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

[Utsikt]

For me it feels more like a “brain” or “energy” limit than a muscle limit. Take an example of “paralysis”-like which happened to me at one point when extremely severe. The problem didn’t feel like it was weakness or cramping, it was subjectively that I was unable to concentrate or have the energy, to properly give my brain the signal to move. So in a sense my it felt like my subjective stream of consciousness was unable to properly get the body to do what I wanted it to. Almost locked in like.

I’ve spoken on this in a very severe Me group and this wasn’t the only experience interestingly. A lot of people related.

I’ve had the same on three occasions, but it was only for a few hours at a time.

It’s been too long since I’ve actually pushed my muscles to failure, so I can’t remember exactly what it felt like.

 

[ME/CFS Science Blog]

• a part of the brain that integrates information on the body's health to understand the overall level of sickness/injury/functional capacity/energy reserves/etc. is receiving distorted signals
• this part of the brain is also involved in creating various awful and unpleasant feelings, in response to sickness/etc. that also alter the behaviour of the person.

Or are you saying that the distortion happens in the part of the brain, and not somewhere along the transmission?

For simplicity, I would place the pathology in (or as close to) the symptom-causing pathway itself. The pathways that interpret/evaluate signals coming from the body or help with the transmission of those signals seem less crucial.

That sounds similar to a biological version of the psychological model that has been applied to ME/CFS.

A major difference is that thoughts and behavior do not really play a role in this theory, while it's central to the BPS theory of ME/CFS.

And in this theory, the pathology is caused by an immune response (e.g., to an infection) while in the BPS theory, the infection only acts as a trigger because it causes resting behavior and unhelpful beliefs.

The main view that they have in common is that there's no clear peripheral pathology, and so the reason for symptoms lies in the brain.

Why is exertion in particular perceived as problematic, and not for example, an ordinary flu?

Perhaps because exertion is mostly voluntary and less essential compared to the response to the flu, hence less need to provide a negative feedback effect for it.

If the signal triggered by the flu received by the brain was as amplified in a similar way as the effect of exertion, even ordinary infections would be horrible experiences.

I suspect that for many patients, they are. But because healthy people also feel worse after an infection, it isn't seen as a particular phenomenon like PEM, just the add-on effect of a chronic illness + infection making you feel extra bad.

 

[ME/CFS Science Blog]

Would this theory imply that (what we currently call) ME/CFS and post-viral fatigue/illness are the same thing, just that in some people it resolves fairly quickly and in others it doesn't?

Could be both, I guess. My hunch is that they are different. For example that post-viral fatigue results in pressing the button of the symptom signal a bit longer, while ME/CFS is mainly about the button being broken (and constantly on).

 

[ME/CFS Science Blog]

Can this theory also explain how so many of us have peripheral immune symptoms and comorbidites after getting ME? MCAS, worsening of preexisting autoimmune or autoinflammatory disorders, sudden new autoimmunity. Could central signaling issues directly trigger these?

I don't think so. I think if we found strong evidence of things like this, it would refute the theory.

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.

It also leaves room for pathologies like immune signalling that we cannot detect and cause the errors in the brain but since we do not have evidence for this yet, it's easier to just expect the main pathology to be in the neurons.

 

[Utsikt]

Could be both, I guess. My hunch is that they are different. For example that post-viral fatigue results in pressing the button of the symptom signal a bit longer, while ME/CFS is mainly about the button being broken (and constantly on).

Can’t PVF last for months or even years? That seems like more than «a bit longer», and I’m not sure how you’d distinguish that from where the button is just broken.

Do we know of other illnesses that spontaneously resolves within a year or two? Are there any common threads with those?

 

[Yann04]

I can understand how this theory fits well with recovery rates, ie. when the neural pathway isn’t too established recovery is somewhat common but with time or severity if the pathway gets quite established it would be harder to “turn off”.

But I’m not sure I see how it can explain the fluctuations some experience. Like how can the pathway go from counting eating with a spoon as surpassing the threshold for the “button” to like being fine unless someone tries to bike. Like some people have illness patters where theyre changing severity a lot.

 

[Jonathan Edwards]

Do we know of other illnesses that spontaneously resolves within a year or two? Are there any common threads with those?

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.

 

[ME/CFS Science Blog]

My first impression is that I think it may be quite hard to construct a testable theory from this, given the vast complexity of the brain and that "something faulty in neurological signaling related to synapses" still seems quite vague for the beginning.

Yes, the theory isn't very specific, but I don't think anyone can be at this stage.

It does predict that studying the neural pathways that cause sickness behavior and synapse communication involved in this will be more fruitful for ME/CFS than all the things the field is pursuing now.

I think the main points I outlined are pretty straightforward, logical, and based on the (few) reliable data that we have. Yet the entire field seems to be pursuing almost everything else but this, and in (what seems to be at least) a chaotic, non-systematic way. Blood clots, endothelial dysfunction, reduced blood flow and hypoxia, viral persistence, antibodies, mitochondrial dysfunction, red blood cell deformity, the mTOR pathway, reduced microbiome diversity, CCI, mRNI, extracellular vesicle cargo, invasive cardiopulmonary exercise testing, etc. Most of these do not fit well with the framework and datapoints that we already have about ME/CFS. Not saying they should not be studied or that it is foolish to do so, but they do not seem the most obvious places to look.

Part of it is probably that brain neurology is hard to study.

Suppose ME/CFS is similar to a ongoing sickness response in acute infection, does one then see if one can characterise a sickness response in mice and see which drugs can elevate this response?

Yes, this sounds interesting. I haven't read much about what is known about this. Hope this is something that we can pursue more on the forum.

 

[Jonathan Edwards]

Suppose ME/CFS is similar to a ongoing sickness response in acute infection, does one then see if one can characterise a sickness response in mice and see which drugs can elevate this response?

I would be careful about using terms like sickness response. The mouse scientist may say 'ah, yes, I know how to induce that, whack in some TNF'. But we are pretty sure that we are not dealing with systemic circulating TNF. So you would get the wrong answers. Sickness response includes fever, which is not a regular feature of ME/CFS, even when severe.

It may be the right ball park but scientists so easily go off at a tangent with inappropriate models.

 

[Utsikt]

So you would get the wrong answers. Sickness response includes fever, which is not a regular feature of ME/CFS, even when severe.

I thought fever was common when in PEM? I get it every time.

 

[Jonathan Edwards]

I thought fever was common when in PEM? I get it every time.

What temperature does it go to?

I don't think fever has been documented reliably in ME//CFS. If it hasn't and it occurs then it is about time it was documented. It would be of crucial importance to our understanding.

 

[EndME]

I thought fever was common when in PEM? I get it every time.

I think there is no evidence of this and that such evidence should be easy to establish. I think there is the fact that people feel hot or feel like there is temperature dysregulation, but that might be something rather different to actual fever.

 

[OrganicChilli]

Yet the entire field seems to be pursuing almost everything else but this, and in (what seems to be at least) a chaotic, non-systematic way.

Do you think DecodeME will bring in new researchers with new approaches, or that existing groups will change their main focus? And what are some practical ideas to test your hypothesis?

 

[EndME]

Do you think DecodeME will bring in new researchers with new approaches, or that existing groups will change their main focus?

Computational neuroscientists love to model things with no practical relevance, so they might have a field day here.

 

[Utsikt]

What temperature does it go to?

No idea, I haven’t measured it regularly. I don’t think it’s that high.

Maybe I’ll get one of the no touch thermometers so I can measure myself without the whole sanitising ordeal.

 

[EndME]

Maybe I’ll get one of the no touch thermometers so I can measure myself without the whole sanitising ordeal.

Underarmpit temperature should have a good enough accuracy to tell you whether it's a thing, without having any extra hassle. Is that not what most people do?

 

[forestglip]

A gene set analysis pointed to the synaptic membrane.

Neurons and their synapses were also highlighted by the Zhang et al. preprint by the group of Michael Synder.

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:

Rank in Zhang et al HEAL2	Gene	Quote	Link
6	SYNGAP1	"SynGAP1 is shown to localize at the postsynaptic density on the dendritic spines of excitatory synapses."	- https://en.wikipedia.org/wiki/SYNGAP1
8	NLGN1	"has been shown to localize to the postsynaptic compartment at excitatory synapses"	- https://en.wikipedia.org/wiki/NLGN1
9	DLGAP4	"membrane-associated guanylate kinase found at the postsynaptic density in neuronal cells."	- https://en.wikipedia.org/wiki/DLGAP4
13	SHARPIN	"Sharpin is enriched in the [postsynaptic density]"	- https://www.sciencedirect.com/science/article/abs/pii/S1044743100909400
19	CAMK2A	"Activated CaMKIIα is targeted to dendritic spines and the postsynaptic density"	- https://pmc.ncbi.nlm.nih.gov/articles/PMC5338762/

 

[Utsikt]

Underarmpit temperature should have a good enough accuracy to tell you whether it's a thing, without having any extra hassle. Is that not what most people do?

Never even heard of that! Might be a me thing. I’ll look into it, it sounds a lot easier to get done on my own.

 

[forestglip]

We have moved some posts about whether people experience fever as a part of PEM to a new thread:

Do you have fever as a part of PEM?

 

[Kitty]

So if I'm understanding you correctly doing a specific very task that is largely cognitive in nature often let's you get normal sleep and you wake in a way akin to healthy people, whilst pretty much all other tasks give you "ME/CFS unrefreshed sleep, foggy brain and ME/CFS symptoms the next day". So if ME/CFS was some sort of "neurological sleep-reparation process dysfunction" there's some process that let's the "neurological sleep-reparation process dysfunction" work normally for a bit.

It sounds crackers, doesn't it?

I think it could be simpler than that, though. Maybe the ME/CFS brake doesn't normally allow us to get properly tired; fatigue forces us to stop way before we get there. Perhaps the "in the zone" type concentration you need to play from memory with a group of people is able to causes tiredness without triggering PEM.

I dunno. All I know is that when it happens it's brilliant, and it really underlines just how terrible ME/CFS sleep is!