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

Here is the heatmap they show of metabolites they see at q < 0.05 in the CSF of their cohort. They're all low in ME. They are arguing generally that they see reduced catechol derivates (which make up hormones like adrenaline).upload_2024-2-21_13-41-18.png

Some of these are familiar. I looked back at Glass and Hanson 2023's urine metabolomics study where they saw a surprising positive flux of mostly nitrogen related metabolites in controls following CPET but not in ME/CFS (a striking result with a small sample size n=8, other concerns at the time about deconditioned controls etc)

from the list above, these ones were significant in Glass et al @ q=0.05:
orotidine
kynurenine
arginosuccinate
N-formylmethionine
GPC (in this list above it is stearoylated and the non stearoylated version was found in the urine paper - still potentially relevant)

these ones @ p=0.05
gluconate
N-deltaacetylornithine

and these ones were nominally high but not significant (but I still think taken all together is interesting):
0.08 5-methylcytidine
0.09 5,6-dihydrouracil
0.12 creatine
0.12 guaiacol sulfate

Kynurenine obviously features in Davis/Phairs metabolic trap - but in the urine study its precursor tryptophan was also low, as well as related metabolite serotonin.

Arginosuccinate and N-deltaacetylornithine are both involved in the urea cycle which is involved in nitrogen homeostasis and ammonia detoxification. Creatine synthesis is also closely related to urea cycle metabolites. N-formylmethionine is an amino acid which I know as being required to synthesize proteins in bacteria, but apparently is also required to initiate protein synthesis in mitochondria (which come to think of it makes sense given its ancestry).

Guaiacol sulfate I hadn't heard of before but is apparently a chatecholamine related metabolite.

Orotidine is involved in the metabolism of cytidine and uridine (The nucleosides in DNA/RNA), and sure enough there are cytidine and uracil related metabolites methylcytidine and dihydrouracil.

GPC is glycerophosphocholine, which may be interesting given recent discussions because it is related to the synthesis of acetylcholine.
 
Dakota15 said:
Take a lap, buddy.

17 US patients, who are human beings, went through an awful lot and sacrificed their bodies / baselines in this study. Some of those patients are on this forum. Do better than blasting 'US advocacy groups.' If that's your glaring takeaway from today, I strongly consider you to reassess your priorities.
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Not your buddy. This has nothing to do with the patients, obviously. If these patients have Fukuda ME/CFS and no POTS, frankly they should not have been selected. And yes, I think US advocacies deliver subpar political advocacy work measured on outcome, that is no slight on any single person involved trying their best and making themselves worse by trying. Do I think there are people involved that are a little too friendly with the NIH? Yes. Am I grateful for every single person engaged? Yes.
 
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butter. said:
Not your buddy. This has nothing to do with the patients, obviously. If these patients have Fukuda ME/CFS and no POTS, frankly they shoud not have been selected. And yes, I think US advocacies deliver subpar political advocacy work measured on outcome, that is no slight on any single person involved trying their best and making themselves worse by trying. Do I think there are people involved that are a little to friendly with the NIH? Yes.
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I agree with you, the NIH is clearly taking the piss, with this study but also the long COVID funds they are wasting. I can't see anything good coming out of licking their toes and cheering them on. You're just playing their game.
 
The Dutch MELines consortium set up in the Netherlands is set up to achieve pretty much the same result btw. It's led by a psychologist with a terrible track-record(Rosmalen), they initially didn't use PEM to select patients but somehow plan to do this later and they're waffling about what it is they're trying to achieve. Gonna be a similar farce. I hope the other project that was set up in the Netherlands will fair better.

I also think one of the politicians fighting on our side managed to get an additional chunk of funding, because the 4.4 million going to the MELines consortium was so callously squandered.

*edit*

Nico Drost (€4.4 million to compensate for the subsidy wrongly awarded to ME/CFS Lines by ZonMw from the budget of the ME/CFS Research Program): accepted!
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Nico Drost got his motion accepted and 4.4 million will get put back into the research coffers.

https://mecentraal.wordpress.com/2024/02/15/en-de-uitslagen-zijn/

Don't know if this topic is really the place, but a ray of sunshine might be nice.
 
Well this is all very disappointing. Not the results, the effort. An alteration of effort perception is right on the nose, but it doesn't describe the patients. There is definitely a strong mismatch between what the researchers thought they could achieve and how they performed. They can definitely do better than this. We can't, but we don't have a say in it. It's our lives, but their show.

Seeing how the NIH has mostly botched a $1.15B fund studying Long Covid, this is really all highlighting how medicine simply cannot perform from a basis of symptomatology alone. They just can't handle it. They pretty much ignored PEM in a study where this is the defining symptom. WTactualF. Everything springs from a biological finding and derives from it. Without it, medicine clearly has not developed relevant skill to account for it, and instead seem to perform worse than amateurs, since they clearly lack any meaningful insight into the reality of illness, of symptoms and their burden.

It's deeply ironic. One of the hardest problems in medicine remains unsolved because most MDs don't even understand that there is a problem to solve, and consider it mild and easy. Which is like facing a final training challenge where you don't even know that this is what's happening, so aren't putting in not only the efforts, but the right skills. All that training amounts to nothing because they simply fail to use them by misunderstanding the question.

So we are really only going to solve this with the help of AI after all. It's what I thought, but I was hoping it wasn't going to be needed for the whole thing.

There are still good things in this, but they can't make up for decades of malfeasance and ideological fanaticism built on traditional delusional fantasies. The institutions of medicine continue to be badly disappointing in their ability to muster up effort and sustain it. Which is so damn ironic again given that this is what they think is happening with us. I guess the common thread with the BPSers is that a lot of what they say about is projection.
 
Sean said:
I am very skeptical of any ME study that fails to find any evidence of hemodynamics problems, especially one that did not control for PEM.

That is a huge red flag for me.
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Yes, I have obvious problems with initial orthosttic hypotension. You don't need sophisticated tests to see it. It's easy to replicate if you listen to me to understand the conditions in which it tends to occur.



I'm very disappointed how they are framing the effort preference thing. This seems to be another case where listening to patients would have done more good than carrying out a long and complicated study. We struggle to keep ourselves from doing too much and having crashes from overexertion. In other words, we have a habit of doing less, especially when we can get away with it.



Is the part about reduced dopamine interesting?
 
Just seen this Science article about it: https://www.science.org/content/art...-brings-clues-not-clarity-mysterious-syndrome

But functional magnetic resonance imaging revealed decreased activity in brain regions that, among other functions, help control movement. The researchers suggest brain signals may flash stop signs to prevent physical activity—similar to how a bout with illness forces rest. “When we have a bad flu, [we] can’t get out of bed,” says Jonathan Edwards, a rheumatologist at UCL. “It’s a central signaling problem” in the brain, he says. “There’s nothing wrong with your muscles.”
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I'm quite concerned by this.

It's not a central signaling *problem*. It's a protective mechanism.
 
This is what the paper says about "effort preference" in the discussion section:
We first determined the physiological basis of fatigue in PI-ME/CFS participants. The notion of fatigue, as we use it, is a limit on ability or a diminution of ability to perform a task. Effort preference is how much effort a person subjectively wants to exert. It is often seen as a trade-off between the energy needed to do a task versus the reward for having tried to do it successfully. If there is developing fatigue, the effort will have to increase, and the effort: benefit ratio will increase, perhaps to the point where a person will prefer to lose a reward than to exert effort. Thus, as fatigue develops, failure can occur because of depletion of capacity or an unfavorable preference.
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Can anybody translate this into coherent scientific language for me? What is an "unfavourable preference"? What are they actually saying?
 
They basically found nothing that stood out which isn't very surprising giving the very low sample size and the fact that ME/CFS is probably a heterogeneous syndrome with multiple causes.

Most of the attention in the paper goes to the 'alteration of effort perception' hypothesis which presumably comes Brian Walitt. It is based on data from the Effort-Expenditure for Rewards Task (EEfRT) and repetitive grip testing with fMRI. Both do not look very convincing.

If this data was published separately it likely wouldn't have received a lot of attention given the low sample size and speculative nature of how they interpret their data. But because this was mixed in with all the impressive in-depth measures they did at the NIH, it is now receiving a lot of attention and credibility. As if all the expensive physiological tests they used at the NIH supports this effort perception theory, rather than just the EEfRT and grip testing.

Quite disappointing. The study did not reach its target sample size (which was already very low) and was basically abandoned because of the pandemic. And now it seems that its main paper was used to promote a controversial theory on effort perception that is not supported by strong data.
 
Andy said:
They are saying that we choose not to do something because we perceive it as too much effort.
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If so, it seems to be a contradiction. If patients are choosing not to try harder because the cost outweighs the benefit (because of PEM), that is rational. If the cost of trying harder (ie exertion) does not outweigh the benefit, then patients don't have PEM, and therefore don't have ME/CFS.

"Unfavourable" seems to be a deliberately obscure and ambivalent term, as with much of the language in the paper. Is it unfavourable to be rational?

[edited typos for clarity]
 
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Andy said:
They are saying that we choose not to do something because we perceive it as too much effort.
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Is that really what they mean? I haven't read the paper, but if their conclusion is that simple, it's just objectively wrong, at least for me and many other CFS sufferers. I would absolutely love to go on a long hike this weekend. The reason I don't is that for the next week at work I'll have intense anxiety, have no ability to think, and be exhausted the entire time.

If anything, my brain often perceives it as *not* too much effort, I overwork myself, then I'm paying for it.
 
Sly Saint said:
Study offers clues about the cause of chronic fatigue syndrome post infection

Study offers clues about the cause of chronic fatigue syndrome post infection (msn.com)
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I’ve just read this.

There is an opening statement that sounds good for people with ME, and like everyday English, that straightforwardly means what it says. Then the rest of the article still appears on the page just like everyday English, rather than like the technical English of a scientific paper. But it was completely incomprehensible to me.

The difficult to read part could be technical researcher language, meaning the opposite of what it would mean in everyday English, and therefore supportive of the opening statements in this article, as well as people with ME?

Or

It could be everyday English, unconventionally written, that means what you might guess it to mean, and then it’s not good for people with ME?
 
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Robert 1973 said:
Can anybody translate this into coherent scientific language for me? What is an "unfavourable preference"? What are they actually saying?
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Not entirely, no.

Thus, as fatigue develops, failure can occur because of depletion of capacity or an unfavorable preference.
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I think this is saying the person either can't complete the task, or abandons it because completing it isn't worth the payback.

To me, the second point's irrelevant, and—given the history of psychologisation of ME—shouldn't be highlighted. Almost everyone makes an assessment partway through a demanding task, even when the consequences aren't likely to be as nasty as PEM. People may abandon something because they've realised it's a waste of time; or because they've worked out a better way to do it; or because it's making their back ache. It's a normal response that tells us nothing about ME.
 
Lucibee said:
It's not a central signaling *problem*. It's a protective mechanism.
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It may be for 'flu and the sequence of sentences is not ideal, but if the mechanism is driving symptoms in ME it IS a problem. We don't even know quite what it is protecting against in 'flu and it may well be unneeded there too. It may have evolved as a protective mechanism against food poisoning as much as anything.

In ME we have no evidence that there is anything to protect against. Rather like in food allergy, there is no need to protect oneself against foods.
 
I looked at the cohort characteristics a bit more. 100% of ME patients met the IOM criteria, 82% met the Fukuda Criteria and only 53% met the Canadian Consensus Criteria.

Fatigue is necessary in all criteria. Now the discussion becomes a bit more involved because PEM is a necessary symptom in the IOM criteria as well (it’s not necessary for Fukuda).

Now after a post-infectious onset the only criteria that have to met in the Canadian Consensus Criteria are (the illness duration of at least 6 months has automatically been met by all patients in this study):
  • Fatigue
  • PEM*
  • Two or more Neurological / Cognitive Manifestations from a list of symptoms
  • At Least One Symptom From Two of the Following Three Categories (autonomic, neuroendocrine, immune) from a list of symptoms

The IMO criteria furthermore requires patients to either have orthostatic intolerance or cognitive impairment. Since none of the patients in this study seemed to have orthostatic intolerance, this means they have all had to have had cognitive impairment (I will look at the study data at a later time point to see if this can actually be verified by their data when they assessed subjective cognitive impairment).

So where do the 47% come from that don’t meet the Candian Consensus Criteria? The most logical explanation would be that they don’t have at least one symptom in at least 2 categories from the list of symptoms in the autonomic, neuroendocrine, immune list of symptoms in the CCC (I'm working under the additional assumption that people with cognitive impairment in the IMO criteria will have at least 2 cognitive symptoms in the CCC list). There's a caviat* to this mentioned below.

Fukuda is of course extremely vague. It requires fatigue and at least 4 symptoms from the following list: substantial impairment in short-term memory or concentration, sore throat, tender lymph nodes, muscle pain, multi-joint pain without swelling or redness, headaches of a new type/pattern/ severity, unrefreshing sleep, post-exertional malaise lasting more than 24 hours.

Since allegedly all patients had PEM (with the caviat * mentioned below) and cognitive impairment (assuming it aligns with "substantial impairment in short-term memory or concentration") as well as unrefreshing sleep are also a necessary symptom of the IMO criteria this automatically means that 18% of patients didn’t have another symptom of the above list (i.e. 18% didn't have a concurrent occurrence of any of the following symptoms: sore throat, tender lymph nodes, muscle pain, multi-joint pain without swelling or redness, headaches of a new type/pattern/ severity).

*The caviat to this discussion is PEM. The IMO criteria aren’t specific to what PEM exactly is or how long it should last, so some subtle differences could arise there when applying different criteria in the above discussion, it’s not necessary in Fukuda but has to last more than 24 hours to count as one of the symptoms and in the CCC there should be a pathologically slow recovery period – usually 24 hours or longer. It should be noted that in none of the above criteria is a delayed onset necessary.

A whole different question would be who actually assessed these patients and what is their rigor and background. Someone that uses the CCC might be far more rigorous and might not classify something as PEM, whilst others do. Apart from the fact that patients couldn't be sick for longer than 5 years and had to have an infectious onset, I cannot understand how you start off with over 400 patients and only end up studying 8 patients that meet the CCC. Do you have some more details on how the recruitment and assessment worked @B_V ?

Edited: I'd also like to know which out of the 4/17 patients that recovered met which criteria. That could be revealing.
 
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Looking at the article @Lucibee, I think this is OK. She sent me this 'quote' which was her paraphrase, and I said I thought it captured the message.

The reason we cannot get out of bed with flu IS a brain problem rather than a muscle problem, as far as we know. It may be partly mediated by hypotension, but again probably brain mediated through vagal and sympathetic tone. The mechanism may have evolved because it acts as a protective mechanism but that is not in conflict with it being the reason why you cannot get out of bed.

What I think the journalist reasonably tries to get across is that the central signalling is not overridable, any more than insomnia or sleepiness on a long car journey are.

I agree that the paper itself muddies the waters dreadfully with terms like effort preference. I decided not to open that can of worms with a journalist simply because I did not think it would help in a Science journalism piece. Let the science world know that there has been some research into biological mechanisms in ME. Don't drag up the authors' inability to make sense of things. I discussed that with the journalist and she was very much of the same view. She didn't want to open the can either.
 
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