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NIH ME/CFS Deep Phenotyping Study: Part 4. Discussion

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 NIH study demonstrates clear biological differences – spanning multiple body systems – in individuals with ME/CFS compared with healthy controls. According to the authors, the study obtained a “more extensive set of biological measurements in people with PI-ME/CFS than any previous study. Although the number of study subjects was small compared to the prior literature, it identified biological alterations and confirmed some previously reported biological alterations.” In concurrence, 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. However, with fewer than 20 ME/CFS participants, the sample size is incredibly small (especially for an NIH study) and, as the authors acknowledge, many of the findings have been demonstrated in previous studies.

Participant characteristics

The participants with ME/CFS should be commended for their willingness to undergo multiple assessments, despite the potential impact on their health. Additionally, the healthy individuals who volunteered for the study should be acknowledged for their contribution to advancing our understanding of ME/CFS.

The study aimed for a homogenous ME/CFS cohort to minimise confounding factors. Furthermore, participants needed to be willing and able to undergo multiple intensive assessments, notwithstanding travel considerations. Hence, as mentioned in a statement from the Bateman Horne Center, the study fell short by not including enough individuals with moderate to severe ME/CFS, a frequent occurrence in ME/CFS research.

The paper highlights that, within four years, four out of the 17 individuals with ME/CFS experienced “spontaneous full recovery”. Whilst rare, it is important to acknowledge that recovery from ME/CFS can occur. Potentially, there will be a greater representation of recovery amongst those in earlier stages of the illness, with fewer comorbidities, and the capacity to undertake multiple assessments. Nevertheless, considering almost one-quarter of ME/CFS participants recovered, concerns have understandably been raised.

None of these points should take away from the huge effort and sacrifice of participants, as volunteering for ME/CFS studies is what keeps research into the condition moving forward.

An argument against the psychologisation of ME/CFS

Psychiatric disorders, like other conditions, can occur alongside ME/CFS as a comorbidity. However, individuals with ME/CFS often face disbelief and stigma due to psychologisation – i.e. the false attribution of ME/CFS symptoms to psychiatric/psychological causes.

The cohort selected for this study did not have a history of psychiatric disorders, and undertook extensive psychiatric and psychological assessments. The study noted that the ME/CFS cohort “endorsed more depressive and anxiety symptoms” which is not a surprise considering the challenges of living with ME/CFS. However, participants with ME/CFS were not found to meet psychiatric diagnostic criteria, therefore “psychiatric disorders were not a major feature in this cohort and did not account for the severity of their symptoms”. This could be interpreted as meaning the biological findings of this study should not be attributed to psychiatric factors. Nevertheless, the paper at times seems to have a psychological undertone, or at least seems to be insensitive in language choice considering the study is about a condition that has been stigmatised.

Effort preference monopolises the paper

Effort preference(s) appears 26 times throughout the paper and is often woven into the explanation of other findings. Despite all of the mentions, the wording of the sections addressing effort preference is often difficult to understand. Are the researchers suggesting that individuals with ME/CFS can physically do tasks, but they are not putting in the effort because an area of the brain responsible for perception is malfunctional? Furthermore, what was the initial reasoning behind studying effort preference?

In the section of the paper addressing altered effort preference, the authors mention a decline in button-pressing rate over time in the ME/CFS cohort, suggesting “participants were pacing to limit exertion and associated feelings of discomfort”. Following discussion on how effort preference correlated with “time to failure” in the grip task and reduced brain activation in the right temporal-parietal junction, they state that “conscious and unconscious behavioral alterations to pace and avoid discomfort may underlie the differential performance observed”. They also brought up the fact that interviews with participants revealed “sustained effort led to PEM” (one of three mentions of post-exertional malaise in the paper), although it is not clear whether this was a general statement, as opposed to referring to the grip task.

Perhaps effort preference should be tested in other illnesses that cause fatigue, as it may not come as a surprise that given the option an unwell individual would choose a task which requires less effort, or slow down in order to preserve their energy, as they likely do through pacing on a daily basis. However, it is important to recognise that this is a theory proposed to explain the differences in performances, hence it would be interesting to hear if the researchers have any alternative explanations or other routes of investigation they would like to pursue.

Pacing in many ways is a learned skill. From a hypothetical standpoint (as it would be near-impossible to assess), it would be interesting to know whether people who never learned to pace would perform similarly in the tests. For example, many individuals take months or years to be correctly diagnosed with ME/CFS, and despite being unwell (boom and bust cycle) they may not suspect they have ME/CFS, and thus are not aware of energy management techniques.

An important takeaway, as is aptly included in the limitations of the paper, is that “these data assess correlation, not causality”.

Where is PEM?

The researchers appear to recognise the importance of PEM because participants were required to have PEM in order to be included in the study. Yet, in contrast to effort preference, it is mentioned once in the recruitment section and briefly at two other points in the paper. It is not clear why PEM has not been adequately addressed considering it is the cardinal feature of ME/CFS.

It should be noted that the researchers did conduct qualitative interviews following CPET about PEM – which is important for a holistic view of ME/CFS. However, if the ultimate objectives of the three-phase intramural study (of which this phase one study is a part) are to understand underlying pathophysiology, identify biomarkers and potentially develop treatments, it is not clear why two-day CPET, the current main method for testing PEM, was not conducted.

In relation to CPET, repeat testing on the following day is a necessary step to see how PEM affects performance, as studies have reported a decline in measured variables on day two of testing specifically in ME/CFS cohorts. Considering this, it would be useful to know if there are plans to utilise two-day CPET in phase two of the intramural study.

Distinguishing significant findings from interpretations

During Dr David Tuller’s interview with neuroscientist Dr Michael VanElzakker, several key points about the study were highlighted. Dr Tuller aimed to gain an impression from Dr VanElzakker, on the disparity between the “generally respectful” media coverage of the study, emphasising immune dysfunction and other biological factors, and the understandable concerns about the paper within the community.

Dr VanElzakker also noted the positive aspects of the media portrayal of the study, whilst acknowledging issues with the phrasing of the paper, suggesting there should have been a clearer delineation between the direct findings and the interpretation of those findings. For example, as a neuroscientist, he expresses reservations about the focus on the temporal-parietal region of the brain in relation to effort, as this area of the brain has multiple functions. The brain is a highly complex organ with the ability to multitask.

Dr VanElzakker encourages the community to ask for a follow-up on significant findings, for example further exploring the possibility of persistent antigenic stimulation in order to understand the antigens that are driving the immune response. Ultimately, if certain aspects of the study are explored further, it could advance the field of ME/CFS research.

Multidisciplinary collaboration

It is important to recognise that the study has contributions from many different research groups, each with their own area of specialty. Considering the extensive multidisciplinary collaboration involved, it would not come as a surprise if some researchers, who were not actively involved in the final write-up, were disappointed at the framing of the paper in which “effort preference” overshadows other significant findings.

Critically analysing the study and highlighting weaknesses is justified, especially if the limitations are related to core areas of the study. Addressing these critiques presents an opportunity to propel ME/CFS research forward. Amidst the scrutiny, it is crucial not to overlook the numerous significant findings. It is evident that the researchers invested substantial effort into assessments and data analysis, and it also must have been challenging to coordinate such a large study.

Next steps

This was not meant to be a standalone project, rather the first part of a three-phase study. The aim of Phase two is to “validate select biomarkers” from Phase one “in a longitudinal study and establish objective end points for an intervention study”. Therefore, it will be interesting to hear what the researchers intend to do with the results generated and how they are planning to incorporate the feedback from the ME/CFS and research community.

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

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