A Thought Experiment on Muscles

AliceLily said:
I was having great difficulty walking up a hill. It was like my legs at the top back were paralyzing on me. My whole concentration was on trying to move each leg forward. I didn't know how I was going to get up the hill and was very conscious that someone might be noticing I was having difficulty.

Has anyone else experienced this with their ME?
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Yes, I have certainly experienced something like this. I wouldn't use the term 'paralysing' for what I experience but, after walking for some time, and particularly walking uphill, it can take enormous concentration to make my legs work, to make the movements needed for walking.

Separate to that, I think there can be an issue with a hamstring stretch. If I bend down to pick something up, there can be an overwhelming sensation of fatigue. I'm not sure how to explain that better - I'll try to watch out for the sensation and make better notes. It doesn't happen every time I bend down.
 
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V.R.T. said:
For me it began when I was still mild but pushing and crashing all the time.
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yes me too

hotblack said:
Well it’s all wonderfully confusing and interesting.
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it certainly is, I'm not keeping up with the thread never mind all the science on it, but I'm fascinated by it all even if i dont understand most of it. And its just so heartening to be reminded that so many brght minds are working on it! When i get so low i want to give up, i remind myself of this, & it gives me hope!
 
Jonathan Edwards said:
That is the elephant in the room maybe. Neuroimmune communication has been talked about for decades. Cytokines making nerves feel lousy is easy but nerves making cells do cytokines has always seemed a bit of a stretch. It might be very important but I am still waiting of the 'aha' moment.
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All this talk of afferent nerves & the spinal column... apologies if this is idiotic & totally unconnected scientifically but i wonder about the post mortem dorsal root ganglionitis findings & whether they have any connection or anything relevant to tell us?

I know the DRG are not part of the spinal chord, but arent they involved in sensory input/signalling too?
 
JemPD said:
I know the DRG are not part of the spinal chord, but arent they involved in sensory input/signalling too?
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Absolutely, they are where the primary afferent neuron cell bodies are, with axons carrying on up the cord. So yes, I agree that the observations on DRG could be very important.

I recently went to a lecture on people who cannot feel pain and there is one form of the disease due to a genetic error in a gene that encodes for a long non-coding RNA that controls development of these cells. That would not be directly relevant to ME/CFS but it made me wonder whether in ME/CFS these cells are being changed by signals like LNC-RNAs that we wouldn't see or measure normally. `maybe only in very severe cases there might be a local cellular response of 'ganglionitis'.
 
I haven't managed to keep up on the whole discussion here, so please forgive me if this is out of scope.

I was wondering if there is indeed increase lactate buildup in pwME compared to HC?

And whether an intervention with beta-alanine has been looked into? It supposedly increases carnosine which has acid buffering abilities, to my understanding.

Seems like it also increases VO2max in healthy volunteers?
meta-analysis
 
Evergreen said:
and what Amann 2012 said here https://pmc.ncbi.nlm.nih.gov/articles/PMC3351566
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Yes, that is kind of out of date.

Sidhu and Gandevia have made major contributions to the field and coincidentally have coauthored a review with Amann, which I strongly recommend anyone interested to read, including @Jonathan Edwards and @Simon M

"Critical considerations of the contribution of the corticomotoneuronal pathway to central fatigue"
https://www.researchgate.net/public...orticomotoneuronal_pathway_to_central_fatigue

Aman 2022 said:
As with nearly all indices of fatigue, the MEP and SP are influenced strongly by the parameters of the fatiguing task. Accordingly, there is no characteristic response that allows a categorical statement about the influence of fatiguing exercise on motor cortical excitability, particularly because few studies have controlled for both spinal and peripheral influences on the MEP. Even with an isometric task, which is the predominant mode of exercise studied because it allows the most experimental control but suffers from a lack of functional relevance, the findings are mixed for the MEP. For example, regardless of the muscle, MEP size typically increases as a percentage of Mmax during both fatiguing submaximal (Hoffman et al., 2009) and maximal (Taylor et al., 1999) tasks (note
that motoneuronal excitability is reduced and so cannot enhance MEP size). However, data are equivocal for intermittent tasks. Specifically, non-normalized MEPs were previously reported to increase during repeated maximal voluntary contractions (MVCs) of the dorsiflexors (Mileva et al., 2012), remain unchanged during intermittent plantar flexor MVCs (Iguchi & Shields, 2012) and, when normalized to Mmax, remain unaltered from before to immediately after an intermittent submaximal quadriceps contraction protocol (Hilty et al., 2011). Even when accounting for subcortical influences, it is not clear whether motor cortical excitability is increased or unaffected by a fatiguing isometric task.
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MEPs are motor evoked potentials after a transcranial or cervicomedullary stimulus.

Importantly, during some types of exercise, such as maximal intensity single-joint contractions, the excitability of the corticomotoneuronal pathway is typically increased (Gandevia, 1996). In theory, this could mean that a given degree of synaptic input into the motorcortex might lead to greater motor unit activation and thus offset the development of central fatigue during exercise
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Note this depends on whether the motor unit pool was only partly or completely recruited during the tasks and hence the degree of motor units that are fatigued.

If the fatiguing task involves locomotor exercise,changes in MEP and SP differ from those obtained during isometric, single-joint exercise (Weavil & Amann, 2018). Specifically, when recorded from the contracting quadriceps muscles, the MEP, normalized to Mmax, remains unchanged during exhaustive cycling exercise (Sidhu et al., 2017; Sidhu et al., 2018; Weavil et al.,2016). However, when accounting for the fatigue-related increase in neural drive (Sidhu et al., 2012; Weavil et al., 2016) or changes at the spinal level (Sidhu et al., 2017; Sidhu et al., 2018), MEP size actually decreases. Furthermore, the duration of the SP recorded from the quadriceps is not affected by exhaustive cycling exercise (Sidhu et al., 2017; Sidhu et al., 2018). Interestingly, SP duration is reduced and the exercise-induced decrease in motor cortical excitability (MEP normalized for CMEP) is prevented when a given fatiguing cyclingtask is performed after pharmacological blockade of group III/IV muscle afferent feedback from locomotor muscles (Sidhu et al., 2017; Sidhu et al., 2018). These findings suggest a considerable impact of these sensory neurons on corticomotoneuronal excitability during locomotor exercise
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Large muscle groups can invoke larger reductions in motor cortex excitability due to having a greater number of feedback driving afferents. Which is important since this feedback mechanism is key to proper ventilatory regulation as metabolism becomes less efficient in those muscle groups. It is important to note that this increase in ventilation to compensate for fatiguing tasks is NOT driven by other types of CO2-induced chemoreceptor stimulation as found in this study: "Note the persistence of the hypoventilatory response in the presence of type III–IV afferent blockade – especially during mild and moderate intensity exercise – despite the presence of increased CO2-induced chemoreceptor stimulation." (https://pmc.ncbi.nlm.nih.gov/articles/PMC4578297/)


But this also begs the question about the persistence of this feedback post exercise - it persists longer than the fatiguing task itself even in healthy participants.

Why did Walitt et al. resort to hypothalamic function to explain reduced motor drive if altered afferent feedback could have explained it?
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The problem I have with Walitt is they performed the TMS study inadequately.

Firstly, the use of 50% MVC isometric contractions of the Abductor pollicis brevis compared to a versus a dynamic/locomotor task because it doesn't generate the strong attenuation of the motor cortex due to afferent feedback because it is a minor muscle that does not consume that much oxygen even when working hard.

Secondly, they could have utilisied paired transcranial magnetic stimulation along with cervicomedullary magnetic stimulation so that they can contrast the corresponding differences in excitability in the motor cortex and the spine. Alterations in spinal excitability occur during fatigue due to the need of altering motor unit recruitment patterns as motor units fatigue. So their observed results may well be the result of afferent feedback in the spine, yet they concluded something very different.

They also fail to state their TMS methodology, such as the interstimulus interval. (eg short

Walitt fails to consider the most obvious answer: that the reduced voluntary drive can be because the participants are literally feeling a sensation of fatigue and reducing their output as a result. Walitt doesn't even consider this because he has already discarded all hypotheses that include the role of the peripheral afferents.

If Walitt bothered to read Amann 2022, the Deep phenotype manuscript would have a quite different conclusion, and if they read it before performing the experiment, then there might have been actual progress in the field.
 
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rapidboson said:
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..
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I bet it would, because the afferent feedback is there still. But there is no way anyone is going to ethically set up EMS to lift 50kg on a leg machine.

Hutan said:
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'.
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I think JE is looking at it from a hypothesis generation point of view, but then again we could just explain it away with risk of EBV/CMV exposure and potentially a generalised hormonal risk factor in women.

Kitty said:
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.
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Periodic paralysis can indicate other things - typically hypokalemia which can be due to adrenal insufficiency, kidney disease, thyroid overactivity etc.

https://pmc.ncbi.nlm.nih.gov/articles/PMC11501104/

All this talk of afferent nerves & the spinal column... apologies if this is idiotic & totally unconnected scientifically but i wonder about the post mortem dorsal root ganglionitis findings & whether they have any connection or anything relevant to tell us?

I know the DRG are not part of the spinal chord, but arent they involved in sensory input/signalling too?
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Yes! There are a few different related findings in addition to the autopsies that make for very curious suggestive evidence.

In certain cases I believe this IS the primary cause (damage and resulting sensitisation of afferent nerves). But it might be only in a minority rather than a majority of patients. Maybe in some severe cases in particular. That is one of the key findings that overlap between Guillain Barre Syndrome and ME/CFS that could explain why the former can lead to long-term symptoms that mimic the latter.
 
Snow Leopard said:
Sidhu and Gandevia have made major contributions to the field and coincidentally have coauthored a review with Amann, which I strongly recommend anyone interested to read,
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Snow Leopard said:
If Walitt bothered to read Amann 2022, the Deep phenotype manuscript would have a quite different conclusion, and if they read it before performing the experiment, then there might have been actual progress in the field.
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Wallit's prejudices about ME/CFS are likely to mean he is not receptive to changing his approach.

Given that there are experts in this field researching central and peripheral mechanisms for fatigue in healthy people, do you think there is any chance of persuading Sidhu, Gandevia and colleagues to research these mechanisms in ME/CFS?
 
Yeah I find the whole "ROS keeps a vicious cycle alive" too "easy" to be true. I do believe he truly wants to find a solution but I can't help feeling like he's forcefully trying to build his hypothesis around patents he has on PDE7 and NHE1 inhibitors. Building a case for his solution rather than elucidating the case first and then finding a solution.
 
Hutan said:
Yes, I have certainly experienced something like this. I wouldn't use the term 'paralysing' for what I experience but, after walking for some time, and particularly walking uphill, it can take enormous concentration to make my legs work, to make the movements needed for walking.
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Now that it seems nerves in skeletal muscle could be triggering PEM perhaps conductivity is a better description of the problem in muscle?
 
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