How would a deficit in processing of physiological signals lead to ME/CFS?

Hoopoe

Senior Member (Voting Rights)
Something like this has been mentioned by @Jonathan Edwards on multiple occasions, and the term memory has come up, and I'm curious what is meant and how it would work.

I'm getting the impression that the idea is information related to physiology accumulating over the course of the day in neurons, and there being insufficient decumulation of that information.
 
the term memory has come up, and I'm curious what is meant and how it would work.

I've been assuming memory is something to do with signalling not returning to normal after being activated, e.g. by an infection. What keeps it going once the stimulus is gone? If it's a purely reactive process, it shouldn't 'remember' the state of activation.

I might have misunderstood though.
 
If it's a purely reactive process, it shouldn't 'remember' the state of activation.
Feedback loops can get locked into a state. In digital circuits, one "memory element" is a flip-flop, which is a bistable positive feedback loop.

In mathematical terms, I think what you mean by "purely reactive" is an equation of first order (derivative = a scalar?). When you have higher order equations, you can get responses that could be considered "memory" ... and oscillations and other chaotic behaviour.
 
I think there may be confusion between two discussions.

I have talked about disease memory in the sense that it is where the information lies that keeps a disease going - in a cancer cell clone or in autoantibody producing B cell clones maybe.

I think the reference here is to the idea that information collected by the brain during the day that is normally forgotten or at least sorted and filed by the next day during sleep may not be sorted properly. So symptoms like being unrefreshed in the morning might arise because information has not been 'forgotten' during sleep properly.

That would not be a cause of ME/CFS as a whole. Some disturbance of brain function would cause the forgetting problem which would then cause symptoms.
 
I think the reference here is to the idea that information collected by the brain during the day that is normally forgotten or at least sorted and filed by the next day during sleep may not be sorted properly. So symptoms like being unrefreshed in the morning might arise because information has not been 'forgotten' during sleep properly.

I'm interested in this idea. Would this information be memories of events, or more things like information about physiological?
 
I'm interested in this idea. Would this information be memories of events, or more things like information about physiological?
In my head it’s neither of those things, but more related to a “neurological recuperation period” that however has not been pinned down in neuroscience (it's not sufficient to just say "plasticity"). However, every healthy person will be familiar that after having a hard day of cognitive load where the brain can take no more and one is confused the thoughts being much clearer in the next morning and everything sitting nicely. This sorting happens continuously throughout the day (for example after a light bit of cognitive work someone will already be refreshed after a relaxing walk or a nice lunch), but maybe sleep has some special role as well. I think the idea is that that this recuperation is not working properly or getting triggered at a much lower threshold in ME/CFS. The memory overwriting is not working correctly, rather than memory not working correctly.
 
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Either or both. I was interested in one o the genes that came up on DecodeME being linked to the CLOCK circadian rhythm gene, but I foget which one at the moment.
 
I have a potential loss of function mutation in one allele of the PER1 gene. It works together with the CLOCK gene and some others to create the circadian rythm. This probably doesn't have a serious impact on its own but the genes in this category seems like good candidates for risk factor genes.
 
The problem is no one has the foggiest idea of how this could possibly happen without actual brain damage. All the ideas about brain 'plasticity' are just vague and not demonstrated as to how this leads to such pathology.
I’m in agreement, synaptic pruning does happen but I don’t see a logical jump between that occurring in actual learning and memory-formation processes and a neurological “memory” mechanism tracking activity that gets “wiped” with rest. All the evidence we have for central fatigue, poor cognitive performance after prolonged effort, and even the negative effects of sleep deprivation point to byproducts of actual cellular activity and metabolism, whether peripherally or in neurons themselves. I would need specific details of how a neural “accounting mechanism” actually works in order to see explanatory value in the theory—otherwise, it’s superfluous to the details we already know.
 
Interestingly, given the paper I linked above, it seems pretty likely that this gene’s role in circadian rhythm is mediated by its role in mitochondrial fission and fusion.
 
even the negative effects of sleep deprivation point to byproducts of actual cellular activity and metabolism


"To gain a comprehensive, unbiased perspective on molecular changes in the brain that may underlie the need for sleep, we have characterized the transcriptomes of single cells isolated from rested and sleep-deprived flies."

Yer, well, you would do it that way wouldn't you?

Why is travelling involving flight transits more tiring than a ten mile walk?

I don't think there is any good evidence either way, to be honest.
People write reviews, and Tweet tweets, about what they want to get grants on.
 
Maybe I’m extra brain foggy today, so I can’t make heads or tails of most of your reply.

Why is travelling involving flight transits more tiring than a ten mile walk?
The paper outlines a mechanism in a specific cluster of neurons in which their mitochondrial capacity mediates sleep behavior in flies. It is a mechanism of metabolism-based regulation, just one that isn’t equivalent to global “caloric expenditure” in the crude layman’s sense. I don’t think anything useful will come from discussions where any mention of metabolism is consistently misinterpreted as a matter of overall ATP consumption or other drastically oversimplified notions. The comment here is a non-sequitur

I don't think there is any good evidence either way, to be honest.
Two of my examples—peripheral metabolite sensing mediating central fatigue and adenosine buildup after repeated neuron firing—have been confirmed in multiple studies in humans, mice, other animal models, and in-vitro. Both I and Snow Leopard have posted links repeatedly in other threads, so I won’t rehash them here. I’ve critically analyzed those papers myself and haven’t found cause to dismiss the findings—you’re welcome to post on those threads if you find methodological issues that make those results worthless.

In comparison, a synapse-based neural accounting mechanism for tracking activity is pure conjecture with no support in the literature beyond vague references to “plasticity,” as Snow Leopard has already mentioned. If any positive evidence emerges that a synapse-based accounting mechanism independent of metabolic sensing actually exists, I’m happy to revisit. In the mean time, the evidence we have points in other directions.
 
All the evidence we have for central fatigue, poor cognitive performance after prolonged effort, and even the negative effects of sleep deprivation point to byproducts of actual cellular activity and metabolism, whether peripherally or in neurons themselves.
DecodeME results aside, I agree that almost everything we see or know about ME/CFS, especially clinical presentations, is the downstream consequences.
 
Maybe I’m extra brain foggy today, so I can’t make heads or tails of most of your reply.

I think you are focusing too hard on one aspect of the problem.

I have not read the fruit fly paper this time around but my guess is that it describes a mechanism that may provide a regular diurnal clock system through some cyclical use of a metabolic pathway. That would make sense as fruit flies like us are likely to benefit from an 'invariant' 24 reference frame system for timing activities.

But we also know that the human brain superimposes complex varying behavioural structures on this background. I sense the need for a cup of tea at 4.15 pm, not at 11.30 a.m. or 7.30 p.m.. When working my autopilot would manage a vast complexity of timed behaviours, like bringing an outpatient interview to a close after approximately 30 minutes, getting to Grand Rounds, grabbing a sandwich on the way and then rechecking for emails before meeting a PhD student. Complex brain accounting for activity is not a speculation. It is eveyone's universal experience.

Fruit flies may have less complicated schedules but even the spotted crake can be relied on to start calling at precisely 9.15 pm in May on the Poland/Belarus border. But not in April. Migrating crakes integrate over complex mixtures of information to arrive at precisely the same pool year on year.

But you might argue that illness tends to be driven just by simple metabolic levels. I am sceptical. You were not on the forum when some years back I described my wife's illness in some detail because it had some features that overlapped with very severe ME/CFS. It appears to have been triggered by an antimalarial medication, which I understand affects basic metabolic functions selectively, but not entirely so, in plasmodia.

The illness started with hallucinations but these stopped after stopping the drug. What persisted was a psychotic illness that included major changes in sleep cycle and an inability to eat, such that she had to be put on parenteral nutrition to keep her alive. She would always take just enough water to avoid renal failure but was progressively less able to take food and reached under 40kg. Fortunately she was treated and is now entirely healthy.

I do not think for a minute that ME/CFS is the same thing as she had but the DecodeME findings remind me of the sense that the same sorts of systems may be disrupted in both illnesses.

One thing that particularly interested me is that the psychotic state varied during the day. In febrile illness fever tends to have two peaks, with one at night and one in the early afternoon. My wife's illness was worst at night and for a period of weeks at least would almost completely lift around 11.00 a.m. for an hour or so, such that she had insight into her ill state. By mid afternoon a 'different person' had returned. The psychiatrists recognised this phenomenon.

So my analysis is that although we have a CLOCK system that may use a simple metabolic mechanism to standardise the 24 day frame, that frame interacts with extremely complicated accounting processes that assess activities, achievements, and needs way beyond simple physiology (giving a patient full attention or getting to Grand Rounds).

The example of travelling intrigues me because in this case sitting around for hours with nothing to do, but in several different places, with uncertainties about when transitions will occur, appears to shorted my circadian timing frame consistently by about one hour where vigorous physical (off piste skiing) or mental (attending a key small conference) activity does not. So I suspect that even the metabolic clock system can be de-tuned, which it obviously can when you spend a fortnight in a new time zone.

And then of course there is the study in mice suggesting that complement proteins are needed to forget things from day to day, because complement is involved in synaptic plasticity.
 
So my analysis is that although we have a CLOCK system that may use a simple metabolic mechanism to standardise the 24 day frame, that frame interacts with extremely complicated accounting processes that assess activities, achievements, and needs way beyond simple physiology (giving a patient full attention or getting to Grand Rounds).

The example of travelling intrigues me because in this case sitting around for hours with nothing to do, but in several different places, with uncertainties about when transitions will occur, appears to shorted my circadian timing frame consistently by about one hour where vigorous physical (off piste skiing) or mental (attending a key small conference) activity does not. So I suspect that even the metabolic clock system can be de-tuned, which it obviously can when you spend a fortnight in a new time zone.

What we were taught at UCL as an undergraduate was that the CLOCK system is slightly out of sync with the day night cycle and if you put a human (or mouse) in total darkness or lightness it will shift - backwards or forwards by some magnitude depending on the person. The day night cycle constantly resyncs your CLOCK circadian rhythm by interacting with light sensing cells in your retina (not the ones that you see with but different ones). If you're travelling this day-night cycle may be interrupted somewhat which could go part of the way to explaining what you describe maybe.

The CLOCK protein and maybe proteins dependent on CLOCK has been implicated in ME/CFS genetics and patients report of unrefreshing sleep - so I think it could be a reasonable hypothesis that this background system is directly affected.

The sense of timing of daily events that you've described (having a feel for how long half an hour is, when to have lunch etc) are not things patients experience distortions in (are there diseases in which this sense of timing is lost?), so I'm not so sure - but I guess you're implying it would be a different more unconscious part of this timing apparatus that's affected.
 
are not things patients experience distortions in

I don't think that would be suggested. I am invoking the detailed accounting that controls such behaviours as evidence of an extended accounting system across the day. Actions are constantly being logged with reference to the (nearly) constant clock. The next day you want to have the whiteboard wiped and the process started afresh (refreshed).
 
I sense the need for a cup of tea at 4.15 pm, not at 11.30 a.m. or 7.30 p.m.. When working my autopilot would manage a vast complexity of timed behaviours, like bringing an outpatient interview to a close after approximately 30 minutes, getting to Grand Rounds, grabbing a sandwich on the way and then rechecking for emails before meeting a PhD student. Complex brain accounting for activity is not a speculation. It is eveyone's universal experience.

I'm interested to know what the evidence basis is for this being 'everyone's universal experience', because it isn't mine at all. To use your examples, I sometimes sense the need for lunch at 11.30 am and sometimes at 4 pm, and there's no way I'd be able to bring an interview to a close after approximately 30 minutes unless I had been frequently checking the clock. When I had to have a DWP assessment by phone, I thought at the end of it that we'd probably been talking for 30 or 40 minutes - it was actually over two hours.
 
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