Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses, 2022, Tate et al.

I think a problem is we are taught to write this way at university, to "tell a story". The whole "present the background in a nuanced manner" is not really cutting it, readers won't bother. It's boring. Also don't overstate the limitations, you wouldn't want anyone to think what you did was useless? Experiences may vary between universities/courses.

 

Members' comments here are spot on I think.

There's definitely a breathless naivety in the way preliminary findings are stacked up to support what is a pretty vague and handwavy sort of hypothesis. Really it isn't much advanced on the typical circular diagrams the BPS people so often add to their vague handwavy sort of hypotheses.

For example, here's part of the diagram illustrating the hypothesis:



All the usual suspects get taken for a walk. Apparently there is a 'chronic stress response'. Here's just a sample of the references to the idea.

So, never mind that there is no evidence for anything pathological in cortisol levels in people with ME/CFS, in this paper the levels are reported as being low. And apparently the ME/CFS response to the low levels is the same (or even greater) than in controls. Umm, so wouldn't that mean that the outcome ends up being the same? And what is the reference provided for this crucial link in their vicious cycle hypothesis?

Yes, that Cort's blog.
And reference 107 is a 1991 paper. There have been numerous studies since that time that have not provided evidence for this idea that cortisol levels are somehow wrong or there is cortisol sensitivity.

We need researchers to get beyond what reads like a Year 1 university essay that was done with not enough time to properly read the papers referenced. There's very much a sense of 'oh, this reference is saying what we want it to say, that will do the job'.

 

Some more examples of what I'm talking about:

ANZMES. ANZMES Preliminary survey findings. (2021). Available online at: https://anzmes.org.nz/ (accessed February, 2022).
This statement gives the impression that one in 4 people with ME/CFS suffer severe ongoing impacts as a result of being vaccinated. This is just not true; also the source is a voluntary survey that must surely have a high level of selection bias.

This suggests that therapeutic options are in fact benefiting some patients, while they do not benefit others. I don't think we have any good evidence of there being any therapeutic options benefitting some patients.

I don't think the use of the microclot finding to support a hypothesis is going to age well. Certainly it should not be presented as bolstering the hypothesis without some words suggesting uncertainty at this time.

 

Here's another example - this statement is used to support the idea that the gastrointestinal system may be contributing to the neuroinflammation.

The reference given is: Wang J, Song Y, Chen Z, Leng SX. 2018 Connection between systemic inflammation and neuroinflammation underlies neuroprotective mechanism of several phytochemicals in neurodegenerative diseases.
The paper makes a whole lot of claims for cucurmin, resveratrol, propolis, PUFAs and ginsenosides. It only makes one reference to the myricitrin, green tea and mulberry mentioned in the Tate paper - and that's in the Introduction. Here is the entire relevant paragraph:

The referenced paper therefore provides no convincing evidence relevant to the argument made in the Tate et al paper. Following the references back, the Wang et al paper references
Polyphenols: Multipotent Therapeutic Agents in Neurodegenerative Diseases, a 2013 review article that talks about animal models and promise. It mentions green tea is an inhibitor of acetylcholinesterase - which incidentally is what the neurotoxin sarin gas does, rather more permanently. With sarin gas being implicated as a, perhaps the, cause of Gulf War Illness, .... perhaps green tea isn't ideal. ...Or perhaps ingested green tea doesn't have the same impact as when it is applied directly to rat synapses in a Petri dish.

I mean, I'm a fan of green tea, I drink at least several cups of it a day. As far as I can tell, it makes no discernible difference to my illness. Throwing the suggestion about the healing properties of green tea and mulberry and a particular flavone into this hypothesis paper seems speculative, diversionary and grasping at straws.

 

It appears that Warren Tate is primarily responsible for this paper, building on the work he did with Angus Mackay. I've no doubt that Warren is a brilliant biochemist and certainly motivated to help people with ME/CFS, but, in my view, this hypothesis paper would have benefited from much more review. I've got a page more of notes jotted down that I haven't addressed. I don't think the editor or reviewers provided the necessary critical review.

I'm sure the reviewers are busy, and what incentive would a busy researcher have to spend half a day checking references and generally making the paper of someone who is not in their team great? I was talking to a journal editor the other day and he was saying how hard it is to find peer reviewers, and when they do get someone, they might just spend half an hour reading the paper and writing a quick response, because that is all they have time for. But, a person with ME/CFS on the other hand has an enormous incentive to make sure things are right. I can think of plenty of members here who could provide good-natured useful feedback on trial designs and draft papers and hypotheses, members who have a very good knowledge of the ME/CFS literature. I think we could help researchers make break-throughs more quickly, and cause less harm to patients in the process.

So, why is it so hard for these researchers to take on wider input? I expect some of the ideas set out in papers like these don't help. I mean, if I was a researcher, I wouldn't be lining up to work with people who have issues with memory and mood, who are liable to fall apart in the face of every day emotional and psychological stressors

The unfair accusations of the BPS people about angry irrational patients stick too. I don't recognise myself in those descriptions, or my son. We can think and remember well at least some of the time. We, and many of the members of this forum, deal calmly with stressors that many healthy people can not begin to imagine. 'Stress' is an unhelpfully vague term.

I'm sure all the researchers who contributed to this hypothesis paper are smart and want to help people with ME/CFS, but I think this paper is counter-productive.

 

Thanks for taking a thorough look at the paper, Hutan. I've just started reading it and am already having arguments with it. Even the description of the illness feels incomplete and unbalanced. Nothing about muscle fatiguability and pain, no mention of PEM, instead a confusing reference to relapsing and recovery which makes no sense to me. And why 'poor response to even small stresses' without specifying what is meant by 'small stresses' - sensory sensitivity? psychological problems???

 

I don't have the energy to read it all so I skipped to a few bits:

There's an assumption all the way through, as far as I can see, that the core explanation of ME is brain inflammation. I don't think that should be presented with such certainty.

They seem very keen to describe PEM as a stress reaction. I don't think there's any evidence to support that.

There's also a lot about excess serotonin which would surely suggest that SSRI's would be useful but they're not. They also describe the tryptophan and IDO2 metabolic trap hypothesis which as far as I know isn't established as anything but an idea, so not really appropriate to include in a paper building hypothesis on hypothesis.

I give up. Hutan has done a much more thorough review than I have.

 

No, I haven't. I just picked out a few mostly minor issues, because it was easy to illustrate the problems with them. But I agree with those two big issues you identified - the idea of brain inflammation, specifically in the paraventricular nucleus, and HPA axis dysfunction - as lacking evidence.

I think perhaps attitudes about people with ME/CFS held by the researchers (e.g. that they are delicate flowers wilting in the face of everyday stresses) are making it difficult for them to get past the idea of 'problems processing stress' and move on to ideas that are more specific and helpful. Is it a lack of energy to deal with things? Is it difficulty filtering sensory inputs? Is it orthostatic intolerance? I mean it all gets a bit ridiculous when brushing your teeth is an 'external life stressor'- it really calls for a bit of finessing around what is meant and exactly what the process is.

I find the circular diagrams (Figures 1 and 4) which are the core of the hypothesis little better than BPS circular diagrams.

Another issue is the uncritical acceptance of the idea of an early stage and late stage of ME/CFS, seemingly based on the findings (I think) by Hornig, Lipkin and Montoya who couldn't differentiate people with ME/CFS from healthy controls on the basis of the cytokines. So, they made subsets based on illness duration and did find some differences. But it wasn't very convincing, and I don't think there has been much replication of the result.