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

It is interesting to see this people getting themselves tied in knots about terminology.

If psychological and biological cannot be distinguished then presumably there is no point in talking about a biopsychosocial model or publishing, as Wyller has, in 'Biopsychosocial Medicine'.

He is being disingenuous, though. No research has shown that no distinction can be made. The confusion, which Nath has walked right into, is the idea that they are alternatives. The mainstream scientific view is that psychological causal processes are a subset of biological processes. All psychological processes are biological but most biological processes are not psychological.

The distinction that matters to the public debate is that a psychological process involves the mediation of formulated ideas. The pain of treading on a sharp stone does not involve formulation of any ideas so it is not psychological in the relevant sense. Compulsive gambling involves the idea of winning money so is.

Nath's problem is that invoking 'effort preference' as a mediator of disability would make the disability psychologically caused. But only if the effort preference was the thing that was not right. A preference not to eat gluten for coeliacs does not mean that coeliac is psychological.
 
John Mac said:
ME/CFS may be caused by an imbalance in the brain
"We may have identified the physiological centre of fatigue," says the researcher behind a comprehensive study that has received a lot of attention.

Vegard Bruun Bratholm Wyller is the head of research at the Department of Pediatrics at Akershus University Hospital, and professor at the University of Oslo's Institute of Clinical Medicine.

He has been researching ME/CFS since 2003.

Wyller previously explained ME/CFS as being due to a hypersensitivity in the brain. This leads to signals from the outside world being overinterpreted because the nervous system is on continuous high alert.

"The findings in the new study fit very well with both what I have said and with a number of studies about the central mechanism of fatigue," he tells sciencenorway.no.

But Avindra Nath, senior author of the study, tells The New York Times that the results confirm that ME/CFS is biological, not psychological.

Wyller thinks this statement goes further than the study has evidence to support.
“It’s highly unusual to make a distinction between the biological and the psychological brain. There's a lot of research showing that such a distinction can't be made," he says.

The brain is not damaged

The finding in Nath's study concerns a functional change in the brain that disrupts how ME/CFS patients handle exertion and fatigue. “This doesn’t mean that the brain is damaged or broken in any way. The change lies in how the brain functions in people with ME. It might be that their brain is continuing to respond as if the body is ill, even though the infection is long gone,” says Wyller.
Our brains are constantly working to predict what will happen next.

“If your brain tells you that a task is much more demanding than it actually is, then you won’t be able to mobilise the necessary areas of the brain to do the task. This aligns well with what we generally know about fatigue, regardless of whether we’re talking about ME or other forms of fatigue,” he says.

https://www.sciencenorway.no/chroni...e-caused-by-an-imbalance-in-the-brain/2340918
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Incredible how out of touch and obtuse these people are. The problem I've had consistently in my life is underestimating the effort something would take and the energy I'm using.
 
Sid said:
The 2-day CPET literature isn’t clear-cut at all and different studies have reported different abnormalities (and lack thereof). This has been discussed at length in different threads. I do think this was a missed opportunity, as 2-day CPET findings require independent replication. Though with the tiny sample size they had of patients able and willing to undergo CPET, it wouldn’t have been useful anyway.
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There is one clear-cut funding - reduction in power at the ventilatory threshold on the 2nd day. This is the variable least subject to confounds so it is probably why it is the one that shows up in all studies. Reductions in VO2Peak are hard to measure when so many patients fail to reach a true VO2Max (I know some people don't want to hear this, but it is true). I'd also expect studies that measure muscle sense of effort also show a non-linear breakpoint at lower power output too, as the ventilatory threshold is always associated with a non-linear increase in sense of effort in all participants healthy or otherwise.

Trish said:
I think it's already been done by Maureen Hanson's big 2 day CPET study that collected lots of subjective and biological data from 80 patients. Adding previous studies, and I think it's already established. I doubt we need 300 more.
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I disagree, specifically I suggest if they did the electrophysiology/TMS testing utilising the 2 Day CPET rather than handgrip testing, they would have had far more useful results - their conclusions about the TMS results are just wrong - inconsistent with prior studies and inconsistent with current interpretation of such data - which also suggests that locomotor activity is what they should have chosen rather than grip testing.

See: "Critical Considerations of the Contribution of the Corticomotoneuronal Pathway to Central Fatigue"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9772161/

They also fail to understand that sense of effort during a motor task is not complicated it is simply the strength of the upstream signal - there is no lower level feedback that modifies the sense of effort. That said, cognitive activity can confound reporting of sense of effort on scales (such as the Borg scale), such as difference in anchoring effects, due to muscle pain for example - but this is not the sense of effort itself that has changed.
 
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Dakota15 said:
Just sharing this message today from Koroshetz, for visibility, when I had asked for paper amendment of ‘effort preference’ term.

“Understand the anxiety but it’s very important that the community understands the finding.

To simplify how the brain works I could say that the brain circuits are constantly estimating the difference between the effort required and the reward to be gained from executing an action. This applies to all behaviors, even to what I am typing now. This is easier to understand in estimating the degree of force you need to exert to pick something up something, but even the more automatic behaviors like whether we are “hungry” enough to eat. So the finding is very important. In the persons with ME/CFS the circuits that do this estimation of effort are malfunctioning. They even see an abnormality in brain activation related to this finding. They see alterations in dopamine metabolites (potentially related to the reward signals). And they speculate that it is abnormalities in the immune system that are driving the abnormality.

So this has nothing to do with “psychological”, this is a real abnormal finding in how our neural systems are supposed to work.

Planning a hybrid workshop to explain the findings to the subjects and the general community soon.”
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This is a very uninformed answer. He appears to be conflating the concept of reward-prediction error in dopamine processing and the initiation of motor actions. The fMRI results did not show any changes in blood flow to areas of the brain associated with reward calculation - ventral tegmental area, striatum, substantia nigra. They did observe differences in neurotransmitter metabolites in the CSF of ME patients, but CSF metabolites don't provide any information about neurotransmitter signaling at the synapse in the central nervous system. They are not equivalent at all. The region that DID show differences was the TPJ, a cortical structure that seems to participate in many different processes. As a preclinical neuroscientist I do not think they have proven that "estimation of effort" is malfunctioning at all - the only thing we know is that TPJ activity seems to be different in fatigued ME patients versus non-fatigued HVs. I don't see any evidence that would actually implicate circuit-level dysfunction outside of the MEP data that also contradicts the major findings in the papers they've cited. Do not have high hopes for this.
 
Janna Moen PhD said:
This is a very uninformed answer. He appears to be conflating the concept of reward-prediction error in dopamine processing and the initiation of motor actions. The fMRI results did not show any changes in blood flow to areas of the brain associated with reward calculation - ventral tegmental area, striatum, substantia nigra. They did observe differences in neurotransmitter metabolites in the CSF of ME patients, but CSF metabolites don't provide any information about neurotransmitter signaling at the synapse in the central nervous system. They are not equivalent at all. The region that DID show differences was the TPJ, a cortical structure that seems to participate in many different processes. As a preclinical neuroscientist I do not think they have proven that "estimation of effort" is malfunctioning at all - the only thing we know is that TPJ activity seems to be different in fatigued ME patients versus non-fatigued HVs. I don't see any evidence that would actually implicate circuit-level dysfunction outside of the MEP data that also contradicts the major findings in the papers they've cited. Do not have high hopes for this.
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As a layperson I could actually follow this somewhat (with the help of other online sources). What you say makes sense: I understand why you say what you say, and the content of your criticism.

When I try to make sense of what Koroshetz and other NIH officials try to make of the study results (like the reply resulting in this comment, but also the reply of Koroshet's NINDS office on behalf of the Trans-NIH ME/CFS Working Group sent to @Robert 1973 , and the study Q&A) I get stuck because I can't make it make sense. (The Q&A really does my head in: it talks about internal regulating processes but like the brain equals mind and like it consciously "decides" to expend an amount of energy and effort, which is subconscious but also the same as conscious reward-based decisionmaking. They literally go:
"Effort preference is a measurement of the decisions the brain makes of how to utilize its energy based on difficulty and value of a task. We are often not aware that these processes are happening.
In this study, a series of tasks were given in which people with PI-ME/CFS and healthy volunteers had to choose between doing an easy or hard pushing task."
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)

It does make more sense if I look at it from the notion that Koroshetz and Walitt are trying to work backwards towards making the study confirm a desired model - if I know that Walitt has had long-held beliefs about ME/CFS as "interoceptive disorder" and that he has been trying to prove fibromyalgia is a sensation-based delusion that leads to unsuitable behaviour for at least 15 years now, and that Koroshetz is collaborating and leading an effort to prove and establish a hypothesised redefined "interoception" model (basically One Brain=Mind To Rule Them All), an "expanded framework" that adds and emphasises "interpretation" (how it feels and how you interpret that feeling) and "regulation" (a "descending body regulation component", making interoception "bi-directional", which "provides many potential routes and methods for targeted interventions in the case of interoceptive dysfunction and related disorders", like CBT)
And if I know that several members of the Trans-NIH ME/CFS Working Group are connected to Walitts activities and the NIH/NCCIH/NINDS interoception project. And if I know that Koroshetz has already established a unit for "interoceptive disorders" to deal with ME/CFS, headed by Walitt (for whom this is his second unit for "interoceptive disorders"), in his institute three years ago.

What he says the ME/CFS intramural study shows does not fit what the study actually proves, but it does fit this redefined interoception framework and notions on biologically determined delusion and behaviour, which looks like the approach Koroshetz' and Walitt's "interoceptive disorder" unit are taking.

I'm guessing the "explanations" are probably vague and weird because that framework hasn't been substantiated yet, the NIH effort to research and prove it (and the whole current "interoception" trend) is still in its very early stages, so he struggles to make the claim that it is a solid biological find that proves psychosomatics, that the key characteristic of ME is that patients are misinterpreting internal signals and then make inappropriate behavioural choices based on that ("avoiding" effort because they can't gauge its effects right).
 
I can't comment on the neuroscience but I get the feeling that they got it backwards.

Ever since illness onset I've struggled to manage the mismatch between how capable I feel, and the drastic drop in function that occurs when actually trying to do things.

I don't know how I continue to find motivation, courage, enthusiasm and constructive willingness to confront my problems and make my life better, but I do. And everyone seems to think that if there is a will and good feelings, that it will be enough. But no, it's not enough. My experience has been consistently this: within a short time of starting an activity, the energy disappears and I begin feeling sick and all that positive mental energy disappears and turns into its negative forms. The time for that to happen varies a lot and is unpredictable, but it always occurs eventually, after a sufficient dose of activity.
 
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Mods feel free to move, but sharing here if this wasn't already shared.

3/25/24: 'A Discussion with Dr. Avindra Nath: Ted Burns Humanism Award Winner’ (around 12:20 minute-mark)

Dr. Nath: “What is really challenging my mind at the moment, and I think what it is is in broad terms, it is the post infection syndromes. I say that because with the current pandemic, it's long COVID, prior to that it was chronic fatigue syndrome, and there's significant overlap. I think that’s another segment of society that has not been taken seriously. So often times, they come to the physician, and they get all the testing done and nobody finds anything wrong with them and they are labeled as being psychological, but really they have a biological basis. So, we spend a huge amount of effort trying to understand these diseases, understanding the overlap between them. We just recently published a paper showing that there are specific immune abnormalities that drive these two syndromes. There is a possibility that there is a residual antigen that is still present from the past infection that precipitated the event. There are similar syndromes: post Lyme disease, Gulf War Syndrome, sick building syndrome. They all, I think are one of the same. They just have different names. I think if you can solve one, you can solve them all. That is what I am very passionate about at the moment because I think it's a huge segment of society that's been impacted by this and we need to do something to fix this."
 
Dakota15 said:
We just recently published a paper showing that there are specific immune abnormalities that drive these two syndromes.
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Not that I noticed, Dr Nath.
Some slight differences in rather peripheral immunological measures in a few cases maybe.

Dakota15 said:
There is a possibility that there is a residual antigen that is still present from the past infection that precipitated the event.
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Sure there is but you didn't find any evidence for it that I could see. And nobody has found any residual antigen in any of the other conditions much (Gulf War antigen?) despite looking hard in some.

PWME need researchers who are passionate about the illness but ones who are well informed about the existing literature and can see research findings in perspective. At the moment the PWME are much better at that than the researchers on average.
 
Mods, feel free to move to most appropriate.

4/18, Neurology Today: 'Are Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID Part of the Same Disorder? A New NIH Initiative Aims to Find Out’

Some excerpts:

'A study of 17 patients with myalgic encephalomyelitis/chronic fatigue syndrome revealed that there is an absolute biological basis for the condition. Researchers say that exposure to an infection leads to concomitant and persistent immune dysfunction and changes in gut microbiome, which results in decreased concentrations of metabolites that then impact brain function.’

'“We believe these are virtually the same disease, although there are some differences, and they should be managed and studied in multidisciplinary clinics focused on post-infectious syndromes,” said lead author Avindra Nath, MD...

''We hypothesize that these changes are driven by antigen persistence of the infectious pathogen.”

"Hector Bonilla, MD, clinical associate professor of medicine at Stanford University and co-director of Stanford's ME/CFS and Post-Acute COVID-19 Syndrome Clinic, called the study “extremely important.”

"'Dr. Nath's group has begun recruiting study participants for a clinical trial of intravenous IG (IVIG) in long COVID. “In order to bring treatments to people with ME/CFS quickly, we need to do trials in long COVID, because there are so many of them, they are closer to the infectious process, and we know exactly what the infectious process was,” he said.”
 
Dakota15 said:
"'Dr. Nath's group has begun recruiting study participants for a clinical trial of intravenous IG (IVIG) in long COVID. “In order to bring treatments to people with ME/CFS quickly, we need to do trials in long COVID, because there are so many of them, they are closer to the infectious process, and we know exactly what the infectious process was,” he said.”
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Little that Nath says appears to have any logical basis. There are lots topple with ME/CFS too. Being closer to the infectious process is not necessarily an advantage since a good number are likely to get better anyway - diluting any chance of measuring benefit of a drug. It might be useful to know what the infection was but for most ME/CFS patients we know it wasn't Covid - so Covid clearly isn't critical to what we need to know about ME/CFS.

Dakota15 said:
they should be managed and studied in multidisciplinary clinics focused on post-infectious syndromes,
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Why multidisciplinary clinics again? Why bundle them in with 'post-infectious syndromes' - does that mean reactive arthritis, which is better dealt with by a specialist rheumatologist, and rheumatic fever, best dealt with by a cardiologist? It all seems to be words pulled out of a hat like an AI device to be honest.
 
From the article:

This is the second time that Nath has alluded to the demoralizing effect that attacks can have on researchers. (The first had to do with efforts to remove Brian Walitt, even though Walitt was administering the study – not doing the research.)

…

Certainly Nath has earned our respect and trust
​
 
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The thing that caught my eye was him saying that 8 other studies have resulted from the intramural one, which is new information to me at least. Here's his paragraph on that:

"The intramural study findings have prompted a bevy of further studies. A Veterans Administration / intramural NIH study on ME/CFS has begun. The team doing the modelling work on immune signaling is using a “drug targets selection process” to look for potential drugs that could return the immune system to normal. The exciting low brain norepinephrine finding is being explored further. Further gut studies that aim to understand the cause of the gut issues are underway. Hwang is following up on his WASF3 finding. Comparisons between the ME/CFS study findings and Nath’s long-COVID study will be made."
 
RaviHVJ said:
The thing that caught my eye was him saying that 8 other studies have resulted from the intramural one, which is new information to me at least. Here's his paragraph on that:

"The intramural study findings have prompted a bevy of further studies. A Veterans Administration / intramural NIH study on ME/CFS has begun. The team doing the modelling work on immune signaling is using a “drug targets selection process” to look for potential drugs that could return the immune system to normal. The exciting low brain norepinephrine finding is being explored further. Further gut studies that aim to understand the cause of the gut issues are underway. Hwang is following up on his WASF3 finding. Comparisons between the ME/CFS study findings and Nath’s long-COVID study will be made."
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Yes, the fact they are planning a follow up on PEM I am thankful for.
 
Two things caught my eye —

Exercise physiology – the exercise study found widely variable results, with some people with ME/CFS performing well and others not performing well. In general, people with ME/CFS were unable to generate normal amounts of energy to the extent that “performing activities of daily living would be difficult”. They did not find problems with low CO2 or oxygen saturation of the muscles but did find a lowered heart rate response (chronotropic incompetence).

The metabolic chamber did not show problems with CO2 or altered energy expenditures while resting or sleeping.
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In a video, Sanna related that she’d become ill in 2014 and by 2018 was essentially bedbound. She used her wheelchair and cane to get around during the study but was so crashed after one test that she had to be carried on a stretcher, needed a bedpan, and at one point was too weak to raise her hand and was unable to participate in the CPET exercise test or metabolic chamber.
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And

Dave Goldstein, the Director of the Autonomic Section, was up next. He did not find evidence of increased postural orthostatic tachycardia (POTS) in ME/CFS – in part because he found fairly high levels of it in the healthy controls. (It’s possible to have POTS and be completely healthy.)
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[A participant's] healthy sister, Susan, also participated in the study but then came down with long COVID herself after catching the virus (!).
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