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

[John H Wolfe]

No - never had cause to, and I am 60!

I see, well personally I would be inclined to get a professional opinion before discounting the possibility that such abnormalities exist completely - not that I am advising you, specifically, to do so, nor that you're not a good judge or osteos are infallible!

I gather that you are talking about hypermobility

Hypermobility is one risk factor for neuromuscular tension yes

I don't have any evidence of that either

I don't so much myself either, except for clicky joints and perhaps other mild signs that I'm unaware of

I also sleep pretty well after switching to a gluten-free, low-sugar, low-grain diet plus certain supplements, albeit with a little help from mild sedatives

Until I started experimenting with nerve mobilisation techniques my sleep was pretty decent in terms of getting off to sleep, remaining asleep, not being conscious of having disturbed sleep, and being able to get up

However, there remained that quality of un-refreshing sleep ~ it not having the rejuvenating effect that it should, and feeling physically/cognitively sluggish and irritable in the AM, often waking with a bad head (low grade headache, tired eyes). I wonder how this compares to your experience with sleep?

My own feeling is that my ME originates in the gut, especially as I had IBS on and off for decades before, and especially bad just prior to developing ME, plus the many benefits experienced from the new diet.

I focused on gastrointestinal disorder as a possible primary source of key symptoms associated with ME/CFS at one stage, and I too have seen the benefits of a more regimented dietary regime

However I am now fairly convinced that gastrointestinal disorders are secondary to a problem of insidious mounting 'background' chronic neural sensitisation in the context of various predisposing (genetic) factors (that gastrointestinal disorder associated with ME/CFS is of course also influenced by) e.g.

"..pro-inflammatory immunomodulation, compromised cellular energy production, stress tolerance thresholds, cognitive and memory function, sleep, mood, ‘fight or flight’ sympathetic response, neurotransmitter regulation, and potentially elevated neuroexcitation and neuroinflammatory responses" - Draft hypothesis article

 

[MeSci]

However, there remained that quality of un-refreshing sleep ~ it not having the rejuvenating effect that it should, and feeling physically/cognitively sluggish and irritable in the AM, often waking with a bad head (low grade headache, tired eyes). I wonder how this compares to your experience with sleep?

It varies. When I have been able to keep exertion to sustainable levels, everything, including sleep, is pretty good, and I wake feeling good, able to get through the day with an alert mind and reasonably-functioning body.

But life tends to get in the way of adequate pacing, so when I am suffering after-effects of exertion, everything - including sleep quantity and quality - is worse.

 

[John H Wolfe]

It varies. When I have been able to keep exertion to sustainable levels, everything, including sleep, is pretty good, and I wake feeling good, able to get through the day with an alert mind and reasonably-functioning body

Excellent

Rowe's theory came out of trying to work out why exercise was better tolerated in some adolescents referred with CFS than in others. He thinks noxious afferent input (under neurogenic sensitisation) may explain at least part of this 'exercise intolerance', encountered by PWME. I am inclined to agree, both in terms of my research and personal experience

It may provide the basis for a neat explanation for (some of the) consequential PENE, for example: neural stress signalling ~ neruoexcitation ~ neuroinflammation ~ neuroimmune responses ~ sickness behaviour initiation, for example

life tends to get in the way of adequate pacing

Tell me about it!

I've experienced a slow onset relapse not, to my knowledge, associated with viral infection/reactivation in which I really tightened up re: getting enough rest, staying stress free, and pacing myself but still my health continued to spiral downwards over subsequent months. Looking at it retrospectively I believe there were postural elements involved (hunched at desk in a crap chair at uni + sleeping posture + possibly dietary factors)

Btw, going back to your comments re: diet ~ one thing I've just noticed in Marco's series is the link made between dietary glutamate and symptoms in fibro/IBS, so I'm adding a bit to my article - seems there's quite a bit of overlap with foods I've found symptom worsening and/or seen included on 'avoid' lists in various dietary protocols:

"Foods relatively high in glutamate and/or aspartate (another neurotransmitter associated with excitotoxicity) include grains (especially wheat, barley, and oats), dairy products (especially cheeses), beans (especially soy and lentils), seeds (especially sunflower, pumpkin), nuts (especially peanuts, cashews, pistachios and almonds), diet drinks (containing aspartame), prepared foods and soups, meats (especially rabbit and turkey). Foods relatively low in glutamate and/or aspartate include fruits, vegetables, potatoes, lamb and eggs, and tree nuts e.g. pecans and walnuts.(Symes, 2013)" - Draft hypothesis article

Diet soft drinks usually give me a headache so I've been aware of aspartame intolerance since childhood

 

[John H Wolfe]

Updated incarnation of my hypothesis abstract:​

​

NEURAL SENSITIVITY IN THE PATHOGENESIS OF ME/CFS (abbreviated title)​

​

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) a debilitating condition of unknown aetiology, classified as a disease of the central nervous system by the World Health Organisation. In recent years the disease has been linked to neural sensitisation specifically and in this speculative article, I describe a new hypothesis for the etiopathogenesis of ME/CFS in the slightly broader context of neural sensitivity.

The discussion primarily touches on neurogenic sources of sensitivity and irritation, peripheral-central sensitisation mechanisms, and the theorised role of sensitisation feedback loops in subsequent, purportedly increasingly noxious, afferent input.

The article further discusses how, in a significant subset of patients, symptom aggravation and illness complication has recently been hypothetically explained in terms of a exaggerated ‘sickness behaviour’ that can occur when sensory ganglia or paraganglia are infected. Pathological disarray linked to pernicious and persistent nature of the pathogens commonly involved, and associated humoral immune responses, in the context of elevated neural sensitivity, may account for this exaggeration.

Adverse neuroexcitatory and neuroimmune themes are discussed in relation to neuroendocrine, mitochondrial, metabolic and autonomic function, as well as theoretical predisposing risk factors, the effects of which can elevate central sensitivity. The neural sensitivity disease model I present contends that there are important common genetic, epigenetic, and in many instances behavioural and environmental, factors involved in the precipitation, complication and modulation, of the fundamental disease pathophysiology.

Drawing upon relevant findings from the neurology literature I present a rudimentary model for the etiopathogenesis of ME/CFS centred on neural (hyper)sensitivity. Sensitising propensities theoretically lead to excitotoxicity, neuroinflammation, and possibly also central sensitisation and sensory gating irregularities, and enhance the potential for pathogen activation and adverse neuroimmune responses including autoimmunity and the central initiation of ‘sickness behaviour’.

This neuroimmunological model may explain why only a small proportion of the general population infected with pathogens commonly associated with ME/CFS go on to develop the condition. The model provides a platform, and suggestions for, future exploration and testing of component hypothetical pathological links, as well as insights into the efficacy of existing treatment strategies and ideas for the development of fresh approaches.

Keywords
ME/CFS; Myalgic encephalomyelitis; M.E; Chronic fatigue syndrome; CFS; Neural sensitivity; Central sensitisation, Microglial activation, Neuroexcitation; Excitotoxicity; Neuroinflammation; Neuroimmune; Etiopathogenesis; Pathophysiology;

© John H Wolfe (2013)​

 

[Valentijn]

So what exactly do you believe are those "behavioral . . . factors involved in the precipitation, complication and modulation" of ME/CFS.

 

[John H Wolfe]

So what exactly do you believe are those "behavioral . . . factors involved in the precipitation, complication and modulation" of ME/CFS.

I haven't commented too much on behavioural factors in the discussion but any behaviours that may contribute directly to 'nervous sensitivity':

Neurogenic factors * ~ nerve damage, restriction and strain ~ peripheral-central sensitivity inducement

Also things like neurotropic pathogenic activity (inc. exposure to parasitic, viral, bacterial, and toxic substances), and mitochondrial energy and heat shock protein depletion

..as well as behaviours that may further the associated:

Neuroinflammation and neuroexcitation ~ glutamate activation ~ extracellular glutamate ** ~ excitoxicity

..and the effects that this has e.g. on glutamate:GABA (excitation vs. inhibition) balance ***

* e.g. activity that places a high demand on the core, particularly in young people still developing and/or those with oseto-inflammatory disorders, daytime/nocturnal postures (level of ankle and hip flexion), and relative lack of nerve mobilisation following injury or illness have been noted by Perrin and Rowe as possible aggravating factors in ME/CFS. I believe straightness of spine and neck posture also contribute in some cases of chronic nerve tension

** e.g. dietary glutamate

*** e.g. excitation (including engaging in prolonged mental stimulation and exposure to stress) vs. meditation

Beyond those relatively direct factors, really any behaviours with adverse psychoneuroimmune impacts may presumably aggravate symptoms/complicate the condition e.g. through contributing to neuroinflammation, neuroimmunodeficiency, or metabolic or autonomic dysfunction

Another way of looking at it is that there are plenty of behavioural avenues through which to potentially reduce some of the burden on our systems

 

[Undisclosed]

So what exactly do you believe are those "behavioral . . . factors involved in the precipitation, complication and modulation" of ME/CFS.

Well I guess what one should do is define in concrete terms what they mean by 'behaviour'. For instance does it refer to internal/external, conscious/subconscious, overt/covert, voluntary/involuntary factors.

Is it referring to a human psychological response or the response of a system as a whole. Personally, I would find another word that has less negative connotations.

 

[John H Wolfe]

For instance does it refer to internal/external, conscious/subconscious, overt/covert, voluntary/involuntary factors

I suppose in essence it relates to any action on the part of the patient (whether they are conscious of it or not, whether they are conscious as to any health benefits/costs it may have or not)

A lot of the things mentioned ostensibly relate primarily fairly innate physiological or environmental factors ~ the degree of choice we have in the matter, never mind awareness, may in many cases be minimal, at least historically, and associated aggravating behaviours may well be no different from the ordinary behaviours of our (healthier) peers

Personally, I would find another word that has less negative connotations.

It's pretty standard language for articles of this ilk, and I'm not sure there is one that is as concise, but if you can think of any feel free to suggest them

I think when viewed in its entirety - it's 5,000 words atm, and the only elucidated reference to behaviour is "... lengthy periods of minimal movement of neuromuscular tissues, can lead to movement restrictions" (Rowe, 2013) - perhaps such mention will seem less incendiary

It's certainly not included in the sense of blame, but its inclusion is necessary in order to build a more complete theorised picture of disease aetiology and progression in a subset of patients (presumed to be significant)

 

[Undisclosed]

I suppose in essence it relates to any action on the part of the patient (whether they are conscious of it or not, whether they are conscious as to any health benefits/costs it may have or not)

A lot of the things mentioned ostensibly relate primarily fairly innate physiological or environmental factors ~ the degree of choice we have in the matter, never mind awareness, may in many cases be minimal, at least historically, and associated aggravating behaviours may well be no different from the ordinary behaviours of our (healthier) peers

It's pretty standard language for articles of this ilk, and I'm not sure there is one that is as concise, but if you can think of any feel free to suggest them

I think when viewed in its entirety - it's 5,000 words atm, and the only elucidated reference to behaviour is "... lengthy periods of minimal movement of neuromuscular tissues, can lead to movement restrictions" (Rowe, 2013) - perhaps such mention will seem less incendiary

It's certainly not included in the sense of blame, but its inclusion is necessary in order to build a more complete theorised picture of disease aetiology and progression in a subset of patients (presumed to be significant)

The thing is John, when you are developing a hypothesis or theory, you need to operationalize what you are talking about or meanings become fuzzy and people tend to attach their own meanings to things. This is of utmost importance when dealing with the concept of 'behaviour' especially when 'behaviour' is so contentious in the realm of ME -- as in your behaviour is keeping you sick. You really can't 'build' any kind of theory if you fail to define in full what you are discussing. This is pretty much a gold standard in research. So again, what do you mean by 'behaviour'?

 

[John H Wolfe]

The thing is John, when you are developing a hypothesis or theory, you need to operationalize what you are talking about or meanings become fuzzy and people tend to attach their own meanings to things

Fair point, although unfortunately in an article that is an attempt to present relatively complex concepts in a more formal manner, hence with a need for conciseness and the minimum of (additional) speculation I'm not sure I can afford to flesh out abundant hypothetical behavioural themes

I shall (continue to) do so in my blog article protocol however as it's not much use from the community's POV for me to simply spell out a new, hopefully promising theory (when it's finished), without exploring/elucidating potential practical ramifications as much as poss!

So again, what do you mean by 'behaviour'?

"Any action on the part of the patient (whether they are conscious of it or not, whether they are conscious as to any health benefits/costs it may have or not)" .. "involved in the precipitation, complication and modulation, of the fundamental disease pathophysiology"

For the avoidance of doubt, in relation to your points yes that may theoretically include actions concerning/reactions to internal/external, conscious/subconscious, overt/covert, voluntary/involuntary factors

 

[John H Wolfe]

Hi Elph,

Thanks for the response. I'm quoting you here as I'd already steered that thread off topic to some degree! (oops)

Pretty much everybody has been infected with EBV, whether they have CFS or not ...

By the time they reach adulthood yes, but that is not to say that such neurotropic infections do not play a role in the disease pathogenesis/complication of the disease

enterococcus faecalis uses gelatinase to cross the epithelial barrier and causes inflammation and triggering an auto-immune response

e.faecalis also reactivates EBV and interaction between the two aggregates inflammatory reaction, possibly mediated through good old NF-κB Gu et al. (2009, 2010)

Take these with streptococcus and lactobacillus pumping out H2S2 and lactic acid into your system with a big pile of other toxins and you are going to get real sick .... common sense really ....

I wonder what evidence there is for elevated H2S2 and the efficacy in use of appropriate antibiotics in the treatment of ME/CFS patients?

The neurological disease of CFS is caused by the physiological disease, and you were right .... the science says it starts in your gut ...

Do you have any references to that effect? Would be interested to further explore this avenue

Cheers, JHW

 

[Elph68]

Mate .... I have so much on this .... where would you like to start??

Stop by the website I have put up .... www.superbugskill.com I have a heap of scientific papers for people to grab ... and e-mail me if you want something specific ...

Cheers.

 

[John H Wolfe]

Stop by the website I have put up .... www.superbugskill.com I have a heap of scientific papers for people to grab ... and e-mail me if you want something specific ...

Cheers.

Thanks, if you have any papers linking GI infection to ME/CFS pathology I'd be interested to see them aye

 

[MeSci]

I think when viewed in its entirety - it's 5,000 words atm, and the only elucidated reference to behaviour is "... lengthy periods of minimal movement of neuromuscular tissues, can lead to movement restrictions" (Rowe, 2013) - perhaps such mention will seem less incendiary

I am guessing that you are referring to this paper. Considering the positive slant it gives on CBT/GET, and the implication that we have contributed to our illness by resting too much, I don't think it could be much more incendiary!

 

[MeSci]

Thanks, if you have any papers linking GI infection to ME/CFS pathology I'd be interested to see them aye

Have you not seen this section?

 

[John H Wolfe]

I am guessing that you are referring to this paper. Considering the positive slant it gives on CBT/GET, and the implication that we have contributed to our illness by resting too much, I don't think it could be much more incendiary!

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)

Have you not seen this section?

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!)

 

[Elph68]

Have you not seen this section?

Down here in Australia the Melbourne University (Dr Henry Butt) is the leader in this research .... This De Meirleir quotes a lot of Henry's research .... I rang and spoke to the researchers in Melbourne and found out a lot more than has been published yet ....

I have a couple of papers here but they are too big to upload ..... putting all this neurological science aside .... if your gut allows H2S, lactic acid, and various other toxins and proteins to enter your bloodstream through a 'leaky gut' it is going to make you sick .... It makes me sick just thinking about it .... What causes guts to leak .... Pathogenic bacteria that contain gelatinase, cytolisin, mytolisin and hylaundranise (just for starters) ..... and these enzymes and proteins fire up the immune system ......

You add this into the rest of your hypothesis and you got the whole picture ....

Stop the inflammation, stop the disease ....

 

[Valentijn]

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

Numerous studies have proven that denial-based CBT doesn't help ME/CFS patients.

 

[MeSci]

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.

What about those of us who, like myself, have very little pain? We have the other classic symptoms of 'ME/CFS'. This suggests to me that pain is not an essential aspect of the condition, so does not represent a fundamental part of causation.

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.

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...

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)

[re leaky gut section]

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!)

Yes, ASDs do seem to co-exist with ME/CFS in many of us. ASDs also have a gut aspect which appears to respond well to leaky-gut diets. As does anxiety, as I know from my own experience. I know that not everyone agrees, but as ME/CFS is looking more and more to be an autoimmune disease, and as there is good reason to believe that autoimmunity can develop from leaky gut, I think that this could be fundamentally involved in at least many - perhaps most - cases of ME/CFS (and indeed ASDs).

 

[MeSci]

Down here in Australia the Melbourne University (Dr Henry Butt) is the leader in this research .... This De Meirleir quotes a lot of Henry's research .... I rang and spoke to the researchers in Melbourne and found out a lot more than has been published yet ....

I have a couple of papers here but they are too big to upload ..... putting all this neurological science aside .... if your gut allows H2S, lactic acid, and various other toxins and proteins to enter your bloodstream through a 'leaky gut' it is going to make you sick .... It makes me sick just thinking about it .... What causes guts to leak .... Pathogenic bacteria that contain gelatinase, cytolisin, mytolisin and hylaundranise (just for starters) ..... and these enzymes and proteins fire up the immune system ......

You add this into the rest of your hypothesis and you got the whole picture ....

Stop the inflammation, stop the disease ....

I don't suppose those papers, or articles referring to them, are online, are they?