Eccentric medium spiny neuron (eMSN)

[Jonathan Edwards]

Why would having a buffer that tots up and remembers physiological states over multiple days be necessary when you can just read the physiological states off of the sensors right now?

To optimise daily routines in competition with all the other guys with an eye on your girl.
What you may want to keep track of is enough time to do what needs doing. You cannot read 'enough time' off sensors right now. People focus on conserving energy usage but surviving for vertebrates has just as much to do with conserving time I suspect. And I suspect that fatigue is intimately connected to time accounting. Having to hurry alters fatigue perception.

But I am not suggesting that "fatigue" in ME/CFS is just due to poor accounting according to the normal rules. The idea is that it may involve a corruption of the rules that puts things completely out of gear. Maybe as in narcolepsy or Parkinson's.

And I am not sure that necessity not being obvious is a strong argument. You could argue that since there is no necessity for a human being to be able to judge the perfect structural balance of the opening prelude of Bach's First Cello Suite we should not propose any such capacity exists. Presumably Bach was able to make use of a deep insight into some set of rules of accounting for repeated 'musical' sounds that lie in human brains. Goodness knows why.

 

[chillier]

And I am not sure that necessity not being obvious is a strong argument. You could argue that since there is no necessity for a human being to be able to judge the perfect structural balance of the opening prelude of Bach's First Cello Suite we should not propose any such capacity exists. Presumably Bach was able to make use of a deep insight into some set of rules of accounting for repeated 'musical' sounds that lie in human brains. Goodness knows why.

It isn't negative evidence, but I think if a proposed system has both no evidence of existing and also has no particular need to exist then what reason is there to assume it does? I would say the fact some people seem to enjoy Bach suggests there necessitates some process there facilitating that enjoyment, but maybe perfect structural balance is really found in Ornette Coleman's free jazz?

 

[chillier]

To optimise daily routines in competition with all the other guys with an eye on your girl.
What you may want to keep track of is enough time to do what needs doing. You cannot read 'enough time' off sensors right now. People focus on conserving energy usage but surviving for vertebrates has just as much to do with conserving time I suspect. And I suspect that fatigue is intimately connected to time accounting. Having to hurry alters fatigue perception.

But I am not suggesting that "fatigue" in ME/CFS is just due to poor accounting according to the normal rules. The idea is that it may involve a corruption of the rules that puts things completely out of gear. Maybe as in narcolepsy or Parkinson's.

On a tangent about time sensing, I don't know if others in the forum pointed this out already but the top hit for G93.3 (postviral fatigue syndromes) in the astrazeneca rare variant analysis is CLOCK (also seen twice in the precisionlife analysis of ukbiobank mecfs and long covid):

AstraZeneca PheWAS Portal

azphewas.com

CLOCK is not a decode gene, but it is expressed predominantly in the hypothalamus and appears to have some connections with leptin. CLOCK knockout mice appear to have high leptin, low orexin and develop metabolic syndrome (Turek 05). Even if CLOCK itself is not directly relevant in MECFS is think it could provide a connection between the activity of the hypothalamus that has been discussed and the lipid and leptin findings.

Tagging @DMissa for his interest in lipids.

 

[Jonathan Edwards]

I see bucket-loads of evidence of a long term accounting system for effcient activity as existing. Something organises almost everything I do in a day in an efficient manner. I think we take this for granted or assume it is conscious decision-based. As I get older I find I have a limited capacity each day - maybe even a bit like someone with ME/CFS. I try to plan consciously but I sense that all sorts of things I do have been sifted and accounted for without me being aware of it.

 

[Jonathan Edwards]

CLOCK knockout mice appear to have high leptin, low orexin and develop metabolic syndrome (Turek 05).

Well there you go.
Time presses.
Time waits for no man.
The enemy.
...

 

[chillier]

Well there you go.

I don't think so!
I think this conversation has happened somewhere else on the forum but for things like routine and sense of time passing I don't see why that needs to be a centralised process, and not an ongoing roundabout of different routines each running with their own timer before attenuating, maybe backed up by external stimuli like getting hungry, the sun moving through the sky and so on. Maybe fatigue is the result of asking some set of neurons for some information (like a memory) and not getting a result back / not getting a result back very quickly.

 

[Evergreen]

I wonder if in ME/CFS, updating relating to 'exertional cost' accounting and prediction of how it should affect action decisions gets distorted. Every time you do something your brain re-writes its accounting sums for the predicted cost of that action.

But I am not suggesting that "fatigue" in ME/CFS is just due to poor accounting according to the normal rules. The idea is that it may involve a corruption of the rules that puts things completely out of gear. Maybe as in narcolepsy or Parkinson's.

Isn't this just the NIH's idea about disrupted effort discounting, complete with pointing out a supposed similarity with Parkinson's as in their symposium? (See symposium, Nicholas Madian's section on the EEfRT results, starts at about 2:21:20, https://videocast.nih.gov/watch=54675)

(Not similar at all. In unmedicated PD there was reduced reward motivation. We had normal reward motivation. But it's plausible that differences in things other than dopamine could affect effort discounting.)

So what do you think about their idea which seems to be to target norepinephrine/the norepinephrine pathway? (See thread on Aregawi 2026.)

There was a BBC article yesterday where Carly Simon described her experience of apathy in Parkinson's:

"The apathy is particularly strange," she observed. "You can find yourself lying there like a starfish drying in the sun, arms pointing in all directions, while nothing inside is telling you to get up, read, watch, write, sing, call someone, or do much of anything at all.

"That has been one of the hardest things to explain. It is not simply sadness or laziness. It is as though the part of the brain that sends out invitations to participate in life has temporarily misplaced the guest list."

I've certainly never experienced anything like that (beautiful description, though), but maybe others with ME/CFS do, or maybe that's specific to low dopamine?

It is interesting to me that nobody seems very bothered about the idea that ME/CFS might involve 'dysautonomia' in the sense of failure of regulation within the autonomic nervous system yet once we start talking about the brain some people get a bit emotional.

Are people bothered about the idea that ME/CFS is a brain disease? I haven't seen that. Sure it's been called neurological for ages, and people like that.

 

[Evergreen]

However, given that PEM is a common/frequent symptom as reported by most, relapses must be relatively rare because most people are not severe/ very severe.

Could you define relapse as you're using it? If relapses would render most people severe/very severe, then are you using the term to mean a permanent drop in functioning?

 

[Jonathan Edwards]

for things like routine and sense of time passing I don't see why that needs to be a centralised process, and not an ongoing roundabout of different routines each running with their own timer before attenuating,

But most of us can only do one or two thing at a time and every task has dozens of knock on effects on the efficiency of the next task. Making marmalade is an example. There about five ways to cut up the oranges, recommended by different cookbooks. Each component has knock-on effects on the others. The easiest way to slice the peel optimally can only be achieved if the handling of the pith is slow and messy. The pips can be removed about three different ways. The easiest is hard to do if you want efficient peel slicing. Peel slicing produces finger fatigue and is best done intermittently rather than all at one go but that has other knock on effects.

Making forty jars of marmalade for a year, as I do, is exhausting because of all the time taken in preparing the fruit and monitoring the cooking process. Over the years I come back to it having tried all the tricks. For the last ten years I have settled with a routine that gives me least sense of impendng fatigue. I have no idea how I came to that but I assume that somewhere in my brain a computation made that chose this routine, combining about five separate tasks. It may not be the most efficient but it is the routine that my automatic processes take me to.

 

[Jonathan Edwards]

Isn't this just the NIH's idea about disrupted effort discounting

I am not sure. They seem to have a simplistic idea of peoplw ti ME/CFS 'preferring' to reduce effort. I did not see any suggestion that pathways for effort accounting were subverted.

Are people bothered about the idea that ME/CFS is a brain disease? I haven't seen that. Sure it's been called neurological for ages, and people like that.

There are people on Reddit who seem seriously affronted by any suggestion that it might be a brain disease rather than due to bad mitochondria, lymphocytes, blood vessels etc.. And I think a number of members here have agreed that a brain mechanism is threatening. As you say, the irony is that sometimes the same people are the ones who like to believe in neuroinflammation.

 

[chillier]

But most of us can only do one or two thing at a time and every task has dozens of knock on effects on the efficiency of the next task. Making marmalade is an example. There about five ways to cut up the oranges, recommended by different cookbooks. Each component has knock-on effects on the others. The easiest way to slice the peel optimally can only be achieved if the handling of the pith is slow and messy. The pips can be removed about three different ways. The easiest is hard to do if you want efficient peel slicing. Peel slicing produces finger fatigue and is best done intermittently rather than all at one go but that has other knock on effects.

Making forty jars of marmalade for a year, as I do, is exhausting because of all the time taken in preparing the fruit and monitoring the cooking process. Over the years I come back to it having tried all the tricks. For the last ten years I have settled with a routine that gives me least sense of impendng fatigue. I have no idea how I came to that but I assume that somewhere in my brain a computation made that chose this routine, combining about five separate tasks. It may not be the most efficient but it is the routine that my automatic processes take me to.

This all sounds good to me, why would it require a centralised fatigue buffer though? It makes sense to me that the thought of doing something that has been unpleasant for you in the past would generate a small dose of suffering to stop you from doing it again. It also makes sense that repeatedly making marmalade many times would slowly iron out into one big smooth routine where you don't have to work too much mentally and everything feels good and flows nicely into the next action - like learning a tune on the piano. Routines fighting each other probably feels terrible. The thought of an activity making you feel bad doesn't sound like it requires a buffer to me.

 

[SugarSquared]

I don't think so!
I think this conversation has happened somewhere else on the forum but for things like routine and sense of time passing I don't see why that needs to be a centralised process, and not an ongoing roundabout of different routines each running with their own timer before attenuating, maybe backed up by external stimuli like getting hungry, the sun moving through the sky and so on. Maybe fatigue is the result of asking some set of neurons for some information (like a memory) and not getting a result back / not getting a result back very quickly.

I have no knowledge of this CLOCK gene and I may be misinterpreting what you all are saying, so disregard my anecdote if it is not relevant to the conversation.

Something being off about our internal clock would make sense to me. In terms of my circadian rhythm/sleep schedule, it feels like it has been shifted and can’t be moved back easily.

I used to be a morning person. Never super early like 5 or 6 am wake times, but I would get up at 8 or 9 even on weekends. No need for coffee or any caffeine, I was fully awake 5 minutes after waking. My best hours were in the morning and early afternoon, and I would go to bed between 10:30-11:30 pm. I was always proud of how I valued sleep.

Half a year in my illness, I started struggling to fall asleep. My sleep schedule just shifted to falling asleep between 12-2 am, even if I was regular about going to bed at 10:30 pm. I tried to shift it with an alarm at 9 am or earlier every day, but it didn’t help. I just woke up feeling worse. So, I started not waking up with an alarm, and would naturally wake up between 10-12 am. My best hours in the day have also shifted. I normally have the most energy starting at 8 or 9 pm, which is really frustrating because I have to go to bed soon after. It’s like my circadian rhythm has shifted and I can’t do anything about it.

 

[Jonathan Edwards]

This all sounds good to me, why would it require a centralised fatigue calculator though?

Maybe because all our sensations are derived from 'central calculators'. Even seeing a red blob is based on a complex inference involving thousands of cells in the visual cortex. Hearing a 'click' involves complicated inferences from shifts in signals to hundreds of auditory cortex cells. I thin we would expect signals like fatigue and nausea to reflect an integrated response to a whole lot of such inferences. Integration requires an integrating locus or centre.

 

[neophyte32]

I am not sure. They seem to have a simplistic idea of peoplw ti ME/CFS 'preferring' to reduce effort. I did not see any suggestion that pathways for effort accounting were subverted.



There are people on Reddit who seem seriously affronted by any suggestion that it might be a brain disease rather than due to bad mitochondria, lymphocytes, blood vessels etc.. And I think a number of members here have agreed that a brain mechanism is threatening. As you say, the irony is that sometimes the same people are the ones who like to believe in neuroinflammation.

On Reddit, people only talk about high-profile researchers like Carmen Scheibenbogen, Klaus Wirth, the Polybio team, Pretorius, Iwasaki, and Ron Davis (though we haven't heard from him at all in two years—he is getting on in years, after all...).

S4me.info—and you in particular—have a bad reputation because the place is supposedly run by bitter, pessimistic people. I find these numerous criticisms baffling. S4me.info is an absolute godsend.

As for our concern regarding a brain-related issue, you can imagine why... It will take longer than the immunology side of things; we had hopes for Daratumumab, but I’m convinced that’s a lost cause—even though the Germans are investing heavily in it. The results were a long way off for a severe case like mine—and for many others (2028)—but still...

We know brain issues are hard to treat—look at depression... an easy example, perhaps a clumsy one, but valid nonetheless.

A brain issue forces us to rethink everything, and frankly, you realize we’re looking at another 10 to 15 years before there’s any hope of a treatment, however minor.

 

[chillier]

I have no knowledge of this CLOCK gene and I may be misinterpreting what you all are saying, so disregard my anecdote if it is not relevant to the conversation.

Something being off about our internal clock would make sense to me. In terms of my circadian rhythm/sleep schedule, it feels like it has been shifted and can’t be moved back easily.

I used to be a morning person. Never super early like 5 or 6 am wake times, but I would get up at 8 or 9 even on weekends. No need for coffee or any caffeine, I was fully awake 5 minutes after waking. My best hours were in the morning and early afternoon, and I would go to bed between 10:30-11:30 pm. I was always proud of how I valued sleep.

Half a year in my illness, I started struggling to fall asleep. My sleep schedule just shifted to falling asleep between 12-2 am, even if I was regular about going to bed at 10:30 pm. I tried to shift it with an alarm at 9 am or earlier every day, but it didn’t help. I just woke up feeling worse. So, I started not waking up with an alarm, and would naturally wake up between 10-12 am. My best hours in the day have also shifted. I normally have the most energy starting at 8 or 9 pm, which is really frustrating because I have to go to bed soon after. It’s like my circadian rhythm has shifted and I can’t do anything about it.

I think this is the right interpretation from what is currently known about CLOCK, the connection to insomnia seems very plausible.

 

[V.R.T.]

So what I and others find intimidating about brain only is well exemplified by the (important and interesting) recent conversation in this thread. It is all very much 'well maybe this neuron does this but we don't know' and 'maybe fatigue is x or y'. As opposed to 'well this sort of t cells behaves like this and interacts with these cells and tissues in this way, maybe we should do x kind of assays or test y kind of drug'. It just shows how much less we have to go on if there does turn out to be no immune element to the MECFS signalling loop.

While I don't agree that we're definitely looking at 10-15 years minimum til treatment in the case of a brain only loop, its a far cry from 'we're going to discover what the immune side of this is very soon and treatments could well follow quickly.' Which is sort of where we were at last year.

Hopefully things will suddenly become much clearer soon, whatever the answer is.

 

[V.R.T.]

I have no knowledge of this CLOCK gene and I may be misinterpreting what you all are saying, so disregard my anecdote if it is not relevant to the conversation.

Something being off about our internal clock would make sense to me. In terms of my circadian rhythm/sleep schedule, it feels like it has been shifted and can’t be moved back easily.

I used to be a morning person. Never super early like 5 or 6 am wake times, but I would get up at 8 or 9 even on weekends. No need for coffee or any caffeine, I was fully awake 5 minutes after waking. My best hours were in the morning and early afternoon, and I would go to bed between 10:30-11:30 pm. I was always proud of how I valued sleep.

Half a year in my illness, I started struggling to fall asleep. My sleep schedule just shifted to falling asleep between 12-2 am, even if I was regular about going to bed at 10:30 pm. I tried to shift it with an alarm at 9 am or earlier every day, but it didn’t help. I just woke up feeling worse. So, I started not waking up with an alarm, and would naturally wake up between 10-12 am. My best hours in the day have also shifted. I normally have the most energy starting at 8 or 9 pm, which is really frustrating because I have to go to bed soon after. It’s like my circadian rhythm has shifted and I can’t do anything about it.

Incredibly bad sleep that was unresponsive to sleep hygiene was the first and in many ways most debilitating symptom of my prodromal phase.

 

[Jonathan Edwards]

So what I and others find intimidating about brain only

But nobody has said brain only, as far as i am aware.

I am discussing in the context of a likely model with maybe fifty steps, like RA. Some of those may well lie in immune cells.

As I think I have said, when in the 1990s we realisede might be able to treat autoimmune rheumatic disease effectively, five different strategies emerged for RA, each with a different target. None of those targets was the central problem, which probably lies in the way immunoglobulin VDJ genes are rearranged and mutated. They all worked remarkably well.

There is a different objection to brain involvement that i hear and that is that it implies a psychological approach. I have seen people claim that I take a psychological view. And nothing could be further from the truth. Psychology is bunk. The problem needs to be understood in neurological terms.

 

[V.R.T.]

But nobody has said brain only, as far as i am aware.

I am discussing in the context of a likely model with maybe fifty steps, like RA. Some of those may well lie in immune cells.

The initial context of this debate was me (rather poorly and emotionally I admit) arguing against a 'brain only' interpretation of the DecodeME evidence and the claim there was no evidence at all of immune involvement.

But yes I appreciate what you're saying and the kind of model you have proposed is not what I was talking about.

 

[Kitty]

A brain issue forces us to rethink everything, and frankly, you realize we’re looking at another 10 to 15 years before there’s any hope of a treatment, however minor.

I'm not sure there's any reason to think that.

Immune signalling hypotheses are being pursued even though we're still pretty much in the dark. Capable researchers are working through potential mechanisms and trialling drugs. The same process could be applied to neuronal signalling hypotheses.