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

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.

 

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

 

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.

 

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.

 

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.

 

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).

 

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...

 

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.

 

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.

 

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).

 

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

 

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

 

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

 

Cort has done a write up on this and the author (Mackay) was responding to some questions in the comments.
https://www.healthrising.org/blog/2020/05/27/neuroinflammatory-paradigm-chronic-fatigue-me-cfs/