Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome

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Wishful

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I can't judge the quality of the study, but it definitely fits my beliefs about ME: that the "fatigue-like symptom" is effort preference based, rather than metabolic, and the autonomic system isn't working properly. Also that there are relatively small shifts in a number of factors (immune, metabolic) that possibly reinforce the dysfunction, rather than one factor that is blatantly abnormal.

In a simple system, such as two gears meshing, one factor being a bit off-spec may not cause problems. If the teeth one one are worn and the teeth on the other are worn and the bearing is worn, then you may get a malfunction. In ME, there might be similar factors that are just a bit off, all in directions that end up causing an abnormal state, and they feed back to each other to lock us into that state. Instead of a single drug, treating ME might require a number of different drugs and supplements and maybe dietary avoidances, to push the various factors away from that feedback loop.
 
Judee

Judee

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Wishful said:
is effort preference based
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Yeah, but that terminology...doesn't that makes it sound like we have a choice and just are not preferring to make the effort? I just hate that word "preference" used there.

It should be more ability focused than a word that implies choice because all of us here would definitely prefer to be able to do everything healthy people are doing.
 
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W

Wishful

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Yes, their chosen term is quite awful. I read it as meaning that the part of our brain that creates our willingness to exert ourselves is malfunctioning due to a biological mechanism. I expect psychologists will interpret it differently. We can't "push through" our fatigue-like state because the part of the brain responsible for the ability to "push through" isn't working properly.

I can't off-hand think of a good term for that factor. "Drive" and "motivation" seem like psychological terms, lacking in biological processes.
 
necessary8

necessary8

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Broooo... Who wrote this paper? There is some really good data hidden deep in it but the conclusions completely ignore it and contradict it!

They found energy metabolism impairments in the muscle! This is the first study ever that finally checked gene expression in skeletal muscle. I was saying for many years that if you have an illness that gets worse from using muscles, why is no one looking in the muscles? This is still not exactly what I wanted, what I wanted was full proteomics, and I wanted it on muscle cells cultured with contact to patient plasma, which is crucial. But I'll take RNAseq as a consolation prize any day, cause for some ungodly reason no one else even tried it yet.

And even with this very limited approach, even though the subjects were mild cases, they found energy metabolism impairments! The data there very clearly separates patients from controls! Aaaaand they try to blame it on deconditioning, omitted this finding entirely from the abstract and discussion and conclude "No fatigue because grip strength is good and motor cortex lights up on fMRI. Instead, patients have decreased effort preference". WTF. Yeah no shit muscles correctly contract and motor cortex works. No one was doubting that. That's not the nature of fatigue or impairment in this illness. Of course patients will prefer not to exert themselves. Because the true impairment is that when you use those muscles, you get increased symptoms next day. Which if they followed up on those metabolic dysfunctions in the muscle, maybe they could explain how that happens.

Oh wait...
1708543410476.png

This is who wrote it. This guy is the lead author. Now everything is clear.
 
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hapl808

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Wishful said:
We can't "push through" our fatigue-like state because the part of the brain responsible for the ability to "push through" isn't working properly.
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I was often able to push through with doctor's encouragement. That's what got me from mild to moderate to severe - pushing through my limits and crashes. It only 'works' when you're very mild and likely young.

necessary8 said:
This is who wrote it. This guy is the lead author. Now everything is clear.
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I don't often wish harm and calamity on someone and their loved ones, but when I do…
 
necessary8

necessary8

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Wishful said:
I read it as meaning that the part of our brain that creates our willingness to exert ourselves is malfunctioning due to a biological mechanism. I expect psychologists will interpret it differently. We can't "push through" our fatigue-like state because the part of the brain responsible for the ability to "push through" isn't working properly.
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Except we can? And we get worse from it? That's completely different from some brain dysfunction making it so you always have a preference to not push through. What you're saying is literally contrary to the clinical picture of the disease and all the experimental data, including the ones from this study.
There are at least hundreds of thousands, if not millions of patients who for the first few years don't even know they have ME/CFS and very clearly have a preference and ability to push through, until someone sits them down and explains that this is why they keep getting worse. And then they have to learn over sometimes quite a long period of time to stop doing that. So no, you are 100% wrong and so is mr Walitt here.
 
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Tsukareta

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NIH are useless ( long drawn out end syllable ), I read in one of the latest Health Rising articles that it was the NIH that stopped the progress of the NanoNeedle. All this stuff is why I started looking for my own explanations and strategies to deal with CFS, because I had success at recovering from newer things that are not part of the core symptoms, for example I recovered from Multiple Chemical Sensitivity and now just have issues with a few specific ones like Febreeze, but if people come near me with clothes washed in random laundry detergent is doesn't seem to bother me much anymore. Maybe I wont solve the problem but I feel like the scientists wont either.
 
BrightCandle

BrightCandle

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Marylib said:
https://twitter.com/i/web/status/1760457561768067322
So Brian Walitt says PEM was indeed required for the study...and kind of off-topic but @Tsukareta - Febreeze is the devil's work...that stuff is horrible...
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But the method of the actual paper says its not required. On top of that they never tested for PEM, they did a single day of CPET but not both days so they couldn't quantify and confirm PEM so its just a self report in the supplement information. This is the second paper I have seen that said PEM wasn't in the selection criteria and yet magically by the conclusion they totally pinky swear did account for it despite having written nothing about it and ignored it completely throughout the paper.

There are other issues here with patient selection beyond just PEM, they were happy with Fukuda as a criteria, which even if they had PEM is just chronic fatigue + PEM. 4 recovered after the study. None of them had POTS. Nothing even mentioned on MCAS. These are not representative patients of the disease most of us suffer from at all.

Whatever the disease is they tested these people for it probably wasn't ME/CFS, or least they weren't required to meet the current research definition of ME/CFS. The method is garbage and that mens we can't trust any of its findings, some of which are extremely dismissive of the disease we suffer from.
 
Murph

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Here's the abstract:​

​

Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome​

Nature Communications volume 15, Article number: 907 (2024) Cite this article

Abstract​

Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping.

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.

Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease in switched memory B-cells. Alterations in gene expression profiles of peripheral blood mononuclear cells and metabolic pathways were consistent with cellular phenotypic studies and demonstrated differences according to sex. Together these clinical abnormalities and biomarker differences provide unique insight into the underlying pathophysiology of PI-ME/CFS, which may guide future intervention.
 
Judee

Judee

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Murph said:
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.

Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease in switched memory B-cells. Alterations in gene expression profiles of peripheral blood mononuclear cells and metabolic pathways were consistent with cellular phenotypic studies and demonstrated differences according to sex. Together these clinical abnormalities and biomarker differences provide unique insight into the underlying pathophysiology of PI-ME/CFS, which may guide future intervention.
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And we already had a recent study about LC focusing on serotonin so that plus this, esp that top paragraph, still sounds like "future intervention" is still going to be the same old misguided interventions of SSRIs and SNRIs (or something similar)

In other words, it still sounds like they're pushing to keep this disease thought of as just a form of Depression. :bang-head::bang-head::bang-head:
 
Murph

Murph

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This is an interesting wide-ranging paper with two big weaknesses:

1. It began so long ago that it isn't looking at some things that have been shown to be interesting more recently, like monocytes and platelets. it's a fishing expedition, but we've learned some great new fishing spots while this expedition was out searching.

2. sample size is small.

I've long believed me/cfs has an autonomic aspect, an immune aspect, a metabolic aspect and a vascular aspect. (I have no idea what's upstream of what). This paper seems to emphasise the autonomic aspect, with a bunch of good findings on heart rate and heart rate variability.

41467_2024_45107_Fig2_HTML.png


But that's not all, not by a long shot. It has muscular and immune findings too.

Now, it is disappointing to find the term "effort preference" used so prominently in this study when it is not in common use in any medical papers I could find on pubmed.


1708568598963.png


nb they do link effort preference to measurable changes in tryptophan metabolism and dopamine precursors, so while some may conclude fault lies with patient effort, the paper doesn't go that far.

Also there's plenty of other actual findings in this paper. They would be less stigmatising to lead with. I hope we can bring attention to those findings too and not just spend the whole thread pushing back on this. The streisand effect is in play here. If all anyone hears from mecfs patients is that we're mad about a finding on 'effort preference' then people will pay attention to that instead of the real differences the paper found.

For example these immune findings.

41467_2024_45107_Fig8_HTML.png

The paper emphasises how different male and female population responses are to the disease (which ironically renders their small mixed sex sample (6 male patients, 11 female) even less well-powered to detect differences)
 
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