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

[Jonathan Edwards]

But even if you don't equate our consciousness with an 'I', surely there is something with within us that has intention and is making decisions? If not, how come my fingers are moving across this keyboard to type a message?

As far as we know the decisions arise from the whole nervous system operating in response to inputs. There is nothing that decides over and above that. Intention does not have a scientific meaning. We can propose mechanisms that might account for an appearance of intention but they remain the events of neurobiology - synapses and potentials and stuff.

As to 'how come my fingers are moving', the reality is that science provides no answers to 'how come' anything at root. It is the way the universe works. For us it seems to be closely associated with experiences of 'intending' or 'deciding' which presumably means that biological material can support events that at a fundamental level have these properties. But why that should be is almost certainly unanswerable. We happen to be in a universe where things are that way, and if we weren't nothing would be experiencing this discussion in that way.

 

[Jonathan Edwards]

If our only defence to, 'You can push through your exhaustion' is 'There is no me' then we're done for.

Why? That is a basic assumption of mainstream medical science, that there is no me involved. (Which is what the BPS people weirdly call dualism when it is them that are dualist.)

I am afraid you are unlikely to get many people to understand this stuff. Although the mainstream view denies a 'me' an awful lot of biomedical people secretly still believe in a me but also believe that they are not allowed to let that colour their science. And when you get to the scientists who study consciousness, almost none of them have a coherent understanding of the problem. A bit like psychology, which is populated by people who are the least good at understanding the human mind, consciousness studies is populated by another lot of people who are the least good at understanding the human mind.

 

[Peter T]

If they ask why, we tell them we don't know yet. There is no explanation, and if we pretend otherwise we're as bad as they are.

We do have the explanation that though a small percentage of people with ME/CFS do improve the majority have experienced that ‘pushing through makes them worse’, and for a significant percentage that worsening becomes permanent. My experience over my x years of the condition is that ‘pushing through makes my condition worse.

Then you ask the person why none of the people advocating exercise and psychological intervention cite the existing studies on the prognosis for ME/CFS suggesting only some 6% experience a full recovery including those who have had PACE type CBT/GET, and none of them who are researchers have attempted meaningful long term follow ups.

We don’t know why exertion makes us worse, but we do know that for the majority it does.

 

[Kitty]

We do have the explanation that though a small percentage of people with ME/CFS do improve the majority have experienced that ‘pushing through makes them worse’

Yes exactly. And we can't give a reason, so we have to say we don't know.

 

[Utsikt]

If BPS proponents are confused about this, then a lot of PwME are probably confused about it too (me included, obvs). I think we should discuss it so that we can understand it, so that we can communicate about the new theory in a way that doesn't hurt us. If our only defence to, 'You can push through your exhaustion' is 'There is no me' then we're done for.

I agree we don't want to go down a massive rabbit hole about this but maybe we can go far enough down one to resurface and think about comms.

Regardless of if there is some kind of «me» or «you», pushing through symptoms when you live with PEM is like eating sugar as a diabetic without access to insulin. It’s like running on a broken leg in a cast. Like going to a concert with a cluster headache. Like smoking with lung cancer. It’s a terrible idea.

 

[JemPD]

here's another symptom of mine of which I wonder about:

When I'm rested and at my baseline (no PEM) there's a certain level of activitiy that I can comfortably do. ... After this I sometimes feels like I hit a wall. It takes immense effort to push past it. It feels like my muscles are out of energy. Like my brain doesn't function anymore. 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. During PEM it's kind of the same as above, just that the threshold for hitting the wall is way lower.

But, when I'm already a bit stressed out at my baseline (short sleep, anxious, excited, or even just feeling great) the threshold for hitting the wall is higher and it's easier to do too much and trigger PEM (I get less warning signs).

Now what I find really curious is that it really feels like a sudden lack of energy (like my battery ran out), and that the only way to overcome it is through an excessive stress response (as if my body needs to tap into emergency reserves).

Do other people experience something similar?

Yes, exactly this.

(edited to remove the bit in Jesse's quote about cycling/working for 4 hrs as have never been able to do that much, but the bit about the certain amount of activity stands - the amount of activity that provoked hitting the wall has just got less as severity worsened as is usual)

 

[JemPD]

Yes. If you put a metal spike in a place where it would dig in and produce severe pain with a certain movement, as soon as the nervous system has logged that it is going to do that you will be incapable of
causing yourself severe pain by doing that movement. More commonly, if a torn muscle or tendon insertion produces severe pain from an injury it becomes impossible to override that.

Wow... so would that be the phenomenon that happened to me with my excrutiatingly painful "frozen shoulder"? To move my arm in particular ways higher than a certain point was incredibly painful for a few months, then one day it just stopped hurting and i bacame literally unable to lift my arm up higher than had been the point that caused the pain. Previously it had been the pain that limited my raising my arm, then overnight it went from agony to inability to lift it past the point where it used to hurt.

I thought it was very strange because there had been so trace of stiffness, just agony, and now i simply couldnt move it up past that point where the pain kicked in. It was a very odd experience it seemed to be stuck - rigidly prevented from raising (hence how it developed the term 'frozen' i suppose).
I must say it was very nice to be without the pain, because I kept triggering the pain by accident, and once the 'freeze' kicked in, all that happened was i found i couldnt reach the thing i was reaching for, couldnt put my elbow on the chair arm etc. Instead of realising I shouldnt & getting a jolt of agony while i tried to do it without thinking about it. It was a huge relief to have the thing essentially frozen to prevent my causing myself pain by inadvertently pushing my arm up too high/wrong direction.

Would that be an example of the phenomena you're describing?

 

[Kitty]

Yes, exactly this.

Me too, it's a good way to set it out.

 

[Jonathan Edwards]

Would that be an example of the phenomena you're describing?

Probably not in fact. Shoulder problems are various and difficult to sort out but 'frozen shoulder' is a name supposed to be restricted to a condition called adhesive capsulitis. The block to movement occurs because what should be a layer of highly mobile lycra-like lining tissue around the ball and socket joint suddenly becomes more like a plastic plaster cast. It may have to do with bleeding into the joint followed by fibrosis. So the shoulder will not even move if you are anaesthetised. In fact one treatment is to anaesthetise the person and deliberately tear the lining free again - which doesn't work very well, as might be expected. Another sort of shoulder problem is a tendon or cuff rupture where you cannot lift the arm because the tendon the does the lifting, which was under friction, has snapped (so doesn't hurt any more).

 

[hotblack]

On control of the body and overriding it two things come to mind

Firstly..

Do you choose when your heart beats? No, you can indirectly influence but there is no ‘I’ that controls it.

Can you stop yourself breathing? Or control how fast? There’s a mix but limits on your control. We certainly don’t consciously control our breath or heart while asleep.

Can you shut off pain by thinking to? Nope, maybe there’s a layer present of how much you focus on it, but severe pain takes that focus.

Do we control when liver, kidney or other organs produce chemicals or do all sorts of things essential to life? No.

There’s lots of things that just happen. A myriad of things out of our control.

Maybe someone will argue that’s a different part of the nervous system… but there are also a lot of things that are sometimes automatic or sometimes conscious.

More philosophically, there is no ‘I’ that is all knowing and all controlling. Emotions, thoughts, we don’t choose these, things spring into our minds and our bodies all the time. We can focus on something or do something which modifies them but if anyone says there is an ‘I’ that has complete control and choice over these things I would have questions.


Secondly

How about Parkinson’s or numerous other neurological conditions, they’re ‘just a signalling’ problem and yet have devastating physical impacts. I see this daily in a family member. Other ‘just signalling’ issues don’t get dismissed.


I think we give the BPS crowd far too much time and we’d benefit from being concerned about what they may think. Move on and focus on the greater group of rational people who we will be able to work with new knowledge and information. That’s going to be enough of a challenge but one we can make progress with. And telling them some signalling thing is broken would be accepted by the great many people.

 

[JemPD]

Me too, it's a good way to set it out.

lol @Jesse 's only been here 5 mins & he's started describing my own experience much better than I ever could!

They did it higher up on this thread too asking about stress hormones.
Cheers Jesse

 

[JemPD]

Probably not in fact. Shoulder problems are various and difficult to sort out but 'frozen shoulder' is a name supposed to be restricted to a condition called adhesive capsulitis. The block to movement occurs because what should be a layer of highly mobile lycra-like lining tissue around the ball and socket joint suddenly becomes more like a plastic plaster cast. It may have to do with bleeding into the joint followed by fibrosis. So the shoulder will not even move if you are anaesthetised. In fact one treatment is to anaesthetise the person and deliberately tear the lining free again - which doesn't work very well, as might be expected. Another sort of shoulder problem is a tendon or cuff rupture where you cannot lift the arm because the tendon the does the lifting, which was under friction, has snapped (so doesn't hurt any more).

Ah, thats interesting thanks, wont say more as off topic

 

[Sean]

I have only just seen this comment but this would absolutely 100% fit with what happened to me as a young man, and also explain the 'neuro-only' form of long covid that is observable in support groups.

Interesting. I had not heard of this. Thanks.

 

[Jesse]

lol @Jesse 's only been here 5 mins & he's started describing my own experience much better than I ever could!

They did it higher up on this thread too asking about stress hormones.
Cheers Jesse

Thanks for the kind words. I've spent a lot of times thinking, experimenting and analyzing my symptoms lol.

Also good to hear others have similar experiences. It's interesting because I've also read experiences of people that do not get any symptoms when overexerting and only get delayed symptoms. Which does happen to me too sometimes, but it's not necessarily the norm. Especially after I started focussing more on pacing, resting, staying out of stress mode it feels harder to (over)exert (which is both a good and a bad thing).

Edit: an example of the above would be that it's a lot easier to overexert myself doing very intense/explosive activity. Like let's say strenght training or running. These almost immediately trigger a stress response as well as endorphins etc. making me feel good and not feeling any warning/fatigue signals until many hours later. While if I went for a walk I would be much more sensitive to feeling I'm overdoing it at some point.

(edited to remove the bit in Jesse's quote about cycling/working for 4 hrs as have never been able to do that much, but the bit about the certain amount of activity stands - the amount of activity that provoked hitting the wall has just got less as severity worsened as is usual)

No worries I've become bedbound since

 

[Jesse]

@Jonathan Edwards let me know if I should stop tagging you on unanswered questions but I'll take my chances for now haha.

In the context of your hypothesis I think the part we talked about previously makes sense. Stress hormones can make us feel better and able to do more by overriding signals / inhibitions. Would it make sense that this also works the other way around? Like the example I gave in my previous post:

Now what I find really curious is that it really feels like a sudden lack of energy (like my battery ran out), and that the only way to overcome it is through an excessive stress response (as if my body needs to tap into emergency reserves).

Because it feels like this sympathetic activation is a response to a lack of available energy. Like if a person goes for a run the stress system gets activated to ramp up the required metabolism. Or if a person gets scared: to prepare to be able to fight or flight.

But why would this system get activated when I'm doing an activity that healthy people could sustain for hours (like walking or working) if there is no problem with metabolism? What could trigger this sudden feeling of complete depletion of energy? Could that also be signalling? And would it at all make sense that pushing through leads to an unavoidable excessive activation of the sympathetic nervous system?

I have even experimented with sedating drugs like benzos to see if calming this system allows me to do more without overexerting. And while it helps, I always seem to reach a point where it's either: stop the activity, rest and stay relaxed. Or: push through and get excessively stressed out with potential PEM as a consequence.

I'm also still trying to gauge how common my experience is. Maybe my nervous system is just very sensitive..
See the rest of my previous post for more context.

 

[JemPD]

's interesting because I've also read experiences of people that do not get any symptoms when overexerting and only get delayed symptoms

Yes this often happens to me when emotionally stressed at the outset - ie angry or scared. I won’t say I never hit the wall but it certainly takes a lot longer.

 

[Sean]

I won’t say I never hit the wall but it certainly takes a lot longer.

And the payback is greater.

 

[Jonathan Edwards]

But why would this system get activated when I'm doing an activity that healthy people could sustain for hours (like walking or working) if there is no problem with metabolism? What could trigger this sudden feeling of complete depletion of energy? Could that also be signalling?

I am suggesting that it may be due to a shift in neural signal responsiveness and that something similar may apply when you have the onset of flu. I rather like the idea of T cells making gamma interferon, upregulating FcRI on DRG nerves which then pick up antibodies that tell them to shift their sensitivity. Basically, the immune cells turn the 'squelch' knob (if you have ever used an old VHF radio) such that normal background signals become a deafening white noise NO signal.

We think that when we raise an arm our brain just sends a signal down the spinal cord that tells three muscles to contract and raise the arm. But the reality is way , way more complicated. The signal going down the spinal cord may actually be a negative signal that says 'specifically stop blocking the reflex arm-raising routine please'. The arm raising is done by a ring of nerve cells with highly sophisticated feedback loops, co-ordinating the action of each muscle in relation to the others.

If you damage the nerves that send signals down the spinal cord to move your arm the weird thing is that you end up with a stiff, spastic arm, that is permanently trying to do all movements at once. In the arm elbow flexion wins out and the arm bends up. In the leg extension wins and you have a stiff peg of a leg - which is what you always see for someone with a stroke affecting one side of the cortex.

 

[Andy]

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

 

[Jesse]

I am suggesting that it may be due to a shift in neural signal responsiveness and that something similar may apply when you have the onset of flu.

So could that responsiveness also directly cause symptoms on exertion (feeling depleted), rather than it being delayed like in PEM? Because to me there's a bit of distinction there. The depletion feeling feels more like a warning to stop and doesn't really include the malaise symptom like in PEM.

But I'm even more interested in the other part of my question on 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?