Variation in Repeated Handgrip Strength Testing Indicates Submaximal Force Production in Patients With [ME/CFS], 2025, Popkirov

forestglip

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Variation in Repeated Handgrip Strength Testing Indicates Submaximal Force Production in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Stoyan Popkirov

Background
Changes in handgrip strength have recently been adapted as clinical biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) under the assumption of a disease-specific peripheral neuromuscular dysfunction. However, some have proposed that strength impairments in ME/CFS are better explained by alterations in higher-order motor control. In serial measurements, exertion can been assessed through analysis of variation, since maximal voluntary contractions exhibit lower coefficients of variation (CV) than submaximal contractions.

Methods
Serial handgrip strength measurements of 105 ME/CFS patients and 66 healthy controls from a previously published biomarker validation study are analyzed post hoc regarding their CV. CV is separately compared in a subsample of participant with normal indexes of fatigability.

Results
Compared to healthy controls, patients had significantly higher CV, largely over the conservative 15% cutoff associated with submaximal exertion. In the subsample of study participants, whose within-session fatigability was within normal bounds, CV was still significantly higher in female patients; the difference in male patients was not statistically significant (p = 0.06).

Conclusions
This analysis suggests that loss of grip strength is likely compounded by alterations in higher-order motor control, challenging its utility as a biomarker of peripheral dysfunction. Functional weakness is discussed within a framework that sees motor fatigue as a result of reduced implicit self-efficacy acquired in the context of chronic dyshomoeostasis and disability.

Web | PDF | European Journal of Neurology | Open Access
 
 
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In studies on strength exertion, a higher variation in repeated strength production has been used as a sign of submaximal contraction [7]. The physiological assumption is that maximal contraction is a lower-order task of complete motor unit recruitment, while submaximal force production requires proprioceptively guided grading of strength, which entails higher-order complexity and, with it, increased variation of output. Handgrip strength testing in patients with ME/CFS can be reanalyzed in this light to assess whether within-session variation is abnormally high and thus indicative of higher-order motor control disruptions.
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There are no sources for the key assumption in this article.

Does anyone have any ideas about what is meant by «higher-order complexity»?
 
I can’t say I’m impressed by the discussion in this paper. There’s talk about allostasis, predictive fatigue processes, disruption of self-agency as an explanation for PEM (which I don’t think the authors has understood the meaning of), and of course treatments:
In conclusion, the increased variation in maximal self-initiated handgrip strength in ME/CFS patients suggests alterations in higher-order motor control as a cause of limb weakness in ME/CFS.

Recent experimental studies suggest that these changes in force production are not enacted on a consciously accessible level of neural computation but emerge from sensorimotor decision-making related to reductions in implicit motor self-efficacy.

Treatment should accordingly aim at iterative reinforcement of explicit and implicit self-efficacies of movement by demonstrating untapped strength reserves, addressing maladaptive exertion avoidance and providing guidance on coping and recovery strategies.
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It’s interesting to have another piece of data against the effort preference interpretation, but their suggested alternative interpretations and solutions are equally flawed.
 
forestglip said:
This is a re-analysis of the hand grip strength data from: Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome, 2024, Walitt et al
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I don't think it is. It seems to be a reanalysis of data from a Charite study:

B. Jäkel, C. Kedor, P. Grabowski, et al., “Hand Grip Strength and Fatigability: Correlation With Clinical Parameters and Diagnostic Suitability in ME/CFS,” Journal of Translational Medicine 19, no. 1 (2021): 159, https://doi.org/10.1186/s12967-021-02774-w.
 
I haven't read this paper yet, but it seems to me that they aren't considering all of the possibilities. If there is a higher variation in strength production in the ME/CFS people, it may be because maximal capacity involving motor unit recruitment is varying more quickly. If motor units are taking longer to recover than in the healthy controls, that could lead to a pattern of alternating higher and lower force production.

abstract said:
Compared to healthy controls, patients had significantly higher CV, largely over the conservative 15% cutoff associated with submaximal exertion. In the subsample of study participants, whose within-session fatigability was within normal bounds, CV was still significantly higher in female patients; the difference in male patients was not statistically significant (p = 0.06).
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I think close reading of this study might indicate problems. The headline result gets one short sentence with no quantitative details. But a post-hoc analysis of a subset gets more words and is used to suggest that the lack of consistency in force production is largely a female problem.
 
The author is committed to the BPS viewpoint. He is a coauthor, along with Alan Carson, Mark Edwards and Jon Stone, of a recent paper on a functional disorder. Like the paper this thread is about, it was published in the European Journal of Neurology.

Perspectives on the diagnosis and management of functional cognitive disorder: An international Delphi study
Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details.
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It's just so frustrating to see someone who is really trying to understand what is going on here, land again at what is essentially GET and CBT as the recommendation. He appeals to the well-worn argument that it's poorly implemented GET that is the problem.

The author writes:
The framework also offers an explanation for the reported worsening of symptoms in some ME/CFS patients during physical rehabilitation [38]: Exercises that push beyond individual thresholds of pain or fatigue can confirm and potently reinforce implicit sensorimotor biases of low motor self-efficacy. This is especially likely to happen if expressions of pain and fatigue are disregarded due to a categorical misunderstanding of ME/CFS.
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38 is Kindlon's Reporting of Harms paper.

My own experience of simultaneous GET and CBT would contradict the author's view. I was able to increase exercise, and was not pushed beyond thresholds of pain or fatigue, but during that time I lost functioning outside of exercise.
 
Utsikt said:
That’s very generous towards the author.
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I agree. The paper basically says that people don't try hard because they want to go on being disabled - even if it is conveyed in code. It just isn't 'preference', according to him - maybe so that he can give a different opinion and have a paper of his own.

The whole thing is absurd because we know that voluntary movement is driven by the cortex - in other words higher centres. That doesn't stop elite athletes doing less well when they have bad toothache or jetlag.
 
Evergreen said:
My own experience of simultaneous GET and CBT would contradict the author's view. I was able to increase exercise, and was not pushed beyond thresholds of pain or fatigue, but during that time I lost functioning outside of exercise.
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V.R.T. said:
This was my experience too.
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Do I take this to mean that you were able to avoid PEM while completing both the physical exercises and CBT but still saw deterioration of function during this period and attribute it to the exercise program?
 
DHagen said:
Do I take this to mean that you were able to avoid PEM while completing both the physical exercises and CBT but still saw deterioration of function during this period
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Essentially, yes. My PEM was not in the form of crashes at the time. Instead, I would just feel worse. And that did not happen, until it did, by which time it was too late.

DHagen said:
and attribute it to the exercise program?
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Not necessarily. At the time, I did not. Now, I think it's possible, and there are a few reasons why I think it's probable. Since I might write it up some day, I'll just mention one reason: the negative experiences of other people with ME/CFS with exercise.
 
Utsikt said:
That’s very generous towards the author. IMO this is not in any way an earnest good faith attempt at understanding. It’s a severely biased mess of self-gratification at the cost of the patients.
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Maybe. My point is not that he has reached a good understanding, but that in the discussion he gives the question a lot more thought than any other neurologist in the FND camp ever has (in writing). It's a very lengthy discussion for a very simple post-hoc analysis.

He's as limited by bias as anyone else. But what other neurologist has put in writing that they quibble with Walitt et al.'s "effort preference" notion? Now, Walitt et al. would just argue that Popkirov, like patients, doesn't understand neurobiological terminology, and that "preference" can be "unconscious" as well as volitional. But Popkirov deciphered that code pretty accurately.

He cites a blog by Bolecek, as well as Tom's paper. He is at least reading what patients are saying, and the citations are not as tokenistic as they can sometimes be. A citation of Kirvin-Quamme et al. 2025 would have been nice, but it came out after Popkirov revised his manuscript. He cites a wide range of studies from a number of different fields. Maybe there's cherry-picking there, I don't know the literature to be able to judge. But he's grappling with things, and trying to come up with a theory that fits all the facts he sees, including PEM, even if we still think he's coming to all the wrong conclusions.

Will he and other neurologists notice when patients' "implicit sensorimotor biases of low motor self-efficacy" don't improve long-term with exercise? Probably not, because enough will be spontaneously improving at the time or will be able to temporarily increase their activity that they'll think they were right. How many clinicians have read Rekeland et al. 2022 or have a clear idea of just how much spontaneous change there is in ME/CFS? Will they notice if patients deteriorate with exercise? Probably not, because it'll be filtered through a physio who is unlikely to update them by saying "I made your patient worse", and the patients themselves are likely to quietly exit stage left. Alternative explanations are nearly always available e.g. "They were having a tough time at home." I think the same is true of clinicians considered "the good guys" by a lot of pwME/CFS.

What's interesting to me is that Walitt et al.'s interpretation relied on the lack of difference in maximal voluntary contraction between their teensy sample of PI-ME/CFS and controls, while Jäkel et al. 2021 found a clear difference in their larger sample. Walitt et al. needed that lack of difference to argue that patients were able to do it and just didn't, but it was likely a type II error. As far as I can see, Walitt et al. didn't discuss the literature on grip strength in ME/CFS at all. It would have undermined their narrative.

Jonathan Edwards said:
I agree. The paper basically says that people don't try hard because they want to go on being disabled - even if it is conveyed in code.
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While I'm no fan of ME/CFS being absorbed into FND, it really doesn't. Am fluent in code. Can you point me to where you think he says that in code? I might well have missed a sentence.

Jonathan Edwards said:
The whole thing is absurd because we know that voluntary movement is driven by the cortex - in other words higher centres. That doesn't stop elite athletes doing less well when they have bad toothache or jetlag.
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Agree with you there.
 
Evergreen said:
Maybe. My point is not that he has reached a good understanding, but that in the discussion he gives the question a lot more thought than any other neurologist in the FND camp ever has (in writing). It's a very lengthy discussion for a very simple post-hoc analysis.
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I read it as a lengthy justification for his pet theory, not a neutral discussion of the evidence. I see no reason to give any merit to anyone that’s still very wrong, just for different reasons than those he criticise.

This treatment recommendation does not look like someone that has listened to the patients..
Treatment should accordingly aim at iterative reinforcement of explicit and implicit self-efficacies of movement by demonstrating untapped strength reserves, addressing maladaptive exertion avoidance and providing guidance on coping and recovery strategies.
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ME/CFS Science Blog said:
The difference seems quite large. So apart from the authors interpretation what would be the most likely explanation for this? Is it simply that being ill/having lots of symptoms causes the variation in handgrip strength measurements?
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It needn't have anything to do with illness but could simply be an artefact of study design. In the recently published Charite study, not giving people medication vs giving them medication also seems to have caused large differences in handgrip strength measurements. I wouldn't be suprised if something similar applies to some other illnesses as well. I think handgrip strength isn't always quite that "objective" but can be suggestive. I think the possible reasons are endless (some might be pressing less hard on the second time not because they have PEM but simply to avoid it, other might not etc) and will depend on the specific study.
 
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