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

[Jonathan Edwards]

The wording was not as clear cut as yours.
May not be particularly effective (or something on those lines) was what registered with me which unfortunately still leaves the door slightly ajar.

They certainly leave the door more than ajar but I cannot see this as being cited in a Cochrane review in a conclusion that says 'Even if the efficacy data look dismal some very clever scientists think it should work so we conclude it probably does'.

 

[FMMM1]

I am not sure that propping up ideology can have any impact on a review of evidence for efficacy of treatments.

And in as much as this study says anything specific it says that CBT and GET wouldn't address the problem itself.

Although we don't know if fMRI is measuring a real effect (correct?)--- if it is then these folks would need to demonstrate that CBT and GET --- undo that problem. So if fMRI is validated then I reckon that would wreck a lot of CBT and GET careers!

 

[Evergreen]

While figure 10 is only a hypothesis about the pathophysiology of ME/CFS based on their findings, I think it makes it visually very clear that intervening at the level of reduced activity would be foolish.

 

[Snow Leopard]

And if they only gave 'strong encouragement' to the patients then they purposefully biased their results.

I disagree, "strong encouragement" is absolutely necessary for untrained individuals who haven't done a maximal CPET before, if you want them to reach a true VO2Max, or close. It is standard practise in studies like this to strongly encourage all sets of participants.

Declines in submaximal CPET measures corresponding with PEM symptoms and signs on the second day of a two day CPET have nothing to do with effort preference in people meeting accepted physiological criteria for maximal exertion. You can’t choose or fake your anaerobic threshold.

Those declines have a lot to do with 'effort preference', only it is the other way around - the decline in performance and afferent feedback (sensations associated with fatigue) causes the 'reduced effort preference'.

 

[siobhanfirestone]

I find this very strange. As far as I know nobody as found any evidence of residual antigen and the weight of evidence in post-infective syndromes is that persistent antigen is not the problem. So there is no reason to use checkpoint inhibition on the basis of the current study.

Moreover, if ME is driven by continued immune activation checkpoint inhibitors are most likely to take it worse. I don't buy this story of immune exhaustion. If the immune system is exhausted you may be a risk of catching new infections but in inactive system is not going to be producing ME symptoms.

for once we are in complete agreement haha, this worries me greatly

 

[Andy]

I disagree, "strong encouragement" is absolutely necessary for untrained individuals who haven't done a maximal CPET before, if you want them to reach a true VO2Max, or close. It is standard practise in studies like this to strongly encourage all sets of participants.

I think you missed the point that the authors of this paper highlight that they encouraged the patients but not the controls. Encouraging one set of participants and not the other, if that is what has occured, is introducing bias.

 

[Ash]

He thinks the brain of the ME patient has assessed their muscles as less capable than they actually are (that's his "mismatch between what someone thinks they can achieve and what their bodies perform"), so it sets a lower goal at the start of the strength task than a healthily functioning brain would. Because the goal is lower the muscles accomplish it sooner, i.e. there's little or no mismatch between the expected result and the actual one, therefore the brain regions monitoring it go quiet sooner. Meanwhile the healthy volunteer had a higher expectation of how they would perform in the task, so there's more chance of mismatch between expected and actual results, so in their case those brain regions stay active longer.

(I think that's it? Though it's moot anyway because a) he's extrapolating a hypothesis from a bit of data noise and b) it has basically no relevance to what pwME are experiencing in real-world situations.)

From the quotes I’ve read in various articles only, as my own effort preference prevents me from reading the whole study, featuring parts of the abstract and including the term effort preference, I had assumed that if this term were to be taken as a technical term related to some specific measurement of some kind, that it would mean very much what @Eleanor describes here.

It just so happens that such a combination of words has a very much more well known meaning in everyday English. Often applied to people perceived as having a preference for putting in low effort in situations where a higher effort is what’s called for by the nature of the task. People who say coast along on minimum effort whilst others are forced to pick up their slack. The non-conscientious worker. Or the ‘layabout’. Also applied to people who are perceived to be conscientious. Maybe perfectionist even. But instead of bad characters, these well meaning people are perceived as those who have lost their confidence. Become so afraid of failure, that they become timid and afraid of trying. Therefore their skills have naturally gone a little rusty. People who need a polish to get their shine back. Some rehabilitation perhaps?

It so happens that the everyday English meaning of the words preference and effort, are very well known to be frequently applied by non disabled people to disabled people. Very often by non disabled professionals who are charged with managing various aspects of disabled persons lives. Generally treating a disabled persons inability to perform a given task as a matter of preference or a failure due to a lack of effort. See, ‘cannot help them if they won’t help themselves’, ‘personal responsibility’, ‘will power’, ‘the mind is and the mind is very powerful you know’, ‘just do it’ and ‘you can do whatever you set your mind towards achieving’.

Or in the medical profession, ‘
to paraphrase ‘Have you tried just not being sick?’


A preference, is one factor that influences the choice a person might make. Effort is the power the person puts behind the choice.

People with ME have often been spoken about as people who are sick, only or principally, because they prefer not to risk failure. A natural part of life. So because of this quite literally ‘crippling’ fear and this only you see, they hide away from the world from life. Or they prefer to stay sick to avoid the putting in necessary hard work physically and mentally to rehabilitate themselves back to a state of health. Just won’t make the effort.

So it’s interesting that the author of this NIH study decided to use the terminology that he did, give the context.

I wonder if anyone involved in the this study tried to request different wording for the press release?

I’m trying to imagine the conversation in the actual or metaphorical room if anyone disagreed with his choice of terminology.

Him
this terminology is accurate.
Them
Maybe, but even so, there are multiple other ways we convey this in the abstract that is for public consumption, to an audience that will probably understand the term in the colloquial sense, the current wording could be confusing.
Him
It’s the most accurate description.
Them
To us maybe. But could we not make it just as clear, clearer even to our audience by describing it in terms more friendly to common understanding?
Him, I really don’t think so.
Close of meeting.
Them,
Could I have a word off the record?
Him,
Sure.
Them
You don’t really want people to misunderstand this do you? Him
No of course not.
Them
Yet in this context it seems so likely that they, that they will. So I don’t quite understand why you’re so committed the using such language?
Him,
This conversation isn’t going anywhere. I think it’s best we move on.

 

[Snow Leopard]

I think you missed the point that the authors of this paper highlight that they encouraged the patients but not the controls. Encouraging one set of participants and not the other, if that is what has occured, is introducing bias.

That's not what the paper says.

The target endpoint was exertional intolerance defined as the participants’ expressed desire to stop cycling despite strong verbal encouragement from the testing staff. Endpoints for stopping the tests were those recommended by the American College of Sports Medicine96.

Encouragement applied to all participants.

 

[Evergreen]

I think we have to be realistic in terms of the starting point for Walitt. People can, of course, change their minds about an illness. But to me, the effort preference business in this paper, and a few other parts, are consistent with what he thought 10 years ago (quotes below). Since he was the clinical lead on this project, the research itself and the publications were always going to be, or have elements that were, unpalatable to patients.

My hope is that other researchers are reading the paper, ignoring the effort preference stuff, and getting good ideas for what to look at next in the immune system, central nervous system etc to ultimately move us towards effective treatments. I’m imagining people like Maureen Hanson writing NIH funding applications for studies that might actually get us somewhere. Others will, of course, keep doing what they do.

Here are quotes from his published papers and interviews up to 2015
(previously posted on PR https://forums.phoenixrising.me/threads/walitt-and-shorter-again.48115/page-2).

The first few quotes are on fibromyalgia. You will see further on that he placed “chronic fatigue syndrome” in the same category as FM, so these quotes are relevant.

Wolfe & Walitt 2013: “The very strong resemblance of fibromyalgia to neurasthenia is a key observation. Time brings clarity to confusing illnesses of the past, and we now recognize that hysteria, neurasthenia and railway spine were almost always psychogenic disorders.”

Wolfe & Walitt 2013: “The rise of fibromyalgia and the disputes it has engendered represents the age-old battle over psychogenicity. All other things being equal, fibromyalgia should have failed. It began as a simple local pain disorder, but evolved over time in one that had multiple somatic symptoms and features that many considered psychosomatic. If these features were the death knell of neurasthenia, they should have also spelled the death of fibromyalgia. But they didn’t. The era was different, and powerful cultural forces stood being fibromyalgia and fought against the idea of a psychogenic illness.”

Wolfe and Walitt conclude: “Fibromyalgia seems to be a somatic symptom disorder with remarkable similarities to neurasthenia. It represents the end position on a continuum of distress. While psychological issues are clear, powerful societal forces are marshalled on behalf of fibromyalgia and it seems likely that they will sustain the fibromyalgia, at least for the present.”

In an interview with Dr Walitt's from September 2015 (link no longer works), he said:

"The experience of fibromyalgia is very much real to the people who have it...we don't really understand how the physicality of that chemistry becomes our thoughts and feelings. And in people with fibromyalgia they clearly feel these ways, and there's probably an underlying biology to it, but the idea that that's an abnormal biology is less clear."

In Wang, Walitt et al’s 2015 chemo-brain paper available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4750385/, Walitt and his co-authors state

“Both of these illnesses [fibromyalgia and chronic fatigue syndrome] have disputed causal triggers, such as trauma in fibromyalgia and infection in chronic fatigue syndrome, whose validity is also not answered by the scientific literature to date.”

In the same paper, further clarification is given that Walitt places chronic fatigue syndrome firmly in the same somatoform category where he places fibromyalgia:

“The discordance between the severity of subjective experience and that of objective impairment is the hallmark of somatoform illnesses, such as fibromyalgia and chronic fatigue syndrome.”

Dr Walitt describes his research interests in this researcher story, dated August 2012 available at http://georgetownhowardctsa.org/researchers/researcher-stories/brian-t--walitt-

Dr Walitt: “My research interest is perceptual illness. In these disorders, a person experiences a range of different bodily sensations, such as pain and fatigue, without any clear external cause. In some, these sensations can be bothersome while in others they can be disabling. The perceptual illnesses that interest me change their names with every generation, with current disorders being called fibromyalgia, chronic fatigue syndrome, and post-Lyme syndrome.”

Dr Walitt continues: “My involvement in the field started during my medical training as I saw my first patients with fibromyalgia. The complaints of these patients were very familiar and made me realize how common they are in the general population, even amongst my friends and family. The desire to figure out a way to alleviate this particular type of suffering drew me into the field. As I have become more involved in research over the years, I have become convinced that unraveling the mysteries of perceptual illnesses will also shed light into the mechanisms that enable all people to feel and think and expand our understanding of the human condition.”

Edited to add 2 quotes referencing "CFS" that I had omitted by accident.

 

[Andy]

That's not what the paper says.



Encouragement applied to all participants.

Great, thanks for pointing that out. The question still remains though of why they should feel the need to imply that encouragement of patients and patients achieving RER of 1.1 demonstrate proof for their effort preference theory.

 

[bobbler]

apparently "Avi Nath at NIH tells me UCSF is trying to launch a clinical trial of a class of drugs called checkpoint inhibitors in ME/CFS. The paper he published yesterday mentions these drugs as a target for testing in the disorder, on the theory that they can help clear persistent antigens. They're cancer drugs & I don't know much about them"
I am quite worried about this as, whilst we both disagree about how to interpret the exact data regarding the specific immune manifestations and cells that might be driving ME, wether its innate or adaptive these drugs will FUCK patients up, like they literally can CAUSE autoimmunity at worse case: https://pubmed.ncbi.nlm.nih.gov/32390537/
We know that there are likely sub-sets within ME, maybe in general between a sort of active virus VS immune system hyperactivity/autoimmunity-esque line. If the trials do not make a serious effort to work out which sub-set someone is in i strongly encourage people to stay the fuck away for their own safety frankly

I guess one good thing is they'd need to have tested it on more than 17 people before it becomes licensed. It sounds like given their struggles to even find that many that fit their rather specific criteria and with rather a large sum of funding they might need to compromise on one thing or another: numbers or 'special recipe' of criteria.

Doesn't sound nice for those who do sign up for it, and perhaps that is another interesting conundrum of self-selection and who might

 

[Evergreen]

Great, thanks for pointing that out. The question still remains though of why they should feel the need to imply that encouragement of patients and patients achieving RER of 1.1 demonstrate proof for their effort preference theory.

I think they're saying "Unsupervised, pwME avoid exertion. With supervision, we can hound them into exerting normally."
If I've misunderstood your point, just ignore this! And if I've misunderstood their point, well, brain fog.

 

[Andy]

I think they're saying "Unsupervised, pwME avoid exertion. With supervision, we can hound them into exerting normally."
If I've misunderstood your point, just ignore this! And if I've misunderstood their point, well, brain fog.

Exactly this. Yet, as Snow Leopard has confirmed, both patients and controls received the supervision, so it is as much proof of exertion avoidance in controls as it is in patients.

 

[Eleanor]

Supplementary Information p. 52, discussing the cardiopulmonary exercise test: "Effort preference did not correlate with peak power in PI-ME/CFS participants (r(6)=0.13, p=0.8) which suggests that effort preference did not impact CPET performance, perhaps related to experimental incentives to push their limits."

Seems effort preference is one of those useful things that apply when we want them to and not when we don't...

 

[Evergreen]

both patients and controls received the supervision, so it is as much proof of exertion avoidance in controls as it is in patients.

I don't follow. They're not saying that the fact that patients achieved an RER of 1:1 with hounding is proof of exertion avoidance in patients. They're saying it's further proof that patients don't have central or peripheral fatigue. I think.

 

[Ash]

I think we have to be realistic in terms of the starting point for Walitt. People can, of course, change their minds about an illness. But to me, the effort preference business in this paper, and a few other parts, are consistent with what he thought 10 years ago (quotes below). Since he was the clinical lead on this project, the research itself and the publications were always going to be, or have elements that were, unpalatable to patients.

My hope is that other researchers are reading the paper, ignoring the effort preference stuff, and getting good ideas for what to look at next in the immune system, central nervous system etc to ultimately move us towards effective treatments. I’m imagining people like Maureen Hanson writing NIH funding applications for studies that might actually get us somewhere. Others will, of course, keep doing what they do.

Here are quotes from his published papers and interviews up to 2015
(previously posted on PR https://forums.phoenixrising.me/threads/walitt-and-shorter-again.48115/page-2).

The first few quotes are on fibromyalgia. You will see further on that he placed “chronic fatigue syndrome” in the same category as FM, so these quotes are relevant.







In an interview with Dr Walitt's from September 2015 (link no longer works), he said:



In Wang, Walitt et al’s 2015 chemo-brain paper available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4750385/, Walitt and his co-authors state



In the same paper, further clarification is given that Walitt places chronic fatigue syndrome firmly in the same somatoform category where he places fibromyalgia:

Dr Walitt describes his research interests in this researcher story, dated August 2012 available at http://georgetownhowardctsa.org/researchers/researcher-stories/brian-t--walitt-





Edited to add 2 quotes referencing "CFS" that I had omitted by accident.

Railway Spine.
Well this one’s put his cards on the table hasn’t he?
A real friend to the robber, Baron. Or 19th century carriage manufacturer. Or modern day automobile insurance industry perhaps? ….

 

[Andy]

I don't follow. They're not saying that the fact that patients achieved an RER of 1:1 with hounding is proof of exertion avoidance in patients. They're saying it's further proof that patients don't have central or peripheral fatigue. I think.

As Eleanor points out immediately above, the authors seem confused on this point as well.

 

[Simon M]

I doubt it. My main concern is that PWME are bound to be in a different autonomic state because they are the ones being tested for an illness - the ones with a threat.

Thanks. I guess regardless of its purpose, the battery of testing is also likely to be more challenging for PwME than for healthy volunteers, which might well add to the stress.

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..., with consequences on autonomic functioning and physical conditioning.

So the autonomic functioning element looks a miss and physical conditioning probably applies to most chronic illnesses - where I assume it normally doesn't warrant a mention in a study abstract.

 

[Sid]

They don't comment much on this but I found it buried in a supplement that 24% of ME/CFS patients had positive antinuclear antibodies and only 5% of controls (p=.09 but I wouldn't pay much attention to lack of statistical significance in such a tiny sample).

 

[butter.]

Thanks. I guess regardless of its purpose, the battery of testing is also likely to be more challenging for PwME than for healthy volunteers, which might well add to the stress.

So the autonomic functioning element looks a miss and physical conditioning probably applies to most chronic illnesses - where I assume it normally doesn't warrant a mention in a study abstract.

I think the HRV and heartrate issues are quite likey to be a real signal. Other people/teams have found this too and it's the main reason for why some of the pacing Apps are somewhat helpful for many patients.