ME/CFS as a biological information processing problem

I have recently had thoughts organising in my head so wrote them down to help. This is maybe a continuation of discussions or ideas in A Thought Experiment on Muscles and possibly outright theft of other people’s ideas but maybe I can pretend I’m standing on the shoulders of giants or it helps the discussion along.

There is no damage there is no persistent infection. There are just a few cells in a particular place in the body shouting at each other.

Think of this as a problem of communication, of noise, of interfaces. The body is an information processing system. Our nerves carry information in to and out of the central nervous system. Different sets either bring information in from our senses or send out information to control our actions.

When they do, that is activity, activity creates signals. This is normal. But for some reason in people with ME these signals may be creating other signals between the nerves and the immune system. If there is just a little activity the signals are small, maybe nothing too bad happens, if there’s more activity then perhaps it does.

Think of this as two people talking, they can communicate well in a quiet room, one to one, but if it’s crowded with lots of people talking or there’s loud music playing it gets harder. Maybe the conversation gets out of sync, maybe information is lost.

A lot of biology seems quite probabilistic. Our immune systems vary enormously in precise makeup which allows us to fight off different pathogens and survive as a species but also means we have different susceptibilities. So exactly how this communication problem arises will be variable between people to a degree, how dense receptors are or exactly what receptors or signalling molecules look like.

To me this all explains a lot of the issues we have and the variability and why different people can be affected in slightly different ways. But the same underlying concept is at play.

When we perform a physical or mental activity there is an increase in synaptic activity. So there is a proportional increase in this type of aberrant ME signalling. And perhaps the signals between our nervous and immune system bounce back and forth like echoes in a cave and that confuses things further. But there are many factors which can mean exactly how varies.

Maybe only the inputs are overloaded at first but it can increasingly affect the output gates too which means we start to have issues with coordination or whatever. The build ups may be very localised at the nerves or synapses, at the interfaces. So we don’t find problems when looking elsewhere.

This could also be why passive activity is easier. Or we may be okay with one activity but not multiple at the same time. And why things can stack and accumulate over time. It takes a while for whatever extra signals are being created to dissipate and this rate of reduction varies too. If we’ve passed a threshold where things are cascading and echoing it’s even harder.

And perhaps why immune triggers are an issue for some of us. Certain things may be increasing overall immune activity and signalling which as a sort of accidental byproduct is increasing this localised effect too.

I’d be interested in what other people think.

 

Absolutely fair Thanks Trish. It’s definitely something I thought about before sharing. It doesn’t add anything in terms of evidence or understanding. Just represents me getting my head around ideas floating around.

 

I take different view. This is how I always worked. You try and enunciate a very broad brush analogical or metaphorical dynamic model and wait for the people in the room to fire off questions. Which signals?
Why doesn't it stop?
Why doesn't it get worse and worse and never stop?
Why does it stop people walking across a room?

And on and on until the wine bottles are empty and everyone has to go home for supper.
And if each of those people has a deep knowledge of some part of the biology, or just knows how to recognise a sloppy argument, you get there.

 

I think that once we get an explanation of the biomedical cause(s) of ME, we're going to need an explanation for lay people, and analogies are going to help.

 

If we put all S4ME minds to it we can have a pretty good idea of what ME/CFS is, or what the main two ME/CFS's are, by Christmas, is my guess.

 

I missed/forgotten the bit about the two kinds - is it a signalling kind and a 'something wrong with synapses' kind, that would amount to the same thing in terms of symptoms?

That would be an excellent Christmas present. Are you thinking that your paper with Jo Cambridge and Jackie Cliff might be pushed back that far?

 

This is the bit that interests me. A lot of people struggle to recover, but a minority feel much better in the early stages of an infection.

The first AZ Covid vaccine was like the treatment I've been imagining, the one that won't need anyone carefully sanding the edges off the outcome stats because it'll be a profound change. This one only lasted five to six days, but those days were glorious.

So sometimes, your people having a conversation—one that perhaps progresses to an argument—goes the other way. Rather than being fuelled by beer and testosterone, it gets damped down by a giant spliff and Mick O'Brien's Bb pipes. Or maybe the participants are so busy trying to calm down a fight that's threatening to break out next door, they forget about their own disagreement.

Why, though? Why is it disastrous if there's raised voices in the lounge, but if actual fisticuffs breaks out in the tap room it's amazing? It's all in the same pub.

 

The question that I always ask is: how would this explain PEM?

Signaling could be functioning fine. It could be the (brain's) response to the signal that went astray instead.

Inflammation is inevitable and often-delayed consequence of all activities. And the inflammation delay and duration nicely coincide with typical PEM delay/duration. Bad PEMs lasting more than a few days could be explained with the hypersensitivity getting worse and then rebounding after weeks or months. The hypersensitivity tends to get worse even after a typical PEM in my experience. I used to be more vulnerable than usual for a few more days after a typical PEM is over.

 

Well, you've gotta start from somewhere. With practically nothing known, metaphors and speculations are as good a place to start as any. In fact, I'd rather start there than some random anomaly that "scientific studies" have been spewing out. As long as the speculation does not contradict the observed anomalies.

 

It could be, but the delay seems unlikely to occur in brain since brain signalling is very quick. Signalling in immune cells can take hours.

I don't think that is the case. Normal daily activities are not associated with subsequent inflammation, although some cell activation and trafficking may occur. The problem that I have with the idea of local inflammatory responses to use is that by and large PEM does not seem to be limited to the bit that was used. If it was there would be a neat test where a patient exercised only brachioradialis in the right arm and had pain and weakness in brachioradialis in the right arm four hours later. Generally speaking people seem to find they are generally exhausted and ill, regardless of which bit of them exerted.

 

Hi @hotblack! I’ll take a position bridging @Jonathan Edwards and @Trish—I certainly agree that spinning wheels like this can be useful (I spend more than enough time doing it myself), it just needs to be backed up by plausible mechanisms from the literature, or pinpoint an exact place where the literature is incomplete.

Here is my (hopefully helpful) attempt to poke holes to guide your further digging:

1) Unlike autism, which also seems to share many of the potential features you describe here, ME/CFS is not present at birth. How would a problem like you describe be acquired later in life such that an individual can get “stuck” but some may also recover? How could it be triggered by e.g. viral infection?

2) I’ve already said on the Thought Experiment thread that I am skeptical of neural pathways that could explain the symptoms of ME/CFS without somehow sensing metabolic input. Snow Leopard pointed to systems within the brain that sense and regulate its own metabolic capacity, suggested an extension of those systems to large muscle groups, and including some interesting links to nerve systems involved in “central fatigue.”

If your proposed system does not include changes at a metabolic level, then it needs to include explanations for how those systems responsible for central fatigue are stimulated independent of metabolic input. If your explanation relies on sensitization thresholds or something else affecting the neuron, it would have to explain why only those particular neuronal systems would be affected as opposed to all neuronal systems.

3) as a general point, I’m not against the idea of neuro-immune crosstalk potentially driving an exacerbated immunological response leading to PEM. But what really needs to be fleshed out here is the specifics. What specific signals might be at play here? Are they normally triggered in healthy people as well? Is the difference in ME/CFS a difference in trigger, or simply a difference in magnitude of response to the same triggers as in healthy people? What’s the constant thing that stays “broken” to facilitate that aberrant transient signaling?

obviously no need to respond to all of these points unless you want to. I have my own opinions on all these points, but would be happy to be challenged by someone else’s well-thought-out responses.

 

Just as a devil’s advocate point, my experience of more immediate PEM after I started taking a stimulant seemed very clearly to start in the places that were being “used” and spread from there.

It’s likely that I was able to sense this at all because stimulants induced a prostaglandin response that wasn’t there normally. If my previous experiences of delayed PEM was primarily mediated by something like interferons on their own, I probably wouldn’t feel much locally until the signaling escalated to a point to reach the circulation.

However the end result, if I was to keep pushing myself through the immediate pain, was the same system-wide flu-like symptoms at a later time point as in delayed PEM. Which leads me to believe that the new prostaglandin signaling is part of the response to the same trigger causing both immediate and delayed PEM, it’s just suppressed somehow (or perhaps all the right pieces aren’t in place to trigger it fully) in the absence of a stimulant.

[Edit: also several mild/moderate folks on here including myself have reported that the parts of the body that were most “used” definitely feel more affected during PEM even when there are system-wide symptoms]

 

These are the sort of discussions, sharing of ideas and questions I’d hoped to help along. Lovely to see. Thanks everyone for joining in.

Of course I’m in the fortunate position of not really being able to answer any of them with mechanistic detail, but maybe others are! Having space to explore ideas (especially in an accessible way as @Sasha and @poetinsf allude to) is hopefully useful for non scientists and scientists alike.

And I enjoy thinking about them too, so if anything comes up I’ll give it a go, but tbh I have no explanations for the questions like @jnmaciuch poses, I don’t know why we’d need an explanation of metabolic input or metabolic capacity because I don’t really understand what they are yet let alone where they fit in, but thanks for giving me more to explore.

And while I like @Kitty ’s question and framing and do still feel qualified to talk about pubs despite my loss of familiarity with them over recent years, I don’t have any good explanation. But shall also feed it all in and ponder these things some more.

 

Brain function is more than just signals; there are morphological changes and changes in the components that probably don't fit into the category of "signals". If glial cells are constantly adding or removing certain molecules from synapses, which affects signal transfer, and ME somehow changes the rate of molecular transfer, that will affect communication and processing. My hypothesis for my ME-caused double-vision is that something is altering the feedback loop that directs one eye. It might be undesired crosstalk of signals, or it might be a change in transfer function due to structural of functional alterations of those specific cells. In other PWME, it might show up as hypersensitivity, muscle weakness, digestive problems, etc.

Just as an example, normally slightly raised levels of a cytokine alters glial function, which in turn alters various neural processing functions, which in turn alters large-scale changes in the body. Does PEM cause muscles to function improperly in a way that causes pain, or does PEM cause some neurons to work differently giving the perception of pain even though the signals from the sensing nerves are normal?

My physically-induced PEM had a consistent 24 hr delay, which (from what I read) matches IFN-g rise after exertion. My cognitively-induced PEM had a much shorter (< 1 hr) and less consistent delay, so one possibility is that PEM involves glial cells, and cognitive effort triggers those glial cells more or less directly, while triggering by cytokines has a delay due to how that part of the immune system works. My ME symptoms initially came as a type IV food sensitivity, which involves t-cells and has a characteristically long and consistent delay. I was really impressed at a 48 hr delay with only a few minutes variation. 48 hrs after consuming a food, +/- a few minutes, the symptoms would flare up, and my temperature would rise a few tenths.

Here's an experiment: have a subject ( who experiences PEM after a 24 hr delay) do the exertion and monitor IFN-g. Does it correlate with the onset of PEM symptoms? Not proof, but if it's consistent for many subjects, it might be meaningful.

I see PEM as glial activation, and it doesn't matter what the activation signal is or where it came from, whether it's lifting weights or a viral infection or an injection of the cytokine.

 

It could be but which glia and which pathway is activated? Without that detail I doubt one can make any useful predictions.

 

I've had thoughts along these lines before. The devil's-advocate-phamaceutical-engineer on my shoulder from my previous career always asked me if this wasn't "just some sort of "bro-science" in my head" but I also believe in @Jonathan Edwards line of thinking. Somewhat akin to a clinician like House MD "Tell me something that could make sense, anything, and we work it out from there."

I've been wondering at times - and I'm not trained in neuroscience so bare with me - if the different symptomology in patients could have something to do with their "entrenched" neural pathways. That somebody who's more "trained" to use their cognitive on a daily basis - say a scientist - is more susceptible to cognitive dysfunction while an athlete might feel physical symptoms such as muscle weakness more. Not saying these would be their only symptoms, but maybe the ones that are most debilitating for them.

Question obviously being whether these two patients are just "more aware" of their respective symptoms, as that's their "livelihood", their "thing" (and it doesn't have to be career based, just "personality" based if that makes sense) - or whether there could actually by a physiological background to this, like neural pathways that are used more frequently, that have had more reinforcement to build strong connections over the years are for some to me unknown reason more susceptible to disruption than less strong connections. (Again, scientist in me is asking for data on this, pragmatist is just spitting out ideas.) @jnmaciuch maybe it doesn't have to be hereditary, but rather be based on learned neural connections over the years? What physiological mechanism could this be? Good question.


For some to me still inconceivable reason, low to medium doses of gabapentinoids (say 75-150 mg pregabalin) do wonders to my cognitive dysfunction most of the times. It feels like the "pressure" in my forehead is somehow relieved and I can start thinking straight again. As if somehow everything was firing at the same time before and the synaptic inhibition through (VGCC inhibition) is somehow able to turn down the noise and only let the "strong connections" remain in tact to a degree that still allows them to effectively transmit signals, while the other pathways fade into low constitutive neural activity ("noise") that's filtered out by the brain.
Maybe in your case of stimulants it "turns up the gain" and allows your body to pick out the signal from noise better somehow and subsequently adjusts the brain's filter to only allow the strongest connections to remain.

How would this cause PEM? Good question.
Again, overall just throwing things at the wall and seeing if anything sticks.

 

Neural circuits and their components change over time. Those changes normally don't cause problems, but there could be large-scale feedback loops, and if one part shifts one way and another part shifts a different way, it could turn the overall transfer function of that loop to positive feedback, and it snaps into the ME state. Initially, it might be possible to snap it back to the non-ME state, and further changes could push the loop back to more normal factors, or the body-wide changes due to being in the ME state could push those factors further into the positive feedback mode.

I don't see a problem with it. I'm listening to FM radio. If I were to detune an IF amplifier section, I'd have worse reception, or even lose lose the signal completely ... without the radio signal changing. If a few neurons responsible for maintaining a hormone at a certain level based on various inputs change their "tuning", you'll get incorrect hormones levels in muscles. Your thyroid gland maintains its output depending on various inputs, but if your glial cells' kynurenine metabolism is altered, you might alter picolinic acid production, which alters Trh, and I doubt that the thyroid gland is monitoring kynurenine metabolism in those cells.

Since my ME symptoms had been indistinguishable from flu infection at times, my guess is that at least part of the mechanism causing the symptoms is involved in both.

My guess is the latter. If your feedback loop factor is negative, you get some symptoms, and when the trigger (viral infection) drops again, so do the symptoms. If the feedback factor is positive, you snap into the full symptom state and stay locked there even after the trigger is gone.

Feedback loop transfer function. With a really complex feedback loop, and billions of instances (humans), it's not unreasonable for some to drift into a positive value for feedback.

 

Others will have heard this before, but you may not have @jnmaciuch. My wife had a serious neurological reaction to an antimalarial that persisted for many months after taking a two week course. There was clearly a feedback loop going on. Even to the extent that one could make inroads into inhibiting it at certain times of day only for it to come back that night. In the end she found a treatment that returned her to complete normality - which has continued for 17 years now. Without reversal of the loop she would have died of inanition much like people with very severe ME/CFS.

 

That I don't know, and it could vary with the individual. Those individual variations could explain why some people have severe weakness and others don't, and some have hypersensitivity to some sense, and others have it for a different sense, and most don't have any. One of my eyes doesn't seem to be able to remain positioned properly with respect to where the other eye is pointing. Structural difference in a few critical cells? Maybe one has different vasculature or glymphatic network pattern? Maybe one eye is dominant, and the other has a "follow the leader" structural function that makes it more susceptible to whatever ME does.

Posing the hypothesis means that someone who does have the right knowledge of brain function might see a connection. Maybe someone did a study on eye positioning and found that the glial cells (or vasculature or whatever) is different for the dominant eye.