Eccentric medium spiny neuron (eMSN)

[ScoutB]

I also think it's early to say how subtle or treatable a neurological cause/part of ME/CFS would be when we have not yet really tried to look. E.g. you can find a near endless list of PET scan studies in people with Parkinson's, ADHD, schizophrenia, depression etc. In comparison, I think we know of 3 PET studies ever done in ME/CFS? The dopamine PET study and the CRH autopsy study are the two main recent neurological investigations I know of, and both are coming back claiming to have immediately found something (we'll see if either hold up).

It feels to me like there's a lot of potential information sitting on the table. And if we had a rough idea of which systems were involved in making life with ME/CFS so horrible, it doesn't seem out of the question that some already-existing treatment could at least bump people a few rungs up the ladder.

 

[neophyte32]

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.

Thank you for your reply. What do you mean by that? Do you have an example of a study or a molecule currently undergoing trials? What condition are they being tested for?

 

[Concentric_Spiral]

I never experienced relapse as discussed above. A little over nine years ago I got sick with ME/CFS and my energy has been roughly the same the entire time. I do, of course, 'crash' from what I assume is PEM where I feel like I'm coming down with a flu, get headaches, stronger exhaustion, etc., but I always rebound to the same baseline low energy level.

 

[Utsikt]

The question is what would necessitate such a system? I can see why ants would need to have complex mechanisms to navigate home, but why would fatigue need to work that way? 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?

If the purpose of fatigue is to affect the likelihood of someone doing something, wouldn’t it be useful for it to be able to account for more than just what the sensors are saying right now?

If your e.g. your mood can be affected by things from the past, or even imaginary things or the future, why not fatigue?

 

[chillier]

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.

Calculations and integrations of signals to produce fatigue in the here and now sound fair enough. To be clear what I'm specifically debating is the presence of memory/a buffer that tots up things and remembers over a period of time like days.

For fatigue you could get a physiological read out from sensors in the periphery like muscles, or from cognitive sensors from information from the eyes or ears. Or it could be you try to get information from a memory or from circuits that interpret sounds or sights and you get the feedback slower than expected. All or any of that - happening right now - could be integrated to generate a sense of fatigue. If you've done a certain activity a lot maybe circuits involved in that activity change responsiveness, so when you try to use them you don't get the feedback you expect and those signals are integrated to generate the feelings of fatigue.

As for the sense of time passing, there are just so many cues. When you meditate with a bit of experience you can get a bit of a sense of when the timer is about to go off - but even with the low amount of external stimulation there's still so many cues to make that assessment with eg how many different thoughts or topics have come up, the subtle changes in how my body feels after this amount of time has passed.

My argument is not that there isn't a buffer, but that the information may already be available without one.

 

[chillier]

If the purpose of fatigue is to affect the likelihood of someone doing something, wouldn’t it be useful for it to be able to account for more than just what the sensors are saying right now?

If your e.g. your mood can be affected by things from the past, or even imaginary things or the future, why not fatigue?

It could be, but I want to know is if it must be, or if it seems really likely given what we know about how humans work.

There are lots of things that affect the likelihood of someone doing something. Most of the time what is stopping me from exerting myself is not the feeling of fatigue but the knowledge of the consequences and suffering if I do.

 

[Jonathan Edwards]

Calculations and integrations of signals to produce fatigue in the here and now sound fair enough. To be clear what I'm specifically debating is the presence of memory/a buffer that tots up things and remembers over a period of time like days.

OK, but I am not sure that is what I am arguing for. I think our brains tot up things during activities maybe over minutes or hours. The longest I can think of is following the musical shape of Tristan (~5 hours) or running a conference from 8.00 a.m. to 6.00 p.m.. They then retain the totting up conclusions over long periods as calibrators for fatigue responses to situations. Having been to Edinburgh a few times I can judge quite well how heavy a bag I could reasonably carry from where Prince's Street runs below the castle to the Philosophy Department. I have no idea of how many miles or even how long it would take but I have a sense of the fatigue accounting.

 

[Utsikt]

It could be, but I want to know is if it must be, or if it seems really likely given what we know about how humans work.

I fear we won’t get an answer to that anytime soon.

There are lots of things that affect the likelihood of someone doing something. Most of the time what is stopping me from exerting myself is not the feeling of fatigue but the knowledge of the consequences and suffering if I do.

And what are the key consequences? Fatigue, unpleasantness and a reduced ability to do things.

So even the «thought» of future fatigue is enough to get you to not do something. So there should be some bits in the brain that are able to connect having done something for a duration of time to the effect of having done that.

I’m not able to see how you could get that just by reading the gauges in real time, because then you would have no sense of what’s gone on before or what happened after.

It’s far more complex than the immediate pavlovian response of hear bell ring and get food now.

 

[Jonathan Edwards]

I’m not able to see how you could get that just by reading the gauges in real time, because then you would have no sense of what’s gone on before or what happened after.

And even in simpler terms I don't quite see what the gauges are going to be telling the brain that would explain fatigue. Anyone who has run 10,000 or 5,000 metres will know about 'second wind'. In fact it gets more complicated the more you do it. I only did it for a season or two. I recognised three sorts of fatigue. The first comes on and you call on second wind, which becomes a reliable response. You get a second fatigue around half to three quarters of the way through depending on how you are pacing. That is what makes you lose a place at the front. Then you have a third fatigue after your attempt at a final sprint. The last one probably relates to a formal metabolic threshold but I don't think the others do. For much of the race I suspect that metabolic gauges are reading much the same. The most obvious metabolic gauge that does pop up to begin with is the 'stitch' but that is independent of the sense of fatigue. It is just a nuisance.

 

[Kitty]

What do you mean by that? Do you have an example of a study or a molecule currently undergoing trials? What condition are they being tested for?

Daratumumab, low dose Abilify, low dose LDN, and others I can't recall at the moment but will be in the threads about current/new research in Germany. They're being tested for ME/CFS and long Covid.

The same approach—come up with a hypothesis about what might be going wrong, try an existing drug that targets it—could potentially be tried to disrupt neuronal signalling patterns that may have got stuck in a loop.

 

[Robert 1973]

And even in simpler terms I don't quite see what the gauges are going to be telling the brain that would explain fatigue. Anyone who has run 10,000 or 5,000 metres will know about 'second wind'. In fact it gets more complicated the more you do it. I only did it for a season or two. I recognised three sorts of fatigue. The first comes on and you call on second wind, which becomes a reliable response. You get a second fatigue around half to three quarters of the way through depending on how you are pacing. That is what makes you lose a place at the front. Then you have a third fatigue after your attempt at a final sprint. The last one probably relates to a formal metabolic threshold but I don't think the others do. For much of the race I suspect that metabolic gauges are reading much the same. The most obvious metabolic gauge that does pop up to begin with is the 'stitch' but that is independent of the sense of fatigue. It is just a nuisance.

One type of fatigue I get with my ME/CFS feels more like “the wall” that marathon runners describe, or “the bonk” in cycling. In both cases that is caused by the depletion of glycogen, which athletes seem to be able to avoid these days by consuming the right carbohydrate gels and drinks while racing.

 

[Eddie]

If the purpose of fatigue is to affect the likelihood of someone doing something, wouldn’t it be useful for it to be able to account for more than just what the sensors are saying right now?

If your e.g. your mood can be affected by things from the past, or even imaginary things or the future, why not fatigue?

Your mood is dependent on the state of your experience now, not things in the past. Those things in the past can only matter in so far that they present you with an experience right now.

You can't be angry or sad at something in the past if you have no recollection that some event occurred. If lost your wallet and then forgot you ever had a wallet, the "fact" that some past event occurred is irrelevant. What matters is that you are presented with a current experience of losing your wallet and that is what annoys you.

I don't think that is in contention with what Jonathan is arguing. But however the calibration data is stored must be as some information that exists now not some past event.

One question is why such a fatigue calibration system would be useful evolutionarily? Why limit activity beyond what puts a strain on the body? If one person is fatigued early in a hunt, before any stress on body systems has occurred, surely they would be less likely to survive. Maybe they would occasionally save some energy, but surely nowhere near enough to compensate for the decreased performance.

 

[Eddie]

Having been to Edinburgh a few times I can judge quite well how heavy a bag I could reasonably carry from where Prince's Street runs below the castle to the Philosophy Department. I have no idea of how many miles or even how long it would take but I have a sense of the fatigue accounting.

Isn't that related to an understanding of past walking events? I don't see how that necessitates the brain producing the feeling of fatigue via some remembered accounting.

If I have never tried skipping before and I start skipping after a while I will get tired. Surely in this case, there is no prior accounting that the brain can be doing. When I get tired there must be some sensory apparatus that gets triggered. The next time I try skipping, perhaps now the brain could use the prior accounting of fatigue but why bother? The fatigue from the first skipping session wasn't only triggered by a brain accounting system so why not just use that same signal?

We all have a sense of what activities are fatiguing but that is independent of an accounting memory system that triggers the feeling of fatigue.

 

[Hutan]

I can imagine that the system allows for 'borrowing on account' when it comes to settling issues of exertional cost. On a 25 mile hike you carry on under conditions where you would normally go home for tea. Swatting for exams you stay up later than is comfortable. The year I was running my first riuximab trial on my own I borrowed a lot and it shows in the photographs of me that year.

I am not suggesting that ME/CFS is burn-out, but I am suggesting that nerve networks may store up 'debts' over quite long periods, based on how synapses have been re-tuned each day. Paying off those debts when normally burnt out is just a matter of letting the accounting system pay itself off. But maybe in ME/CFS it turns out that you borrowed from a scam bank that suddenly isn't there. The synaptic re-tuning does not tune back automatically.

I know that some people find discussion of mechanisms like this threatening but I think there is reason for optimism. In ME/CFS other brain functions do not get mistuned. You do not develop a Parkinsonian tremor. You do not forget who your sister is. If there is a synaptic tuning problem it seems to be quite restricted to this 'exertional cost' accounting and at least in some people it is quite clearly possible for it to reverse spontaneously.

I struggle to see how something like a neuronal debt accumulating over years accounts for the situation in my family, where three of us developed ME/CFS at the same time. Certainly when I became ill, I had had years of working hard, many working mothers do. So, if it was just me, maybe I could be persuaded that I have a history of "working too hard" and that is what caused my ME/CFS to happen.

But, my two children were of an age where surely they did not have exactly the same accumulation of burnout as me (if any at all)? So, it seems hard to see how our respective nervous systems could each do their accounting and all come to the same conclusion of 'time for ME/CFS now'. And that is before we take into account my children's personalities, different from mine and different from each other.

Plenty of young people get ME/CFS, and I find it hard to believe that all of them could have managed to accumulate such a stock of nerve network debt over 'quite long periods'. Of course, plenty of people work very hard in stressful careers and don't get ME/CFS. So, we end up still needing some extra feature to cause ME/CFS.

And if the problem is at the microstructural level of synaptic tuning it is perhaps more likely to be reversible by a treatment than if there is permanent cell death, as in Parkinson's disease or rheumatoid arthritis. We just need to think out of all the old boxes.

I'm not sure the suggested idea of some neuronal debt accumulated over years sounds like it is outside the old boxes. In fact, it sounds a bit like existing boxes containing things like childhood trauma, embodied stress, Type A personalities, problematic people-pleasing personalities and "the body keeps count". I expect that is not what you mean, but perhaps you can clarify, because I'm sure I won't be the only one puzzled by what you wrote.

 

[Deanne NZ]

For this discussion about fatigue, is there any useful insight in the known side effects of some medications where the mechanism of the side effect is understood? The obvious ones to me as a lay person are some pain meds & antihistamines - but perhaps that is more drowsiness than actual fatigue. There must be others that cause something more akin to the fatigue of MECFS.

 

[ScoutB]

For this discussion about fatigue, is there any useful insight in the known side effects of some medications where the mechanism of the side effect is understood?

It’s a really good question. Withdrawal from (prescription) stimulants will do this. I would guess it’s at least partially due to the sudden reduction in dopamine release? Stimulants do have both central and peripheral effects though so I’ve been meaning to see if there’s any research into exactly what’s going on.

 

[AliceLily]

For this discussion about fatigue, is there any useful insight in the known side effects of some medications where the mechanism of the side effect is understood? The obvious ones to me as a lay person are some pain meds & antihistamines - but perhaps that is more drowsiness than actual fatigue. There must be others that cause something more akin to the fatigue of MECFS.

The only thing I took at very severe ME/CFS that gave a similar effect to how I felt with one component of fatigue was Prozac. I was given 20mg dose, it felt like I had been given a lead coat to wear and I was already feeling a crushed exhaustion at that particular time of my illness.

Other types of fatigue I experienced was exhaustion where it felt I had run a marathon and breathing was laboured for hours. Also I felt an exhaustion like hitting a wall, knock down. Another type was like how you can feel in hot weather, heavy and sluggish exhaustion. I can't recall medications with like symptoms for these at this moment.

 

[Amw66]

This may be irrelevant!

Re rhinitis, postnasal drip,cough, sneezing.

On another thread it has been mentioned that myalgia could be caused by normal muscle metabolites triggering an abnormal neural signal.

Could the above symptoms be something similar?

Could normal/ low levels of irritants e.g. dust, pollen,chemicals trigger abnormal neural signaling which results in a normal protective immune mechanism of rhinitis or mechanical cough reflex?

I used to have rhinitis with migraine and always assumed that the trigeminal nerve was involved.

There is also the photic sneeze reflex, sneezing in direct sunlight.

When the sun prickles your nose: an EEG study identifying neural bases of photic sneezing - PubMed

We propose that the photic sneeze phenomenon might be the consequence of higher sensitivity to visual stimuli in the visual cortex and of co-activation of somatosensory areas. The 'photic sneeze reflex' is therefore not a classical reflex that occurs only at a brainstem or spinal cord level but...

pubmed.ncbi.nlm.nih.gov

In addition there was a paper a few years ago about mucus in ME/ CFS being different to healthy controls, so is our nasal mucosa less well protected from irritants? The authors proposed that it caused ‘chronic inflammation”??

The potential role of ocular and otolaryngological mucus proteins in myalgic encephalomyelitis/chronic fatigue syndrome - Molecular Medicine

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness associated with a constellation of other symptoms. While the most common symptom is unrelenting fatigue, many individuals also report suffering from rhinitis, dry eyes and a sore throat. Mucin proteins are...

link.springer.com

Thanks @obeat
Daughter has huge mucus issues!

 

[Evergreen]

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.

They/Dr Nicholas Madian outlined their idea, which is essentially what you are proposing, if I've understood what you have said correctly, in the symposium. (See symposium, Nicholas Madian's section on the EEfRT results, starts at about 2:21:20, https://videocast.nih.gov/watch=54675)

Some excerpts:

To generate feelings of effort that can change based on context, the brain must have systems that account for both energy being spent as well as the rewards to be gained and the punishments to be avoided for expending that energy. Furthermore, these systems must be able to create some kind of ratio of cost to benefits, the results of which influence how the effort feels.

The process by which the brain figures out this cost-benefit ratio is called effort discounting.

The inter-individual variability throughout this process is effort preference.

A lot of this process is thought to occur within a cluster of brain regions called the valuation network. Another region of the brain that may be important to this process is the locus coeruleus, a tiny region in the brainstem that produces the neurotransmitter norepinephrine for the rest of the brain.

Importantly, the functioning of these brain regions does not appear to be under conscious control.

[Note: in my view, there seemed to be a difference of opinion between team members here, with Madian and Nath always emphasising the involuntary nature of effort preference, and Walitt always emphasising voluntary pacing.]

To test whether there were any behavioural signs of disrupted effort discounting in ME/CFS, we administered the [EEfRT].

This all leads on to Aregawi 2026, where they propose central noradrenergic deficiency, measured by CSF norepinephrine+DHPG+MHPG. (See thread on Aregawi 2026.)

So basically, they think we have disrupted effort discounting due to central noradrenergic deficiency, while those with Parkinson's have disrupted effort discounting due to central dopamine deficiency. They suggest checking if it's pathophysiologically significant

by examining effects of manipulations of central norepinephrine release, reuptake, or metabolism on neurobehavioral measures

Let's hope that by the latter, they do not mean effort tasks. And then, my guess is, trials of norepinephrine modulating drugs.

 

[chillier]

I fear we won’t get an answer to that anytime soon.

And what are the key consequences? Fatigue, unpleasantness and a reduced ability to do things.

So even the «thought» of future fatigue is enough to get you to not do something. So there should be some bits in the brain that are able to connect having done something for a duration of time to the effect of having done that.

I’m not able to see how you could get that just by reading the gauges in real time, because then you would have no sense of what’s gone on before or what happened after.

It’s far more complex than the immediate pavlovian response of hear bell ring and get food now.

This to me sounds like learning from experience in the most general sense. Applies to anything from getting stung by a bee to trying a new food that i like or the satisfaction from solving a tricky puzzle. Everything will form memories/associations that will inform my behaviour in the future. What is the need for a dedicated fatigue buffer?

OK, but I am not sure that is what I am arguing for. I think our brains tot up things during activities maybe over minutes or hours. The longest I can think of is following the musical shape of Tristan (~5 hours) or running a conference from 8.00 a.m. to 6.00 p.m.. They then retain the totting up conclusions over long periods as calibrators for fatigue responses to situations. Having been to Edinburgh a few times I can judge quite well how heavy a bag I could reasonably carry from where Prince's Street runs below the castle to the Philosophy Department. I have no idea of how many miles or even how long it would take but I have a sense of the fatigue accounting.

It does just sound like learning a skill to me. Is learning how much fatigue you are likely to feel at different time points along a journey any different from learning a new language? I've now learnt English so well that it would be impossible for me to unlearn it, and if someone starts talking English at me the meaning will appear in my mind whether i like it or not.