Is ME a metabolic problem or a signalling problem?

Maybe because brain cells are hard--and expensive--to scan in high detail? It's hard to measure how tightly astrocyte feet are clamped around a blood vessel, or how much quinolinic acid is being produced in a small clump of cells, and it probably doesn't take all that much variance to cause noticeable symptoms. I recently came across three studies using complex processing of EEG signals that seem to accurately identify PWME from controls. One study was from 1990 IIRC. So, here's a technique that might be a reliable clinical exam for ME, more or less duplicated twice ... and no one is funding development of it. The latest study was done by an undergrad, paid for by himself and the test subjects. I suppose a better answer to your question is: lack of funding.

I'm not a biologist, and certainly not a specialist in the specific fields of brain/body communication, so I lack the specific knowledge to form a strong detailed hypothesis. The brain has very strong control over various body processes, so to me it seem reasonable that altering even a few brain cells could affect production of exosomes or whatever might be the 'something in the blood'.

I can't be that certain about that. My cytokine profile only showed a few cytokines slightly or mildly elevated, but maybe it doesn't take much. Maybe the glial cells are much more sensitive to those cytokines (tougher to test than measuring cytokine levels in serum). The positive feedback loop could be restricted to the brain, and extra cytokines from the body could add to that to make symptoms more severe. Viral infections seemed to create the same increase in symptoms for me that physical exertion did, and cytokines could explain that.

I looked up creatine kinase. I found this study: https://www.hindawi.com/journals/jnme/2012/960363/

"The appearance of creatine kinase (CK) in blood has been generally considered to be an indirect marker of muscle damage, particularly for diagnosis of medical conditions such as myocardial infarction, muscular dystrophy, and cerebral diseases. However, there is controversy in the literature concerning its validity in reflecting muscle damage as a consequence of level and intensity of physical exercise."

I skimmed the paper, and it seems that CK levels aren't a completely reliable measurement of how much muscle cells are damaged, and thus how much IFN-g might be released. How the tests are done and when the samples are taken are important. I found it interesting that they clearly differentiate between accustomed vs unaccustomed exertion, so my experiences with the two types of exertion does fit. Also interesting is that CK peaks 24 hrs after the exertion, although that depends on various factors.

 

There have been more than a few of each sort of brain imaging method and the results, at least in terms of specific regions have been inconsistent.

The expectation is that if something goes wrong then this will cause damage and this will show up on a scan.

Generally speaking, brain pathology will lead to some kind of specific neurological outcome, but ME/CFS doesn't fit the pattern as other such diseases (from MS to Alzheimers), particularly the progressive nature of the pathology in the brain.

Cytokines are part of localised cell to cell communications. By the time they spill over into circulation, they are no longer useful and as such, in circulation they are degraded to levels where they are no longer going to have much effect. If a test reveals high levels of cytokines in blood serum, the problem isn't the activity of those cytokines in the serum, the problem is the cause of the high level of cytokine signalling in the periphery.

Cerebrospinal fluid cytokine studies of ME/CFS have been inconsistent. It is indeed possible that there could still be aberrant feedback loops in specific/localised parts of the brain or periphery, but the key conclusion of this is that cytokines are not the "something in the blood".

There have also been a variety of experiments (in healthy people) that show that no particular cytokine causes/maintains those symptoms we associate with viral infections. The converse is still possible, namely when damage associated with such symptoms occur, this can cause the release of cytokines.

Any hypothesis based on pathogenic exosomes has the same limitations - exosomes are a part of cell to cell communication. The spilling over into the blood itself is unlikely to be perpetuating the disease, so the key question is where are they coming from?

Unless we can propose specific mechanisms, our beliefs/opinions don't really count for much.

(this last bit isn't aimed at anyone in particular)

A key point that many seem to miss (including discussions in peer-reviewed manuscripts) is the importance of scale - phenomena at a biochemical level is quite different from phenomena at a cellular level, which is different from phenomena at physiological scales. Plausible hypotheses need to respect this and appropriate perspective to describe how the phenomena on each scale is linked.

A classic example of this lack of respect of scale is how aspiring students (high school and even undergraduates) are taught this nonsense model of "lock and key" receptor-ligand binding.
While the emphasis is on the importance of shape and structure of the receptor matching the ligand, this tells us very little about biochemical signalling! The truth is there are always multiple types of locks (multiple receptors for the same ligand) and many keys (ligands).

Some receptors may bind to ligands that you expect to have different effects (such epeniphrine, acetylcholine, dopamine, serotonin), yet there are receptors that bind to these neurotransmitters that trigger similar cellular signalling cascades (Gi alpha subunit coupled receptors). Secondly, ligands that tightly bind to receptors aren't considered to be agonists, but instead antagonists since they are blocking the signal - the rate of competitive binding determines the rate of signalling!
It's better to think of a single binding event as a small voice in a vast crowd.
The cell too, based on it's response to it's microenvironment (which leads to it's development over time, with respect to it's DNA 'cookbook') determines how it wishes to respond to such signals based on which types of receptors and how many it expresses.
Thus the biochemical signalling of a cell could be imagined more like a vast orchestra, performing a complex composition, rather than a simple biochemical cascade.

But even then, this is just a single cell and tells us nothing about the other trillions of cells in the body. Even if one cell makes a series of persistent mistakes and manages to survive, this itself does not cause disease (even neoplasms are not a purely cellular phenomena). If the symptoms we are trying to predict requires that cells that are on opposite sides of the body are all somehow making the same mistakes, then it is clear we also require a physiological scale explanation. This is why many hypotheses for ME/CFS, such as the "it's the mitochondria" hypotheses fall flat, because at best, they are inherently incomplete.
Genetic causes are the exception (since this defect really is in every cell), but based on epidemiological research and genetic studies so far, this doesn't seem like a strong factor, however the DecodeME study will tell us for sure.

Hypotheses based on persistent latent viral infections, or pathogenic feedback loops induced by prolonged viral infection (in specific physiological regions where those feedback loops can be maintained) are plausible. But this still begs the question, what are the actual feedback loops, why do they persist for years, and how do they explain the symptom kinetics on a physiological level? (and any differences between patients)

On the other side, there are hypotheses that consider the physiological scales, but are lacking at other scales. These are mostly brain-based hypotheses, and include autonomic dysfunction, HPA-axis dysfunction, central sensitivity and so on. These hypotheses often off a simplified description of biochemical pathways in addition to hypothesised phenomena at a physiological scale. Yet they fail to explain the overall pattern of symptoms, and fail to explain what occurs at a cellular level (and the most replicated objective sign so far, the reduction in the gas exchange threshold on the 2 day CPET). Such hypotheses also don't explain why the hypothesised biomarkers are not found in the serum or CFS many patients (abnormal levels of neurotransmitters or hormones).

The remaining hypotheses tend be limited by the lack of ease by which we can experiment on humans. There have been many studies of red blood cells or peripheral blood mononuclear cells, but this testing assumes that these cells will have a pathogenic marker, despite the fact that there are a wide range of cellular microenviroments in the body that are quite different to that of blood circulation. Likewise, it can be difficult to take biopsies of various organs without disrupting the relationship between the cells and their microenvironment.

Lastly, I'd like to point out that the title of the thread is a false dilemma - accumulation of metabolites could be part of a signalling feedback problem.

 

So I think you are saying they are not necessarily mutually exclusive, but the title implies they are?

 

Yes, otherwise it would say 'and, or'.

Of course my memory failed me a little (mentioning the point again), because Adam literally pointed this out in the first reply!

 

There's a lot that isn't covered by the available methods of brain imaging. I'm not sure what the smallest range of chemical signalling is, but I expect it's only a few cell diameters. Available methods just don't scan that scale, and not at a relatively huge distance through a thick skull. The lack of a clear signature for ME isn't surprising to me. Given those limitations, I think we'd be more likely to discover the key to ME by experimenting with a wide range of chemicals, and hoping to find one or more that strongly affect ME symptoms.

As for the 'something in the blood', I think it's likely a downstream effect of ME, so I'm not all that excited about figuring out what it is. Maybe it will point to an obvious cause, or maybe the cause will be many steps upstream. I don't have the typical physical limitations of ME, so I'm not sure that my blood has that 'something'.

True, but the process of learning about the various biochemical functions is still useful, and discussing them here is useful for thinking about them and possibly making new connections. Someone might post an impressive hypothesis, and someone else had read an obscure paper with information that destroys the hypothesis. That's good science. Maybe someone will post a vague hypothesis or an observation, and it will trigger a line of thoughts in someone else that will eventually prove useful.

My--admittedly vague--hypothesis for ME is that a fairly small number of brain cells get switched into an abnormal state by an immune-activating event, and in some individuals, other metabolic pathways are such that there's a positive feedback loop maintaining the abnormal state. It's possible to switch back to the healthy state quite rapidly, giving temporary remission, but after the first triggering, the factors forming the feedback loop shift more towards maintaining the abnormal state. Some sort of viral infection might be predisposing us to that positive feedback state, and the ME could in turn feed back to maintain the infection. The microbiome is another possibility for shifting and maintaining abnormal states.

My experiences convinced me that abnormal levels or ratios of kynurenines are involved in most if not all of my ME symptoms, so I have a special interest in glial cells.

 

This is a difficult question. The first suggestion is to stop wasting funds on superficial studies that have already proven fruitless and instead base research on deeper hypotheses that are more consistent with existing researcher and patient experiences.

The most promising "objective" foothold is the 2 day CPET results. The key point is that the ventilatory threshold has neurological correlates - namely activity of specific afferents and is associated with a significant increase in neural drive (and effort), which is why the metabolic balance shifts in a non linear way after this threshold is reached. I believe that this can further be explored by measuring the reduction in myographic and electromyographic fatigue thresholds on the second day. The role of specific afferents in mediating this reduction in fatigue thresholds can be tested using pharmacology, initially anaesthetic agents to block specific afferent. If the afferents are not directly involved, then this suggests the fatigability is a purely metabolic/mechanical problem. If specific afferents are involved, then more detailed research (using pharmacology and biopsies) to uncover which receptor pathways are being stimulated, which could provide the key clues as to what is going wrong.

Many studies would be improved by utilising post-exercise challenges: other avenues include testing biopsies (for gene expression/DNA methylation, proteomics/ubiquination etc., rather than focusing on peripheral blood mononuclear cell. Detailed spectral imaging of muscles/microcapillaries, peripheral axons focusing on specific metabolite signatures.

Brain imaging should focus on changes induced through somewhat long cognitive challenges when patients start to experience more severe brain fog.

All of these suggestions are more invasive than many prior studies, but if what has been done hasn't worked, due to the superficiality of the hypotheses or looking in the wrong places, then we need to start doing it differently.

 

muscles can be damaged without high ck, like you can have mitochondrial disease without raised lactate, etc.

 

@Snow Leopard, if at any point you felt like blogging something like this as a sort of 'friendly challenge' to the research community – which could be shared more easily than posts on S4ME – I'm sure it would be welcomed by a lot of patients who lack the understanding of biochemistry/physiology to put it together themselves!

I realise it's not an easy thing to do, because going public can expose people to a lot of criticism, but it does often feel as if we're missing detailed, patient-generated responses to the direction of biomedical research.

 

Sure, there can be a modest amount of micro damage, but this isn't substantial - or there would be CK spillover into circulation and it also isn't enough to cause a mechanical loss of peak force.

Now some have suggested "neuromuscular strain" as a pathogenic factor in ME/CFS (Rowe and colleagues), or "neural microdamage" (Sonkodi and colleagues) or deep fascia sensitisation (Nosaka and colleagues) as an explanation for delayed onset muscle soreness in healthy people. The latter point is based on observations that the deep fascia is more sensitive to eccentric contractions than the muscle fibres themselves.

Lastly, I also note that most, if not all of the infections that are associated with ME/CFS have documented interactions with key receptors involved with extracellular matrix signalling, (particularly integrins, proteoglycans, neuropilins and associated growth factor receptors). These factors tend to be associated with wound healing/angiogenesis and axonal guidance. This suggest that a key place to look may be the deep fascia of skeletal muscle (which include afferent nerves and associated glia) and the basement membrane surrounding capillaries. Signalling abnormalities may be found here, that might not be found in PBMCs due to very different microenvironments.

 

are you aware of post polio syndromde?

 

Yes, why do you ask?

 

(Apologies if this has been mentioned or asked before -- the post just wanted to be released from my drafts folder.)

To me it feels like not my energy production per se is ineffective. Rather it seems as if the by-products of being active bahave in a way or produce some additional stuff that somehow counteracts different aspects of being active -- cognitive, motor and muscle fatigability but also flu-like sickness, coordination problems, vertigo etc.

Maybe this view could explain why in mild to moderate ME people are still able to overdo things (sometimes without even perceiving this as an effort) or push through?

But why would those by-products be produced?

Are those normal by-products but the process of clearing them is broken?

Or is there a malfunction in the energy production, delivery or consumption, or a malfunctioning in signalling that leads to too much or otherwise abnormal by-products?

Where could those by-products originate?

Location of production and locations of effects/symtoms?

Is this systemic or tissue-bound or both?

Could there be very small abnormalities in tissue that don't interfere with normal functioning as such but only with the clearance of by-products of normal functioning?

Based on this view, could the different locations and manifestations of symptoms in people with ME give a clue on which tissues /systems could be structurally damaged or don't work properly for other reasons?

 

There is discussion that it might be ammonia due to using too much protein for energy. This is unproven as yet. I think it was in connection with an OMF post that this was mentioned, maybe something from Ron?

 

I've often thought this too.

Edit: I definitely feel like I'm 'poisoned' after exertion, which gets worse the 2nd and 3rd day after it.

 

I have had similar thoughts about activity either depleting something good or causing accumulation of something bad. It's not that I'm unable to exert myself, it is just abnormally stressful for the body to do so.

Usually my PEM is delayed until the day after which makes me think that something happens (or fails to happen) during sleep. It seems that the body only becomes fully aware that there is a problem during sleep, and once it's aware, some sickness response begins and we begin feeling sicker.

Recently I read that the purpose of sleep is to allow removal of toxic waste products from the brain. It could be that our waste product removal system is not working well.

PS: this autumn, I had PEM begin immediately after severely overexerting myself (I had no real choice). That would seem to confirm that different PEM timing may simply be due to how susceptible a person is to PEM and how much they usually tend to overexert.

 

I also find the PEM doesn't start until I have slept. If I really need to complete a specific task I have always aimed to do it on the same day, knowing it may be weeks or months before I can return to it if it's left unfinished. When I was less severe I was able to get a lot more done around the house using this system. I'd never tell a healthcare professional that though, because I think this is what leads the BPS people into accusing ME/CFS patients of 'boom and bust', rather than of course using the information to try to understand what's happening in our disease.

 

My daughter, who is severe and thus never turns up on this site, stated the identical thing you just did. She keeps saying this illness is due to some kind of issue with the aftermath of exertion, mental or physical, and the body not being able to tolerate exertion and becoming sicker once the activity has been completed. Sleep is also disordered, but when the exertion has been a little out of the range, even falling asleep becomes impossible, and the sick feeling really starts to mount throughout the night and the next day is hell, and it can last for days.

 

The more severe I've become, the more difficulty I have with falling asleep too, and like your daughter, the sick feeling gets worse through the night. I think @strategist has summed up this experience really well. I think I need to put this in writing to my GP, who still focuses on the fatigue aspect!