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

[rvallee]

On the "mismatch" between what we think we can do and what we can do, is the direction of that mismatch established/discussed? Because however much it doesn't fit at all as a cause, explanation or mechanism for fatigue, the mismatch is definitely there, just in the opposite direction of what is typically argued. We definitely think that we can do more than we actually can, rather than the other way around. Or rather, we want to do more than we can actually do. So in that sense if there is a brain region that actually does that in a verifiable way, it would light up, just in the opposite direction as the traditional belief.

Because when we say that we can't do something, it's based on experience not being able to do something requiring a similar level of effort. Which is similar to being asked to run 4 marathons, after having completed one. There are people, extreme endurance athletes, who actually literally do that. But 99.999% of humans know that they can't, and will say so because it's a simple statement of fact.

We are intelligent beings after all. Most of intelligence is being able to predict the future, this is how we avoid jumping from a tall height, because we know that we will fall and hurt ourselves. We should see the same response if someone asked to put 20L of stuff (that can't be compressed) into a 2L bag. "No, I cannot do that, it is impossible". I also cannot jump 50m in the air, not even dunk a basketball. Those are all things we know because we can predict based on our knowledge of reality and the abilities of our bodies. In our case, walking 100m is something we definitely think and want to do, but sometimes our bodies don't allow it, for reasons that are so hard to explain and even harder to predict.

Of course this has nothing to do with fatigue or PEM, but if that brain network does exist and it does do what they claim it does then it's definitely expected that it would light up. The question is whether they can tell which direction is the signal going. Of course the quote in the paper very much alludes to the typical "we can actually do more than we think we can", so if the direction can't be established and they just argued whatever fit their expectation, that's really appalling on their part. But this would be an expected result, if neuroscience can actually do what it claims here reliably.

 

[bobbler]

Hmmm - does this muddy the waters just enough for Cochrane...

Do we have a term yet, like dualist, for people who think the brain is separate from the rest of the body? Even an electrical trip-switch board is more complex than their interpretation of the brain bit. By this view if the power went out on the 'kitchen appliances' part then the only possibility could be someone turning it off (albeit they offer the option of 'unconsciously' not just consciously, so it 'isn't motivation'), as it doesn't seem to consider the idea the brain is attached to the body in any more than a one-way messenger and won't acknowledge the body equivalent of an applicance tripping the fuse or anything else in the circuit going awry.

I'm also quite confused about how they are so sure that the indication is 'less effort' from lower activity in that part of the brain. There seem to be different ideas for the area of the termporoparietal junction when I look online, so is it really a very specific part of that which has had such 'only could possibly be effort' that has been discovered or is this a bit of an abstraction? Maybe there is now more forensic brain-mapping, I wasn't aware it was likely to for many more years get anywhere near the point where you can be absolutely sure on such precise 'ideas' as he has suggested rather than approximate ideas of what areas do given the complexity involved with all tasks you might have someone doing when scanning etc.

For example the area named in this as being lower activity in those with CFS is the temporoparietal junction.

"The anatomical heterogeneity of the TPJ is matched by its seemingly ubiquitous involvement in different cognitive functions that span from memory to language, attention, self-consciousness, and social behavior." from the following: The role of the right temporoparietal junction in attention and social interaction as revealed by ALE meta-analysis - PMC (nih.gov)

"Damage in the left temporoparietal junction causes Wernicke's aphasia, a syndrome characterized by language comprehension deficits, which in turn have been explained by impaired integration of the order within and/or between phonemes or more generally in auditory temporal order judgment (von Steinbüchel et al., 1999)" FromThe Temporoparietal Junction as a Part of the “When” Pathway - PMC (nih.gov)

Does that sound somewhat familiar to any people with ME/CFS who might be exhausted because they are in the middle of a trial?

 

[Hutan]

@Woolie - have you caught up with this study yet? You might like to weigh in on the brain imaging findings?

I'm looking forward to really understanding how the authors support this effort preference idea - I haven't got to that bit yet.

 

[Snow Leopard]

Maybe the central fatigue itself is an effort preference problem. But the term "effort preference", whether intended or not, connotes volition whereas central fatigue does not. A big difference to an average reader. Their speculation about pacing as the cause does not help. Not sure if their discussion about MECFS as a central fatigue problem at the end of the paper would remedy that.

Whoever wrote this "effort preference" stuff has never properly listened or understood what it feels like to have ME/CFS.

Sense of effort is an entirely brain derived signal and is related to the upstream signals before generating thought or passing a signal to the motor cortex. Central fatigue means greater upstream effort is needed to maintain the same motor output! So this is why there is altered "effort preference" because patients have to increase their effort compared to controls!

Central fatigue is an alteration of the excitability of spinal or supraspinal (brain) pathways (but empirical studies show it's mostly in the brain), but this alteration in excitability is driven by peripheral feedback from the muscles - studies have shown what happens when the signal is blocked. And a neurovascular unit coupling equivalent within the brain (though blocking this has obviously not been demonstrated). This sensing of metabolism is the bit the authors of the NIH manuscript have deliberately chosen to ignore. They've instead chosen the dualistic approach where they look at the brain and ignore the body.

 

[Evergreen]

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.)

Yes, I think you're right. Nicely explained too! And that would cause fatigue by causing deconditioning? Oof.

 

[SNT Gatchaman]

Interesting that muscles are considered to be deconditioned when that's the explanation being offered for a person's disabled state, but the same muscles are considered to be working normally when we're talking about "effort preference" and "mismatch between what someone thinks they can achieve and what their bodies perform”?

Yeah. The paper's quotes are —

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.

EDIT:

The groups did not differ in composition by wholebody dual energy X-ray absorptiometry or in slow-to-fast muscle fiber atrophy 14 as measured by Type 2: Type 1 muscle fiber median Feret diameter ratio (Type2:1 mFd) using ATPase pH 9.4 stain of the vastus lateralis.

Vs

At maximal performance, a substantial group difference in cardiorespiratory capacity became apparent, which was related to both chronotropic incompetence and physical deconditioning.

With time, the reduction in physical activity leads to muscular and cardiovascular deconditioning, and functional disability. All these features make up the PI-ME/CFS phenotype.

Physical deconditioning over time is an important consequence.

 

[bobbler]

Supplementary Information p. 52, discussing the cardiopulmonary exercise test: "Effort preference did not correlate with peak power in PI-ME/CFS participants (r(6)=0.13, p=0.8) which suggests that effort preference did not impact CPET performance, perhaps related to experimental incentives to push their limits."

Seems effort preference is one of those useful things that apply when we want them to and not when we don't...

Is it really the temporoparietal junction that he keeps citing as the 'proof' of this? From what I'm checking it makes no sense for this area.

I've found the following paper as one of the first ones I can even find when looking for the claimed links between the area cited and 'exertion':

(PDF) The right temporoparietal junction encodes efforts of others during action observation (researchgate.net)

As the link says it notes:
The right temporoparietal junction encodes efforts of others during action observation

"Neuroimaging studies have demonstrated that the temporoparietal junction (TPJ) plays an important role in the understanding of such mental states. During the observation of non-intended or deceptive actions, not only AON but also the TPJ is activated17,18. These findings suggest that mental states behind an other’s action aect activity in the “understanding” systems. However, it remains unclear as to whether the front-parietal AON during action observation is also related to the inference of an other’s feeling (i.e. the “how” of an action)."

"An example of when we could infer the feeling of someone else, such as the effort level, would occur if we were to see an elderly adult lifting a heavy object. We would be likely to make an inference of other’s feeling of effort even when viewing their back (without watching their face)."

Studies utilizing transcranial magnetic stimulation (TMS) have demonstrated that corticospinal excitability during action observation of an effortful movement (lifting a heavy object) is greater than that during action observation of an effortless movement (lifting a very light object)21,22. However, these studies did not clarify whether the enhancement of corticospinal excitability reflected the effort level of the actor or the absolute weight of object. This is because the effort level and the object weight
were confounding variables.

In the present study, we utilized four different movies to dissociate the effort level of the actor and the absolute weight of the object lifted, we used four types of movies: a thin actor or a built (muscular) actor lifting heavy or light weights. To investigate the brain regions that respond to the forming of an inference of other’s feelings (the actor’s effort level) with action observation, we recorded brain activity using functional magnetic resonance imaging (fMRI). We used the dumbbell curl to depict a movement requiring effort. In the case of the thin actor lifting the heavy dumbbell, the actor’s effort would be higher than for the other conditions.

"We hypothesized that activity in the TPJ would be related to others’ effort levels during action observation because the TPJ is the key structure for inferring other’s feelings."

I really cannot understand how this man thinks that he has detected what he claims when at the very least you would have had to have ruled these other effects out, and do we even know whether for example healthy controls were watching pwme doing the test and so it's actually this effect and therefore the reverse (healthy controls are noting the effort of pwme)

And are these results from Day 1 or Day 2 EDIT: 'like' CPET? if so then surely the literature on CPETs (anything done by those who acknowledge 2-day CPET results after a certain date) would show that the claims on fatigue are silly from a timing perspective. Why are their CPET findings not discussed in the context of the literature? eg Properties of measurements obtained during cardiopulmonary exercise testing in individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - PubMed (nih.gov)

 

[Creekside]

"An example of when we could infer the feeling of someone else, such as the effort level, would occur if we were to see an elderly adult lifting a heavy object.

An fMRI of my brain while lifting a heavy object would observe activity in the part of my brain repeating "Lift with your legs, not with your back!". That would probably alter my facial expression and posture and muscle tension, etc.

 

[bobbler]

An fMRI of my brain while lifting a heavy object would observe activity in the part of my brain repeating "Lift with your legs, not with your back!". That would probably alter my facial expression and posture and muscle tension, etc.

mine should, but it might also be showing the 'language' part of my brain too.

But it appears the fMRI they did measures the part of the brain that looks at social aspects like whether someone else has false beliefs or how they feel. ie 'insight/theory of mind' into what others might be feeling? ie not your own effort.

 

[Jonathan Edwards]

Can anyone help me here with figuring this out because I'm starting to wonder whether it is just me being tired and missing things as to why this stuff so obviously doesn't add up.

From past experience @bobbler I suspect you are missing nothing. My brain is too old and my attention span too short to help but I suspect there will be someone here who could. @Woolie comes to mind!!

It took us several months, maybe a couple of years, to discover just how dreadful PACE was. That included getting minutes from steering group meetings that showed that people were actually cheating. It will all unravel with time. I am impressed how much people have uncovered in three days.

 

[bobbler]

I'm now looking at the Walitt et al (2024) paper, and the hand-grip figures: Fig. 4: Impaired sustained effort and motor performance was observed in PI-ME/CFS cohort compared to HV. | Nature Communications

I'm now really puzzled. The first figure shows 'blocks' goodness knows why, and the latter 3 are apparently fatigued blocks, with the first 2 apparently 'before fatigue'. How did they measure this fatigue?

I've then looked at the labelling for 'd' which is a brain scan of one brain with some yellowy area and it is labelled within 'e' saying "e Brain activation of the regions depicted in d measured in the blocks of four over the course of the experiment in HV (blue; n = 10 independent participants) and PI-ME/CFS (red; n = 8 independent participants) cohorts. "

and for ME/CFS graph e just shows a line going down for brain activation vs time across these 'blocks' (labelled 1-4, 5-8, 9- 12, 13-16) .

In trying to work out what these 'blocks' were I've read.

"On single grip task, maximal voluntary contraction (MVC) was not different between groups (Fig. 3c) and correlated with lean arm mass but not effort preference or Type2:1 mFd (Supplementary Fig. S6A–C). Time to failure, the inability to maintain grip force at 50% of maximum contraction, was significantly shorter (p = 0.0002) in the PI-ME/CFS participants (Fig. 3d) and correlated with effort preference (Fig. 3e) in PI-ME/CFS but not in HVs. Time to failure did not correlate with lean arm mass or Type2:1 mFd in either group."

So OK, that's like doing a single CPET or whatever. Those with ME/CFS weren't less strong but lasted less long.

Then it says:

"Repetitive grip testing was performed on a subgroup of participants."

So not all? So how can any of their results they claim be in any way be suggested as inferrable to the whole ME/CFS population?

Then the next big para is befuddling me. I will start with the last part:

"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."

NOw the reference 20 that you can see as the last thing before the quote ends is paywalled, but the very title of the paper states the opposite to what Walitt et al (2024) have found, and the opposite to what you would assume a reference they have thrown in at the end of a line saying the opposite would be demonstrating?

Decreased postexercise facilitation of motor evoked potentials in patients with chronic fatigue syndrome or depression | Neurology

and just to check I wasn't reading it wrong. The abstract confirms the following:

"We studied the effects of exercise on motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) in 18 normal (control) subjects, 12 patients with chronic fatigue syndrome, and 10 depressed patients..........

......The mean amplitude of MEPs recorded from the resting muscle immediately after each exercise set was 218% of the mean pre-exercise MEP amplitude in normal subjects, 126% in chronic fatigue patients, and 155% in depressed patients, indicating postexercise MEP facilitation in all three groups. The increases in the patient groups, however, were significantly lower than normal."

 

[Sean]

I think it's a stretch to say low levels of these molecules are a problem in ME/CFS when there is so much overlap with the healthy controls.

The more results I see across the board, the more I am convinced that all we know so far (to the extent we know anything for sure about ME) are just downstream secondary consequences of the patients biology and psychology trying to deal with the (opaque) primary underlying problem.

What has Walitt et al (2024) actually measured?

Not clear to me either.

Nice work on this. Thanks. @Hutan too.

Frankly, I find this task a joke in terms of providing insight into the supposed pathological psychology of people with ME/CFS. I feel appalled that conclusions are being made about the 'effort preference' of people with ME/CFS on the basis of this 15 minute study with 15 ME/CFS participants.

Really is making a mountain out of pebble. My guess is that this is literally all the more psychosomatically oriented advocates on the team had that could be twisted to say that. Nothing else in the study (that I know of) offers a shred of evidence for their views.

This indicates that the primary motor cortex remained excitable for PI-ME/CFS, suggesting reduced motor engagement from this group20."

Which, if true, could be interpreted as patients wanting to move, to be active, but being unable to, being limited by some other factor between drive or motivation, and action.

 

[FMMM1]

Jonathan
"I think it may be useful to examine their attempts to analyse brain activity and the role of sympathetic drive. I am not convinced so far that they are not looking at an artefact of being a test subject in a study. That could be overcome with studies of a range of other conditions."
https://www.s4me.info/threads/usa-n...ramural-me-cfs-study.2980/page-23#post-515598

Long way of getting to the above (as usual!) -
If NIH had included e.g. an MS control and they showed the same/similar fMRI signal then this paper would presumably have stated "fMRI was the same/similar as observed in well understood chronic illnesses like MS --". So, this is like a cliffhanger --- will NIH run a study to actually test whether fMRI can separate ME/CFS from well understood chronic illnesses like MS?
At best fMRI is a potential biomarker(?) for ME (giving a clue to underlying pathology) but we're a long way from testing that theory.

 

[FMMM1]

Jonathan
"I think it may be useful to examine their attempts to analyse brain activity and the role of sympathetic drive. I am not convinced so far that they are not looking at an artefact of being a test subject in a study. That could be overcome with studies of a range of other conditions."
https://www.s4me.info/threads/usa-n...ramural-me-cfs-study.2980/page-23#post-515598

Long way of getting to the above (as usual!) -
If NIH had included e.g. an MS control and they showed the same/similar fMRI signal then this paper would presumably have stated "fMRI was the same/similar as observed in well understood chronic illnesses like MS --". So, this is like a cliffhanger --- will NIH run a study to actually test whether fMRI can separate ME/CFS from well understood chronic illnesses like MS?
At best fMRI is a potential biomarker(?) for ME (giving a clue to underlying pathology) but we're a long way from testing that theory.

Decided to post this on Twitter i.e. in response to a Tweet by Janet Defoe ---
It is, of course basically Jonathan's comment above but unattributed!
Perhaps those on social media (Twitter --) would similarly challenge NIH to actually do a proper fMRI study i.e. to test the hypothesis that fMRI is a biomarker for sickness behaviour/ME (& Long covid & Lyme).

 

[SNT Gatchaman]

A little more on the right TPJ findings. The results say —

HV and PIME/CFS participants showed force-related brain activation in the left M1, right cerebellum, and left putamen during the task. We next assessed group differences with t-test (at p = 0.01, k > 65), but there was no difference between the groups.

Left M1 would be expected, being the primary motor cortex for the right hand. They likely had right-hand dominant subjects for uniformity and in the initial handgrip tests they said: "Each participant sat with their right forearm placed in a rigid-frame dynamometer". Similarly left putamen. The right (ie ipsilateral) cerebellar hemisphere would also be expected (although cerebellar neuroanatomy is not necessarily so straightforward).

We also assessed changes across blocks with a two-way ANOVA (2 groups × 4 blocks), which showed that blood oxygen level dependent (BOLD) signal of PI-ME/CFS participants decreased across blocks bilaterally in temporoparietal 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). TPJ activity is inversely correlated with the match between willed action and the produced movement.

So there was a reduction in BOLD signal in the three brain regions: bilateral TPJs and bilateral superior parietal lobules, but just the right "temporal gyrus" (they don't specify whether superior, middle, inferior or transverse temporal gyri). These regions were said to be increased in HCs, but we'll need to look at the source data. I haven't yet located the relevant data file.

The discussion focuses on the right TPJ but makes no mention of the other regions. —

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.

Additionally, the results suggest the impact of effort preference, operationalized by the decision to choose a harder task when decisionmaking is unsupervised and reward values are held constant, on performance. 32–74% of the variance in time to grip failure for the PI-ME/ CFS participants correlated with effort preference, which was not seen in HVs. This was accompanied by reduced brain activation in the right temporal-parietal area in PI-ME/CFS participants.

Concluding —

Together these findings suggest that effort preference, not fatigue, is the defining motor behavior of this illness.

What was the correlation between fatigue and decreased activity in left TPJ, both superior parietal lobule and the right temporal gyrus?

 

[sneyz]

Wait, what? I will assume this has been mentioned before but they state that:

“We also assessed changes across blocks with a two-way ANOVA (2 groups × 4 blocks), which showed that blood oxygen level dependent (BOLD) signal of PI-ME/CFS participants decreased across blocks bilaterally in temporoparietal junction (TPJ)…”

and simultaneously:

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

But this is not the whole story, or what? Reduced influx of fresh blood would also lead to a decrease in BOLD. If the BOLD signal is assumed to be the net effect of oxygen consumption and new influx of oxygenated blood, it leaves a room for this second possibility: reduced cerebral blood flow.

Never heard of that before in ME….
https://doi.org/10.3390/medicina59122153

 

[SNT Gatchaman]

Another question is with the assumptions behind the fMRI technique, which emphasised the right TPJ finding. The paper's methods for "Functional MRI repetitive grip testing" says —

We used a 3T Prisma SIEMENS scanner equipped with a 64 channel head-coil in the Nuclear Magnetic Resonance Center at the National Institutes of Health. We acquired T2*-weighted EPI with TR = 2 s, TE = 30 ms, image matrix = 64 × 64, flip angle: 70˚, FoV: 100, voxel size 3.5 × 3.5 × 3.5 mm.

But I could not find further detail. See background to the various techniques of BOLD imaging for fMRI in Validation of a new 3D quantitative BOLD based cerebral oxygen extraction mapping (2024, Journal of Cerebral Blood Flow & Metabolism).

One question is which fMRI technique was used: calibrated or quantified. I assume the latter, with reference to T2*-weighted EPI. I doubt they would use gas breathing calibration technique as that's not necessarily well tolerated by subjects, healthy or otherwise.

However even if calibrated to try and get absolute values for oxygen extraction fraction and the cerebral metabolic rate of oxygen consumption, there may be a problem with drawing inferences from any observations. The assumption behind fMRI is that changes shown from a person's baseline or variance from healthy controls is due to neurovascular coupling, ie that specific neural demand leads to a regional vascular response to meet it.

But what if there is a generalised cerebral microvascular problem? If oxygen extraction is pathologically impaired +/- microvascular endothelial dysfunction, then we might be seeing a purely vascular signal in certain anatomical brain locations, that has nothing to do with what that part of the brain is responsible for and more that they are anatomically vulnerable, eg a borderzone between vascular territories.

 

[SNT Gatchaman]

From BOLD signal physiology: Models and applications (2019, NeuroImage) —

The BOLD contrast in functional MRI results from the fact that oxygenated hemoglobin is diamagnetic, while deoxygenated hemoglobin (dHb) is paramagnetic. Because dHb is paramagnetic, water spins in partly deoxygenated blood experience increased dephasing. This dephasing attenuates the T2*-weighted signal from venous blood and tissue containing dHb.

When the brain is performing a task, active regions consume oxygen to function, leading to a localized increase in dHb. To meet the need for additional oxygen, nearby blood vessels dilate, causing an increase in local blood flow. The inflowing blood is fully oxygenated, thereby diluting the dHb concentration and leading to an increased BOLD signal.

Because the activity-driven BOLD signal increase is due to vasodilation and dilution of dHb, the BOLD signal conflates changes in oxidative metabolism, blood flow and blood volume. This hemodynamic response is thought to be tightly regulated in healthy brains, but changes in neurovascular coupling in aging and disease make it problematic to compare BOLD signals across groups.

These group comparisons are problematic both because of the physiological ambiguity of the BOLD signal and because BOLD contrast measures a relative signal change from an unknown baseline. Any change in coupling or in the baseline cerebral blood flow (CBF), cerebral blood volume (CBV) or oxygen metabolism will result in a different BOLD signal change. Therefore, the vascular and metabolic sub-components should be taken into account for the accurate interpretation of task-evoked and resting state BOLD signal changes.

 

[Hutan]

There were a number of grip strength experiments.
A. grip strength, time to failure
B Electrophysiology and repetitive grip testing; Transcranial magnetic stimulation
C. fMRI repetitive grip testing

A. Grip strength

Hand grip strength measured with a dynamometer - for each hand:

1. maximum possible grip force for about five seconds >>outcome = maximum grip force
2. repeat 1, then minute of rest
3. maintain maximal grip for as long as possible, stop when grip force reduced to 50% of maximum >> outcome = time to failure, duration to 50% MVC



3c. No difference in maximum grip force. If the ME/CFS patients were deconditioned, somehow their strength was not different to the controls.
Maximum grip force correlated with lean arm mass. So, presumably lean arm mass was still normal.
Maximum grip force didn't correlate with that ridiculous effort preference measure.


3d. Time to failure.
But time to failure (i.e. to not maintain at least 50% maximum grip strength) was lower in the ME/CFS group. It looks like a real result. But was it just the
ME/CFS people giving up when things got hard? Time to failure was not correlated with lean arm mass or muscle fibre type.

Time to failure and the so-called effort preference measure were plotted against each other in 3e.




And yes, the so-called effort preference correlates with time to failure for people with ME/CFS, not for the healthy controls. If effort preference really predicted time to failure, why wouldn't it also work for the healthy controls? I don't think the ratio of hard task to easy task choices that is supposed to be 'effort preference' actually means anything. But, even if it did, a more likely explanation may be that the people with ME/CFS who fatigue particularly quickly are more likely to have both a low time to failure and to opt for less demanding physical tasks as their muscles tire?

Either way, I guess neither we nor they can prove our opposing stories with this data from this experiment.

 

[Hutan]

B. Repetitive grip testing, electrophysiology, transcranial magnetic stimulation

Note that only a subgroup of the participants did the experiment - I think just 8 ME/CFS and 6 healthy controls. The problem with this subsetting is that we don't know if the groups were well matched (maybe the raw data would tell us).

The core is blocks of 30 seconds where the participant tries to maintain 50% of their maximal voluntary contraction, (squeeze blocks) and then 30 seconds of rest. Most participants did 16 squeeze blocks. There was electromyography to measure the muscle activity. 'Muscular fatigue' was defined as inability to maintain at least 40% MVC for more than three seconds.

The first step was determining the maximal voluntary contraction, and again there was no difference between ME/CFS and controls.

Fig 4a below shows that grip force decreased over the repeated blocks of 30 seconds in ME/CFS, but remained constant in the controls. The number of blocks that the ME/CFS participants were able to do was less than the controls - that's what the chart with the horizontal red and blue lines is showing.

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 index17,18 (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.

Fig 4b above shows that the slope of Dimitrov index declined over the blocks in ME/CFS, but not in the controls. I'm still trying to understand how this suggests that the 'decline of force was not due to peripheral fatigue or a neuromuscular disorder', and how certain the result is. If anyone knows, please share.

Fig 4c gives the results from the transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) was performed to probe the excitability of the primary motor cortex (m1) via motor evoked potentials (MEPs). A 70 mm figure-8 coil was used to determine the optimal position for evoking MEPs by holding the coil tangential to the scalp and slightly displacing it until the highest MEP amplitude was recorded in the APB muscle. The positions of the participant’s head and TMS coil were tracked with a neuronavigation system (rogue Research, Cambridge, MA, USA) in order to maintain the stimulation position over the hotspot. The TMS Input-Output curve was recorded, collecting MEP responses for intensities 5–100%, in increments of 5%, of stimulation output, in order to calculate the S50. The S50 value was defined as 50% of maximum MEP amplitude. This curve value was also used to estimate resting motor threshold (rMT), which was confirmed using single pulse TMS as the stimulation intensity that would evoke a ~50 µV response in roughly 50% of pulses delivered.

The paper says that the results in 4c indicates that the primary motor cortex remained excitable for PI-ME/CFS, suggesting reduced motor engagement from this group.

The maximum M-wave was also determined prior and after the repetitive grip task by applying electrical stimulation over the nerve innervating the FCR muscle.

I didn't see the result for this. I think it might be used as a methodological control:

Evoking the maximum M-wave (Mmax) by supramaximal stimulation is the electrical equivalent of the recruitment of all motor units within the motor neuron pool [1]. The Mmax is a methodological control to ensure that the effective stimulus intensity to peripheral nerves is consistent across recording sessions [2]. Using a stimulus intensity that produces M-wave responses corresponding to a consistent percentage of Mmax ensures that the same numbers of motor axons are recruited in each trial [3].