This month’s Research Digest highlights the importance of carefully measuring the lived and biological complexity of ME/CFS. The featured studies examine how post-exertional malaise, sleep disturbance and cellular energy pathways are investigated, while also showing that standard measures do not always capture the full experience of illness. Together, these articles point to the need for more sensitive approaches, including symptom tracking after exertion, multi-night sleep assessment, and standardised research methods that consider whether people are experiencing PEM at the time of sampling.
Contributing Digesters: Lauren, Anna, Sarah & Anna.
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.
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BIOLOGY
Cardiopulmonary exercise test results do not change over two sequential days in patients with chronic fatigue syndrome
Authors: Mancini DM, Cook DB, Brunjes DL, Soto T, Blate M, Quan P, … Natelson BH (Icahn School of Medicine at Mount Sinai, United States).
Publication: Frontiers in Physiology (May, 2026)
Link: https://doi.org/10.3389/fphys.2026.1816082
Easy Read Overview: This study looked at whether doing two cardiopulmonary exercise tests (CPETs) on two days in a row could identify post-exertional malaise (PEM) in people with ME/CFS. It found that people with ME/CFS did not show greater drops in exercise performance on the second day than healthy people. However, people with ME/CFS felt the exercise was much harder and reached lower maximum heart rates, even though their test results were similar. The researchers concluded that two-day CPET alone is not a reliable way to measure PEM, and that tracking symptom worsening after exercise may be more useful.
Two-day cardiopulmonary exercise testing (CPET) has been proposed as an objective measure of post-exertional malaise (PEM), based on reports that exercise capacity declines on the second day of testing. However, previous studies have produced inconsistent findings. This study aimed to determine whether two-day CPET reliably distinguishes people with ME/CFS from sedentary healthy controls.
This cross-sectional study included 58 people with ME/CFS meeting modified Fukuda criteria requiring post-exertional malaise, and 25 age- and sex-matched sedentary controls. Participants completed maximal CPETs on two consecutive days, with measures including peak oxygen consumption (VO₂), ventilatory threshold, heart rate, and perceived exertion.
No significant differences were found between Day one and Day two for peak VO₂, ventilatory threshold, or other exercise measures in either group. Although some participants showed reduced performance on the second day, this occurred in both groups at similar rates. People with ME/CFS consistently reported significantly greater perceived exertion throughout both exercise tests and achieved lower maximum heart rates than controls, despite comparable objective exercise performance.
The authors conclude that changes in CPET performance over two consecutive days are not a reliable marker of PEM or disability in ME/CFS. Instead, the consistently higher perception of effort and lower peak heart rate suggest altered physiological responses to exercise that are not captured by standard CPET measures. They propose that monitoring symptom worsening after exercise may provide a more sensitive assessment of PEM than repeat exercise testing alone.
BIOLOGY
Sleep in myalgic encephalomyelitis/chronic fatigue syndrome shows marked night to night fluctuation under free living conditions—results from a matched case control study
Author: Saurel M, Fornasieri I, Del Sordo GC, Chatain C, Fantini ML, Gruet M, Saidi O (University of Toulon, France)
Publication: Journal of Clinical Sleep Medicine (March, 2026)
Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC13172179/pdf/44470_2026_Article_79.pdf
Easy Read Overview: This study compared the sleep of 38 adults with ME/CFS and 38 healthy adults by monitoring their sleep over seven nights with a wrist-worn device and sleep questionnaires. People with ME/CFS slept for about the same amount of time as healthy participants, but they took longer to fall asleep, woke up more often during the night, and had more night-to-night changes in sleep quality and efficiency. The study did not find clear differences between people with milder and more severe ME/CFS, but the sample was small and people with the most severe illness could not take part. The authors concluded that changes in sleep quality from night to night may be a key feature of ME/CFS and should be explored in larger studies.
As non-restorative sleep is a hallmark symptom for people with ME/CFS (pwME/CFS), and there is a paucity of evidence about real-world sleep of pwME/CFS, this case-control study seeks to increase knowledge about sleep patterns and variability of pwME/CFS.
Adult participants consisted of 38 pwME/CFS (who met the International Consensus Criteria (ICC)), and 38 controls (matched by age, sex and BMI). Participants were interviewed to collect socio-demographic data and medical history. To assess sleep, participant’s movement was monitored via an accelerometer-based wristband worn for 7 days. Participants also completed the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), and a sleep diary (which was aligned with accelerometer data). Three indices were calculated to assess intra-individual sleep variability. Participants with ME/CFS were stratified by severity using the Bell Disability Scale. PwME/CFS with severe symptoms at rest were excluded due to inability to tolerate data collection.
Total sleep time did not differ between the ME/CFS and control groups. Although participants with ME/CFS spent more time in bed and had a more regular sleeping time, they had poorer and greater variability of sleep efficiency. Participants with ME/CFS also had greater sleep onset latency, wake after sleep onset, and wake time instability.
Sensitivity analysis indicated that employment status was not associated with the sleep outcomes. Analyses by ME/CFS severity subgroup found no differences in mean sleep duration or sleep variability. However, the authors acknowledged that the study may not have been adequately powered to detect differences between subgroups due to the small sample size and the exclusion of people with the most severe illness.
Participants with ME/CFS exhibited lower sleep efficiency than controls, while total sleep time did not differ between the groups. This suggests the sleep disturbance in ME/CFS may be related to the capacity to initiate and maintain sleep (rather than sleep duration). The magnitude of night-to-night sleep variability among participants with ME/CFS was similar to that observed in clinical insomnia and has been associated with inflammatory processes and autonomic dysregulation.
The authors conclude the findings point to sleep continuity variability as a distinct feature of ME/CFS. Thus, multi-night intra-individual sleep variability may be a clinically relevant measure of sleep health for pwME/CFS. Larger, more complex studies are needed to clarify the findings and examine how disease ME/CFS severity impacts sleep variability. This may enable greater understanding of non-restorative sleep for pwME/CFS, and development and testing of management strategies.
BIOLOGY
Indistinguishable mitochondrial phenotypes after exposure of healthy myoblasts to myalgic encephalomyelitis/chronic fatigue syndrome or control serum
Author: Ryback AA, Hillier CB, Loureiro CM, Ponting CP, & Dalton CF (Sheffield Hallam University, United Kingdom)
Publication: PLOS One (February 2026)
Link: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0341334
Easy Read Overview: This study tested whether blood serum from people with ME/CFS changed how healthy muscle cells produced energy. Unlike an earlier, smaller study, the researchers found no differences between muscle cells treated with serum from people with ME/CFS and those treated with serum from healthy people. The authors suggested this may be because blood samples were not collected when participants were experiencing post-exertional malaise (PEM), or because of small differences in the study methods. They concluded that future research should use standardised methods and compare samples taken during and outside of PEM to better understand whether blood contains disease-related factors.
Previous studies have found that exposure of cultured cells to the serum or plasma of people with ME/CFS causes phenotypic changes to the cells. A study by Fluge et al (2016) found that treating myoblasts with serum from participants with ME/CFS resulted in an increased maximal respiratory capacity of the myoblasts, compared to treating with serum from healthy controls. The authors sought to replicate this study with a larger sample size.
Sixty-seven participants with ME/CFS (Canadian Consensus Criteria and/or Institute of Medicine criteria) and 53 healthy controls were included in this study. Due to ME/CFS affecting more women than men, and to reduce heterogeneity, all participants in the study were female. Blood samples were taken from all participants, and the sera were used to treat healthy cultured myoblasts. Myoblasts then underwent Seahorse mitochondrial stress tests.
In contrast to the original study, the authors observed no significant differences between the cultures that were treated with sera from people with ME/CFS and healthy controls. Oxygen consumption rate at maximal respiratory capacity (the primary outcome of this study) was not significantly impacted, nor were secondary outcomes of oxygen consumption rate under three other conditions.
While this study aimed to replicate the Fluge et al (2016) study, the authors noted some small differences in methodology, which may have impacted the results. The authors recommended that future studies use standardised protocols to improve replication and comparison between studies.
The authors also noted that study participants may not have been experiencing post-exertional malaise (PEM) when blood samples were collected, and that it is possible that any effects of ME/CFS serum may only be detectable during PEM. They recommend that future studies take samples over time, on both PEM days and non-PEM days, to determine whether serum effects differ.
The results of this study provide evidence against the hypothesis that ME/CFS sera can affect healthy myoblast mitochondrial phenotypes differently than healthy sera in vitro. The authors note that these findings do not rule out the possibility of serum containing ME/CFS-biased factors, but suggest that the methodology of this study is unlikely to detect any such factors. The authors suggest that future studies may benefit from exploration of compartments other than blood for disease-specific factors.
BIOLOGY
Central noradrenergic deficiency in post-infectious chronic fatigue: Neurobehavioral correlates
Author: Aregawi L, Walitt B, Sullivan P, Norato G, Benjamin RN, Goldstein, DS (National Institutes of Health, USA)
Publication: Brain Communications (May, 2026)
Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC13202209/pdf/fcag173.pdf
Easy Read Overview: This study looked at whether people with ME/CFS or long COVID have changes in brain chemicals involved in alertness, energy and body regulation. Researchers found lower norepinephrine pathway activity in people with ME/CFS and long COVID compared with healthy controls, but no clear differences in dopamine activity. Lower norepinephrine activity was linked with poorer physical and mental health measures, reduced hand-grip endurance and, in long COVID, post-exertional malaise. However, the study was small and cannot show whether these changes cause symptoms. Further research is needed to confirm the findings and explore whether this pathway could inform future treatments.
To date, no specific neurotransmitter abnormalities had previously been clearly identified in post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) or post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (PASC, long COVID).
This observational, cross-sectional study investigated whether people with PI-ME/CFS and/or PASC showed shared abnormalities in the central catecholaminergic pathways, specifically the norepinephrine and dopamine pathways. The study included 38 participants with PI-ME/CFS or PASC, along with healthy volunteers and people with Parkinson’s disease as comparison groups. Parkinson’s disease (PD) was included as a positive control group, as it is associated with both central noradrenergic and dopaminergic deficiencies.
The PI-ME/CFS, PASC, and PD participants had previously been evlauated at the National Institutes of Health (NIH). Cerebrospinal fluid (CSF) was collected by lumbar puncture to measure levels of catecholamines and their metabolites. Investigators used these measures to calculate indices of central norepinephrine pathway and dopamine pathway activity, and examined their associations with clinical, neurobehavioral and physiological outcomes.
Self-reported questionnaires assessed health, well-being, quality of life, pain, cognition, fatigue and sleep. Neuropsychological tests assessed visual and verbal memory, grip strength, and task-related fatigue. Orthostatic hypotension was assessed using blood pressure measures, while postural tachycardia syndrome was assessed using tilt-table testing, including heart rate measures.
Compared with healthy volunteers, the PD, PI-ME/CFS and PASC groups had lower mean norepinephrine pathway activity, consistent with noradrenergic deficiency. Lower norepinephrine pathway activity was associated with poorer physical and mental health measures, as well as reduced hand-grip duration. In the PASC group, norepinephrine pathway activity was associated with post-exertional malaise (PEM).
In contrast, the PI-ME/CFS and PASC groups did not differ from healthy volunteers in dopamine pathway activity. For the PI-ME/CFS and PASC groups, norepinephrine pathway activity did not correlate with other symptoms, including pain, cognition, or memory. When PI-ME/CFS and PASC participants were considered together, norepinephrine pathway activity was also not related to orthostatic hypotension or excessive tachycardia.
The authors conclude that PI-ME/CFS and PASC are associated with a central catecholaminergic pattern marked by noradrenergic, but not dopaminergic, deficiency. They also report that reduced activity in the norepinephrine pathway was associated with key clinical features, including PEM.
The authors hypothesise that reduced norepinephrine pathway activity may reflect reduced ATP availability for vesicular uptake and retention, which could help explain symptoms such as fatigue, poorer general health measures and reduced hand-grip duration, although this mechanism was not directly tested in the study, and that the small sample size may limit generalisability.
The authors suggest that, if further research confirms significant noradrenergic deficiency in these conditions, the findings could have implications for future treatment development.
