ME/CFS as a biological information processing problem

[wigglethemouse]

If we put all S4ME minds to it we can have a pretty good idea of what ME/CFS is, or what the main two ME/CFS's are, by Christmas, is my guess.

My first thought is Dr David Systrom has very strong data for two mechanisms to explain the differences in his results. I think they are
(1) Oxygen utilisation in the tissues
(2) What seems like peripheral shunting causing poor Oxygen uptake by the tissues.

Someone please correct me if I am wrong with the descriptions.

 

[Jonathan Edwards]

Structural difference in a few critical cells?

I agree that it might be different clusters of cells in different brain areas but I think a viable model is going to need to specify the general type of glia - astrocyte, microglia, oligodendrocyte or whatever, and what pathway we are talking about. The neuroinflammation pole talk of microglial activation but microglia can switch on all sorts of different pathways for different conditions. If there is tissue damage then a general repair response makes sense but we don't see damage.

But yes, we have to start somewhere.

 

[jnmaciuch]

Just as a general response to the comments I’ve been tagged in (thank you all for the discussion): I want to reiterate that in principle, I'm not against the idea of some neural or neuro-immune circuit being important to the disease.

What I'm hoping to push forward through my questions is a search through the literature for specifics. Granted, this is an area that doesn't have the benefit of decades of in-depth research outlining all the important sub-systems.

But in order for a discussion like this to have substance, I always feel that it needs to be grounded in some specifics:

Is there a particular signaling pathway or point of known crosstalk that might be a good candidate for explaining features of the disease? Have similar issues been found in other diseases? How have those phenomena been measured, and are those methods applicable here? Not all of my questions have to be answered for a theory to be viable, but answering at least some of them propels a theory from idle chit-chat to something actionable.

To me, that feels much more substantial than allusions to unspecific hypersensitivity or radio tuning (no shade meant at @Creekside, just picking an example from the thread). And answering those questions very well may be a slow process if you're starting from little background knowledge--but in my opinion as someone who is almost entirely self taught in my biology knowledge, it's extremely worthwhile.

 

[Sasha]

as someone who is almost entirely self taught in my biology knowledge, it's extremely worthwhile.

You're a very impressive example of someone whose biology knowledge is self-taught! How did you do it?

 

[jnmaciuch]

You're a very impressive example of someone whose biology knowledge is self-taught! How did you do it?

Thank you, that's very kind! I think much of it was a very slow process over long periods of time, and it was definitely unconventional learning since I had to work around the cognitive deficits.

To describe the basic process, I have gotten extremely comfortable with diving headfirst into literature where I know very little about what's going on and it reads as complete gibberish. I'll find blog posts that are meant to be "simple" explanations that still go over my head, and jump from linked blog post to linked blog post to wikipedia article defining basic terms and then go back to reread the first paper, even if it's still nonsensical. For complex topics, I might even spend several weeks or months wading through the gibberish here and there, feeling like a complete idiot.

What ends up happening is that my brain latches on to little bits that connect to whatever existing understanding I have. And the more I come back to it, the more little things I latch onto. Over time I find that my brain has put together a little puzzle I wasn't even aware of solving. Particularly I've found that sleep does remarkable things for letting the brain find patterns amongst the gobbledygook.

It's also a bit of an exponential growth process. The more I had even a tiny bit of understanding in a related field, the more my brain can latch onto familiar words and piece together that new topic. Honestly the best way to describe it is sort of like how young children acquire language--it's just a matter of not completely tuning it out if it doesn't make sense immediately.

I should note that I've definitely had the benefit of being able to ask questions to other more experienced researchers, or sit through formal lectures. But in all honesty, the lectures from my grad school program are quite terrible, either because the lecturers themselves aren't good at conveying information, or because they assume so much prior knowledge that I was never able to acquire since my illness prevented me from taking many basic science courses in undergrad. So while I am technically gaining knowledge from a formal academic setting, very little of it is formally "educating" me outside of the same exposure process I described above.

Hopefully there's something comprehensible in there, unfortunately I don't have much actionable advice beyond "jump into something that makes you feel stupid and then keep doing it persistently for a period of time until something magically happens"

 

[Sasha]

To describe the basic process, I have gotten extremely comfortable with diving headfirst into literature where I know very little about what's going on and it reads as complete gibberish. I'll find blog posts that are meant to be "simple" explanations that still go over my head, and jump from linked blog post to linked blog post to wikipedia article defining basic terms and then go back to reread the first paper, even if it's still nonsensical. For complex topics, I might even spend several weeks or months wading through the gibberish here and there, feeling like a complete idiot.

What ends up happening is that my brain latches on to little bits that connect to whatever existing understanding I have. And the more I come back to it, the more little things I latch onto. Over time I find that my brain has put together a little puzzle I wasn't even aware of solving. Particularly I've found that sleep does remarkable things for letting the brain find patterns amongst the gobbledygook.

It's also a bit of an exponential growth process. The more I had even a tiny bit of understanding in a related field, the more my brain can latch onto familiar words and piece together that new topic. Honestly the best way to describe it is sort of like how young children acquire language--it's just a matter of not completely tuning it out if it doesn't make sense immediately.

That's a really interesting and very surprising process! Thank you for explaining it. It gives me hope! I will give it a go myself!

 

[jnmaciuch]

That's a really interesting and very surprising process! Thank you for explaining it. It gives me hope! I will give it a go myself!

Please do! It's definitely way more possible than people think, it mainly just requires a lot of stubbornness. I can't emphasize enough that it took a long time before I felt like anything was falling into place when I first started. But looking back retroactively every few weeks, I could definitely notice a trend.

If you're diving right into published literature, just focusing on the discussion sections and introductions was helpful to avoid feeling overwhelmed. You're going to be completely dependent on the author's interpretations, but as your knowledge base grows you'll be able to go back to those papers with a more critical eye.

I was also hoping that an "explain like I'm brain foggy" thread would be able to help facilitate some of that learning on here. If the committee decides to implement it, I can definitely help get that up and running so people can bounce things off of each other as they learn.

I'd be interested to hear how the process goes for you

 

[Jonathan Edwards]

But in all honesty, the lectures from my grad school program are quite terrible, either because the lecturers themselves aren't good at conveying information, or because they assume so much prior knowledge that I was never able to acquire since my illness prevented me from taking many basic science courses in undergrad.

When I were a lad, working in a lab with wooden benches and Bunsen burners, nobody'd heard of lectures or computers or t'internet. We had to look everything up in a great big book called Index Medicus and filch textbook from t'library or visit t'bowels of t'Royal Society of Medicine to read papers in German. Not surprised to hear the lectures are bad. They send in the dummies to do those!

Plus ça change as they say in Italy.

 

[wigglethemouse]

"jump into something that makes you feel stupid and then keep doing it persistently for a period of time until something magically happens"

It's exactly the same process you go through as an engineer when you design a new piece of high tech equipment. You start with the datasheets for the main components and dive in, and much of what you read might be gobbledegoop to start with. Overtime you learn how to scan large documents for the important information quickly. And by the end of the process you become THE expert on the new product.

The same applies to Scientific biomedical papers when you have no background training in the area. You dive in and scan for what seem to be the important bits of information, maybe a key table or figure. For example many here have learnt to look at the methods section and look for clear gotchas in patient recruitment. Others read the abstract and if it's not very good quality move on.

 

[jnmaciuch]

It's exactly the same process you go through as an engineer when you design a new piece of high tech equipment. You start with the datasheets for the main components and dive in, and much of what you read might be gobbledegoop to start with. Overtime you learn how to scan large documents for the important information quickly. And by the end of the process you become THE expert on the new product.

I suppose it's reaffirming that this basic process happens everywhere. It's how I got all my computational knowledge as well. Someone tells me I should start using a package for something, the documentation is absolutely nonsensical, but stick with it for a few weeks and suddenly I'm the lab's preeminent expert on GSEA and RNA velocity programs.

 

[wigglethemouse]

I think there has been a missing piece to the Scientific literature on ME/CFS that has only started to change in the last few years. That has been to study before, during, and after PEM. There have been a few good day, bad day studies as well lately, and hopefully they will report soon. I like to think that will help the "biological information processing problem".

It's something that seems to be missing from the Long Covid research. Why hasn't the message reached them yet that this is what they need to study.

 

[Snow Leopard]

There is no damage

You're begging the question there. There are plenty of places we haven't looked for damage and autopsies have found some striking findings (dorsal root lesions etc)

It reminds me of the narrative around persistent back pain. There WAS damage, including nerve damage which can result in incomplete healing and sensitisation of the nerves. That is still the result of a lesion.

 

[Snow Leopard]

Is there a particular signaling pathway or point of known crosstalk that might be a good candidate for explaining features of the disease? Have similar issues been found in other diseases? How have those phenomena been measured, and are those methods applicable here?

edit- I noticed you already mentioned this in a previous post. The brain cannot create such signals, only attenuate them and as far as I know, this only strongly happens during the preparation of movements.

Not "crosstalk", but there is a particular signalling pathway - metabosensitive type III/IV muscle afferent feedback that explains both the persistent sensation of fatigue as well as the phenomena observed on the 2 Day CPET - the reduction in workrate at the ventilatory threshold.

This afferent feedback causes altered spinal (for the specific motor units utilised) and reduced motor cortex excitability ("central fatigue") this signal can be blocked in the spine but the result is poor ventilatory responses and poorer performance:

https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/JP276460

 

[jnmaciuch]

edit- I noticed you already mentioned this in a previous post. The brain cannot create such signals, only attenuate them and as far as I know, this only strongly happens during the preparation of movements.

Not "crosstalk", but there is a particular signalling pathway - metabosensitive type III/IV muscle afferent feedback that explains both the persistent sensation of fatigue as well as the phenomena observed on the 2 Day CPET - the reduction in workrate at the ventilatory threshold.

This afferent feedback causes altered spinal (for the specific motor units utilised) and reduced motor cortex excitability ("central fatigue") this signal can be blocked in the spine but the result is poor ventilatory responses and poorer performance:

https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/JP276460

Thank you for bringing it up again, yes that’s exactly what I had in mind. The way I see it, either those afferent neurons are properly sensing a dysregulated metabolic environment, or (to paraphrase some of the speculation of others on this thread) somehow there is an exaggerated transduction of metabolic sensing when the actual metabolic state is no different from healthy controls.

Obviously I’m quite biased towards the first option, since locally elevated extracellular lactate fits quite nicely with other parts of my pet theories. But I’d be curious if you had other thoughts since you have much more experience in this domain

 

[poetinsf]

The problem that I have with the idea of local inflammatory responses to use is that by and large PEM does not seem to be limited to the bit that was used.

The idea is that the peripheral/local inflammation gets communicated to the brain and the brain reacts abnormally. There was a paper describing how inflammation in liver triggers neuroinflammation. And, more recently, about how peripheral/local inflammation and brain communicates bidirectionally.

Activities inevitably result in cellular damages that have to be cleaned and repaired. That has to involve some sort of inflammation even if you don't normally feel it locally, right?

 

[Jonathan Edwards]

The idea is that the peripheral/local inflammation gets communicated to the brain and the brain reacts abnormally. There was a paper describing how inflammation in liver triggers neuroinflammation. And, more recently, about how peripheral/local inflammation and brain communicates bidirectionally.

Yes but these are just the hyped memes going around at present. We need real science, not marketing blurb. If we cannot find any inflammation there is no reason to invoke. A lot of researchers now think you can call a minuscule rise in some obscure cytokine inflammation. It isn't.

Activities inevitably result in cellular damages that have to be cleaned and repaired. That has to involve some sort of inflammation even if you don't normally feel it locally, right?

No. They don't necessarily result is damage and tissue maintenance does not have to involve any vascular changes that deserve calling inflammation. This is just the sort of one size fits all analysis that gets everybody nowhere very fast.

It is what everybody has assumed must be the case for decades but have never been able to find because it isn't there. If those people had stuck to facts and had a real understanding of the words they used we might have got somewhere instead.

 

[poetinsf]

Just as an example, normally slightly raised levels of a cytokine alters glial function, which in turn alters various neural processing functions, which in turn alters large-scale changes in the body. Does PEM cause muscles to function improperly in a way that causes pain, or does PEM cause some neurons to work differently giving the perception of pain even though the signals from the sensing nerves are normal?

I'm inclined to believe the latter: the cytokine level change is normal, but microglia or brain network is responding abnormally to the slight raise that healthy people don't even notice.

Here's an experiment: have a subject ( who experiences PEM after a 24 hr delay) do the exertion and monitor IFN-g. Does it correlate with the onset of PEM symptoms? Not proof, but if it's consistent for many subjects, it might be meaningful.

If the brain response is super hypersensitive, there may not be an instrument sensitive enough to measure the cytokine level change, say, after walking from bedroom to bathroom. But all-out CPET test on a mildly sick patient may reveal the correlation. We already know the cytokine level changes after maximal exercise, and the correlation between cytokine level change and symptom severity after CPET test would be as close to a smoking gun as any.

 

[Utsikt]

and the correlation between cytokine level change and symptom severity after CPET test would be as close to a smoking gun as any.

Why? Can’t circulating cytokines increase for number of reasons that probably are completely unrelated to ME/CFS?

 

[poetinsf]

Yes but these are just the hyped memes going around at present. We need real science, not marketing blurb.

Sure, we eventually need a real science to back up the speculative theory. But I thought we are speculating at the moment for plausibility. And cytokine/PEM linkage is as plausible as any. We shouldn't shut down theories as a meme long as they make sense without contradicting observed phenomenon, PEM in particular, unless it is already tested and proven false.

 

[poetinsf]

Why? Can’t circulating cytokines increase for number of reasons that probably are completely unrelated to ME/CFS?

If correlated, it should be worth looking into the possibility of cause/effect. It's "as close to smoking gun as any" since there is nothing at the moment.