Researchers found an area in the brain of people with ME that reacts differently to activity than in healthy people.

ME/CFS may be caused by an imbalance in the brain

"We may have identified the physiological centre of fatigue," says the researcher behind a comprehensive study that has received a lot of attention.

Counting the number of researchers, the amount of money, and how many tests were carried out, this could well be the largest ME/CFS study ever conducted.

The number of participants, however, was not as high.

What is ME?

Myalgic encephalomyelitis (ME) – also called chronic fatigue syndrome (CFS) – is a debilitating and complex long-term condition characterised by extreme fatigue that is not significantly improved by rest.

Patients can experience flare-ups after minimal mental or physical activity. 

There is currently no cure for ME/CFS.

The study was backed by the National Institutes of Health (NIH) in the USA, which allocated 8 million USD. The researchers came from NIH's research centres and other national and international research centres. A total of 75 researchers from various fields participated.

The researchers were looking for the biological mechanisms behind ME/CFS.

Participant recruitment was strict.

Unanimous decisions in the expert panel

The researchers interviewed 217 people with ME/CFS and examined their medical records. Of these, 27 were selected for further evaluation. Several of these turned out to have other diseases that had been overlooked, including cancer, muscle disease, and lung disease.

Only 17 were considered to have ME/CFS by a unanimous panel of doctors with expertise in ME. All the participants had developed ME following an infection. 21 healthy participants were recruited for a control group.

Then came the pandemic, stopping the further recruitment of participants.

But the study started.

Every conceivable test

The participants spent at least one week at the NIH to undergo a whole lot of medical tests.

The researchers took every sample and test they could think of, according to Avindra Nath, clinical director of the U.S. National Institute of Neurological Disorders and Stroke (NINDS), in

Samples of blood, skin, muscles, and all bodily fluids were taken. The participants underwent physical and mental examinations through many different tests. Their brains were scanned. They spent time in specially designed chambers, allowing the researchers to examine their digestion, energy expenditure, metabolism, sleep, and bowels. They underwent physical tests to see how their heart, lungs, and muscles reacted to exercise.

The results have now been published in Nature Communications.

They point towards ME/CFS being caused by a dysfunction in the brain.

Change that disturbs

“We may have identified a physiological focal point for fatigue in this population. Rather than physical exhaustion or a lack of motivation, fatigue may arise from a mismatch between what someone thinks they can achieve and what their bodies perform ,” lead author of the study, Brian Walitt, says in an NIH press release.

The researchers scanned the brains of the ME patients. From these images, they conclude that there is a change in a specific region of the brain in those with ME/CFS. It interferes with patients’ tolerance for exertion and perception of fatigue. Analyses of spinal fluid support this finding.

This area of the brain contributes to determining how much effort should be put into a task. The researchers took pictures of the participants' brains when they were asked to do something physical. They observed that the brain region had lower activity in ME patients, whereas it became more active in healthy participants.

The immune system affects the brain

Other tests showed that the participants with ME/CFS had a chronically activated immune system. Even without viruses or bacteria being present, their immune system continued to fight off invaders.

The researchers believe that the active immune system affects the brain and leads to biochemical changes, which in turn create problems in the body.

The study has received a lot of attention in international media. Many ME/CFS researchers have commented on it.

Several praise the thoroughness and scope of the study, including Professor Karl Morten, who conducts research on ME at the University of Oxford in England.

“This is such an important paper. We've had lots of little studies showing there might be a problem with this cell or that cell, but no one has really looked at everything in one patient before,” Morten told The Guardian.

Nancy Klimas studies and treats ME/CFS at Nova Southeastern University in the USA.

Klimas told Science that her big takeaway from the study "is that this is a disease of the brain. The inability to sustain energy was coming from” that organ.

Researchers have long had disagreements about the causes of ME/CFS.

One or two brains?

Vegard Bruun Bratholm Wyller is the head of research at the Department of Pediatrics at Akershus University Hospital, and professor at the University of Oslo's Institute of Clinical Medicine.

He has been researching ME/CFS since 2003.

Wyller previously explained ME/CFS as being due to a hypersensitivity in the brain. This leads to signals from the outside world being overinterpreted because the nervous system is on continuous high alert.

"The findings in the new study fit very well with both what I have said and with a number of studies about the central mechanism of fatigue," he tells

But Avindra Nath, senior author of the study, tells The New York Times that the results confirm that ME/CFS is biological, not psychological.

Wyller thinks this statement goes further than the study has evidence to support.

“It’s highly unusual to make a distinction between the biological and the psychological brain. There's a lot of research showing that such a distinction can't be made," he says.

The brain is not damaged

The finding in Nath's study concerns a functional change in the brain that disrupts how ME/CFS patients handle exertion and fatigue.

“This doesn’t mean that the brain is damaged or broken in any way. The change lies in how the brain functions in people with ME. It might be that their brain is continuing to respond as if the body is ill, even though the infection is long gone,” says Wyller.

Our brains are constantly working to predict what will happen next.

“If your brain tells you that a task is much more demanding than itactually is, then you won’t be able to mobilise the necessary areas of the brain to do the task. This aligns well with what we generally know about fatigue, regardless of whether we’re talking about ME or other forms of fatigue,” he says.

Four of the participants with ME recovered during the NIH study.

Everything they didn't find

“This could have to do with the brain being plastic, about learning in the broadest sense. If the brain has learned something wrong, like that the body is still ill, it can learn something new. That makes sense given the fact that four of the study patients have recovered,” says Wyller.

There is no difference between the biological and psychological brain, according to Vegard Bruun Bratholm Wyller.

Participants with ME/CFS did not perform worse than the healthy controls on a wide range of tests, such as sleep, memory, learning, mental health problems, lung function, transport of oxygen to muscle tissue, muscle fibres, nerve fibres, how the body transforms energy into work or rest, energy production in the cells, or the ability to fight infections. Each of these areas has previously been linked to ME/CFS.

“The strength of this study is that the researchers carried out a very thorough survey, and they had many negative findings, which are important to publish,” he says.

“The tendency in the ME/CFS field is to publish only positive findings, even though they could be accidental or the methods might have been faulty. This study, conducted by reputable research institutions with substantial resources, carried out extensive testing, lending credibility to their negative findings.” 

Yet, the study has not been without its critics.

Too few participants

Lucinda Bateman, who treats ME patients at the Bateman Horne Center in the USA, is critical of how the participants were selected.

All the participants in the study had developed ME/CFS following an infection and had been ill for less than five years. They also had to endure both the journey to the clinic and all the sample collecting and tests.

This means that the results do not fully reflect all those who have ME/CFS, Bateman writes in a Facebook post.

Karl Johan Tronstad, a professor at the University of Bergen's Department of Biomedicine, also points to the number of participants, which was far fewer than originally planned.

The researchers cannot find as many differences with so few participants as they would have with more, according to Tronstad.

He is also critical of how the researchers are interpreting the results from the samples and tests.

Other explanations

"The researchers' interpretation of a possible causal relationship between the findings concerning brain dysfunction and fatigue is based on a weak foundation. The way we look at it, other explanations for ME/CFS are significantly more likely,” Tronstad writes in an email to 

Karl Johan Tronstad will use data from the new study in his own research on ME/CFS.

However, he also sees positive aspects of the study:

“The most important thing about the new NIH study is that it contains measurements that can undoubtedly be valuable in illuminating aspects of the nervous system, immune system, and energy metabolism in those with ME/CFS. But unfortunately, the study hasn’t provided us with many new answersat this time,” he writes.

Tronstad studies how the cells in ME patients utilise and convert energy. The body needs more oxygen after activity, but Tronstad and his colleagues found that in some people, less oxygen travels from the blood into the cells.

“Our findings regarding the energy supply to the cells in ME patients are based on studies with significantly more participants. This allows us to delve deeply into the data and identify subgroups of patients with different patterns in the changes,” he writes.

The way forward

"The new NIH study does not directly provide new insights that affect our conclusions from previous studies. The researchers have not gone as far in comparing the new data with previous findings, and we ourselves will investigate whether there is anything in the large dataset that can shed new light on what we have worked on," writes Tronstad.

The new study made a discovery from muscle samples that strengthens Tronstad's hypothesis about a reduced supply of oxygen to the cells.

However, the tests from the NIH study do not show differences in cellular energy metabolism among participants with ME.

The researchers behind the new study plan to publish further studies based on the data they have collected. Among other things, they found several differences between men and women with ME/CFS.

They also hope that researchers will test whether the findings apply to larger groups of ME patients, as well as those with long Covid, according to NIH. And most of all, they hope that their results can be used to find treatments.


Walitt et al. Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndromeNature Communications, vol. 15, 2024. DOI: 10.1038/s41467-024-45107-3


Translated by Ingrid P. Nuse

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