The symptom signaling theory of ME/CFS involving neurons and their synapses

It sounds crackers, doesn't it?
I think it can be consistent with the sort of neurological models that are being proposed here, something along the lines of "A typically noisy network is calmed down by a specific firing constellation of neurons" (for example acting like a sink that removes too much excitation) but of course these constellations and systems are all somewhat outside of your control, just how you can't tell a person with dementia to just fire more neurons to remember stuff.
 
The mechanisms seem central (in the brain) rather than peripheral (in the muscle).
It leaves some room for subtle peripheral pathology because biology likes to recycle things in different parts of the body. So whatever is causing the synapses to go wrong might cause some (difficult to detect) disruptions elsewhere in the body. These might not seem related until we understand that the molecular parts used are the same.
Yes, I think this is an open question at this stage. Any peripheral features may well be downstream consequences of neuronal/synaptic dysregulation in the CNS.

Another feature that needs explaining is the often highly dynamic variability of symptom expression in short time frames.
 
I'm wondering if the delay exists because could be a fault in the repair mechanisms involved in fixing the wear and tear of the exertion,
The delay is a normal part of recovery. The cytokine signal to invoke the repair usually does not kick in till 12-24 hours later. That's why you get DOMS.

The recovery time would also be prolonged because of the faulty repair mechanisms.
3-4 days for recovery is normal. That coincides the typical PEM duration.

PEM is telling us that the issue is not during exertion but later.
PEM could be thought of as pathological response to the normal recovery/repair signal which is delayed and imperceptibly low for minimal exertion. It could be a hypersensitivity to normal low grade inflammation, in other words. That can also explain hypersensitivity to alcohol, flu shot, etc.

Why is exertion in particular perceived as problematic, and not for example, an ordinary flu?
Flu involves high grade inflammation. So, both healthy people with normal threshold and ME/CFS people with low threshold respond to it the same way. Think of it as a fire alarm with high/low tolerances. They will respond the same way to thick smoke. For minute amount of smoke, only the low tolerance alarm will go off.

If the problem is a distorted signal then it must be a signal
The problem is more likely with the sensor, not the signal. No pathological signal has been found in ME/CFS patients so far.

I sudpect it's metabolic
That wouldn't explain the PEM delay.
 
Nevertheless, I am interested in the phenomenon of unrefreshing sleep and have wondered if an ongoing problem with updating/deleting daily data (via synapses) may be part of the origin of symptoms in ME/CFS.
Flu patients wake up unrefreshed. If ME/CFS is chronic flu-like sickness, unrefreshing sleep being part of it wouldn't be that remarkable.
 
So to me, PEM is a response to glial response to immune activation.
That would be my pet theory, and it explains every symptom. But I can't rule out the possibility of brain/neurons being directly responding to immune signals without the mediation of glial cells. If there is a direct (bidirectional) communication between the brain and peripheral immune system as one recent paper claims, the mediation by neuroimmune cells may not be necessary.
 
Both rheumatoid arthritis and reactive seronegative arthritis can come in resolving forms lasting a few months. For rheumatoid the most common trigger is post-partum - after childbirth. For seronegative it is an intracellular infection. Both can also have life long forms.

To me the difference with ME/CFS from PVF is that PVF is basically monophasic. You may have good and bad days but you do not improve for weeks and then relapse for months before maybe impriving again and relapsing again. It seems like there is a prolonged period of around six months where infection signals can linger on. ME/CFS is more than that.
Rheumatic fever and Post-streptococcal glomerulonephritis also do this I believe, where they last months then resolve.

They seem to be autoimmune in nature but don’t develop into full autoimmunity for some reason.

Lots of people talk about post viral illnesses but I think it’s good to bring up this type of “post” immune challenge illness can happen with bacteria as well
 
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Rheumatic fever and Post-streptococcal glomerulonephritis also do this I believe, where they last months then resolve.

They seem to be autoimmune in nature but don’t develop into full autoimmunity for some reason.

Lots of people talk about post viral illnesses but I think it’s good to bring up this type of “post” immune challenge illness can happen with bacteria as well

A far as I remember, the acute syndrome of rheumatic fever resolves very rapidly once the organism has been cleared with antibiotics. I think it is probably an immune complex disease that is infective rather than post-infective, in that it requires foreign antigen to be present. Recovery of joints is usually quite rapid. Cardiac problems may take longer to resolve if there is carditis and of course late sequelae of valve scarring appear up to decades later.

I am less sure about PSGN but one would expect that also to beanimmune complex disease dependent on foreign antigen. Glomerular recovery may take months but the driving pathological process probably resolves as soon as bacteria are cleared.

I don't think we have evidence of autoimmunity in either, simply an immune response to foreign antigen that has knock on effects. The idea of molecular mimicry comes from rheumatic carditis but I don't think was ever substantiated.

Truly post-infective processes, that can go on actively for months mostly fall in to the spondarthropathy/ psoriasis group associated with MHCClass I. The inciting agent tends to be bacterial but intracellular.
 
Flu patients wake up unrefreshed.

Is that true, though?
My memory is that for febrile illness like flu there is normally a symptom profile with peaks at lunchtime and late evening, with corresponding fever. My memory of having flu is that the delirium of the night before tends to have passed and one is often quite good for a bit. You may still feel a bit grim but that may be because sleep was so disturbed.
 
Regarding a table of genes including neuroligin-1,

Checking again in the top 20 now, seeing if any are mainly related to synapses in a quick Wikipedia or GeneCards search, I see five, and all of them seem more involved with the postsynapse specifically:


Not necessarily exclusively though. Neuroligins are cell adhesion molecules that may be involved in immune cells also (both CNS and peripheral). They also relate to endothelial and vascular smooth muscle cells. There may be links to mitochondria. Eg vascular —

The synaptic proteins neurexins and neuroligins are widely expressed in the vascular system and contribute to its functions (2009, Proceedings of the National Academy of Sciences)

Genome-Wide Analysis of Blood Pressure Variability and Ischemic Stroke (2013, Stroke)
 
My hunch is to follow Ockham's razor, keep things simple, and only add things if we really need to. At this point, I think there is strong evidence of an immune trigger, but not necessarily of immune pathology maintaining the illness.
How does this square with the practicalities of basic science and clinical trials though? Are there experiments that could prove this model, or drugs that could treat it?

And both JE and Jnmaucich have said that the immune pathology that could underlie this might well not be detectable in the blood.

I'm not saying a 'brain only pathology' hypothesis is impossible by any means, but I don't know that a purely brain mediated feedback loop as opposed to an immune mediated one is the simpler or more logical explanation.

I understand whats brought you to that conclusion though and it's definitely a valid approach to take.
 
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I do believe that ME/CFS is predominantly a central nervous system issue, essentially a problem of the neurons and synapses, in how the network itself is functioning. (I do think there will be quite a bit of tissue damage, too, though.)

But at the same time, we haven’t covered all the possible roads outside the CNS. It could make sense, given the current data, to “Occam” the situation down to a network dysfunction in the CNS, but it could also be very foolish, since we may simply be missing the main puzzle piece(s) that tie(s) everything together.

Part of why the CNS/neuron/synapse angle hasn’t been explored more is practical: it’s extremely expensive, neurology as a field is biased against ME/CFS, and we lack proper models (cell, animal, organoid) to study this disease. That makes it very difficult to address the “hardware vs. software” problem in a network sense other than via beuroimaging techniques (many of which are disputed in their very usefulness). It’s frontier research, and the tools aren’t really there yet (for us).

So given all this, it actually makes a lot of sense that people investing money in ME/CFS research have not focused on the CNS. With such extreme resource constraints, it’s rational to put more emphasis on peripheral avenues that are cheaper and easier to explore. At the end of the day, it’s always a balance of cost-risk and cost-benefit – so until now, that may meant concentrating more on peripheral mechanisms, even if the real story ultimately lies in the CNS and its networks.

Saying all that, as a very severe ME/CFS patient, I personally put most of what little energy I have left for advocacy into trying to convince neurologists and neuroscientists to take this matter more seriously and actually do research on it.

Unfortunately, they still mostly dismiss the condition, but I see quite a bit of change in the under 50 year old segment of neurologists. I think this is one of the most important battles to fight next to fundraising (which is by far the most important, imo).

(If it is indeed mostly a CNS issue, much will come down to much more basic science than anyone of us could wish for, I am afraid. The Allen Institute is a body that does a lot of interesting stuff in that direction.)
 
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Flu involves high grade inflammation. So, both healthy people with normal threshold and ME/CFS people with low threshold respond to it the same way. Think of it as a fire alarm with high/low tolerances. They will respond the same way to thick smoke. For minute amount of smoke, only the low tolerance alarm will go off.
My flu experience is definitely far worse with ME. Like my heart starts going 140 and I feel like I’m dying. While pre-ME it was more just I feel groggy and sneezy.

While I know others paradoxically feel better in flu since ME?
 
I'm not saying a 'brain only pathology' hypothesis is impossible by any means, but I don't know that a purely brain mediated feedback loop as opposed to an immune mediated one is the simpler or more logical explanation.

I think this is an interesting pivotal question.
The attraction of continuing immune signalling in a 'loop' is maybe it could explain the delay in PEM through RNA and protein production. I am interested in the idea that temperature profiles might give us a clue there.
 
While I know others paradoxically feel better in flu since ME?
I have an interesting feature of ME in that the 24 hours or so before a flu or cold becomes obvious I usually (though not always) feel distinctly better, sometimes a lot. To the point where it has become a reasonably reliable indicator that a flu or cold is about to fire up.

Once the flu/cold kicks in fully it usually feels more like a normal flu/cold than ME.

This seems to support a key role for the immune system in ME/CFS.
 
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