Scientists have uncovered compelling evidence for abnormalities in the brain and immune systems of patients with chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME).
The findings, in one of the most rigorous investigations to date, begin to illuminate the biological basis for the illness that can cause disabling fatigue. The study is the first to demonstrate a link between imbalances in brain activity and feelings of fatigue, and suggests that these changes could be triggered by abnormalities in the immune system.
“People with ME/CFS have very real and disabling symptoms, but uncovering their biological basis has been extremely difficult,” said Walter Koroshetz, director of NIH’s National Institute of Neurological Disorders and Stroke (NINDS) in the US. “This in-depth study of a small group of people found a number of factors that likely contribute to their ME/CFS.”
The study involved only 17 patients and the findings need to be confirmed in a larger group before they can be claimed as a roadmap towards new treatments. It is also not clear to what extent the findings apply to long Covid as the patients were recruited and assessed before the pandemic. But scientists have described the work as a long overdue deep dive into the biology of the condition.
“This is such an important paper and one I am so pleased to see come out,” said Prof Karl Morten, who researches ME/CFS at the John Radcliffe hospital, University of Oxford, and was not involved in the latest work. “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.”
Patients in the study, carefully selected from an initial pool of 300, had all experienced an infection prior to becoming ill. During the study, they stayed at an NIH clinic for a week and were given a wide range of physiological assessments.
Results from functional magnetic resonance imaging (fMRI) brain scans showed that people with ME/CFS had lower activity in a brain region called the temporal-parietal junction (TPJ), which may cause fatigue by disrupting the way the brain decides how to exert effort. The motor cortex, a brain region that directs the body’s movements, also remained abnormally active during fatiguing tasks. However, there were no signs of muscle fatigue.
This suggests that fatigue in ME/CFS could be caused by a dysfunction of brain regions that drive the motor cortex and that changes in the brain may alter patients’ tolerance for exertion and their perception of fatigue.
“We may have identified a physiological focal point for fatigue in this population,” said Brian Walitt, associate research physician at NINDS and first author of the study, published in Nature Communications. “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.”
Morten said that the discovery of abnormalities in brain function does not suggest that patients are psychologically driving their own illness or have any control over it. “The brain can respond to stimuli and impact on the body,” he said. “The brain is physically, biochemically not functioning properly and it’s the illness that’s doing that, not the patient.”
The patients also had elevated heart rates and their blood pressure took longer to normalise after exertion. There were also changes to patients’ T cells, sampled from cerebrospinal fluid, suggesting these immune cells were trying to fight something off. This could indicate the immune system has failed to stand down after an infection has cleared or that a chronic infection is present, undetected, in the body.
The authors trace out a possible cascade of events, starting with a persistent immune response, which could cause changes in the central nervous system, leading to alterations in brain chemistry and ultimately affect the function of specific brain structures that control motor function and the perception of fatigue.
“We think that the immune activation is affecting the brain in various ways, causing biochemical changes and downstream effects like motor, autonomic, and cardiorespiratory dysfunction,” said Avindra Nath, clinical director at NINDS and senior author of the study.
The findings have been welcomed by scientists as an important step towards uncovering the underlying biological causes of the illness. Until now, the lack of any clear biological basis for the illness has led to patients being dismissed, stigmatised and having to navigate ineffective treatment options.
