If you had to guess ME/CFS cause, what'd you say?

[Jonathan Edwards]

Would brain hypoperfusion trigger glial activation?

I think only if it led to sufficient starvation of brain tissue to produce unconsciousness for a significant time. People who are resuscitated from cardiac arrest who do not regain consciousness for hours may well do. Lowish perfusion in people otherwise conscious and moving about I think not.

 

[Peter T]

Yes, but the important word there is "complete". For an electrical circuit, the model might match the real-life device perfectly with inputs ranging from 0 to 12V, but provide completely unexpected results outside that range. We don't know the range of inputs for ME. We don't even know what all the inputs are. So, you can make a model that works well on a very limited range of inputs, but be very different from the real thing. Like any tool, models can't be trusted beyond their designed limits.

Yes, this. We still don’t have a good ‘natural history’ of ME.

 

[Jonathan Edwards]

glial theory is in vogue

Very much so - all over the shop.

 

[Eddie]

In ME we have no primary injury to blame glial activation on and so far there seems no good evidence there is any.

I don't know if I have missed something but it seems like there is much literature that certain viral infections can cause glial activation. I agree that in concussion the primary problem is the mechanical damage. However, I don't think we know what symptoms are a result of the mechanical damage and which symptoms are a result of the glial activation that occurs in response to that damage. At least something that seems plausible and deserves more research in my relatively uninformed opinion.

If glial activation is driving the symptoms of ME I don't know why we don't see more progressive changes. Perhaps the activation doesn't drive a degenerative process it just doesn't go away and continues to cause problems without becoming worse over time. I agree though it seems like most diseases that affect the brain get worse over time.

It looks like there are four or five PET studies currently underway in ME and Long Covid. If these studies show a similar result to the VanElzakker study would we be able to draw any conclusions from that?

Thanks for the input, I'm newer to ME/CFS and find this area interesting.

 

[Creekside]

You DON'T have to work out the underlying mechanism to model the workings of a system if you have complete set of inputs and outputs.

I was thinking more about this. How complete is your set of inputs and outputs when PWME respond so differently to inputs? Supplement x makes person A feel better, person B feel worse, and other people notice no effect. Also the system isn't just ME's core dysfunction; all the other systems in the body can affect the outputs, so a person with a comorbid condition, or even just an individual peculiarity, could have a reaction from a given input, possibly involving a large number of intermediate reactions. Nope, I don't see modelling ME as being effective. You can make a model of a very limited set of inputs and outputs, but then the model is only valid for those specific inputs and outputs. If the system outputs were measured on several discrete values of inputs, the model wouldn't necessarily be valid for inputs between those discrete ones.

A mouse that doesn't run around as much as the control mice is not a valid model for ME.

 

[poetinsf]

I was thinking more about this. How complete is your set of inputs and outputs when PWME respond so differently to inputs?

That would be impossible to know for something as complicated as MECFS. I was speaking only in theory. Personally, I'm not trying to model the entire MECFS. I'm just looking at the response to exertion. There are some universal observations, like being able to walk much farther if you incorporate rests. Or, my observation that I can walk twice as far if I reduce the speed by 5% before triggering PEM. (Not sure yet if this universal). You can use inputs/outputs like this and come to a limited model that gives you certain numerical predictions as to how much of what you can do without falling back to rule of thumbs like 50% rule or 95bps HR.

A mouse that doesn't run around as much as the control mice is not a valid model for ME.

If you subject it to, say SARS-COV-2 virus or overtraining, and then observe MECFS behavior, you can make a non-random reference. Not perfect, but a reasonable proxy. Then you can always try the solution that works for mice on humans for the validity.

Like in any system debugging, I think reproducing the problem will the key in solving MECFS. You obviously can't do that with humans. Animal cruelty notwithstanding, I think it'll be a great leap forward if you can reproduce MECFS in mice.

 

[poetinsf]

If glial activation is driving the symptoms of ME I don't know why we don't see more progressive changes.

This is what I've been think about too. I've heard that microglia has multiple states, not just on and off. Perhaps there is a state that it gets activated but not chew up neurons. Just my guess.

 

[poetinsf]

If the PET portion of this study https://www.biorxiv.org/content/10.1101/2023.10.19.563117v1?ct= were to be replicated in ME, perhaps with a larger sample size, would that be good evidence that glial activation is somehow involved in ME?

Ha, this was exactly what I was saying a while ago when they came up with the study showing vascular damage in long-COVID: whatever was causing vascular damage could be also causing neuro-inflammation. People, including those in academia, are too quick to extrapolate correlation to causation. Of course, you can't make wave with just correlation, so there are motivations for such despite knowing better..

 

[Eddie]

whatever was causing vascular damage could be also causing neuro-inflammation

That is one of the things I find compelling about this theory. It offers an explanation why a number of seemly different unconnected triggers (viral infections, vascular issues in Long Covid, chemicals in GWI, and physical damage in PCS) could result in smilingly similar symptoms. If these triggers cause the glial cells to become activated, then some other more universal genetic or environmental factors might mean they aren't able to turn off correctly. Given that the rates of long term symptoms following these triggers seems to be 5-20%, maybe it isn't the trigger that is particularly important but the glial cells failing to turn off in that percentage of the population. Either way hopefully DecodeMe will provide some insight!

I am also one of the people who found LDN quite useful. I have tried most of the common POTS/ME medications and LDN was the only one I am convinced did anything for my PEM symptoms. I am aware this isn't necessarily good evidence that the hypothesis is correct, I just wanted to put it out there.