Multimodal neuroimaging of fatigability development, 2025, Bedard/Nath/Walitt et al

[Dolphin]

https://direct.mit.edu/imag/article/doi/10.1162/IMAG.a.132/132607/Multimodal-neuroimaging-of-fatigability

Bedard, P., Knutson, K.M., McGurrin, P.M., Vial, F., Popa, T., Horovitz, S.G., Hallett, M., Nath, A., & Walitt, B. (2025). Multimodal neuroimaging of fatigability development. Imaging Neuroscience, Advance Publication. https://doi.org/10.1162/IMAG.a.132

August 12 2025

Multimodal neuroimaging of fatigability development​

Patrick Bedard, PhDCorresponding Author

,

Kristine M. Knutson, MA,

Patrick M. McGurrin, PhD,

Felipe Vial, MD,

Traian Popa, MD PhD,

Silvina G. Horovitz, PhD,

Mark Hallett, MD,

Avindra Nath, MD,

Brian Walitt, MD MPH

Author and Article Information
Patrick Bedard, PhD

Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20892-1428.
Kristine M. Knutson, MA
Behavioral Neurology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20892-1428.
Patrick M. McGurrin, PhD
Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20892-1428.
Felipe Vial, MD
Clínica Alemana Universidad del Desarrollo, Santiago, Chile.
Traian Popa, MD PhD
Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20892-1428.
Silvina G. Horovitz, PhD
Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20892-1428.
Mark Hallett, MD
Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20892-1428.
Avindra Nath, MD
Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20892-1428.
Brian Walitt, MD MPH
Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20892-1428.
*Corresponding author: Patrick Bedard, E-mail: patrick.bedard@nih.gov

Received: February 13 2025
Revision Received: August 06 2025
Accepted: August 09 2025


Imaging Neuroscience (2025)
https://doi.org/10.1162/IMAG.a.132
Article history

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Abstract​

Fatigability refers to the inability of the neuromuscular system to generate enough force to produce movements to meet task challenges. Fatigability has a central and a peripheral component linked via the neuromuscular system, but how these two components interact as fatigue develops lacks a complete understanding. The effects of fatigability are experienced in healthy humans but also accompanies various disorders often exacerbating their symptoms.

We studied how fatigability develops in the neuromuscular system using multimodal neuroimaging. We recruited healthy participants to perform a fatiguing grip force task, while recording force, electromyography of forearm muscles (EMG), electroencephalography (EEG), and functional magnetic resonance imaging (fMRI) in 30 sec blocks of grip task alternating with 30 sec of rest. The task entailed maintaining 50% of the maximum force. We combined EMG and EEG to compute corticomuscular coherence and combined EEG and fMRI to compute EEG-informed fMRI. We selected eight task blocks specific to each participant to represent how the neuromuscular system adapted from pre-fatigability to actual fatigability. Those included five blocks for pre-fatigability in which participants could generate enough force to match the required 50% of maximum force and three blocks when the force fell below that limit.

Across blocks of the grip force task, we observed changes in the neuromuscular system that preceded grip force changes. We found that electromyography of arm muscles shifted from high to low frequency, EEG in the channel covering the contralateral sensorimotor area increased steadily up to the fifth block and then plateaued and fMRI signal also increased in the cerebellum. Corticomuscular coherence increased within each of the 30 sec blocks of the grip task. EEG-informed fMRI revealed areas of the brain that the traditional regression did not, including the bilateral sensorimotor cortex, temporal-parietal junction, and supplementary motor area. Thus, as fatigability developed, the neuromuscular system experienced changes earlier than the actual behavior. While we found evidence for fatigability of central and peripheral origins, peripheral fatigue seems to occur first.

Fatigability, fMRI, EEG, EMG, corticomuscular coherence

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[Sean]

Thus, as fatigability developed, the neuromuscular system experienced changes earlier than the actual behavior. While we found evidence for fatigability of central and peripheral origins, peripheral fatigue seems to occur first.​

If I am reading that correctly, it means that physiological changes occur both before behavioural ones, and in the periphery before in the CNS.

So, not caused by the mind, then?

Or will the definition of 'mind' now just be expanded by the psychosomatic activists to include any region of the body, central or peripheral, containing even the barest trace of neurological tissue?

Just asking for several friends who can't anymore.

 

[Trish]

This looks potentially interesting as a test in ME/CFS that can be used once this is established with healthy volunteers as here, and replicated.

 

[Utsikt]

So much for the effort preference..

Edit: this might have been a rushed conclusion. The effort preference study still has its own faults, but this study might not be part of that.

 

[ME/CFS Science Blog]

This looks potentially interesting as a test in ME/CFS that can be used once this is established with healthy volunteers as here, and replicated.

So much for the effort preference..

They did this in the intramural NIH study (some of the participants in this paper were healthy controls in the ME/CFS study).

They reported that ME/CFS patients had faster declines in grip strength but that there were no signs of peripheral fatigue. This reported the slope of the Dimitrov index for this, which was a bit hard to interpret.

Instead of peripheral fatigue, the authors highlighted that the primary motor cortex of patients was more excitable using transcranial magnetic stimulation, suggesting reduced motor engagement. Here's their quote:

Repetitive grip testing was performed on a subgroup of participants. MVC did not differ between groups. 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. 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.

I have little trust in these authors, but I think this experimental setup is quite interesting and might be able to confirm e.g. that fatiguability in ME/CFS has a central (brain) rather than peripheral (muscle) origin if it was repeated by other authors using a larger sample size.

 

[EndME]

Would be interesting to know what the EEG data offers because otherwise this is pretty much the experiment that was done in the intramural study that was used to argue in favor of effort preference (the experiment there addiotionally had TMS data).

 

[Utsikt]

5 Conclusion

Humans can generate enough forces to perform various tasks, but at some point, we reach a limit and the motor output decreases; this is when fatigability becomes behaviorally manifest.

However, changes inside the neuromuscular system, i.e. brain and muscles, have already taken place well before that limit. When fatigability became behaviorally manifest both the muscles and brain and their interaction have reached a peak of activity.

This appears to indicate that fatigability only manifested as reduced output after both the muscles and the brain have reached their limits.

A plethora of factors such as psychology (e.g., motivation, reward, personality), pain, and context (e.g., competition vs recreational) will also influence fatigability development. Therefore, fatigability should be approached as a whole-body experience engaging muscles and brain simultaneously, rather than a binary problem of peripheral vs central.

This sounds very speculative to me. «Whole-body experience» make no sense as a concept - and muscle and brain is not the whole body.

In all, fatigability helps to maintain homeostasis in the brain and muscles to prevent catastrophic depletion of resources and avoid brain and muscles damages due to exertion (Hureau et al., 2018; Mosso, 1915; Noakes, 2012).

Citing Noakes in the conclusion is telling - apparently they are trying to make this fit into a predictive coding narrative.

Our results in healthy volunteers will provide new insights into the typical neuromuscular process of fatigability and in turn better understand fatigability in diseases.

It might, but it won’t if you’re not able to interpret the results neutrally.

 

[EndME]

This sounds very speculative to me.

Maybe I'm not bright enough, but the sentence by the authors you quoted here seems quite sensible to me. If anything I see it as one of the things that lacked understanding in the effort preference conclusions, in that all of the above factors couldn't be accounted for.

 

[Jonathan Edwards]

Maybe I'm not bright enough, but the sentence by the authors you quoted here seems quite sensible to me.

I think mentioning all the unknowns is great but I agree that 'whole body experience' is a garbage concept - and of course a very popular one with those who believe in 'embodied experience' and 'enactive' theories. These are popular with philosopher types but, as Ken Aizawa and Fred Adams have nicely argued, wrong. You have to work out where the problem is, you cannot hand wave and say it is whole body.

 

[Utsikt]

Maybe I'm not bright enough, but the sentence by the authors you quoted here seems quite sensible to me. If anything I see it as one of the things that lacked understanding in the effort preference conclusions, in that all of the above factors couldn't be accounted for.

I have no doubt that contextual factors affect fatigability, but I don’t think we have good enough proof to say definitively that those specific factors affect fatigability, because I doubt that any of the studies have been sufficiently controlled and neutrally interpreted.

Personality is probably the worst speculation, especially considering that you’ll have a hard time defining what personality even means.

 

[ME/CFS Science Blog]

If these experiments could show that the problems likely do not lie in the muscles itself (peripheral fatigue): wouldn't that affect theories about mitochondrial and endothelial dysfunction as being less likely causes of ME/CFS symptoms?

 

[Tree]

If these experiments could show that the problems likely do not lie in the muscles itself (peripheral fatigue): wouldn't that affect theories about mitochondrial and endothelial dysfunction as being less likely causes of ME/CFS symptoms?

And what about the Rob Wüst study on muscle mitochondria?

 

[petrichor]

I have little trust in these authors, but I think this experimental setup is quite interesting and might be able to confirm e.g. that fatiguability in ME/CFS has a central (brain) rather than peripheral (muscle) origin if it was repeated by other authors using a larger sample size.

I think to be truly useful it would need to be done during PEM, which is what primarily disables in ME/CFS, rather than immediate fatigue.

Even then it seems a bit hard to interpret, as far as I can see. It could be that there's a non-central cause, but that also affects the Central Nervous System, and could still give a result of apparent earlier "fatiguability" in the CNS. And it's not clear to me how much you can infer from looking at these correlates of other types of "fatiguability" (dimitrov index, BOLD signal in certain brain areas) in ME/CFS, where the fatigue probably has different mechanisms and probably has different correlates.

 

[Trish]

Thanks for pointing out that this was just the same thing they did in the Walitt infamous intramural study. I should have guessed from Walitt and Nath being authors. (If I hadn't wasted so much effort fighting impossible battles with Cochrane and other BPS rubbish, I might have more capacity to keep up with things like this.)

 

[butter.]

If these experiments could show that the problems likely do not lie in the muscles itself (peripheral fatigue): wouldn't that affect theories about mitochondrial and endothelial dysfunction as being less likely causes of ME/CFS symptoms?

I think it's extremely unlikely that ME is a classical muscle disease, however even if it is predominantly a central or peripheral neurological phenomenon (I believe it is,...), mitochondrial and endothelial dysfunction are probably unavoidable in the muscle tissue for anyone more severe than moderate?

Mitochondrial and endothelial dysfunction could be relevant in the CNS too, of course.

 

[SNT Gatchaman]

Intro on how they define fatigability (fatiguability?) vs fatigue, ie objective vs subjective —

Fatigability is a reduction of the output of the neuromuscular system that fails to generate enough force to elicit movement despite willed effort. The feeling or perception of fatigability is referred to as fatigue and can be independent from fatigability. Fatigability can have both a central or peripheral origin within the neuromuscular system. Fatigue is a major complaint in many disorders, such as multiple sclerosis, movement disorders, cancer, and Myalgic-Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and can be quite debilitating. The relation between fatigue and fatigability is still not well understood.

The term "Fatigability" does not appear in Walitt et al (2024). But note that objective fatigability here is defined is reduction in output despite willed effort. If "fatigue" is the subjective perception of fatigability, does that not mean that fatigue is also "despite willed effort"?

Some quotes on EEG-informed fMRI —

Functional magnetic resonance imaging (fMRI) studies have reported an increase in the blood oxygen level dependent (BOLD) signal in brain areas, including the sensorimotor cortex, cerebellum, and cingulate gyrus, during fatigability development

However, a broader understanding of fatigability should be possible by combining neurophysiologic and neuroimaging techniques. […] Combining EEG with fMRI allows for EEG-informed fMRI measurements

A major issue in many of these studies is that fatigability is not measured as it is occurring. In general, measures are collected before and after a fatiguing task, rather than during the development of fatigability.

Multimodal approaches have the potential to broaden CMC [corticomuscular coherence] understanding as it relates to fatigability.

In a typical block design fMRI experiment, the hemodynamic response function (HRF) that is used to estimate the task regressor of the BOLD signal is held constant across trial blocks and individuals. In EEG-informed fMRI, the EEG features are used to modulate the height of the HRF […]. EEG informed fMRI allows for both positive and negative associations between the EEG and fMRI, depending on the frequency bands and brain areas

We were especially interested to study how corticomuscular coherence and its directionality and EEG-informed fMRI change during the development of fatigability.

To our knowledge this is the first study to use EEG-informed fMRI to study fatigability.

 

[Utsikt]

Fatigability is a reduction of the output of the neuromuscular system that fails to generate enough force to elicit movement despite willed effort. The feeling or perception of fatigability is referred to as fatigue and can be independent from fatigability.

If "fatigue" is the subjective perception of fatigability, does that not mean that fatigue is also "despite willed effort"?

I think they might be trying to say that fatigue is when you feel like you can’t generate as much force, regardless of how much force you’re actually generating.

Maybe to be able to say that these people just feel like they are tired, but their bodies are actually fine.