Is chronic fatigue syndrome all in your brain?

Graphic showing 4 small scientists in white coats viewed from behind looking at a large computer screen with an image of the brain; background is light green

Chronic fatigue syndrome (CFS) –– or myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), to be specific ––  is an illness defined by a group of symptoms. Yet medical science always seeks objective measures that go beyond the symptoms people report.

A new study from the National Institutes of Health (NIH) has performed more diverse and extensive biological measurements of people experiencing CFS than any previous research. Using immune testing, brain scans, and other tools, the researchers looked for abnormalities that might drive health complaints like crushing fatigue and brain fog. Let’s dig into what they found and what it means.

What was already known about chronic fatigue syndrome?

In people with chronic fatigue syndrome, there are underlying abnormalities in many parts of the body: The brain. The immune system. The way the body generates energy. Blood vessels. Even in the microbiome, the bacteria that live in the gut. These abnormalities have been reported in thousands of published studies over the past 40 years.

Who participated in the NIH study?

Published in February in Nature Communications, this small NIH study compared people who developed chronic fatigue syndrome after having some kind of infection with a healthy control group.

Those with CFS had been perfectly healthy before coming down with what seemed like just a simple “flu”: sore throat, coughing, aching muscles, and poor energy. However, unlike their experiences with past flulike illnesses, they did not recover. For years, they were left with debilitating fatigue, difficulty thinking, a flare-up of symptoms after exerting themselves physically or mentally, and other symptoms. Some were so debilitated that they were bedridden or homebound.

All the participants spent a week at the NIH, located outside of Washington, DC. Each day they received different tests. The extensive testing is the great strength of this latest study.

What are three important findings from the study?

The study had three key findings, including one important new discovery.

First, as was true in many previous studies, the NIH team found evidence of chronic activation of the immune system. It seemed as if the immune system was engaged in a long war against a foreign microbe — a war it could not completely win and therefore had to keep fighting.

Second, the study found that a part of the brain known to be important in perceiving fatigue and encouraging effort — the right temporal-parietal area — was not functioning normally. Normally, when healthy people are asked to exert themselves physically or mentally, that area of the brain lights up during an MRI. However, in the people with CFS it lit up only dimly when they were asked to exert themselves.

While earlier research had identified many other brain abnormalities, this one was new. And this particular change makes it more difficult for people with CFS to exert themselves physically or mentally, the team concluded. It makes any effort like trying to swim against a current.

Third, in the spinal fluid, levels of various brain chemicals called neurotransmitters and markers of inflammation differed in people with CFS compared with the healthy comparison group. The spinal fluid surrounds the brain and reflects the chemistry of the brain.

What else did study show?

There are some other interesting findings in this study. The team found significant differences in many biological measurements between men and women with chronic fatigue syndrome. This surely will lead to larger studies to verify these gender-based differences, and to determine what causes them.

There was no difference between people with CFS and the healthy comparison group in the frequency of psychiatric disorders — currently, or in the past. That is, the symptoms of the illness could not be attributed to psychological causes.

Is chronic fatigue syndrome all in the brain?

The NIH team concluded that chronic fatigue syndrome is primarily a disorder of the brain, perhaps brought on by chronic immune activation and changes in the gut microbiome. This is consistent with the results of many previous studies.

The growing recognition of abnormalities involving the brain, chronic activation (and exhaustion) of the immune system, and of alterations in the gut microbiome are transforming our conception of CFS –– at least when caused by a virus. And this could help inform potential treatments.

For example, the NIH team found that some immune system cells are exhausted by their chronic state of activation. Exhausted cells don’t do as good a job at eliminating infections. The NIH team suggests that a class of drugs called immune checkpoint inhibitors may help strengthen the exhausted cells.

What are the limitations of the study?

The number of people who were studied was small: 17 people with ME/CFS and 21 healthy people of the same age and sex, who served as a comparison group. Unfortunately, the study had to be stopped before it had enrolled more people, due to the COVID-19 pandemic.

That means that the study did not have a great deal of statistical power and could have failed to detect some abnormalities. That is the weakness of the study.

The bottom line

This latest study from the NIH joins thousands of previously published scientific studies over the past 40 years. Like previous research, it also finds that people with ME/CFS have measurable abnormalities of the brain, the immune system, energy metabolism, the blood vessels, and bacteria that live in the gut.

What causes all of these different abnormalities? Do they reinforce each other, producing spiraling cycles that lead to chronic illness? How do they lead to the debilitating symptoms of the illness? We don’t yet know. What we do know is that people are suffering and that this illness is afflicting millions of Americans. The only sure way to a cure is studies like this one that identify what is going wrong in the body. Targeting those changes can point the way to effective treatments.

About the Author

photo of Anthony L. Komaroff, MD

Anthony L. Komaroff, MD, Editor in Chief, Harvard Health Letter

Dr. Anthony L. Komaroff is the Steven P. Simcox/Patrick A. Clifford/James H. Higby Professor of Medicine at Harvard Medical School, senior physician at Brigham and Women’s Hospital in Boston, and editor in chief of the Harvard … See Full Bio View all posts by Anthony L. Komaroff, MD

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