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

[Jonathan Edwards]

To avoid an epilepsy-like phenomena one might invoke something that stops synchronisation or something of that sort but of course there's things that can allow for that given the complexity of possible dynamics.

Presumably loops of neural communication underlie obsessive behaviour or having Radio Gaga going in your head all day. We don't need to go near epilepsy.

 

[Braganca]

Presumably loops of neural communication underlie obsessive behaviour or having Radio Gaga going in your head all day. We don't need to go near epilepsy.

Yes.. Songs on repeat in my brain for days / weeks is such a problem for me that I cannot listen to music.. (also music causes immediate symptom exacerbation)

 

[Jonathan Edwards]

This discussion might be very vague, handwavy and a full of belief but of course an actual model would not be that (and nobody has ever even tried developing a neurological model of ME/CFS).

This is the point for me. And you may only need to be specific about one key thing. When we treated RA with rituximab we made a very simple prediction - that inflammation in RA was due to antibodies after all. Take away the antibodies and the patients felt wonderful.

If we think we are dealing with a signalling problem in brain, that may involve both cytokines and neurotransmitters, perhaps some rather local neuropeptide if we are lucky, then the theory allows for testing of inhibitors.

Nobody has ever seen an immune complex stimulate a macrophage to make TNF inside someone with RA, but it doesn't matter. The high-level analysis is all you need.

 

[EndME]

Whilst I find repeated Radio Gaga in the head quite an amusing analogy I find it to be quite a fitting abstraction for some of the problems pwME/CFS report.

 

[forestglip]

what about benzos.

I know very little about the specifics of how all these drugs work. I think ideally you'd test with a drug that reduces neuron firing relatively globally in the nervous system since we wouldn't know what specific neurons or regions might be more important.

A person would do an intense exercise, and take the drug so that it is active throughout the exercise and for a long time after, maybe up until a crash would be expected. I'd probably expect that it would prevent the "wired" feeling, but that might not necessarily mean it's turning off the "problem" circuit. And then see if in the following days there is a crash.

Of course, there'd be the issue of it being difficult to do any kind of blinding when the drug is a strong nervous system depressant.

And take the following with a huge grain of salt since it's just one isolated anecdote, but when I search "gabapentin" on Phoenix Rising, the second result from a few days ago is someone saying that taking it before exertion helps. Unfortunately, quickly scanning through the hundreds of other results, I didn't notice others that discussed this.

 

[Jonathan Edwards]

Snow Leopard seems to be arguing both that if the sense of 'fatigue' in ME/CFS was due to an error in brain circuit we could image it and, on another thread, that accounts of trying to do just that are not very helpful because they may reflect all sorts of epiphenomenal events. In other word you cannot tell if you are imaging the bit you want to blame. Can you calrify @Snow Leopard

 

[EndME]

The context of this thread for me is that it seems possible that there's genetic data pointing towards the brain rather than other things and quite possibly that things are different then elsewhere because not only is the illness different and nothing has revealed any anormalities yet, but even the genetic signals seem somewhat different. Those observations will certainly require more work and context to go from "maybe pointing towards the brain" to "making a prediction on what exactly could go wrong" but that's the whole point. I'm only just pushing out vague nonsense but I think it deserves mentioning that @ME/CFS Science Blog opened this thread in part because nobody seems to have ever thought about this properly and to encourage that. Personally, I'd probably feel much less inclined to push out wish-washy stuff if someone had already invested serious thought into this.

If anything I hope someone smart somewhere is able to see these things as an invitation to think differently for a moment.

 

[jnmaciuch]

The context of this thread for me is that it seems possible that there's genetic data pointing towards the brain rather than other things and quite possibly that things are different then elsewhere because not only is the illness different and nothing has revealed any anormalities yet, but even the genetic signals seem somewhat different. Those observations will certainly require more work and context to go from "maybe pointing towards the brain" to "making a prediction on what exactly could go wrong" but that's the whole point. I'm only just pushing out vague nonsense but I think it deserves mentioning that @ME/CFS Science Blog opened this thread in part because nobody seems to have ever thought about this properly and to encourage that. Personally, I'd probably feel much less inclined to push out wish-washy stuff if someone had already invested serious thought into this.

For what it’s worth, my thoughts on the subject come from chatting with quite a few experts in the field about the possibility of studying neuroscience under them to solve the illness. And what I walked away with is essentially what I’m saying now—in order to test any of the specific ideas I had, I’d need to wait years if not decades for more advanced understanding across the whole field of neuroscience.

Even the suggestions for testable hypotheses they provided me didn’t come remotely close towards understanding how the illness could be treated. They were the ones who basically said that if you were absolutely certain the problem is somewhere abstract in the brain, it’s a “throw medications at a wall and see what sticks” scenario to try to guess relevant signaling networks. I don’t believe for a second that there’s simply a lack of neuroscientists who have even considered ME/CFS—I was shocked by the amount I talked to who already knew about it. I think it’s more of an issue of anyone legitimate who might be interested in the question realizes that there’s not much to be done currently. Even the neuroscientist who runs the long covid research program at my university is no longer going in a neuroscience direction.

Maybe I just didn’t talk to enough neuroscientists, I’d be happy for someone with robust experience in the field to give a different perspective with more concrete details. But ultimately there’s a reason why I personally chose a different direction. I don’t see any reason to believe that complex brain loops are the only logical place to look for a pathological mechanism and it seemed silly to throw my eggs in that basket if I wasn’t already enamored with the brain.

 

[Holinger]

And take the following with a huge grain of salt since it's just one isolated anecdote, but when I search "gabapentin" on Phoenix Rising, the second result from a few days ago is someone saying that taking it before exertion helps. Unfortunately, quickly scanning through the hundreds of other results, I didn't notice others that discussed this.

My 2 cents worth. Unfortunately gabapentinoids don’t do anything like that. They may ease suffering during a crash at best.

 

[Utsikt]

For what it’s worth, my thoughts on the subject come from chatting with quite a few experts in the field about the possibility of studying neuroscience under them to solve the illness. And what I walked away with is essentially what I’m saying now—in order to test any of the specific ideas I had, I’d need to wait years if not decades for more advanced understanding across the whole field of neuroscience.

Even the suggestions for testable hypotheses they provided me didn’t come remotely close towards understanding how the illness could be treated. They were the ones who basically said that if you were absolutely certain the problem is somewhere abstract in the brain, it’s a “throw medications at a wall and see what sticks” scenario to try to guess relevant signaling networks. I don’t believe for a second that there’s simply a lack of neuroscientists who have even considered ME/CFS—I was shocked by the amount I talked to who already knew about it. I think it’s more of an issue of anyone legitimate who might be interested in the question realizes that there’s not much to be done currently. Even the neuroscientist who runs the long covid research program at my university is no longer going in a neuroscience direction.

Maybe I just didn’t talk to enough neuroscientists, I’d be happy for someone with robust experience in the field to give a different perspective with more concrete details. But ultimately there’s a reason why I personally chose a different direction. I don’t see any reason to believe that complex brain loops are the only logical place to look for a pathological mechanism and it seemed silly to throw my eggs in that basket if I wasn’t already enamored with the brain.

Isn’t that kind of the equivalent to only looking for the lost keys under the street lamps?

Besides, who knows if we need to understand exactly what’s going on in the brain in order to treat it? If SequenceME comes up with specific genes, we might be able to go from throwing spagetti at the wall to throwing tailor made molecules at it.

If that doesn’t work, and it turns out that ME/CFS is in the brain, and it can’t be treated by targeting downstream processes, we might have to do the neuroscience after all.

 

[EndME]

For what it’s worth, my thoughts on the subject come from chatting with quite a few experts in the field about the possibility of studying neuroscience under them to solve the illness. And what I walked away with is essentially what I’m saying now—in order to test any of the specific ideas I had, I’d need to wait years if not decades for more advanced understanding across the whole field of neuroscience.

Maybe I just didn’t talk to enough neuroscientists, I’d be happy for someone with robust experience in the field to give a different perspective with more concrete details.

I chose to not accept a neuroscience position a couple of years ago, before falling ill, for very similar reasons and decided to rather go somewhere else, essentially because I didn't feel like studying my favorite abstractions of Hodgkin-Huxely without any relevance, but at the same time I find it possible, even if not very likely, that with some necessary further observations one higher level prediction can already get yourself quite far.

But ultimately there’s a reason why I personally chose a different direction. I don’t see any reason to believe that complex brain loops are the only logical place to look for a pathological mechanism and it seemed silly to throw my eggs in that basket if I wasn’t already enamored with the brain.

That seems like the most sensible and rationale approach to me, I think it would be very delusional to say to anbody "you should become a neuroscientist if you want to solve ME/CFS" but of course that doesn't matter to the nature of the problem which doesn't care whom it is being studied by.

 

[jnmaciuch]

If that doesn’t work, and it turns out that ME/CFS is in the brain, and it can’t be treated by targeting downstream processes, we might have to do the neuroscience after all.

Sure, but you’d have to wait for neuroscience as a field to develop much farther anyways to answer the vast majority of viable questions related to ME/CFS. So my choice was either to spend my whole career doing basic science that could maybe one day contribute to a complex neurological answer on the off chance that’s where the answer is, or look into other more accessible but equally (or more promising) perspectives.

Thankfully I’m not the only scientist in the world so it doesn’t particularly matter where I choose to devote my time in the grand scheme of things. But if the heart of this thread is asking why there isn’t much neuroscience focus in ME/CFS when it might seem like a promising direction from the outside, I’m basically just trying to give perspective for why that might be, and why it’s not a simple matter of “well nobody has thought about it seriously or no good neuroscientist has been interested”

 

[Utsikt]

Sure, but you’d have to wait for neuroscience as a field to develop much farther anyways to answer the vast majority of viable questions related to ME/CFS. So my choice was either to spend my whole career doing basic science that could maybe one day contribute to a complex neurological answer on the off chance that’s where the answer is, or look into other more accessible but equally (or more promising) perspectives.

Thankfully I’m not the only scientist in the world so it doesn’t particularly matter where I choose to devote my time in the grand scheme of things. But if the heart of this thread is asking why there isn’t much neuroscience focus in ME/CFS when it might seem like a promising direction from the outside, I’m basically just trying to give perspective for why that might be, and why it’s not a simple matter of “well nobody has thought about it seriously or no good neuroscientist has been interested”

I completely understand the rationale for going a different route on a personal level.

But that’s a different question compared to «what’s the most plausible explanation of ME/CFS».

My worry as someone on the sideline, is that most science people will focus on their speciality, instead or trying to follow the logical conclusions from all of the evidence. So we might end up looking in the wrong places because it was more convenient to go looking there.

I don’t know if that actually happens, but it seems inevitable that it will happen with diseases that we haven’t been able to pin down already.

Although getting the broader category right might not be enough, as JE showed with RA and the B vs T cells divide. Plenty of immunologists were barking up the wrong tree.

 

[jnmaciuch]

I completely understand the rationale for going a different route on a personal level.

But that’s a different question compared to «what’s the most plausible explanation of ME/CFS».

My worry as someone on the sideline, is that most science people will focus on their speciality, instead or trying to follow the logical conclusions from all of the evidence. So we might end up looking in the wrong places because it was more convenient to go looking there.

I don’t know if that actually happens, but it seems inevitable that it will happen with diseases that we haven’t been able to pin down already.

Although getting the broader category right might not be enough, as JE showed with RA and the B vs T cells divide. Plenty of immunologists were barking up the wrong tree.

I don’t think that’s a particular worry here—if it is something immune acting on the brain, then the techniques that would uncover that mechanism are almost certainly going to be methods employed in immunology. If it does happen to be something that is purely abstractly neurological, then the research that needs to be done is a buttload of basic neuroscience. Which is already being done and won’t particularly go any faster with our advocacy. If the tools exist, people use them.

But I don’t think it’s necessarily a matter of convenience or wanting to stay in one’s field—I’ve seen plenty of scientists make hard rights in their career path based on where the questions take them. If neuroscience advances drastically in the next few years and a neurological explanation looks like the only viable one for ME/CFS, I’ll personally jump ship in a heart beat. I think the particular issue with this flavor of “neuroscience” we’ve been discussing is not that it’s hard but that there’s nowhere to take a hard-right to in that direction

 

[Sasha]

my thoughts on the subject come from chatting with quite a few experts in the field about the possibility of studying neuroscience under them to solve the illness. And what I walked away with is essentially what I’m saying now—in order to test any of the specific ideas I had, I’d need to wait years if not decades for more advanced understanding across the whole field of neuroscience.

Even the suggestions for testable hypotheses they provided me didn’t come remotely close towards understanding how the illness could be treated. They were the ones who basically said that if you were absolutely certain the problem is somewhere abstract in the brain, it’s a “throw medications at a wall and see what sticks” scenario to try to guess relevant signaling networks.

Thanks for telling us about this - this is fascinating. An ignorant question from me - is it likely that the use of AI will accelerate this field to a useful degree for us in the next few years?

 

[chillier]

But the important part of the epilepsy-like phenomena I’m referring to here is that repeated firing of the same single neuron would cause death in that neuron as it effectively doesn’t have time to recoup metabolic homeostasis. Restoring action potentials is one of the most (if not the most) ATP-demanding cellular activity in the human body, not to mention the time needed to restore ion gradients themselves. If a neuron can’t do this [edit: and keeps firing, it dies because it can’t keep up with basic processes for keeping the cell alive].

But this would be the most extreme possible scenario and I dont think is what is being suggested here. You could have subsets of neurons fire more without them having to die.

Maybe I just didn’t talk to enough neuroscientists, I’d be happy for someone with robust experience in the field to give a different perspective with more concrete details. But ultimately there’s a reason why I personally chose a different direction. I don’t see any reason to believe that complex brain loops are the only logical place to look for a pathological mechanism and it seemed silly to throw my eggs in that basket if I wasn’t already enamored with the brain.

It does sound like a bad situation doesn't it... but I agree with you, I dont think it has to be that, or a generalised hyperexcitability either. The idea I suggested on the 'list of hypotheses' thread was about how the threshold for excitotoxicity or synaptic downscaling could be reduced in pwME leading in some way to long term PEM dynamics. I would be curious for people to poke holes in it.

How about something like this as a model for how fragile synapses could produce ME/CFS like disease dynamics:



- Using here a hypothetical set up of two neurons that could explain the dynamics of PEM, and how you to get locked into a disease state that could be escapable in some situations. Obviously it would have to scale up to many neurons.

- assuming that the problem the genetics point to with synapses is that they are fragile and prone to downscaling, breakdown, and/or loss of connectivity.

- There would be a threshold you cross that leads to the disease state based on the ratio of rate of synapse breakdown:rate of synapse repair

- Neuron A is the presynaptic neuron that connects to the postsynaptic neuron: Neuron B

- When neuron A fires it triggers neuron B to fire, in the process the AB synapse would be slightly weakened because of local downscaling of the postsynapse. This weakening could be made more pronounced by genetic background (lack of energy supply, loss of shank complex, lack of receptor recycling etc)

- In steady state conditions the maintenance and repair of the synapse would balance the downscaling due to the firing of neuron A.

- If neuron A bombards synapse AB with signal, firing again and again, synapse repair would not keep up and the synapse loses a lot if not all of its ability to signal.

- The rate of synapse repair would not be constant, and would be much slower for a highly compromised synapse, and now even if neuron A returns to a normal or low level of firing, it is now still too much for synapse repair to keep up with, and we are now trapped in this state, unless neuron A massively reduces its firing rate to not interfere with synapse repair (aka, forcing the individual to rest).

- meanwhile, over the next 24-48 hours, neuron B realises it has lost signal from neuron A and is not firing as much as it was previously. To maintain homeostatic firing rates, neuron B would increase its sensitivity (via global synaptic upscaling of all the other synapses and other changes) and start amplifying and firing noise. In this way you could have a loss of signal that leads to things like brain fog, but also in other situations things like sensitivity to bright lights, that all occur on a PEM timescale.

- To knock someone into a disease state, you would either need excessing firing of a neuron(s) (achievable by acetylcholinesterase inhibitors or overtraining), or an increased fragility of the synapse (maybe inducible by inteferon??). Having both would help.

- Once you're in the disease state, you're in a trap where if your neurons fire much more, it pushes you further into the disease state, repeatedly inducing PEM as it does, tightening the trap each time.

I've said this before but problems with autophagy, protein degradation, redox and the types of onset including head trauma and organophosphates suggest there could be some problem with neurons actually being a bit fragile and easy to damage. I want to look again at the spermine findings too.

 

[jnmaciuch]

But this would be the most extreme possible scenario and I dont think is what is being suggested here. You could have subsets of neurons fire more without them having to die.

Like I said earlier this was specifically in response to the idea that if a constantly active brain loop was causing ME/CFS, it hasn’t been detected so far because it is on the scale of a tiny cluster of neurons.

It does sound like a bad situation doesn't it... but I agree with you, I dont think it has to be that, or a generalised hyperexcitability either. The idea I suggested on the 'list of hypotheses' thread was about how the threshold for excitotoxicity or synaptic downscaling could be reduced in pwME leading in some way to long term PEM dynamics. I would be curious for people to poke holes in it.

I've said this before but problems with autophagy, protein degradation, redox and the types of onset including head trauma and organophosphates suggest there could be some problem with neurons actually being a bit fragile and easy to damage. I want to look again at the spermine findings t

sure, lots of things could affect neuron function and I don’t disagree with you on that.

If it is a general phenomenon affecting the basic function of all neurons to some degree then that would be much easier to sort out because it could be modeled in vitro. If it’s a specific neurological process like what has been discussed in this thread, though, that would take a lot more basic neuroscience to even zero in on. hoping for the former, I guess

[Edited for clarity since I initially misinterpreted one part of your reply]

 

[jnmaciuch]

Thanks for telling us about this - this is fascinating. An ignorant question from me - is it likely that the use of AI will accelerate this field to a useful degree for us in the next few years?

Unfortunately I’ve become somewhat of an AI pessimist while being forced to use it despite it continually giving me garbage, so my answer will always be “I’ll believe AI will be useful in that specific context when I see it”.

 

[Snow Leopard]

Snow Leopard seems to be arguing both that if the sense of 'fatigue' in ME/CFS was due to an error in brain circuit we could image it and, on another thread, that accounts of trying to do just that are not very helpful because they may reflect all sorts of epiphenomenal events. In other word you cannot tell if you are imaging the bit you want to blame. Can you calrify @Snow Leopard

That is a misunderstanding,

Forestglip posted a hypothesis:

impaired ability to turn off excitatory neural circuits (or alternatively, inappropriate activation of these circuits)?

I argued that we don't see any ***consistent*** patterns like that in brain imaging studies.

"selective excitation of a small proportion of neurons" in the brain isn't what we are talking about and I don't see how that would cause the hypothesised fatigue anyway.

I'm simply not interested in untestable hypotheses and you shouldn't be either.

There must be a neural correlate for subjective experiences. To me your second sentence provides an example of that, assuming reduced excitability of motor cortex always correlates with the subjective feeling of fatigue. If it doesn't, then there must be other neurons elsewhere that do.



So am I right in saying that the point you are disputing is there being a global increase in excitability that affects the whole brain, or certain whole brain regions? That seems like a fair point, but isn't the same as talking about hyperexcitability of particular circuits or individual neurons. In the example you give, the peripheral afferents could be hyperexcitable right? something like that would be consistent with what forestglip originally said (albeit in the periphery in that case) :

If the peripheral afferents are hyperexcitable, that isn't a brain problem.

The reduced excitability of the motor cortex isn't the same as the sensation of fatigue, though it can co-occur. It's a result of metabolic sensing in the muscle and the purpose is to require increased effort to maintain activity, which also results in increased ventilation per the amount of muscular force at the same time.

Which is part of my point, there doesn't seem to be any consistent magic brain "fatigue" sensation pattern, only behavioural responses to fatigue.

That seems like the most sensible and rationale approach to me, I think it would be very delusional to say to anbody "you should become a neuroscientist if you want to solve ME/CFS" but of course that doesn't matter to the nature of the problem which doesn't care whom it is being studied by.

That is literally what an 'expert' in Australia told me - if I want to understand ME/CFS I must study neuroscience. (Rob Loblay - colleague of Hickie, Lloyd)

There are breakthroughs happening in neuroscience right now - uncovering the mechanisms of neurovascular coupling - and that might provide more clues than the other vague, often untestable hypotheses about 'signalling'.

Although getting the broader category right might not be enough, as JE showed with RA and the B vs T cells divide. Plenty of immunologists were barking up the wrong tree.

The mistake was they (the T-cell people) were making untestable assumptions/hypotheses, it was simply putative. Whereas the B-cell stuff was demonstrable.

The first genuine link to show T-cell autoimmunity was a subset of Guillain Barre Syndrome patients, where they demonstrated T-cell receptor autoreactivity through sequencing in 2024. Interestingly, those who had T-cell autoreactivity didn't have autoantibodies and vice versa.

But for the analogy to hold, the people who putatively insist that ME/CFS must be a problem with the brain but say that it needs future breakthroughs in neuroscience or whatever to demonstrate are more likely to be on the wrong side of history.

 

[Braganca]

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