What are the necessary conditions and criteria for a theoretical model of ME/CFS?

[Amw66]

I'm hoping this isn't too much of a sidetrack but this comment made me think of having recently read this (as I thought of clock genes / clock cells and this came up) and thought if it is correct then it begins to undermine the simplistic 'hardware-software / brain controls the body one-way analogy' so popularly used by BPS etc : Liver cells control our biological clock | CNRS

I know ... it is on a mouse model sooo... , and I haven't been able to dissect in depth, but here is an excerpt:

"Scientists from CNRS, Université Paris Cité1 and the University of Queensland2 , however, in the framework of a joint EU endeavour3 , have just shown that the liver also influences peripheral clocks. Teams studied a chimeric mouse model with a liver containing human hepatocytes and observed that the daily cycle of these usually nocturnal animals had advanced by two hours.

The mice became active and began feeding two hours before nightfall, thus becoming partly diurnal. The researchers believe this shift comes from the mice’s central clock being taken over by the human liver cells in this chimeric animal model. These cells can thus affect the entire rhythmic physiology of the animals, including the clocks of the peripheral organs.

Findings suggest that a change in liver clock — for example in pathological condition such as cirrhosis — could affect the synchronisation function of the central clock. This in turn could affect the entire circadian physiology, including the sleep/wake cycle, and contribute to the development of metabolic disease. It also suggests that restoring disrupted liver biological rythm could benefit the entire body metabolism. The hormonal and nervous mechanisms driving this dialogue between the brain, liver and biological clock remain to be identified."

Liver is a key modulator/ driver/ synthicizer for so many processes , has gut and vagus connections - definitely part of picture .
Given it's role in hormone synthesis it could also perhaps play into male/ female differences
It didn't seem to have been considered in any great depth.
Many hepatic processes are supposedly nocturnal , perhaps as the amount of energy needed must be significant , so if sleep is poor, energy is low and clocks are off there may be epigenetic feedback loops to prioritise key functions, which must in turn have knock on effects to many other systems .

 

[Ravn]

This isn't right. I was taught that MS was commoner in women as a medical student, long before MRI became clinically available. Men got dismissed as imagining things just as much as women, in my experience.

Maybe different stories were told in different places and times? It's what I was told by my local MS society back when I was misdiagnosed with MS and also what was passed down the in-laws' family who had a member die from severe MS in the mid 1900s. Maybe the male vs female MS diagnosis issue was more in the early to mid 1900s when Freudian ideas were booming?

Anyway, whether the specific MS example holds or not, my main point relevant to this thread is that there remains a small possibility - extremely small I think, but not zero - that our ideas about female preponderance in ME could be an artifact of how ME is being diagnosed and, more broadly, that much of the data we currently have on ME are to varying degrees and for varying reasons unreliable. Until there's more replication and bigger and better studies it's difficult to decide what should be on a list of core features any proposed model must account for

 

[bobbler]

This thread is a valuable thought exercise even if it turns out to be impossible to agree on the ultimate list at this stage due to too little reliable data. Anything to help sharpen reasoning.

A major issue is the difficulty in distinguishing what is core and what is secondary. I think we too often try to squeeze too much into a single or unifying hypothesis and then can't see the forest for the trees

The branching tree analogy is useful to keep in mind here. We all have a unique combination of genetic predispositions, epigenetic profiles, microbiomes, immune systems etc etc etc which means even if we postulate a single disease entity - a big if for starters - and no comorbidities - an even bigger if - we would expect different phenotypes, different tree-branching patterns, growing out of the same type of trunk

Two lists could well be helpful, as a reminder of things to consider when you're in danger of getting carried away with one particular train of thought while cobbling together your hypothesis.

List 1 would be very short and only contain the corest of core and most specific to ME observations, the must-explains.

List 2 would be longer and contain all the other frequently reported signs and symptoms (but not every single symptom ever reported), these would only be should-be-considereds. Still, any proposed hypothesis shouldn't contradict the possibility of them occuring, or at least provide a clear explanation of why the hypothesis disregards a particular item on the list

As we learn more some items may end up moving between the lists, not least because of the risk of false attributions and insufficient or low quality data leading us astray at times. Two examples of where this risk may be at play

1) The observation that more women than men are affected:

This looks to be some of the most solid data we have and, for the record, I'm strongly inclined to believe it is correct. However, before MRI it was thought MS was primarily a male disease, women with the same symptoms were being diagnosed with hysteria instead. Best to keep an open mind to the tiny possibility that we're dealing with differences in rates of diagnosis rather than differences in prevalence. Or to the possibility that male and female ME are different entities that resemble each other only superficially

2) The debate about whether all ME is postinfectious:

This debate can't be settled for now because we have no way of testing for recent asymptomatic or near asymptomatic infections when people first turn up with ME-like symptoms. If they didn't notice or can't remember such an infection but something else major or at least more memorable happened in their life around the time they'll naturally link the onset of ME to that. It remains an open question despite all the stats regularly and confidently thrown about on how many % are supposedly postinfectious versus how many are not

[There are dedicated threads to discuss the pros and cons of the views in the examples so no need to derail this thread by arguing about them here, I just wanted to demonstrate how some of the data we take for granted may yet turn out to be unreliable, or be further strengthened]

Right now I'd put #1 on the core list and #2 on the secondary list, but with a mental footnote for both reading *subject to change

There's also an argument for a third list to record things that don't need to be (re)considered in any new hypothesis because they have been investigated enough to establish they are just an epiphenomenon or otherwise irrelevant (the deconditioning hypothesis springs to mind, obvious to us but not necessarily to anyone new to the field)

ON point 1.

I was thinking similarly on the more women than men affected stat too, based simply on the history of it being used as a dumping bucket when CFS (and probably still now). I thought of autism and women. I'm also all too aware of watching over the years on social media people trying to describe the difference between ME/CFS and other conditions like fibro and the heuristics which probably still are used seem to be more pain = FM, more fatigue = CFS or dependent on the 'ology' or doctor that someone sees. The stats seem like they might be incredibly poor.

On the other hand one thing that surprises me is how many people I have come across over the years who you eventually find out also have ME/CFS and I don't think there is one that I doubt has the same thing - even when I was going through my phase of assuming CFS was 'tiredness all the time' inferring seeming slow always (even tho a consultant I saw actually explained it back then as 'energy at strange times' so was more accurate than most) so I had something pretty different given my pattern was not like that. Except there are some who espouse very different things to what would work for me (like routine) which is why I assume types.

So this rumour BPS will try and push (if they are the marketers I think they are) of some might have this PEM thing but what about most who have this CFS/ME thing (as justification of their keeping the old treatments - and of course their funding for it) doesn't add up. And if there are potentially lots of men out there with very 'PEM-y' symptoms then they still might not relate and be being identified. Or if, like autism in women, there is any possibility of there being slight different symptoms or 'how it looks' in men etc.

On the other hand I found the interim findings of DecodeME suggesting that women tended to have more severe symptoms etc or for longer or something to be more of a useful clue suggesting gender could play a role. But perhaps that can be hard to separate from the history of suggested treatments/bad old guideline and other cultural aspects interacting.

I have a male family member of a not too dissimilar age who had similar 'vulnerabilities' and got some of the same illnesses to similar levels as me (as well as some of their own with medication for those) and doesn't have what I have level-wise but I do wonder whether they also don't/didn't have something either less bad or different in presentation. Add in culture and stereotypes, the behavioural mindset-lens and assumptions coming from medics and them not knowing us well or wanting to really get who people are underneath vs going by a limited list I could see how something similar could get bucketed in different directions.

I think my point is that the traditional 'epidemiology' approach has been somewhat distorted (understatement there) and we might indeed want to be very careful about bringing in old assumptions based on old definitions, processes and 'initiatives' vs observations.

And I'm more confident in a theory suggesting 'different between men and women' than I am in anything particularly about statistics collected based on old systems and ideas which suggest overall prevalence (because that 'what' is so recently defined - hence the autism in women thing).

 

[Ravn]

The immune response is generally thought of in terms of white cell like lymphocytes and macrophages, although it would be legitimate to include neural control pathways. I think it is very unlikely that white cells actually in the brain are involved in any feedback loop. Assuming there is no infiltration of lymphocytes as in MS the 'white cells' in the brain are the microglia. These may be recruited to clean up damaged nerve cells but I don't see that as likely to involve any 'flip switch' feedback.

Younger is doing a study using some fancy new scanning tech to determine if white blood cells from the periphery infiltrate ME brains. Hopefully this will give us a clear yes or no answer on that point. Though I'm not sure if he's planning to scan after exertion or during PEM, it's conceivable any brain infiltration by leukocytes only happens under specific circumstances. But it would be so nice to have some clear finding for a change where you can conclusively say, yes a model needs to account for this or not

 

[Ravn]

If you were diagnosed with infection, then you had an infection. If you didn't, then you probably didn't. (Unless it was something obvious like COVID). Some people say that "you could've had an infection and didn't know about it". Well, anything is possible. But saying anything is possible is not exactly a science. We should accept the percentages (something like 30%, I think?) since that is based on the diagnosis.

I suspect that there are more people assuming that they had an infection when they did not, than people who had infection and didn't know about it, because sudden onset so much resembles an infection. I keep using Bruce Campbell as an example. He and his doctor assumed that he had some kind of infection. But he showed signs of ME/CFS prior to it, which he managed to recover from by reducing his load by 10%.

Public health surveillance studies show many viruses produce asymptomatic infections, and in significant numbers. For some, like some enteroviruses it's even a majority of infections that remain asymptomatic

 

[Ravn]

Is it too early to propose models? I propose an abnormal immune response in the brain as the root cause

I'm working my way through some lectures on microglia*, nothing to do with ME, just how the things function in general. One key message is: there's an awful lot we don't know about their workings yet, especially about their roles beyond cleaning up undesirable stuff in the brain, e.g. their interactions with neurons and their communication with the peripheral immune system. To my limited understanding there looks to be plenty of room for discovering stuff that could go wrong here beyond the 'ME microglia are in a permanently primed state' idea which seems just a little too simplistic in isolation (but should absolutely be investigated, they may not be the whole answer but could be a significant part). But I don't think any of the microglia or "neuroinflammation" findings to date are strong enough to be included right now in a general checklist for a model

Related technical questions: microglia produce cytokines & we've had very conflicting cytokine findings in ME (which makes it hard to know whether or how a model should be required to account for the data)

So, do the cytokines measured to date in ME reflect only what's produced by the peripheral immune system? Or are cytokines produced by microglia in the brain included?

Can you measure cytokines in the brain? Directly in the brain seems unlikely? In the CSF? Or is it a case of what's produced in the brain stays in the brain?

*the link to the podcasts if anyone's interested, note they're in French and there are frequent annoying references to visual supports used in the original lecture so if you can watch video I suggest seeking out the Youtube version
https://www.college-de-france.fr/fr/chaire/sonia-garel-neurobiologie-et-immunite-chaire-statutaire

 

[bobbler]

Is it too early to propose models? I propose an abnormal immune response in the brain as the root cause, involving a feedback loop that is normally negative, but in ME, it goes positive, locking us into this abnormal state. The vagus nerve could be part of the feedback loop.

This model fits any initial trigger that would activate or involve the immune systems. The reason why these normal events push the feedback loop positive might be genetic, developmental, environmental, or some other reason.

If the mechanism in the brain depends on specific characteristics of brain cells, it could affect different parts of the brain to different degrees in different individuals, resulting in the wide range of symptoms and sensitivities. I don't think any of Kitty's core symptoms can't be explained by this model. For example, in one person, the brain cells connected to the gut are affected, resulting in digestive symptoms. In someone else, the cells processing vision are affected, resulting in light hypersensitivity. Studying the brain structure and comparing with symptom frequency (how many people have it) might reveal something. For example, is there something unique about the brain cells processing pain signals front thigh muscles? Maybe it's the largest grouping, or is closest to some other specific part of the brain, or has more/less blood supply? That's the muscle that is the first for me to have ME pain, and maybe it's just an artifact of artwork, but the Mayo Clinic's diagram of symptoms has "Pain" pointing at that muscle group, so maybe that's common among PWME, and thus indicating something.

Changes in severity can be explained by slight changes in the cells involved in the feedback loop or cells receiving communication from these. For example, changing the ratio of fatty acids in the diet could affect the structure of the cell membranes, changing the "equation" of chemical processing in the cell.

I like the model of a feedback loop because the abrupt switching of state (full ME to full non-ME) is what I would expect from an amplifier that changes the sign of the feedback loop factor. In electronics, making the feedback loop even slightly positive causes the output to snap into the maximum output voltage, whether positive or negative. For brain cells, the output could be production of some protein or change of membrane transport of certain molecules, or some other such thing.

As for why this model doesn't show obvious markers, the changes in the brain cells don't need to be dramatic. What percentage change in protein production, number of a certain type of transport channels, or rate of glial process growth would be required to cause brainfog, lethargy, malaise, etc? Some of these factors probably can't be measured in dead tissue, and we might still not have the technology to measure them in-situ. Experimenting with (safe) brain cell altering chemicals might be a way of testing that model.

I include the vagus nerve as a possible part of the model because it's bi-directional, including immune system control signals, connects to most if not all of the parts of the body that show ME symptoms, and involves the gut microbiome.


So, go ahead and take your shots at this model. That's what it's there for.

I'm trying to add the bits together that might relate to muscle here, because the pain I'm thinking of I don't think is 'brain/nerve-related'. For me I think the earliest and most obvious was always the calves. Full-on deep soreness to a level I'd never felt before, and definitely not caused by deconditioning (as I couldn't stop exercising more than most due to committments at first) and actually I'm pretty sure from this and witnessing at later points where things like carparks were moved away, that it visibly caused muscle wastage actually exercising/using them (and there is something that saying it could get me send to the mad house) not the opposite way around.

The pain would be like the shin bone was hurting and the flesh behind it bruised, as well as in the early days me remembering the deep muscle pain through my calves that felt rheumatic, affected my gait significantly even though I always tended to walk a certain way with fervour (and tried to still) and at certain specific points I knew was caused by driving / pushing the pedals with my feet for long enough as happened a specific time length after doing said journey (like 30mins).

As a complete guess I think my other muscles were bigger to begin with vs how much they are all used (I think I use/used my calves the most vs their capacity in general) so for example thigs/quads just bigger muscles, whereas arm muscles used less in general although I also have in those a situation where over-use causes/caused me to be unable to lift them. Again not caused by deconditioning - this phenomenon was most obvious when I went to the gym and did light weight routines in order to try and build them up, which worked at first with very small repetitions (they looked better, I don't think there was much change in exhaustion) but I suspect that the longer term effect of that was the opposite (after 6months my arms looked better but I started having those symptoms after carrying a light carrier bag for a short bit then couldn't lift a drink to my mouth in a way I hadn't before , and the 'look' didn't maintain).

I also think that this effect / these issues vary depending on where the illness is at the time, and that exerting when in a 'downward' phase where the illness is bad and going downhill vs when things aren't great but perhaps more stable and years on gives slightly different effects and doing any of this 'rehab' when someone is where they are after being diagnosed is cringingly the worst timing possible.

 

[alex3619]

unpredictability of PEM and maybe the idea that the deficit/threshold can also be reached cumulatively as well as a single over-exertion.

I suspect this is correct, but also a good break in activity in the middle can also short circuit PEM in some cases. I do think its a threshold, and the idea is that if we operate below that we do not crash. Its also a threshold in that the further we go over our limit the harder we crash. Of course it would be nice if we had some hard data to use in these discussions, but there is inadequate research.

In pacing we want maximum benefits from doing as much as possible without crossing that threshold. Its difficult because, at least in my case, the threshold can vary day by day. I wonder if in part this is caused by residual over activity from previous days even if we did not crash. This might be amenable to some kind of points system, though it would not be very accurate at best.

Alternatively its quite likely that the threshold is lowered if we do too much. I see signs of that too.

 

[bobbler]

I'll see where the discussion goes and try to keep track of what comes out. I can't really do this on my own, just hoping this generates enough discussion and refinement to have a few items no one can poke holes in.

To me, is it OK to go at the list / concept of testability from a different angle and suggest that it needs to be something that can explain or accommodate the idea that with sufficient REST - but that being in ME/CFS terms so a lot of rest when someone needs it and until they naturally feel ready / OK - those less severe can feel 'better' or 'MORE OK' as long as they aren't exerting and often that only lasts for a while (that bit is variable too, but I have noticed that the body can 'knock itself off kilter' for seemingly no reason sometimes).

Particularly in the 'sleeping off PEM / a crash' type idea those who kept on working and then used annual leave and weekends to 'perform' for said work hours whilst often noone realised they literally had no life other than that and bed is that something that is quite specific to ME/CFS vs certain other fatiguing illnesses too?

I just want to add this in because I think the deliberate wording used in the past of 'doesn't improve with rest' is a bit misleading and unspecific compared to the quite specific phenomena that are and aren't true underneath that. It might seem useful as a short 'what to look out for' on a list for a GP faced with someone who hasn't got back to normal after getting x 12months ago despite having a lot more rest than usual. And sometimes I wonder whether it is the 'rest' (and increased need for that in proportion to what has been accumulated or just immediately done) or the 'exertion' that is important or some calculation that will be ever impossible given the iller you get the more uncompleteable the outcome of that equation seems to be.

I hope I'm not going too wild here in thinking if you had people who were mild doing 2 x CPETs but... they weren't one day apart and you could somehow matched pairs to see whether those who could go to bed as needed for the week (or 4 days or what not, I just think week because that was when I went from needing to rest to be out of pain and get good sleep --> good sleep --> wake up feeling as before and ready for work) vs those who couldn't or varying levels of rest. We all know you couldn't predict that so it would need to be 'natural / restrospective' in that grouping somewhat because planning only gets you so far with having a restful week.

I think what I'm saying is that there is a lot I become doubtful of or start thinking of heterogenity or other issues re: the one thing I'm sure is distinctive of 'ME/CFS' (you never know if there are comorbidities or what they are), but I don't know whether if we could firm up the different elements of this it might be one area where there is consistency?

And because - as a guess - it seems there is a point around the severe /very severe boundary where things can switch into the horrible territory of not being able to get into that rest (or even rest to rest) territory at all with the term 'upregulation' from a descriptive rather than technical point of view sort of being the one thing that captures what your body sort of can get caught in. It makes sense only because it sounds like a term that describes the 'wired' after 'going through the wall' of your threshold where you've got so tired that you can't rest you get at other levels (and sometimes can feel great because on adrenaline feeling or something, but often awful because exhausted but can't sleep or rest yourself well and you can feel it is the bit that almost does the most damage) being 'stuck on' or your body just can't get through it to the other side where it can get better rest.

I dislike the term because of BACME's dysregulation red herring, and I describe to 'norms' that situation more as like when they have the worst flu or tonsilitis and they have really bad days where they might sleep solidly for more hours then they normally would but the worst is when they feel so poorly they can't even do that ... and the bliss of finally getting that pain relief or something just easing enough you finally can sleep through it.

 

[poetinsf]

Public health surveillance studies show many viruses produce asymptomatic infections, and in significant numbers. For some, like some enteroviruses it's even a majority of infections that remain asymptomatic

That some viruses are asymptomatic does not mean they trigger ME/CFS, or anything else for that matter, on people not known to be infected with it at the time. It's still "anything is possible" argument. If they are arguing that some ubiquitous/harmless/undiagnosed virus is the cause, they'll need to prove that. Till then, we should just accept that non-viral cases caused by chronic/repeated stress are non-viral.

 

[poetinsf]

But I don't think any of the microglia or "neuroinflammation" findings to date are strong enough to be included right now in a general checklist for a model

The microglial m0, m1, m2 and primed states are well established, I think. So is the transition between them, and that they cause fatigue, pain, and other maladies when they are in inflammatory state. What is not established is whether ME/CFS patients indeed have more than usual microglial cells in primed state.

When they are in primed state, they'll change into m1 inflammatory state with slight peripheral inflammation signal. Any exercise will trigger peripheral inflammation the day after, so that would explain PEM if you have many microglia in primed state. All neurological symptoms are easily explained by neuroinflammation, of course. How microglia gets into the primed state -- through acute immune assault, repeated/chronic insult -- also can explain the trigger.

I think it would be the equivalent of smoking gun if they can establish that ME/CFS patients indeed have more microglial cells in m1 or primed state.

Can you measure cytokines in the brain? Directly in the brain seems unlikely? In the CSF? Or is it a case of what's produced in the brain stays in the brain?

That's a good question. I'd think it would be as easy as inducing PEM and then check the brain cytokine level to test the theory, if that could be done. That it hasn't been done seems to mean that it is not possible or not easy, I think.

 

[Eddie]

I suspect that ideas of loops within brains are not so popular with a number of members because in a sense they imply that ME/CFS is indeed a 'functional neurological disorder' if we take that to mean a disorder driven by disturbed regulation in the brain without any structural pathological change.

I don't think such an idea should worry people, although I understand the concern.

The weird thing about the neurologists and psychiatrist who try to build feedback theories in brain in 'FND' terms is that they get it back to front. Because they are stuck with this idea that people with ME/CFS feel ill because they are expecting to feel ill they come up with this 'predictive coding' idea that PWME feel ill because their brains predict feeling ill and then when signals come in they really do feel ill.

And of course, this is back to front because if your brain predicts feeling ill and normal signals come in you ought to feel really well in comparison to expectation. So they have got the feedback idea wrong. Just as I think Walitt has got it wrong with effort preference.

I'm not opposed to the idea as I think it is clearly true that the feeling of PEM, just like fatigue and pain, must be produced within the brain. However, my pushback is that rouge neuronal firing doesn't really clarify the problem for me. If we think about what a theory of ME/CFS should explain, issues with the functioning of the brain could hypothetically explain everything. However, saying the issue lies within some neural functioning in the brain doesn't address why it is occurring or provide any routes to fix the issue.

That being said, if this were occurring, what is it about exercise, stress (or anything else that triggers PEM) that causes these neural pathways to fire? Given that they are triggered by certain stimulus, there has to be some specific signal or chemical that they are responding too. If the trigger is vagal signals or a lymphocyte response then that surely is a testable and treatable issue. It is also not clear to me why these neuronal issues would cause orthostatic symptoms. Are the parts of the brain that govern the autonomic nervous system simply not working correctly?

 

[Trish]

I suspect this is correct, but also a good break in activity in the middle can also short circuit PEM in some cases. I do think its a threshold, and the idea is that if we operate below that we do not crash. Its also a threshold in that the further we go over our limit the harder we crash. Of course it would be nice if we had some hard data to use in these discussions, but there is inadequate research.

In pacing we want maximum benefits from doing as much as possible without crossing that threshold. Its difficult because, at least in my case, the threshold can vary day by day. I wonder if in part this is caused by residual over activity from previous days even if we did not crash. This might be amenable to some kind of points system, though it would not be very accurate at best.

Alternatively its quite likely that the threshold is lowered if we do too much. I see signs of that too.

This is where I think longitudinal studies are needed, with good quality wearable motion sensors and heart rate and hrv monitors, and apps to record easily symptoms and activities, including cognitive activity every day across months.

If all the data is recorded instantly via the app, then it must be possible for someone to design algorithms to analyse the data, so we could see things like cumulative activity triggering PEM.

 

[butter.]

While I appreciate the creator of this thread very much for his insights and intelligence, I think this won't work.

What might have a chance of giving us a better grip on the situation in terms of 'what is this', besides GWAS, is large scale, 'multi-generational' epidemiology.

Such work requires a lot of funding and long-term commitment by institutional bodies.

There is only on nation (besides the EU, and maybe Germany and Japan) who could undertake such a project: The USA.

For that to happen we need much more effective political advocacy and charity work in the U.S. Many more people with skin the game must engage and help with their energy, time and cash to drive change to get us there.

 

[EndME]

That some viruses are asymptomatic does not mean they trigger ME/CFS, or anything else for that matter, on people not known to be infected with it at the time. It's still "anything is possible" argument. If they are arguing that some ubiquitous/harmless/undiagnosed virus is the cause, they'll need to prove that. Till then, we should just accept that non-viral cases caused by chronic/repeated stress are non-viral.

But that in itself is an assumption. Assuming that non-viral cases are caused by chronic/repeated stress. I haven't seen much evidence for it, beyond people trying to explain what could have occured to them and many people being more or less "stressed" relatively frequently. So just by chance alone you'll find people that were somehow stressed and had an onset of ME/CFS during such a time period, whilst most people only have glandular fever once or twice in their life-time. It seems the literature reports that autoimmune disease can sometimes flare up under stress, but that doesn't mean stress is in any way causative.

I think it's perfectly fine to say that there's a large chunk of onsets that happen post infection (possibly somewhere around 70% of cases) and then many cases where it not known what the onset was (according to DecodeME possibly around 30% of cases), but that any model should account for the fact that post-infectious and non-post infectious ME/CFS appears to exist.

 

[FMMM1]

If there is a reversal of feedback in brain it is much most likely that it will involve the sort of feedback/regulatory processes that the brain does very well - but note that these processes are completely invisible to pathological analysis. We have absolutely no way of telling neurons are firing in a positive loop that should be negative because we have no real idea what the firing of any particular brain cell contributes to brain function. In an epileptic seizure negative feedback is override by positive feedback to the extent that the entire brain fires off. But we don't see any pathological changes.

I'm a bit concerned by this i.e. thought that the ME/CFS disease processes may be "completely invisible to pathological analysis" -

• I guess that may explain mental health diseases which are poorly understood; &
• (in a similar vein) I recall a scientist saying that they thought it would take a technological breakthrough to understand ME/CFS.

However, too early to say, re ME/CFS, i.e. there could be a biomarker [e.g. identified as a consequence of GWAS - DecodeME] which provides a clue to disease mechanism & drug target.

 

[poetinsf]

I think it's perfectly fine to say that there's a large chunk of onsets that happen post infection (possibly somewhere around 70% of cases) and then many cases where it not known what the onset was (according to DecodeME possibly around 30% of cases)

But they are not unknown. Many of those cases are traceable to common denominators just like infectious cases are. There are diseases that are caused by other than virus and it's still valid to attribute the cause to the common denominators other than virus. We don't go looking for the viral cause for all hypertension after all, even if some of them could be (?) caused by virus.

 

[EndME]

But they are not unknown. Many of those cases are traceable to common denominators just like infectious cases are. There are diseases that are caused by other than virus and it's still valid to attribute the cause to the common denominators other than virus. We don't go looking for the viral cause for all hypertension after all, even if some of them could be (?) caused by virus.

Sure, they certainly exist, injuries/accidents etc but tracing something back to stress is probably a lot more tricky then one might think. I might be misremembering but from what I recall from the DecodeME data the amount of cases where the onset is not known is quite large, larger than glandular fever and also larger then those known not to have an infectious onset.

 

[Creekside]

The question is whether we need to propose positive feedback in the brain or maybe between brain and immune system or just immune system.

My proposed model has the symptom-generating black box in the brain. Other studies have shown that many of the flu-like symptoms that ME shares are generated by the brain. It's not proof that ME symptoms are generated by the brain, but it's reasonable to accept that unless proven otherwise. The feedback loop might involve the vagus nerve and various organs or organelles or other body functions that we aren't yet aware of. The loop could involve many factors. These factors would vary to some degree from average between individuals, so in a small percentage of the population, these variations could add up in a way that makes the feedback factor cross zero and become positive, even though the individual variations all fit in the category of "normal". That would explain why no one has found a definite marker yet: they're all within normal ranges individually. Here's a test of the model: check whether the various factors measured in PWME vary in the same directions. For example, the majority have factor x 6% low, and factor y 3% low, and factor z 8% high.

It's been a long time since I studied feedback theory, but I think the amplifier gain doesn't make a big difference. As long as the feedback is positive, it will lock up in one state. If the loop is non-linear, the system would oscillate (vary between highs and lows without any inputs), so I suppose that rules out factors having that sort of non-linear behaviour. This model would also explain why some PWME get temporary remissions early, but less often as time progresses: some of the factors adapt to this new state and maintain it.

but note that these processes are completely invisible to pathological analysis.

It's not the model's fault that there isn't an easy way to measure those processes. If an engine has a problem due to a part hidden deep inside, looking at easier-to-reach parts won't solve the problem. The thing I dislike most about my model/hypothesis is that it does mean that there's no simple clinical test available and no simple treatment available. Other hypotheses are much more attractive because they offer easier tests and treatments. Chronic viral infection? We know how to search for those and how to create vaccines, so fund our study!

 

[Jonathan Edwards]

Maybe different stories were told in different places and times? It's what I was told by my local MS society back when I was misdiagnosed with MS and also what was passed down the in-laws' family who had a member die from severe MS in the mid 1900s. Maybe the male vs female MS diagnosis issue was more in the early to mid 1900s when Freudian ideas were booming?

My experience is that this myth has largely been generated in the last 50 years. My parents were medical and we had friends with MS. I was told about MS probably at the age of about 11. Nobody suggested that there was any psychiatrisation. It was known that there was gross brain pathology. A child could see the neurological damage with spasticity and blindness. Disease societies often pick up myths I suspect. Early MS was often dismissed by lazy or incompetent physicians but in men as well as women - if anything the men were considered even more feeble minded. But I doubt established disease was ever considered psychiatric by the great majority of doctors through the twentieth century.

But I agree, this is not relevant to your main point, which is well taken.