A Thought Experiment on Muscles

[Simon M]

We literally did a poll and found that ~80% of people people reported it did not feel the same.
https://www.s4me.info/threads/poll-physical-vs-cognitive-pem-same-or-different.16948/

Thanks, I hadn’t seen that. I had a feeling I had seen a survey results of a similar question before, but I couldn’t say where.

But just to recap the results For those who have PEM after both physical and cognitive exertion:
Fundamentally different: 9 (13%)
Fundamentally the same: 17 (25%)
Some aspects feel fundamentally the same, others don’t: 42 (62%)

which is a nuanced result. We could say that 87% (corrected from the original 75%) of people say that at least some aspects are fundamentally the same.

I don’t think we should overinterpret such a small sample, but it might suggest there are separate mechanisms for muscle and cognitive-triggered PEM, and also a common mechanism.

 

[Evergreen]

Really helpful post, @Snow Leopard , thank you. I'm on tippy-toes trying to understand, so I hope you might be able to help clarify a couple of things.

I'm looking at what you have said here:

Note that the afferent feedback has both attenuating and excitory aspects (this is an important point as the NIH intermural study researchers fundamentally did not understand this) - there is a generalised reduction in motor cortex excitability due to afferent feedback, however there is also spinally mediated excitory effects that adjust the sensitivity of specific motor units as a compensatory mechanism, allowing for increased turnover of use of motor units as they fatigue as well as an overall compensatory increase in excitation to overcome the reduction in motor cortex excitability during fatiguing tasks.

and what Amann 2012 said here https://pmc.ncbi.nlm.nih.gov/articles/PMC3351566

Group III and IV muscle afferents play a pivotal twofold role for the endurance exercising human. First, continuous afferent feedback from working locomotor muscle is essential for evoking appropriate ventilatory and circulatory responses during exercise - both of which are critical prerequisites for preventing premature fatigue and accomplishing an optimal performance. And second, group III/IV muscle afferents provide inhibitory feedback to the CNS and thereby influence the regulation of central motor drive and limit the development of peripheral fatigue to a critical threshold, presumably to protect the organism from excessive exhaustion and potentially harm.

and trying to understand what it is that Walitt et al. did not understand that led to their story of:

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

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.

Exposure to an infection leads to concomitant immune dysfunction and changes in microbial composition...These immune and microbial alterations impact the central nervous system, leading to decreased concentrations of metabolites, including ...and the metabolites of dopamine (DOPAC) and norepinephrine (DHPG). The altered biochemical milieu impacts the function of brain structures. The catecholamine nuclei release lower levels of catechols, which impacts the autonomic nervous system leading to decreased heart rate variability and decreased baroreflex cardiovascular function, with downstream effects on cardiopulmonary capacity. Concomitant alteration of hypothalamic function leads to decreased activation of the temporoparietal junction during motor tasks, leading to a failure of the integrative brain regions necessary to drive the motor cortex. This decreased brain activity is experienced as physical and psychological symptoms and impacts effort preferences, leading to decreased engagement of the motor system and decreases in maintaining force output during motor tasks.

Why did Walitt et al. resort to hypothalamic function to explain reduced motor drive if altered afferent feedback could have explained it? Is it that they saw there was no peripheral fatigue but hadn't reckoned with the excitory compensation mechanism, so they should not have concluded that there was no peripheral fatigue? If so, how should they have measured peripheral fatigue? Or is it central fatigue that they got wrong? Because this sounds like what they termed effort preference:

Second, group III/IV muscle afferents facilitate “central fatigue” (failure, or unwillingness, of the central nervous system to “drive” motoneurons) by exerting inhibitory influences on central motor drive during exercise.

Can you point me to a more recent summary than Amann 2012?

My questions might make no sense, so just explain whatever does make sense!

 

[Jonathan Edwards]

The reduced power at the ventilatory threshold can ONLY be explained by increased fatigue-sensing type III/IV muscle afferent feedback and the first ventilatory threshold.

Thanks for the helpful posts. I like the idea of focusing on afferent nerves.

 

[jnmaciuch]

I am absolutely sure it is not a change in the lungs.
It is not provision of fuels by the liver, we would see different hormonal responses (insulin, cortisol) if that was the case.
A reduction in the ability to drive the heart due to metabolic factors may limit VO2Max (and cause chronotopic incompetence), but this cannot explain the reduced power at the ventilatory threshold.

I have discussed previously:

The reduced power at the ventilatory threshold can ONLY be explained by increased fatigue-sensing type III/IV muscle afferent feedback and the first ventilatory threshold. Notably this threshold is always coincident with the non-linearity in the reported sense of *****muscular***** effort on the Borg scale during the CPET too (in all participants not just ME/CFS patients). This level of exertion is still way below VO2Max and so participants are far from being out of breath at this level of exertion.

This also matches the experiences reported in this thread, eg. the "lactic acid" feeling is caused by that muscle afferent stimulation.

So the real question is if it is due to a sudden drop in metabolic efficiency leading to increased feedback generating metabolites, or increased nerve sensitivity of these specific afferents, or perhaps both. If it is a metabolic problem, is this problem in the muscles, or is it a problem of oxygen availability? (and there could be related issues with stimulation of autonomic nerves)

Note that the afferent feedback has both attenuating and excitory aspects (this is an important point as the NIH intermural study researchers fundamentally did not understand this) - there is a generalised reduction in motor cortex excitability due to afferent feedback, however there is also spinally mediated excitory effects that adjust the sensitivity of specific motor units as a compensatory mechanism, allowing for increased turnover of use of motor units as they fatigue as well as an overall compensatory increase in excitation to overcome the reduction in motor cortex excitability during fatiguing tasks.

Note that the altering the motor unit recruitment patterns itself can alter muscular metabolic efficiency - there is a spectrum of capillarisation density, O2 transport latency, mitochondrial density etc) and as the recruitment of motor units during a fatiguing task shifts towards fresher but less efficient (in terms of O2 consumption) motor units.

So there is a negative feedback loop whereby lower metabolic efficiency leads to greater fatigue that leads to greater afferent feedback that leads to (compensatory) altered motor unit recruitment patterns (higher threshold groups that have a lower balance of O2 consumption) and so on.

There may be different underlying causes in different ME/CFS patients, I don't assume the underlying pathology is the same in all patients, simply that there is a common factor (persistent and prolonged stimulation of those particular muscle afferents)

Note this also means the effect of afferent feedback can vary based on the task and muscle group that is used. We should not assume there is exactly the same effect in every muscle group or task because the degree of afferent feedback, balance between positive and negative excitory effects, particularly the effect on motor cortex excitability for example, depend on the overall metabolic demand that the muscle group can place on the body - measuring the finger or thumb might have poor sensitivity compared to large muscle groups in the body.

Grip strength during PEM may be reduced, but this is a symptom of altered motor cortex excitability, not the cause of that altered excitability. What new information does it really provide? You can ask the patient if they are experiencing PEM or not.




The brain has it's own parallel system of sensing metabolic state and regulating vascular responses ("neurovascular coupling"). The brain requires a lot of energy/oxygen during intensive tasks and it makes sense that it would have it's own metabolic fatigue sensing mechanism that serves a similar function to that of large muscle groups. And the hypothesis is that problem could go wrong in the brain for the same reason it goes wrong in the muscles.



We literally did a poll and found that ~80% of people people reported it did not feel the same.
https://www.s4me.info/threads/poll-physical-vs-cognitive-pem-same-or-different.16948/

For me, physical activity causes cognitive and physical PEM, whereas cognitive activity does not cause physical PEM, but only cognitive PEM.



I think looking at the absolute calories used is the wrong way to look at it. That is the same mistake as Noakes and others who think fatigue is a result of the brain somehow calculating the overall metabolic consumption of the body and scaling back as a result: "Fatigue is a brain-derived emotion that regulates the exercise behavior to ensure the protection of whole body homeostasis." (Noakes 2012).

We know now that no such system exists (instead, fatigue is regulated by muscle afferents and the effects on the motor cortex) and going down that path of looking at overall energy consumption to explain fatigue sensation is a fool's errand.

The issue is the local metabolic capacity. When that capacity is exceeded, metabolites are generated that stimulate afferents (whether it be the metabolic fatigue sensing afferents in the muscles or the same thing in the neurovascular coupling systems in the brain). Instead of predicting a need for increased ventilation and reduced motor activity a-priori, the brain responds to afferents instead.

There have been studies that show that brain fog is associated with altered metabolism and altered blood flow in the brain, so I still think there is something there to dig into.



The brain doesn't simply go "whoops, I ran out of ATP". Many things have to go wrong before that happens (and I'm not claiming to be an expert in emergency medicine) but the whole point about fatigue is it that it is part of a feedback mechanism that limits that from happening under normal functioning.




Many moderate to severe patients suffer from chronotropic incompetence, so we cannot pretend the performance of the heart is not affected at all.

The heart consumes around 5% of VO2 at rest and is only working at around a tenth of it's (VO2Max) capacity. It has the highest capillarisation density compared to any skeletal muscle in the body. And notably, no scientific study discusses any sort of metabolic fatigue sensing afferent feedback (muscle pressor reflex) within the myocardium itself analogous to that of skeletal muscles.

Thanks so much for your explanation of all this. I’m somewhat familiar with some of the research on metabolic sensing, but it’s quite out of my depth. This was very helpful, and I’m very encouraged that it seems to line up with that I’m hypothesizing on the cellular metabolic level.

I’ll have to go back to the literature to understand more about some of the aspects you mentioned.

And side note, I have the same experience as you re: physical and cognitive PEM.

 

[rapidboson]

Might be a stupid question, but do we know if EMS can cause PEM through muscle contractions? Or does PEM come more frequently through more "systemic" exertion?
Say you could use EMS to contract your quads as strongly as they would contract when lifting 50 kg on a leg extension machine. One group gets this EMS, the other lifts 50 kg on the leg extension machine.

Would we expect PEM and in same strength in both groups?

In the leg extension machine, I'd expect the cardiovascular system to be more involved?

On the other hand, I guess it's similar to the hand grip tests, just that the brain is not actively telling the muscle to contract.

Just something that crossed my mind and might well be irrelevant.

 

[forestglip]

Might be a stupid question, but do we know if EMS can cause PEM through muscle contractions? Or does PEM come more frequently through more "systemic" exertion?
Say you could use EMS to contract your quads as strongly as they would contract when lifting 50 kg on a leg extension machine. One group gets this EMS, the other lifts 50 kg on the leg extension machine.

Would we expect PEM and in same strength in both groups?

In the leg extension machine, I'd expect the cardiovascular system to be more involved?

On the other hand, I guess it's similar to the hand grip tests, just that the brain is not actively telling the muscle to contract.

Just something that crossed my mind and might well be irrelevant.

That's an interesting thought. If you don't get as bad of PEM from externally activating muscles, maybe that's evidence that it has more to do with something on the pathway from the brain to the muscle.

I just worry that there is so much variance in how PEM presents itself (different delays, different amounts, variance from it being subjective, different presentations even within the same people on different days, etc) that you'd need a huge sample size to detect a significant difference. And I can't think of how this would be blinded.

Maybe something to come back to if/when we have an objective marker of PEM.

Edit: Though it might be worth checking in a few people in case the effect is actually really obvious.

 

[Utsikt]

I believe I’ve maybe heard of people that have gotten PEM from a physio moving their legs. But that might be because they were very severe and couldn’t tolerate the situation in the first place.

 

[wigglethemouse]

At the moment I have some potential leads for checking the first part of my hypothesis in-vitro, though unfortunately I can't share many details at the moment since I don't have the explicit permission of those potential collaborators.

FYI - Stanford has a Biolog Omnilog instrument that measures mitochondrial function and in my limited understanding you can try various compounds to see how they affect the function of the mitochondria. I believe it is available to use if any researcher wants to come and run experiments on it.

The manufacturer has a new instrument that has superseded it called Odin but I think it uses the same mitoplates for analysis.
https://www.biolog.com/products/metabolic-characterization-microplates/mitoplate-phenotype/

 

[Hutan]

Perhaps the thing that intrigues me most is that ME/CFS rapidly becomes more common in teenage years. That has to be explainable.

Perhaps you have some clues that would fit with that scenario, but I don't think we should assume that ME/CFS is more common in teenage years as compared to the first decade of life, at least not for any reason intrinsic to the biology of a teenager.

Sorry to divert off-topic for a moment, but:

If a child developed ME/CFS at age 5, it is unlikely that they would get diagnosed with it, at least not quickly. The behaviour might just be dismissed as the child not coping at school, or being a sleepy child or a lazy child. We know that it takes quite a while to get diagnosed in the best of circumstances. That problem will be worse in children who can't always explain what they are experiencing so well, who don't have the life perspective to be able to say that things have changed. Life from 0 to 8 years changes so quickly, with things like sleep hours for example, so often the parents won't have a baseline for the child's behaviour from which to spot ME/CFS changes. Also, children are less likely to be listened to when they try to explain what is going on for them.

If a child develops ME/CFS at age 8 and stays ill for years, they may well not get diagnosed until age 11. If they recover after a couple of years, they may not even get diagnosed at all.

Even if incidence was exactly the same in every year from 0 to 19, and the mean time to diagnosis was also exactly the same in those years, the issue of a diagnostic delay alone is enough to result in more people being diagnosed in their second decade than their first.

We have heard of some cases of ME/CFS in children, but some of the ones I have heard about are in families with other family members with a diagnosis. Perhaps these are enthusiastic mis-diagnosis, but perhaps it's just that those families know ME/CFS when they see it, unlike most of the rest of the population.

Perhaps ME/CFS onset really is more common after age 11. But, that might be due to something as easy and unrevealing as there is increased glandular fever in that age group, triggering ME/CFS. It also might be because young people are growing very quickly and are often very active, with the combined exertion perhaps leaving the body vulnerable to the ME/CFS pathology.

There are lots of possibilities. Unfortunately, we don't have any epidemiological data of sufficient quality to assess whether puberty is making any difference.

All of which is to say that I don't think any hypothesis maker needs to be too concerned about explaining 'ME/CFS is more common in teenage years than in the years before'.

 

[jnmaciuch]

FYI - Stanford has a Biolog Omnilog instrument that measures mitochondrial function and in my limited understanding you can try various compounds to see how they affect the function of the mitochondria. I believe it is available to use if any researcher wants to come and run experiments on it.

The manufacturer has a new instrument that has superseded it called Odin but I think it uses the same mitoplates for analysis.
https://www.biolog.com/products/metabolic-characterization-microplates/mitoplate-phenotype/

Thanks for the info! I’ll definitely look into whether it would be of any use for testing my hypothesis.

 

[jnmaciuch]

Perhaps you have some clues that would fit with that scenario, but I don't think we should assume that ME/CFS is more common in teenage years as compared to the first decade of life, at least not for any reason intrinsic to the biology of a teenager.

Sorry to divert off-topic for a moment, but:

If a child developed ME/CFS at age 5, it is unlikely that they would get diagnosed with it, at least not quickly. The behaviour might just be dismissed as the child not coping at school, or being a sleepy child or a lazy child. We know that it takes quite a while to get diagnosed in the best of circumstances. That problem will be worse in children who can't always explain what they are experiencing so well, who don't have the life perspective to be able to say that things have changed. Life from 0 to 8 years changes so quickly, with things like sleep hours for example, so often the parents won't have a baseline for the child's behaviour from which to spot ME/CFS changes. Also, children are less likely to be listened to when they try to explain what is going on for them.

If a child develops ME/CFS at age 8 and stays ill for years, they may well not get diagnosed until age 11. If they recover after a couple of years, they may not even get diagnosed at all.

Even if incidence was exactly the same in every year from 0 to 19, and the mean time to diagnosis was also exactly the same in those years, the issue of a diagnostic delay alone is enough to result in more people being diagnosed in their second decade than their first.

We have heard of some cases of ME/CFS in children, but some of the ones I have heard about are in families with other family members with a diagnosis. Perhaps these are enthusiastic mis-diagnosis, but perhaps it's just that those families know ME/CFS when they see it, unlike most of the rest of the population.

Perhaps ME/CFS onset really is more common after age 11. But, that might be due to something as easy and unrevealing as there is increased glandular fever in that age group, triggering ME/CFS. It also might be because young people are growing very quickly and are often very active, with the combined exertion perhaps leaving the body vulnerable to the ME/CFS pathology.

There are lots of possibilities. Unfortunately, we don't have any epidemiological data of sufficient quality to assess whether puberty is making any difference.

All of which is to say that I don't think any hypothesis maker needs to be too concerned about explaining 'ME/CFS is more common in teenage years than in the years before'.

That’s a great point. I know a couple pediatric healthcare workers, especially those working in infectious disease, who share your thoughts and concerns here.

They’ve affirmed that you’re basically 100% reliant on parents to notice a difference, and we already know plenty of horror stories of parents dismissing painful musculoskeletal disorders as “growing pains.”

Even as an adult, I don’t think many of my family members could accurately describe the characteristics of my illness (without defaulting to how I’ve already described it, if they’ve been listening).

Puberty also happens to correspond with when children might become articulate enough and good enough at comparing their own experiences over time that they can start reporting for themselves. I suspect it’s massively underdiagnosed in younger children.

 

[Jonathan Edwards]

All of which is to say that I don't think any hypothesis maker needs to be too concerned about explaining 'ME/CFS is more common in teenage years than in the years before'.

I think the data are reasonably convincing though, having looked at graphs from at least two sources. Diagnostic ascertainment issues may well be relevant but ME/CFS is not trivial and the paediatric units would by now have picked this up I think. And as much as anything ME/CFS will present at school and I suspect every head teacher can tell you the ME/CFS age incidence profile. I wondered about EBV but it really doesn't fit - late acquired EBV is almost certainly very dependent on kissing, as the old name implies. The infectors who had early EBV have very low infectivity otherwise.

The profiles in boys and girls rising in adolescence are also different.

Interestingly, there is an analogous situation for seronegative spondarthropathy. It manifests in the student age group because of chlamydia infection but we also have good reason to think that it manifests as knee oligoarthritis in adolescents because of growth events (not puberty). In this case it is a change in structure of ligament insertions that occurs at points where growth is about to cease. Ankylosing spondylitis of the spine in most cases has an onset around the time of achieving maximum height.

 

[Utsikt]

Not sure it’s relevant, but I was reminded of a peculiar aspect of my ME/CFS experience yesterday because I overdid physical activity for the first time in a few months.

Essentially, I walked 20 meters to put away some plates before I walked an additional 10 meters in total in addition to using the bathroom. I normally don’t do those activities back to back but I forgot my own rules.

While sitting on a chair in the bathroom I started experiencing widespread muscular pain in the entire body (especially upper) and a substantial weakening of the muscles. I don’t think it was PoT/OI related because that usually comes with other symptoms as well.

The pain and weakness lasted all night.

 

[rapidboson]

That's an interesting thought. If you don't get as bad of PEM from externally activating muscles, maybe that's evidence that it has more to do with something on the pathway from the brain to the muscle.

I just worry that there is so much variance in how PEM presents itself (different delays, different amounts, variance from it being subjective, different presentations even within the same people on different days, etc) that you'd need a huge sample size to detect a significant difference. And I can't think of how this would be blinded.

Maybe something to come back to if/when we have an objective marker of PEM.

Edit: Though it might be worth checking in a few people in case the effect is actually really obvious.

Exactly, was just wondering whether passive vs active exertion could make a difference and if so, if it could give us hints to pathophysiology of PEM.

As for blinding, indeed quite difficult but maybe not entirely needed? Maybe a dose response trial could work as well - using more and more current or more and more weight and see if there's a difference. Idk I'm no expert in trial design.

Then again, was just something that crossed my mind.

 

[Utsikt]

Exactly, was just wondering whether passive vs active exertion could make a difference and if so, if it could give us hints to pathophysiology of PEM.

As for blinding, indeed quite difficult but maybe not entirely needed? Maybe a dose response trial could work as well - using more and more current or more and more weight and see if there's a difference. Idk I'm no expert in trial design.

Then again, was just something that crossed my mind.

We have reason to believe that PEM can result from an accumulation of exertion. So I think it would be extremely difficult to design a trial that is able to isolate the effect of external activation of the muscles. It would be an interesting thing to test, though.

 

[Yann04]

I believe I’ve maybe heard of people that have gotten PEM from a physio moving their legs. But that might be because they were very severe and couldn’t tolerate the situation in the first place.

1) Yes
2) Yes

For me it felt more like the PEM came from sensory overexertion of having someone touch me than my legs being gently moved.

(And just generally, for what it’s worth, when i was extremely severe it felt like literally anything could cause pem, even moving my toes too much)

 

[Utsikt]

1) Yes
2) Yes

For me it felt more like the PEM came from sensory overexertion of having someone touch me than my legs being gently moved.

(And just generally, for what it’s worth, when i was extremely severe it felt like literally anything could cause pem, even moving my toes too much)

Have you ever experienced temporary paralysation? Not «I can’t move because it causes PEM» but «I literally can’t move»?

I have on three occasions. Two were during extreme PEM and the last one just came out of nowhere many weeks into a crash. I slowly regained movement over many hours.

It felt like I wasn’t able to get my limbs to move even though I could feel them.

 

[Yann04]

Have you ever experienced temporary paralysation? Not «I can’t move because it causes PEM» but «I literally can’t move»?

I have on three occasions. Two were during extreme PEM and the last one just came out of nowhere many weeks into a crash. I slowly regained movement over many hours.

It felt like I wasn’t able to get my limbs to move even though I could feel them.

Yes have experienced decently often.

When in PEM it feels like I have to exert far more mental exertion to get my body to do things. Like my brain is not communicating with my body as well or my body is not accepting the signals unless they are very strong. And well sometimes I just cannot get to that level of mental energy required. To push through. So my limb(s) are essentially paralysed.

It's like a more extreme version of that feeling of feeling like you have weights weighing down on your entire body that seems common among less severe people w ME as well

 

[Utsikt]

When in PEM it feels like I have to exert far more mental exertion to get my body to do things. Like my brain is not communicating with my body as well or my body is not accepting the signals unless they are very strong. And well sometimes I just cannot get to that level of mental energy required. To push through. So my limb(s) are essentially paralysed.

Exactly! Great explanation.

 

[Kitty]

Have you ever experienced temporary paralysation? Not «I can’t move because it causes PEM» but «I literally can’t move»?

Yep. Mostly the same pattern: wake up unable to move my arms and legs, which passed after 45 – 60 minutes. It left me with really heavy-feeling muscles, but I was more or less okay once my limbs had come back online.

It happened enough times that for my whole working life I set the alarm for three quarters of an hour before I needed to be out of bed, just in case. It wasn't weakness or fatigue, it was that my limb muscles (the others were unaffected) wouldn't contract at all.

I don't think it's common in ME/CFS, though, and I've never heard anyone describe that particular morning pattern.