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Biophys Chem. 2015 Jul;202:21-31. doi: 10.1016/j.bpc.2015.03.009. Epub 2015 Apr 4.
In silico analysis of exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome.
Lengert N1, Drossel B2.
Author information
Abstract
Post-exertional malaise is commonly observed in patients with myalgic encephalomyelitis/chronic fatigue syndrome, but its mechanism is not yet well understood. A reduced capacity for mitochondrial ATP synthesis is associated with the pathogenesis of CFS and is suspected to be a major contribution to exercise intolerance in CFS patients. To demonstrate the connection between a reduced mitochondrial capacity and exercise intolerance, we present a model which simulates metabolite dynamics in skeletal muscles during exercise and recovery. CFS simulations exhibit critically low levels of ATP, where an increased rate of cell death would be expected. To stabilize the energy supply at low ATP concentrations the total adenine nucleotide pool is reduced substantially causing a prolonged recovery time even without consideration of other factors, such as immunological dysregulations and oxidative stress. Repeated exercises worsen this situation considerably. Furthermore, CFS simulations exhibited an increased acidosis and lactate accumulation consistent with experimental observations.
Copyright © 2015 Elsevier B.V. All rights reserved.
KEYWORDS:
ATP synthesis; Chronic fatigue syndrome; Exercise intolerance; Exercise recovery; Myalgic encephalomyelitis; Post-exertional malaise
PMID:
25899994
[PubMed - in process]
I think I explained why I thought the Oxford criteria were legitimate at the time. It is legitimate to use whatever set of criteria fit the clinical, physiological or pathological problem you are trying to address. We had an excellent epidemiologist at the meeting yesterday who emphasised that getting worked up about criteria is a waste of time. The important thing is to have some criteria, stick to them and document as well as you can and to use criteria that are relevant to the particular question you are asking. Now I quite agree that the Oxford criteria may be entirely inappropriate for lots of things they have been used for. However, when it comes to PACE there is no problem if the objective was to study the benefits of treatments in such a broad group.
In short I do not think choice of criteria has much to do with quality of science.
I don't know whether my interpretation of Edwards's aims differs from a Wessleyan stress loop - I am not sure what that is. But it would not bear any relation to childhood trauma or likely benefit of CBT. CBT wouldn't help you forget how to walk for instance.
Perhaps now would be a good time to put it into context in light of the fact that the MRC has awarded 600k to Mark Edwards to study "functional neurological disorders". Would it be okay for him to use the oxford criteria in this study just as it appears it was in the PACE study? Who is likely to stop him using it? Will you publically condemn him if he proposes to use it or after the study is published it appears he has used it.
Still on the subject of Mark Edwards's contribution, I'm struggling to see in the passage taken below from his 2012 paper anything fundamentally different from what could be termed a psychogenic theory (I've bolded the salient bit). Am I missing a crucial difference that makes Edwards's theory emphatically not a psychogenic one?
Mark Edwards used the term "interoceptive processes". Peter White loves to go on about interoception and that patients misinterpret normal physical sensations due to abnormal interoception.
I think maybe Edwards's chief mistake is to try to find a single all encompassing model.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC524091/Patients with chronic fatigue syndrome perceive activity as more of an effort than healthy controls and underestimate their cognitive and physical abilities, while being more aware of their internal physiological state, a phenomenon called interoception.1,3,9,10w2 w15 w20-22 How might this be related to being sedentary or having a disabling illness in childhood? Inactivity increases perception of effort with exercise, through both physiological deconditioning and the related cognitive, emotional, and sleep disturbance from being sedentary.11w23 w24 This may enhance or sensitise interoception, perhaps in a similar way to that hypothesised in the related disorder of fibromyalgia.w25 The corollary is that this enhanced bodily awareness or interoception may itself cause sedentary behaviour. When an appropriate trigger supervenes in later life, enhanced interoception may predispose some people to chronic fatigue syndrome.5 Trials of prevention are required to test this idea.11w26 Treatments that “reprogramme” interoception and increased activity, such as graded exercise therapy and cognitive behaviour therapy, seem to help most patients.12
Yes, that's what is mainly worrying. Most of the research seems to show that there might be different disease processes within the group of patients diagnosed with ME. And M. Edward is trying to find an underlying mechanism that would explain all "functional" disorders. All that those so called functional disorders have in common is that they have no known biological cause, that's a "non category".
Here's a sample of what Peter White says on interoception:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC524091/
Yes, admittedly the term psychogenic is potentially a very broad one. I used it quite narrowly.If we take a biomedical viewpoint then 'psychogenic' does not really mean anything. The problem with the people who talk 'biopsychosocial' is that they never really say what they mean. The bit you quote looks entirely biological to me and mostly does say what it means. I think the difficulty lies in the use of the word belief, which is ambiguous.
It is all difficult to tease out but I think if psychogenic means anything it means that some conscious thought process at the sort of level that we normally regard as modifiable by social interaction feeds in to production of symptoms we normally think of as arising from the body. Edwards is definitely not suggesting that. He is putting the error mechanism at a much lower brain level. Many patients may feel that their illness is not generated by an error in the brain at all - and I would agree that is highly likely. However, I think it is entirely consistent with a biological approach to suggest that some cases are. I think maybe Edwards's chief mistake is to try to find a single all encompassing model.
Thankyou for addressing my question. However you still haven't answered this part from the post you quoted......
Perhaps now is the time to address it with the MRC if you think it would be inappropriate for him to use the Oxford criteria or anything resembling it.
After all with a term as broad as "functional neurological disorders" surely the cohort matters and the MRC should be taking a position on it seeing as they are spending 600K of mine and other peoples tax pounds to give us a better understanding of the biomedical issues in neurological ME the term coded at G93.3 in the ICD by the WHO.
That's a reasonably good example of a wrong end of a stick I think!!
Yes, admittedly the term psychogenic is potentially a very broad one. I used it quite narrowly.
Edwards seems to address the question of how consciously the thought processes operate in the section of his paper headed "the problem of voluntariness". He says there:
"However, as discussed in more detail above, we suggest that the majority of symptoms are associated with the (conscious) direction of attention towards abnormal symptom-related prior beliefs."
Maybe the crucial point is that he is not saying it is at a "level modifiable by social interaction"; it's difficult for me to say at present as I've not yet arrived at a coherent understanding of his overall message. I need to read it more closely and probably get my head round some very basic things first. Discussion helps speed up the second bit.
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What bothers me specifically about the business about false 'beliefs' and prediction that draws on the 'predictive coding' sort of idea is that it ought to give the opposite effect. The idea is that everything we perceive is a difference or discordance between internal prediction and input. So when we move our head our brain predicts that the world will spin round and if the images on our retinae do spin round then we see it as staying still, as it really does. On this basis if someone with ME perceives input as horrible when in fact everything is fine then it ought to mean that their brain has predicted too optimistically. The false belief would be that I am superman and can leap over a truck and hardly notice the stings of a swarm of bees. And so when I feel a slight tickle I think it must be a bayonet running through my insides. If the false belief was that I was terribly ill (which seems the psychotherapists idea) then even if I was ill I would feel fine.
Mark Edwards' idea of predictive coding (as described in his hysteria paper) is very much in line with Wessley/White thinking. There is a precipitating factor e.g your leg gets hurt. Your brain comes to expect pain in your leg and predicts that there is pain. When there is no longer pain, there is discordance between what is expected and what is happening. The brain doesn't like this and so, rather than adjust the expectation from 'there is pain' to 'there is no pain', somehow the brain registers pain. This creates concordance.
The person then assumes that they have a physical illness causing the pain and this strengthens the expectation of pain (and therefore the perception of pain). He claims that that there is evidence that people with poor learning styles (ie leaping to conclusions) are more prone to this type of problem happening.
He has hypothesised that CFS works by the same mechanism; a precipitating illness (eg a viral infection) leads the brain to expect to feel fatigue, muscle pain and more. When the illness is over, there is concordance gain if these illness sensation continue to be registered.
How can we give an opinion on the criteria he uses if we do not know what the study is yet?
I guess time will tell. The research is going forward, for better or worse, so we'll know in a couple of years whether Dr Edwards is following his history of hysteria and the like or has made a sudden and unexpected right turn into solid biomedical research without any psychobabble assumptions in play. I'm not holding my breath.
This is where it is so ironic that both the psychiatrists and the neuroscientists go around ridiculing 'Cartesian dualism' when they do not even understand what that means and they commit the crime they are criticising in a far worse form than Descartes himself - but that is getting into philosophy a bit too much for here.
I think maybe Edwards's chief mistake is to try to find a single all encompassing model.
This has been criticized many times. Its a lot like a simplistic notion of communism. Everyone is equal, but some are more equal than others. In this case its more mind and body are one, but mind is what matters. I want to know, if they really hold this view, why they do not talk about mind and body are one, but body is more important. Somehow they never get to that. Nor do things have equal footing.Seems an important point in need of clarification in order to proceed with research.