Endothelial dysfunction in ME/CFS patients, 2023, Sandvik, Mella, Fluge et al

Yes, i remember that, it was definitely published, I'm pretty sure it was done by Julia Newton.

Goodness i hope my response wasnt interpreted like that! I would never think JE was veering towards BPS!
I was merely verbally ruminating about movement changes. @Jonathan Edwards insight is really interesting & valuable, I was just trying to understand the difference between ATP movement changes & what happens to me.

 

Thanks I think this may have been the paper he was referring to, although there may be others:

Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome: a case–control study, Newton at al (2011): https://doi.org/10.1111/j.1365-2362.2011.02567.x

From the Abstract:

I also echo comments above. I’ve never interpreted Jonathan’s comments as “veering towards BPS territory” and I hugely value his input as a disinterested expert observer whose only interest appears to be in understanding the truth – wherever that may lead – and helping patients. I also welcome that fact that he says what he thinks, even if it’s not popular, and is willing to listen to counter-arguments and change his mind. I just wish I could persuade him to call me Rob instead of Robert!

 

But to me faulty signalling makes much more sense than lack of ATP. Lack of ATP should last for a minute or two, maybe twenty minutes after a marathon run. If the faulty signalling involves hormonal signals or sleep centre cycles or other systems that audit activity over longer periods then delayed recovery makes a lot of sense to me.

If I exercise more than usual I may well be aware of the effects for several days. Signals bring in macrophages to muscle for several days. Growth hormone effects that mediate bone responses work over an extended period, and so on. And that is the normal situation.

 

If the signalling is neural, no. If it is cytokine or hormonal maybe but maybe not. We have learnt that a lot of chemical signals act quite locally. If there is a secondary impact on nerve fibres then the effects are all invisible but generalised.

 

I would describe my PEM movements similar to ataxia with less power in my arms and legs and balance problems. I walk into people. I slur and have difficulty processing information.

 

@Jonathan Edwards, how does the inhibitory signal model explains the consequences of overriding that signal?

When we have flu or are ill and press on, we usually feel terrible soon afterwards.

Is that an extra level of inhibitory signal trying to reinforce the message, or is the ill feeling caused by something else?

Similarly, in the case of overdoing things with ME would the model put PEM, or even relapses, down to more inhibitory signals or some other mechanism?

Comparison with the central sensitisation theory

 

I think I was also wondering this, though not sure how to articulate it. Thanks for articulating it so clearly @Simon M !

 

I don't think anyone knows.

I think discussion in terms of 'faulty interpretation of normal signals' ends up meaning whatever you like unless one is specific. All signals will have a normal function at the right time. Interpretation may just mean the way another sort of signal follows the first and then you go round in circles asking which is the first one to be inappropriate.

My post-Covid fatigue feels like peripheral sensitisation in that I have no doubt that I am getting sensory signals that would normally indicate I am ill. In ME light sensitivity suggests a more central problem but still not necessarily thalamic.

I suspect that there is maybe some abnormal dialogue between peripheral sensory structures and hypothalamus in ME. Certainly the 'central sensitisation' story I hear from the BPS crowd seem to me to be disingenuous pseudo models that justify a psychodynamic narrative that is conveniently hidden.

There is a world of difference between hypothalamus and thalamus/insula/cingulate, limbic structures etc.

 

Yes, I raised light sensitivity because it might seem central but it is still not central in the central sensitisation sense. So case unproven.

Tipping into PEM where any stimulus is too much seems to me to distinguish the valid concept of ME from what I have (and had fifty years ago). My symptoms are frustrating but not more than that. If you have to go to work to pay the rent then what I have had would be a big problem but not ME. I suspect that the problems I am left with are old age even if I never had tingling in my hands before, or pains at night in my shins.

I think the severity thing is relevant. I sort of see this a bit like what laptops do when software screws up. First of all there is a pink dotted box with red words saying 'error, username or password incorrect'. Then there is a new page saying 'three incorrect entries have been made, the site is no longer accessible'. Then there is the page and you cursor freezing so that you have to reboot. And so on. I suspect that our neuroimmune apparatus has a complex repertoire of such inhibitory signals. The irony is, of course, the the origin of the problem might be you having your password written wrong in your diary or it might be somebody has devised some lousy software or there has been an update not recognised by your system or all sorts of other things. The battery might be nearly run down and the connection need a certain voltage (what happens with my hearing aids).

 

Me: how does the inhibitory signal model explains the consequences of overriding that signal?

I was hoping that, at least in the case of illness, we would know what causes the reaction to overexertion – because that would good be a clue to what is going wrong in ME.

Do you see a way to investigate the idea of an inhibitory signal being at the heart of the illness?

 

Good points @Simon M.

Feeling terrible when trying to move with flu is attributed to cytokines like TNF and Interferon sensitising nerves. The precise mechanism may not be clear but release of prostanoids (potent neural sensitisers, as indicated by the effect of ibuprofen) would be an obvious intermediary.

But I think we recognise more than that. We soldier on with flu for a bit and then suddenly go to pieces with sweating, nausea, and weakness, all of which are likely to be mediated by autonomic discharge. Something similar happens in cold exposure - you can go on coping for a good while feeling very cold and then suddenly you are overcome with uncontrollable shivering and inability to even walk (in my experience).

The best way to investigate the idea of an inhibitory signal would be to find some blocking mediator. But where to find it who knows. It might be that guanoabana juice is rich in such an inhibitor but unlikely because someone would have discovered that it cured ME in Ecuador a while ago!

 

Thanks. Could you explain a bit more about autonomic discharge, and also if that ties into the point you made earlier about a key role for the hypothalamus?

 

I probably cannot give much more detail of any reliability. The hypothalamus is where temperature is regulated and where the central nausea centre is. It almost certainly controls shivering as well as fever.

Autonomic discharges are features of various adverse states and I am not good on the classification. Fear produces tachycardia but fainting at the sight of blood involves bradycardia. It all depends on whether it is sympathetic or parasympathetic I thin but somebody else might know a lot more.

 

Thanks again to Simon for asking the questions that I was struggling to formulate.

If I’m understanding correctly, it seems like it would be bad news for patients if the primary cause was faulty neural signalling, as it would be hard to test or treat unless one happened to stumble on a drug that helps.

If it was a neural signalling problem, would you expect there to be abnormal physiological effects of those faulty signals which could be objectively identified?

Apologies if this is a dumb question (as you know, I’m not a scientist) but do you think it’s plausible there may be something as yet unidentified which is interfering with the signals – ie that there is a signalling problem but it’s not primary?

[edited formatting]

 

We tend to focus on uses that are the most usual but compounds/ molecules multi task, and signalling is a key other aspect for many.

ATP is also a signalling molecule .
If there's a problem, signalling may be prioritised over energy use

If the set points for part of a system are wrong then it may be in some form of feedback loop and not switch back fully ? ( Or knock onto other areas)

Relationships and ratios with other compounds / molecules may offer insights rather than simple high / low individual statuses.
Machine learning plus genetics / epigenetics may be a game changer - I just hope we don't have to wait a lifetime to unlock some answers and treatment .

 

Gate / gait (?) Is one thing that noticeably changes for my daughter in PEM.
It's as if the body is trying to minimise energy expenditure ( plus increased pain) .

Perhaps this is a case of if you don't look you don't find..has anyone been asked about this by a medical professional ?

 

This is as accurate a description of my ME as I have ever seen. Stop completely, wait a couple of minutes then start again. It has been like that right from the start when I was still able to go to school and live a fairly normal life. It has never been a fluey feeling or general fatigue that has characterised my symptoms. They happen but only in episodes while the stop and start is constantly with me.

I get that too Mij. When people talk about ME, a lot of the time it does not
match what I get.

It is interesting discussing symptoms with medical professionals. If we do not accumulate lactate acid what causes the deep burning, acid in the muscles and bones feeling you get with ME?

 

@Jonathan Edwards Just giving you a nudge in case you didn’t see these questions.