Preprint A Proposed Mechanism for ME/CFS Invoking Macrophage Fc-gamma-RI and Interferon Gamma, 2025, Edwards, Cambridge and Cliff

Would this theory align with ME/CFS-like symptoms after brain injury?

It probably would if we make the very vague proposal that shifting neural circuit balance in someone with a genetic predisposition to an ME/CFS type process could be an adequate triggering event. We emphasise that we think that infection as a trigger is probably doing something nonspecific. The theory as presented in the paper focuses on the immune side but if neural signalling responsiveness is an important element then a neural trigger is plausible too.

I am hoping that DecodeME will test some of these aspects of the model ;).
 
So could that responsiveness also directly cause symptoms on exertion (feeling depleted), rather than it being delayed like in PEM?

Yes, sorry, @Jesse, to answer your original question, I think it would fit. The immediate reaction is the smoke alarm in the barn going off. PEM might be the T cell nightwatchman saying 'not the bloody smoke alarm again, when I've had my tea I will drag myself over there and re-set it'. Except that the nightwatchman has got the wrong glasses on and keeps re-setting the sensitivity even higher.
 
Hi all, long time lurker, love this thread and the paper.
This really confuses me. Surely I can, under normal circumstances, tell my body what to do at the macro level, even if I can't directly order my macrophages about. Are you suggesting that I can't decide (assuming I'm not exhausted) to raise my arm? Or that I haven't decided to type this message?
A fun example of something like this is when we're stretching and feel that we've reached the limit. It *feels* completely physical -- like a bungee chord stretched to its maximum amount -- but actually that sensation of a limit is caused by a inhibitory neural feedback loop. AFAIK without this "false" limit your muscles and tendons could indeed stretch further (and eventually get badly hurt). Sometimes I kind of want to ask the BPS folks to please mind-over-matter this arguably purely functional limitation to doing the splits...
 
Hi all, long time lurker, love this thread and the paper.

A fun example of something like this is when we're stretching and feel that we've reached the limit. It *feels* completely physical -- like a bungee chord stretched to its maximum amount -- but actually that sensation of a limit is caused by a inhibitory neural feedback loop. AFAIK without this "false" limit your muscles and tendons could indeed stretch further (and eventually get badly hurt). Sometimes I kind of want to ask the BPS folks to please mind-over-matter this arguably purely functional limitation to doing the splits...
Welcome!

Power lifters do just that. They are able to completely tear their muscles when doing max lifts. And lots of sports injuries are not caused by contact - someone just went beyond their physical limits. But I suspect adrenaline is involved in making it easier to override those limits. And that’s the exact opposite of that the BPS people preaches.
 
Yes, sorry, @Jesse, to answer your original question, I think it would fit. The immediate reaction is the smoke alarm in the barn going off. PEM might be the T cell nightwatchman saying 'not the bloody smoke alarm again, when I've had my tea I will drag myself over there and re-set it'. Except that the nightwatchman has got the wrong glasses on and keeps re-setting the sensitivity even higher.
No worries, we do seem to be getting there. That's a fun analogy, happy to hear it fits theoretically!

I'm still very curious on the involvement of the sympathetic nervous system when trying to push through:
I'm usually able to push it (hard as it is), which would trigger a huge stress response in my body (hr/bp going up, sweating, GI upset, frequent urination, overstimulated brain, restlessness). When trying to rest afterwards I get stuck in tired but wired state and get insomnia. Then PEM starts the next day.
what happens if we push through this, and in my experience the activation of the sympathetic nervous system. Is there a mechanism that makes sense there?
@Jonathan Edwards any idea how that could work?
 
Exertion beyond a certain limit does seem to increasingly cause "sympathetic nervous system activation" during the same day. This can also be caused by being upright for too long or too much socialising. It feels like tired-but-wired and returning to a relaxed resting state is impossible. The same night, sleep quality will be poor. The next day, I will wake up feeling unrefreshed, more symptomatic and less able to function.

I suspect that the experience of PEM without warning may be due to being unaware of the SNS activation or even experiencing it as not unpleasant state of excitement.

The SNS activation may also favor overactivity because of its stimulating effect.

I wrote "sympathetic nervous system activation" because I'm not certain what it really is, but it seems to be the closest concept in terms of how it's experienced.
 
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I don't have any specific suggestion. The trouble with the nervous system is that it is very complicated and predicting how it will behave, beyond very simple reflex events, is hard.
That's too bad. It's one of the things I'm really curious about. I've been trying to figure it out for a long time (how it works for myself) because it's a pretty prominent symptom for me. If you ever manage to tie this into a hypothesis I would love to hear it.

Do you think it could be more readily explained by metabolic issues? Or does this observation not point us in any specific direction?
And do you think it's a common feature from what you've seen over the years? Another interesting thing is that I don't have OI.
 
Do you think it could be more readily explained by metabolic issues?
My general feeling is not.
And do you think it's a common feature from what you've seen over the years?
Remember that all I know about ME/CFS comes from reading posts here. It was not my field before that. I am not in a better position to judge that than other members
 
The preprint has been up for two weeks now and still no reviews. Is that weird?

Qeios does not seem to be operating quite as well as it was a year or two ago so I wonder if there has been a glitch. But this may be the sort of paper people are not quite sure how to review. It doesn't bother me particularly. My main objective was to get the ideas put together in the public domain.
 
And do you think it's a common feature from what you've seen over the years?

My general feeling is not.

Remember that all I know about ME/CFS comes from reading posts here. It was not my field before that. I am not in a better position to judge that than other members
Jesse we do have a few threads - at least 2 IIRC - on the 'adrenaline effect' a term people seem to use to represent different things, but you might find them interesting. If you do a search for threads with adrenaline in the title im sure you'll find them - just to give you a flavour of others' experiences.

I've found the way i feel so much better when I'm scared or angry, every single symptom improving, to be the most extraordinary thing so have been wondering about it for 20 odd yrs. And why overdoing it (when you're not aware youre overdoing it, should provoke an SNS activation I dont know, but I think its very common from what i've heard/read from others
 
Qeios does not seem to be operating quite as well as it was a year or two ago so I wonder if there has been a glitch. But this may be the sort of paper people are not quite sure how to review. It doesn't bother me particularly. My main objective was to get the ideas put together in the public domain.
Certainly it's getting no shortage of attention - it's had over 6,500 views and has been downloaded nearly 1,000 times.

Hopefully, some people are starting to think about empirically testing some of the key ideas. Do we know if anyone has started work? (People may have said so on this thread but it has got away from me!)
 
Here’s what the Altmetric stats say
  • In the top 5% of all research outputs scored by Altmetric
  • Among the highest-scoring outputs from this source (#18 of 1,556)
  • High Attention Score compared to outputs of the same age (97th percentile)
  • High Attention Score compared to outputs of the same age and source (87th percentile)
It seems to have more views, downloads and a higher attention score than the Concept of ME/CFS paper.

It would be interesting to hear what all those outside the forum reading it think though.
 
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