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

I agree with @ME/CFS Science Blog that ME/CFS is a “brain signaling disorder” but I believe that it is immunomediated.

Why?

Most/many ME/CFS patients respond (in some cases dramatically) to the dopamine system stabilizer drugs (Abilify, Rexulti, Vraylar, OSU-6162), indicating that there are postsynaptic signaling issues (@forestglip) causing symptoms.

But like psychiatric drugs, the effect ends when you stop taking them or when they poop out. If the poop out/tolerance phenomenon wasn’t so common then these drugs would be good treatment options for many.

By contrast, for the (limited number) of patients who responded to immuno drugs like dara and cyclo, the obvious neuro symptoms like fatigue and brain fog dissipate and the effects are (or can be) long lasting or possibly permanent, perhaps indicating a reset of certain aspects of the immune system.
 
Responding to deleted post suggesting muscle stiffness might indicate something happening in the muscles, not the brain.

Could the perception of muscle stiffness be caused by incorrect signals? For muscles to work properly, they need the correct signals with the correct timing. Getting a "contract" signal at the same time as a "relax" signal might cause the perception of stiffness or weakness or fatigue. It would also reduce muscle efficiency.
 
Last edited by a moderator:
forestglip said:
With all due caution regarding my attempt at the MAGMA gene set analysis, I just want to note that there's a further similarity to the Zhang results that might allow us to go a bit further than "synapse" to "postsynapse".

The most significant synapse related gene set is specifically "postsynaptic membrane". And gene sets 9 and 10 are "dendritic tree" and "somatodendritic compartment", with dendrites being the post synaptic extensions of a neuron that receive a signal (as opposed to the presynaptic axons that send a signal).

I previously remarked that there were a lot of postsynapse-related proteins near the top of the list from the Zhang model. 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:
Click to expand...
Just want to post the following because it slightly goes against the postsynapse specifically part. @hotblack and I managed to get standalone MAGMA working. The results were similar to doing it on FUMA, but not exactly the same (probably because of mapping to rs ids instead of liftover to grch37).

For gene sets, again none significant after correction, but when looking at the C5 gene set collection, the number one gene set was "GOBP presynaptic membrane assembly", which somewhat goes against that postsynaptic theory. Though it only consists of 6 genes (only 6 of 9 were also in the GWAS genes). There's also "GOBP presynaptic active zone organization" near the top with 11 genes in this analysis while it was ranked >2000 on FUMA.

Some of the other top gene sets still match the top gene sets I got on FUMA like "somatodendritic compartment" and "macrophage colony stimulating factor production", so not totally different.

Just wanted to add this so that no one discounts the presynapse because of what I posted.
 
Responding to a deleted post.

Noticeable 'stiffness' on stretching a muscle, technically known as increased 'tone' although confusingly so, is nearly always neural rather than muscle and mostly due to central reflexes.
I wouldn't trust an acupuncturist to report anything reliably!
 
Last edited by a moderator:
Replying to a post about muscle stiffness, present not only when stretching:

OK, but central causes of stiffness are not just when stretching either.
A crackling sound ("crepitus") is going to be coming from tendon or joint synovium flicking over rigid structures, sometimes in association with a local vacuum. It isn't a known association with muscle pathology as far as I know except in gas gangrene. For thirty years I stretched people's muscles as part of routine exams every day. I never felt crackling from muscles but most days there was some crackling from synovia.
 
Last edited by a moderator:
Replying to a deleted post about muscle stiffness being compared to that of professional athletes with repeated muscle strains and tears:

A friend of mine is a PT and he's said the exact same thing. He was shocked to hear that I spend most of my time sedentary given the state of my muscle mass.
 
Last edited by a moderator:
Whilst I can understand that people might be reluctant to such a model, because it might currently not be explain muscular problems in a straightforward way, there’s been an abundance of metabolic, muscular and so forth theories on ME/CFS but none of those have even tried to explain the “information processing problems in ME/CFS” (a bit like Rob Wüst saying he has no idea how the PEM that is reported after exercise and the things they are believing to see in muscles which they believe to be related, could be caused by cognitive activity).

@ME/CFS Science Blog raises the question: If the disability is even higher than in conditions that are muscular/metabolic/viral and the problem is supposed to be muscular/metabolic/viral or so forth why are we not seeing anything?

However, one can also have to ask this question to a neurological hypothesis: Say the problem are “broken synapses” as in the hypothesis by @chillier , should a brain scanning study tagging synapses not have to show a clear result? If the problem is something more of “hyperexcitable neural networks” why are we not seeing anything on EEG’s? My understanding is that in EEGs for epilepsy people have their “hyperexcitable neural networks” triggered (by looking at some display) and then the results are rather clear. Now one can argue that EEGs in ME/CFS haven’t found the “right trigger” (like an EEG before and after a CPET or an EEG before and after certain cognitive exercises), but the same argument put forward by @ME/CFS Science Blog here can also be used: If the disability put forward is larger then in epilepsy why are we not seeing anything? I'm not quite sure whether arguing about disability is really the right angle. If more subtle neurological problems can cause greater disability then in illnesses with more obvious neurological problems and clear pathology, can't the same apply to other theories and bodily systems as well?

I like the idea of pursuing the neurological angle a bit. Perhaps it might be sensible to forget about the physical/CPET angle in ME/CFS for a moment and try to understand what the cognitive problems in ME/CFS entail, devise a test on how they can be measured and in particular devise a test on how they can be triggered, somehow showing a descrepancy before and after trigger? If "hypersenstivity to sound" in some people with ME/CFS is supposed to share some features to "hypersenstivity to flashing lights" in epilepsy maybe those are the angles one wants to pursue for a bit.
 
What is not quite clear to me about a neurological hypothesis: Why are these problems apparently more common after glandular fever? How does EBV seemingly have more influence on synapses or neurons than other viral infections?

If we accept a comparison to something like a "ongoing sickness response", then I see no reason to also not see a similarity to the PVF that EBV causes in many people, but why is EBV particularly good at doing that?
 
EndME said:
If we accept a comparison to something like a "ongoing sickness response", then I see no reason to also not see a similarity to the PVF that EBV causes in many people, but why is EBV particularly good at doing that?
Click to expand...
EBV specifically seems to increase the risk of the neurological damage of MS, so maybe there's some common pathway, even if totally different neurological effects.
 
EndME said:
I'm not quite sure whether arguing about disability is really the right angle. If more subtle neurological problems can cause greater disability then in illnesses with more obvious neurological problems and clear pathology, can't the same apply to other theories and bodily systems as well?
Click to expand...

I don't think so. Other bodily systems tend to work in pretty predictable ways based on good functioning of structural and metabolic elements that we can study under isolation conditions. The brain isn't like that. There are lots of brain problems that produce very severe disability without any signs on EEG. The problems are presumably at a different level of functional organisation.

But I agree that the failure of muscle-based theories to explain cognitive PEM is something to think hard about.
 
forestglip said:
EBV specifically seems to increase the risk of the neurological damage of MS, so maybe there's some common pathway, even if totally different neurological effects.
Click to expand...
Yes, but if I'm not wrong the 2 theories for that are: Increasing the likelihood of "bad B-cells doing bad things" or "something to do with viral persistence" and of course these effects take place years, sometimes decades after infection so how could a common pathway look (especially if we don't want to make use of something like a B-cell theory).
 
Jonathan Edwards said:
I don't think so. Other bodily systems tend to work in pretty predictable ways based on good functioning of structural and metabolic elements that we can study under isolation conditions. The brain isn't like that. There are lots of brain problems that produce very severe disability without any signs on EEG. The problems are presumably at a different level of functional organisation.
Click to expand...
So in short, the argument might really only work in one way due to the complexity of the brain and the inability to somehow view it as isolated?
 
EndME said:
If we accept a comparison to something like a "ongoing sickness response", then I see no reason to also not see a similarity to the PVF that EBV causes in many people, but why is EBV particularly good at doing that?
Click to expand...

The immune response to EBV is quite different from and more prolonged than that for most infections. It involves a 'civil war' between activated B cells and cytotoxic T cells. The virus infects B cells and threatens to produce a generalised quasi-neoplastic polyclonal proliferation. It takes cytotoxic cells recognising EBV a while to expand and bring the infected B cell pool under control.

For most viruses the febrile period with major viraemia lasts no more than a few days. The febrile response in EBV infection can last a month. Immune cell expansion is sufficient to produce splenomegaly in a proportion. So the propensity to produce a protracted sickness response is not very surprising.

The link to MS is probably different in that the risk of MS continues long term, it seems, and is not directly linked to the infection period. That to me suggests that the quasi-neoplastic proliferative state of B cells remains a subclinical state that allows otherwise forbidden B cell clones to expand during future immune responses.
 
Jonathan Edwards said:
The immune response to EBV is quite different from and more prolonged than that for most infections. It involves a 'civil war' between activated B cells and cytotoxic T cells. The virus infects B cells and threatens to produce a generalised quasi-neoplastic polyclonal proliferation. It takes cytotoxic cells recognising EBV a while to expand and bring the infected B cell pool under control.

For most viruses the febrile period with major viraemia lasts no more than a few days. The febrile response in EBV infection can last a month. Immune cell expansion is sufficient to produce splenomegaly in a proportion. So the propensity to produce a protracted sickness response is not very surprising.
Click to expand...
Is the suggestion then simply that EBV is more likely to cause some problems in neurons/synapses because the febrile response takes longer, or will there be 2 separate arguments for why EBV is good at causing PVF and good at causing ME/CFS?
 
Jaybee00 said:
Most/many ME/CFS patients respond (in some cases dramatically) to the dopamine system stabilizer drugs (Abilify, Rexulti, Vraylar, OSU-6162), indicating that there are postsynaptic signaling issues (@forestglip) causing symptoms.
Click to expand...
Brain chemicals not only effect synaptic signaling, but they can also affect brain immune system. Microglial cells in particular have multiple dopamine receptors and there are several papers that say that dopamine downregulates microglial cells, even deactivating activated ones. So, the dopamine response doesn't necessarily indicate the signaling issue. It could indicate hypersensitive neuroimmune system issue just as well.

Jaybee00 said:
But like psychiatric drugs, the effect ends when you stop taking them or when they poop out. If the poop out/tolerance phenomenon wasn’t so common then these drugs would be good treatment options for many.
Click to expand...
There are ways to increase dopamine naturally. I'm sitting in my back porch as I type this hoping that more natural light, and being outdoors all day long, would promote dopamine.
 
ME/CFS Science Blog said:
Perhaps AIDS (before it was adequately treated) might also be a good comparison to highlight. This is an example of a persistent virus that causes widespread immune dysfunction, a popular theory in ME/CFS and Long Covid research.

Yet several physicians (Peterson, Klimas etc.) commented that AIDS patients only developed the same degree of debilitating symptoms as in ME/CFS around 2 months before their death. Meanwhile it caused opportunistic infections, rare cancers, muscle wasting, damages blood vessels, and dementia.

So even if we assume some non-brain pathology like a virus in ME/CFS it must be extraordinary good at causing symptoms without destroying or disrupting other functions in the body.
Click to expand...
I'm top end of severe grade but slowly deteriorating and recently have started to develop opportunistic infections.
 
You must log in or register to reply here.
Back
Top Bottom