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

For as long as we don't know if there are ME subtypes - and currently we have no idea - we need to think about ME in both ways. That is whenever we're considering a proposed mechanism we need to think through very carefully
1) what observations/data the proposed mechanism can and cannot explain if ME is a single disease with a single subtype and
2) what observations/data the proposed mechanism can and cannot explain if ME is several diseases/subtypes
Many hypotheses only attempt one of the two, and only for the 'can explain' part, even fewer pay much attention to the equally crucial "cannot explain" bit

It's difficult to keep so many what-if balls in the air all at once but for now it's important to keep our thinking open and flexible. Constantly move between investigating something in detail then stepping back and looking at how the detail fits into various larger what-if scenarios, based on that go back to detail, step back again and repeat until the puzzle comes together

I wish more people had that attitude

 

That sounds about right. The minute inflammation from, say, walking a block, won't be detectable with C-reactive testing. It's been shown that IL-6 shoots up something like 100 times the day after maximal exercise in healthy people. There probably is a minute elevation after a short slow walk as well, and that could be causing PEM because MECFS folks are hypersensitive. Any metabolic activity would cause damage and immune system will have to kick in to clean up and repair.

 

That's the thing: we don't know, and we are imagining something that we don't know without any proof. It's like saying there may or may not be God, and we should leave the possibility that there is. That's not how science is supposed to work. The "subtype" hypothesis should propose ways to test it, and someone should test it. Till then, it should be considered a single disease. Otherwise we'll be lost in millions of what-ifs combinatorial without any ways of testing for the truth.

I think this idea of subtypes came about from the waste basket theory of MECFS of yesteryears that, since it is a diagnosis of exclusion, MECFS could be anything that is not something. I don't think that is true anymore. Even though we don't have the biomarkers yet, MECFS is now a well-defined and clearly recognizable disease by the set of {fatigue, PEM, brain fog,...} that differs from patients to patients in severity depending on where you are on the disease spectrum.

 

(This is a long thread and I'm catching up whenever I have time) Michelle Monje of Stanford recently showed that the microglial activation in hippocampus area is the cause of the brain fog in long-COVID using the mouse model developed by Akiko Iwasaki. Would that count as some evidence? Also, what do you think of the work Jared Younger has been doing? I know nothing has been replicated yet, but they are at least in the right direction, it seems to me.

 

That's my view too, that even normal levels of cytokines can be worsening ME symptoms. I don't think that microglial hypersensitivity is the root cause of ME, but it's something that adds to the severity. I also think other glial cells might be involved; there are some highly specialized and localized glial cells that aren't well understood, and difficult to study in live brains, but which could have serious effects on the rest of the brain and thus body.

I still think it's some supposed-to-be-homeostatic process, possibly in glial cells, that shifted to a higher than normal positive gain, locking it into an abnormal state, which might render those cells hypersensitive to normal levels of cytokines or other signals.

 

Yeah, no idea if microglia is the ground zero or not. But the microglial activation, perhaps as the result of the hypersensitivity somewhere else, could explain most, if not all, of the symptoms. Mental exertion triggering PEM seems to point to somewhere in the brain though.

 

Yes. My cognitively-induced PEM had a short and fairly variable delay (15-60+ minutes). My physically-induced PEM had a consistent 24 hr delay, which matches the rise in IFN-g following exertion. It seems reasonable that the delayed rise in cytokines or other messengers triggered glial cells in the same way that cognitive exertion did without the immune system delay.

There are so many functions of brain cells that are still unknown, and still very difficult to observe in live patients. A brain scan might show glial cells appearing normal, but maybe they're exchanging tiny messenger-filled vesicles at an abnormal rate, or those molecules are malformed. Can present technology observe that? If the technology does exist, has anyone used it to look for that? In the last few years I've read about new discoveries about brain function (including some fairly major ones such as the glymphatic network) and new technologies that can reveal never-observed-before functions (I'm thinking of a microscopic technique that can now image tiny tendrils on astrocytes). I think ME's core dysfunction is likely to be one of these hard-to-observe functions of glial cells. A typical CPU today has billions of transistors and connections, and it only takes one to have a few atoms shift or react with an errant oxygen atom to shut down a powerplant or city traffic control system.

 

I have a theory that there are a few types of CFS.

One type is from an autoimmune disease attacking the mitochondria,
Second type is mechanical cause of ME like in CCI
Third type is non autoimmune but also involves ATP and mitochondria being messed up by chemicals or radiation. Just not with an autoimmune cause
There is a possible fourth type which consists of the people we occasionally hear about having their CFS caused by antibodies to NMDA neurotransmitters or autoimmune encephalitis or some other obscure thing that most doctors miss.

 

I also have differences between physical and mental PEM.

Physical PEM tends to hit 3-12 hours after activity, the more intense it was, the shorter the delay. The fatigue is different for ordinary tiredness, which I experience too. When I have PEM I'm so tired it's almost like I've been tied down, and my brain feels like a car that won't start. I can't make myself concentrate on any useful task (my executive function is totally shot) but I don't feel mentally tired and can often read, listen to music and play simple games. The onset and recovery are fairly distinct.

Mental PEM is harder to characterize. It seems to have less/no delay, and no distinct onset or recovery. I don't see a hard boundary between very mentally tired and mental PEM. When I have mental PEM I don't feel as tired or have as much trouble with executive function. But I need breaks from concentration and sensory stimulation, and I can have neuropsychiatric symptoms like irritability, mild mood swings, and adrenaline dumps/panic attacks.

I agree that the lack of delay for mental symptoms may point to the brain having a central role in the pathology. As I've said before, my current guess is dysregulated microglia.

 

Do you notice any difference from the type of physical activity? Physical activity does involve some cognitive exertion, so a mindless task might result in longer delay or lesser symptoms than playing basketball or some other activity requiring concentration.

 

No way.
If you make a model that jiggers up the brain the brain will be jiggered. It does not tell you that the brain is jiggered in people. And how can mice have brain fog? I am afraid this is the worst sort of junk science. Nobody has any idea of the pathways in Long Covid so nobody knows how to build model of them.

Why are they 'in the right direction'? I haven't seen anything from Younger indicating microglial activation in ME or Long Covid. I may have missed it but the only thing I am aware of is the Nakatomi study that did not seem to pan out.

 

I only notice that if I go way past my PEM threshold, I'll be immediately tired but it shifts into full-blown crippling PEM, but if I go just over my threshold, I will feel ordinary tired, recover, but then experience PEM later.

 

I don't know brain physiology well enough to comment, but here is a Statnews article and the actual paper. She is actually a chemo fog researcher, not MECFS or long-COVID.
In ‘chemo brain,’ researchers see clues to unravel long Covid's brain fog (statnews.com)
Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain | bioRxiv

Because microglial activation explains all the symptoms? Unlike michrocondrial, viral, vascular, muscle anomaly, etc, etc.

 

You cannot possibly make an 'mouse model' of ME, you cannot make an animal model of something that you do not know what is biologically causing it.

You can make an animal possibly behave in ways that are similar, but then drunk people, people with hypoxia, people who have just run a marathon, severely depressed people all behave in what seem to the observer to be similar ways to a person with ME. But lots of things make a person behave in ways that seem to the observeer to be similar to the way PwME behave, But studying them tells us nothing about ME. You cannot 'give' a mouse ME and TBH anyone who thinks they can simply doesnt understand what ME is - what it is like to have it. Its not 'i feel like i ran further than was comfortable for me' PEM is not PEF

So training them to exhaustion or doing anything else to them, doing something to their brains or whatever, will only tell you about the bodies of mice that have had whatever the researcher did to them, done to them. That tells us bugger all about ME.

I'm not thrilled about animal experimentation full stop... but torturing them to try to create something that at best 'looks like' ME, when the mouse cant even describe how they feel to check if its the same..... its an absolute outrage, as its utterly utterly pointless. Not to mention the waste of time & money & the blind alleys this research has the potential to send us down.

 

One reason for glial (astrocytes and others might be involved too) activation to be a more likely cause is that those other possibilities are much easier to study and already much better studied, and don't show a clear sign of being involved. The brain is much less understood, so there's greater potential for clear signs to still be hidden. There's still mysteries in the other possibilities, so new techniques for measuring oxygen transport into cells might reveal something, but shouldn't a physical cause with such dramatic effects (totally bedridden) show clear effects in muscles, blood vessels, or whatever? Neural circuits can work as high-gain amplifiers, so even small shifts in some factor can result in significant downstream effects.

I still think that someone should do electrostimulation of muscles of a severe patient, to see whether the muscles respond normally (proper power output, O2 consumption, lactic acid production, etc). While not an absolute test of "is it physical or neurological", it might be quite revealing.

 

this

 

I have been thinking about this. I don't think microglial activation in the brain asa primary event would fit at all. Microglial activation in brain would be expected to produce disturbances of cognition like hallucinations or irrational thought or memory or function disturbance.

One of the striking things about PWME is that however bad they feel, their minds seem to be functioning completely normally. There is brain fog but PWME do not show mental aberration. They do not have paranoid delusions etc.

The more I think about it the more I suspect the problem is to do with peripheral signalling via nerves that may lead to disturbed hypothalamic control of 'danger responses' but it leaves the rest of the brain quite normal.

 

The paper by the chemo brain lay seems to conflate changes in human brains from people presumably dying of overwhelming Covid and mice who have had their brains poisoned by something quite different. It looks entirely non-specific to me and almost certainly irrelevant to LC.

 

Assume you mean by this gross delusions - of the 'aliens have taken over the planet and are trying to kill me type delusion you would see in paranoid schizophrenia etc? I only mention it because wow in a really bad bout of PEM when my cognitive function is very bad & i feel really drunk/drugged, i often think my carer is angry with me or that people have fallen out with me, and i do cry a lot, i feel very low and somewhat paranoid about people not liking me.

After it passes i wonder what on earth i was thinking. I think perhaps i am unusual in this, or that we dont talk about this aspect much because the BPS lot would want to twist it from effect to cause. But its definitely downstream for me, or at least it comes on significantly after - it follows the terrible suffering.

although i think i used to feel like that when i got a really bad bout of flu as a well person too, i remember crying for no reason during my many bouts of tonsilitis as a teen. I think Dr S talks about emotional lability.

but thats presumably not what you mean when you talk about the effects glia issues would cause?

 

I'll have to disagree. You don't have to know what is under the hood to build a model to study or predict. This is routinely done in systems engineering. I can model a transfer function just based on the input and output to reasonably predict how the system will behave.

And that is the point. You give mouse alcohol (input), it outputs a measurable drunken stupor, and you can reasonably conclude that drunken mouse is a proxy for alcohol effect that can be used for drinking study. The real thing is preferrable, of course, but there are many instances where that is not possible. Brain, in particular, is not amenable to study without post-mortem exam.

Well, I won't get into ethics of animal study. But science only can deal with what is measurable, not how one feels.