Eccentric medium spiny neuron (eMSN)

[Utsikt]

I appreciate that the metaphor is a bit abstract. I am suggesting that the neurons keep accounts of things in a way designed to optimise future decisions on actions by constantly re-tuning synapses. In doing so the system 'borrows' the use of computational pathways, maybe vaguely in the way a Scrabble player might borrow extra letters from another set being used on the next table to make words. If the system does not pay back this usage options for optimising computational routines in the future can get more and more limited. What are borrowed are computational pathways dependent on particular patterns of synaptic tuning.

I still don’t understand, but that’s okay!

I think many find it frightening to realize that research into the brain aspects of ME/CFS is still in its infancy; we are starting almost from scratch.

It’s not like we’ve got much more to go on in any other domain either. For some reason I find that a bit comforting because there are probably many low hanging fruits left that good researchers would be able to pick off in an instant.

I want to get to the answer, whatever it is. I just worry we're dismissing the immune aspect rather rapidly and prematurely.

I don’t think I’ve seen anyone dismissing them. To the contrary I’ve seen many being unwilling to accept null results, and e.g. the Germans seem intent on pursuing the immune angle no matter what.

It’s fairly obvious the neurons are involved somehow just from looking at symptoms, so it’s about time they got some focus as well. And as others have mentioned, it doesn’t look like a zero sum game.

 

[Simon M]

Can I ask why you would put so much emphasis on relapses? I know it was a prominent feature in old ME descriptions but not sure if they are an essential aspect of ME/CFS.

A good question. I agree they are not essential to ME/CFS, but equally I have always understood that they were a common experience, especially for those with severe ME, where I believe people often become severe through one or more relapses rather than though gradual decline. Until you had put it like that, I hadn't realised that some would find this view surprising.
My view is based partly on people I know, as well as my own experience, but mostly from reading and hearing many accounts of people with ME.

Is there data showing that relapses are characteristic of ME/CFS compared to other diseases?

You won't be surprised that there isn't, as far as I am aware, but that is a characteristic of the field; there isn't even good data on this for PEM, which is odd for what most consider the defining feature of the illness.

This seems to me just an issue of terminology. Members constantly emphasise that PEM can involve a major step down in function long term. How is that different from 'relapse'? I am personally not that much of a fan of the focus on PEM as a term and think long term relapse is much more important but I find it difficult to see what the distinction really is.

Interesting. I had also seen that link. What isn't clear is how often PEM leads to long-term loss of function, and even how long they mean by long-term. I'm also not clear if they mean the PEM and loss of function are both long-term (though a lot of people point out that when severe/very severe, PEM often becomes constant). 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. That would give us:
PEM - frequent
PEM with relapse - much rarer.
In my experience, which might be unusual, relapses always start with PEM, but the PEM does not persist for anything like as long

 

[ME/CFS Science Blog]

A good question. I agree they are not essential to ME/CFS, but equally I have always understood that they were a common experience, especially for those with severe ME, where I believe people often become severe through one or more relapses rather than though gradual decline.

Maybe its also a different interpretation of the term 'relapse'? To me that suggests frequent oscillation between good and bad periods like in multiple sclerosis or in depression.

When it comes to prognosis I've seen/heard multiple trajectories including people whose decline was gradually or who stayed the same for years/decades. The one thing that stands out to me is that for the majority (not all) ME/CFS isn't like a degenerative disease such as Alzheimer, Parkinson, ALS, etc. Suspect this means that ME/CFS doesn't involve ever increasing tissue damage or neuron loss.

there isn't even good data on this for PEM, which is odd for what most consider the defining feature of the illness.

Yes, I do think there's sufficient data that PEM is a characteristic feature of ME/CFS, just not that PEM is unique to ME/CFS as some people claim.

So when it comes to the core issues a model for ME/CFS needs to take into account I tend to focus on things like:
- certain infections and female sex are risk factors
- enormous symptom burden
- chronic but not degenerative
- no clear tissue damage or other measurable pathology
- possibly also the bimodal incidence age as shown in your recent paper.

 

[Kitty]

Interesting. I had also seen that link. What isn't clear is how often PEM leads to long-term loss of function, and even how long they mean by long-term. I'm also not clear if they mean the PEM and loss of function are both long-term (though a lot of people point out that when severe/very severe, PEM often becomes constant). 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.

Part of the problem is that the usage is quite individual, but might also be defined by severity.

For me, PEM and relapse are so different they couldn't be confused. PEM is a reaction to over-activity (it never comes as a surprise) and it has a trajectory a bit like a head cold. It affects me for between one and five days, but none of those days are the same symptom-wise. I go through the process of having a cold/PEM and then recovering from it.

A relapse isn't necessarily connected to anything, and is a fairly abrupt step-change in severity level. The time scale is years, not days. At least two thirds of that time is a plateau, where I'm past the worst but don't improve any further. That often seems to last around two years; the beginning of the end is usually signalled by noticing things that need doing, which I was oblivious to before. I begin to tackle small tasks; if they don't knock me straight back down again I know I can start testing my limits.

 

[AliceLily]

This is an interesting discussion about relapses and PEM. Relapse to me would be a shift to a severer level. I have never noticed a relapse because my ME/CFS has always gone along a line of mild to very severe and then to moderate. And this has been my pattern for the 30 years of having ME/CFS.

PEM frequency and intensity follows severity level for me. Very severe ME/CFS = constantly going through PEM and what feels like layers of PEM on top of each other, very hard to get a 'breather' (respite) from it and then it could be an hour or few hours 'breather' then back in PEM.

Relapses can also sound like someone had recovered completely the illness and then got sick again. So I think that term can confuse the perception of others or has too many variables in the understanding what is actually meant?

 

[Jonathan Edwards]

For me, PEM and relapse are so different they couldn't be confused. PEM is a reaction to over-activity (it never comes as a surprise) and it has a trajectory a bit like a head cold. It affects me for between one and five days, but none of those days are the same symptom-wise. I go through the process of having a cold/PEM and then recovering from it.

But if, as is reasonably claimed by many members, activity like GET leads to long term and signficant worsening, otherwise know to me at least as 'relapse', then you seem to be using a limited definition of PEM different from others. If PEM is only brief worsening, then fine. Maybe long term worsening or relapse should be separated. But PEM is defined as worsening and said to be so important precisely because it has long term implications does it not?

I think we are getting tied in knots by words rather than disputing people's experiences here. But if members cannot agree then maybe onlooking medical people may be a bit confused too?

 

[AliceLily]

PEM is a sign you have done too much, it will give you a bout of deeper malaise (extremely unwell, ill). The more you provoke this bear with too much activity over time you will deteriorate to a severer level. PEM is a sign, a warning that it will get worse and increase in intensity over time if you do not halt activity levels.

 

[AliceLily]

But PEM is defined as worsening and said to be so important precisely because it has long term implications does it not?

The implications are that it is important because it is a sign that needs to be listened to. Not listening to it telling you to halt activity will cause more serious deterioration to the severer levels. If those with diabetes ignore high blood sugars as a sign...

 

[ChronicallyOverIt]

I’ve never had a “relapse” without PEM. Sometimes PEM lasts a week, rarely that becomes new baseline. In the beginning it was harder for me to get into that “stuck” new baseline state. I’d oscillate and could take bigger PEM hits. Slowly though I would never recover back to the same baseline previously. As my new baseline was worse these big PEM hits put me into the latter where it would stick around. There have definitely been some PEM episodes where I’ve fully expected it to be my new normal but will wane over the course of week-weeks.

I think there was a good ball in a stuck declining valley animation I watched. Where the ball rolls down a hill of every lower valleys. It oscillates up the sides of valleys but never really goes back up to the last valley, always down to the next eventually.

 

[ChronicallyOverIt]

Sorry one other thing, it seems that these relapses are independent of sleep the night of exertion. I’ve overexerted felt like crude and got good sleep but still sometimes this is a relapse. I’ve over exerted slept like crap and had the PEM turn into a lowered baseline.

 

[Felis Catus]

pwME/CFS can relapse after a vaccination or trying a new medication, which may or may not be examples of a relapse without PEM.

 

[AliceLily]

pwME/CFS can relapse after a vaccination or trying a new medication, which may or may not be examples of a relapse without PEM.

I'd call that a 'hit' like the flu that tipped me into very severe ME/CFS. It's a sudden hard hit.

 

[Yann04]

I don’t like the term relapse. It implies I have better in between periods. When for me its like a river it’s basically only gone downhill. Sometimes it’s mostly flat and sometimes its a waterfall, but the direction (downhill) is always the same.

 

[Felis Catus]

I don’t like the term relapse. It implies I have better in between periods. When for me its like a river it’s basically only gone downhill. Sometimes it’s mostly flat and sometimes its a waterfall, but the direction (downhill) is always the same.

Seconded

 

[Snow Leopard]

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.

The problem is that fatigue is just... Not sensed like that, as in there is no evidence (in humans or animal models) for predictive systems at the brain level you propose - any predictive systems are cognitive in nature and that is separate from our sense of fatigue. Peripheral fatigue sensing signals can be blocked - the result is dramatic, an absence of central fatigue, but rapid peripheral fatigability - because the spinal and supraspinal feedback mechanisms that modulate the motor cortex excitability (thus requiring more upstream "sense of effort" to maintain activity) and also turnover of motor units used as they fatigue by modulating spinal excitability.

An argument could be made about these fatigue sensing pathways being sensitised in the brain, but not predictive in the way you suggest, just general overreactivity.

 

[Kitty]

But PEM is defined as worsening and said to be so important precisely because it has long term implications does it not?

Yes...and no. I guess it depends what we're talking about.

If we're describing the various presentations of ME/CFS, we need to include the model where some people seem able to limit PEM to short term episodes for years without triggering major relapses. And even relapses don't necessarily mean permanent worsening; some people will eventually recover to their previous level.

We suspect that repeated PEM episodes close together can eventually lead to relapse, which is why pacing is advised. Some people won't recover back to their previous level after a relapse, and it's impossible to predict whether or not an individual is in that category.

Biologically it very likely is all part of the same thing, but in the absence of treatment recently ill people need to understand why pacing is recommended. It's difficult to explain this without the invoking—at least implicitly—the concepts of mild PEM that may only be symptomatic for half a day, and crashes that can take someone from living independently to needing care. PEM is pretty much inevitable, but relapses may not be.

 

[Jonathan Edwards]

The problem is that fatigue is just... Not sensed like that, as in there is no evidence (in humans or animal models) for predictive systems at the brain level you propose - any predictive systems are cognitive in nature and that is separate from our sense of fatigue.

Sorry @Snow Leopard but I think that is off target. The nervous system involves multiple layers of inferential computations, most of which are 'sub-personal' even if we think it is 'me' thinking. Some of the more peripheral ones we can study but most of them are beyond analysis with current methods.

I am not actually talking about predictive systems, at least not in the sense of predictive coding. We have been having discussions pointing out that a predictive coding model gives the wrong answer for an 'FND' type model. But predictive processes are not just 'cognitive', or at least they are basic to all sensation at low level. The classic case of prediction is vertigo and the classic study Pat Merton having his eyeball moved by a colleague with forceps.

How fatigue is sensed is clearly very complicated and is affected by things like cytokines and also by sleep over periods of hours or days. To suggest that we know all about it and can therefore exclude any further complexity seems to me unwarranted!

And I come back to the fact that we cannot explain disease with the rules of normality. The rules of normality explain normality. In disease the rules no longer apply in the same way. The task is to understand in what circumstances the rules might fail to apply.

 

[Snow Leopard]

How fatigue is sensed is clearly very complicated and is affected by things like cytokines and also by sleep over periods of hours or days. To suggest that we know all about it and can therefore exclude any further complexity seems to me unwarranted!

The other sensory systems you mention necessitate prediction, but fatigue sensing doesn't need to be real time and there is no real way of the brain to do any sort of complex whole-body homeostasis computation, and it doesn't really need to. This is why there isn't much prediction involved because there doesn't need to be. The need of such a system has to be justified, it is not enough to say oh it's complicated and we don't know

 

[Jonathan Edwards]

no real way of the brain to do any sort of complex whole-body homeostasis computation

How on earth can one say that? Ants do whole body homeostasis computations when they find their way home. Most homeostasis is done by a bit of brain - hypothalamus. If two separated offcuts of a bamboo plant can accurately count for a hundred years and flower simultaneously I think we need to respect the remarkable ability of even single cells to do complex computations over long periods.

 

[chillier]

How on earth can one say that? Ants do whole body homeostasis computations when they find their way home. Most homeostasis is done by a bit of brain - hypothalamus. If two separated offcuts of a bamboo plant can accurately count for a hundred years and flower simultaneously I think we need to respect the remarkable ability of even single cells to do complex computations over long periods.

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?