I think the problem is that the possibility of chance findings there is extremely high as there's lots of noise. If the sort of problems that exist in ME/CFS are not tied to a specific region, not global and not very stark either but more like "occasionally a bit of extra neurological noise here and then there" then those studies maybe shouldn't have picked up anything in the first place, because it's a different problem all together.
The symptom signaling theory of ME/CFS involving neurons and their synapses
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Only thing I'd say is that from my quick search, the trend seemed to be that consistently (the above five studies), abstracts highlight findings in the activation direction and not people with ME/CFS having larger decreases in brain activity after exertion. Though I might have been biased in my quick search and missed some of the opposite findings.
Yes but increased activitation in one region in one study (but not other regions) then increased activation in a different region (but not the previously mentioned one) is pretty much an opposing finding already in that it doesn't support the previous results. There is nothing consistent in the findings so it might as well just be noise which is tremendously common in such studies. If there's many regions and many signals, one region might occasionally pop out just like that (and some difference might simply come from "I'm a patient I'm gonna have to do my best to represent ME/CFS" vs "I'm a control that's looking for a quick buck").
Good points in your post. I have no idea how an infection would suddenly trigger such a disease, or how it could suddenly go back to normal.
In terms of testing, I'd want to see more studies with larger sample sizes just testing if the above studies are noise or not.
If they are actually showing the effect I propose, it would probably have to be fairly widespread activation to get different regions activated, and maybe the pattern of which regions are most over-activated differs between patients. So if you have small sample sizes, the region you see light up might vary a bit. The difference in regions might relate to different symptoms experienced by different patients, or whether physical or cognitive exertion affects them more, and so on.
Apart from that, just spitballing: can you test it by decreasing brain activation during and immediately after exertion? I'm thinking something like taking gabapentin. Of course, I expect many people with ME/CFS have already tried gabapentin. 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.
Snow Leopard
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What I'm seeing is different patterns in each study.
Jonathan Edwards
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If there is selective excitation of a small proportion of nerves then not necessarily. And since quite a lot of neurons in brain are inhibitory in function I think it all gets too complicated to predict. also I have not personally seen evidence that one can image things like nucleus caeruleus activity or hypothalamic appetite centre reliably.
jnmaciuch
Senior Member (Voting Rights)
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.
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.
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
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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) :
Yann04
Senior Member (Voting Rights)
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.
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.
jnmaciuch
Senior Member (Voting Rights)
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.
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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?
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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
Senior Member (Voting Rights)
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
Senior Member (Voting Rights)
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.
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.
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.
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
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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
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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.