1. Patients launch $1.27 million crowdfunding campaign for ME/CFS gut microbiome study.
    Check out the website, Facebook and Twitter. Join in donate and spread the word!
The Pathway to Prevention (P2P) for ME/CFS: A Dangerous Process
Gabby Klein gives an overview of the P2P process, shedding light on the pitfalls with advice as to what we can do in protest ...
Discuss the article on the Forums.

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

Discussion in 'General ME/CFS Discussion' started by John H Wolfe, Sep 13, 2012.

?

Does this theory seem plausible?

  1. Yes

    9 vote(s)
    24.3%
  2. Didn't read it

    5 vote(s)
    13.5%
  3. Not sure I fully understand it

    5 vote(s)
    13.5%
  4. No

    18 vote(s)
    48.6%
  1. MeSci

    MeSci ME/CFS since 1995; activity level 6

    Messages:
    3,835
    Likes:
    4,593
    Cornwall, UK
    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?
     
    Valentijn likes this.
  2. philpot

    philpot

    Messages:
    48
    Likes:
    69
    UK
    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.
     
    Last edited: Feb 26, 2014
  3. John H Wolfe

    John H Wolfe Senior Member

    Messages:
    220
    Likes:
    36
    London
    Well said. Some of my theories are a little 'out of this world'/require a 'giant leap [of faith] for mankind'.. hehe

    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)
     
  4. Leopardtail

    Leopardtail Senior Member

    Messages:
    1,034
    Likes:
    620
    England
    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
     
  5. Leopardtail

    Leopardtail Senior Member

    Messages:
    1,034
    Likes:
    620
    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
     
    leela likes this.
  6. Leopardtail

    Leopardtail Senior Member

    Messages:
    1,034
    Likes:
    620
    England
    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.
     
    Snowdrop likes this.
  7. John H Wolfe

    John H Wolfe Senior Member

    Messages:
    220
    Likes:
    36
    London
    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
     
    Last edited: Apr 12, 2014
  8. John H Wolfe

    John H Wolfe Senior Member

    Messages:
    220
    Likes:
    36
    London
    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 :)
     
    Last edited: Apr 13, 2014
  9. A.B.

    A.B. Senior Member

    Messages:
    764
    Likes:
    2,255
    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.
     
    Last edited: Apr 13, 2014
    Leopardtail and Kina like this.
  10. Leopardtail

    Leopardtail Senior Member

    Messages:
    1,034
    Likes:
    620
    England
    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.
     
    Last edited: Apr 13, 2014
  11. Leopardtail

    Leopardtail Senior Member

    Messages:
    1,034
    Likes:
    620
    England
    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'.
     
  12. John H Wolfe

    John H Wolfe Senior Member

    Messages:
    220
    Likes:
    36
    London
    Indeed

    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
     
  13. John H Wolfe

    John H Wolfe Senior Member

    Messages:
    220
    Likes:
    36
    London
    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’

    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!

    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

    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)

    [​IMG]

    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)
     
    Last edited: Apr 15, 2014
  14. Leopardtail

    Leopardtail Senior Member

    Messages:
    1,034
    Likes:
    620
    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
     
  15. John H Wolfe

    John H Wolfe Senior Member

    Messages:
    220
    Likes:
    36
    London
    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)!
     

See more popular forum discussions.

Share This Page