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

[Hoopoe]

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

It would vaguely fit with some aspects.

I noticed that concentrating intensely on something can switch on something that feels like an overexcited mental state that does not dissipate easily and has negative effects.

 

[Snow Leopard]

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

The various brain imaging studies have largely eliminated that as a specific and sensitive predictor. The evidence is just not there.

 

[Jonathan Edwards]

The various brain imaging studies have largely eliminated that as a specific and sensitive predictor. The evidence is just not there.

I don't see that brain imaging in its present form can eliminate anything much.

In a sense forstglip's proposal is a truism. For there to be the symptoms there are in ME/CFS some neural circuits conveying those symptoms from one part of the brain to another must be either inappropriately active (not turned off or turned on). The same applies if you have symptoms with a broken leg or a bad cold. We do not have imaging techniques for showing the mechanisms in the brain for those.

 

[Snow Leopard]

I don't see that brain imaging in its present form can eliminate anything much.

In a sense forstglip's proposal is a truism. For there to be the symptoms there are in ME/CFS some neural circuits conveying those symptoms from one part of the brain to another must be either inappropriately active (not turned off or turned on). The same applies if you have symptoms with a broken leg or a bad cold. We do not have imaging techniques for showing the mechanisms in the brain for those.

We might not understand the patterns but there still necessarily will be a pattern. The brain can't be active in certain regions or have unique connectivity patterns as a causative factor without those showing up consistently across studies.

 

[Braganca]

For there to be the symptoms there are in ME/CFS some neural circuits conveying those symptoms from one part of the brain to another must be either inappropriately active (not turned off or turned on).

When I had a qEEG done, the researcher who ran it said my brain looked by some signals like I was standing in front of a firing squad and by other signals like I was fast asleep.

 

[Braganca]

This might be totally off track, but I remember reading this article from years ago and feeling very much as if it explained my brain. Since ME, I cannot see properly despite my eyes being 20/20. My brain does not process visual signals normally, or auditory, and it seems as if my brain is in a low power mode with only low energy data processing tasks happening. I wonder if there is anything in the protective shut down mechanism explained in this paper that was related to ME/CFS. For me, this visual processing issue started off only in PEM for the first two years of illness, and then became permanent as I became severe, along with sound sensitivity and photophobia.

The Brain Has a ‘Low-Power Mode’ That Blunts Our Senses | Quanta Magazine

Neuroscientists uncovered an energy-saving mode in vision-system neurons that works at the cost of being able to see fine-grained details.

www.quantamagazine.org

https://www.cell.com/neuron/fulltext/S0896-6273(21)00839-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627321008394%3Fshowall%3Dtrue

 

[Jonathan Edwards]

The brain can't be active in certain regions or have unique connectivity patterns as a causative factor without those showing up consistently across studies.

If you know what studies to do, for sure. But if they involve the roles of individual neurons, which they may well do, then we are hopelessly ignorant of how to image and analyse such processes. There was the study of London taxi drivers who were supposed to have a bigger hippocampus or something, which ended up being ridiculed for being completely uninterpretable.

If we had imaging studies that could do this then my wife's illness could have been tracked down to the causation from antimalarial to hallucinations and paranoia. We have nothing like that.

 

[Braganca]

If we had imaging studies that could do this then my wife's illness could have been tracked down to the causation from antimalarial to hallucinations and paranoia. We have nothing like that.

Wouldn’t DAT imaging be useful to look at dopamine activity at least? DAT imaging shows higher dopamine activity in ADHD which is similar to the executive disfunction we have in ME, or lower dopamine activity in conditions that include hallucinations and dementia like Parkinson’s and Lewy Body. I would love to see what it shows for ME patients and I don’t think anyone has ever looked.

 

[chillier]

We might not understand the patterns but there still necessarily will be a pattern. The brain can't be active in certain regions or have unique connectivity patterns as a causative factor without those showing up consistently across studies.

This surely can't be right because pwME are all experiencing fatigue and the direct experience of that must be encoded by neurons in the brain. If there is a common experience of any kind between individuals there must be a pattern hypothetically observable by the activity of neurons in the brain. That doesn't in itself mean that that is the part that has gone wrong in ME but would nevertheless need to be a common endpoint.

 

[Jonathan Edwards]

Wouldn’t DAT imaging be useful to look at dopamine activity at least?

I might be fascinating but we would still have no idea where in the causal chain the changes would fit. It might still be due to changes in muscle afferents, gamma delta T cells or leptin abnormalities. Even in Parkinson's there is intense debate about where the problem all starts.

 

[Jonathan Edwards]

If there is a common experience of any kind between individuals there must be a pattern hypothetically observable by the activity of neurons in the brain.

A small point is that experience is input, not activity, so a given experience does not necessarily have to derive from a specific set of activities in other neurons providing the input, although there is likely to be a good fit.

The real problem is that if the abnormality is in specific neuronal connectivities at the individual cell level no imaging technique we have at present will get anywhere near it.

Take a particular problem that I have - I cannot play the trumpet. How are you going to image that defect? Nobody has a clue. Or as another example - Castillian Spanish children are unable to hear the extra e/i vowel that occurs in Catalan if they do not learn it before the age of 4. The brain simply does not pick it out. I doubt anyone has any idea how to image that deficit.

Hopefully, if ME/CFS pivots on a brain signalling problem it will involve a specific neurotransmitter, maybe a neuropeptide that is imageable but not yet imaged. But there is no guarantee of that.

 

[Snow Leopard]

This surely can't be right because pwME are all experiencing fatigue and the direct experience of that must be encoded by neurons in the brain. If there is a common experience of any kind between individuals there must be a pattern hypothetically observable by the activity of neurons in the brain.

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).

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 real problem is that if the abnormality is in specific neuronal connectivities at the individual cell level no imaging technique we have at present will get anywhere near it.

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

 

[forestglip]

The various brain imaging studies have largely eliminated that as a specific and sensitive predictor. The evidence is just not there.

I'm just learning the basics of neuroscience, so a lot of this is very foreign to me. But when I search for papers related to MRI, exercise, and ME/CFS, several highlight increased brain activation in one form or another after exertion that is absent in controls.

The following are just from a quick search and I haven't read much past the abstracts yet, so just posting to see if there's anything to discuss here.

Absence of BOLD adaptation in chronic fatigue syndrome revealed by task functional MRI, 2025, Journal of Cerebral Blood Flow & Metabolism | Article | S4ME

Participants completed two blocks of a Symbol Digit Modalities Test, with 30 trials per block split into two sets. The fMRI signal changes between blocks and sets were compared within and between groups. Thirty-four ME/CFS participants (38 years ± 10; 27 women) and 34 HCs (38 ± 10; 27 women), were evaluated.

In the second task block, ME/CFS participants exhibited increased activation in the right postcentral gyrus, contrasting with decreased activation in multiple regions in HCs.

These results were further confirmed by significantly higher bilateral dynamic changes (2nd vs 1st set) in the motor, sensory and cognitive cortex in ME/CFS compared to HCs and significant correlations between those changes in the left primary motor cortex with fatigue severities.

Submaximal Exercise Provokes Increased Activation of the Anterior Default Mode Network During the Resting State as a Biomarker of Postexertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2021, Frontiers in Neuroscience | Article | S4ME

Method: Blood oxygenation level dependent (BOLD) scans were performed while at rest on the preexercise and postexercise days in 34 ME/CFS and 24 control subjects. Seed regions from the FSL data library with significant BOLD signals were nodes that clustered into networks using independent component analysis. Differences in signal amplitudes between groups on pre- and post-exercise days were determined by general linear model and ANOVA.

Results: The most striking exercise-induced effect in ME/CFS was the increased spontaneous activity in the medial prefrontal cortex that is the anterior node of the Default Mode Network (DMN). In contrast, this region had decreased activation for controls. Overall, controls had higher BOLD signals suggesting reduced global cerebral blood flow in ME/CFS.

Modulatory effects of cognitive exertion on regional functional connectivity of the salience network in women with ME/CFS: A pilot study, 2021, Journal of the Neurological Sciences | Article | S4ME

Methods
A total of 16 women, 6 with and 10 without ME/CFS, underwent clinical and MRI assessment before and after cognitive exertion. Resting-state FC [functional connectivity] maps of 7 seeds (3 for the SN [salience network] and 4 for the DMN [default mode network]) and clinical measures of fatigue, pain and cognition were analysed with repeated-measure models. FC-symptom change associations were also investigated.

Results
[...] Significantly higher FC increases in patients than in controls were found only between the right insular seed and frontal and subcortical areas; these increases correlated with worsening of symptoms.

Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2020, Brain Communications | Article | S4ME

Here, we used functional magnetic resonance imaging to measure neural activity in healthy controls and patients with Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome during an N-back working memory task both before and after exercise.

Whole brain activation during working memory (2-Back > 0-Back) was equal between groups prior to exercise.

Exercise had no effect on neural activity in healthy controls yet caused deactivation within dorsal midbrain and cerebellar vermis in Gulf War Illness relative to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients.

Further, exercise caused increased activation among Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients within the dorsal midbrain, left operculo-insular cortex (Rolandic operculum) and right middle insula.

Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2017, Brain, Behavior, and Immunity | Article | S4ME

Fifteen female Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients and 15 healthy female controls completed 30 min of submaximal exercise (70% of peak heart rate) on a cycle ergometer. [...]

Functional brain images were obtained during performance of: 1) a fatiguing cognitive task – the Paced Auditory Serial Addition Task, 2) a non-fatiguing cognitive task – simple number recognition, and 3) a non-fatiguing motor task – finger tapping. [...] Brain responses to fatiguing and non-fatiguing tasks were analyzed using linear mixed effects with cluster-wise (101-voxels) alpha of 0.05. [...]

For the Paced Serial Auditory Addition Task, there was a significant Group by Time interaction (p < 0.05) with patients exhibiting increased brain activity from pre- to post-exercise compared to controls bilaterally for inferior and superior parietal and cingulate cortices. Changes in brain activity were significantly related to symptoms for patients (p < 0.05).

 

[EndME]

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

I was watching an Intro to Neuroscience lecture, where the teacher described different kinds of micro neural circuits (at 24:30). There are positive feedback, negative feedback, and other little neuron networks.

I'm imagining various types of "exertion", whether physical or mental, trigger some types of excitatory neurons. A positive feedback loop starts that keeps them active.

In healthy people, soon after the exertion ends, the circuit would be "turned off". For some reason, in ME/CFS, it stays on.

How does this fit the symptoms?

The "wired", "adrenaline-like", or insomnia symptoms that begin shortly after exertion:
This would be the excitatory neurons just continuing to fire far longer than needed, maintaining a state of alertness.

Delayed fatigue and other symptoms:
After a while of the neurons firing for too long, the circuit is finally turned off. Maybe the mechanism that is meant to turn it off kicks in very late.

Maybe something like a drug tolerance mechanism happens, like in stimulant (cocaine, amphetamine, etc) withdrawal. The neurons are continually firing inappropriately, spewing out too many neurotransmitters, so other parts of the brain eventually notice and inhibit the circuits, become less sensitive to the neurotransmitters, or both. As in drug withdrawal, the crash is worse than baseline.

Yes, I think the models that are being discussed here are all more or less a version of such thoughts (maybe not specifically regional hyperexcititation which should possibly be seen in EEGs so things have to be more subtle).

The problem of course is anybody is in their right to say: This is too vague of an idea to be testable (at least if you say the events occuring, here excitiability, isn't straightforward enough to be picked up by standard brain imagining techniques and much more subtle). You have to get to the specifics because that's what matters. The problem is that nothing currently points at specifics, so any such idea that accounts for the basics is as good as the next (a bit of slighlty increased excitability that is somehow neither bound to one local region nor global that comes from an increase of ion channel noise, a problem in partially reduced refractory periods at certain point leading to more noise, a problem in local synchronisation without turning into epilepsy, "something to do with synapses", the "vague ideas that are meaningless" are endless....). I think in the ideal scenario you have some more genetic work that confirms the likelihood of brain involvement being central and then a serious neuroscientist becoming involved where meaningless ideas turn into concrete notions.

In @chillier 's idea the model was then married to the idea of synapes being centrally involved on the basis of the DecodeME data.

There's one thing every such model has to do: It has to live on 2 timelines in 2 different regimes. On the short timescales, as the ones in your model, you "get a bit of too much excitability" (but not the sort seen in epilepsy) after something has occured (cognitive activity leading to cognitive confusion, i.e. excitatory leading to some form of hyper excitation, physical activity leading to muscle pain etc) but there's also slightly more normal dynamics (not feeling "too confused" after not having engaged in any cognitive activity). At the long timescales you have sudden onset and remission from ME/CFS leading to bistable dynsamics. These long-time scales are essentially not seen by the short timescales as they essentially happen at infinite time (hyperexcitiability after cognitive activity vs remission from ME/CFS 10 years after illness onset essentially live on different scales), however it has to be somehow accounted in the dynamics even if the push into (and out of) the ME/CFS dynamics are purely random. It's not hard to come up with such dynamics but marrying them to the presentation of ME/CFS is the tricky part. Why does the hyperexertability tend to be married to muscle pain rather than stomach or joint paint, why do you get "brain fog" but not strokes, hallucinations or memory loss, etc, I think this requires quite a bit of neurological knowledge to make things match.

If I remember correctly in @chillier 's synapse model the long-timescale bistability essentially came from some threshold in synapses, which at some point could not recover their usual function anymore.

I think it's fair to say that somewhere along such lines is how things could be, but I think it's equally fair to say these ideas don't provide anything new on how things could be. I think any researcher seriously pursuing these ideas (not just us discussing things) will have to ask themselves: How do I test my model?

 

[EndME]

I'm just learning the basics of neuroscience, so a lot of this is very foreign to me. But when I search for papers related to MRI, exercise, and ME/CFS, several highlight increased brain activation in one form or another after exertion that is absent in controls.

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.

 

[forestglip]

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.

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.

 

[EndME]

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").

 

[forestglip]

There's one thing every such model has to do: It has to live on 2 timelines in 2 different regimes.

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.

I think any researcher seriously pursuing these ideas (not just us discussing things) will have to ask themselves: How do I test my model?

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]

I'm just learning the basics of neuroscience, so a lot of this is very foreign to me. But when I search for papers related to MRI, exercise, and ME/CFS, several highlight increased brain activation in one form or another after exertion that is absent in controls.

The following are just from a quick search and I haven't read much past the abstracts yet, so just posting to see if there's anything to discuss here.

What I'm seeing is different patterns in each study.

 

[Jonathan Edwards]

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

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.