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A compromised paraventricular nucleus within a dysfunctional hypothalamus: A novel neuroinflammatory paradigm for ME/CFS, 2018, Mackay, Tate.

Discussion in 'BioMedical ME/CFS Research' started by adambeyoncelowe, Dec 11, 2018.

  1. adambeyoncelowe

    adambeyoncelowe Senior Member (Voting Rights)

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    A compromised paraventricular nucleus within a dysfunctional hypothalamus: A novel neuroinflammatory paradigm for ME/CFS
    Angus MackayWarren P Tate
    First Published December 6, 2018
    https://doi.org/10.1177/2058738418812342

    Bolding in the quoted text mine for clarity.
     
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  2. Lidia

    Lidia Senior Member (Voting Rights)

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    This is my theory of ME/CFS.

    The PVN is involved in physiological stress responses, as evidenced in this old study:

    The hypothalamic–neurohypophysial system regulates the hypothalamic–pituitary–adrenal axis under stress: An old concept revisited
    Mario Engelmanna, Rainer Landgrafb, Carsten T. Wotjakb

    Moderator note: Discussion of this theory and paper have been moved to a new thread here
     
    Last edited by a moderator: Dec 14, 2018
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  3. JES

    JES Established Member (Voting Rights)

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    I'm skeptical to stress response being the root cause, whether physiological or psychological. Speaking of that, Cortene Inc. is currently trialing a drug (CT38) for ME/CFS patients that targets the stress receptors in the limbic system. I think ME/CFS is more complicated than that and that there are other factors that maintain the dysfunction of the immune and autonomic nervous system, but I hope I'm wrong and that CT38 or similar drugs would be able to "reset" the whole array of dysfunctions.
     
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  4. Trish

    Trish Moderator Staff Member

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    I have only read the abstract so far. The thing that strikes me about the last paragraph is that is doesn't mention my core symptoms, namely PEM, rapid muscle fatiguability and muscle pain.

    I'll try to read the full paper to see whether these are addressed.
     
    Last edited: Dec 14, 2018
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  5. adambeyoncelowe

    adambeyoncelowe Senior Member (Voting Rights)

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    I, too, don't think this proposed mechanism could account for the entirety of ME symptoms. I'm wondering, though, if each of the major subgroups has one unifying/primary pathology in common (let's say it's aggravated glial cells which trigger a neuroimmune cascade, just as an example), but with different areas of the central and peripheral nervous system affected secondary to that which might explain the varied symptoms between patient groups?

    So GWI, for instance, has a theory that symptom clusters depend on whether it's the brainstem, dorsal root ganglia or both which are affected. Subtle variations are explained by the site of the lesion.

    In this case, perhaps this model explains a secondary effect on the CNS which might explain a post-traumatic (e.g., surgery or a car crash) onset in a subgroup. The (usually physical) stressors at or around onset might cause a different symptom cluster to a purely post-viral group, for instance.

    The core pathology creates the shared symptom complex (PEM, muscle fatiguability, etc) and secondary processes create the 'additional' or non-core symptoms.
     
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  6. Trish

    Trish Moderator Staff Member

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    I have now read (rather quickly and sketchily) the whole paper.

    I am bemused by the repeated insistence that depression is a core symptom of ME and emotional trauma one of several possible triggers and emotional stress listed among the perpetuating factors. I can see that emotional stresses can cause exacerbation of some symptoms, and depression can be a secondary result of coping with chronic illness, but to include these as core factors seems to me to have no foundation.

    I am having difficulty connecting the fact that right from the start of my ME, my legs felt like they were going to collapse, after walking short distances, and became painful, and if I walked too far I got PEM. How can that be caused by alleged emotional trauma or perpetuated by emotional stress?

    And how do we get from brain inflammation to muscle cells running out of energy?

    I clearly don't understand physiology...
     
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  7. Hutan

    Hutan Moderator Staff Member

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    I can see that this is an attractive theory, that does potentially explain some symptoms. But I do wonder about how strong the foundations on which it is built are. This and other papers assume HPA axis dysfunction. I'm really not sure how strong the evidence is for that in ME/CFS.

    This is from the Mackay Tate paper:

    Screen Shot 2018-12-13 at 11.33.28 PM.png

    The Tomas, Newton, Watson paper that is referenced is also free access. It notes that:
    I think the evidence of hypocortisolism in ME/CFS is weak, as is evidence for other possible HPA axis dysfunctions. It appears to me that researchers have found the idea of childhood trauma causing HPA axis damage so compelling that they can only view studies of HPA axis function in ME/CFS in a certain way. Although perhaps I haven't read the right studies yet.

    For example this from the Tomas, Newton, Watson paper:
    Perhaps the theory of damage to the paraventricular nucleus holds up without evidence of cortisol levels (or DHEA or responses to ACTH challenge) being abnormal? I haven't read far enough yet.
     
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  8. NelliePledge

    NelliePledge Senior Member (Voting Rights)

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    This might be controversial but I think that very high levels of stress due to caring responsibilities for both parents may have contributed to my gradual onset ME. There was a 5 year period where the unpredictable and aggressive behaviour of parent with severe dementia affected my sleeping pattern even when I wasn’t in the same town as them let alone the same house. I believe caregiver stress has been documented in research and I consider as well as being psychologically hard to cope with that it had physical consequences for me. I had had chicken pox as an adult several years earlier and also in years following the worst caring experiences I had a lot of flu type infections and laryngitis which were sufficiently frequent to get me a bad sickness absence record at work and told my performance was unreliable. I couldn’t pinpoint exactly when I started getting the what I now know is PEM but it was after several years of pushing through frequent viral infections.
     
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  9. adambeyoncelowe

    adambeyoncelowe Senior Member (Voting Rights)

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    Aha! The abstract reads like it's more about physical stress (such as surgery or car crashes) than psychological stress. I've not read the full paper yet. Does it focus more on psychological stress then?

    Yes, I think the evidence of hypocortisolism is very patchy and unconvincing. I also would expect more obvious HPA markers (such as high or low adrenal levels) if it were core to the illness. We don't see that.
     
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  10. Trish

    Trish Moderator Staff Member

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    No, but it lists emotional trauma among the triggers, and psychological stress among the perpetuating factors, and depression among the key symptoms.

    I just singled them out as un-evidenced assumptions I'm not comfortable with that suggest to me a problem with diagnosis, possibly including things like burnout and depression which I would class as misdiagnoses.
     
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  11. adambeyoncelowe

    adambeyoncelowe Senior Member (Voting Rights)

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    Fair enough. Those are worrying signs, yes, and suggest taking research at face value (which we've all learned not to do, for the most part, because the conclusions are often so sketchy).
     
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  12. Inara

    Inara Senior Member (Voting Rights)

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    I agree that 'stress' in the common sense of today (psychological stress) is not the root cause, which is my personal opinion. Klimas speaks of several stressors, like viral infection. "Stress" could be a contributor.

    I came across endoplasmic reticulum stress which is defined as the increased misfolding of proteins in the ER and the start of a pathway that puts them away (like autophagy or apoptosis); amongst others, a certain enzyme is increased for this to work. ER stress can be the result of viral infections, hypoxia, starving, radical oxygen species etc. etc.

    If anything doesn't work properly there, I ponder, the accumulation of misfolded proteins (and maybe the lack of correctly folded proteins?) maybe leads to certain biochemical processes and - maybe via feedback loops - to a pathomechanism. (The inhibition of pyruvate dehydrogenase is one consequence, amongst many others (there are many reasons for an inhibition of it).)

    In fact, this leads to the biphasic model suggested by Davis, Phair, Klimas, where something pushes the body from a homeostasis in another homeostasis that leads to problems. Although I think they are considering another explanation.

    I only hypothesize...
     
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  13. Ravn

    Ravn Senior Member (Voting Rights)

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    After trying to skim read this article I was forced to diagnose myself with an acute allergy to the word 'stress'. This really ought to be added to the list of possible ME symptoms. Like for ME, there's currently no cure for this allergy but symptom reduction may be achieved by placing heavy weights on one's knees to suppress the worst knee jerk reflexes. Keeping the broad dictionary definition of 'stress' on hand helps, too.

    Anyway, I reread the article more carefully and noticed that the word 'stress' was in quotation marks throughout. Are the authors co-suffers of my allergy? Mind you, other words are consistently in quotation marks, too, so not sure what the intention with that is.

    Next thing that struck me was the relative weight given to discussing fatigue and PEM. Compared to most other papers fatigue is less prominent and PEM gets more consideration. This is a welcome change. It's probably explained by this at the end of the article (bolding mine):
    Digging deeper, as far as I can make out the key idea of the paper is that ME is primarily a neuroinflammatory condition of the CNS. That neuroinflammation just happens to hit a specific part within the hypothalamus, the hypothalamic paraventricular nucleus (PVN).

    And the PVN has a central position in the brain. 'Stress' messages arrive there via different pathways. Psychological 'stress' signals come in from one path, viral infection 'stress' signals come in from a different path and so on.

    These incoming signals cause and/or perpetuate and/or exacerbate inflammation in the PVN in (genetically?) susceptible individuals.

    The inflammation then messes with outgoing signals, causing all sorts of symptoms. Areas located close to the PVN may also be affected so symptoms can differ depending on where exactly the inflammation in bad in an individual patient at a given time.

    The above would explain why there are patients who believe their trigger was psychological stress and other patients who believe psychological stress had nothing whatsoever to do with it but that it was all due to a virus or some toxin. It would also explain why some patients suffer psychological symptoms and others do not.

    Not saying that the proposed mechanisms are correct - I've no idea TBH, I'm not equipped to judge how strong the evidence is for the different dysfunctional processes referred to in the article - but there does seem to be some internal logic at least.

    Where the paper really challenges my limited understanding of biology is where it discusses possible disease mechanism similarities between ME and some other major diseases.
    Is somebody able to explain, in very simple terms, when and how this unidentified 'endogenous' factor enters the picture, and its exact role?

    If either of the authors is reading this, maybe you could respond? Correct any of our probably many misunderstandings? And it would be great to discuss your ideas further.
     
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  14. Trish

    Trish Moderator Staff Member

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    Thank you @Ravn for a more thorough reading of the paper than I managed. I also watched Jarred Younger's latest webinar yesterday. He has found signs of microglial inflammation in parts of the brain, but as far as I recall, in different areas.

    I really should go back and watch the video again and re read this paper if I am going to make any sense of it all. Younger talked about the areas he found in terms of the sickness response (flu like malaise) rather than the stress related areas, I think. Clearly lots more to learn

    Edit: The thread about the Jarred Younger research is here
     
    Last edited: Dec 14, 2018
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  15. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    Evidence for HPA axis dysfunction in ME or CFS patients in general is very weak/inconsistent and any small groupwise differences found could be due to a few patients having another illness, or simply due to different day to day activity patterns between paitients and controls.

    I get quite frustrated when seeing hypothesis papers like this, because it shows that when researchers develop hypotheses, they are often unable to obtain the resources to test them, but instead publish yet another unverified hypothesis to add the large pile.
     
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  16. Inara

    Inara Senior Member (Voting Rights)

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    At least for AD (and I remember PD and ALS were also discussed), research of the past < 5 years hints at a role of ER calcium homeostasis, and a disruption there seems to be the cause of why proteins misfold (in AD, it's amyloid beta proteins) and then accumulate. Details of Ca signaling pathways are the topic of very recent research, and there are still many gaps, including the consequences for disease, but it looks like a field that might change therapeutic options and our understanding of (at least some) diseases (like cancer).
     
  17. Sunshine3

    Sunshine3 Senior Member (Voting Rights)

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    Hasn't Gordon Broderick looked at HPA dysfunction and Klimas. Biology in chaos. We need further work on it.
     
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  18. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    They have come up with a variety of novel hypotheses, but they tend to be inconsistent with what has actually been measured.
     
  19. Sunshine3

    Sunshine3 Senior Member (Voting Rights)

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    I doubt that tbh. We will have too see what Klimas trial brings.
     

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