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

[Murph]

When it comes to effort preference the findings seems to hinge on this one test about whether you'd choose to press a button with the little finger of your non-dominant hand 98 times in 21 seconds or prefer to do 30 button presses with your usual index finger, for seven seconds, in return for various small prizes (the hard task prizes are bigger).

The relevant outcome is not how you do at the test - but which test you choose.

Here's how patients and controls did (this chart is in the supplementary material). At the beginning, about 45% of patients chose the hard task, compared to about 55% of controls. (presumably this is 8 of 17 patients and 12 of the 21 controls?). It went down from there (the data in this chart is smoothed not raw). The decay rates were similar between groups. By about trial 15 patients were as likely to choose the hard task as patients had been at the start.

The p-value for between group difference was p=.04.

It's a funny sort of a test, invented in 2009 to measure anhedonia in the depressed. It is regularly cited, so I guess it's part of the accepted literature on effort. An important question to ask is whether it has been validated for use in a group with a fatiguing illness, or whether that might confound the conclusions drawn from it.

Another question might be whether it was controlled for biological sex; the total control group had ever so slightly more men in it and the original 2009 paper finds men more likely to choose the hard task.

 

[bread.]

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.

'Effort preference based'.

I guess we had kind of an unrepresentative group of patients in this study. I am not even speaking about the bogus assumptions that have been made in terms of 'effort'.

How severely are you affected physically by this disease, do you share that information?

I guess it might be informative in what direction someone is biased. If I had to guess you were physically relatively healthy or mildly affected? You certainly don't have to share this with me, obviously.

 

[Murph]

Since we are all talking about the effort preference, I got the source data and plotted it in full granular detail.

First, a replication of the smoothed graph above, with a bit more detail. The downward sloping lines on my chart below are basically the same as the ones on theirs above, so their chart seems fine to me. What my chart adds is two columns for every of the ~50 times participants played, showing the proportion of controls(red) and patients (blue) who played on hard mode. There's also a dot representing the value of that round in terms of prizes.
I've included the four practice rounds too.

In the next chart, we can see the exact choice patterns made by every participant. Healthy volunteers (HV) in red; pwme in blue (PI-ME/CFS).

These charts show a line that pings from the easy choice at the bottom (press button with index finger for 7s) to the hard choice at the top (press button with little finger for 21s). There is a chart for each participant. The horizontal axis is the ~50 times they played this game. Reminder: they choose easy or hard then do the button mashing.

So the toughest participant is HV H, who started off choosing easy but later did a big string of hard choices in the middle. Ten consecutive turns of little finger button-mashing, almost 1000 presses with the non-dominant pinkie though that stretch! impressive

The second and third places are taken by HV P and HV K. One of us is in fourth, PI-ME/CFS K. Go patient K !

Then it goes all the way down to PI ME/CFS-B who only tried to do the hard button pushing twice in the last 25 turns. She mostly stuck with the easy choice, pushing the button with her index finger for 7 seconds.

Why am I showing all this detail? What's the point? Because I want to draw attention to the actual thing the construct "effort preference" is based on. It's not some all-encompassing insight that describes eternal truths about us. It's a very specific game involving deciding to push a button with your pinkie finger.

An eagle-eyed observer might note the letter sequence among the HV shows a missing value. Data for HV F was thrown out. Not sure why but missing data is not uncommon in these sort of things. It's also possible HV F was wasted - the blood work shows one healthy control with a heroic blood ethanol content !!! (In truth I have no way of knowing if this effort test was on the same day as the blood work). But who shows up to NIH drunk?!

MOTIVATION VS LEARNING?

Overall my take on these data is we don't know why the PWME chose the hard choice less often overall. I'd say the dominant effect is going to be a learning effect. If you learn you usually can't push a button 90-something times with your little finger, you probably stop trying to do so. The data doesn't say if they succeeded. And if you learn that you find the whole thing tiresome, and you have 25 iterations left, you probably will repeatedly choose the test that goes for 7 seconds, not the one that lasts 21 seconds.

Really only the first few shots are especially instructive about intent and base level of motivation, and we can see above that in 3/4 practice rounds and the first two rounds of the real thing, pwme were more likely to choose hard than healthy controls

So my overall take is that learning is doing to dominate motivation after the first couple of tries, and so the trend over 50 trials is going to be driven be learning effects. I don't think it shows what they seem to imply it shows.

 

[junkcrap50]

What a crock of shit!

Lol this is what the effort preference test and methods science is? Wow. And they chose to lead with THAT in in big paper and all the press releases?!?

Heroic work @Murph for digging into it and explaining it - in actuality, really, exposing it!

What day of testing was this effort preference test conducted? On day 3 of a patient's trip to the NIH after hours of grueling other testing and PEM from previous days? Even if you ignore whether this button pressing test is really valid to begin with, who thought it would be good to apply to ME/CFS patients? Idiots.

 

[Marylib]

Short radio program.
https://www.npr.org/2024/02/21/1232...ght-new-attention-to-chronic-fatigue-syndrome
Someone mentions using 'checkpoint inhibitors' as treatments. I guess these are the kinds of drugs?
https://www.cancercenter.com/treatm...-medicine/immunotherapy/checkpoint-inhibitors

 

[Wishful]

I was often able to push through with doctor's encouragement.

No, you were able to physically exert yourself despite the "fatigue-like" symptoms, but you weren't able to make the "fatigue-like" symptoms diminish. The psychologists would like to believe that the fatigue-like state is psychological, so you can reduce that symptom by simply thinking positive thoughts. Even if there was a psychological mechanism to "think yourself better", that would fail if the "think yourself better" mechanism was broken.

 

[RYO]

Not surprising when you Google the term “effort preference” it shows paper written by psychology researchers. Why would NIH use this language?





From ncbi.nlm.nih.gov

 

[RYO]

Also by not performing 2 day CPET, you greatly underestimate/underreport the physiologic and autonomic effects of PEM.

 

[hapl808]

So my overall take is that learning is doing to dominate motivation after the first couple of tries, and so the trend over 50 trials is going to be driven be learning effects. I don't think it shows what they seem to imply it shows.

The whole thing is such a mind bogglingly stupid way to measure anything. I literally can't think of a single solid conclusion you can make from that, especially with a small number of participants. And to the small degree you can hypothesize anything - it makes sense that when someone is badly affected by an activity, they would then do less of it.

That's not effort preference, that's common sense. If eggs make you sick, you start to prefer foods without eggs. This preference is not causative.

Like, people who need right knee ACL surgery seem to PREFER to put more of their weight on their left knee. This 'weight preference' is a major finding - who's ready to publish? Maybe we can also come out with a program to encourage people with a torn ACL to put more weight on their damaged knee.

I haven't been able to read the whole study yet - just excerpts. Do they use this 'effort preference' theory as a basis of anything? It seems like such a bad way to frame things, yet all I can see it showing is that extra effort causes more pain - which is not how the finding is coming across. Especially when they don't bother with 2 Day CPET or other objective markers.

 

[Marylib]

Let's not forget that Mr. Walitt's reputation goes back awhile...

https://twitter.com/i/web/status/1760810128184684766

"I wish we had been wrong eight years go predicting something along the lines of Effort Preference, but we had a preview via Walitt of what they would find. The fix was in."
https://thoughtsaboutme.com/2016/03...amatic-risk-to-long-term-disability-benefits/
If "Effort Preference" gets taken up and cited by not only doctors, the general public, but also insurance companies, NHS, etc. - can you imagine how difficult this would be to fight? Remember how long the struggle was to update NHS guidelines? Sigh... how utterly tone-deaf can you get?

 

[RYO]

I agree with the comment about streisand effect. There are plenty of meaningful data from this study. Not sure concept of effort preference relative to MECFS patients will stand up well over time.

The immune dysregulation findings and possibility of persistent antigen are very important. I believe immune profiling done by Mark Davis at Stanford draw similar conclusions. Hopefully, either Dr Davis, Dr Maureen Hansen, and/or Dr Unutmaz will further research what is the persistent antigen causing T cell exhaustion. Despite the fact finding of dysbiosis was not discussed much, it deserves equal attention as it may be related to the immune dysregulation / persistent antigen. Is the persistent antigen a virus or viral particle? Could the persistent antigen be related to leaky blood brain barrier or vagus nerve infection?

I would like to also hear more about what Dr Nath thinks about significance of reduced catecholamines in CSF. How do catecholamine levels change with PEM? Is the catecholamine nuclei in the brainstem damaged? Can therapeutics effectively modulate catecholamine levels and result in improvement of any symptoms?

 

[Dakota15]

If any are curious on questions like this, @RYO, I do encourage outreach to Dr. Nath. HIs e-mail is listed on the NIH site and he engages with outreach to patients, from what I can tell. His e-mail is avindra.nath@nih.gov and he's generally timely with communication.

I would be curious his input on these follow-up questions, and I do hope you will consider reaching out (and hopefully sharing back any correspondence).

 

[Rufous McKinney]

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.

52 times....the word effort shows up (I'm tired. so thats it for my Find search).

Regarding effort preference (to keep beating up on that).....

I am shocked at their descriptions of pushing a button over and over again, and the assumptions they had there.

They describe:

"the participant either completed 30 button presses in seven seconds with the dominant index finger if they chose the easy task, or 98 button presses in 21 s using the non-dominant little finger if they chose the hard task."

(the reward for doing tasks was money, BTW: that was flabbergasting)

Then they observed the following and conclude:

"There was no group difference in the probability of completing easy tasks but there was a decline in button-pressing speed over time noted for the PI-ME/CFS participants (Slope = −0.008, SE = 0.002, p = 0.003; Fig. 3b). This pattern suggests the PI-ME/CFS participants were pacing to limit exertion and associated feelings of discomfort16"

Participants were pacing? Why do they think that? Participants slowed down because, well if I was asked to do this, I'd be slowing down...this requires concentration and muscles working and nerves operating correctly.

My hand/little finger would don't be able to push 96 times.

Why are they calling slowing down, pacing?

I have peripheral neuropathies in my hand and glitchy ligaments in my index finger/thumb and swelling veins.

And since I'm 70 nobody would be studying me.

Anyway, I find this very bizarre.

Meanwhile: I agree we should try to focus on other aspects of their studies which were more fruitful from our point of view. There is always this baggage following us around. I mostly disregard all this psych stuff. They are on thin ice.

 

[Rufous McKinney]

It's a very specific game involving deciding to push a button with your pinkie finger.

not to beat this rather dying horse too badly, I play a flute. I once played a flute. My joints in my hand "lock up"...I might say I'm double jointed (a misnomer, I assume). Related to the fun, more flexible bendy stuff.

so my non dominant pinkie would likely lock up somewhere into this test if I was trying to push a button 96 times.

Is the patient counting? Because when I had to count 39 stitches, while knitting, yarn over, I became crashed and exhausted from counting the stitches.

 

[Rufous McKinney]

If you learn you usually can't push a button 90-something times with your little finger, you probably stop trying to do so.

Yes.

Is there rest of spacing in between indviidual rounds of the game?

I guess these are the kinds of drugs?

used in cancer treatment, immune system would be suppressed...sounds very dangerous and not fun.

pwme were more likely to choose hard than healthy controls

what might account for that interesting detail?

I'm thinking initially pw ME are motivated to succeed. thats because we are NOT depressed people, we are sick people who often were once very successful normal humans.

Then, over a few minutes the pwME cohort discovers it quickly gets more difficult from the concentrating, counting, muscle moving, nerves firing etc.

 

[Rufous McKinney]

Several threads are going on regarding this paper:

https://forums.phoenixrising.me/thr...phalomyelitis-chronic-fatigue-syndrome.91602/

 

[SlamDancin]

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.

I agree and especially for those who have an underlying neuromuscular condition

 

[LaurelW]

Here's a comment from the article in the New York Times. This is what really bothers me about it.

"At least it confirms other researchers findings of dysregulated immune system, persistent antigen and dysbiosis. Important researchers such as Dr Maureen Hanson, Dr Dnutmaz, and Dr Ian Lipkin. However, the authors use psychology language/framework such as “effort preference” as if patients who constantly feel like they have the flu, orthostatic intolerance and constant muscle pain have a choice in engaging in every day activities that result in PEM/worsening symptoms."

 

[RYO]

The concepts of central fatigue and interoception are interesting theories but not established bedrock science. This study was conducted for deep phenotyping. It is an over reach by authors to draw conclusions from the data. It should have been presented as theories to consider. It was also very disappointing that they didn’t elaborate at all about such important findings as immune dysregulation, persistent antigen and dysbiosis. These are concepts sited in other neurological disorders such as Parkinson’s disease and multiple sclerosis. The authors also need to defend why they chose Modified effort expenditure for rewards task as part of their study design. Would they include a psychology based test on a study of other neurologic conditions?

 

[Wishful]

Would they include a psychology based test on a study of other neurologic conditions?

Good point. Have psychologists produced any useful studies on neurologic diseases that have a clearly-identified physical cause? Have they produced any useful treatments for such diseases? Conversely, have they proposed treatments for such diseases that resulted in harm to the patients? (We have examples for ME: CBT and GET).