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.
1. Overview | 2. Methods | 3. Results | 4. Discussion
The hypothesis underlying phase one of the study, which has been published in the journal Nature Communications, is that post-infectious ME/CFS is “triggered by a viral illness, resulting in immune-mediated brain dysfunction”. To investigate the underlying mechanisms of post-infectious ME/CFS, the researchers performed deep phenotyping of 17 people with ME/CFS post-infection, in comparison to 21 healthy individuals. This involved a comprehensive analysis encompassing multiple clinical and biological aspects of the illness.
What were the aims of the study?
Principal investigator and specialist in neuroimmunology, Dr Avindra Nath, highlighted four aims of the study during a 2016 CDC Grand Rounds presentation.
Aim 1 – Defining the clinical phenotype
“…define the clinical phenotyping using in-depth assessments of all domains of the illness …”
Further elaborating in a Solve ME/CFS initiative webinar, he stated “…this means that we are going to have very detailed history and physical examination, neurological assessment, cognitive assessment, psychiatric evaluation, pain, headache, infectious disease and rheumatology – which really means autoimmune … [and] look at the endocrine function, fatigue testing, exercise capacity, but we’re also looking at the autonomic nervous system at the same time. So that should give us a … decent understanding of the kinds of symptoms that the patients are experiencing.”
Aim 2 – Determining underlying physiology of fatigue (pre and post exercise)
“… define the physiological basis of fatigue using functional MRI scan of the brain to define the brain circuits that are involved. Do detailed metabolic studies in a metabolic chamber and do transcranial magnetic stimulation as well as very detailed autonomic testing. Each of these tests will be performed before and after exercise.”
Aim 3 – Determining if there are abnormal immune and microbiome profiles
“…conduct a detailed immunological study in blood as well as cerebrospinal fluid including a screen for autoantibodies to neural antigens. We will also fully explore the gut and oral microbiome and apply proteomics [study of proteins] and metabolomics [analysis of molecules known as metabolites] approaches to the cerebrospinal fluid.”
Aim 4 – Determining if features can be produced in ex-vivo studies
“…utilise a variety of novel approaches to explore whether cells or [blood] serum, from patients can be used to experimentally reproduce some of the features of the illness.”
It is not clear to what extent this aim was addressed in the published study.
Study findings
After obtaining results from the extensive assessments, the authors posit that post-infectious ME/CFS is a “centrally mediated disorder”; i.e. a condition where the central nervous system plays a significant role in maintaining symptoms. They hypothesised that “exposure to an infection leads to concomitant immune dysfunction and changes in microbial composition”. These statements imply that an initial infection triggers alterations in both the immune system and microbiome, and the central nervous system contributes to the persistence of ME/CFS symptoms.
Key findings in participants with ME/CFS compared with healthy controls:
- Immune dysregulation: Differences in B-cell and T-cell numbers/markers.
- Sex-based differences in gene expression: Differences in gene expression often related to immune and energy production processes, clustered based on sex.
- Metabolic differences: Downregulation of several metabolites involved in key physiological roles.
- Microbiome dysbiosis: Differences in microbiome composition and reduced species diversity.
- Autonomic dysfunction: Diminished heart rate variability and abnormal blood pressure control.
- Reduced cardiorespiratory capacity: Lower peak respiratory rate, heart rate, and oxygen consumption during maximal performance in exercise testing, in addition to lower anaerobic threshold.
- Increased cognitive symptoms but normal neurocognitive testing: Similar performance on neuropsychological tests (e.g. word recall) despite ME/CFS participants reporting more cognitive symptoms.
- Decreased activity in brain area correlated with lower grip task performance: Reduced hand grip task performance associated with decreased activity in the temporal-parietal junction of the brain, which is “focused on determining mismatch between willed action and resultant movement”.
- “Altered effort preference”: Individuals with ME/CFS were less likely to choose harder tasks during the Effort-Expenditure for Rewards Task.
- Differences in catecholamine-related molecules: Whilst the catecholamines, dopamine and norepinephrine, did not differ between groups, there were differences in certain related molecules.
Discussion
This study demonstrates multiple biological differences between people with ME/CFS and healthy controls. It is also a major multidisciplinary feat as the study is the presentation of the work of multiple research groups with differing expertise. Therefore, being included in the extensive author list of the paper does not necessarily mean that a researcher has been involved in every aspect of the study, rather they have likely contributed within their own specialty area.
As acknowledged, many findings have been previously demonstrated in other studies – for example, differences in immune abnormalities involving T-cells, and evidence of autonomic dysfunction in ME/CFS. This study stands out in the sense that it simultaneously tested multiple factors in individuals with ME/CFS enabling a complex picture to build up of each participant. Nevertheless, there are concerns that have been raised within the ME/CFS community such as the lack of discussion of post-exertional malaise (PEM), frequent mentions of “effort preference”, and the small sample size.
Minimal mention of post-exertional malaise
It should be noted that the study required PEM within the inclusion criteria, utilised cardiopulmonary exercise testing(CPET), and conducted qualitative interviews about participants’ experiences of PEM following CPET. Despite this, PEM was not given an in-depth analysis in the paper and was briefly mentioned three times. Furthermore, one-day CPET was conducted as opposed to two-day CPET, which is the main method for testing PEM. The lack of attention given to PEM in the paper was surprising considering the centrality of this feature to ME/CFS, and the growing interest in exploring PEM in ME/CFS research.
Assessment of effort and fatigue
Dr Brian Walitt, lead clinical investigator and first author, states “We may have identified a physiological focal point for fatigue in this population… 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.”
In contrast to minimal mention of PEM, “effort preference(s)” appeared twenty-six times in the paper. Effort preference is a measure of “how much effort a person subjectively wants to exert” and was assessed through the Effort-Expenditure for Rewards Task (EEfRT) – a test introduced in 2009 to assess motivation and anhedonia (a psychiatric symptom characterised by the inability to experience pleasure or find enjoyment in activities that one typically finds enjoyable).
The researchers state that participants with ME/CFS were less likely to choose harder tasks than healthy controls, indicating an “altered effort preference”, and they further suggest “conscious and unconscious behavioral alterations to pace and avoid discomfort may underlie the differential performance observed”. To assess fatigue, repetitive grip testing was conducted, and muscle and brain activity were monitored. Performance in grip tasks correlated with effort preference. Based on the pattern of performance observed, the researchers suggest that “effort preference, not fatigue, is the defining motor behavior” of ME/CFS. Thankfully, this has not been quoted in media headlines because phrasing such as this has the potential to perpetuate stigma by encouraging the notion that ME/CFS is behavioural.
The parts of the paper related to fatigue and effort preference are difficult to understand, and a lay summary from the researchers explaining the relevance of findings and the reasoning behind their conclusions would therefore be useful. Furthermore, it would be helpful to know the justification for conducting EEfRT – i.e. what hypothesis were they testing, and why did they choose to use this novel behavioural measure that does not feature in other ME/CFS research?
Results need to be validated in a larger population
During the 2016 webinar, Dr Nath stated, “You can do a lot of patients and do few things to them, or you can take a few patients and do a lot of things to them. And the intramural program is good at studying small sample sizes but studying them extensively.”
Whilst having a small sample size was intentional, the study fell short of its original target of including 40 individuals with ME/CFS. It seems the major reasons for ending up with 17 ME/CFS participants were the stringent exclusion criteria and the onset of the pandemic halting further recruitment. The participants needed to be able to complete all assessments which undoubtedly excluded those with severe ME/CFS, which should be noted when considering the applicability of findings. It should be acknowledged that, by taking part in numerous cognitive and physical assessments, the ME/CFS participants did risk potential health deterioration and therefore should be commended for their involvement in the study. The study, however, had full ethics clearance and the participants gave informed consent as part of the recruitment process.
The small sample size affects the generalisability of findings – a common issue in ME/CFS research with smaller budgets that can be afforded by the NIH. It is within the remit and capability of NIH to confirm findings in a larger population. As mentioned by Dr Nath in 2016, “the first order usually should be to study a small number of patients, well-defined groups, and… look at them extensively, and that will allow you to define a set of parameters that you can then take to larger studies… [a] Phase Two study would then validate the biomarkers in a longitudinal study”. Hence, we encourage the NIH researchers to continue exploring ME/CFS, building on significant findings, whilst also take into consideration concerns raised about the present study.
1. Overview | 2. Methods | 3. Results | 4. Discussion
