Central origin of fatigability in Myalgic encephalomyelitis/chronic fatigue syndrome revealed by multimodal neuroimaging, 2026, Bedard, Nath, Walitt+

[SNT Gatchaman]

Central origin of fatigability in Myalgic encephalomyelitis/chronic fatigue syndrome revealed by multimodal neuroimaging

Spoiler: Authors

Bedard; Knutson; McGurrin; Vial; Popa; Horovitz; Hallett; Nath; Walitt

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating chronic disease characterized by physical and mental fatigue, post-exertional malaise, muscle pain, headaches, and unrefreshing sleep. Fatigability refers to a reduction of muscular force over time despite willed effort and has a central and a peripheral component. We studied whether fatigability in ME/CFS is related to central or peripheral mechanisms.

We recruited fifteen patients with ME/CFS and nineteen age- and sex-matched healthy volunteers (with seven females in each group). Participants performed a fatiguing grip force task, requiring them to maintain 50% of their maximum voluntary force during alternating 30 s blocks of grip and rest. We simultaneously recorded grip force, forearm muscle activity with electromyography, and brain activity with electroencephalography and functional magnetic resonance imaging. Fatigue onset was based on grip force performance and was set individually for each participant.

ME/CFS patients generated the same level of maximum voluntary force than healthy volunteers but developed fatigue much earlier. Healthy volunteers increased their muscle and brain activity from the beginning of the task until the onset of fatigue. Specifically, muscle activity shifted from high to low frequencies and brain activity increased steadily in cortical and subcortical areas. Then, muscle and brain activity declined slowly. In contrast, in ME/CFS, the muscles and brain activity only showed minimal fluctuations across all the task blocks.

The earlier onset of fatigue in ME/CFS is related to central mechanisms, as their brain did not increase its output to drive muscle activity like healthy volunteers did.

While this is a small sample study, and caution should be taken regarding the generalizability of the results, the earlier onset of fatigue in ME/CFS was observed to be related to central mechanisms. The brain in ME/CFS participants did not increase its output to drive muscle activity like healthy volunteers did.

HIGHLIGHTS
• We studied physical fatigue in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and healthy volunteers with multimodal neuroimaging.

• Participants performed a fatiguing grip force task in alternating grip and rest blocks.

• We simultaneously recorded grip force, brain activity with functional magnetic resonance imaging and electroencephalography, and muscle activity with electromyography.

• ME/CFS fatigued earlier than healthy volunteers. While healthy volunteers increased their brain and muscle activity, ME/CFS only showed minimal fluctuations across all the task blocks.

• We concluded that physical fatigue in ME/CFS is of central nature.

Web | DOI | PDF | NeuroImage: Clinical | Open Access

 

[Utsikt]

It will be interesting to look at the procedures and the data.

I wonder how they were able to do electromyography and fMRIs at the same time, wouldn’t the magnetic field from the fMRI affect any electric measurements?

It doesn’t seem like they are able to keep their terminology straight. They start out talking about fatigability,

Fatigability refers to a reduction of muscular force over time despite willed effort and has a central and a peripheral component. We studied whether fatigability in ME/CFS is related to central or peripheral mechanisms.

but the rest of the abstract talks about fatigue,

Fatigue onset was based on grip force performance and was set individually for each participant.

ME/CFS patients generated the same level of maximum voluntary force than healthy volunteers but developed fatigue much earlier.

The earlier onset of fatigue in ME/CFS is related to central mechanisms, as their brain did not increase its output to drive muscle activity like healthy volunteers did.

While this is a small sample study, and caution should be taken regarding the generalizability of the results, the earlier onset of fatigue in ME/CFS was observed to be related to central mechanisms.

and finally physical fatigue.

We concluded that physical fatigue in ME/CFS is of central nature.

 

[John Mac]

"The earlier onset of fatigue in ME/CFS is related to central mechanisms, as their brain did not increase its output to drive muscle activity like healthy volunteers did."

With Walitt being one of the authors I hope they are not going to say that this "central mechanism" is their pet theory of "effort preference".

 

[Amw66]

Central origin of fatigability in Myalgic encephalomyelitis/chronic fatigue syndrome revealed by multimodal neuroimaging

Spoiler: Authors

Bedard; Knutson; McGurrin; Vial; Popa; Horovitz; Hallett; Nath; Walitt

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating chronic disease characterized by physical and mental fatigue, post-exertional malaise, muscle pain, headaches, and unrefreshing sleep. Fatigability refers to a reduction of muscular force over time despite willed effort and has a central and a peripheral component. We studied whether fatigability in ME/CFS is related to central or peripheral mechanisms.

We recruited fifteen patients with ME/CFS and nineteen age- and sex-matched healthy volunteers (with seven females in each group). Participants performed a fatiguing grip force task, requiring them to maintain 50% of their maximum voluntary force during alternating 30 s blocks of grip and rest. We simultaneously recorded grip force, forearm muscle activity with electromyography, and brain activity with electroencephalography and functional magnetic resonance imaging. Fatigue onset was based on grip force performance and was set individually for each participant.

ME/CFS patients generated the same level of maximum voluntary force than healthy volunteers but developed fatigue much earlier. Healthy volunteers increased their muscle and brain activity from the beginning of the task until the onset of fatigue. Specifically, muscle activity shifted from high to low frequencies and brain activity increased steadily in cortical and subcortical areas. Then, muscle and brain activity declined slowly. In contrast, in ME/CFS, the muscles and brain activity only showed minimal fluctuations across all the task blocks.

The earlier onset of fatigue in ME/CFS is related to central mechanisms, as their brain did not increase its output to drive muscle activity like healthy volunteers did.

While this is a small sample study, and caution should be taken regarding the generalizability of the results, the earlier onset of fatigue in ME/CFS was observed to be related to central mechanisms. The brain in ME/CFS participants did not increase its output to drive muscle activity like healthy volunteers did.

HIGHLIGHTS
• We studied physical fatigue in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and healthy volunteers with multimodal neuroimaging.

• Participants performed a fatiguing grip force task in alternating grip and rest blocks.

• We simultaneously recorded grip force, brain activity with functional magnetic resonance imaging and electroencephalography, and muscle activity with electromyography.

• ME/CFS fatigued earlier than healthy volunteers. While healthy volunteers increased their brain and muscle activity, ME/CFS only showed minimal fluctuations across all the task blocks.

• We concluded that physical fatigue in ME/CFS is of central nature.

Web | DOI | PDF | NeuroImage: Clinical | Open Access

@Snow Leopard

 

[Creekside]

With Walitt being one of the authors I hope they are not going to say that this "central mechanism" is their pet theory of "effort preference".

My first thought on it was a feedback loop--or multiple loops or input factors--that isn't responding properly. For example, it could be glial cells not properly assisting the neural pathways involved. No need for a psychological effect.

 

[chillier]

It does seem to look as though the onset of fatigue in pwMEcfs is not caused by fatigue of the muscles itself - as measured by the dimitrov index, which I gather is a proxy for muscle fatigue. The dimitrov index does not increase really at all in the pwMECFS as they become weaker and weaker, whereas it does increase in the Healthy group prior to fatigue. That does seem to suggest fatigue in MECFS is not peripherally mediated.

They make some conclusions in the discussion that seem a bit back to front to me:

ME/CFS did not change their muscular and brain activity as measured via DI, EEG, BOLD, and CMC, and as a result, they demonstrated fatigue earlier than HV as shown by the earlier occurrence of the Bn block and the steeper decline of grip force across the five task blocks.

Not sure I agree with this analysis of the causality here. They say no change in muscle/brain activity in mecfs causes fatigue. To me it seems more likely that the patients experienced fatigue faster therefore the experiment was over before any muscle fatigue or brain activity in the TPJ etc ever have the need to kick in. The question of why they felt the fatigue/ had a difference in fatigability in the first place remains.

 

[Axel]

Not sure I agree with this analysis of the causality here.

Yes, it really is hellish. What’s more, whilst this rapid fatigue could in fact indicate a major brain problem, the entire grammatical structure of the report focuses on muscular function problems.

 

[Eleanor]

Not sure I agree with this analysis of the causality here. They say no change in muscle/brain activity in mecfs causes fatigue. To me it seems more likely that the patients experienced fatigue faster therefore the experiment was over before any muscle fatigue or brain activity in the TPJ etc ever have the need to kick in. The question of why they felt the fatigue/ had a difference in fatigability in the first place remains.

Do they give any consideration to whether the patients are already experiencing more fatigue than the controls at the start of the experiment?

 

[chillier]

Do they give any consideration to whether the patients are already experiencing more fatigue than the controls at the start of the experiment?

In terms of the handgrip assay the initial strength between the healthy and mecfs groups is the same, but the mecfs group lose strength much faster that the healthy group with repeated rounds of handgrip strength testing. The testing stops once strength falls below 50% of their starting strength, which means the healthy participants are going for much longer. They only compare the final few testing blocks in their analysis for the most part, so it figures they would have more muscle fatigue because they've used their muscles much more.

 

[Utsikt]

They only compare the final few testing blocks in their analysis for the most part, so it figures they would have more muscle fatigue because they've used their muscles much more.

What’s muscle fatigue in this context?

 

[chillier]

@Utsikt An increase in the dimitrov Index when doing an EMG. Something along the lines of a reduction in high frequencies and an increase in low frequences reflecting slower waves of depolarisation across muscle cells due to energy limitations within those cells.

 

[Turtle]

Using the same participants as in the Wallitt 2024 study, WOW!

 

[InitialConditions]

I think a central mechanism is much more likely given cognitive effort causes very similar or identical issues to physical exertion/effort.

 

[Medfeb]

I think a central mechanism is much more likely given cognitive effort causes very similar or identical issues to physical exertion/effort.

Is it possible that some factor that affects both brain cells and muscle cells make the central versus peripheral distinction less important? For instance, mitochondrial role/energy production which could have an impact on both central and peripheral and also be a factor with any type of exertion?

 

[InitialConditions]

Is it possible that some factor that affects both brain cells and muscle cells make the central versus peripheral distinction less important? For instance, mitochondrial role/energy production which could have an impact on both central and peripheral and also be a factor with any type of exertion?

But wouldn't such mitochondrial or energy issues be downstream of some sort of 'signalling' ultimately coming from the brain?

 

[Jonathan Edwards]

For instance, mitochondrial role/energy production which could have an impact on both central and peripheral and also be a factor with any type of exertion?

People have wanted to believe that there is an energy defect since the 1980s at least. Science has failed to find it since the 1980s at least. And it doesn't fit the clinical picture of delayed PEM.

In the AfME webinar today there was a lady called Maree who did an excellent job of explaining PEM and what we do and don't know about it. She was followed by two exercise scientists who, interestingly, made no mention of 2 day CPET being a measure of PEM. Maureen Hanson discussed changes in proteins after exercise and they were mostly immune and neural I think.

I think one explanation is better than two and I would agree with @InitialConditions 's succinct comment.

 

[Violeta]

Would be interesting to see a parallel type study done and measure oxygen use, type of metabolism (aerobic, anaerobic), and lactate levels.

Does anyone know if there is a study like that?

Because:
"The tetramer has a higher enzymatic activity and has a high level of affinity for PEP, thus can quickly catalyse PEP to form pyruvate. On the other hand, the PKM2 dimer has a lower catalytic activity and cannot produce pyruvate at a normal rate, resulting in accumulation of upstream glycolysis intermediates."

The tetramer and dimer of PKM2 regulate glycolysis and gene...​

www.researchgate.net › figure › The-tetramer-and-dimer-of-PKM2-regulat...
https://www.google.com/url?esrc=s&q...IQFnoECBAQAg&usg=AOvVaw38510H0UuIhen5bvQRGVHy
and:

PKM2 accelerated the progression of chronic fatigue syndrome via promoting the H4K12la/ NF-κB induced neuroinflammation and mitochondrial damage​

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Cortical neurons benefit from lactate, but what happens if cells are running on PKM2 glycolysis.

Influences of Blood Lactate Levels on Cognitive Domains and Physical Health during a Sports Stress. Brief Review - PMC

The present review aims to examine the effects of high blood lactate levels in healthy adult humans, for instance, after a period of exhaustive exercise, on the functioning of the cerebral cortex. In some of the examined studies, high blood lactate ...

pmc.ncbi.nlm.nih.gov

"The results obtained suggest that lactate in the blood can play a protective effect against fatigue, at the primary level cortical areas "

 

[ryanc97]

To disrupt mitochondria the disease would need to be on a very micro scale. Like mitochondria are tiny

 

[Violeta]

There is something very small the lack of which can severly affect mitochondria.

 

[Utsikt]

The terminology issue continues in the introduction:

First they talk about physical and mental fatigue, but they do not defined either:

Physical fatigue and mental fatigue are core aspects of the ME/CFS pathophysiology.

Then they try to define fatigability:

Fatigability is a reduction of the output of the neuromuscular system that causes a failure to generate enough force to elicit movement despite willed effort and thus refers to an objective decline of performance over time (Enoka and Duchateau, 2016; Kluger et al., 2013).

Failure to generate enough force to elicit movement would mean that the muscle is effectively paralysed. Alternatively, it would also mean that a person pushing against an unmovable object would be classified as experiencing fatigability.

I’m assuming that objective decline of performance over time refers to reduced power output, i.e. generating less force when pushing, pulling or squeezing something that is designed to move/deform when subjected to forces within the normal range of humans.

Then they define fatigue, but do not specify if it’s the physical or mental kind:

Fatigue refers to the feeling or perception of fatigability (Kluger et al., 2013) and can be independent from fatigability.

And finally fatigability gets another definition where they claim that it can occur in the brain, even though the brain isn’t generating any force by itself, and they just defined fatigability as a reduced ability to generate force.

Fatigability occurs in the brain and in the muscles and can thus have a central or a peripheral origin (Gandevia, 2001).

I’m assuming that their point is the last one, that fatigability can occur from reduced signals from the brain, or from the muscles failing to keep up the same output despite the same neuronal input.