASE, and the Cochrane Library using defined keywords related to FM and AI/ML. Studies were included if they addressed ML applications in FM patients. Following PRISMA-ScR guidelines, 43 studies published between 2011 and 2024 were included and analyzed for ML techniques used, diagnostic targets, data types, and clinical relevance.

Results: As expected, the majority of studies done so far focused on improving diagnostic accuracy through supervised algorithms such as support vector machines, neural networks, and ensemble models, as well as unsupervised clustering and dimensionality reduction techniques. Notable findings include the identification of neurophysiological signatures via fMRI, gene expression patterns, retinal imaging changes, and metabolomic biomarkers that distinguish FM patients from controls. For instance, one study investigating circulating microRNAs used a Random Forest model to identify 11 microRNAs (e.g. hsa-miR-28-5p, hsa-miR-29a-3p, hsa-miR-150-5p) capable of differentiating patients with FM, ME/CFS, and healthy controls, suggesting their potential as biomarkers for more accurate diagnoses. Reported model accuracies ranged from 82% to 100%, although most studies were pilot-based with small and imbalanced samples, limiting generalizability.

Conclusion: AI and ML offer promising tools to overcome longstanding limitations in FM diagnosis and treatment. While current findings demonstrate significant potential, larger, multicenter studies with rigorous validation protocols are essential to finally establish these approaches as clinically reliable solutions.

Source: Clempi Almeida E Silva AL, Reis VHPF, Lamoglia ASA, Souza Desidério C, Freire Oliveira CJ. Use of artificial intelligence and machine learning for the management of fibromyalgia: a scoping review. J Man Manip Ther. 2026 Feb 17:1-17. doi: 10.1080/10669817.2026.2630999. Epub ahead of print. PMID: 41700030. https://pubmed.ncbi.nlm.nih.gov/41700030/

Altered Pain Perception and Modulation in Individuals With Post-COVID-Condition: Insights From Quantitative Sensory Testing

Abstract:

Introduction: Chronic pain is a significant and debilitating symptom observed in individuals with post-COVID condition (PCC), yet the underlying mechanisms remain poorly understood. This study aimed to investigate whether changes in psychophysical indicators of myofascial pain perception and modulation are present in individuals with PCC compared to symptom-free healthy controls (HC), and whether these changes correlate with the severity of clinical symptoms.

Methods: The study involved 84 individuals with PCC and 50 HC, assessing pain detection and tolerance thresholds (PDT and PTT), spatial and temporal summation of pain (SSP and TSP), and conditioned pain modulation (CPM) using phasic cuff pressure on the legs.

Results: Results indicated that individuals with PCC exhibited lower PDT and PPT (PDT: d = -0.557, p = 0.0022; PTT: d = -0.575, p = 0.0016), increased TSP (d = 0.424, p = 0.02) and decreased SSPPTT (d = -0.532, p = 0.0038) compared to HC CPM effects (CPMPDT: p = 0.058; CPMPTT: p = 0.43) did not differ significantly between groups but post hoc analysis revealed a significantly higher proportion of inhibitory responders among HC. Subgroup analyses highlighted that these effects were particularly pronounced in participants that reported chronic pain among their PCC symptoms, as well as those with more severe PCC symptomatology.

Conclusion: The findings suggest that individuals with PCC demonstrate altered myofascial pain perception, indicative of central sensitization. These results underscore the need for further research into targeted therapeutic strategies for managing chronic pain in PCC.

Significance statement: Individuals with post-COVID condition (PCC) often experience persistent pain. Using quantitative sensory testing of deep tissue pain, we found that individuals with PCC had lower pain detection and tolerance thresholds, stronger spatial and temporal summation, and a higher proportion of facilitatory conditioned pain modulation compared to healthy controls. This pattern is consistent with nociplastic pain, suggesting altered central pain processing in PCC. Understanding these mechanisms is essential for developing targeted treatments of chronic pain in this growing patient population.

Source: Lange H, Reichert J, Vock S, Hermes M, Beiner E, Eich W, Friederich HC, Treede RD, Tesarz J. Altered Pain Perception and Modulation in Individuals With Post-COVID-Condition: Insights From Quantitative Sensory Testing. Eur J Pain. 2026 Feb;30(2):e70203. doi: 10.1002/ejp.70203. PMID: 41699921. https://pubmed.ncbi.nlm.nih.gov/41699921/