Fatigue in post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may stem from dysfunction of integrative brain regions that drive the motor cortex, a deep phenotyping study suggested.

In an exploratory analysis of 17 ME/CFS patients and 21 healthy controls, those with ME/CFS had lower activity in the temporal-parietal junction on functional MRI (fMRI) than did controls, reported Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Maryland, and co-authors.

Cerebrospinal fluid (CSF) neurotransmitters like dopamine and other molecules varied between the two groups, the researchers observed in Nature Communications. People with ME/CFS had increased naive B cells and decreased switched memory B cells compared with controls. Men with ME/CFS had altered T-cell activation and markers of innate immunity, while women had abnormal B cell and white blood cell growth patterns.

Substantial differences during physical tasks also were noted in ME/CFS participants. Compared with controls, people with ME/CFS failed to maintain a moderate grip force, even though there was no difference in maximum grip strength or arm muscle mass. This correlated with decreased activity of the right temporal-parietal junction, a part of the brain focused on determining mismatch between willed action and movement, Nath and colleagues said.

“We did not find any structural abnormalities but multiple functional abnormalities, which gives hope that the illness is treatable and possibly reversible,” Nath told MedPage Today.

“The brain appears to be potentially driving the patient response,” said ME/CFS researcher Karl Morten, PhD, of the University of Oxford in England, who wasn’t involved with the study. “The big question is why? Is something still going on we are not yet aware of?” Morten posted on the U.K. Science Media Centre website. “The immune system is dysregulated and appears to still be showing an antigen response. Is this suggesting a foreign entity is still present, or has the system gone rogue?”

ME/CFS is a chronic multisystem illness characterized by activity-limiting fatigue. Its cause is unknown, but many people develop ME/CFS after an acute infection. There is no diagnostic test or FDA-approved treatment for the condition. An estimated 1.3% of U.S. adults — 1.7% of women and 0.9% of men — have ME/CFS.

Some ME/CFS symptoms overlap with long COVID symptoms, and it’s possible ME/CFS research may improve understanding of long COVID or other post-infectious syndromes. “Likely, if we are able to treat one of these illnesses, we will be able to treat them all,” Nath said.

Nath and more than 75 co-authors from 15 NIH centers and institutes used a deep phenotyping approach to isolate meaningful differences between healthy individuals and people with ME/CFS. They recruited people with ME/CFS symptoms between December 2016 and February 2020. A total of 217 individuals had detailed telephone interviews and medical record reviews. Of these, 27 came in person for a week-long research evaluation, which adjudicated 17 as having post-infectious ME/CFS by the unanimous consensus of an expert panel.

All ME/CFS participants had severe fatigue and post-exertional malaise that developed within 5 years after acute viral or bacterial infection. The group was matched with 21 healthy controls without clinical fatigue.

There were no group differences in age, sex, or body mass index. Patient-reported outcomes for fatigue, emotional distress, sleep disturbances, anxiety, and other symptoms were greater in the ME/CFS group than in healthy controls (P<0.05).

ME/CFS participants also had more self-reported total cognitive complaints and complaints in each of the five cognitive domains measured — attention, verbal memory, visuoperceptual, language, and visual memory — than controls (P<0.05). There were no group differences in the performance of any of the 15 neuropsychological tests administered, and no association emerged between any neuropsychological test and physical effort preference.

Post-infectious ME/CFS appears to be a centrally mediated disorder, Nath and colleagues concluded.

“We posit this hypothetical mechanism of how an infection can create a cascade of physiological alterations that lead to the post-infectious ME/CFS phenotype,” they wrote. “Exposure to an infection leads to concomitant immune dysfunction and changes in microbial composition. Immune dysfunction may be related to both innate and adaptive immune responses that are sex dependent. One possibility is that these changes are related to antigen persistence of the infectious pathogen.”

In turn, they added, “[t]hese immune and microbial alterations impact the central nervous system, leading to decreased concentrations of metabolites” that impacts the function of brain structures. This effect on the autonomic nervous system leads to decreased heart rate variability and decreased baroreflex cardiovascular function. In addition to those effects that reduce cardiopulmonary capacity, altered hypothalamic function “leads to decreased activation of the temporoparietal junction during motor tasks, leading to a failure of the integrative brain regions necessary to drive the motor cortex.”

The study “is useful to investigate correlations, but is unable to highlight causes of ME/CFS,” noted Chris Ponting, DPhil, of the University of Edinburgh in Scotland, who also wasn’t involved with the research.

The findings “will be helpful to reprioritize future, more mechanistic, experiments,” Ponting posted on the U.K. Science Media Centre website. “These should involve more than the 17 cases participating in this study, and should include people with ME/CFS without an infection prior to onset, and people who have been diagnosed for more than 5 years, the maximum for this study.”

Clinical trials also need to evaluate the pathophysiology of ME/CFS, Nath noted. “One such method might be to consider a platform trial where multiple agents can be studied and compared against one another with a single placebo arm,” he said.

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