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New insights into ME/CFS help guide intervention

MDlinx May 10, 2024

Researchers at the NIH have found brain, metabolic, and immune abnormalities in people with post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), for which no disease-modifying treatments exist. Results from this small study were published in Nature Communications.

Walitt B, Singh K, LaMunion SR, et al. Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome. Nat Commun. 2024;15(907).


“People with ME/CFS have very real and disabling symptoms, but uncovering their biological basis has been extremely difficult,” said Walter Koroshetz, MD, director of NIH’s National Institute of Neurological Disorders and Stroke, in a press release.

National Institutes of Health. NIH study offers new clues into the causes of post-infectious ME/CFS [press release]. February 21, 2024.

“This in-depth study of a small group of people found a number of factors that likely contribute to their ME/CFS." 


Now, researchers hope to apply these findings to larger cohorts, aiming to improve treatment options for this often-debilitating condition.


Multidimensional approach


Previous studies show inconsistency in how immune and microbiome abnormalities relate to ME/CFS. In this cross-sectional, exploratory case-control study, the NIH researchers investigated the underlying pathophysiology of ME/CFS using a phenotyping approach that included physiological measures and performance testing, along with immunological, biochemical, and microbiological assays.


The approach also utilized measurement of gene expression, proteins, metabolites, and lipids, and it accounted for factors such as physical capacity, effort preference, and deconditioning that could affect the results.

The study included 17 individuals with ME/CFS, which had developed after a viral or bacterial infection within the past 5 years, and 21 matched healthy individuals. The participants underwent numerous evaluations, including tests for physical and cognitive performance, tests for autonomic function, fMRI, skin and muscle biopsies, and blood and cerebrospinal fluid (CSF) analyses. Also evaluated were the gut microbiome, diet, energy consumption, metabolism, and sleep patterns. Cardiopulmonary exercise testing was also conducted.


Brain abnormalities and imbalances


Results from fMRI brain scans undertaken while participants completed a grip test suggested those with ME/CFS failed to maintain a moderate grip force, despite a lack of difference in maximum grip strength or arm muscle mass compared with healthy participants.

The fact that ME/CFS participants showed lower activity in the right temporal-parietal junction may explain this fatigue.

In terms of the cognitive aspects of fatigue, participants with ME/CFS had difficulties making decisions about exerting and sustaining physical effort. Although there were no signs of muscle fatigue, their motor cortex remained abnormally active during fatiguing tasks.

“We may have identified a physiological focal point for fatigue in this population,” said primary author Brian Walitt, MD, MPH, in the press release. “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.”

CSF analysis revealed low levels of catecholamines in individuals with ME/CFS, which were associated with poorer motor performance, behaviors related to effort, and cognitive symptoms. Immune blood testing showed that participants with ME/CFS had higher levels of naive B cells and lower levels of switched memory B cells. According to the release, immune activation affects the brain in “various ways, causing biochemical changes and downstream effects like motor, autonomic, and cardiorespiratory dysfunction.”


Differences between the sexes


The study analyses also disclosed differences between the male and female participants with ME/CFS. They had distinctly different patterns of inflammation markers, gene expression, immune cells, and metabolic markers. 

In particular, men showed altered T cell activation and markers of innate immunity, while female participants had abnormal B cell and white blood cell growth patterns.

“Men and women were quite divergent in their data, and that tells you that ME/CFS is not one-size-fits-all,” explained Dr. Nath. “Considering male and female immune differences in ME/CFS, the results may open up new avenues of research that could provide insight into other infection-associated chronic diseases.”


Treatment implications


The authors proposed that post-infectious ME/CFS appears to be a centrally mediated disorder, consequent to immune dysfunction and microbial alterations that impact the central nervous system. 


This leads to decreased metabolite concentrations followed by alterations in brain function. Both autonomic and central motor dysfunction result in reduced physical activity, eventually leading to physical deconditioning.

In discussing the implications for treatment, the study authors pointed to the role of immune exhaustion.

“The finding of possible immune exhaustion,” they wrote, “suggests that immune checkpoint inhibitors may be therapeutic by promoting clearance of foreign antigen. Immune dysfunction leads to neurochemical alterations that impact neuronal circuits, which may be another point of intervention. Therapeutically targeting downstream mechanisms, with exercise, cognitive behavioral therapy, or autonomic directed therapies, may have limited impact on symptom burden, as it would not address the root cause of ME/CFS. However, combination therapy affecting multiple pathways could be considered.”

What this means for you

Post-infectious ME/CFS appears to be a centrally mediated disorder, with distinct brain, metabolic, and immune effects. Knowledge of these pathophysiologic mechanisms may help guide treatment targets. However, the findings from this small study need to be confirmed in a larger investigation.


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