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Wolfe Hypothesis ~ Key causative processes involved in CFS/CFIDS/M.E.

Does this theory seem plausible?

  • Yes

    Votes: 9 23.7%
  • Didn't read it

    Votes: 5 13.2%
  • Not sure I fully understand it

    Votes: 5 13.2%
  • No

    Votes: 19 50.0%

  • Total voters
    38
Messages
48
Location
UK
Let us discuss 'critical thinking' because this is something which is applied, or should be, by those who have the highest qualifications, i.e., doctors. In order to research you have to be able to critically analyse and also be objective, of course this also means ourself in order to remove our own bias from the subject we are researching.

This is sometimes difficult when people have been ill for a long time because they bring thier own biases into the things they report.

Doctors even critically analyse each other's work, after all that is what researchers are taught to do. I think one of the issues we ill people have is that we tend to want to sometimes lash out at others who present ideas, experiences, theories, etc., and maybe tell them what they suggest is insulting to us whilst actually it is not, it's just an idea or thery for discussion and to be critically analysed.

Let us discuss this thing called 'evidence' and get rid of the myth that many people seem keep alive. Let us say that Me Sci were to tell me that she had a pain in her muscle, i.e., her brain was registering a pain, she would not be able to offer any peer reviewed scientific evidence at all to prove she had that pain. Therefore if I were to always ask for evidence then of course I would have to conclude the pain was a figment of her imagination.

Rather like ME/CFS, yes it's all a figment of the imagination, or is it! Funny how we who are often accused of making up our illness often then often ask everyone else for evidence for many things they suggest. :)

It's good to ask for evidence of course but let's not forget that sometimes we just need to be open minded and discuss things through and see where we end up. We landed on the moon because someone had the initial idea; the evidence for it did not exist until we had made the idea work. People made that idea work by working together as a team, drawing on each others strengths.

Now my point is that Me Sci knows 100% and without any doubt that she has this pain and therefore she knows something to be true that the outside world cannot prove either way. Now let us say that philpot was then to say 'hey guys' Me Sci has a pain in her muscle. Again I would have no peer reviewed scientific proof and yet Me Sci would know 100% and without any doubt that I was 100% correct about something which I had no evidence for.

My point is that it is perfectly possible and reasonable for someone to be 100% correct about something even though they cannot provide peer reviewed science/evidence to back it up. So on the basis that there is no peer reviewed science which states without any doubt what is the cause of ME/CFS or else what the solution is then all the theories and ideas etc., proposed by all people in these forums could be 100% correct, we do not know.

If everytime we who are often accused of inventing our illness start going on about evidence we should remember two things:

1. We may well be asked to provide the scientific peer reviewed evidence to prove we are ill.
2. We may just snub out the idea/theory which may have otherwise ended up leading to the road to our cure.

I am all about hearing people's ideas and theories and discussing them openly and honestly and collectively and without thowing my dummy out of the pram or prentending to be offended or insulted just because someone suggests something may be in my mind; because this also needs to be explored and discussed.

I am also not about asking for peer reviewed science on everything because this is an area where the science thus far does not amount to much. It may be our discussion which develops the evidence and this will not happen if we 'shout' people down.

Also for each of us when we try something ourselves in order to improve our lives so we need to think critically about the other things which may be happening and which may have instead improved things, we need to be careful about this because otherwise we may ourselves miss the thing which actually helped because we were blinded by the particular thing we were trying.

Regards.
 
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MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
Let us discuss 'critical thinking' because this is something which is applied, or should be, by those who have the highest qualifications, i.e., doctors. In order to research you have to be able to critically analyse and also be objective, of course this also means ourself in order to remove our own bias from the subject we are researching.

This is sometimes difficult when people have been ill for a long time because they bring thier own biases into the things they report.

Doctors even critically analyse each other's work, after all that is what researchers are taught to do. I think one of the issues we ill people have is that we tend to want to sometimes lash out at others who present ideas, experiences, theories, etc., and maybe tell them what they suggest is insulting to us whilst actually it is not, it's just an idea or thery for discussion and to be critically analysed.

Let us discuss this thing called 'evidence' and get rid of the myth that many people seem keep alive. Let us say that Me Sci were to tell me that she had a pain in her muscle, i.e., her brain was registering a pain, she would not be able to offer any peer reviewed scientific evidence at all to prove she had that pain. Therefore if I were to always ask for evidence then of course I would have to conclude the pain was a figment of her imagination.

Rather like ME/CFS, yes it's all a figment of the imagination, or is it! Funny how we who are often accused of making up our illness often then often ask everyone else for evidence for many things they suggest. :)

It's good to ask for evidence of course but let's not forget that sometimes we just need to be open minded and discuss things through and see where we end up. We landed on the moon because someone had the initial idea; the evidence for it did not exist until we had made the idea work. People made that idea work by working together as a team, drawing on each others strengths.

Now my point is that Me Sci knows 100% and without any doubt that she has this pain and therefore she knows something to be true that the outside world cannot prove either way. Now let us say that philpot was then to say 'hey guys' Me Sci has a pain in her muscle. Again I would have no peer reviewed scientific proof and yet Me Sci would know 100% and without any doubt that I was 100% correct about something which I had no evidence for.

My point is that it is perfectly possible and reasonable for someone to be 100% correct about something even though they cannot provide peer reviewed science/evidence to back it up. So on the basis that there is no peer reviewed science which states without any doubt what is the cause of ME/CFS or else what the solution is then all the theories and ideas etc., proposed by all people in these forums could be 100% correct, we do not know.

If everytime we who are often accused of inventing our illness start going on about evidence we should remember two things:

1. We may well be asked to provide the scientific peer reviewed evidence to prove we are ill.
2. We may just snub out the idea/theory which may have otherwise ended up leading to the road to our cure.

I am all about hearing people's ideas and theories and discussing them openly and honestly and collectively and without thowing my dummy out of the pram or prentending to be offended or insulted just because someone suggests something may be in my mind; because this also needs to be explored and discussed.

I am also not about asking for peer reviewed science on everything because this is an area where the science thus far does not amount to much. It may be our discussion which develops the evidence and this will not happen if we 'shout' people down.

Also for each of us when we try something ourselves in order to improve our lives so we need to think critically about the other things which may be happening and which may have instead improved things, we need to be careful about this because otherwise we may ourselves miss the thing which actually helped because we were blinded by the particular thing we were trying.

Regards.

I will not address the personal comments as I find them rather unpleasant and unnecessary.

You appear to be confusing a number of different things: government advice (which is often based on little or no evidence or is at least ten years behind the science), the medical profession, and medical research. They are very different disciplines. Medical research is by no means perfect, but is the most rigorous and evidence-based. Good research papers are based on what has been learned before, and they have clear reference lists allowing the previous evidence to be accessed and investigated. They feature hypothesis, methods, statistical analysis, etc.

Many research papers are published and discussed on Phoenix Rising, and this is a major way that we are trying to advance knowledge and speed the development of various treatments. Many of us (including myself) are already trying evidence-based treatments.

Most of us who do this do not claim to know 100% about anything, and we tend to object when people do make such claims. Nor do we usually do this in associated blogs - we usually feature adequate and clear disclaimers. Things that do not have clear evidence to back them up may indeed be 100% correct (although, as you say, ME/CFS is complicated, as indeed is most science). But the fact that it is hypothetical should be made abundantly clear. In fact, Phoenix Rising has clear guidance on how information should be presented here. Most of us strive to adhere to this, but all probably transgress from time to time in our enthusiasm. Some do this more than others.

Why not join us in reading and discussing scientific evidence? There's a lot of it, e.g. here.

Many other forums here also discuss treatments that we are trying. Why not check them out?
 
Messages
48
Location
UK
I will not address the personal comments as I find them rather unpleasant and unnecessary.
They are not intended as personal comments and instead are intended as a critical thinking discussion. That I use for example 'Me Sci' to discuss about evidence is not, for example, criticising you and instead it is mearly making a discussion. I could have used 'Daffy Duck' as a 'third person' but that would make no sense. :) But anyway if you have found the discussion unpleasant then I apologise as this was not the intention. However, many thanks for the communication, I will now move on with my discussions.

Thanks again for the links, I have read around quite a lot myself and I think there is something missing here in all of this. Scientific evidence is of course vitally important but there are also other ways of accumulating 'evidence' and which can be equally valuable.

All the best, philpot.
 
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John H Wolfe

Senior Member
Messages
220
Location
London
It's good to ask for evidence of course but let's not forget that sometimes we just need to be open minded and discuss things through and see where we end up. We landed on the moon because someone had the initial idea; the evidence for it did not exist until we had made the idea work. People made that idea work by working together as a team, drawing on each others strengths
Well said. Some of my theories are a little 'out of this world'/require a 'giant leap [of faith] for mankind'.. hehe

It may be our discussion which develops the evidence and this will not happen if we 'shout' people down
Absolutely right, although you need not worry in this case - wild horses couldn't keep me from developing the model I have, I see it not just as a pet project (addictive problem to solve), of personal benefit (as a PWME), or a casual contribution to online discourse, but as a personal crusade to help to uncover and elucidate important pieces of the jigsaw puzzle that may deliver insights that will be of benefit to the community at large (not just PR, or even just PWME)
 

Leopardtail

Senior Member
Messages
1,151
Location
England
Essentially a shorthand colloquialism for what I've been talking about in relation to what Rowe describes as: "irritable peripheral tissues" subject to: "movement restrictions" and "neural provocation" associated with "biomechanical and behavioural factors", and hence "neuromuscular strain"

I did the same during the autumn last year so I suppose that could also have been a factor with me

Does PEM include a sinus issue for you then?

I'm no clinician but, on a theoretical level, partial remission perhaps, yes, but there are many potential sources of temporal summation, or ‘wind-up’, including cognitive/emotional yes, but not limited to those, nor limited to anxiety within that group

Furthermore, because such forebrain products appear both psychophysiological and, to an extent, psychosocial, products of the illness, as well as psychopathological contributors to it (via descending pain facilitation, and other adverse mechanisms related to 'stress' and central sensitisation), it is difficult to disambiguate contributory cause and effect. If anxiety or depression are reduced that may only mean that one part of the symptomatological picture is improved, whilst core processes remain active, albeit probably at a lower level

I'm not sure about prevalence rates for anxiety but I understand that:

"..the Val(158)Met [COMT gene] polymorphism is associated with obsessive-compulsive disorder in men and with anxiety phenotypes in women.(Harrison & Tunbridge, 2008)"

I do not suffer with anxiety and nor do many of the (admittedly relatively few) men I have met who have ME/CFS but I do have compulsive traits, and I have met quite a few female members of the community who do suffer with anxiety. In one study 88% of those ME/CFS patients who had 'depressive symptoms' were female, but only 35% of those who did not were female

This narrow/anecdotal picture is, to me, suggestive that anxiety and depression are relatively highly correlated with illness in female patients owing to things like sexually dimorphic effects (associated with distinct hormone interactions) and distinct brain structure (enhanced limbic systems etc) and that an improvement in those features of the disease could be expected to be associated with a more general remission I suppose - rather loose to say the least but there you go!

Oh right, it says: "enhanced potential for" e.g. puts patients at a higher risk of developing such co-morbid disorders

Indeed, and my sense is that psychological issues are in many cases a 'psychophysiological and, to an extent, psychosocial, product of the illness'
John,

I saw a very basic abstract on your links, where are the (more) fully joined up thoughts?

There are several quite central issues with these 'psychological' hypotheses:
  1. most people with ME/CFS are remarkable cheerful given the low quality of life they enjoy.
  2. most are also relentlessly positive and willing to try anything that might help
  3. PWME respond (if at all) only to very small doses of anti-depressant, many find them profoundly harmful.
  4. people with major depressive order suffer a fraction of the range or severity of symptoms
  5. the fundamental science behind all 'psychosomatic illness' of any kind is just not there. This is religion masquerading as science once one understands the neuroscience and biochemistry of the brain the influence of cognition on health is very limited unless you have a physical condition that makes you vulnerable (e.g. excitement and heart failure).
  6. If cognition played any significant part then hypnosis would cure it completely.
You need to clear up one error before publishing your hypothesis:
  • ADH is produced in the hypothalamus not the adrenal glands and bears no relation to 'adrenal insufficiency'.
  • ADH is one of two hormones that control urination the other IS produced in the adrenals.
A suggestion:
The hallmark symptom of ME is 'post exertional malaise' - find an explanation for that and you will be much nearer the root of the disease and will waste less of your time.

regards,

Leo
 

Leopardtail

Senior Member
Messages
1,151
Location
England
@John H Wolfe
John,

In my view @Kina was completely correct. You are developing a scientific hypothesis, hence precise definition of terms is a must.

The term 'sickness behaviour' for example is used in immunology to mean the body's defensive responses and the resulting patient's behaviour. Hence is means both immune response and rest/sleep for example.
By contrast the psychotics use it to refer to "behaving as though you were really ill' or "making yourself ill through your own behaviour".

You need the higher and more precise standard of language Kina referred to in her analysis.

Leo
 

Leopardtail

Senior Member
Messages
1,151
Location
England
Correct. I understand your POV, however I would suggest that to denigrate/ignore authors/other factors examined in works because they contains words we're not keen on perhaps risks missing out on valuable insights. The guy objectively states that "these treatments offer suboptimal relief for those with more profound illness"

Whether we like it or not, CBT is one route to actively reducing descending pathway pain facilitation. If ME/CFS, like FM, relates to central pain, and there are plenty of reasons to suppose it does, then there is a clear physiological argument for the use of such techniques in relevant patients. There are also other reasons that managing stress/anxiety etc is helpful in mitigating symptoms, with less direct fundamental links to what some (including myself) consider to be 'core processes' at play, but still impactful. Although now I think about it, encouraging GABA stimulation through CBT-NLP-meditation type techniques might be argued to be directly helpful ~ rebalancing glutamate:GABA

For me psychological factors may serve as to aggravate the condition but are not fundamental to it (I presume that's the link Rowe would make, nothing in what I've seen from him suggests otherwise). Indeed, interestingly, any developmental, personality or depressive-like disorders associated with our condition e.g. by 'psychobabblers' may well be themselves a function of these core processes e.g. neuroexcitation / neuroinflammation

In his series on neuroinflammation Marco draws parallels with ADHD and ASDs, both of which seem to be on the rise. I sense that ME/CFS has been on the rise too and for me a common link may be elevated environmental toxicity in the post industrial age ~ particularly affecting disorder in (pre-, peri-, postnatal) infants (that may lay the seeds for [mounting / co-acting] health problems later in life)

I haven't explored that sub-forum in a while that's for sure, however I am familiar with some of the work of both De Meirleir & Maes, including some of their stuff on gastro linked autoimmunity and treating ME/CFS with a leaky gut diet (Maes' 2008 paper was why I became interested in designing my own leaky gut protocol in the first place!) :)
John,

there are some fundamental issues at Mitochondrial level going on in ME-CFS converting glutamate->GABA requires significant energy, as does producing many of the calming Neurotransmitters. Many PWME find they that high energy B-Vitamers are very helpful in calming them down and promoting sleep, hence CBT alone simply won't work - one must be capable of benefiting from it and it requires significant cognition.

I have seen severe harm to done to PWME before my very eyes in NHS facilities. Such value as CBT has lies in using energy better, developing a thicker skin etc. However no person with ME has the mental energy needed to make proper use of it. It's role is thus very limited in scope (patients it can serve) and effect (amount of improvement possible).

They key issue though is the model in use within the NHS is fundamentally flawed.

Leo.
 

John H Wolfe

Senior Member
Messages
220
Location
London
Scientific evidence is of course vitally important but there are also other ways of accumulating 'evidence' and which can be equally valuable
Agreed. Many of us (in the ME/CFS community, and the research sphere) are attempting to do that, some in a more tutored/scientific/structured way than others

It is indeed important to recognise the limitations of any particular approach, and, further, if one has the time, energy, patience, and capacity, to try to take something of a combined approach to get the 'best of both worlds' in seeking to arrive at certain solutions, or at least to provide ideas to help one, or to help others, to seek solutions. A classic example is (aerobic/neuro-stimulative) exercise intolerance - in the absence of particular, narrow, irrefutable, objective evidence, researchers will have had to form hypotheses prior to achieving objective evidence, based, in part, on the intuition/experience of patients

One work that strikes a great balance between the traditional, narrow approach, and striving to achieve something of an overview or 'big picture', that I have seen, is the ME Association's 'Key Clinical Issues' Purple Booklet. This is more 'accessible' than a lot of the papers/disease models I have looked at, if still not particularly accessible (readily intelligible) to the average lay person (it is intended for people with medical training after all)

My paper attempts to present a similarly broad research summary but structured, and expanded upon, in line with my own particular neurological disease model (informed, among other things, [relatively] objectively by the reading that went into the basis for the summary), centred on neuroinflammation/sensitisation and presented following the general research summary
 
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John H Wolfe

Senior Member
Messages
220
Location
London
where are the (more) fully joined up thoughts?
In my working paper, some of them outlined in this thread

There are several quite central issues with these 'psychological' hypotheses
I'm not sure which hypotheses you're referring to specifically?

You have quoted a section that should indicate to you quite clearly my interpretation of the potential relationship with psychological issues in the pathophysiology of many/most cases of ME/CFS yet have gone on to list statements that do not appear to contradict anything I have said* (and indeed that I largely concur with, as it happens)

* The exception being your final point - some patients do demonstrate considerable improvement following hypnosis/NLP/CBT, although I believe that in correctly diagnosed cases, where present, psychological factors likely have a modulating/complicating, rather than a pure (exclusive), causal, function; hence I would not expect hypnosis to cure anyone correctly diagnosed, in the absence of relief from the core disease process (neuro-glial dysfunction/inflammation)

ADH is produced in the hypothalamus not the adrenal glands and bears no relation to 'adrenal insufficiency'
Thanks, not sure where I made that mistake here but in my paper do mention ADH but don't mention it's origin, except to say that, along with aldosterone, "levels of both hormones have been found to be low in ME/CFS patients,(Bakheit et al., 1993) consistent with dysfunction of the HPA axis and with SNS dominance.(Boneva et al. 2007)"

The hallmark symptom of ME is 'post exertional malaise' - find an explanation for that and you will be much nearer the root of the disease and will waste less of your time
Thanks for your suggestion. I do not believe I am wasting any of my time thank you, and can assure you that PEM/PENE comes up a number of times in the discussion :)
 
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A.B.

Senior Member
Messages
3,780
The exception being your final point - some patients do demonstrate considerable improvement following hypnosis/NLP/CBT,

The existing research on the placebo effect indicates that it cannot cure illness. It merely gives a temporary illusion of improvement on subjective measures, without affecting objective measures.

In the interventions that you have cited, the placebo effect is generally completely unaccounted for, and the interventions themselves are built around the goal of changing perceptions, which to me suggests that they are nothing more than placebo, and if the placebo effect was ever fully accounted for, these interventions would be revealed as ineffective. Yes, I am accusing practitioners of intentionally avoiding the hard facts because there is no other good explanation as to why a practitioner would not want strong confirmation of the efficacy of their work.

For example, recently a meta review of CBT for major psychiatric disorders found that CBT appears effective for schizophrenia, bipolar disorder, and depression only in unblinded studies. In single blinded studies, there is only a minimal effect for depression, and even that is in doubt because double-blinding is required to eliminate bias. Link to article.
 
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Leopardtail

Senior Member
Messages
1,151
Location
England
In my working paper, some of them outlined in this thread

I'm not sure which hypotheses you're referring to specifically?

You have quoted a section that should indicate to you quite clearly my interpretation of the potential relationship with psychological issues in the pathophysiology of many/most cases of ME/CFS yet have gone on to list statements that do not appear to contradict anything I have said* (and indeed that I largely concur with, as it happens)

* The exception being your final point - some patients do demonstrate considerable improvement following hypnosis/NLP/CBT, although I believe that in correctly diagnosed cases, where present, psychological factors likely have a modulating/complicating, rather than a pure (exclusive), causal, function; hence I would not expect hypnosis to cure anyone correctly diagnosed, in the absence of relief from the core disease process (neuro-glial dysfunction/inflammation)

Thanks, not sure where I made that mistake here but in my paper do mention ADH but don't mention it's origin, except to say that, along with aldosterone, "levels of both hormones have been found to be low in ME/CFS patients,(Bakheit et al., 1993) consistent with dysfunction of the HPA axis and with SNS dominance.(Boneva et al. 2007)"

Thanks for your suggestion. I do not believe I am wasting any of my time thank you, and can assure you that PEM/PENE comes up a number of times in the discussion :)
The paper I have seen mentioned ADH and adrenal insufficiency in the same paragraph. Hence my clarifying this with you. It was unclear.

You show causal links between Neurotransmitters and other biochemistry that imply psychological causation although I now realise that was not your intent. If your paper is published in the form I saw it would however be abused to support that view. Hence my picking these points up.
The whole area of Glutamate, NDMA receptors etc is a thorny one that needs careful handling. The biochemical possibilities for high Glutamate need to be discussed (in my view).

The comment regarding 'PEM' was well meant. When looking through the endocrinology and biochemistry it was critical to evaluating what could or couldn't be close to Etiology. It also acts as an excellent filter when evaluating research. Most obviously some of the possible causes of PEM indicate whether Glutatmate is likely to be at cause or effect.
 
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Leopardtail

Senior Member
Messages
1,151
Location
England
The existing research on the placebo effect indicates that it cannot cure illness. It merely gives a temporary illusion of improvement on subjective measures, without affecting objective measures.

In the interventions that you have cited, the placebo effect is generally completely unaccounted for, and the interventions themselves are built around the goal of changing perceptions, which to me suggests that they are nothing more than placebo, and if the placebo effect was ever fully accounted for, these interventions would be revealed as ineffective. Yes, I am accusing practitioners of intentionally avoiding the hard facts because there is no other good explanation as to why a practitioner would not want strong confirmation of the efficacy of their work.

For example, recently a meta review of CBT for major psychiatric disorders found that CBT appears effective for schizophrenia, bipolar disorder, and depression only in unblinded studies. In single blinded studies, there is only a minimal effect for depression, and even that is in doubt because double-blinding is required to eliminate bias. Link to article.
We could so do with a thread that discusses the ins and outs of placebo and what it can and can't do, would be invaluable when dealing with research. I have however seen one bit of research showing that PWME are 'placebo resistant'.
 

John H Wolfe

Senior Member
Messages
220
Location
London
The term 'sickness behaviour' for example is used in immunology to mean the body's defensive responses and the resulting patient's behaviour. Hence is means both immune response and rest/sleep for example
Indeed

You need the higher and more precise standard of language Kina referred to in her analysis
I can assure you that I have tried to be as clear and precise as possible in my work (given my untutored background, and the level and complexity involved, you will understand I’m sure that this is not without its difficulty)!

If you have any specific, actionable, suggestions I welcome them, along with all constructive criticism
 

John H Wolfe

Senior Member
Messages
220
Location
London
The paper I have seen mentioned ADH and adrenal insufficiency in the same paragraph
Ah ok. I’m afraid my work has evolved a great deal since I first posted here, so historic ideas/thoughts may no longer relate very much, if at all, to my working paper (adrenal insufficiency is not mentioned, for example)

Unfortunately, if I remember correctly, a mod deleted a new thread I made, which provided a fresher, clearer reflection of the more recent (and developed) incarnation of my ongoing aetiopathogenesis work and made it clear that I was not to post ‘duplicate threads’

You show causal links between Neurotransmitters and other biochemistry that imply psychological causation although I now realise that was not your intent
There is room for psychopathological modulation but not, or extremely rarely, as a sole pathological pathway, and certainly not as a (sole) aetiological factor. It’s all a bit complicated (and interwoven, sometimes interrelated) really, so don’t worry, easy to get the wrong impression. To be honest I confuse myself at times!

The whole area of Glutamate, NDMA receptors etc is a thorny one that needs careful handling. The biochemical possibilities for high Glutamate need to be discussed (in my view)
Indeed so, and there are a number of glutamate-linked possibilities, not limited to high levels, of course. Like Marco et al. I strongly believe it is one of the most important avenues for future ME/CFS biomed research

Most obviously some of the possible causes of PEM indicate whether Glutatmate is likely to be at cause or effect
How theorised (processes relating to) Glutamate:GABA idiosyncrasies relate to (processes that may underlie) PEM is anyone’s guess but e.g.

1) Peripheral-central sensitisation e.g. associated with neuromuscular tension
Postural and biomechanical factors have been posited as a possible partial explanation for PEM/PENE, and cortical excitability has been associated with sustained muscle activity resulting in varied magnitudes of descending corticospinal volleys.(Brouwer & Packer, 1994)

wprx.jpg

2) Mitochondrial deficiencies, secondary to, and further complicating 1.
To compound all other energy related issues touched upon in this paper, ME/CFS patients typically have a level of resting energy expenditure (REE) markedly higher than the norm.(Watson et al. 1998) Switching to anaerobic metabolism when short on ATP, as is often observed in ME/CFS,(Behan et al. 1999) results in lactic acidosis, associated with alterations of muscle membrane excitability and hence aches and pains in most cases, and neuromuscular atrophy in some cases.(Jammes et al. 2005) ‘Enzyme efflux’ theory offers another explanation: slowing of ATP Ca(2+) transport and Ca(2+) accumulation in muscles subject to microtrauma (further) inhibits cellular respiration, causing protease/phospholipase activation, in turn a source of muscle protein degeneration, (Stauber, 1989) and inflammation and associated pain.(Cheung et al. 2003) Naturally these observations and theories may be pertinent to the neuromuscular sensitisation, and PEM/PENE, thematics.

3) Glucocorticoid deficiencies, secondary to 1.
Fatigue in ME/CFS may be a function of ostensive hypocortisolism,(Johnson & DeLuca, 2005) in turn a probable function of pro-inflammatory cytokine elevation in ME/CFS.(Jason et al. 2011) Such cytokines are believed to alter the metabolism of serotonin* and dopamine, (Felger & Miller, 2012) causing dysregulation of associated neurotransmitters including norepinephrine (NE), or ‘noradrenalin’, and glutamate. Damage to hippocampal neurons, reduced neurogenesis, altered sensitivity/resistance to glucocorticoids … may result.

Both increased glucocorticoid resistance,(Kavelaars et al. 2000) and increased, glucocorticoid sensitivity have been implicated in ME/CFS, with the later associated with PEM symptoms,(Meyer et al. 2013) and glucocorticoids are associated with interrupted pain modulation, including via their effect on decreasing microglial activation.(Schwartzman, 2012)


4) COMT idiosyncrasies & central sensitisation
Catechol-O-methyltransferase (COMT) gene alterations in adolescents have been linked to increased SNS activity,(Sommerfeldt et al. 2011) and increased post-exertional expression of COMT genes has also been observed in ME/CFS.(Light et al. 2009) COMT modulates dopamine and GABA and the Val(158)Met polymorphism is associated with obsessive-compulsive disorder in men and with anxiety phenotypes in women.(Harrison & Tunbridge, 2008)

It would appear that excessive physical exertion may stimulate (further) central sensitivity and SNS activity, a partial explanation for PEM/PENE, given the combination of relations: 1) Increased post-exertional expression of COMT, in the context of COMT gene alterations associated with increased SNS activity in ME/CFS, potential GABA dysregulation, personality disorders associated with vigilance/arousal (which have the potential to interfere with nociceptive mechanisms); 2) Idiosyncratic post-exertional hyperalgesia – theoretically associated with neuromuscular strain induced chronic nociception,(Rowe et al., 2013b) and also with dysfunction of the central anti-nociceptive mechanism.(Meeus & Nijs, 2007)


Feel free to criticise these excerpts, I can use all the constructive corrections/feedback I can get! :)

(same goes for anyone else reading)
 
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Leopardtail

Senior Member
Messages
1,151
Location
England
John,

Would you please post a link to your current paper please so that we are all discussing the same version of it?

Leo
 

John H Wolfe

Senior Member
Messages
220
Location
London
Would you please post a link to your current paper please so that we are all discussing the same version of it
When I first posted my work took the form of a blog article that was a sort of working brain storm come research project. I’ve subsequently taken it offline, conducted a great deal more rigorous research, properly referencing, and turned it into something that resembles an academic paper/thesis (10,000 words)

For the time being I am looking to get it evaluated by a few (qualified) members of the research community ahead of seeking to submit it for publication e.g. as a ‘medical hypothesis’, so I am afraid I do not have the bulk/whole of the paper posted anywhere online nor will I until I have submitted it for publication and either had it accepted or else resorted to self publishing

I would like to have it out in the public domain in its entirety ‘like yesterday’ but am at the mercy of the busy schedules of those who have kindly offered to evaluated it for me, as well as the requirements of publications who might consider publishing such material (I may have to chop the thing in half)!