Breaking ME/CFS News: 8 Years and 17 Patients Later, NIH Publishes Study

“Clues but not clarity” Science magazine reporter comments

A much-anticipated study of ME/CFS, conducted by the National Institute of Health’s National Institute of Neurological Diseases and Stroke (NINDS), was finally published February 21, 2024, eight years after it began in 2016.

Investigators described the roadblocks they’d encountered, including the challenge of enrolling individuals who fit their definition of “post-infectious ME/CFS” (PI-ME/CFS) patients, as well as the Covid-19 pandemic, which interrupted recruitment. The end result was a study performed with a cohort of only 17 PI-ME/CFS patients and 20 “healthy volunteers” (HV). (1)
 
The study was directed by Avindra Nath, Clinical Director of NINDS. His main areas of research are the neuropathogenesis of HIV infection, the role of endogenous retroviruses in neurological diseases, and undiagnosed neuroimmune and neuroinfectious diseases. The lead author on the publication is Brian T. Walitt, a staff clinician with NINDS who focuses on “deeply phenotyping” individuals who develop averse symptoms after exposures to infections.

Of the approximately 73 other coauthors, only six are not employees of NIH or another government health agency (such as the National Heart, Lung and Blood Institute, located in Bethesda near NIH). Those six researchers are associated with universities.

This will not be a comprehensive overview of the eight-year, 17-patient study, but if you would like to learn about the levels of dopamine, tryptophan, norepinephrine, butyrate, polyamine, and tricarboxylic acid (TCA) pathway metabolites, threonine and glutamine—and others—measured in this study, you can read it for free by using this shareable link: https://rdcu.be/dzgL6 (1).

“ME/CFS often occurs following an acute infection, designated post-infectious-ME/CFS (PI-ME/CFS), with an estimated incidence of 10–12% after certain infections,” the publication began. “The most well-known association of PI-ME/CFS has been with the Epstein-Barr Virus, but as the full extent of the sequelae of the COVID-19 pandemic are better understood, SARS-CoV-2 may become an even stronger correlate.”

Whatever one thinks of those prognostications of possible roles played by EBV and/or SARS-CoV-2, these investigators noted that, at present, “A major obstacle to rigorous ME/CFS research is case assessment due to the absence of a diagnostic biomarker.”

While describing the difficulties they’d encountered in recruiting study participants, they also introduced a main feature of the study: “effort preference.”

 “We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping,” Nath and colleagues reported. “Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue....” (1)

So, what is “effort preference” and how does it relate to fatigue?

As Nath et al. explained it, effort preference is “the decision to avoid the harder task.”

“The Effort-Expenditure for Rewards Task (EEfRT) [test] was used to assess effort, task-related fatigue, and reward sensitivity. ... Given equal levels and probabilities of reward, HVs chose more hard tasks than PI-ME/CFS participants.”

In other words: Healthy volunteers were confident they could undertake a difficult physical task and chose to do so, while ME/CFS patients did not. Could that be because ME/CFS patients knew the toll that a difficult physical task would take on their health? Nath and colleagues didn’t ask that question.

A difference in brain activity was identified as causing the relative physical weakness of ME/CFS patients as “...a failure of the integrative brain regions necessary to drive the motor cortex. This decreased brain activity is experienced as physical and psychological symptoms and impacts effort preferences, leading to decreased engagement of the motor system and decreases in maintaining force output during motor tasks.”

They explained this impaired brain activity in more detail:

“This difference in performance [between ME/CFS patients and HVs] correlated with decreased activity of the right temporal-parietal junction, a part of the brain that is focused on determining mismatch between willed action and resultant movement. Mismatch relates to the degree of agency, i.e., the sense of control of the movement. Greater activation in the HVs suggests that they are attending in detail to their slight failures, while the PI-ME/CFS participants are accomplishing what they are intending. This was further validated by measures of peripheral muscular fatigue and motor cortex fatigue that increased only in the HVs. Thus, the fatigue of PI-ME/CFS participants is due to dysfunction of integrative brain regions that drive the motor cortex, the cause of which needs to be further explored. This is an observation not previously described in this population.”

 “We measured peripheral fatigue (high:low ratio) and central fatigue (post exercise depression),” they continued. “Both types of fatigue were seen in the HVs but not in the PI-ME/CFS participants. Moreover, testing of effort preference and the participants’ own words are consistent with this finding. Together these findings suggest that effort preference, not fatigue, is the defining motor behavior of this illness.” [Emphasis added.]

How did they reach that conclusion?

“We first determined the physiological basis of fatigue in PI-ME/CFS participants. The notion of fatigue, as we use it, is a limit on ability or a diminution of ability to perform a task. Effort preference is how much effort a person subjectively wants to exert. It is often seen as a trade-off between the energy needed to do a task versus the reward for having tried to do it successfully. If there is developing fatigue, the effort will have to increase, and the effort:benefit ratio will increase, perhaps to the point where a person will prefer to lose a reward than to exert effort. Thus, as fatigue develops, failure can occur because of depletion of capacity or an unfavorable preference. There were no differences in ventilatory function, muscle oxygenation, mechanical efficiency, resting energy expenditure, basal mitochondrial function of immune cells, muscle fiber composition, or body composition supporting the absence of a resting low-energy state. However, substantial differences were noted in PI-ME/CFS participants during physical tasks. Compared to HVs, PI-ME/CFS participants failed to maintain a moderate grip force even though there was no difference in maximum grip strength or arm muscle mass. This difference in performance correlated with decreased activity of the right temporal-parietal junction, a part of the brain that is focused on determining mismatch between willed action and resultant movement.”

In other words: The failure of PI-ME/CFS patients to maintain grip strength—one way to measure fatigue—was not due to muscle weakness. It was caused by “decreased activity” in the part of the brain that governs movement.

Nath and colleagues’ assessment of patients’ cognitive symptoms were presented in a section titled “Increased Cognitive Symptoms But Normal Neurocognitive Testing in PI-ME/CFS.”

“PI-ME/CFS participants had more self-reported total cognitive complaints and in all five cognitive domains measured: attention, verbal memory, visuoperceptual, language, and visual memory,” they reported. “In contrast, there were no group differences in performance of any of the 15 neuropsychological tests administered or differential degradation of performance over time. No correlations were noted between any of the 15 neuropsychological tests administered and effort preference.”

 In other words: According to these investigators, ME/CFS patients complained about experiencing cognitive disabilities, but when tested, there were no differences between them and the healthy volunteers. There was no single cognitive test in which ME/CFS patients did more poorly than healthy volunteers, there was no lessening of performance over time, and patients did not seem to be protecting their energy—by lowering the effort expended, i.e., effort performance—during cognitive tests.

What does this mean? Are ME/CFS patients just world-class complainers, or is there another way of assessing the cognitive dysfunction they experience?

Nath and colleagues attempted to explain:

“A frequent complaint in our PI-ME/CFS cohort was cognitive dysfunction. This did not correlate with anxiety or depression measures. Standard clinical laboratory tests, brain imaging, measures of brain injury, and sleep architecture were unremarkable. Neuropsychological testing showed that even though the HV and PI-ME/CFS participants started with different levels of perceived mental and physical fatigue, there were no differences in cognitive performance. Further, both cognitive performance and perceived fatigue changed at the same rate during testing in both groups. This is consistent with the absence of a homogenous cognitive deficit in ME/CFS. ... Taken together, this evidence suggests that physical and cognitive fatigue may be mechanistically different. Interestingly, PI-ME/CFS participants’ catechol levels in cerebrospinal fluid correlated with grip strength and effort preference, and several metabolites of the dopamine pathway correlated with several cognitive symptoms. This suggests that central nervous system catechol pathways are dysregulated in PI-ME/CFS and may play a role in effort preference and cognitive complaints.”

Is it possible that both the “physical and cognitive fatigue” experienced by PI-ME/CFS patients are due to dysregulation of nervous system pathways, despite the fact that these investigators also found “no differences in cognitive performance” between HVs and PI-ME/CFS patients? These two conclusions do not exactly add up.

With respect to the immune system in PI-ME/CFS, Nath and colleagues identified dysfunctional B-cells—the cells that produce antibodies—in PI-ME/CFS patients. They also tested the activity of natural killer (NK) cells and looked for “exhausted CD4/T4 cells” in both groups (patients and healthy volunteers). Here they found a small but detectable difference:

“PD-1, a marker of T-cell exhaustion and activation, was elevated in the cerebrospinal fluid of PI-ME/CFS participants,” they reported. “Although NK cell function was not different between groups in blood, they [PI-ME/CFS patients] showed decreased expression of a cytolytic function marker in the spinal fluid. Previous studies suggest that NK cell function is decreased in ME/CFS, which may not be evident in our study due to the small sample size.”

At the conclusion of many more biochemical (and other) tests than reported here, Nath and coworkers created a model to explain how PI-ME/CFS works:

“Considering all the data together, PI-ME/CFS appears to be a centrally mediated disorder. We posit this hypothetical mechanism of how an infection can create a cascade of physiological alterations that lead to the PI-ME/CFS phenotype. Exposure to an infection leads to concomitant immune dysfunction and changes in microbial composition. ... One possibility is that these changes are related to antigen persistence of the infectious pathogen. ... This model suggests places for potential therapeutic intervention and explains why other therapies have failed. The finding of possible immune exhaustion 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.”

“In conclusion,” these investigators wrote, “PI-ME/CFS is a distinct entity characterized by somatic and cognitive complaints that are centrally mediated. Fatigue is defined by effort preferences and central autonomic dysfunction. There are distinct sex signatures of immune and metabolic dysregulation which suggest persistent antigenic stimulation. Physical deconditioning over time is an important consequence. These findings identify potential therapeutic targets for PI-ME/CFS.”

In these rather lengthy excerpts from the Nath paper, you may have noticed that the word “complaints” is sprinkled generously throughout. Perhaps if doctors and researchers could be convinced to hear not complaints from their ME/CFS patients but rather reports of what they’re experiencing, more progress could be made in developing specific and effective treatments.

Meanwhile, these researchers complained themselves about the inconsistent results they (and others) found in most areas. “Hence, there are currently no effective disease modifying treatments for ME/CFS, and even developing and testing of potential new treatments is hampered by difficulty in defining cases or tracking response through symptoms or biomarkers.”

Oddly, this study didn’t include any investigation of viruses, endogenous retroviruses, or comparisons to similar lab findings in people with AIDS—which is particularly inexplicable since Nath specializes in exactly those areas. If these ME/CFS patients are to be described as “post-infectious,” why didn’t Nath assign one or two of the 79 or so researchers working on this study to investigate what their PI-ME/CFS patients had been infected with?

This publication was greeted in the media with the academic version of a tickertape parade (more on that at a later date). Of the lay pieces I read, only Science News reporter Jennifer Couzin-Frankel pointed out that these investigators didn’t identify the infectious agent blamed for causing this allegedly post-infectious condition. (2)

“A protein called PD-1 was also elevated in T cells from patients’ cerebrospinal fluid, suggesting these immune cells were trying to fight something off, even if no invader could be detected,”  Couzin-Frankel pointed out. (2)

When considering the resulting good or ill accomplished by this study, one measurement in academia is the Impact Factor of the journal in which it’s published. Impact Factors are used to measure the importance of a journal by calculating the number of times selected articles have been cited during the last few years. The higher the Impact Factor, the more highly ranked the journal. Unlike Nature’s Impact Factor of 64.8, Nature Communication’s Impact Factor is 16.6.

“This study obtained a more extensive set of biological measurements in people with PI-ME/CFS than any previous study,” Nath and colleagues asserted. “Although the number of study subjects was small compared to the prior literature, it identified biological alterations and confirmed some previously reported biological alterations.”

At a ratio of approximately 79 researchers to 17 patients, one would hope that something helpful would come from this study.

BIBLIOGRAPHY
1.        Walitt, B., Singh, K., LaMunion, S.R. et al. “Deep Phenotyping of Post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Nat Commun 15, 907 (2024). https://doi.org/10.1038/s41467-024-45107-3
2.        Jennifer Couzin-Frankel. “Sweeping Chronic Fatigue Study Brings Clues but not Clarity to Mysterious Syndrome: ‘Megaworkup’ revealed brain and immune differences in a small patient group.” Science, February 21, 2024. https://www.science.org/content/article/sweeping-chronic-fatigue-study-brings-clues-not-clarity-mysterious-syndrome

Two of my books about ME/CFS can currently be found on Amazon:  America’s Biggest Cover-Up: 50 More Things Everyone Should Know About The Chronic Fatigue Syn­drome Epidemic And Its Link To AIDS, Updated 2^nd Edition and Ampligen: The Search for a Promising ME/CFS Drug.