Eccentric medium spiny neuron (eMSN)

[N_Dina]

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.

I tried Spironolactone for PCOS in the past (before ME/CFS) and after severe fatigue discontinued it immediately (I think the fatigue was not due to any blood pressure changes). There are also Finasteride and Flutamide which are supposed to tackle high androgens and cause similar exhaustion symptoms. Perhaps there is some research on the fatigue these medications cause?

PS: I am quite upset about the quality of academic papers in which fatigue in PCOS is presented through psychological lens, and the only advice there for drs and patients is to implement integrated psychological and sleep management strategies.

 

[V.R.T.]

sleep management strategies.

Are these even useful for anybody? As someone who they weren't useful for I got a decade of 'you just didn't do it right' type patronising shit that makes me think of the attitude of brain retrainers when I look back on it.

 

[N_Dina]

I tried Spironolactone for PCOS in the past (before ME/CFS) and after severe fatigue discontinued it immediately (I think the fatigue was not due to any blood pressure changes). There are also Finasteride and Flutamide which are supposed to tackle high androgens and cause similar exhaustion symptoms. Perhaps there is some research on the fatigue these medications cause?

PS: I am quite upset about the quality of academic papers in which fatigue in PCOS is presented through psychological lens, and the only advice there for drs and patients is to implement integrated psychological and sleep management strategies.

But this comment of mine may not be that helpful, as if my memory serves me well steroid profiles of people with ME have been normal in comparison to healthy controls (please correct me if I am wrong)? In one study they highlighted “disruptions in overall steroid network dynamics” though.

 

[Jonathan Edwards]

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.

That is not at all what I was implying. I agree it makes no sense.

 

[Jonathan Edwards]

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 we can say that. From what I know of experimental pscyhology it is much more likely that subpersonal processes generate both emotional signals and informational signals and the experience is a synthesis of both. Feeling angry must involve certain cells getting signals that generate a sense of feeling angry, just as seeing red must involve cells receiving signals that generate a sense of seeing red.

 

[Jonathan Edwards]

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,

As indicated, this is not any where near what I was discussing. The whole thing is extremely complex and I was speculating on various pathways breaking down in a way unrelated to any rules that people might suggest would normally apply. The main purpose was to explore the idea that fatigue accounting is likely to occur and that it might, for some completely unknown reason, undergo a regulatory failure, rather as antibodies do in RA.

 

[Jonathan Edwards]

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.

The bits you quote certainly overlap a lot with what I was considering. What I am not sure about is the effort preference idea. I don't see how a disruption of the accounting/discounting system is a 'preference'. The difference between Wallitt and Nath may be relevant as you say.

Preference would surely relate to how you respond to the accounting, not the accounting itself? If I cannot get up off the floor because my effort discounting tells me that, if I try, past experience indicates that I will both have severe knee pain and usually fall on my face causing further pain and as a result generates involuntary inhibition of my muscles that I cannot overcome, where does 'preference' come in? Does the person with Parkinson's 'prefer' to take small steps and bend forwards?

 

[Jonathan Edwards]

What is the need for a dedicated fatigue buffer?

I thin my idea is that fatigue is the 'quale' brains cells use to tell each other that they perceive cost relating to activities. I am not sure what you mean by a fatigue buffer. Cost is likely to depend imortantly on how long activity is likely to last - tendinitis, muscle cell damage, not getting adequate food and drink, no sleep, encroachment on nightfall when hyenas can get close without being seen or whatever. I can imagine that for early hunter gatherers fatigue would have been a useful discipline for ensuring that a day's activity away from the safety of a group home might be crucial to survival.

 

[MrMagoo]

Are these even useful for anybody? As someone who they weren't useful for I got a decade of 'you just didn't do it right' type patronising shit that makes me think of the attitude of brain retrainers when I look back on it.

I knew someone who was advised to stop drinking coffee at night and it improved their sleep massively.

So, that sort of person it works for.

 

[Evergreen]

The bits you quote certainly overlap a lot with what I was considering. What I am not sure about is the effort preference idea. I don't see how a disruption of the accounting/discounting system is a 'preference'. The difference between Wallitt and Nath may be relevant as you say.

Here are more excerpts that may illuminate their thinking:

The weights that are given to the energy costs, obtained rewards and avoided punishments seem to differ on a person-to-person or brain-to-brain basis. For example, to the exact same energy costs, in the exact same context, two brains can assign very different weights, which means that the feeling of effort can be different for different people. The same brain might even assign different weights to the same cost at different points in time, for example, when one is just starting a task versus when one is fatigued. In fact, this change in weighting may be an important part of the experience of fatigue itself. [bolding added]

The weights of rewards and costs are not something people choose. Rather, it seems that the valuation network may simply be wired differently from person to person, resulting in different people experiencing the feeling of effort in different ways.

Some variability in effort preference is normal. For example...[two people offered money to do push-ups may assess energy costs and rewards differently, leading to one being more likely than the other to take up the offer]. Though different, both are examples of healthy valuation network functioning. But sometimes the network does not function properly. It appears that certain neurological diseases can disrupt or even damage the valuation network, affecting the effort discounting process and radically changing the way that effort is experienced. Diseases like Parkinson's or fronto-temporal dementia, certain types of strokes and certain types of brain damage have all been found to damage valuation network brain regions, affecting effort discounting, effort preference and the feeling of effort itself. We wondered whether something similar might have happened to people with ME/CFS...

Where should I send the bill for my transcription services?!

Note in Parkinson's and FTD we're dealing with apathy - not something that has been reported or found in ME/CFS, to my knowledge.

Preference would surely relate to how you respond to the accounting, not the accounting itself? If I cannot get up off the floor because my effort discounting tells me that, if I try, past experience indicates that I will both have severe knee pain and usually fall on my face causing further pain and as a result generates involuntary inhibition of my muscles that I cannot overcome, where does 'preference' come in? Does the person with Parkinson's 'prefer' to take small steps and bend forwards?

I think (and could be wrong here) that in Parkinson's they're referring to the apathy that prevents people from getting up to take those steps in the first place, like Carly Simon described here:

"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."

and the apathy and/or motivation deficit that reduces their reward motivation on tasks like the EEfRT (unlike pwME).

I struggle to apply all of this to (at least my experience of} ME/CFS, to be honest. It feels like the punishments are the problem, not the weightings attached to the punishments. But if the weighting itself is what creates the punishment, then what changed the weighting? I'd prefer to tackle that, since I don't think that ship has sailed in the way it has in PD or FTD.

In the bigger picture, something to do with wonky neurotransmitters feels right to me - e.g. the wired feeling between overexertion and crash - so I think there's something here, or rather, in this general area.

 

[Jonathan Edwards]

But if the weighting itself is what creates the punishment, then what changed the weighting? I'd prefer to tackle that,

That is what I thought might be worth pondering, too. And the weighting IS the punishment.

 

[Jonathan Edwards]

The alternative, of course, is that the problem occurs much earlier at the dorsal root ganglion where CA10 is busy and the eccentric medium spiny neuron was a decoy!

 

[Axel]

This discussion is fascinating! But for the past few days it has been beyond my capacity to visualise and process. It feels as though there are simply ‘too many’ ideas.

The main purpose was to explore the idea that fatigue accounting is likely to occur and that it might, for some completely unknown reason, undergo a regulatory failure

I feel as though I’ve more or less grasped this line of reasoning, and so I’m wondering what might happen during the PEM, where the calculation seems to be done in reverse. We’re in a really bad way and getting worse and worse, until a peak where the system seems to decide it can revert to its usual (abnormal) calculation. (Or not quite, as Simon pointed out).
However, whilst for some of us this might be linked to getting more rest, for others who are already very immobilised, it’s not so clear. In fact, staying still offers no guarantee as to the duration of the PEM.
In my experience, I can even start counting down during one PEM for the next one, with the resolution of the first occurring between the onset of the next.

 

[Utsikt]

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.

I’m pretty sure I was sad for a long time after I lost a close family member, and it affected my mood when I wasn’t thinking of them.

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

What are you basing this on?

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.

Of course the information must exist now for it to be able to affect anything. I’m arguing that events you experience can affect neurons in a way that persist into the future, which would affect the behaviour of those neurons in the future.

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.

Because there’s no use in succeeding in a hunt if you can’t get back to shelter or your group. It serves as one of many ways to enable complex behavioural patterns that would outperform «hunt when hungry», «stop when you can’t go any further» in the long run.

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?

If it’s so elementary, why would it not exist? What’s the point of learning from being stung by a bee?

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.

It might be.

 

[Jonathan Edwards]

It feels as though there are simply ‘too many’ ideas.

It does.

 

[AliceLily]

The alternative, of course, is that the problem occurs much earlier at the dorsal root ganglion where CA10 is busy and the eccentric medium spiny neuron was a decoy!

It is going to be interesting to see all the steps. I just hope I am alive to see it. I think too the CA10 comes before the EMSN in steps and there are other steps before CA10 which could be metabolic and immune.

 

[Eddie]

I’m pretty sure I was sad for a long time after I lost a close family member, and it affected my mood when I wasn’t thinking of them.

Of course, that is very understandable. My position is that your experience is determined by whatever is immediately presented to you at the moment you experience it. You continue to feel sad because you continue to be presented with signals that are experienced as sad, not because of the past event itself. Even if that experience impacts some subconscious part of the brain, the only way you can ever have any understanding of that is if it impacts on your experience. It is possible after all that the past event never happened but I don't think it matters because you can only experience now.

Of course the information must exist now for it to be able to affect anything. I’m arguing that events you experience can affect neurons in a way that persist into the future, which would affect the behaviour of those neurons in the future.

At a broad level I agree. But all of those events impact each other at the immediate moment. Whenever they occur there is no future to be impacted except in the constructed future that exists in the brain.

Because there’s no use in succeeding in a hunt if you can’t get back to shelter or your group. It serves as one of many ways to enable complex behavioural patterns that would outperform «hunt when hungry», «stop when you can’t go any further» in the long run.

But why couldn't you get back to your group if your body is not suffering any stress that could be used as a fatigue signal? I guess it is a question of what 'thing(s)' gets added up by the brain to produce the feeling of fatigue.

 

[Hoopoe]

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.

I have to eat often to maintain adequate performance, both in daily life and when cycling. It seems more often than everyone I know, so it may be related to the illness. It is often surprising how much eating changes my state.

Re. apathy, I find that I'm frequently frustrated and stressed by the fact that I want to do things but can't. On some level, the drive is there but it's difficult to translate it into action.

 

[Jonathan Edwards]

@Eddie, I think you may be at cross purpose with Utsikt. Utsikt is saying that what cells deep in the brain experience is not just based on what is currently coming in through primary sensory channels like peripheral nerves from muscles. It is based on complex inferences derived from signals over time. Even hearing a "G" sound depends on such complex inference.

Some have argued that it seems unlikely that fatigue sensation is based on similar complex inference on primary sensory inputs over hours. To me such an inferential system makes sense since fatigue seems to be our index of how to pace and schedule activity over extended times.

 

[chillier]

Some have argued that it seems unlikely that fatigue sensation is based on similar complex inference on primary sensory inputs over hours. To me such an inferential system makes sense since fatigue seems to be our index of how to pace and schedule activity over extended times.

It kind of seems like a specifically human ability to be able to do this, at least to the extent that you have given in your examples - predicting how tired you'll be at the nth hour of a conference / how tiring it would be to carry something across edinburgh at different stages. Forming memories, associations, learning etc is something humans are so so good at in a way that my dog is able to do to a much more limited extent - and Audrey and I insist our dog is very intelligent.

In contrast the ability of dogs and humans' hypothalamus to maintain homeostasis in all other respects is probably the same.

My point being that the ability to detect specific timings of fatigue development over a long duration could come alongside the evolved ability in humans to memorise, rationalise and contextualise information - and all of that sits on top of more ancient functions of the hypothalamus.