Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome, 2024, Walitt et al

So far read only the abstract and some of the media coverage. Meh.

I wonder what the 17 pwME are feeling right now. Mixed emotions I guess. Whatever the case, a great big huge enormous thanks for putting your bodies and health on the line for us. Thanks, too, to the healthy controls who chose to take time out of their lives for us.

As for the authors, some will undoubtedly have done a massive amount of good work and thank you unreservedly for that.

But was there really no one among the dozens of authors who stopped and thought that maybe the term "effort preference" was just a teensy weensy tiny bit problematic to use let alone to highlight in the abstract where everybody sees it? What with the well-known history of ME mischaracterisation and all?

From my limited reading I also get a sense that they might be muddling up neurons making "decisions" based on their chemical/electrical environment, and people making conscious decisions. That's certainly what comes across in some of the media coverage. Which is the entirely predictable result of using a term like "effort preference"

And I am sooo tired of reading yet again about effing fatigue fatigue fatigue with nary a mention of PEM. I didn't like it at the time but I now think it's a shame SEID didn't catch on. At least it would have put problems with exertion at the centre of people's thinking, with fatigue relegated where it belongs: just one of the many symptoms arising from the core problems with exertion

Anyway, I admit I'm still clinging to the hope there's something more substantial and substantive hiding out in the raw data, and that the existence of the raw data will attract some funding and some good new brains to the field, some that don't look at ME primarily through the lens of fatigue
 
I pored through this paper all day long to figure out what is new. We already knew MECFS is a centrally mediated disorder. There isn't much in the paper that 2-day CPET test already found: A) MECFS patients are capable of exerting, and B) if they do, they keel over the next day. The only difference is the use of term "effort preference" to denote that the fatigue in non-PEM state is the product of pacing, not peripheral fatigue. That and not tackling PEM at all. They mentioned PEM 3 times: twice in the context of screening the subject, and once to surmise pacing is the cause of effort preference and short time to failure. But they did nothing to figure out the PEM mechanism.

The CSF-NE being proportional to effort preference and CFS-DA to time to failure were the only thing I could get something out of it. (Fig 6-e/f were stunning.) But the fact that HV did not show similar correlations seems to tell me that it is yet another symptom, not the cause or a part of the mechanism. The fact that nicotine, a powerful agent for dopamine and norepinephrine, not working to prevent PEM seems to point to the same thing. (I was hoping it would work since I've been responding to novel stimuli and positive stress).

But I do think this paper further dispels the notion that MECFS fatigue is the product of mitochondrial/metabolic dysfunction. MECFS patients are not incapable of generating energy/power when they are not in PEM state. It's only that they suffer nasty PEM that tanks their QOL and ability to function if they do.
 
Good:
Hence, there are currently no effective disease modifying treatments for ME/CFS
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Nothing, not even CBT and GET, are regarded as effective disease modifying treatments. So, that's helpful.


Bad:
Matching
They claim that there were no significant differences.
They only had to match 17 people. And yet the percentage of males is quite different (48% in the healthy volunteers;41% in the people with ME/CFS sample), And, while the mean age might not be very different (37.8 in ME/CFS versus 42.2 in HV), the age composition is different (way more people in the 18-30 range in the ME/CFS sample (about 45% versus 24%), way less people in the 50-60 range (about 23% versus 45%).

Seriously, with only 17 people to match, why are the sex ratios and age ranges not perfectly matched? Why were there 21 people in the healthy controls and 17 in the ME/CFS group - that's not matching.

Typo in Figure 1c
"Lanugage" - this is an NIH paper in a Nature journal - really, they couldn't find a decent proofreader?

The Multiple Ability Self-Report Questionnaire (MASQ): results in figure 1c
A questionnaire that assesses the subjective appraisal of cognitive difficulties in five cognitive domains: language, visual-perceptual ability, verbal memory, visual-spatial memory, and attention/concentration. Higher scores mean worse ratings.

It seems like a waste of space to include participants' ratings of their language ability or verbal memory, for example. We don't really want to know how the participants rate themselves, we want to know to what extent and in what way people with ME/CFS are impaired by the illness. I assume the charts are there to somehow underline the way people with ME/CFs are constantly complaining of being impaired, but look! later in the paper, it turns out they aren't impaired? (I don't know, I haven't got there yet).

And I have no idea how I'd answer those questions myself - sometimes the abilities are good, other times they aren't. I imagine the ME/CFS participants had similar difficulties knowing whether to rate themselves based on a good moment or during PEM. So, those self-ratings really aren't worth much at all. Not to mention the possible age/sex influence. Is it possible that a sample with more older males might rate themselves better at the abilities compared to a sample with more young women anyway? Without proper matching, we are just guessing from the beginning.

Also issues with BMI matching.
 
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Ravn said:
But was there really no one among the dozens of authors who stopped and thought that maybe the term "effort preference" was just a teensy weensy tiny bit problematic to use let alone to highlight in the abstract where everybody sees it? What with the well-known history of ME mischaracterisation and all?
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In Scientific American: People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome May Have an “Exhausted” Immune System —

Beyond the immune system, Nath’s team searched for changes in the brain. When participants were asked to grip an object, those with ME/CFS had decreased activity in their right temporal-parietal junction, a brain region involved in self-agency, whereby the brain predicts an action before one becomes consciously aware of it. Though other brain differences in people with ME/CFS have been known for some time, “this particular finding of that particular region is new,” Hanson says. Nath hypothesizes that this dip in activity suggests the brain is cautioning people with ME/CFS against exerting force during the grip test, which he says makes sense because ME/CFS symptoms often intensify if people with the condition overwork themselves. The finding is preliminary, however, and further experiments are needed to corroborate it.
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And yet there it is headlined in paper and abstract —

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, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning.
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Together these findings suggest that effort preference, not fatigue, is the defining motor behavior of this illness.
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Nath explains that the pandemic stalled recruitment. “We were hoping to recruit at least 10 if not 20 more [people with the condition],” he says. His team enrolled people with moderate to severe ME/CFS in the study, but bedbound people with extreme ME/CFS couldn’t participate because of their physical limitations.
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I don't know if those are Nath's words, but that wouldn't be my descriptors. I can't for a moment think that moderately to severely affected people would be capable of submitting to the study.

Mild = "mostly able to work, unlikely full-time, and with accomodations and recovery eating in to social activities to compensate"; moderate = "Essentially housebound" (which is my situation); severe = "completely or mostly bedbound"; extreme = "unable to tolerate touch, light, sound; gut failure etc" (eg Whitney, Maeve and Merryn).
 
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Some other information on recruitment that I found in Supplementary Data 2.

There were 484 people that applied for the study. Of those, 137 were found to have other diagnosis during the initial screening. Not too sure while you'd apply for a ME/CFS study if you knew you had an autoimmune disease or cancer (likely in addition to their ME/CFS diagnosis) but they did. Of those 137, 78 were labeled as having "other diseases". I have no idea if that includes things like POTs or Fibromyalgia, would be nice if they had given more clarity on that.

Of the 484 that applied, 217 went on to a medical records screening. 37 of these 217 applicants then were found to have other diagnosis. These other diagnosis are pretty varied with inflammatory disorder, psychosis, head injury and endocrine disorders being the most common. Again, it looks like most of these people also had a diagnosis of ME/CFS.

Besides other diagnoses, the most common reasons for rejection in the application and medical review stages were greater duration of illness than 5 years and no documented infection.

Of the 27 that the NIH investigated in person, only 4 were found to have other diagnosis that I presume the participants had not previously know about. These four conditions the participants were found to have were cancer, atypical myositis, primary biliary cholangitis and parkinsonism. That means that about 15% of the participants that made it to this stage ultimately had other explanations for their ME/CFS.

My takeaway from this is that there are many people who have a diagnosis of ME/CFS in addition to other diseases. Also, although it was a small sample size by the time they came for the in-person investigation, it doesn't seem like many people had a new condition that wasn't ME.

The numbers also don't add up so I think there must be overlap in the reasons for why people were excluded (ie. I think they included certain people under multiple exclusion categories)
 
There were no clinically relevant findings on physical examination, psychological evaluation, or laboratory testing in either group (Supplementary Data S8, 9).
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First off, it's important to note the small sample size. For these basic investigations, they've mostly all been done before, and generally haven't shown anything. I guess they had to repeat them, but, with that small sample size, they aren't telling us anything new, or in a newly convincing way.

As someone has already pointed out, we should be grateful for small mercies - there were no differences in psychological status. Supplementary Data S8 and S9 give no information about the psychological evaluation. The lab tests are, on the whole, nothing very exciting - mostly just the usual sort of blood tests that we've all had repeated by each consultant we've seen, with them all happily telling us that 'there's nothing wrong!'.



Measurements of small nerve fiber density and neuronal injury markers in blood and cerebrospinal fluid were not different between groups (Supplementary Fig. S1).
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I confess I briefly wondered why they were assessing small nerve fibre density in blood and CSF... Anyway, no evidence of differences in small fibre density, certainly no indication of lower small fibre density - biopsies in 'distal leg' and 'distal thigh'. No evidence of differences in neuronal injury markers, which is in line with the studies that I can recall e.g. NfL, Tau not different
 
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Hutan said:
No evidence of differences in neuronal injury markers, which is in line with the studies that I can recall e.g. NfL, Tau not different
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In peer review, AK also commented —

The figures display a number of comparisons between the cases and the healthy controls in which there are substantial quantitative differences that apparently do not achieve statistical significance. For example, the higher level of GFAP, a neuronal injury marker (Fig. S1G). If the authors do not want to report power calculations for each of these differences, the text could at least acknowledge that the study may have been underpowered to recognize some of the quantitatively great but statistically nonsignificant differences as “real”.
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Response —

Response: We agree that the issue of effect size is an important one. We had addressed this in the Supplement but have now added a sentence to the Limitations section in the main text to emphasize this point on page 13:

Post-hoc calculations of the effect size, for a phenotyping sample of 21 and 17 volunteers, to achieve a power of 80% is 0.94, suggesting only large effects will be noted to be statistically significant.
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Screenshot 2024-02-22 at 5.39.53 PM copy.jpg
 
Creekside said:
I read the article, and while I don't like the term "effort preference", to me it fit with my experience that my body is capable of exertion, but my willingness to exert is reduced by ME, through a biological mechanism. It's not a psychological problem that you can simply "push through", because the circuits of the brain that allow you to "push through" are malfunctioning. Sadly, the wording in the paper is so vague that the proponents of psychological causes will view it as supportive of their theories. I hope there will be follow-ups on verifying the physical differences in brain function.
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Thanks for sharing. First off, this is not my experience at all. There is no lack of willingness to act or exert in my experience of ME. I very simply can't exert energy without getting worse. Wouldn't an experience of lack of willingness be indicative of depression or asked differently what would be different to depression then? If there is a lack of willingness and/or no payback for exertion, is that ME then? I guess the authors of this study conclude it is, and I disagree. Depression is of course a biological disease too, but, it is distinct in my experience.
 
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Creekside said:
I read the article, and while I don't like the term "effort preference", to me it fit with my experience that my body is capable of exertion, but my willingness to exert is reduced by ME, through a biological mechanism. It's not a psychological problem that you can simply "push through", because the circuits of the brain that allow you to "push through" are malfunctioning. Sadly, the wording in the paper is so vague that the proponents of psychological causes will view it as supportive of their theories. I hope there will be follow-ups on verifying the physical differences in brain function.
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Its not so much that my brain is somehow preventing me from pushing through. I can push through but I understand that comes at a cost. I generally don't push through just because the costs exceed the benefits. When I was a rower I pushed through all the time because the costs weren't very high and mostly immediate. Now I don't push through as the costs are higher and affect me for longer. I guess you could technically say that's an effort preference but in the same way I have a preference not to put my hand on the stove. The question is why is there a larger cost at all.
 
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"Differential cardiorespiratory performance in PI-ME/CFS

Cardiopulmonary exercise testing (CPET) was performed on eight PI-ME/CFS and nine HVs (Supplementary Fig. S8A). During testing, all but one PI-ME/CFS participant reached the peak respiratory exchange ratio (RER) of ≥1.1 and there was no difference between the groups. Effort preference did not correlate with peak power in PI-ME/CFS participants (Supplementary Fig. S8B). The ratio of Ventilation/VCO2, oxygen saturation levels in the quadricep muscle as measured by Near Infrared Spectroscopy, and gross mechanical efficiency were not different between groups (Supplementary Fig. S8C–E). These results suggest that PI-ME/CFS participants performed to the best of their abilities.

Peak power (p = 0.08), peak respiratory rate, peak heart rate (p = 0.07), and peak VO2 (p = 0.004) were all lower in the PI-ME/CFS participants (Fig. 5a–d), a difference of approximately 3.3 metabolic equivalent of task units (METs). These peak measures did not correlate with effort preference in PI-ME/CFS."

Can anybody explain how this section fits, or not, with the whole "effort preference" concept. Peak RER was met, so patients exercised to their capacity, and other measures showed that, despite that, what was possible for patients was lower than controls. Surely, if "effort preference" was a thing, then either peak RER wouldn't have been met or peak RER would have been met but there wouldn't have been a difference on the other measures?
 
This makes me a bit angry.
Polysomnography did not reveal clinically relevant findings (Supplementary Information, Sleep dysfunction).
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From the Supplementary Information Page 8
PI-ME/CFS participants complained of significantly more disordered sleep symptoms than HVs, with increased scores on the Pittsburgh Sleep Quality Index (3.2 +-2.5 versus 7.8 +-3.4, p=0.0001), PROMIS Sleep Disturbance (40.4 =-6.0 versus 55.3 +-9.5, p=0.00002), and PROMIS Sleep Related Impairment (40.0 +-7.1 versus 61.3 +-6.9, p=0.000001). The qualitative experience of disordered sleep is evoked in this participant description: 'There are times since I've been ill, I'm so sleepy I can't stay awake. I sleep a few hours and then I wake up [and feel like] I have a hangover for a couple of hours. But the vast majority of the time, I don't sleep, but I'm horizontal."

All PI-ME/CFS participants underwent polysomnography in a sleep laboratory. Two had mild periodic limb movements (PLM >=5, <25), two had mild sleep apnea (Apnea Hypopnea Index >=5, <15 per hour), and one had moderate sleep apnea (Apnea Hypopnea Index >=15, <30 per hour). None of these individuals noted substantial improvement after a six week trial of CPAP. Sleep fragmentation was noted in 10 PI-ME/CFS participants (three mild, five moderate, two severe). Thus, PI-ME/CFS participants reported moderate sleep dysfunction not explained by polysomnographic evaluation.
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Clearly the ME/CFS participants were reporting a lot more disordered sleep symptoms, but the conclusions in the paper and the supplementary information suggests that the sleep lab found nothing. But, "sleep fragmentation was noted in 10 PI-ME/CFS participants'. They don't give us any data from controls. In the absence of that context, sleep fragmentation problems sound pretty significant to me - 10 out of 17 participants had fragmented sleep that was noted in a sleep lab. 7 had moderate or severe fragmentation. How can they then say that the sleep lab investigation found nothing?

And, what part of 'fluctuating illness' do they not understand? My sleep is, on the whole, great. I usually go to sleep when I want to, I usually wake up at the same time every morning, I usually sleep right through. I'm at the more severe end of mild, probably the type of patient who would turn up at a demanding investigation. But when I have PEM, or even just over do things, I will sleep longer and I will certainly have trouble going to sleep, and I wake with pain. Do the investigators not understand that people who are currently sleeping 20 hours a day are not the sort of people who make it across the country to participate in two weeks of investigations?

Sleep issues are not necessarily particularly important in terms of defining ME/CFS pathology. But, the way the authors have presented the information, it gives the impression of 'those whiny ME/CFS patients, they complain of sleep problems, but look! We found nothing.' 17 ME/CFS participants, presumably one night of evaluation... They could have given the participants wearable technology to evaluate their sleep over a couple of months. Maybe then what they say about sleep dysfunction would have been credible.
 
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the paper said:
Cardiopulmonary exercise testing (CPET) was performed on eight PI-ME/CFS and nine HVs (Supplementary Fig. S8A). During testing, all but one PI-ME/CFS participant reached the peak respiratory exchange ratio (RER) of ≥1.1 and there was no difference between the groups. Effort preference did not correlate with peak power in PI-ME/CFS participants (Supplementary Fig. S8B). The ratio of Ventilation/VCO2, oxygen saturation levels in the quadricep muscle as measured by Near Infrared Spectroscopy, and gross mechanical efficiency were not different between groups (Supplementary Fig. S8C–E). These results suggest that PI-ME/CFS participants performed to the best of their abilities.
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Andy said:
Can anybody explain how this section fits, or not, with the whole "effort preference" concept. Peak RER was met, so patients exercised to their capacity, and other measures showed that, despite that, what was possible for patients was lower than controls. Surely, if "effort preference" was a thing, then either peak RER wouldn't have been met or peak RER would have been met but there wouldn't have been a difference on the other measures?
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Here's Supplementary Figure S8B. It's the one that supposedly relates to the effort preference for the CPET study. I don't know what the 'Proportion hard task choices' are. @Snow Leopard?

Edit - I understand now - the choice of hard tasks has nothing to do with the CPET - it was a separate evaluation
The Effort-Expenditure for Rewards Task (EEfRT)15 was used to assess effort, task-related fatigue, and reward sensitivity (Supplementary Fig. S5A–D). Given equal levels and probabilities of reward, HVs chose more hard tasks than PI-ME/CFS participants (Odds Ratio (OR) = 1.65 [1.03, 2.65], p = 0.04; Fig. 3a).
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They just plotted on a chart a result from the CPET and a result from a task choice investigation.


From S8A, it looks as though people with ME/CFS had to do the CPET with a ramping up of 15 w/min, while the healthy volunteers were able to choose (?) a ramping up of 15 to 25 w/min. Might this affect what peak power is achieved?
 
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Is this the same research that is in the following Daily Mail article: Proof chronic fatigue syndrome IS real: Researchers probing poorly-understood illness find subtle differences in brains and immune systems of patients for the first time | Daily Mail Online

This included taking MRI scans of people asked to perform repetitive tests where they gripped a device to measure how their brains responded to fatigue.

CFS patients displayed less activity in the temporal-parietal junction, a part of brain key to exerting effort.

As such, the experts now theorise that disruption to this area is what is behind the tell-tale fatigue.
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A comparison of the immune systems also showed CFS patients had lower levels of memory B cells.

These are a part of the immune system designed to remember foreign substances, like bacteria or viruses, to ensure the body has longer-term protection and doesn't repeatedly risk falling ill every time a person encounters them.
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dave30th said:
sorry, can you explain what this means?
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A barn door is usually a door twelve feet high and twenty feet wide. So a barn door case is a case about which there is no reasonable doubt.

I was just implying that although the CCC is a bit over-imaginative in what it asks for if only 17 people were picked out of 200 and everyone agreed one would expect those cases to be typical enough even to satisfy a slightly quirky CCC.

I am personally not convinced that diagnostic criteria are a major problem with studies. I never took much notice of them for RA. I studied people who obviously had the pathology I was interested in investigating at that time. If all these patients satisfied IOM criteria which needs PEM then I doubt the diagnostic selection process was a major problem. What I do think may be a major problem is that only pretty well people with minimal PEM could volunteer and much of the study is about looking for explanations for significant disability.
 
DMissa said:
"The target endpoint was exertional intolerance defined as the participants’ expressed desire to stop cycling despite strong verbal encouragement from the testing staff"

That is not a pleasant image.
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Nor is it what exertion intolerance is intended to mean, to my mind. The EI in SEID I have assumed implied something like 'food intolerance' in the sense of adverse reaction with PEM. Here they are just using it to mean having had enough. Again it suggests that the authors have no real idea of the concept of ME/CFS. (Which might also be relevant to their claim that the patients satisfied IOM.)

DMissa said:
"An increase in percentage of naïve and decrease in switched memory B-cells in blood were observed in PI-ME/CFS participants"

Thoughts @Jonathan Edwards ?
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The UCL group found something consistent with this. However, we have seen enough studies to know that lymphocyte subsets in ME are generally fairly normal with maybe a slight shift of this sort and it is hard to give any precise interpretation in terms of mechanisms. Almost any shift in signals could give you a shift in populations either way, depending on trafficking shifts.

DMissa said:
I really hate this modern trend of "well 5/9 of these genes "involved" in X process are elevated in expression so X process is probably upregulated".
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Indeed. And whether or not it is annoying it is bad science. The data should be about what was found, not a pre-interpretation of what pathways are implicated. And in discussion implications need spelling out carefully.
 
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