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NIH ME/CFS Deep Phenotyping Study: Part 3. Results

The US National Institutes of Health (NIH) intramural study on ME/CFS is a three-phase initiative to explore post-infectious ME/CFS in depth, and potentially to identify biomarkers and find treatments. The study was launched in 2016, and the first part, involving more than 70 researchers from a wide range of specialties, has just been completed after almost eight years.

There is a lot of information to digest, so we have split our article into four parts. This third part describes the results of the study.

1. Overview | 2. Methods | 3. Results | 4. Discussion

The following are the findings of the study for participants with post-infectious ME/CFS compared to healthy controls.

Immune dysregulation 

As part of the immune response, B-cells produce antibodies, and T-cells play various roles such as attacking abnormal/infected cells and coordinating the actions of other immune cells. In this study, participants with ME/CFS exhibited differences in numbers of certain types of B-cells (increased naïve B-cells and decreased switched memory B-cells in blood), and T-cell markers.­­­ When stratified by sex, different subpopulations of immune cells were “enriched” (increased in proportion) in male versus female ME/CFS cohorts. The researchers are not clear about the cause of immune dysregulation but suggest the possibility of “persistent antigenic stimulation” (prolonged exposure to specific antigens which is thought to lead to the exhaustion/dysfunction of certain immune cells).

Despite being described in previous research, there was no consistent pattern of autoimmunity (immune cells attacking own cells/tissues) in the ME/CFS cohort.

Sex-based differences in gene expression

There were differences in gene expression in muscle in individuals with ME/CFS compared with healthy controls, and sex-based clustering was also noted with certain genes upregulated (becoming more active) or downregulated (becoming less active)  according to sex. Also, there were sex-based differences in gene expression in the ME/CFS cohort in pathways related to immune regulation, and in genes related to fatty acid oxidation (important for energy production) and mitochondrial processes.

The researchers note that both male and female ME/CFS participants had increased oxidative stress (excessive production of reactive oxygen species which can lead to cell/tissue damage), but distinct pathways were altered in both groups.

Metabolic differences

Analysis of metabolites in cerebrospinal fluid revealed significant differences in tryptophan (essential amino acid) metabolites in the ME/CFS cohort compared with healthy controls. Individuals with ME/CFS also exhibited reduced levels of dopamine 3-O-sulfate, glutamate (excitatory neurotransmitter), butyrate (fatty acid produced by gut bacteria), polyamine (organic compound with multiple physiological roles), and tricarboxylic acid pathway (energy production pathway) metabolites. There were also sex-based differences in a number of metabolites.

Microbiome dysbiosis

In comparison with the ME/CFS cohort, healthy controls had greater alpha diversity (i.e. more types of microbes within their sample) but a similar abundance of these microbes. There were significant differences in beta diversity (i.e. composition of the microbiome) between the two groups.

Autonomic dysfunction

Responsible for regulating involuntary body functions, the autonomic nervous system has two branches: the sympathetic and parasympathetic. The researchers assessed for abnormalities within this system by exploring cardiovascular responses.

Tilt table testing did not reveal any significant differences in “frequency of orthostatic hypotension, excessive orthostatic tachycardia, or tilt-related symptoms requiring test cessation”. However, 24-hour ECG monitoring revealed diminished heart rate variability in the ME/CFS cohort. Individuals with ME/CFS had increased heart rate throughout the day, suggesting heightened sympathetic activity, and a “diminished drop” in heart rate at night suggesting reduced parasympathetic activity. Additionally, there were abnormalities in mechanisms related to blood pressure control.

Reduced cardiorespiratory capacity

The anaerobic threshold is the point during exercise when the body’s demand for oxygen exceeds the amount available, leading to a shift from aerobic respiration (energy production with oxygen) to anaerobic respiration (energy production without oxygen). During cardiopulmonary exercise testing (CPET), participants with ME/CFS reached the anaerobic threshold “at a lower level of work and ventilation” than the healthy controls. Additionally, at maximal performance, the peak respiratory rate, heart rate and VO2 (maximal oxygen consumed during exercise) were lower in the ME/CFS cohort. The authors suggest that these differences could be due to autonomic dysfunction, hypothalamic-pituitary-adrenal axis hyporesponsiveness (malfunctioning stressor response system), and muscular deconditioning (decreased muscle strength/function due reduced physical activity).

“Absence of a resting low-energy state”

According to the researchers, “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”. Yet substantial differences were noted during physical activity. They suggested that these findings support the “absence of a resting low-energy state”. This statement seems to imply that when people with ME/CFS are not engaged in physical activity they have similar energy levels to healthy individuals.

Psychiatric disorders do not account for ME/CFS symptom severity

Participants undertook extensive psychiatric and psychological assessments. There was “no difference in psychiatric history or reporting of traumatic events between the two groups”. Whilst individuals with ME/CFS “endorsed more depressive and anxiety symptoms” than healthy controls, they did not meet psychiatric diagnostic criteria. Hence, the researchers state, “psychiatric disorders were not a major feature in this cohort and did not account for the severity of their symptoms”. 

Decreased brain activity (temporal-parietal junction) correlated with lower grip test performance

Individuals with ME/CFS had difficulty maintaining a moderate grip during physical tasks, despite having a similar maximum grip strength (highest force a person can squeeze with their hand) to that of healthy controls. According to the researchers, “time to failure” (inability to maintain target level of grip force) correlated with effort preference (described below). They also state that the discrepancy was associated with a decreased activity of an area of the brain “focused on determining mismatch between willed action and resultant movement” known as the right temporal-parietal junction. The term mismatch refers to the “degree of agency, i.e., the sense of the control of the movement”.  A reference is included for a study exploring the neural processes underlying self-agency which is defined as “the individual’s perception that an action is the consequence of his/her own intention”.

“Effort preference, not fatigue, is the defining motor behavior”

Effort-Expenditure for Rewards Task (EEfRT) is the “behavioural measure” used to assess the “number of times the hard task was selected compared to the number of times the easy task was selected”. EEfRT assesses “effort preference” – a measure of “how much effort a person subjectively wants to exert“. The study shows that individuals with ME/CFS were less likely to choose harder tasks than healthy controls, indicating an “altered effort preference“. The authors also suggest that the “decline in button-pressing speed over time noted” for individuals with ME/CFS suggests “participants were pacing to limit exertion and associated feelings of discomfort”.

Within the paper, fatigue is defined as “a limit on ability or a diminution of ability to perform a task”, and two types are assessed: peripheral fatigue (related to issues within the muscle) and central fatigue (related to a reduced ability of the central nervous system to drive muscle during physical activity). To assess fatigue, repetitive grip testing was performed, and electromyography (EMG) and transcranial magnetic stimulation (TMS) were used to measure muscle activity and brain activity – specifically, the excitability of the primary motor cortex of the brain which is responsible for planning and executing movement.

Despite a rapid decline in grip force production in the ME/CFS cohort during repetitive grip testing, the researchers suggest that this performance pattern is not indicative of peripheral fatigue. The excitability of the primary motor cortex of the brain increased in participants with ME/CFS during the task but decreased in healthy controls – the researchers suggest this does not indicate central fatigue. The researchers state, “Both types of fatigue were seen in the HVs [healthy volunteers] 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.” The researchers further assert that “consistent with this observation, with strong encouragement during CPET, all but one of the PI-ME/CFS participants reached a respiratory exchange ratio of 1.1″ – i.e. during exercise testing, when encouraged, most ME/CFS participants were capable of exerting themselves to a high degree. However, as two-day CPET was not done, it cannot be said that participants would have been able to reproduce this performance the next day. Furthermore, as persistent fatigue is a requirement for an ME/CFS diagnosis, in their conclusions it would have been useful to reiterate that they are referring to fatigue as defined in the study.

The sections of the paper related to fatigue and effort are complex and unclear in wording. Therefore, it is not certain whether the researchers involved are, at least in part, suggesting that ME/CFS is a behavioural issue. As this is a contentious topic, it would be helpful if the researchers address this by providing a lay summary of the fatigue/effort assessments and findings, alongside well-reasoned discussion.

“Increased cognitive symptoms but normal neurocognitive testing”

The authors state that participants with ME/CFS had “more self-reported total cognitive complaints and in all five cognitive domains measured: attention, verbal memory, visuoperceptual, language, and visual memory. In contrast, there were no group differences in performance of any of the 15 neuropsychological tests administered or differential degradation of performance over time.” Reports of cognitive dysfunction “did not correlate with anxiety or depression measures”. The researchers state that “even though the HV [healthy volunteers] and PI-ME/CFS participants started with different levels of perceived mental and physical fatigue, there were no differences in cognitive performance”.

Included in the references, a 2022 systematic review and meta-analysis notes heterogenous cognitive deficits in ME/CFS. The authors of the current paper suggest that this deep phenotyping study did not find cognitive deficits either because the sample size was small or because performance validity testing was not conducted in other studies, thus “invalid performances” could have been included impacting the accuracy of findings.

“Perception and behavior… are related to catechol levels”

The researchers measured catecholamines, a category of catechols which primarily includes neurotransmitters – dopamine, norepinephrine and epinephrine. Dopamine plays multiple roles including in regulation of mood, movement, cognition and motivation. Norepinephrine and epinephrine play a role in the “fight-or-flight” response (stress response) which leads to increased heart rate and blood pressure.

Levels of dopamine, cys-DOPA (dopamine-related) and norepinephrine did not differ between groups. Levels of DOPA and DOPAC (both dopamine-related), and DHPG (norepinephrine-related) were significantly lower in the ME/CFS cohort.

Additional analysis was performed looking for correlations with effort preference, neuropsychological testing, and “time to failure”. The researchers assert that the correlations observed “suggest that perception and behavior, but not cognitive performance, are related to catechol levels in PI-ME/CFS participants”. There were a number of negative findings. For example, “standard clinical laboratory tests, brain imaging, measures of brain injury, and sleep architecture were unremarkable”, although it is important to mention that a larger sample size would be needed to validate the findings of this study. Further investigation of sleep in a larger population would be useful as sleep dysfunction is often required for an ME/CFS diagnosis.

1. Overview | 2. Methods | 3. Results | 4. Discussion

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