Has current research established cause of PEM

[perrier]

Many problems have been established in the current research, everything from brain inflammation to red blood cell deformability problems.

Has anyone out there established what causes the patient to have such horrible malaise with the most minor ( reading one email, or trying to brush teeth, or even talking) physical or mental exertion.

This cardinal symptom of he disease needs to be explained. Are we there or not? Thank you.

 

[roller]

"I am excited to report that Dr. Jose Montoya’s Stanford ME/CFS Initiative will be joining in a new collaborative research effort with Columbia University to further understand the association between exercise, the human microbiome and ME/CFS.

The purpose of this study is to evaluate the immune system and microbiome of ME/CFS patients before and then during a post exertional malaise episode."
from the other site, by webdog

1. physical exam
2. blood collection
3. BICYCLE exercise
4. blood collection
5. stool & saliva samples

 

[prioris]

getting physically exhausted from just mental exertion and not moving has always been a curious symptom to me

 

[perrier]

1. physical exam
2. blood collection
3. BICYCLE exercise
4. blood collection
5. stool & saliva samples

Thanks for this reminder Roller. It is very discouraging that we are only at this rather elementary stage of investigating what happens/ or brings on PEM. I know that Nancy Klimas has been doing bicycle testing for ages, and her colleagues have determined the person goes into anaerobic mode rather than aerobic. But anaerobic surely does not cause PEM.

Anxious to hear if there is more detective work on the causes of this singular symptom.

 

[ljimbo423]

Many problems have been established in the current research, everything from brain inflammation to red blood cell deformability problems.

Has anyone out there established what causes the patient to have such horrible malaise with the most minor ( reading one email, or trying to brush teeth, or even talking) physical or mental exertion.

This cardinal symptom of he disease needs to be explained. Are we there or not? Thank you.

This is what these researchers have found. My feeling is, the more research that's done on the body wide affects of the gut microbiome and leaky gut, particularly after exercise or even mental stress.

The more the evidence found in this study, will be validated and replicated in relationship to PEM. For the severely ill, the physical or mental stress of just brushing one's teeth or reading an email etc, might be enough to increase intestinal permeability and bacterial translocation and cause PEM. Just as exercise does in those of us that are less ill.

We hypothesized that the ecology of the gut microbiota of ME/CFS patients would differ from that of matched healthy controls and that these differences would be associated with increased

bacterial translocation from the gut to the circulatory system following exercise challenge with corresponding worsening of symptoms (i.e, pain, fatigue, and mood).

The results presented here add further to the previous findings suggesting that ME/CFS patients have an altered gut microbiome and further suggest that increased bacterial translocation following exercise provides a potential explanation for the profound post-exertional malaise experienced by some ME/CFS patients.

Link to study

 

[percyval577]

If - it´s my personal favourite - the symptoms came from
a geometrical trap of synaptical connections in these geometrical structures inside the brain
(which would probably influence other systems),
could such a misproportion show up in an neuroimaging??

I have read that deseases which invovlve disbalance of receptors can show up in PET.
But maybe here it´s only a slight disbalance. Maybe it would be only a geometrical misproportion?
Then how long would we need to wait until it could become investigable?

More generel, a very recent and reasonable assessment:

Russel et al 2019 Persistent fatique induced by interferon-alpha ...
last paragraph

In conclusion, findings from this study support the hypothesis that abnormal immune mechanisms are important in CFS, but only early in the course of the illness, around the time of the trigger, rather than when the syndrome is established. Moreover, our study confirms the importance of the acute fatigue response to the trigger, rather than of the recovery period preceding the illness. Future research will need to examine the molecular mechanisms that underlie an exaggerated immune response and that are involved in the conversion from acute to persistent fatigue symptoms.

(They also had a very good look at IDO, BTW)
---
However, in my case I can support my beloved geometrical pronounced structure(s),
(1) -- but I would think that the influence on my immunesystem is prerequisite (I know my history of two infections, and the pathway that has become altered can be influenced, I have given it in the signature below)
(2) -- I have found out in my case: A) neurotransmitters and/or precursors (gaba together with taurin // tyrosine, together with very little tryptophan which can get strange) B) Metals like in chocolate (in fact in my experience there evolves too much chaotic action if the amount of chololate is too high, so 0.25-0.5g/kg bw) Chocolate drink?? C) Medicals (alkaloids, hops and alcohol in autumn, one drop of ambroxol) D) a quarter drop of vinegar while gettig better (for ASIC in the the accumbens, therefore not together with alcohol).
(3) -- Thanks to Fluge 2016 p3 f1 the TCA could (can in my experience) be fueled by some aminoacids. Fluge referres to PBMCs (immunesystem), if I am remembering right.

In my case its progredient, still not fast a miracle. I also was fine in beween. Additional remarks:
ad (1) -- The idea to reverse the impact in a its special target(s?) is not mentioned by the nice article Russel et al 2019. Naviaux 2014 says that all stuff which can catch electrons might be a cause of deseases including mecfs. Maybe (I think so) it would needed to specify. But who knows, maybe not in mecfs??
ad (2) -- The metals I am talking about are nickel, chromium, zinc, aluminium, not in chocolate is silver (as far as I know) -- How long would it take until these ultra-trace metals are investigated any further? The intelligent article Naviaux 2014 (cell danger response) mentions some of these metals only as per se toxic.
ad (3) -- Some of us have reported good effects from BCAAs. I though have so far tested lysine, methionine (seems to be strange in conjunction with lysine, sadly), histidine (but very ambivalent now?!), proline (makes my rosacea worse when it works towards the eyes).

(So, this is almost all my wisdom. It might look a bit humpty dumpty like. And I do eat a lot of eggs now indeed.)
---

 

[perrier]

This is what these researchers have found. My feeling is, the more research that's done on the body wide affects of the gut microbiome and leaky gut, particularly after exercise or even mental stress.

The more the evidence found in this study, will be validated and replicated in relationship to PEM. For the severely ill, the physical or mental stress of just brushing one's teeth or reading an email etc, might be enough to increase intestinal permeability and bacterial translocation and cause PEM. Just as exercise does in those of us that are less ill.


Link to study

Thanks Jim for reminding us of this 2015 study. We are now in 2019; 4 years beyond the study. If bacteria is being translocated into the blood stream, then what can be done about this; blood is normally sterile, and so if this is true, it is a sort of poisoning that the patient feels (which is often what patients do feel).

Now where are we now with this? Who is working on repeating this experiment and finding serious treatment. The Severely ill are truly fragilized and need intervention soon.

Those here on PR who have had fecal transplants are not reporting ME resolution; and I bet there is not a soul on this site who isn't plying himself with probiotics. And still not resolution.

But the larger question is: is this area not worthy of exploring further? The article is from 2015.
Thanks for the reminder.

 

[perrier]

If - it´s my personal favourite - the symptoms came from
a geometrical trap of synaptical connections in these geometrical structures inside the brain
(which would probably influence other systems),
could such a misproportion show up in an neuroimaging??

I have read that deseases which invovlve disbalance of receptors can show up in PET.
But maybe here it´s only a slight disbalance. Maybe it would be only a geometrical misproportion?
Then how long would we need to wait until it could becomes investigable?

More generel, a very recent and reasonable assessment:

Russel et al 2019 Persisitent fatique induced by interferon-alpha ...
last paragraph

(They also had a very good look at IDO, BTW)
---
However, in my case I can support these geometrical pronounced structure(s),
(1) -- but I would think that the influence on my immunesystem is prerequisite (I know my history of two infections, and the pathway that has become altered can be influenced, I have given it in the signature below)
(2) -- I have found out in my case: A) neurotransmitters and/or precursors (gaba together with taurin // tyrosine, together with very little tryptophan which can get strange) B) Metals like in chocolate (in fact in my experience there evolves too much chaotic action if the amount of chololate is too high, so 0.25-0.5g/kg bw) Chocolate drink?? C) Medicals (alkaloids, hops and alcohol in autumn, one drop of ambroxol) D) a quarter drop of vinegar while gettig better (for ASIC in the the accumbens, therefore not together with alcohol).
(3) -- Thanks to Fluge 2016 p3 f1 the TCA could (can in my experience) be fueled by some aminoacids. Fluge referres to PBMCs (immunesystem), if I am remembering right.

In my case its progredient, still not fast a miracle. I also was fine in beween. Additional remarks:
ad (1) -- The idea to reverse the impact in a its special target(s?) is not mentioned by the nice article Russel et al 2019. Naviaux 2014 says that all stuff which can catch electrons might be a cause of deseases including mecfs. Maybe (I think so) it would needed to specify. But who knows, maybe not in mecfs??
ad (2) -- The metals I am talking about are nickel, chromium, zinc, aluminium, not in chocolate is silver (as far as I know) -- How long would it take until these ultra-trace metals are investigated any further? The intelligent article Naviaux 2014 (cell danger response) mentions some of these metals only as per se toxic.
ad (3) -- Some of us have reported good effects from BCAAs. I though have so far tested lysine, methionine (seems to be strange in conjunction with lysine, sadly), histidine (but causes cold limbs now?), proline (makes my rosacea worse when it works towards the eyes).

(So, this is almost all my wisdom. It might look a bit humpty dumpty like. And I need to eat eggs now indeed.)
---

Thanks, but you still must be able to tolerate all this; the severely ill can't even eat normally, let alone take supplements. So, help is needed urgently.

Are you suggesting that PEM results from a problem in the synoptical connections? Then it is a signalling problem.

 

[ljimbo423]

Thanks Jim for reminding us of this 2015 study. We are now in 2019; 4 years beyond the study. If bacteria is being translocated into the blood stream, then what can be done about this; blood is normally sterile, and so if this is true, it is a sort of poisoning that the patient feels (which is often what patients do feel).

Yes, we certainly need more studies to further validate these findings and connect them to PEM and other symptoms. Although there have been at least 6 studies that show an increase in bacterial translocation in cfs that I know of. As far as to what can be done about goes.

I think the bacterial dysbiosis they have found needs to be re-balanced, so the leaky gut can heal. Unfortunately, for most of us that is much easier said than done. Because of the worsening of symptoms when treating the gut and that the microbiota is often very difficult to re-balance once dysbiosis is well established.

This is a quote from @roller's post, the second post in this thread-

"I am excited to report that Dr. Jose Montoya’s Stanford ME/CFS Initiative will be joining in a new collaborative research effort with Columbia University to further understand the association between exercise, the human microbiome and ME/CFS.

The purpose of this study is to evaluate the immune system and microbiome of ME/CFS patients before and then during a post exertional malaise episode."
from the other site, by webdog

I'm not sure when this study will take place but it seems like it will be soon. This should give us more info about how the gut microbiome, leaky gut and the immune system are causing symptoms in cfs.

I understand all to well that we need more information and good treatments now. I'm doing everything I can to treat my cfs but it's very slow. At 59 years old and being disabled with this illness for 30 years it's very slow going and very scary.

 

[percyval577]

Are you suggesting that PEM results from a problem in the synoptical connections? Then it is a signalling problem.

Yes, this I would think. So the hypothesis includes:
-- There is too much plasticity, every doing induces a huge huge amount of new synapses. With such an exaggeration there is no (good) human life possible. A member said it: %("+&§"=(
-- Of difficulty could be that the body is wise, he might preserve such a chaos, but slows down the overall action, and then the summ of new synapses might not differ to healthy people.
-- If you ask me, there is no other possibility to explain delayed PEM. It´s a processing of informations. This also should be the explanation of different mixtures of symptoms (due to different histories and genetics), the processing machinery is differently affected.
-- In addition it will be able to explain the exhaustion, which would correlate with a bunch of new synapses, and to explain the lack of a nice tiredness, because the resolution of synapses is to every time again competed by a lot of new synapses again. There is no dreaming possible.
-- There is no principle problem to connect the nerves to other systems, and the possibility is commonly accepted.

... but you still must be able to tolerate all this; the severely ill can't even eat normally, let alone take supplements. So, help is needed urgently.

I see this problem. Maybe very good luck would be needed to find a point to start. I am not severe, and (at least after having found out how to influence my immunesystem) I can feel what is good or not good, I can feel that I now should take this or that (after having catched the ideas).
I guess that a monitoring would be required. But it doesn´t look as if already possible.

 

[perrier]

Yes, this I would think. So the hypothesis includes:
-- There is too much plasticity, every doing induces a huge huge amount of new synapses. With such an exaggeration there is no (good) human life possible. A member said it: %("+&§"=(
-- Of difficulty could be that the body is wise, he might preserve such a chaos, but slows down the overall action, and then the summ of new synapses might not differ to healthy people.
-- If you ask me, there is no other possibility to explain delayed PEM. It´s a processing of informations. This also should be the explanation of different mixtures of symptoms (due to different histories and genetics), the processing machinery is differently affected.
-- In addition it will be able to explain the exhaustion, which would correlate with a bunch of new synapses, and to explain the lack of a nice tiredness, because the resolution of synapses is to every time again competed by a lot of new synapses again. There is no dreaming possible.
-- There is no principle problem to connect the nerves to other systems, and the possibility is commonly accepted.

I see this problem. Maybe very good luck would be needed to find a point to start. I am not severe, and (at least after having found out how to influence my immunesystem) I can feel what is good or not good, I can feel, that I now should take this or that (after having catched the ideas).
I guess that a monitoring would be required. But it doesn´t look as if already possible.

If there is this problem, dear Percyval, what hope is there; we are talking about a problem of brain wiring then. But the obvious question is: how come the person functioned normally for two decades before contracting this?

 

[percyval577]

But the obvious question is: how come the person functioned normally for two decades before contracting this?

By no means it should be any psychological problem (which is also stated in a nice manner by the 2019 article above). If there is a mechanism to process psychological things, than though this mechanism can get mechanistically ill (this is not a surprise). Obviously we are talking about many problems of processing, the uttermost are "technical", in severe cases it may be not able to walk or not able to have light, to name two. Whereas in depression it´s the mechanism of motivation that is affected (my impression is that we have rather minor problems with anxiety asf.).


In my case I know that too much nitric oxide from the immunesystem has caused this wrong wiring (and the possibility will hardly be by accident, as evolution needs to be adroit). Nitric oxide is a molecule of huge complexitiy in its effects, and I think it´s not better understood than reactive oxygen species are, which are similiar broad signaling metabolites. But the effects on nerves are understood not too bad and the interpretation is rather simple thinking: Causing plasticity for the purpose of memoring and learning. More difficult may be to see how this can make you feel and do bad.

However, many disturbances are thinkinkable. In my case it´s nitric oxide from the iNOS in microglia. Microglia are complex, there is also a cNOS, may this can go wrong, there is a glutamate release, maybe this can go wrong. There are also astrocytes, maybe there can go something wrong.
So here the hope is to find out somehow (in my case it was almost easy doing, but don´t think that any doctor was able to put 1 plus 1 equals 2) what has gone wrong and to influence the process towards the other direction.


There would also be a direct impact on the nerves thinkable, eg on the nNOS. There might be more possibilities thinkable. Perhaps same thing than above. Above it´s rather a cycle: (eg) immunesystem <-> nerves, this consideration is not new.


If it is a breakdown in the sense of a geometrical miswiring, then the hope is to help coming out of it. (Again, it might require an influence on other system (in my case the iNOS was/is obviously/probably needed to get influenced). Different things could be a limitation in the speed of getting better.)
My impression is indeed that there is a geometrical trap. I cannot prove it of course (even if it would be possible these years) and I am mathematically not skilled enough to make a model, it might be like in a rectangle where to the one direction more synaptical connections would be than to the other one, and the "short side" would take over.
Here the hope is to support the "long side" with stuff that is needed in these brain structures (the long caudatus, the long thalamus, probably somehow putamen and pallidus, maybe there is a spiral structure?!). In my experience (using this interpretation) the stuff I supplement indeed does like so, there is no relative higher support for the "short side". Neverhteless I see the danger that every supplementation can have more effects than the (guessed) desired one.

 

[Wishful]

This cardinal symptom of he disease needs to be explained. Are we there or not? Thank you.

No. We're not there yet. We have a bunch of hypotheses, mostly with counterexamples. None of the official hypotheses about PEM feel right to me. Furthermore, there are at least two types of PEM: physically-induced and cerebrally-induced, with different delay times and different severity of different symptoms. They have something in common, but also differences, so it's hard to fit that to one hypothesis.

My guess is that PEM triggers the neuroimmune system in a certain way. The two types of triggers have different origins, and probably different ratios of cytokines. The microbiome might be involved for some PWME, but not others. For those where it is an issue, maybe it's triggering some cytokines in a similar way that they're triggered in other people by other means.

 

[Wishful]

getting physically exhausted from just mental exertion and not moving has always been a curious symptom to me

Most of our body systems are interlinked. Mental exertion can change various chemical ratios that in turn have major effects on metabolic processes in muscles or whatever else, and vice-versa. People can easily be convinced that they are too weak to move, even with no physical or chemical changes in their muscles.

To me, it's more amazing that we can most of the time deal adequately with imbalances in our various systems. I suppose that's a result of evolution: the ones who were easily debilitated by minor imbalances were weeded out.

 

[perrier]

No. We're not there yet. We have a bunch of hypotheses, mostly with counterexamples. None of the official hypotheses about PEM feel right to me. Furthermore, there are at least two types of PEM: physically-induced and cerebrally-induced, with different delay times and different severity of different symptoms. They have something in common, but also differences, so it's hard to fit that to one hypothesis.

My guess is that PEM triggers the neuroimmune system in a certain way. The two types of triggers have different origins, and probably different ratios of cytokines. The microbiome might be involved for some PWME, but not others. For those where it is an issue, maybe it's triggering some cytokines in a similar way that they're triggered in other people by other means.

The fact that science is not able to get a handle on this horrid PEM is very distressful; very discouraging; particularly for the very severe who have this non stop.

With regard to the types of PEM: yes, there is physically induced PEM--or collapse and sick feeling, and there is PEM produced by mental activity. ( I am not ill, however, when I was a university student and say, reading middle high German and translating it into English, hour upon hour, upon hour, I became so physically tired, I collapsed onto my student bunk-bed. So, I find intellectual labour now and then to also bring upon fatigue. Yes, it was different from aerobic activity, but still fatigue set in. So, I don't know if the two PEM situations are radically different, though some difference is there for sure. Exertion, or strain or even concentration is at the core of PEM.

I don't know how it could be only a signalling problem as Percyval suggests because this disgusting sick feeling it always there...it's just there at a lower level when lying still.

Does modern science not understand the network of what is involved in exertion?

How can the severely ill hold on much longer?

 

[prioris]

research into disease ...
It is a dimension as vast as space and as timeless as infinity. It is the middle ground between light and shadow, between science and superstition, and it lies between the pit of man's fears and the summit of his knowledge. This is the dimension of imagination. It is an area which we call the Twilight Zone.

 

[Wishful]

Exertion, or strain or even concentration is at the core of PEM.

In my thread 'Stress Makes PEM Worse?', I mentioned that I'm leaning towards increased neural activity being the factor for cerebral PEM, rather than adrenaline. Something about maintaining a highly alert state, and processing inputs and judging responses for driving, and also for following conversations and contributing to them. I'm not sure what biochemical or physical processes are involved with that.

I don't think it's only a signalling problem. Glial cells do affect neural processing, so any abnormality in their function could make us feel brainfogged, achey, and overall 'sick', but I don't think that's the only malfunction. I'm still convinced that abnormal kynurenine levels are involved in at least some of the symptoms.

No, science does not yet understand the full network of what in involved with exertion. We know bits and pieces, but not how it's all interlinked. I'm still hopeful that we can learn enough fairly soon to come up with some treatments that at least work somewhat for some people. A simple cure would be most welcome, but even partial treatment would be good, and would help with further research.

 

[percyval577]

I don't know how it could be only a signalling problem as Percyval suggests because this disgusting sick feeling it always there...it's just there at a lower level when lying still.

Yes, but the brain is always working too. Not only when the being is awakd also when sleeping, the brain never stops to process informations. So, if there is an exeggeration on synapse turnover, then it can principially take place to every time, and if it is strong enough it would be only logical to do so.

Does modern science not understand the network of what is involved in exertion?

A complex question. And scientists like to keep things simple. Why can you have pain? "Well, we observed a firing of c-fibers." Or another context: "If you take the strong serotonin reuptake inhibitor Ecstasy you can dance for days without sleeping."
An interpretatation of exhaustion and tiredness could well be, I think: You feel exhausted if you have learned or memorized a certain amount of informations, and it would correlate with a hight on NMDA receptors. Feeling tired could be the resolving of synapses (say via agmatine, probably).
I don´t know how much water it will hold, but it would fit into a consideration with nitric oxide (my favourite). I think evolution could have used basic spacial facts from making synpases for making you feel sick: an organism then would make some hight on NMDARs, however it might have gotten regulated more and more in the process of evolution.
Hasn´t there also been this finding on shingolipids (-lipids, it was I think)? And haven´t it been these ones which are needed for releasing (eg) neurotransmitters from vesicles? So this would fit in, wouldn´t it? Has the finding tried to be reproduced? probably not already.
And hasn´t it been shown one time each that microglia in FM and CFS make phagocytosis, not complete sure, but this also would fit in. They can phagocyte dead tissue, eg old synapses.

... there are at least two types of PEM: physically-induced and cerebrally-induced, with different delay times and different severity of different symptoms. They have something in common, but also differences, so it's hard to fit that to one hypothesis.

With regard to the types of PEM: yes, there is physically induced PEM--or collapse and sick feeling, and there is PEM produced by mental activity. ( I am not ill, however, when I was a university student and say, reading middle high German and translating it into English, hour upon hour, upon hour, I became so physically tired, I collapsed onto my student bunk-bed. So, I find intellectual labour now and then to also bring upon fatigue. Yes, it was different from aerobic activity, but still fatigue set in. So, I don't know if the two PEM situations are radically different, though some difference is there for sure. Exertion, or strain or even concentration is at the core of PEM.

I would find it at least a bit strange to say: You are moving by your muscles, and you are thinking by your brain, therefore there are two complete different PEM´s. It would even look a bit like two complete different diseases. Of course in a multifactorial disease a lot of things are possible and must be considered in an ongoing manner.
But the first guess should well be to say as well: You are indeed also moving by your brain, therefore you should look at the brain.
An interesting article in respect of different exertations is: Berke 2018 What does dopamine mean? esp. page 8. I don´t think that cfs is restricted to dopmine, but I think that these structures which contain dopamine are the common major key. They allow for connections of different exertations. They can also easily explain why symprtoms can be so different (including mental vs. physical fatique), as well explain why when the state is getting worse, to higher percentage both mental and physical state will get affected, because in these structures the tasks are set in neighbourhood and are possibly intertwined. (And then I would think, other things, say interkeukin-6, might play a role.)

 

[perrier]

No. We're not there yet. We have a bunch of hypotheses, mostly with counterexamples. None of the official hypotheses about PEM feel right to me.
-----------------
Perrier below:

So, the science now is first rate, that is certain; but there is a deficit of money and a shortage of researchers.

And so are we to conclude that at this moment, we do not know why the body is in this horrific non-life state. We are not sure if it is the GI tract, or the immune system, or the the brain, or what is at the root of this nightmare. We are told there is brain inflammation, problems in the blood, and in the GI and in the immune system.

Does anyone think that folks who contract this, are sort of born with this in them, for it to arise? Like the way, MS develops in many folks? Or do you think this is something that one contracts like cancer?

 

[Wishful]

I think it's a genetic predisposition, possibly epigenetic. It biases certain functions so that they can readily fall into a positive feedback loop when triggered by certain events that usually involve immune system activation. Additionally, we are biased against the functions that normally break that feedback loop and return us to normal function. Actually, I think it could be one or the other or both.

It is possible to snap us out of the feedback loop (proven by temporary remissions). We need to figure out how to do that reliably, and to keep us in the normal healthy state.