Grip test results and brain imaging in the NIH study: Deep phenotyping of PI-ME/CFS, 2024, Walitt et al

[Andy]

This post has been copied and many following posts moved from the main thread on the study:
Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome, 2024, Walitt et al

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.

Open access, https://www.nature.com/articles/s41467-024-45107-3

 

[chillier]

In this figure they got participants to exert by a grip test for n repeated blocks (denoted b1 to bn), which were repeated until fatigue kicked in and then continued for three more blocks (denoted f1, f2 and f3). They did fMRI during this to measure brain activity. They argue there's an increase in brain activity in the temporo-parietal junction TPJ (shown in panel D) in controls but not in ME over the course of the experiment.

Panel A shows that grip strength decreases in ME (red line) over the course of the blocks but not in controls even after fatigue kicks in. You can see from the inset below panel A that the controls can do many repeated (b) blocks before fatigue kicks in (perhaps an average of around 20) compared with the patients (maybe average of 5ish).

In panel E they show a reduction in brain activation in the TPJ region in blocks 9-12 and 13-16 in ME compared with controls, who instead exhibit a trend of increasing TPJ activity. The authors argue that this corresponds in someway to a mismatch between the 'willed action and produced movement'. (not quite sure what their point is, they say high TPJ activity means more of a mismatch - so there is less of a mismatch in ME then?)

I think it's interesting that when they compare other parameters in panels b and c they are comparing across the point where fatigue kicks in b1 to bn, f1, f2, f3. However in panel E they are just comparing across the blocks linearly. At blocks 9-12 and 13-16 where they see significant differences, the patients will be fatigued, whereas the controls will not even be close to getting tired - as shown in the inset below panel a. I would like to know wether this difference holds in the f1, f2, and f3 blocks - I don't reckon it would.

Is it possible this is just a product of being tired, not to do with ME/CFS. What would it look like if you got people who were wiped out for other reasons to do this experiment? I don't know anything about the TPJ but a quick look on wikipedia it seems to have to do with processing both external sensory and internal body sensory information as well possibly having to do with the sense of self. Could it be you have less activity in this area if you feel dejected and tired out, and more if you're in your element and proud of your grip strength (if that doesn't sound too daft)? Very basic conjecture.

If however it was a real effect relevant to ME/CFS what could it mean? pwME have issues with processing sensory information after all so maybe there is some dysfunction in this area?

I'm not currently convinced.

 

[Jonathan Edwards]

If however it was a real effect relevant to ME/CFS what could it mean? pwME have issues with processing sensory information after all so maybe there is some dysfunction in this area?

To me the whole problem here is that pWME will be thinking differently throughout the whole process simply because they know that they their disabilities are being studied. Controls will just be happily following instructions. I see no real possibility of extracting any conclusions from fMRI in this way unless some very sophisticated internal control comparisons are being made.

 

[Simon M]

Going back to the idea of effort preference, are the reported differences trustworthy? I've not read the paper yet (it's ***ing huge), but these criticisms look significant:

I'm not currently convinced.

@chillier was commenting on the fMRI data of participants doing repeated hand-grip tests, and pointing out that the comparison of healthy volunteers vs ME folk was not (unlike other experiements in the paper) like-with-like. Specifically, it included data on HV who were not reporting fatigue with ME people who said they were, and therefore the fMRI differences might be generic relating to fatigue. chillier suggested the data for fatigued HV vs fatigued ME might not show the same differences. Which would undermine the key finding.

While Jonathan Edwards questioned the validity of the fMRI setup:

To me the whole problem here is that pWME will be thinking differently throughout the whole process simply because they know that they their disabilities are being studied. Controls will just be happily following instructions. I see no real possibility of extracting any conclusions from fMRI in this way unless some very sophisticated internal control comparisons are being made.

If the findings of effort perception differences are real it could provide an important clue to the illness and we would have learnt something worthwhile from an $8m, 8-year study, however small. But I'm worried

 

[Jonathan Edwards]

If the findings of effort perception differences are real it could provide an important clue to the illness and we would have learnt something worthwhile from an $8m, 8-year study, however small. But I'm worried

I think you are right to be worried if this long list of authors are collectively unable to come to a sensible interpretation of their own data. The raw data might be more interesting.

What may be a useful step forward is showing differences on fMRI between groups in this sort of context. If it becomes possible to interpret the fMRI a bit more precisely then it might actually pick up primary causal mechanisms. On the other hand much the most likely explanation for differences in decision making processes would seem to be the difference between being a patient under investigation and being a control.

 

[poetinsf]

Which maybe is right.

Maybe, maybe not. Another possibility is that parietal junction may be asleep to begin with because of physiological changes. They could've easily put that to the test by subjecting the patient to the maximal exertion test, like they do in 2-day CPET test, and see if the junction lights up. I could do the same thing they did and deduce that they didn't do that because they were either lazy or not bright.

But of course it is then not telling us about what is wrong that makes people need to pace.

Yes, and that is precisely the problem with exclusively focusing on fatigue and not PEM.

 

[SNT Gatchaman]

In the peer review file Anthony Komaroff wrote —

I think the expanded language in the Discussion regarding altered effort preference might be unclear for many readers of a general scientific journal, like Nature Communications. I think the report would have greater impact if the authors eliminated jargon and explained some concepts that may be familiar to neurophysiologists but foreign to some readers. For example, the following two sentences (p. 10): “This difference in performance correlated with decreased activity of the right temporal-parietal junction, a part of the brain that is focused on determining “mismatch”31. In respect to movement, this would relate to the degree of agency32.” Mismatch between what, effort and reward? And what does “agency” refer to in this context?​

The response was —

Response: Thank you for pointing out where we could make the explanation more accessible. These sentences, page 10, now read:

This difference in performance correlated with decreased activity of the right temporal-parietal junction, a part of the brain that is focused on determining “mismatch” between willed action and resultant movement31 . Mismatch relates to the degree of agency, the sense of control of the movement32 .
​

---
I've posted Structural and functional brain alterations in patients with myasthenia gravis (2022, Brain Communications) as a comparison, although it doesn't mention the temporoparietal junction specifically.

 

[SNT Gatchaman]

I'm still struggling with understanding how the conclusions are reached in this section.

Compared to HVs, PI-ME/CFS participants failed to maintain a moderate grip force even though there was no difference in maximum grip strength or arm muscle mass. This difference in performance correlated with decreased activity of the right temporal-parietal junction, a part of the brain that is focused on determining mismatch between willed action and resultant movement. Mismatch relates to the degree of agency, i.e., the sense of control of the movement.

Greater activation in the HVs suggests that they are attending in detail to their slight failures, while the PI-ME/ CFS participants are accomplishing what they are intending. This was further validated by measures of peripheral muscular fatigue and motor cortex fatigue that increased only in the HVs. Thus, the fatigue of PI-ME/CFS participants is due to dysfunction of integrative brain regions that drive the motor cortex, the cause of which needs to be further explored. This is an observation not previously described in this population.

They note that maximal grip strength is normal at the outset, with a moderate grip not able to be maintained as long as HCs. So we can't maintain handgrip strength, a finding repeatedly demonstrated, including in LC cohorts and I think mostly regarded as relating to early fatiguability of muscles.

There is correlation with decreased rTPJ activity in patients. Greater rTPJ activity is seen in HCs which they say indicates that HCs are working on feedback to confirm "no mismatch between willed action and resultant movement" during the task.

But patients are well trained to the effects of rapid fatiguability. There would be no need to pay undue attention to a proven decline in performance, once it's developed during the repetition task.

Then they say measures of peripheral muscular and motor cortex fatigue do not elevate in ME, which indicates that fatigue is due to dysfunction of integrative brain regions that drive the motor cortex.

A rapid decline in force along with a significantly lower number of non-fatigued blocks (Fig. 4a) and a relative decrease in the slope of the Dimitrov index 17,18 (Fig. 4b) occurred in PI-ME/CFS participants but both remained constant in HVs, suggesting that the decline of force was not due to peripheral fatigue or a neuromuscular disorder.

The Dimitrov index relates to electromyography. I'll have to read about that.

Fig 4c shows the motor evoked potentials, described in the legend as —

Mean and standard error of the motor evoked potential of HV (blue; n = 6 independent participants) and PI-ME/CFS (red; n = 8 independent participants) participants spanning the last five grip test blocks prior to fatigue onset. The amplitudes of the MEPs of HVs significantly decreased over the course of the task while the amplitudes of the MEPs of PI-ME/CFS participants significantly increased (−0.13 ± 0.2 versus 0.13 ± 0.2 MEP units; t(12) = 2.4, p = 0.03

In the main text they say —

Motor Evoked Potential amplitudes using transcranial magnetic stimulation of HVs decreased over the course of the task, consistent with post-exercise depression as seen in healthy and depressed volunteers, while they increased in PI-ME/CFS participants. This indicates that the primary motor cortex remained excitable for PI-ME/CFS, suggesting reduced motor engagement from this group.

Shouldn't it stay flat if it "remains excitable"? Why increase to become more excitable? I might have wondered if this wasn't reflecting upregulation of the primary motor cortex trying to overcome a peripheral failure in its end-effector. Hopefully someone has some knowledge of this.

 

[Eddie]

This difference in performance correlated with decreased activity of the right temporal-parietal junction, a part of the brain that is focused on determining “mismatch” between willed action and resultant movement. Mismatch relates to the degree of agency, the sense of control of the movement.
​

Does this actually mean anything? What is the degree of agency? Are they saying that pwME have the physical capacity to exercise but their brains aren't functioning correctly which tells them to stop? If that is the case then it isn't "effort preference" its brain changes that limit activity, but it seems like a stretch to claim that from this study. Its so vague to me, did I miss the part where they go into detail about what these brain changes are, why the occur and how they produce the feeling of PEM??

I think they are looking at the changes in fmri results incorrectly. Because they don't know what PEM is, there is an implication that there is a response to a threat that isn't present. However, we just don't know if that is the case. I think it is plausible that PEM ends up being something like increased brain lactate, hemodynamic changes in the brain or changes in brain immune cells. If this is the case, then there is a very real threat that pwME are trying to protect themselves from by reducing what they do.

And of course we see changes in fmri because the participants know that by exercising they are going to experience the phenomenon of PEM. If would be like if I did fmris on someone who was told to eat raw chicken and compared it to someone eating cooked chicken. I think the fmri of the person eating raw chicken would show all sorts of things because they are scared and worried about sitting on the toilet for hours later. Its not an effort preference, its a preference not to suffer which is universal to all people.

 

[Amw66]

I'm still struggling with understanding how the conclusions are reached in this section.





They note that maximal grip strength is normal at the outset, with a moderate grip not able to be maintained as long as HCs. So we can't maintain handgrip strength, a finding repeatedly demonstrated, including in LC cohorts and I think mostly regarded as relating to early fatiguability of muscles.

There is correlation with decreased rTPJ activity in patients. Greater rTPJ activity is seen in HCs which they say indicates that HCs are working on feedback to confirm "no mismatch between willed action and resultant movement" during the task.

But patients are well trained to the effects of rapid fatiguability. There would be no need to pay undue attention to a proven decline in performance, once it's developed during the repetition task.

Then they say measures of peripheral muscular and motor cortex fatigue do not elevate in ME, which indicates that fatigue is due to dysfunction of integrative brain regions that drive the motor cortex.



The Dimitrov index relates to electromyography. I'll have to read about that.

Fig 4c shows the motor evoked potentials, described in the legend as —



View attachment 21150

In the main text they say —



Shouldn't it stay flat if it "remains excitable"? Why increase to become more excitable? I might have wondered if this wasn't reflecting upregulation of the primary motor cortex trying to overcome a peripheral failure in its end-effector. Hopefully someone has some knowledge of this.

@snowleopard

Snow leopard no longer here ?

 

[Snow Leopard]

I'm still struggling with understanding how the conclusions are reached in this section.

So am I, it appears to be pure speculation. The claim that the reduced TPJ activity represents "mismatch between willed action and resultant movement" is based on a hypothesis paper.

Shouldn't it stay flat if it "remains excitable"? Why increase to become more excitable? I might have wondered if this wasn't reflecting upregulation of the primary motor cortex trying to overcome a peripheral failure in its end-effector. Hopefully someone has some knowledge of this.

Look at the supplementary data, 4c - there is no clear pattern in either patients or controls. Several participants had minimal change, there were both increases and decreases in both patients and controls - I think the results are just noise as removing just one of the data points or comparing different 'blocks' and the finding is no longer 'significant' (P<0.05). The manuscript also fails to mention that the cited references all had the opposite observation - reduced motor cortex excitability.

I'd argue that the patients were already suffering from fatigue and the methodology failed to induce significant change to the MEP recruitment curves - and they didn't publish any of that data, so...

Having said all that, ME/CFS does have altered sense of effort and balance between upstream (motor) drive and motor cortex excitability and this mismatch is highly likely due to increased (Type III/IV) afferent feedback or an increase in sensitivity of these nerves. The purpose of having an altered sense of effort means the ventilatory responses will adjust accordingly to the sensed metabolic balance. But the authors of the manuscript don't seem to understand the relationship between metabolism, afferent sensing of fatigue, ventilatory responses and the impact on the brain.

If the findings of effort perception differences are real it could provide an important clue to the illness and we would have learnt something worthwhile from an $8m, 8-year study, however small.

It is not worthwhile because instead of adding anything new, they've muddied up the waters with their inconsistent results. The effort perception stuff has been known for 30 years.

What we need to know is why, and they failed to even attempt any experiments (based on what is already known in exercise physiology) to find out why.

 

[Jonathan Edwards]

Shouldn't it stay flat if it "remains excitable"? Why increase to become more excitable? I might have wondered if this wasn't reflecting upregulation of the primary motor cortex trying to overcome a peripheral failure in its end-effector. Hopefully someone has some knowledge of this.

I have no knowledge of previous work in the field but I would have thought increased responses were equally consistent with patients being more engaged and that reduced responses in HVs were due to them going on to 'autopilot'.

To be honest, I think if the authors wanted to study brain events using fMRI they should have just done a study on that and published results with extensive background explanations of the validation of their interpretations. Putting this in with all the other stuff produces a paper that does justice to nothing.

 

[Snow Leopard]

Is this the same research that is in the following Daily Mail article

Yes, we're in a strange world where the Daily Mail is more sympathetic than The Guardian.

I have no knowledge of previous work in the field but I would have thought increased responses were equally consistent with patients being more engaged and that reduced responses in HVs were due to them going on to 'autopilot'.

I think they're trying to claim an effect that doesn't exist.

There was little change for 4/6 healthy controls, 1 had a modest reduction, 1 had a large reduction. There was little change for 2/8 patients, 1/8 had a small reduction, 2/8 had a small increase, 1/8 had a modest increase, 2/8 had a large increase.

I'm not seeing a distinct pattern and I think there is too much noise in the method, or the method doesn't consistently invoke the hypothesised effect (reduction in motor cortex excitability)

 

[Jonathan Edwards]

I think they're trying to claim an effect that doesn't exist.

Yes I am getting that now. I am so glad S4ME members are such Trojan data readers. I give up when I cannot see what a result is supposed to mean. It is useful to know there isn't even a result!!

 

[Snow Leopard]

Yes I am getting that now. I am so glad S4ME members are such Trojan data readers. I give up when I cannot see what a result is supposed to mean. It is useful to know there isn't even a result!!

Curiously, while there are a lot of scatter plots, the manuscript seems to eschew scatter plots when the scatter plots don't look so pretty...

When I was an undergraduate, I expected to fail lab reports if I didn't provide scatter plots or tried to claim there was an effect when the scatter plot looked like crap.

 

[Evergreen]

It seems more logical to speculate that it was due to the central fatigue given that the physical correlation between catechol and the effort preference.

I hear you.

They defined central fatigue as post-exercise depression, which they identified when “Motor Evoked Potential amplitudes using transcranial magnetic stimulation… decreased over the course of the task”. They found this in the healthy volunteers but not in patients.

We measured peripheral fatigue (high:low ratio) and central fatigue (post exercise depression). Both types of fatigue were seen in the HVs but not in the PI-ME/CFS participants.

Motor Evoked Potential amplitudes using transcranial magnetic stimulation of HVs decreased over the course of the task, consistent with post-exercise depression as seen in healthy and depressed volunteers19, while they increased in PI-ME/CFS participants (Fig. 4c). This indicates that the primary motor cortex remained excitable for PI-ME/CFS, suggesting reduced motor engagement from this group20.

This seems interesting – when ppl with ME have the opposite result to normals, it feels like we’re getting closer to the interesting bits. Could someone explain how the primary motor cortex remaining excitable suggests reduced motor engagement?

 

[Evergreen]

I don’t think this section heading is accurate:

Equivalent motor performance in PI-ME/CFS and healthy volunteers

It seems to contradict the corresponding figure title

Fig. 3: Impaired effort measures and motor performance were observed in PI-ME/CFS cohort compared to HV.

The patients had a rapid decline in force on repetitive grip testing.

Have I misunderstood something?

 

[Evergreen]

I think the reason I’m struggling to understand the effort preference thing is that it is not explained clearly in the paper. I feel like words are missing or wrong.

In this interview, Walitt talks about the effort preference thing:

“We may have identified a physiological focal point for fatigue in this population,” said Brian Walitt, M.D., M.P.H., associate research physician at NINDS and first author of the study. “Rather than physical exhaustion or a lack of motivation, fatigue may arise from a mismatch between what someone thinks they can achieve and what their bodies perform.” https://www.eurekalert.org/news-releases/1034817

This is ambiguous, does Walitt think patients think they can achieve more than they can? Or less than they can?

In the paper, they write

blood oxygen level dependent (BOLD) signal of PI-ME/CFS participants decreased across blocks bilaterally in temporo-parietal junction (TPJ) and superior parietal lobule, and right temporal gyrus in contradistinction to the increase observed in HVs (F (3,45) = 5.4, voxel threshold p ≤ 0.01, corrected for multiple comparisons p ≤ 0.05, k > 65; Fig. 4d, e).

That decrease in BOLD signal means reduced TPJ activity in patients, right?

They clarify that:

TPJ activity is inversely correlated with the match between willed action and the produced movement.

So that would mean that reduced TPJ activity of patients means a better match between willed action and the produced movement for patients compared to controls. (Right? One goes up, one goes down.)

And that would be consistent with this comment in the discussion:

Greater activation in the HVs suggests that they are attending in detail to their slight failures, while the PI-ME/CFS participants are accomplishing what they are intending.

Doesn’t this mean that patients had less of a mismatch than the controls?

If so, then describing fatigue in ME/CFS as a mismatch between what patients think they can do and what they can do makes no sense at all (even if sold on the effort preference thing).

What am I missing?

 

[Eleanor]

does Walitt think patients think they can achieve more than they can? Or less than they can?

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.)

 

[rvallee]

I think what Walitt is trying to do is to find a new spin on BPS, quite similar to what the new FND brigade is doing.

At the very bottom of the discussion lingers the question and uncertainty of/around 'free will' (not really a question actually, cells behavior, and therefore our behavior, is determined). I guess the 'new spin' consists more or less of:

It's not really anything new. I've seen many times in the past, something in the form of: "those are the patients who think they can't do, but actually can?"

It's the same thinking behind looking at bedbound patients and insisting that they could just get up if they wanted to. They can, they just think they can't. It's the same old piss in the same old bottle with a Sharpie'd label.