Eccentric medium spiny neuron (eMSN)

[Eleanor]

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.

So (trying to understand this very simplistically) if something causes these particular accountancy bits of the brain to miscalculate, they then send out signals to the rest of the body indicating that it urgently needs to rest. That could result in perceptions of being in pain, needing to lie flat, heightened reactions to noise, etc., but might also include signals from those bits of the brain to the digestive system to slow down operations, or to other bits of the brain to slow down higher-order cognitive processes, and so on? Not just feelings involved but functions.

 

[Jonathan Edwards]

I am not clear how this leads to sudden and large functional loss.

Nor am I. But then I have no idea why sometimes if you decide to type at the bottom of the page on Microsoft Word it suddenly change font and size. Maybe the point I am trying to make is that this very strange behaviour of PEM is something that is reasonably plausible for a very complex learning and predictive control system like a brain but way outside anything we expect from the liver or even from the adaptive immune system.

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.

This actually happens to me because of pain inhibition in my knees. I can fight the pain and walk five miles but if I step on some uneven ground I can completely lose the ability to control my fall and it can take me two or three minutes to get in a position from which I can stand again. The situation is different, yes, but there is a similar fragility and extended time frame that makes sense in neural terms but not in much else.

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?

If the brain is as complicated as Microsoft Word then maybe we shouldn't expect to be able to fit a story with personal experience but it seems to me much easier to conecive that for a neural mechanism than for any other.

And no, I am not saying that hurt does not mean harm. Malware on your computer can do any amount of harm, despite all the hardware being normal. (I am sometimes tempted to think Microsoft Word is malware.) If you download it to your hard disc that is real harm. You may need to buy a new computer and very likely will lose all your files. Everything is lost.

To my mind these basic action-regulatory functions performed by the striatum and that go wrong in things like Parkinson's disease, are nothing to do with psychology. 'Neuroplasticity' has been commandeered by the psychodynamics people and completely misrepresented. Learning how to dribble a football or to play the cello in tune is neuroplasticity. You cannot unlearn either of those at the behest of a psychotherapist so why should someone with ME/CFS with a putative shift in synaptic tuning be able to unlearn that by 'positive thinking'.

 

[Jonathan Edwards]

Not just feelings involved but functions.

Absolutely.

 

[ME/CFS Science Blog]

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.

Just speculating but from an evolutionary perspective the advantage of experiencing symptoms such as fatigue and malaise was probably to keep the organism still and quiet - to conserve energy or avoid pathogens from spreading. So if the animal pushes against this signal and remains active, it would make sense if there was a feedback loop where symptoms become worse to ensure that the organism 'listens' and actually becomes still and quiet.

So perhaps people with an infection or another disease like MS experience this to a lesser extend as well. Maybe this pattern is more clearly visible in ME/CFS because here the symptom signal is chronic and pushed to the extreme without other pathology obscuring the picture. In other diseases, people only experience the same severity of symptoms such as exhaustion and malaise if they are at a very advanced stage and other (sometimes life-threatening) complications take center-stage.

People with ME/CFS often have difficulty recognizing PEM and relapses in the first year(s) of their illness so I assume it wouldn't be easily spotted in patients with advanced AIDS, cancer, MS, Parkinson, etc.

 

[Jonathan Edwards]

Not just feelings involved but functions.

I have a neuroscience friend called Ken Augustyn, also interested in human consciousness, and although we disagree on a lot we agree on the idea that conscious mental events may be only a tiny fraction of a mass of similar events going on in the brain. These involve 'perceiving' signals and making inferences and predictions and giving commands but they are invisible to 'us'. What is wrong with the mind/body interaction theory is that 98% of the control of the body by brain is not 'mind' in any psychological sense. The ability of this 'rest of the brain' to be in charge is shown by dreams. The brain can concoct complicated plausible stories and display them to the mind without the mind having the faintest idea where they came from. While doing so it can completely paralyse the body so that the 'mind' senses it needs to run away but can't.

The conscious bits of the brain are a bit like a managing editor that checks the copy before sending it off to print. The real work of making a newspaper is down to hundreds of journalists, photographers, page designers, advertising managers and so on. They are what we call the brain. The eccentric medium spiny neurons are probably the page designers who work out which stories can go together on what pages long before the managing editor gets sight of them. in ME/CFS maybe they are saying 'I think it would be better to have just one sentence on a page.' The whole thing grinds to a halt and there is nothing the managing editor can do about it.

 

[Simon M]

Nor am I.

None of the analogies given really land for me, that's could be partly biases, but we are trying to explain one of the most dramatic and life-changing aspects of the illnesses, and I would like something more robust than this.

And no, I am not saying that hurt does not mean harm. Malware on your computer can do any amount of harm, despite all the hardware being normal. (I am sometimes tempted to think Microsoft Word is malware.) If you download it to your hard disc that is real harm. You may need to buy a new computer and very likely will lose all your files. Everything is lost.

I wasn't aware that problems with malware damages hardware, unless programmed to do so, and I'm not sure this matches the brain network situations described here, which still seem rooted in signalling ideas (which may be a huge part of the explanation of ME/CFS, but I don't think can be enough.

to my mind these basic action-regulatory functions performed by the striatum and that go wrong in things like Parkinson's disease, are nothing to do with psychology. 'Neuroplasticity' has been commandeered by the psychodynamics people and completely misrepresented.

A thread on uses and misuses of neuroplasticity would be fascinating. Is there one?

that this very strange behaviour of PEM is something that is reasonably plausible for a very complex learning and predictive control system like a brain but way outside anything we expect from the liver or even from the adaptive immune system.

PEM is easier to explain, I think. I see relapses as different from PEM because they are on a much longer timescale, and functional loss way outlasts PEM .

Just speculating but from an evolutionary perspective the advantage of experiencing symptoms such as fatigue and malaise was probably to keep the organism still and quiet - to conserve energy or avoid pathogens from spreading. So if the animal pushes against this signal and remains active, it would make sense if there was a feedback loop where symptoms become worse to ensure that the organism 'listens' and actually becomes still and quiet.

Yet before ME/CFS, when I pushed through while struggling with an infection, I felt absolutely terrible and so stopped, as the body intended. But I didn't experience relapses.

People with ME/CFS often have difficulty recognizing PEM and relapses in the first year(s) of their illness so I assume it wouldn't be easily spotted in patients with advanced AIDS, cancer, MS, Parkinson, etc.

Maybe, but it isn't a convincing explanation for arguably the most dramatic aspect of this illness, and the process that leads from mild to severe. I don't think anyone is saying that is true of AIDS or MS.

I'm hoping there is an explanation of relapses that fits with these neuron-based ideas (the evidence pointing to neurones looks very strong to me) but I think we are still a long way from that.

 

[Verity]

I generally agree with @ME/CFS Science Blog. But I think @V.R.T. raised a good point with the clinical presentation

I think I said this before and dont want to derail this thread any further, but 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 may have missed an answer to this in this thread—skimming due to PEM—but I am confused about this too. I get a runny nose and sore throat with bad PEM, which to my layperson self seems immune. Is there some reason to think this could be entirely neurologically driven, and why these specific symptoms if so?

Would be very interested to hear thoughts on this!

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?

I think Audrey Ryback said that based on the fairly robust bimodal age peak data, we are looking at one clinical entity or two.

 

[Kitty]

Imagine you, in an instant, lose most of your walking ability.

Maybe the reverse of diseases like MS, where normal signals are sent via damaged nerves?

If inhibited signals were being sent across normal nerves, it would also affect walking ability. But the degree and type of inhibition could be altered very rapidly, and invisibly.

 

[ScoutB]

I don't see that these two angles need to be pitted against one another in a zero-sum way. There is almost no neurological research into ME/CFS, but also (unfortunately) so little really good immune/lipid/pick-your-favourite-category research that both could easily grow if you somehow magically put S4ME members in charge of research funding.

Also, I could be wrong, but if a bunch of serious neurologists started working on ME/CFS, I assume they'd be pulling in at least some funding from generic sources beyond the ME/CFS charities, not to mention generating a lot of noise around the idea of funding ME/CFS research -- could we not end up with a net increase in resources by pulling in a new field?

For folks asking how neurological problems could manifest ME/CFS worsening, I was reading about GABAnergic neurons a little while ago ("the main inhibitory neurons in the adult brain"). Oversimplifying: but roughly when a GABAnergic synapse fires the post-synaptic neuron is (usually) less likely to fire (in response to inputs from its other synapses) and so less likely to pass along signals. Granted, they're involved in so many things it's easy to draw connections. For instance, here's a study arguing "Firing of these [GABA] interneurons probably contributes to the development of central fatigue during physical activity." (Snow Leopard found this one.)

But I'm interested in this because it seems plausible to me it could be involved in a broken feedback loop.

This study: Drug-induced change in transmitter identity is a shared mechanism generating cognitive deficits reports that after PCP, meth (or manual electrical stimulation of the dopamine neurons activated by PCP and meth), mice had a large number of excitatory glutamatergic neurons transform into (inhibitory) GABA-producing neurons instead. They also developed cognitive problems. Via several experiments (including reversing the change with clozapine and restoring cognitive function) the researchers argued this glutamate/GABA switch was the *cause* of the cognitive problems.

Exercise causes a large release of dopamine and a lot of neuronal activation, followed by synaptic plasticity-type changes (this statement intentionally vague until I dig up the parkinson's papers I was reading on this and get my details straight). In mice, one study reported that exercise caused a similar switch to inhibitory GABA in certain neurons: Exercise enhances motor skill learning by neurotransmitter switching in the adult midbrain.

My very hand-wavy take away from this has been that 'synaptic plasticity' is not just forming memories and associations, but also the re-balancing of excitatory and inhibitory signals. If some activity (drug use or exercise) causes a lot of excitability it may be followed by adaptations of a more inhibitory type. I'm also seeing studies studies of situations where it seems like the brain is too quickly adapting to its own endogenous sedatives that act on GABA receptors (allopregnanolone in PMDD), causing drug-withdrawal like symptoms as these fluctuate.

It seems conceivable that you could get a pathological feedback loop where neurons get stimulated and the natural plastic response to that stimulation goes wrong in some way that sets up the stimulation->response problem to be even worse next time.

 

[Jonathan Edwards]

I wasn't aware that problems with malware damages hardware,

It doesn't. The damage is to the functional output. The only point of a hard disc is its functional output so that is harm.

 

[Jonathan Edwards]

PEM is easier to explain, I think. I see relapses as different from PEM because they are on a much longer timescale, and functional loss way outlasts PEM .

OK, but invoking long term relapse is to me a key part of what makes the PEM concept distinct - and others seem to take that view.

My analogies are not intended to be close parallels, just indicators that when it comes to nerve networks all sorts of long er term shifts are recognised even if we have no real understanding of the mechanics.

 

[Robert 1973]

If the brain is as complicated as Microsoft Word then maybe we shouldn't expect to be able to fit a story with personal experience but it seems to me much easier to conecive that for a neural mechanism than for any other.

And no, I am not saying that hurt does not mean harm. Malware on your computer can do any amount of harm, despite all the hardware being normal. (I am sometimes tempted to think Microsoft Word is malware.) If you download it to your hard disc that is real harm. You may need to buy a new computer and very likely will lose all your files. Everything is lost.

I wasn't aware that problems with malware damages hardware, unless programmed to do so, and I'm not sure this matches the brain network situations described here, which still seem rooted in signalling ideas (which may be a huge part of the explanation of ME/CFS, but I don't think can be enough.

It doesn't. The damage is to the functional output. The only point of a hard disc is its functional output so that is harm.

Are computer hardware/software analogies useful in trying to understand or explain brain mechanisms? I thought not.

 

[Concentric_Spiral]

The eccentric medium spiny neurons are probably the page designers who work out which stories can go together on what pages long before the managing editor gets sight of them. in ME/CFS maybe they are saying 'I think it would be better to have just one sentence on a page.' The whole thing grinds to a halt and there is nothing the managing editor can do about it.

If this theory is correct, what does it mean for treatment prospects? Seems like a challenging neurological problem to solve.

 

[Utsikt]

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 don’t understand what is being borrowed. Is it from an account of «perceived reasonable amount of actions for period X» inside one or more neurons, or are you talking about the «fuel» that goes into firing a neuron or physically (chemically?) passing the signal from one neuron to the next?

And does the brain even keep track of exertion in that way with regards to producing e.g. fatigue? I think I remember @Snow Leopard talking about how you can block the sense of fatigue from exertion by blocking the signals from afferent nerves (but don’t quote me on that).

 

[duncan]

My analogies are not intended to be close parallels, just indicators that when it comes to nerve networks all sorts of long er term shifts are recognised even if we have no real understanding of the mechanics.

Your analogies simply serve to deflect, at least potentially.
You - it seems to me - keep reducing our pathology to some kind of mistake of perception. Er, a magical signaling error of some sort which suggests to me we are not really sick, we just think we are due to that weird signaling issue? Please correct me if I'm wrong.

 

[mariovitali]

Exercise causes a large release of dopamine and a lot of neuronal activation, followed by synaptic plasticity-type changes (this statement intentionally vague until I dig up the parkinson's papers I was reading on this and get my details straight). In mice, one study reported that exercise caused a similar switch to inhibitory GABA in certain neurons:

Dopamine release is also triggered by food consumption such as having chocolate , social interactions and by accomplishing goals. What makes exercise-derived dopamine being the culprit?

 

[mariovitali]

Just speculating but from an evolutionary perspective the advantage of experiencing symptoms such as fatigue and malaise was probably to keep the organism still and quiet - to conserve energy or avoid pathogens from spreading. So if the animal pushes against this signal and remains active, it would make sense if there was a feedback loop where symptoms become worse to ensure that the organism 'listens' and actually becomes still and quiet.

This implies that fatigue and malaise experienced during infection feels exactly the same as Post Exertional Malaise. Is this really the case?

 

[Jonathan Edwards]

Are computer hardware/software analogies useful in trying to understand or explain brain mechanisms? I thought not.

I think they are often misused but I see no reason why they should not be relevant. In terms of recent generations of computers software exists as a mass of tiny microstructural changes in pathways used by the machine to compute outputs. Those tiny structural changes are set up as a result of signals inputs from outside. They can be reversed by further signal inputs, although that may be tricky to achieve. Some software includes inherent tendencies to 'crash' and generate nonsense outputs or stop output.

Brains operate on a very similar basis. Synapses are re-tuned constantly in response to signal inputs, effectively shifting the software status with tiny structural changes. The DecodeME gene CA10 is directly involved in this synaptic tuning by influencing availability of neurexin molecules.

 

[Jonathan Edwards]

If this theory is correct, what does it mean for treatment prospects? Seems like a challenging neurological problem to solve.

See post #147

 

[Jonathan Edwards]

I don’t understand what is being borrowed.

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.