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

[jnmaciuch]

A single neuron or even a small circuit potentially causing ME/CFS symptoms is improbable, because of basic mechanisms that prevent repeated firing and subsequent metabolic injury. It doesn’t take much firing to cause a build up of inhibitory adenosine that suppresses continued firing (discussed here). A failure of this fundamental mechanism would most likely result in epilepsy-like phenomena and neuronal death.

The parts of the brain that need to continuously fire likely manage this by spreading out the load over a larger group of neurons. So in order to keep up a sustained signal which is as constant as our symptoms, it would need to be a larger neural circuit. Which then begs the question that Snow Leopard brought up—even crude techniques are capable of seeing e.g. continuous activity in the medulla.

"Fatigue" doesn't have to be "encoded" at all. We do know that feedback from peripheral afferents in muscles reduces the excitability of the motor cortex (this is central fatigue).

I agree, it is only an assumption that all perceptions/neural phenomena creating noticeable changes are inherently the result of “de novo” neuron firing as opposed to just modulation of existing firing patterns—which could be caused by something like cytokines acting on many regions of the brain, if the paper I posted earlier on meningeal CXCR5 mediating sickness behavior in mice is any indication.

 

[chillier]

You are going to have to explain this to me because (a) we haven't seen it and (b) what are we supposed to see? "Fatigue" doesn't have to be "encoded" at all. We do know that feedback from peripheral afferents in muscles reduces the excitability of the motor cortex (this is central fatigue).

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.

But reduced excitability is quite different from the hypothesis that was impaired ability to turn off excitatory neural circuit/inappropriate activation of those circuits (so they are over active).



The hypothesis was about excessive excitation of certain regions of the brain though and that has metabolic signs that show up in imaging.

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) :

What if ME/CFS is an impaired ability to turn off excitatory neural circuits (or alternatively, inappropriate activation of these circuits)?

 

[Yann04]

gabapentin

what about benzos.

Another thought I’ve had is maybe we’ve been missing effects like this because we only consider drugs that lead to improvement, instead of drugs that prevent permanent/long term worsenings like MS.

 

[EndME]

A failure of this fundamental mechanism would most likely result in epilepsy-like phenomena and neuronal death.

I think it is quite clear that any model would have to avoid such scenarios, but I wouldn't see why there's not enough wiggle room for them to exist but that's probably something where serious neuroscientists have to get involved. 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.

And of course nobody can see any signals in people with CTE related to tremors, but the people are still shaking. Of course things will have to make sense w.r.t. ME/CFS and that's where the details matter.

 

[Yann04]

For what it’s worth I’ve noticed I get tremors whenever I have the wired feeling forestglip mentions.

 

[jnmaciuch]

I think it is quite clear that any model would have to avoid such scenarios, but I wouldn't see why there's not enough wiggle room for them to exist but that's probably something where serious neuroscientists have to get involved. 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.

And of course nobody can see any signals in people with CTE related to tremors, but the people are still shaking. Of course things will have to make sense w.r.t. ME/CFS and that's where the details matter.

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].

My point is more that in order for this idea to be viable, it couldn’t possibly originate from a single neuron or even small cluster of neurons [edit: that would escape detection easily]. So then you’d need a pretty good explanation for why a continuous firing pattern from a large cluster of neurons hasn’t been noticed already.

 

[forestglip]

My point is more that in order for this idea to be viable, it couldn’t possibly originate from a single neuron or even small cluster of neurons. And then you’d need a pretty good explanation for why a continuous firing pattern from a large cluster of neurons hasn’t been noticed already.

The idea is basically something like every time a person does any kind of exertion, their nervous system receives a tiny dose of something akin to caffeine, amphetamine, or cocaine. [Edit: Like stimulants in terms of the effect, not necessarily an actual chemical being added to the brain.] The more exertion, the larger the dose.

Would the neural activation effects of these and other stimulants be visible in the kinds of brain imaging tests that have been done so far on ME/CFS?

 

[EndME]

My point is more that in order for this idea to be viable, it couldn’t possibly originate from a single neuron or even small cluster of neurons. And then you’d need a pretty good explanation for why a continuous firing pattern from a large cluster of neurons hasn’t been noticed already.

Yes, but I don't think there's a need to invoke a very localized theory nor global detactable changes, if I'd guess one would probably anyways want to do the opposite precisely because things would have otherwise been seen. Firing patterns are anyways pretty noisy and complex, if one say was to for example increase some noise a bit and introduce some decoupling to avoid continous network hyperexcitation, I don't a priori see why that should not be enough to get something that is "not normal" but also avoids the above problems. At least that's my extremely wishy-washy layman idea. My layman impression is that pretty much that all neurological network models are complex enough to allow for all sorts of complex scenarios.

 

[jnmaciuch]

Would the neural activation effects of these and other stimulants be visible in the kinds of brain imaging tests that have been done so far on ME/CFS?

I mean many studies have identified a bunch of different changes in brain activity with actual cocaine or caffeine intake using pretty standard methods. Some of those same general screening methods have been done, but whether you can get a meaningful comparison of “is something similar happening in ME/CFS?” is another question though.

 

[jnmaciuch]

Yes, but I don't think there's a need to invoke a very localized theory nor global detactable changes, if I'd guess one would probably anyways want to do the opposite precisely because things would have otherwise been seen. Firing patterns are anyways pretty noisy and complex, if one say was to for example increase some noise a bit and introduce some decoupling to avoid continous network hyperexcitation, I don't a priori see why that should not be enough to get something that is "not normal" but also avoids the above problems. At least that's my extremely wishy-washy layman idea. My layman impression is that pretty much that all neurological network models are complex enough to allow for all sorts of complex scenarios.

Sure, mostly I was responding to JE’s explanation that a signal hasn’t been found yet because it could originate from a tiny circuit or single neuron, which I find implausible.

Your general point here takes us back to the same thing you basically said earlier—any number of things is theoretically possible in something as complicated as the brain, but you’d just be explaining an unknown with another even bigger unknown.

If we were convinced that the only logical explanation for ME/CFS is some complex brain pattern invisible on current imaging methods—which I’m not convinced of—it wouldn’t be a matter of getting a good neuroscientist interested in ME/CFS, it’d be a matter of waiting for neuroscience to do things that are quite beyond its entire ability as a field. But we haven’t even done due diligence investigating known mechanisms of central fatigue, so I just don’t see the benefit of believing the answer must be somewhere in the distant unknown.

 

[EndME]

Your general point here takes us back to the same thing you basically said earlier—any number of things is theoretically possible in something as complicated as the brain, but you’d just be explaining an unknown with another even bigger unknown.

If we were convinced that the only logical explanation for ME/CFS is some complex brain pattern invisible on current imaging methods—which I’m not convinced of—it wouldn’t be a matter of getting a good neuroscientist interested in ME/CFS, it’d be a matter of waiting for neuroscience to do things that are quite beyond its entire ability as a field. But we haven’t even done due diligence investigating known mechanisms of central fatigue, so I just don’t see the benefit of believing the answer must be somewhere in the distant unknown.

To some extent yes, but to some extent no. 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). I'm thinking of something that should be examinable if you know where to look (that's why I've emphasised the testability of the model in previous posts), not that it's a priori invisible to all our current means, but rather invisible to what has been done because it has to be. Just like how any other explanation of ME/CFS will have to involve something invisible to what has been done up till now. Both of those things and the presentation of ME/CFS will cause strong restrinction on how the theory would look like, I think that's where you'd want a neuroscientist involved, because quite clearly the handwavy discussions are insufficient. But any involvement now still seems too early, but say there'd be more concrete results pointing towards synapses from DecodeME replication studies and then some more, things could eventually get somewhere.

 

[Creekside]

I have no idea how an infection would suddenly trigger such a disease, or how it could suddenly go back to normal.

I think of ME's mechanism as a complex feedback loop, possibly involving multiple parts of the body (brain, gut, maybe other squishy bits), which in turn can be represented by a very complex mathematical equation. Changing even one of those many factors, by a microbial infection or other means, can change the overall mathematical function to positive feedback, locking it into that state. Changing another factor could switch it out of that state, but that affects other factors, which could switch it back into the ME state. While we may not know precisely how a virus can do this, I don't question the possibility of it happening.

Why do some people develop ME and others don't? That mathematical equation varies with the individual, and some are more sensitive to various factors than others.

Though maybe it hasn't been tried much specifically with this hypothesis in mind, where they take it immediately after exertion to see if it prevents a crash. If they were expecting it to just improve their general symptoms, I wouldn't expect it to do that (well maybe if they take it all the time), only to specifically prevent the next crash related to the exertion they just did.

That is a problem with experimentation. I might have had cumin many times over many years without noticing that it was blocking PEM. What happened was that I did a chore expecting PEM the next day, and noticed that it didn't show up. I'd eaten curry the previous evening. If I eaten that meal 4 days earlier, or a day after, I'd not have noticed its effect. Other people may have taken something that works well for them as a PEM blocker, but not under the circumstances (timing) that would reveal it. Maybe there are treatments that would work for people, but they have to be taken with the right cofactor. Frustrating!

 

[Jonathan Edwards]

A single neuron or even a small circuit potentially causing ME/CFS symptoms is improbable

We are not talking of a single neuron causing the disease. There are several billion neurons. The fault might lie in a ten thousand - very hard to image if they are thinly spread amongst another ten million. I don't think there are large or small 'circuits' in brain - everything connects to everything both divergently and convergently at each step. A functional loop can occur at any scale.

Nobody seems to be taking note of the point that there are plenty of diseases where we know the problem is abnormal brain signalling and as far as I know no imaging shows what is wrong. As I said, nobody had any way to explain what was wrong for my wife. Why she could not eat or sleep.

The activity in a loop does not need to be constant throughout the day. Re-running the erroneous signal might occur for brief periods, with persistence of symptoms occurring with longer term mediators, either with ephaptic effects or involving glia.

I realise that suggestions have been made in simplistic terms just to propose a rough idea but when you have a system with several trillion connections you are not necessarily going to be able to track malfunctioning that easily.

 

[Jonathan Edwards]

I agree, it is only an assumption that all perceptions/neural phenomena creating noticeable changes are inherently the result of “de novo” neuron firing as opposed to just modulation of existing firing patterns—which could be caused by something like cytokines acting on many regions of the brain, if the paper I posted earlier on meningeal CXCR5 mediating sickness behavior in mice is any indication.

But at some point something feels the symptom crudely described as fatigue. So something must receive messages encoding that information. Perceptions do not arise like ectoplasm out of neuron firing patterns. Something has to get the signals and the signals have to encode what the resulting experience is. Together with half a dozen other people in the consciousness field I do not think there is any alternative to the receiving units being individual neurons, but I appreciate that for most people that causes problems with deeply rooted assumptions.

And yes, that may well involve modulation of firing patterns, and modulation of receptivity, leading to modulation of patterns of dendritic potentials generated by inputs encoding symptoms.

 

[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