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

[Utsikt]

I have not read it, but I remember this study being mentioned elsewhere:

General anesthesia alters the circadian clock of bees that are known for being very good with schedules.

https://www.pnas.org/doi/10.1073/pnas.1201734109

 

[Jonathan Edwards]

I sometimes sense the need for lunch at 11.30 am and sometimes at 4 pm

OK, there can be quite a bit of leeway, but you do not expect dinner on getting up in the morning.

I am not sure if you are referring to problems with timing since having ME/CFS. That would be interesting, but my comment referred to a normal healthy state. Most people have a reasonable sense of timing of things, even if sometimes that is kyboshed by distractions and tends not to work in unusual circumstances like DWP assessments!

 

[V.R.T.]

Pretty much the first noticeable thing that went wrong for me during what I suspect was a prodomal onset was my circadian rhythmn being thrown completely out of whack, with both insomnia and hypersomnia, for what it's worth.

 

[Eleanor]

OK, there can be quite a bit of leeway, but you do not expect dinner on getting up in the morning.

I am not sure if you are referring to problems with timing since having ME/CFS. That would be interesting, but my comment referred to a normal healthy state. Most people have a reasonable sense of timing of things, even if sometimes that is kyboshed by distractions and tends not to work in unusual circumstances like DWP assessments!

No, this was also when I was healthy. Another example: for years I was frequently late to pick up my children from school, even though that was a fixed time point every day, week after week for years - because I had no sense of when 3.30 was approaching unless I constantly checked the clock, and it's easy to get diverted from doing that.

Maybe it fits into your picture: if there is this internal time-passing-accounting function, in some of us it's weak because of some factor or other (edited to add: or it isn't weak per se, but it gets overridden by something else that's unusually strong for some reason?), and that might also be a risk factor for the type of processing that goes awry in ME/CFS.

 

[Jonathan Edwards]

Maybe it fits into your picture: if there is this internal time-passing-accounting function, in some of us it's weak because of some factor or other (edited to add: or it isn't weak per se, but it gets overridden by something else that's unusually strong for some reason?), and that might also be a risk factor for the type of processing that goes awry in ME/CFS.

As I mentioned before, I am not raising this timing ability so much because it is something that might go wrong in ME/CFS. I am raising it to indicate that our brains must be keeping complex accounts of activities during the day. It has been suggested that there is no evidence of such accounting but I would say that most people's daily experience shows that there must be. The only evidence for the way the brain senses what the body is doing may be through metabolic routes (I am not quite sure how that works) but since we have absolutely no methods at present for studying how the brain does more complicated things with data from the senses that is hardly surprising. We are not going to have mechanistic evidence in an area where there are no known methods for gathering that evidence. Nobody knows how we add two and two for instance.

 

[jnmaciuch]

As I mentioned before, I am not raising this timing ability so much because it is something that might go wrong in ME/CFS. I am raising it to indicate that our brains must be keeping complex accounts of activities during the day. It has been suggested that there is no evidence of such accounting but I would say that most people's daily experience shows that there must be. The only evidence for the way the brain senses what the body is doing may be through metabolic routes (I am not quite sure how that works) but since we have absolutely no methods at present for studying how the brain does more complicated things with data from the senses that is hardly surprising. We are not going to have mechanistic evidence in an area where there are no known methods for gathering that evidence. Nobody knows how we add two and two for instance.

Every single one of the examples you’ve provided point to the existence of a part of the brain that can roughly track the passage of time, not anything to do with “activity tracking”. The two seem to be interchangeable for you in a way that is baffling to me. The only argument you’ve provided for why all activity is logged in reference to an internal clock is that it seems to you like this ought to be the case, in ignorance of all evidence to the contrary.

The explanation that makes the most sense is that we have a set of mechanisms that modulate continued activity after a period of cognitive and/or physical activity and mediate the phenomena of central or mental “fatigue”, of which the known components are largely metabolic in nature, and on top of that we have another mechanism which roughly tracks the passage of time, which may also utilize metabolism. There might well be some issue with clock genes in ME/CFS. An issue with clock genes does not support the idea of a neural accountant for activity.

If I’m “focusing too hard on one aspect of the problem,” the opposite problem is getting stuck on a wild goose chase based on an unfounded a priori assumption that there must be some higher order cognitive process explaining everything.

 

[Jonathan Edwards]

which the known components are largely metabolic in nature

But as I pointed out that is imply because those are the things people know how to measure.

 

[jnmaciuch]

But as I pointed out that is imply because those are the things people know how to measure.

And I’m not seeing evidence that those findings should be ignored, or that a separate and purely theoretical higher order cognitive process tied to an internal clock explains activity “tracking” any better than an extension of those known mechanisms.

 

[Kitty]

my comment referred to a normal healthy state. Most people have a reasonable sense of timing of things, even if sometimes that is kyboshed by distractions and tends not to work in unusual circumstances

Very poor sense of clock time is normal in healthy people with dyscalculia. Eating and sleeping times are pretty random, and you can never place past events in a time frame because you have no sense of how fast or slowly time passes.

Same for conscious calculation. Anything beyond basic arithmetic is a closed book, and there are odd anomalies like learning to read the right-hand side of an analogue clock quite readily but needing several more years to get the left-hand side.

But dyscalculia isn't especially common, and there might be some aspects of internal time keeping that are normal.

 

[Jonathan Edwards]

And I’m not seeing evidence that those findings should be ignored,

Well, there isn't any reliable evidence for any metabolic abnormalities in ME/CFS as far as I am aware, so I am not sure why one should go down that route, but for the key factor is that in terms of time profile a story based on a failure to cope with metabolic demand simply doesn't make much clinical sense. In common with most other physicians the idea that metabolic deficit is the key problem for ME/CFS just doesn't seem plausible. And it is hard to relate to the well documented shifts in sleep cycle and PEM following mental demands that for all we know don't have much to do with using metabolites.

 

[jnmaciuch]

Well, there isn't any reliable evidence for any metabolic abnormalities in ME/CFS as far as I am aware, so I am not sure why one should go down that route, but for the key factor is that in terms of time profile a story based on a failure to cope with metabolic demand simply doesn't make much clinical sense. In common with most other physicians the idea that metabolic deficit is the key problem for ME/CFS just doesn't seem plausible. And it is hard to relate to the well documented shifts in sleep cycle and PEM following mental demands that for all we know don't have much to do with using metabolites.

As we’ve hashed out on many other threads, you seem to be operating from a very limited idea of what metabolic involvement could possibly mean compared to what I and others have in mind. Misinterpreting any mention of metabolic involvement to mean “failure to cope with metabolic demand” (which neither I nor any researcher I take seriously is actually endorsing as a statement) is just the same strawman over and over.

To your other points, there is quite a well-characterized bi-directional relationship between metabolism and circadian rhythm. The paper I linked that you didn’t read is one small part of that.

The recent paper I posted relating mtDNA [edit: regulation] to calcium signaling following repeated neuron firing is just one example of a metabolic mechanism which could explain PEM after cognitive activity (and [edit: calcium-dependent mtDNA release] happens to be the same trigger which causes the known interferon response in muscle after physical activity). So neither of your points can be exclusively explained by higher order cognitive processes or make metabolic involvement less plausible.

To avoid derailing the thread further and going around in the same circles, I’ll leave it at “agree to disagree on all points”.

 

[EndME]

As we’ve hashed out on many other threads, you seem to be operating from a very limited idea of what metabolic involvement could possibly mean compared to what I and others have in mind. Misinterpreting any mention of metabolic involvement to mean “failure to cope with metabolic demand” (which neither I nor any researcher I take seriously is actually endorsing as a statement) is just the same strawman over and over.

To your other points, there is quite a well-characterized bi-directional relationship between metabolism and circadian rhythm. The paper I linked that you didn’t read is one small part of that.

The recent paper I posted relating mtDNA [edit: regulation] to calcium signaling following repeated neuron firing is just one example of a metabolic mechanism which could explain PEM after cognitive activity (and [edit: calcium-dependent mtDNA release] happens to be the same trigger which causes the known interferon response in muscle after physical activity). So neither of your points can be exclusively explained by higher order cognitive processes or make metabolic involvement less plausible.

To avoid derailing the thread further and going around in the same circles, I’ll leave it at “agree to disagree on all points”.

I understand that vague references to "something to do with synapses/neurons" are not be more insightful than "something to do with brain-metabolism" but is this not essentially all the same? If the suggestion is simply that there is diminished synaptic signalling that could explain symptoms of ME/CFS are you not largely in agreement or have I missed something?

 

[jnmaciuch]

I understand that vague references to "something to do with synapses/neurons" are not be more insightful than "something to do with brain-metabolism" but is this not essentially all the same? If the suggestion is simply that there is diminished synaptic signalling that could explain symptoms of ME/CFS are you not largely in agreement or have I missed something?

I’m not sure “diminished synaptic signaling” is related to anything I’m talking about from a metabolic perspective. The idea I’m refuting is that there must be some neural accounting mechanism independent of metabolism that logs activity and gets “wiped” with rest. I’m bringing in metabolism since we already have a couple metabolic findings with good explanatory power for why performance worsens with prolonged activity.

Obviously there’s much more to learn in both cases to fully explain mental and physical fatigue from activity, and even cumulative fatigue from both (I’ve discussed elsewhere some preliminary findings pointing to adenosine buildup in the anterior cingulate cortex). But the evidence we do have points to the fact that the body “logs” activity through sensing of actual byproducts of cellular activity, rather than any independent higher cognitive process that infers activity through time or some other proxy.

So we obviously don’t know where the problem re: "fatigue" actually is in ME/CFS—it might be reflected in actual metabolic substrates that haven’t been investigated yet, or maybe dysfunctional modulation of those sensory inputs at neurons. But invoking a synapse-based “memory” log for activity basically just invents a brand new theoretical system that we have no reason to believe actually exists when we already know the metabolic sensing mechanisms that fulfill that function in the body. And you can’t really explain ME/CFS through an issue in a system that we have no reason to believe exists in the first place.

 

[EndME]

I’m not sure “diminished synaptic signaling” is related to anything I’m talking about from a metabolic perspective.

Above you mentioned the mtDNA study that looked at calcium-dependent mtDNA release and synaptic signaling and used that as a possible metabolic mechanism to explain cognitive PEM. I assumed that the explanation was metabolic in the brain but that the symptoms produced come from neurological consequences that follow those and not say caused by metabolic problems in your leg? (Edit: I think I have misinterpreted what you were saying here as you used it as reference for IFN signalling in muscles, but I must admit I don't understand the link).

If there is a "refresher button" that isn't correctly working in ME/CFS or the logging of events has gone haywire or the integration of these memory events passes a threshold quicker than it should one, or just generally some housekeeping processes aren't working one will inevitably have to invoke a mechanism nobody currently understands, at least that is my understanding. My understanding was that neuroscientists don't really understand what is going on here (at least that was the response I got when I asked some), so there might not a priori be a reason reason to invoke anything in particular, but I can understand that it is insufficient to explain something that isn't explained with something that currently isn't explained.

 

[jnmaciuch]

Above you mentioned the mtDNA study that looked at calcium-dependent mtDNA release and synaptic signaling and used that as a possible metabolic mechanism to explain cognitive PEM. I assumed that the explanation was metabolic in the brain but that the symptoms produced come from neurological consequences that follow those and not say caused by metabolic problems in your leg? (Edit: I think I have misinterpreted what you were saying here as you used it as reference for IFN signalling in muscles, but I must admit I don't understand the link).

Ah sorry, my theorizing there was that repeated synapse firing could result in mtDNA release and subsequent interferon production in neurons. The downstream effects would then be mediated by interferon receptors, which could be on other neurons, or microglia, or some other celltype. We don’t know the exact mechanisms by which interferon induces feelings of malaise and fatigue, we just know that it does and that peripherally administered interferon is capable of reaching the circulation—which would likely be how interferon release in the muscle could lead to systemic symptoms, if it is actually the culprit and gets amplified enough from local signaling.

Either that, or both peripheral and central neurons can sense interferon and initiate symptoms—we know that temperature sensing can occur through the same ion channels on both peripheral nerves and neurons in the hypothalamus where that peripheral input is integrated, so perhaps a similar dual mechanism here is not so far fetched.

If there is a "refresher button" that isn't correctly working in ME/CFS or the logging of events has gone haywire or the integration of these memory events passes a threshold quicker than it should one, or just generally some housekeeping processes aren't working one will inevitably have to invoke a mechanism nobody currently understands, at least that is my understanding. My understanding was that neuroscientists don't really understand what is going on here (at least that was the response I got when I asked some), so there might not a priori be a reason reason to invoke anything in particular, but I can understand that it insufficient to explain something that isn't explained with something that currently isn't explained.

You’re right that we don’t have complete answers for those questions (no moreso than most other facets of biology), but we do have pretty good partial answers—for example, we know that blocking inputs from those peripheral metabosensing neurons substantially interferes with expected trends of physical performance decline.

So if we know that those inputs are pretty central to fatigue-related phenomena even if we don’t understand every detail, it makes no sense to posit an additional unknown mechanism completely separate from them. The only reason to believe a refresher button or logging system exists is to explain why performance declines after continuous activity and improves with rest—but the knowledge we already have for fatigue-related metabolic dynamics make that additional mechanism essentially superfluous.

To make a crude but apt metaphor, it’s the difference between not knowing much about how cars work but guessing that an engine warning light came on due to a problem with the engine or engine sensors vs. guessing that the light is tied to an atomic clock that the car uses to track mileage somehow and the count must have gotten thrown off due to some unknown quantum phenomenon. It’s all equally unknown to that person, but the second option clearly has a much higher burden of proof to clear before it should be taken seriously.

 

[Snow Leopard]

I’m not sure “diminished synaptic signaling” is related to anything I’m talking about from a metabolic perspective. The idea I’m refuting is that there must be some neural accounting mechanism independent of metabolism that logs activity and gets “wiped” with rest. I’m bringing in metabolism since we already have a couple metabolic findings with good explanatory power for why performance worsens with prolonged activity.

What I don't understand is why there would need to be such a top-down predictive mechanism in the first place. There are molecular feedback mechanisms in place - in the CNS we have neurovascular coupling. (and ventilatory responses to low oxygen).

I think too many people (especially doctors and scientists who claim to have evidence/science-based views) are using the analogy of proprioceptive prediction (which needs to exist because nerve feedback is too slow) and trying to apply it to domains where it simply doesn't need to exist.

 

[chillier]

As I mentioned before, I am not raising this timing ability so much because it is something that might go wrong in ME/CFS. I am raising it to indicate that our brains must be keeping complex accounts of activities during the day. It has been suggested that there is no evidence of such accounting but I would say that most people's daily experience shows that there must be.

Must there be? Wouldn't a simpler explanation be that all those things you described (Eg meeting for half an hour, going to lunch) amount to a routine that works like a rube-goldberg machine - A ball bounces off a spring, then gets whacked by a mallet and goes down a slide - and the timing of all those events are contained within the kinetic properties of each of the individual components. One the spring has sprung it's done its job, the ball has moved on and the memory of how long the spring took to spring is completely forgotten immediately by the whole system.

In other words, when you have a meeting the sense of timing of how long the meeting is is just kept within the sets of neurons immediately involved in the execution of the meeting itself, combined in large part with external cues such as the sun setting slightly, the person opposite you looking a bit tired, a slight sense of hunger creeping in, all suggesting it's time to move onto the next thing. I don't see why there needs to be a totting up of anything outside of that.

 

[bobbler]

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.

That last para doesn’t apply to me.

I absolutely have my ability to sense time passing internally ie without external cues completely impacted by me/cfs. And have done since start of the illness. And it massively varies within my illness on different days and sometimes independently to whether I know I’m in a crash or tired or am ‘going slow’.

The shower used to be the most obvious place for this because I could get out of what I thought with all genuineness (and been ‘on’ for the whole time so not just a day off chill out go with the fairies shower) was 15-20mins and it has been 45mins or more. It was so weird as I hadn’t zoned out or dropped anything. But yes it happened all the time when I was more tired just because the cumulative exhaustion adding time secretly to each element snuck up vs the accounting too.

And it didn’t just happen with showers of course it’s just that’s where I was most away from looking at clocks. I’d have to ready every morning staring at a tv channel that had a clock in order to keep on schedule. The amount of reminders needed for work meetings etc. I lose track of time talking.

But then part of it all makes sense to me because the brutal life I’ve had of having to push thru and make work due to alternative of ‘you can live on the streets’ keeping not small unhectic jobs with significant moderate me/cfs or worse and that involved working on an hours sleep on at least one day in a week on a pretty common basis and all sorts of tactics to make the body ‘perform’ ie seem to be just about ticking boxes of being there at right time whatever the cost to everything about me. And I’ve had uni courses where at least I didn’t have to and could follow my body a bit more outside exams but the work was still there.

And I know how different my body ‘runs’ and then ‘feels’ when I pushed myself into a ‘high involved zone’ grinding down maybe with lots of caffeine and anything else that helped as a tactic to get my brain going ur body moving and then pushing it until adrenaline clearly kicked in to make it easier.

I’ve mentioned clock genes and proteins before because I find it fascinating as if some part in this just isn’t renewing or lasting as it should, particularly when stuck in an ‘above threshold’ ongoing environment. It’s not the cliche programmed ‘circadian rhythm out of sync’ that the simplistic types want to term it as and assume can be trained and fixed but the clock parts broken so some drain with time maybe but others drain with exertion or whatever health inside body bits are affecting my health too.

The only time I’ve sensed maybe it was coincidence or maybe it was relief short-term from this hard to describe thing was when, as I had a serious enough flu on top of normal things, I was on double steroids for my at that point trying out a higher dose. And was flat on my back with extra help for a fortnight and definitely not attempting any shower etc. The relief of waking and sleeping at normal ish times and that being without alarms and didn’t just slip away by upsetting itself for no reason a few days in, well it had been so long it was weird how suddenly I realised it was just easy when my body could. Easy in comparison to how extreme and impossible and just catching water with hands and obvious it was a fools errand it is at all other times to thus.

I don’t know whether the ‘sense of how much time passed’ changed during that fortnight because I was otherwise really pretty ill.

It very much felt like my body changed where now the exertion side of things plays a part on how much time has gone. I don’t have that same ability to build into myself a routine or clock no matter how brutally I or others forced regiment on myself and believe me that’s what before me/cfs I had ingrained as how it worked so kept assuming. But the body just like exercise didn’t lead to fitness just did not any longer do the training in routine. I had to instead cognitively plan round it based on getting to know it and how it would be based on what it had done to have any chance of controlling to perform anything at any specific point in time. That’s a huge load. But it makes at least more sense to others now my body is so broken there’s less left for them to extract from me under coercion.

 

[bobbler]

Very poor sense of clock time is normal in healthy people with dyscalculia. Eating and sleeping times are pretty random, and you can never place past events in a time frame because you have no sense of how fast or slowly time passes.

Same for conscious calculation. Anything beyond basic arithmetic is a closed book, and there are odd anomalies like learning to read the right-hand side of an analogue clock quite readily but needing several more years to get the left-hand side.

But dyscalculia isn't especially common, and there might be some aspects of internal time keeping that are normal.

That’s interesting. And makes sense particularly given projects I’ve done in slightly tangential to that area re: computation of space vs numbers.

since me/cfs I’ve had the sense of time issue and definitely can’t guess at how long it’s been since x happened unless I’ve a date that suck in my brain. But , maybe weirdly to this, I’m on the opposite end of the spectrum maths-wise, or was, but I think even with the huge depletion me/cfs has given my maths brain (and it feels like that happened almost in three clear ‘hits’ weirdly for that bit) I might be a tiny fraction of what I was but would still be in a top % of a normal distribution for most maths stuff - just don’t think I’d be able to have the working memory for the new or refreshing myself on old to me complex stuff that wasn’t automatic (i might be able to mindlessly pick up processing thru calculations either integration or imaginary numbers etc as long as it was just practice on the ‘do to learn’ or look at the pic and sense the graph , but I bet that’s day-dependent given I do puzzles enough to know some days I do that and I’m spot on and others I do the same and I feel the same and I’ve just filled in all wrong answers) .

BUT having said that I am good at maths but even before I got too ill to work had to get used to there being times where I just couldn’t add 2+2 reliably (just like I’d have times I’d be to tired to get my own name in the right order literally even when I was trying to introduce myself professionally several times over) . Yet if I had a week I had to process complex analysis of several thousand datapoints using excel and it was an afternoon to a days task then it was no biggie because I was obviously picking a good time.

And I think my sense of time passed varies just as fluidly

I’m enjoying this because I’m thinking these ‘what would x only or y only extreme look like’ and then ‘what if the issue is that x and y no longer became linked’ type thing very good to see happen.

 

[hotblack]

but the knowledge we already have for fatigue-related metabolic dynamics make that additional mechanism essentially superfluous.

Isn’t one factor here that we see these mechanisms for activity in healthy people but don’t see them or know why people are more fatigued when ill? Not necessarily with ME/CFS but generally. Additionally almost everyone describes their ME/CFS fatigue as very different from this normal fatigue. That would seem to be people’s motivation for looking for an additional, and indeed different, mechanism?

Must there be? Wouldn't a simpler explanation be that all those things you described (Eg meeting for half an hour, going to lunch) amount to a routine that works like a rube-goldberg machine

Or perhaps just a memory of half hour meetings being about half an hour? We seem to find familiar or routine things more predictable and less familiar or entirely new events less predictable. I’m not sure how much this requires high level accounting as much as common learnt behaviours?