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

Grigor said:
Other diseases do show less disability and impairment, but the ones mentioned all have more access to treatments, care and understanding by MDs that acknowledge their symptoms. We can't underestimate the influences that has on someone's overall health, disability and impairment. Maybe with more recognition and better care that difference would disappear.
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Are there any indications that ME/CFS improves with adequate support and care (excluding direct treatments)?

I think there is a case for assuming that adequate support and care might result in a relatively higher probability of experiencing natural improvements, but I think that would mostly be mediated by the lack of «forced» long or short term worsening from far too excessive PEM.
 
Utsikt said:
Are there any indications that ME/CFS improves with adequate support and care (excluding direct treatments)?

I think there is a case for assuming that adequate support and care might result in a relatively higher probability of experiencing natural improvements, but I think that would mostly be mediated by the lack of «forced» long or short term worsening from far too excessive PEM.
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I don't know if there is, but I can imagine that when there is more support and recognition that it might also improve their overall QOL and experience with the disease as well.

I'm sure if the other mentioned diseases would be treated like people with ME they would score a lot worse as well.
 
Grigor said:
I don't know if there is, but I can imagine that when there is more support and recognition that it might also improve their overall QOL and experience with the disease as well.

I'm sure if the other mentioned diseases would be treated like people with ME they would score a lot worse as well.
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Improving QoL and FC, absolutely. I was more concerned about the underlying disease trajectory because that puts a hard upper limit for most pwME/CFS.
 
Grigor said:
While I like the role of the synapses described in this theory and appreciate this write up and exercise, I personally think we know too little about ME and the importance of the findings to come to these conclusions. Some of the findings are also too much minimized that is in my opinion premature.
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Thanks for the comments @Grigor!

To clarify: it was not my intention to minimize things or argue that peripheral pathology isn't possible in ME/CFS or that it is stupid to suspect or research it. Also agree that we still know very little about ME/CFS, that it hasn't been well researched in the past and numerous explanations are still on the table.

Having said that, there are places that make more sense to look for than others. The genetic studies gave some interesting clues that should probably become priority nr 1. in the field.
 
Grigor said:
Other diseases do show less disability and impairment, but the ones mentioned all have more access to treatments, care and understanding by MDs that acknowledge their symptoms. We can't underestimate the influences that has on someone's overall health, disability and impairment. Maybe with more recognition and better care that difference would disappear.
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I doubt it because we know what happens when those illnesses become more severe and it looks very different from ME/CFS. The pathology builds up and destroys parts of the body: muscles stop working, tumors develop, or there's brain damage, memory loss, joints get destroyed, organ failure, and eventually people die. At the same time the symptom burden is probably still less than in severe ME/CFS. People who are literally crippled by disease, have organ failure or are terminally ill can still do much more than (severe) ME/CFS patients.

So there's still this major discrepancy between the enormous symptom burden of ME/CFS over long periods of time and the lack of measurable pathology or tissue damage.

In other words, it's not so much that ME/CFS causes on average more severe symptoms than in other illnesses. It's that it has a very different development when severity increases. And even considering the lack of care for ME/CFS, I think it can reaches a symptom burden that is hardly seen in other chronic diseases.
 
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Grigor said:
I agree with Trish that my experience is also that you really get stopped in your tracks when you properly overexert. Like the oxygen tab gets closed down. Not just an increase in symptoms.
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I also get this lactic-acid feeling in my muscles and other patients suffer from weakness such as not being able to walk. But there are several reasons to think these are central rather than peripheral: due to things happening in the brain rather than in the muscle.

'oxygen tab gets closed down' is something that researchers would be able to measure for example by abnormal lactacte buildup, tissue damage or metabolic shifts which haven't been found in ME/CFS. Similarly the small and preliminary studies that we have that can simulate the muscle electrically suggest it did not reach its limit and that this limit comes from the brain.

Lastly, if there were a pathology in the muscle it would be pretty complicated to connect this to other symptoms such as photophobia or hyperacusis, gut sensitivity, orthostatic intolerance. So it would need to be connected to neurology anyway and probably to other body systems in order to make sense. And this all while remaining hidden for our current technology and tests, even at its greatest severity when it almost paralyses patients by the severity of symptoms!

If the lactic-acid feeling and weakness, however, could be caused by the brain almost everything would fall into place. it would also help to explain why PEM could be caused by any time of exertion, not just physical activity.
 
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ME/CFS Science Blog said:
I doubt it because we know what happens when those illnesses become more severe and it looks very different from ME/CFS. The pathology builds up and destroys parts of the body: muscles stop working, tumors develop, or there's brain damage, memory loss, joints get destroyed, organ failure, and eventually people die etc. At the same time the symptom burden is probably still less than in severe ME/CFS. People who are literally crippled by disease, have organ failure or are terminally ill can still do much more than (severe) ME/CFS patients.
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I understand what you're saying. The build up of pathology is of course true, but that also depends on if you know what you have to measure. We don't especially know that in ME, so that it may seem as if there isn't any build up of pathology. But once we do understand what happening there may be.

And yes, I have a friend with a very aggressive form of cancer, he can still a lot more than me, but he's also being treated for his illness. Without it things would look a whole lot different. In fact, he would probably not be with us anymore.
 
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I’ve commented on this elsewhere but one specific symptom which leads me to think something must be occurring in the muscle as well as brain is muscle stiffness—much worse after activity but nearly constantly present to some degree.

Interestingly I didn’t even register it for the first few years of my illness (just bled into the background of general aches and pains), but it was commented on separately by my GP when she was checking my joint mobility, a physical therapist, and an acupuncturist when I was in my “trying anything and everything” phase. The acupuncturist said it was like trying to push a needle through styrofoam, which also happens to be what it sounds like when I try to stretch out my neck muscles during PEM.

Maybe it’s not a very common symptom, but I know it’s related to my ME/CFS because it was new onset with other symptoms. Occurs every day even if I get into a diligent stretching regimen.
 
ME/CFS Science Blog said:
I also get this lactic-acid feeling in my muscles and other patients suffer from weakness such as not being able to walk. But there are several reasons to think these are central rather than peripheral: due to things happening in the brain rather than in the muscle.

'oxygen tab gets closed down' is something that researchers would be able to measure for example by abnormal lactacte buildup, tissue damage or metabolic shifts which haven't been found in ME/CFS. Similarly the small and preliminary studies that we have that can simulate the muscle electrically suggest it did not reach its limit and that this limit comes from the brain.

Lastly, if there were a pathology in the muscle it would be pretty complicated to connect this to other symptoms such as photophobia or hyperacusis, gut sensitivity, orthostatic intolerance. So it would need to be connected to neurology anyway and probably to other body systems in order to make sense. And this all while remaining hidden for our current technology and tests, even at its greatest severity when it almost paralyses patients by the severity of symptoms!

If the lactic-acid feeling and weakness, however, could be caused by the brain almost everything would fall into place. it would also help to explain why PEM could be caused by any time of exertion, not just physical activity.
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I agree that the brain is also heavily involved as well, maybe even primarily, that's not really the point, but I think it's premature to state that patients are experiencing an increase in symptoms with no driving pathology for example in the muscles. In my opinion we're really scratching the surface with what we know or we're just getting somewhat started. And also one does not have to exclude the other.
 
It would be very disheartening, and in my opinion difficult for scientists, if ME turns out to be a purely neurological disorder like described in this theory.

Neurological and neuropsychiatric disorders where the source of the disorder is seated more or less completely in the CNS are some of the most difficult to successfully understand and treat illnesses that exist. I strongly feel we would have to wait decades longer until any real progress could be made if this were the case.

I’m still hoping very hard that this is indeed fundamentally an immune system disorder. I think even immune system disorders are more tractable from a research perspective than complex CNS illnesses.
 
Perhaps AIDS (before it was adequately treated) might also be a good comparison to highlight. This is an example of a persistent virus that causes widespread immune dysfunction, a popular theory in ME/CFS and Long Covid research.

Yet several physicians (Peterson, Klimas etc.) commented that AIDS patients only developed the same degree of debilitating symptoms as in ME/CFS around 2 months before their death. Meanwhile it caused opportunistic infections, rare cancers, muscle wasting, damages blood vessels, and dementia.

So even if we assume some non-brain pathology like a virus in ME/CFS it must be extraordinary good at causing symptoms without destroying or disrupting other functions in the body.
 
Grigor said:
I think it's premature to state that patients are experiencing an increase in symptoms with no driving pathology for example in the muscles. In my opinion we're really scratching the surface with what we know or we're just getting somewhat started. And also one does not have to exclude the other.
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Agree with this. So my counterpoint would be that the theory does not really state this, just that it is more likely that the key to ME/CFS lies in the neural pathway involved in generating symptom perception. Whatever else will be found in the future, it will probably have some special relationship to this pathway.

And at the moment there seems to be no strong evidence or clinical phenomena that require adding things to the neural theory except for an immune-trigger.
 
leokitten said:
It would be very disheartening, and in my opinion difficult for scientists, if ME turns out to be a purely neurological disorder like described in this theory.

Neurological and neuropsychiatric disorders where the source of the disorder is seated more or less completely in the CNS are some of the most difficult to successfully understand and treat illnesses that exist. I strongly feel we would have to wait decades longer until any real progress could be made if this were the case.

I’m still hoping very hard that this is indeed fundamentally an immune system disorder. I think even immune system disorders are more tractable from a research perspective than complex CNS illnesses.
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It would be disheartening, but, for me, it is also one of the few things that seems to make sense. My opinion isn't worth much, but before I had ever heard of ME/CFS, I was 100% that was was wrong with me came from my brain, and that sense has never gone away, even though all of the various health care professionals haven't given much credence to the idea - I suspect this is, in part, due to the situation you outline: it means they can't do anything about it, and quite possibly won't ever be able to do anything about it.

The general lack of understanding with regard to the CNS and neurological disorders certainly lines up with the next to zero understand of ME that has persisted for decades.
 
DHagen said:
It would be disheartening, but, for me, it is also one of the few things that seems to make sense. My opinion isn't worth much, but before I had ever heard of ME/CFS, I was 100% that was was wrong with me came from my brain, and that sense has never gone away
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Many of us would disagree somewhat with this belief, because for us the first couple years or so of ME it felt very, very strongly immune system driven, like our immune system was stuck in some strange chronic activation. Many of my lymph nodes were constantly swollen and hard as a rock and I had many other what felt like immune system dysfunction symptoms. All the neurological symptoms really felt like a direct downstream consequence of this immune system activation.

Now yes as the years have gone by the immune activation symptoms have gradually subsided and the neurological symptoms have stayed or gotten worse and now it feels mostly neurological, but I cant help think that the immune system craziness of the first few years still have something really important to do with it
 
ME/CFS Science Blog said:
So even if we assume some non-brain pathology like a virus in ME/CFS it must be extraordinary good at causing symptoms without destroying or disrupting other functions in the body.
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Which might turn out to be the biggest clue, if it is something not limited to the brain. I’m in the same boat as @leokitten re:hoping it’s not only in the brain.

I definitely understand your desire to prioritize the neurological angle, but I’ve had some discussions with coworkers and classmates with more of a neuroscience focus over the years about this exact possibility and the answers to “what’s the next step if ME/CFS turns out to be in the brain?” have left me pretty disappointed. It’s far off in a way that most other biomedical research isn’t—a fact that I didn’t fully comprehend until I was walked through the limited set of neurological phenomena that could be measured [edit: especially without an animal model] and the even more limited conclusions that could be drawn from any of it. The few examples of successes with migraine and epilepsy are mostly due to the triggering phenomena in both cases being substantially different to the sort of “broken loop” mechanism proposed here.

If it does turn out to be a broken neurological feedback loop, we’d more or less end up in a “throw psychiatric medications at a wall and see what sticks” scenario. But since we don’t definitively know that it’s all in the brain only, my sense is that the best use of research is to look at more peripheral mechanisms that could potentially act on the brain directly or indirectly. Looking for mechanisms that wouldn’t cause obvious progressive damage helps narrow the scope quite a bit—its one of the things that led me to a constitutive interferon signaling theory, since the tissue damage in interferonopathies is caused by osteoclast recruitment downstream of interferon signaling and there are several ways to explain why that might not happen in a different set of circumstances.
 
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I think the brain involvement is the progression (door opening) into ME and PEM. Like a latter stage of a lead up to a disease. I think there is a before stage starting with the immune system and then at a latter point ME and PEM gets switched on in the brain by a cold or other. Could be wrong of course but it does feel this way for me.
 
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