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High-fidelity discrete modeling of the HPA axis: a study of regulatory plasticity in biology (2018) Sedghamiz et al.

Discussion in 'BioMedical ME/CFS Research' started by Milo, Jul 20, 2018.

  1. Milo

    Milo Senior Member (Voting Rights)

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    New paper from Dr Broderick’s team. It seems to me that this would be a first paper and that other are in the works.


    Abstract

    Background
    The hypothalamic-pituitary-adrenal (HPA) axis is a central regulator of stress response and its dysfunction has been associated with a broad range of complex illnesses including Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS). Though classical mathematical approaches have been used to model HPA function in isolation, its broad regulatory interactions with immune and central nervous function are such that the biological fidelity of simulations is undermined by the limited availability of reliable parameter estimates.

    Method
    Here we introduce and apply a generalized discrete formalism to recover multiple stable regulatory programs of the HPA axis using little more than connectivity between physiological components. This simple discrete model captures cyclic attractors such as the circadian rhythm by applying generic constraints to a minimal parameter set; this is distinct from Ordinary Differential Equation (ODE) models, which require broad and precise parameter sets. Parameter tuning is accomplished by decomposition of the overall regulatory network into isolated sub-networks that support cyclic attractors. Network behavior is simulated using a novel asynchronous updating scheme that enforces priority with memory within and between physiological compartments.

    Results
    Consistent with much more complex conventional models of the HPA axis, this parsimonious framework supports two cyclic attractors, governed by higher and lower levels of cortisol respectively. Importantly, results suggest that stress may remodel the stability landscape of this system, favoring migration from one stable circadian cycle to the other. Access to each regime is dependent on HPA axis tone, captured here by the tunable parameters of the multi-valued logic. Likewise, an idealized glucocorticoid receptor blocker alters the regulatory topology such that maintenance of persistently low cortisol levels is rendered unstable, favoring a return to normal circadian oscillation in both cortisol and glucocorticoid receptor expression.

    Conclusion
    These results emphasize the significance of regulatory connectivity alone and how regulatory plasticity may be explored using simple discrete logic and minimal data compared to conventional methods

    Link to paper: https://bmcsystbiol.biomedcentral.com/articles/10.1186/s12918-018-0599-1
     
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  2. Hutan

    Hutan Moderator Staff Member

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    I didn't fully understand this paper but my impression is that the modelling is a whole lot less sophisticated than the big words might suggest.

    So, they seem to be suggesting that CFS is a stress-related illness, the result of exposure to chronic stress.

    And there's something wrong with our cortisol levels, with low-medium and medium-high levels seeming to be indicative of pathogenic states.

    But a comparison of cortisol levels in women with CFS and healthy women done by a BPS team suggests cortisol levels in most people with 'CFS' really aren't very different from healthy people.
    https://www.s4me.info/threads/hair-...-syndrome-2018-roerink-et-al.4404/#post-80089

    [​IMG]

    A study with a large sample of civil servants reported a median hair cortisol level in women of 2.4 pg/mg and a mean of 2.9 pg/mg - so I think it is quite a stretch to suggest that CFS is characterised by abnormal cortisol levels.


    So Broderick's paper also suggests that glucocorticoid receptors are upregulated. And maybe that is true.


    from 'How to measure glucocorticoid receptors' sensitivity'

    But if glucocorticoid receptors aren't working properly, there should presumably be some impact on cortisol levels. ? And if the cortisol levels aren't abnormal, what is it that is causing the symptoms?

    If something more complicated is going on than insensitive glucocorticoid receptors causing abnormal cortisol levels, then I suspect that Broderick's simplistic model (with only four parameters - cortisol, glucocorticoid receptor, ACTH and CRH and only a few qualitative levels for each parameter) isn't going to be good enough.

    I'm floundering around here with things I don't know and will be happy to have someone who knows more to explain things. This faulty HPA axis theory is very often trotted out as science, so I think it's important we understand what's going on.

    I note that this study was funded by the (US?) Department of Defence.
     
    Last edited: Jul 22, 2018
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  3. Sunshine3

    Sunshine3 Senior Member (Voting Rights)

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    I'm as braindead as they come but I know Gordon Broderick is an excellent scientist and I know my stress response broke when I became ill....the HPA axis dysregulation idea makes sense to me and my experience. I believe my illness resulted from years of ongoing stress until finally a viral infection pushed me over the edge. I look forward to hearing more from this group.
     
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  4. Hutan

    Hutan Moderator Staff Member

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    From memory, Dr Broderick's clinic was treating people with ME with homeopathy. I have trouble reconciling that with excellent science. But I don't know him and regardless of whether Dr Broderick is an excellent scientist or not, I would like to understand better what the proposed mechanism is.

    My morning blood cortisol is normal and I've had an ACTH stimulation test that was normal (this is where synthetic ACTH is injected and the adrenal glands respond by making cortisol). I and my two children were not particularly stressed prior to developing ME after an infection. But perhaps there are different ways of getting to the same point that the proponents of the faulty HPA axis theory propose, and only some of them require chronic emotional stress? Or perhaps there are different diseases.

    But regardless, I'd like to understand better what this HPA axis theory is, what specifically is thought to be wrong with us and how does that cause the symptoms we experience - because it seems that quite a few ME researchers find it credible. What tests would prove that the hypothesis is correct?

    @Sunshine3, have you had any measurements made of anything related to the HPA axis?
     
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  5. TiredSam

    TiredSam Moderator Staff Member

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    To be fair that would be more effective than GET.
     
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  6. Sean

    Sean Senior Member (Voting Rights)

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    he he he
     
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  7. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    I really don't know as there are no consistent HPA axis abnormalities in CFS studies so far.
     
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  8. JaimeS

    JaimeS Senior Member (Voting Rights)

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    At the very least, do no harm, eh?
     
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  9. TiredSam

    TiredSam Moderator Staff Member

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    I know it's only a subjective n=1 anecdote, but I sometimes find a sip of water can be rather restorative. Perhaps homeopaths should concentrate on marketing the benefits of water rather than the benefits of ingredients that are no longer in the water - at least that way they wouldn't have to rely on arguments that water remembers itself.

    In fact I've been looking for a new project, and if Gwyneth Paltrow can get away with GOOP, it must be time for TiredSam's Homeopathic Remedies - they would be the first alternative remedies to withstand the scrutiny of the scientific method - in double blinded placebo controlled trials TiredSam's Homeopathic Remedies were found to be at least as beneficial as water, which as we all know is essential for life. The trouble will be finding a placebo, but I think I know someone in Bristol who should be able to come up with an idea and might be prepared to run the trial.
     
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  10. TiredSam

    TiredSam Moderator Staff Member

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    I should probably start a separate thread because business possibilities for TiredSam's Homepathic Remedies keep popping into my head:

    1. Draft a proposal to help the UK government reduce medical costs by having TiredSam's Homeopathic Remedies delivered to every tap in the country. I know the NHS isn't really into homeopathy at the moment, but once I've run my trial and got science on my side they're bound to see the sense in it.

    2. Plants - anyone done homeopathy for plants yet? I reckon during this heatwave spraying crops with TiredSam's Homeopathic Remedies could result in something of a public relations coup.
     
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  11. Inara

    Inara Senior Member (Voting Rights)

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    Honestly, @TiredSam, I think you could get a lot of money out of your ideas. :D
     
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  12. JaimeS

    JaimeS Senior Member (Voting Rights)

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    @TiredSam could get a lot of money going on the road with some of these jokes.

    If any of us could 'go on the road' as more than roadkill... :confused:
     
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  13. MSEsperanza

    MSEsperanza Senior Member (Voting Rights)

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    Last edited: Jul 17, 2020
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  14. Aslaug

    Aslaug Senior Member (Voting Rights)

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    Isn't this Wyllers hung up stress response? I don't remember if he says HPA though.
     
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  15. dreampop

    dreampop Senior Member (Voting Rights)

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    I think the question must be is cortisol lower in me/cfs than in other chronic illness.

    I think the last reference I heard was that OMF found cortisol levels slightly lower in the morning but normal throught -out the day. I can't remember where that was from or if it was even published.

    e.g.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165790/

    https://www.sciencedirect.com/science/article/abs/pii/S0306453014000420?via=ihub

    Both use healthy controls. Just googling around it looks like low cortisol is found pretty often in chronic illness, like autoimmune diseases.

    This article talks a little bit about cortisol and fatigue

    https://www.sciencedirect.com/science/article/pii/S0306453013002540

    THis article looks like it's reinveting the wheel with regards to cortisol

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568897/

    Honestly, I don't know much about the cortisol stuff as this has always been found to be normal in me, I never paid much attention to it.

    Just as a thought experiment I decided to check another fatiguing ailment that can be misdiagnosed as me/cfs, sleep apnea, to see the same measurements

    https://www.tandfonline.com/doi/abs/10.3109/07420528.2013.795155



    There seem to be a few key papers linking CBT to ME/CFS to low Cortisol

    https://www.kcl.ac.uk/ioppn/depts/pm/research/cfs/publications/assets/2009/Robertssalivary.pdf

    This one with Wessley and Chalder, and there was I think a dutch one but I can't find it at atm.
     
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  16. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    I don't get too excited about results that largely overlap with healthy sedentary individuals like most of the cortisol studies I have seen.

    If it was a cause, it would already be considered a biomarker.
     
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  17. Aslaug

    Aslaug Senior Member (Voting Rights)

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  18. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    Note how all of the references for "enhanced sympathetic activity" are papers written by Wyller! He takes self-citation to a whole new level.

    Studies of adults have not found differences in levels of catecholamines compared to healthy controls. The concept of "sustained arousal" also contradicts the lived experience of patients who do not report such a feeling. Lastly, Wyller's experiments with clondine failed to have the hypothesised effect. Altogether, the consistent failure of evidence to support Wyller's hypothesis suggests it is a failed hypothesis.

    Likewise, Wyller's SNP gene association study show signs of either p-hacking, or HARKing, quoting p values of 0.046 and 0.044 in the abstract. (neither of the SNPs were rare in the general population, or specific to patients, suggesting they are unimportant)
     
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  19. rvallee

    rvallee Senior Member (Voting Rights)

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    Honestly, the fact that psychosocial fanatics believe that cortisol may be relevant makes it almost guaranteed it isn't. They have an unnatural talent for being wrong about everything, to the point where the opposite of what they believe is almost certain to be true. It's frankly spooky.

    Even the link between "stress", whatever meaning is used as circumstances demand, and cortisol seem very tenuous at best. It's a multi-function hormone, it's simply too reductionist to use weak correlation as having any causative relation. Especially with "stress" being used to mean so many unrelated things.
     
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  20. Snowdrop

    Snowdrop Senior Member (Voting Rights)

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