Hypotheses and Research Directions for ME/CFS
- Thread starter Dude
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jnmaciuch
Senior Member (Voting Rights)
Just a quick note—the brain does account for a very large percentage of “energy expenditure” however you measure it. The issue from several months ago mostly comes down to whether a particular demanding task uses much more “energy” than being at rest. It’s a very difficult thing to measure because at best we can only measure some proxies—for oxygen consumption/blood flow/glucose uptake— none of which are very good correlates, as it turns out. Lactate itself is a major fuel source which can fluctuate wildly in specific brain regions through astrocytic release without reflecting strongly on those other measures of brain “activity”.
What does seem true is that when certain regions of the brain are more engaged (like during a problem solving task) other regions appear less “active,” and at rest you typically see a more diffuse pattern of activity (and, again, still probably an oversimplification). So overall, it won’t add up to a big difference in total “energy expenditure” however that is being defined and measured—but there is the strong suggestion of local changes meant to keep up with the demand of repeated firing and restoring action potentials within specific regions (and the other molecular consequences of the same cell/group of cells firing repeatedly in a short period of time). And local changes could very well end up having more global effects on brain function if various signaling pathways are induced by that group of more “active” neurons—especially if something is affecting how local clusters function to begin with.
This doesn’t mean that cognitive tasks result in an “ATP deficit” or anything related to a critical energy threshold—I think oversimplified ideas about brain metabolism are unlikely to lead us to anything productive about ME/CFS. I’d just caution against overinterpreting some of those studies to conclude that nothing of metabolic consequence changes with concerted brain activity in specific regions.
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Kitty
Senior Member (Voting Rights)
I wish researchers would focus more on questions. Hypotheses have led us up all kinds of sidetracks.
As a non-scientist I find it hard to understand why it's best to start with a whole story when you know very little. It forces you to make stuff up to fill the gaps.
So it's questions for me. The simpler and more stupid, the better.
As a non-scientist I find it hard to understand why it's best to start with a whole story when you know very little. It forces you to make stuff up to fill the gaps.
So it's questions for me. The simpler and more stupid, the better.
V.R.T.
Senior Member (Voting Rights)
Can you explain why you think this? I'm not sure what makes this more likely than there being a single upstream cause of ME/PEM.
I'm not dismissing the possibility here, I'm just interested in your reasoning.
I'm not sure I'm saying something different from you.
All I meant was, for the specific phenomenom of PEM, with the characteristic delay and several days long crash which is weird and so far eludes explanation, it seems fairly likely to me that there's one specific process that causes this same effect in everyone that has it. Other parts of the body may or may not interact with this PEM pathway in various ways to give "subtypes" of different symptoms.
Not really based on anything much except intuition. [Edit: And maybe wishful thinking because it'd mean everybody's PEM would be solved at the same time.]
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V.R.T.
Senior Member (Voting Rights)
Ah right, I think this question was saying could PEM be caused by different things, rather than PEM causes different subtypes of symptoms. As to what you said yes I think were in agreement.
I managed to cure my PEM, but still sufffer from other ME symptoms, so my opinion is that PEM is not a critical part of the ME mechanism. Other people have one trigger but not the other, so neither physical nor cognitive exertion is critical to ME.
My food intolerances produce the same symptoms as PEM, so my theory is that there's a "PEM symptom-generating mechanism" that has multiple triggers, and is common but not a critical part of the ME mechanism.
I don't support the mitochondrial dysfunction, oxygen delivery, or chronic viral infection theories. For the first two, I can do hours of high-level physical exertion (shoveling snow or soil, sawing logs with a handsaw, etc) with no apparent reduction from my pre-ME days, so I see no sign of inadequate ATP production. The evidence for chronic viral infections seems weak: negative findings are downplayed, and antiviral treatments seem to reduce symptoms to some degree for a limited time.
My preferred hypothesis is a feedback loop that gets locking into a positive state. This fits the abrupt switching of state (full ME to full not-ME) I've experienced multiple times. This loop might be long and complex, involving the brain, the vagus nerve, gut microbiome, etc, thus not easy to identify.
I do think that glial cells are a critical part of the ME mechanism, so I'd like to see more research in that area. There's a lot still not understood about brain cells (and overall structure, I think), and it's not easy to study cell functions in-situ, so there's plenty of opportunity to discover something new--and part of ME. There's also the problem that some brain cells are highly specialized, so studying the easy-to-study ones will not necessarily find the ones that are malfunctioning. Common knowledge might be that "astrocytes do not have receptors for <some molecule>", but there might be some specialized astrocytes in a small portion of the hypothalamus that do have those receptors.
I also believe that most of the ME symptoms are generated in the brain, so more mapping of the brain in detail during symptoms (PEM, food intolerance, or whatever other triggers are reliable) might reveal something useful.
jnmaciuch
Senior Member (Voting Rights)
I think part of it comes from the fact that to answer any question, you need an idea of what type of thing you’re looking for. Even if the question is just “what changes during PEM?”—in order to design an experiment to answer that, you need to have an idea of what changes where (blood or specific organ systems or between certain cell types in a specific interaction state?), what type of things might change (and which detection methods will be able to pick up on it ), etc. etc.
Coming up with a bigger theory is often a byproduct of trying to narrow in on a plausible way to answer a question. The only way we can do that is often by asking if potential answers within a specific search space explain other features of the disease (and, in a grant application, thats how you end up getting your question funded over someone else’s question).
Granted, some people can go overboard with this part (and I’m no exception, especially when the time I have to theorize far outpaces the resources I have to answer questions).
But focusing on very simple questions without broader theorizing often leads to an endless rut of asking “is biological process #497 measurably different in cell type #23 under circumstances #23009? No? Well how about cell type #24?” which we see plenty of in ME/CFS research and doesn’t get us anywhere either.
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You have to look at the problem on a much broader scale. Why are there only hypotheses for this disease? Because no single study is strong enough to fully explain the pathomechanism. And when you start defending your own hypothesis, the discussion inevitably ends up with people arguing that the study methods are too weak or that there aren’t any robust studies on the topic. That makes any discussion basically pointless.
On top of that, I simply lack the knowledge. Researchers like Edwards can remember thousands of discussions and have gone through every relevant study in detail. I, on the other hand, listen to these theses and decide based on what I hear whether it seems plausible to me. As I said, I would need to examine each study individually and dissect every argument—but I’m too severely affected to do that. Even though I would like to, I used to work as a data analyst before my illness and am a strong proponent of data-driven decisions.
I believe it will still be a long time before we fully understand this disease. Until then, I think there will likely be a therapy based on one of these hypotheses, which wouldn’t be the first time in medicine. But that’s just my personal opinion.
Betsy Keller’s study isn't the only one; there are plenty of smaller studies on this topic. Repeated cardiopulmonary exercise tests often show a decline in performance, which suggests inadequate microcirculatory adaptation. It seems logically consistent that such functional deficits usually cannot be ruled out by a single measurement or standard imaging.
But as I said, you look into the study details, whereas I mostly follow conference presentations where these findings are frequently cited. I’m aware that presenters often cherry-pick studies that support their hypotheses, so I appreciate the critical perspective here. Returning to the point: can we completely rule out the microcirculation hypothesis based on current data? Or is there simply a lack of high-quality studies? Since this thread is about hypotheses, after all.
I also consider the 'microclots' theory outdated, but I find parts of the rest he mentioned plausible, even if the scientific evidence is currently insufficient.
My perspective might be biased because I was a competitive athlete and experienced this physiological 'crash' firsthand—though I know that’s just an n=1 observation.
I’d be interested to hear your own hypothesis, if you have one?"
I'd say it's because no one has found any clinical evidence or even statistical evidence to turn a hypothesis (wild guess?) into a working theory. Negative findings that should rule out hypotheses are being downplayed, because research funding and prestige are at stake.
However, the brain is also involved in physical performance, so there needn't be any physical dysfunction in the muscles. That's why I support testing muscle performance via electrostimulation, to rule out neurological factors.
ryanc97
Senior Member (Voting Rights)
I strongly believe because of the Dara trial ME/CFS is a LLPC driven autoimmune disease that produces magic autoantibodies that are undetectable with current technology probably because they affect funny signalling pathways and don't bind to tissue. You would put it in with the other autoimmune diseases like SLE and Sjogrens and Myasthenia Gravis but it has weird special properties.
The current suite of detectable signalling antibodies (like GPCR and B2ADR and nACHR or whatever) clearly doesn't cut it. So there is no detectable test for these because no one has a clue what pathways they disrupt.
Terence Tao (famous mathematician) says the unsolved problems in math (like the Riemann hypothesis for example) remain unsolved because the mathematical machinery hasn't been invented yet. I believe its the same case here. The technology isn't there yet. The biggest breakthrough has come from a random fluke (Fluge Mella discovering chemo improves symptoms in ME patients by pure chance).
There are a tonne of problems with existing clinical trials data and I am glad FM are doing a good trial. For example: relying on surveys (self reported outcomes) vs observed outcomes (step counts).
None of the theorists have managed to come up with any solutions. Ron Davis, Wirth, whatever. All have their own complex theories but the biggest progress seems to be made by just a purely random observation.
These things have all failed
1. Trying to work out a mechanism purely from measuring things in the body - this has failed because look at the amount of conflicting papers measuring this and that.
2. Trying to come out with theories from ground up. Also failed to me because none of the theories have led to treatments.
The current suite of detectable signalling antibodies (like GPCR and B2ADR and nACHR or whatever) clearly doesn't cut it. So there is no detectable test for these because no one has a clue what pathways they disrupt.
Terence Tao (famous mathematician) says the unsolved problems in math (like the Riemann hypothesis for example) remain unsolved because the mathematical machinery hasn't been invented yet. I believe its the same case here. The technology isn't there yet. The biggest breakthrough has come from a random fluke (Fluge Mella discovering chemo improves symptoms in ME patients by pure chance).
There are a tonne of problems with existing clinical trials data and I am glad FM are doing a good trial. For example: relying on surveys (self reported outcomes) vs observed outcomes (step counts).
None of the theorists have managed to come up with any solutions. Ron Davis, Wirth, whatever. All have their own complex theories but the biggest progress seems to be made by just a purely random observation.
These things have all failed
1. Trying to work out a mechanism purely from measuring things in the body - this has failed because look at the amount of conflicting papers measuring this and that.
2. Trying to come out with theories from ground up. Also failed to me because none of the theories have led to treatments.
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Kitty
Senior Member (Voting Rights)
I mean really simple questions.
Is that real?
What do we mean by that?
Why do we think that?
Are those things the same?
The trouble with hypotheses and detail is that they can distract people from looking for the truth. That involves stripping away, not building up. It's an uncommon skill, but one that can be learned.
Utsikt
Senior Member (Voting Rights)
If e.g. Daratumumab works for ME/CFS, then that study alone will be enough to tell us that something that Dara affects is involved. We don’t need all of the info, just enough.
Yes, that’s mostly the case in ME/CFS, and science in general. Not because science is useless, but because there are too many scientists doing useless stuff.
Not at all. By dissecting the individual pieces of evidence we get a much better understanding of where the solution might lie. And if the researchers had bothered with the discussions beforehand, they might have been able to design studies that could have provided meaningful data.
I think that by far the most important contribution by S4ME is that people are willing to assess the evidence and not get too caught up in hypotheses.
And I think there is a general misunderstanding among both laypeople and scientists about what science is. You’re supposed to propose a testable hypothesis, figure out what would confirm or refute it, and then gather the data. Far too many pick a hypothesis and go out only looking for data the confirms it, completely neglecting anything that disproves it.
So when someone says «the mitochondria are not producing enough energy», and someone else says that «if that was the case, you’d expect to see symptoms X and Y like in other diseases where the mitochondria are faulty, but you don’t see those in ME/CFS», you’ve already got good data against the hypothesis.
Or pointing out that if ME/CFS is neurodegenerative, then we’d expect to see the symptoms of Alzheimers, Parkinson’s etc., but we don’t. And people have gone from being severe to healthy, so whatever ME/CFS is, it’s probably reversible.
And you don’t have to be a scientist to ask those kinds of questions or make those observations.
jnmaciuch
Senior Member (Voting Rights)
I don’t think it’s necessarily an uncommon skill (it’s certainly the backbone of everything I’m being trained to do every day as a junior scientist), just one that doesn’t really work without theories to give you some place to start in an infinite search spaceI mean really simple questions.
Is that real?
What do we mean by that?
Why do we think that?
Are those things the same?
The trouble with hypotheses and detail is that they can distract people from looking for the truth. That involves stripping away, not building up. It's an uncommon skill, but one that can be learned.
Jonathan Edwards
Senior Member (Voting Rights)
I think you need some patience @Dude. A lot of these discussions help us get clearer what we think the options are. For instance, with the Daratumumab studies the data are inconclusive but very interesting and we have together gone through a range of possibilities and come out with some useful conclusions.
Jonathan Edwards
Senior Member (Voting Rights)
Why does it suggest that? If the microcirculation was inadequate the day I result should be down. If the idea is that microcirculation is reduced n day 2 that makes no sense in terms of stuff about clots or endothelial thickening or stiff red cells or even antibodies to receptors. The story just desn't add up in any detail. And the measures that change on day 2 aren't particularly measures relevant to muscle oxygenation either. To make sense biomedical science has to make sense at each step and for the steps to join up.
Jonathan Edwards
Senior Member (Voting Rights)
I think we probably can. It is a bit like saying the car goes slowly because there isn't enough petrol. If there isn't enough petrol the car stops, it doesn't go slowly.
I have lots of thoughts but nothing I would put money on. I recently published one idea in Qeios (open access, Google Edwards, Cambridge, Cliff maybe) but it was intended more as an exercise in finding an example to illustrate how one might answer some particular questions.
I am pretty sure that ME/CFS is a signalling problem, probably involving both nerves and immune signals. I am intrigued by a possible similarity to narcolepsy and maybe other hypothalamic problems. I think sensory neurons may be functioning abnormally in spinal cord or dorsal root ganglia. I think antibodies and t cells may well be misbehaving but cannot work out how. Those give a rough ball park of where I thin things are at.
I see everyone going for energy deficits and mitochondria because that makes sense to a layman at first glance but having worked in muscle medicine it doesn't ring true to me and that is what most other physicians would say.
Jonathan Edwards
Senior Member (Voting Rights)
Maybe Kitty s referring to making sure we are trying to explain the right thing - is a proposed thing-to-explain real or misidentified?