Eccentric medium spiny neuron (eMSN)

[Kitty]

What treatments do we try? What studies do we do?

The same as with every other angle on ME/CFS, I guess? So far we've got nothing but hypotheses and anecdotes, and all we can do is keep exploring them. Pursuing several lines of enquiry at the same time is almost certainly going to produce quicker results than trying to eliminate one before moving on to another.

I experience symptoms like this in addition to post nasal drip, burning mouth and tongue plus trigeminal pain. I just cant square how this should be solely brain related.

I get a lot of 'immune'-type symptoms too; I also get vastly improved function when I'm ill with a virus. But that doesn't necessarily mean they're generated by an immune system signal. It could just as easily be a neural one.

 

[Timko]

I get a lot of 'immune'-type symptoms too; I also get vastly improved function when I'm ill with a virus. But that doesn't necessarily mean they're generated by an immune system signal. It could just as easily be a neural one.

Yes I agree. Maybe my confusion comes from brain-related vs. neural.

 

[Simon M]

my first guess is that this points to the brain networks that generate our experience of symptoms like fatigue and malaise.

The blog, and all the work behind it, are brilliant, thank you. What you may say makes sense,

I think there's one important extra piece needed to explain the illness. And that's relapses.

If it's simply perception of fatigue, and even malaise, then it wouldn't matter if we pushed through, we would simply feel terrible. But I think it's the experience of most people if they try to keep going regardless, they lose function, not for a few days but much longer term. I would be very keen to see a mechanism that could explain that as well.

I'm afraid I have nothing to offer on this myself, and I think understanding this is a big challenge.

 

[Jonathan Edwards]

If it's simply perception of fatigue, and even malaise, then it wouldn't matter if we pushed through, we would simply feel terrible. But I think it's the experience of most people if they try to keep going regardless, they lose function, not for a few days but much longer term. I would be very keen to see a mechanism that could explain that as well.

There is a theory that there are no long term memories in the brain as such but rather, every time you rehearse a memory you re-write it. For familiar face you keep re-writing them so forget what they were like before. I suspect this is a partial truth but in some respects importantly true.

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. I can imagine that at the end of each day cells synthesise material for re-tuning synaptic arrays both to facilitate what seem like useful connections and to balance that with tuning elsewhere that covers predicted costs.

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.

 

[Braganca]

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.

But how on earth would you go about treating it medically? There are no drugs for things like this are there? I guess people find it threatening bc it still sounds vague and untreatable.

 

[Robert 1973]

From the blog:

While immune and other causes for patients’ symptoms might be too heterogeneous to show up in genetic analyses, they might all converge on neural circuits that generate these symptoms.

Might it not be that causes which are too heterogeneous to show up in GWAS could show up in WGS?

As far as I understand, the assumption of the (excellent) blog seems to be that while ME/CFS may be heterogeneous there is a common pathway. Is that correct? If so, is that a safe assumption?

My view has always been that there may be more than one distinctive disease under the umbrella of the ME/CFS diagnosis, with no common pathway. Do we have any reliable evidence to discount that possibility?

 

[Jonathan Edwards]

But how on earth would you go about treating it medically? There are no drugs for things like this are there?

When I was working on rheumatoid I comforted myself that I would soon enough discover that parsnip juice was the cure. I thought the chances of finding a way to actually unwind the immunology was so remote I needed that comfort. When I finally thought I roughly understood what needed unwinding I discovered that a new type of drug that would do that was just getting licensed for something else.

The lesson I learnt was that one should constantly think outside the box but that quite likely the other box you actually need will turn out to be closer at hand than you thought. Working out what tool you need to use tends to take much longer than designing the tool when you know what it is.

Moreover, you don't necessarily need to know all the exact details of the error in the system, just where it is and its key dynamics.

 

[Creekside]

I dont think this is what the threads on any of those particular studies say. They say 'this study is interesting, lets see if it replicates'.

Different perceptions. The threads--and papers--I've read about inflammation or other persistent immune activity in ME haven't convinced me that there's anything significant found. The lack of a significant finding despite all the desperate (for publication reasons) searching seems fairly telling.

all I'm hearing since DecodeME is neurons this neurons that.

I'm mostly ignoring the genetic findings, because they didn't seem all that clear, while also biased to publish something even slightly positive. ME might simply not have a clear genetic correlation. If genes are involved, it could involve a combination of a large number of them (a liver gene biased slightly one way, and an intestine gene biased slightly, and ...), and two PWME showing nearly identical symptom patterns might have widely different sets of genes responsible.

Should DecodeME's findings of neural targets direct research? While they're not solid findings, there isn't any better information for directing research. Compared to all the other factors in judging whether to fund a study, I'd weigh it fairly low, but non-zero. I favor neural research because IMO it can explain ME's various mysteries better than the alternatives.

Because the brain only hypothesis is incredibly daunting to people like me, to whom the prospect of even another couple of years like this is unfathomable.

There's an important bias to be aware of: rejecting a hypothesis because it offers a slower reward than the alternatives. "Searching under the streetlight because it's easier." Yes, if the neural malfunction hypothesis is correct, solving ME will likely take much longer than for the hidden virus hypothesis. However, if you hinder neural research (by downplaying it and directing resources elsewhere), it will take even longer.

Immunology is more developed than neurology, and measuring immune dysfunction is easier (just take a blood or tissue sample) than measuring processes going on in a delicate and critical organ hidden beneath bone. However, if the problem does happen to be a dysfunction of a few brain cells, you could study blood samples for centuries without finding anything to solve the ME mystery.

There doesn't seem to be a push to ban support for hypotheses involving immune dysfunction, or endothelial dysfunction of any of the others. I don't get the impression that there are hundreds of neural research proposals that are held up by resources going elsewhere. I expect most of the people who could investigate ME neurology simply don't know what to look for where. ME could involve just a few brain cells malfunctioning, but which ones? We don't have a map of brain functions at that level. We can't even explain what brainfog is, much less which brain cells are responsible in what way. We might still be lacking the technology to find the dysfunction. Just think of how many new discoveries and biological surprises are reported each year.

Are EMSNs involved in ME? We don't know if they are, and we don't know if the aren't. However, there's more supporting evidence that they might be involved in ME than there's supporting evidence that kidney cells are involved, so I'd vote for a neural study over a kidney one. I'd vote for a neural study over yet another immunological one too, but as I said, it's a minor bias compared to other factors, such as the prospective quality of the study.

What is the likelyhood of that many people going into prolonged remission in studies done by meticulous MECFS researchers just randomly?

I really don't know. Humans are terrible at judging likelihoods. We tend to believe that some things are too unlikely to happen by chance, yet mathematically, they are actually quite likely. Also, some of those remissions might be highly indirect: the drug isn't working directly on the ME mechanism, but rather on an indirect pathway specific to those individuals. If a treatment does work for 1 in 1000 PWME, but you can't identify which people it would work on, and it has serious risks or costs, it's not a very good treatment. If it worked well for 1/30 PWME, I'd rate it as a very good candidate for further research. What % of success would be required to consider something likely to lead to solving ME's mechanism, rather than just a path leading to an individualistic highly indirect effect on ME?

 

[Robert 1973]

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.

If a scam bank was stupid enough to lend you money, presumably you wouldn't need to repay it. The problem would be if they lend you fake money or if you put real money on deposit with them.

 

[Jonathan Edwards]

The problem would be if they lend you fake money or if you put real money on deposit with them.

Quite so.

 

[V.R.T.]

Yes, if the neural malfunction hypothesis is correct, solving ME will likely take much longer than for the hidden virus hypothesis. However, if you hinder neural research (by downplaying it and directing resources elsewhere), it will take even llonger.

So by questioning whether the evidence all points exclusively to brain I am 'hindering neural research' now? That sounds a bit cultish.

I certainly dont think MECFS is caused by hidden viruses.

There doesn't seem to be a push to ban support for hypotheses involving immune dysfunction, or endothelial dysfunction of any of the others.

I am not avocating banning anything. You have constructed a strawman that you are arguing against.

I simply find the recent push of the idea that all immune system evidence is absolutely worthless and all genes point to the brain, so therefore MECFS is almost certainly brain only, concerning and premature.

 

[BrokenBeaktheBrave]

But how on earth would you go about treating it medically? There are no drugs for things like this are there? I guess people find it threatening bc it still sounds vague and untreatable.

And because it sounds like it falls under the remit of psychiatry or psychology.

 

[duncan]

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.

OR you know, we can just have a couple persistent pathogens which we either cannot treat or have not tried hard enough. The mechanisms behind these pathologies is interesting, to be sure, but on some level it makes more sense to eradicate the pathogen tandems.

 

[Robert 1973]

When I was working on rheumatoid I comforted myself that I would soon enough discover that parsnip juice was the cure. I thought the chances of finding a way to actually unwind the immunology was so remote I needed that comfort. When I finally thought I roughly understood what needed unwinding I discovered that a new type of drug that would do that was just getting licensed for something else.

The lesson I learnt was that one should constantly think outside the box but that quite likely the other box you actually need will turn out to be closer at hand than you thought. Working out what tool you need to use tends to take much longer than designing the tool when you know what it is.

I always find it fascinating -- and to some extent heartening -- when you write about your journey of understanding the mechanism of RA and discovering an effective treatment. Have you, or has anyone else, ever documented that journey? If not, I hope that you or someone else will. My impression is that many doctors, medical researchers and others could learn a great deal from it.

 

[Creekside]

So by questioning whether the evidence all points exclusively to brain I am 'hindering neural research' now? That sounds a bit cultish.

Not at all. I just pointed out that if the research community biases against a hypothesis that is actually correct, solving the problem takes longer. Questioning a hypothesis is healthy. You came across as ranting against the neural hypothesis.

I simply find the recent push of the idea that all immune system evidence is absolutely worthless and all genes point to the brain, so therefore MECFS is almost certainly brain only, concerning and premature.

I find the push based on the genetic studies rather weak, myself. Other evidence for it being a neural dysfunction seems stronger. I think immune activation tends to make ME symptoms worse, but I don't think the evidence for the immune system being the cause of ME is strong.

 

[Kitty]

I simply find the recent push of the idea that all immune system evidence is absolutely worthless

I haven't seen that anywhere. We haven't got that much immune system evidence yet anyway—not positive evidence, at least.

I don't think we should stop looking at the immune system, but I don't think we should ignore other avenues either. The only thing we know for sure is that the answer's well hidden.

 

[neophyte32]

There is a theory that there are no long term memories in the brain as such but rather, every time you rehearse a memory you re-write it. For familiar face you keep re-writing them so forget what they were like before. I suspect this is a partial truth but in some respects importantly true.

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. I can imagine that at the end of each day cells synthesise material for re-tuning synaptic arrays both to facilitate what seem like useful connections and to balance that with tuning elsewhere that covers predicted costs.

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.

Hello Professor, But how, then, do you explain the fact that some people—myself included—are completely bedridden for years? Could it be due to a total exhaustion of synaptic processing? Can that really bring the body to a standstill like that—accompanied by tachycardia upon standing, dysautonomia, and so on?

 

[V.R.T.]

I haven't seen that anywhere.

Well that was certainly MECFS SBs general tack in his reply.

We haven't got that much immune system evidence yet anyway—not positive evidence, at least.

No I agree but we do have a handful of findings that are very interesting and may replicate.

don't think we should stop looking at the immune system, but I don't think we should ignore other avenues either. The only thing we know for sure is that the answer's well hidden.

I absolutely don't think we should stop looking at brain! I think brain is a big part of the problem I just don't think the obvious conclusion at this point is that there is no immune involvement.

I agree, the answer is well hidden. We haven't had a lot of immune tissue studies afaik and there could be hidden signalling there.

 

[Jonathan Edwards]

Can that really bring the body to a standstill like that—accompanied by tachycardia upon standing, dysautonomia, and so on?

There are neurological diseases that can certainly do all those things.

 

[Simon M]

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. I can imagine that at the end of each day cells synthesise material for re-tuning synaptic arrays both to facilitate what seem like useful connections and to balance that with tuning elsewhere that covers predicted costs.

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 am not clear how this leads to sudden and large functional loss. Imagine you, in an instant, lose most of your walking ability. One the PEM has gone, you try again. Still your legs fail, plus you feel terrible, After PEM, you discover even more loss. I'm not saying this loss has to be permanent, but it might happen suddenly, and recovery of the loss, if it happens, is very, very slow.

I know that some people find discussion of mechanisms like this threatening

It's more that it might not adequately address what people experience in relapses.
And does this theory, like CBT and LP/neuroplasticity, predict that 'hurt does not mean harm' ie. symptoms might exacerbate, but nothing is really lost?

There are neurological diseases that can certainly do all those things.

Can you spell out what happens there biologically in specific disease examples?