Welcome to the 122nd edition of the Research Digest. This month’s studies continue to advance understanding of ME/CFS, highlighting biological differences between post-infectious and gradual-onset ME/CFS, uncovering new insights into how extracellular vesicles may drive post-exertional malaise (PEM), and exploring brain metabolism changes following exercise. We also feature a large international survey on patient-reported treatment outcomes across ME/CFS and long COVID, and the RACGP’s launch of a new Specific Interest Group to better support clinicians managing energy-limiting and post-infectious conditions.
Contributing Digesters: Solène, Sarah, Anna and Simone.
Please note: The Research Digest shares current scientific findings for awareness and discussion. It is not a substitute for medical advice or treatment guidance, as much of the research featured is in its early stages and requires further confirmation.
We hope you enjoy the Easy Read Overview and audio summary we’ve included under each article’s title – it’s now even easier to stay informed of the latest ME/CFS and long COVID research!
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Distinct white matter alteration patterns in post-infectious and gradual onset chronic fatigue syndrome revealed by diffusion MRI
Authors: Yu Q, Kwiatek RA, Del Fante P, Bonner A, Calhoun VD, Bateman GA,…,Shan ZY (University of the Sunshine Coast, Australia)
Publication: Scientific Reports (July, 2025)
Link: https://www.nature.com/articles/s41598-025-09379-z
Easy Read Overview: This study looked at whether people who develop ME/CFS after an infection and those who develop it gradually have different changes in their brains. Using MRI scans, researchers compared 76 people with ME/CFS to 76 healthy but inactive people. They found that those with post-infectious ME/CFS had higher brain measurements linked to worse physical health, while those with gradual-onset ME/CFS had lower measurements linked to worse mental health. The results suggest that the two groups may have different brain changes, showing that ME/CFS is a varied and complex disease.
Two different patterns of onset have been observed in ME/CFS in clinics: (i) post-infectious ME/CFS (PI-ME/CFS), in which a viral or bacterial infection triggered the development of ME/CFS symptoms, and (ii) gradual onset (GO-ME/CFS), in which ME/CFS symptoms develop slowly and progressively over months or years without any clear infection event. In this study, the authors used diffusion MRI to investigate whether PI-ME/CFS and GO-ME/CFS share a common neurological basis.
The study included 43 participants with PI-ME/CFS and 33 participants with GO-ME/CFS, as well as 76 matched sedentary healthy controls (HC). All ME/CFS participants were interviewed by two clinicians to confirm their diagnosis (Canadian Consensus Criteria), classifying them into the PI-ME/CFS or GO-ME/CFS groups, and assessing disease severity and duration. All participants underwent an MRI scan, and completed questionnaires to evaluate depression, anxiety and sleep. Participants also wore actigraphs for seven days before and after the MRI, and this data was used, along with age and sex, to match ME/CFS and HC participants.
Axial diffusivities (ADs) in PI-ME/CFS participants were significantly higher than those of the healthy controls in several association and projection fibres. Higher AD in this group correlated with worse physical health. By comparison, ADs in the GO-ME/CFS participants were significantly lower than those of the healthy controls in several brain regions. In this group, lower AD correlated with worse mental health. When investigated, fractional anisotropy, mean diffusivity, and radial diffusivity showed no significant group differences.
This study suggests different microstructural abnormalities in the white matter between PI-ME/CFS and GO-ME/CFS patients and identifies AD as a potential sensitive indicator of pathology. These different AD alterations highlight different pathological processes and pinpoint the heterogeneity of ME/CFS disease.
Extracellular vesicle proteomics uncovers energy metabolism, complement system, and endoplasmic reticulum stress response dysregulation postexercise in males with myalgic encephalomyelitis/chronic fatigue syndrome
Authors:Glass KA, Giloteaux L, Zhang S, & Hanson MR (Cornell University, USA)
Publication: Clinical and Translational Medicine (May, 2025)
Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC12135887/pdf/CTM2-15-e70346.pdf
Easy Read Overview: This study explored whether microscopic parcels released by cells into the blood – called extracellular vesicles (EVs) – play a role in post-exertional malaise (PEM) in people with ME/CFS. Ten men with ME/CFS and twelve healthy but inactive men, did an exercise test, and their blood was tested before and after. The ME/CFS group showed abnormal EV changes linked to problems with energy use, immune activity, and cell stress. The researchers concluded that these findings suggest PEM may be caused by an unhealthy EV response to exercise in ME/CFS.
The biological basis underlying post-exertional malaise (PEM) is not yet fully understood. Extracellular vesicles (EV) play a role in cell-to-cell communication, and in healthy individuals, exercise increases the release of EVs into the circulation. EVs have been found to enhance tissue repair, reduce inflammation, and enhance metabolic adaptation post-exercise. This study sought to determine if EVs are involved in the post-exertional pathophysiology in ME/CFS.
The study included 10 males with ME/CFS (Canadian Consensus Criteria) and 12 matched sedentary controls. Participants were recruited from a larger study already being completed. Participants completed a maximal cardiopulmonary exercise test. Blood samples were collected at baseline, and 15 minutes and 24 hours post-exercise. EVs were isolated from the plasma samples, and proteomic analysis was undertaken.
The ME/CFS group showed altered EV protein responses compared to the control group. This included downregulation of the citric acid (TCA) cycle-related proteins, and upregulation of complement system proteins at 15 minutes post-exertion. PEM severity was seen to be highly correlated to changes in protein folding and the endoplasmic reticulum stress response during the recovery phase. The EV protein changes post-exercise were also associated with both disease severity and unrefreshing sleep. A correlation was found in the control group between EV protein levels and exercise measures, VO2 peak and ventilatory anaerobic threshold, but was not observed in the ME/CFS group.
The authors conclude that this study identified a maladaptive EV proteomic response to exertion in ME/CFS participants. This maladaptive response was characterised by immune overactivation, metabolic impairment, and endoplasmic reticulum stress response dysregulation. The authors suggest that this demonstrates a disrupted EV-mediated physiological process in ME/CFS, and a molecular basis for PEM.
Exertional exhaustion (post-exertional malaise, PEM) evaluated by the effects of exercise on cerebrospinal fluid metabolomics-lipidomics and serine pathway in myalgic encephalomyelitis/chronic fatigue syndrome
Authors: Baraniuk JN (Georgetown University Medical Centre, USA)
Publication: International Journal of Molecular Sciences (February, 2025)
Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC11818353/pdf/ijms-26-01282.pdf
Easy Read Overview: This study looked at how the brains of people with ME/CFS respond to exercise by testing chemicals and fats in their spinal fluid. Researchers found clear differences between the ME/CFS group and healthy but inactive controls, both before and after exercise. People with ME/CFS showed unusual patterns in how their bodies used energy and processed nutrients like folate. The study suggests that ME/CFS may involve an overactive metabolism and brain changes that contribute to problems with thinking and memory.
Post-exertional malaise (PEM) is a hallmark symptom of ME/CFS and involves a provocation that causes disabling exacerbation to physical and cognitive functioning that is not relieved by rest. As the onset of PEM can be delayed, the duration is variable, and the individual effects are varied and unique, the author sought to find objective markers of this pathophysiological dysfunction, by examining brain metabolite and lipid flux through cerebrospinal fluid analysis.
This study included 60 ME/CFS participants (Fukuda and Canadian Consensus Criteria), and 32 sedentary controls (less than 40 minutes per week of aerobic exercise). All participants had a lumbar puncture to collect cerebrospinal fluid. Some participants (15 ME/CFS participants and 12 sedentary controls) completed two submaximal exercise tests 24 hours apart, followed by a lumbar puncture 1-5 hours after the second exercise test. Questionnaires were completed to gather information on disability, impairment, and quality of life.
The author found differences between ME/CFS and controls at the baseline measurements, indicating disease-related pathologies, and also between baseline and post-exercise, indicating PEM-related pathologies. The author found elevated serine as well as its derivatives (sarcosine and phospholipids) with a decrease in 5-methyltetrahydrofolate – this was a novel finding, and indicative of generalised dysfunction of folate and one-carbon metabolism in ME/CFS. The author also found that exercise led to both groups consuming lipids, but that metabolites were also consumed in the ME/CFS group, but generated in the control group.
The author concluded that the ME/CFS group had a hypermetabolic profile, with elevated metabolites and lipids. These results were in contrast to some previous studies, which had found hypometabolism in ME/CFS. In addition, the author proposes an additional hypothesis that the metabolic and phospholipid profiles identified may indicate that white matter dysfunction is a contributor to the cognitive dysfunction observed in ME/CFS.
Patient-reported treatment outcomes in ME/CFS and long COVID
Authors: Eckey M, Peng Li P, Morrison B, Bergquist J, pDavis RW, and Xiao W (Massachusetts General Hospital, USA)
Publication: PNAS (July, 2025)
Link: https://www.pnas.org/doi/epub/10.1073/pnas.2426874122
Easy Read Overview: This study looked at how people with ME/CFS and long COVID rated the benefits of more than 150 treatments. It included 3,925 participants who reported their symptoms and how each treatment affected them. The treatments with the most benefit were pacing, fluids/electrolytes, and compression stockings, while graded exercise therapy (GET) was often reported as harmful. The results suggest that patient experiences can help guide future research and treatment plans, and that ME/CFS and long COVID may be considered together in clinical care.
There are currently no FDA-approved treatments for ME/CFS and long COVID. This study aimed to examine patient-reported outcomes of treatments to help identify management strategies that can improve symptoms and provide new avenues for research.
This study included 3,925 participants: 2125 with ME/CFS and 1800 with long COVID, with the majority reporting formal diagnoses. Participants were surveyed to investigate their perceived benefits of more than 150 treatments. Participants rated each treatment for its perceived benefit to their overall condition and specific symptoms. Summarised results were compared to the use of a Vitamin C supplement as a control.
Both groups reported the same primary symptoms: fatigue, PEM, brain fog, unrefreshing sleep, and orthostatic intolerance-related symptoms (matching Institute of Medicine ME/CFS diagnostic criteria). The perceived treatment benefits reported by both groups were highly correlated. Disease severity, sex, disease duration, diagnosis status, and age had a greater influence on perceived treatment benefit than diagnosis.
Some treatments were considered helpful for a broad range of symptoms. Treatments with the greatest perceived benefit included pacing, fluids/electrolytes, and compression stockings. Graded exercise therapy (GET) received the lowest, with most participants reporting harm. However, as some participants reported harm from certain treatments and the study had limitations, the authors emphasised the importance of tailoring treatment to each patient’s individual needs.
The authors created four participant symptom profiles: (i) multisystemic symptomatology, (ii) POTS dominant presentation, (iii) cognitive and sleep dysfunction with increased pain, and (iv) milder symptomatology. The treatments with the greatest perceived benefits were largely effective across the profiles. However, other treatments showed varying effects across different profiles.
Limitations of the study included self-reported data; symptom, comorbidity and treatment diversity; potential biases; non-randomisation; and low sample size for some treatments.
The authors suggest the findings highlight opportunities to consider combining ME/CFS and long COVID in research and clinical care. Given the lack of FDA-approved treatments, participants’ reported experiences may provide insights to guide the development and testing of potential treatments.
New network to support ‘often misunderstood’ conditions
Authors: Liotta M
Publication: newsGP (30 Sep 2025)
Link: https://www1.racgp.org.au/newsgp/racgp/new-network-to-support-often-misunderstood-conditi
In this article, the Royal Australian College of General Practitioners (RACGP) announces the formation of a new Specific Interest group, the Energy-Limiting and Post-Infectious Conditions group. The group is led by Associate Professor Bernard Shiu, Clinical Director of Banksia Medical Centre and the Geelong Long COVID Clinic, who serves on the NHMRC ME/CFS Clinical Guidelines Committee.
Associate Professor Shiu said, “Conditions such as ME/CFS, long COVID, POTS, and fibromyalgia are increasingly presenting in general practice, yet many GPs feel under-resourced and isolated in managing them. The Specific Interests group will create a supportive community of practice where GPs can access practical tools, case-based learning, and evidence-based resources.”
The group is open to all RACGP members.