In October 2025, a group of clinicians, researchers (including myself), and patient advocates published a peer reviewed letter of correspondence in Nature Communications in response to the NIH “deep phenotyping” study, which involved 75 researchers across a wide range of disciplines.
They examined 17 people with post‑infectious ME/CFS and 21 healthy volunteers, who completed an extensive battery including brain imaging, spinal fluid analysis, immune and autonomic testing, metabolic assays, cognitive tests, and, for a smaller subgroup (8 ME/CFS and 9 healthy volunteers), a single cardiopulmonary exercise test (CPET).
From these data, combined with brain imaging and stress-related chemicals (catecholamines) in spinal fluid, the authors argued that the patients have an “altered effort preference” for avoiding high‑effort, high‑reward options on the Effort Expenditure for Rewards Task (EEfRT). That is, they were less likely than healthy volunteers to select harder trials that offered larger rewards.
They further stated that “effort preference, not fatigue, is the defining motor behavior of this illness” (p. 10). They also suggested that this altered effort preference, together with physical deconditioning, accounts for key manifestations of ME/CFS, thus shifting emphasis away from fatigue and post‑exertional malaise (PEM) as primary feature of the illness.
Our letter highlights two key points in response:
- Given that ME/CFS is multisystemic, heterogeneous, and still scientifically uncertain in many respects, it is not reducible to effort, lack of motivation, or deconditioning. The broader literature and patient reports overwhelmingly demonstrate this.
- To test PEM, the investigators used single cardiopulmonary exercise test (CPET), which does not capture what happens to patients within the 24–72-hour period after exertion, when PEM typically occurs. The study did not adequately test whether PEM is related to “effort preference” because this one-day CPET misses the delayed trajectory of the “crash” that usually follows.
For more than two decades, ME/CFS researchers have used two day CPET to measure PEM objectively. They found that many patients can undergo one maximal exercise test without substantial differences from healthy individuals. However, when these same patients are asked to repeat the same test the next day, they often show clear declines in oxygen consumption, work output, and heart rate responses, even at lower workloads. On the other hand, healthy individuals who are simply deconditioned do not show this kind of consistent, day to day collapse in performance.
This tells us that the problem is not just “being out of shape” or lacking motivation; it reflects a deeper issue with how the body produces and uses energy when stressed.
Our letter also addresses how the authors describe patients’ symptoms. They appear to downplay PEM as “feelings of discomfort” after exertion, and patients’ pacing or activity limits are framed as attempts to “avoid discomfort.” For those living with ME/CFS, this description does not match their lived experience. PEM is not mere discomfort, but rather it can mean:
- Being bedbound or housebound for days after doing minor activity.
- Severe worsening of pain, cognitive problems (“brain fog”), light and sound sensitivity, sleep problems, and autonomic symptoms.
- Loss of the ability to work, study, or care for oneself after relatively small exertions.
Effort preference in the study is defined as “the decision to avoid the harder task when decision-making is unsupervised” and the EEfRT was developed and validated in the context of depression, anhedonia, and psychiatric research. This behavioral explanation appears to suggest that patients could perform work but are not choosing to. Furthermore, it may encourage recommendations that patients find harmful, such as graded exercise therapy, while undermining the legitimacy of patients’ reports of severe, delayed, and prolonged worsening after exertion.
In our letter, we emphasize that research and clinical communications must convey the legitimacy of ME/CFS as a medical disease and recognize the physiological basis of symptoms to avoid reinforcing long standing stigma.
We also raise methodology concerns about the small sample size which affects the generalizability of their findings. This is known as sampling bias and is a major threat to external validity, meaning the findings cannot be inferred to the population they purportedly represent. We argue that these issues mean the results should be interpreted cautiously—and certainly not used to redefine ME/CFS as a problem of “effort preference” and deconditioning.
Why this matters
Publication of our letter was not a quick and easy process. The peer review process was stringent and it took around 18 months from submission to acceptance. The fact that Nature Communications ultimately accepted our critique is important for multiple reasons:
- It shows that patient informed ME/CFS expertise is being taken seriously.
- It places on record that an NIH backed “effort preference” model is not an adequate explanation of ME/CFS and PEM.
- It reminds other researchers that future studies should consider appropriate design that matches study aims (such as two day CPET for testing PEM outcomes).
- It suggests that greater care must be taken to avoid downplaying or mischaracterizing the illness.
Going forward, ME/CFS researchers need to design studies that truly capture the facets of PEM, including delayed and prolonged worsening, not just what happens during or immediately after a single test. Repeated testing with larger sample sizes is needed to further our understanding of PEM and the underlying biology.
If you live with ME/CFS, you should not have to defend whether your illness is psychological or whether you are trying hard enough. This letter is a step toward ensuring the scientific record continues to recognize ME/CFS as a serious organic disease.
If you want to read the letter itself, here is the direct link: https://www.nature.com/articles/s41467-025-64538-0
NIH Study link: https://doi.org/10.1038/s41467-024-45107-3