The Setpoint Trap: A New Way to Think About ME/CFS (Desmolysium.com)

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rapidboson

Senior Member (Voting Rights)
Wanted to share a blog post, an interesting read. The author is an anonymous doctor.

desmolysium.com

The Setpoint Trap: A New Way to Think About ME/CFS - Desmolysium

If I were a researcher and had to decide what to research, I would probably research myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The disease is beyond fascinating (and scary) and I personally know quite a few people who have had their lives derailed by it. ME/CFS is probably the...
desmolysium.com desmolysium.com

Edit: Clearly not a scientific paper - nonetheless expressing interesting thoughts in my opinion.
 
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Contains quite a few ungrounded assumptions ("A very simple formula that helps to predict the development of ME/CFS is disease severity times the time it takes until complete viral clearance"; "Individuals with CFS all have a similar phenotype. They have [...] a host of psychiatric symptoms (e.g., a tendency to be anxious)"; "It seems that type-A personalities are overrepresented among CFS folks"...).

The author should join here and work through those questions!
 
This blogpost is not unhelpful, it's a person with some interest in the disease kicking the tires of some ideas, large and small. This is part of the intellectual environment, alongside forums like this, and formal research.

It contains a few things.

One is the idea of "setpoints" which seems to be another way of expressing the idea of "bi-stability" that so excites Robert Phair. Essentially a system with multipl stable equilibria and the possibility of being shifted from one to another and being unable to get back.

This is also related to Naviaux's idea of salugenesis: that getting from sick back to well is a process that needs to function properly.

The author uses obesity as an analogy for setpoints, which I don't love, but don't mind. it's another metabolic condition that is frustrating to combat and highly stigmatised. Although it can be temporarily defeated by pure suffering (an obese person can be starved thin, there's no parallel where we can be forced from our setpoint).

The post also contains a few hypotheses: fast-clearing viruses don't lead to me/cfs. slow-clearing viruses do. It's a neat idea. And it is presented as a speculation, not a fact, which is a legitimate thing to do. And the idea that exercising during convalescence makes you more prone to getting me/cfs. I know I ran out on the Footscray Hockey field on that ill-fated day in 2002 and felt so strange I had to ask the coach to put me back on the bench in the first half. But I don't know whether staying home that day would have changed the rest of my life. Maybe!

It discusses the possibility that the disease is maintained by epigenetic markers, or maybe by neuron death, which would be much worse.


Yes, this is surely not at a scientific level of what we're looking for here at S4ME!
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I'm not sure I agree ! Hypothesis creation is part of science, meta-cognition about the categories into which me/cfs falls, the parallels it has with other illnesses, and how to conceptualise it- this is a legitimate topic. Not everything has to be, you know, lists of mRNAs with bonferroni-adjusted q-values for their fold changes!

We are allowed to discuss ideas! The ones in this blogpost are well-considered, probably wrong - as are most hypotheses - but worth having read.
 
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Murph said:
This blogpost is not unhelpful, it's a person with some interest in the disease kicking the tires of some ideas, large and small. This is part of the intellectual environment, alongside forums like this, and formal research.
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It includes some sensible thinking but I couldn't find anything new and it labours arguments for far too long. It needs a succinct summary of what is thought to be new thinkning at the start. The 'set point' idea is very standard and not new.
 
I agree with Murph that it's good that people with medical and/or scientific backgrounds are setting themselves to work on reading recent research and on hypothesis generation. I found it interesting, drawing together some of the research we have discussed here and using the obesity analogy. I tripped up as others did over some of the assumptions about ME/CFS.

I hope the author might join us here to discuss and develop their ideas and, importantly, how they might be tested.
 
Murph said:
We are allowed to discuss ideas! The ones in this blogpost are well-considered, probably wrong - as are most hypotheses - but worth having read.
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Absolutely. Ideas are great. Especially new ones.
Trish said:
I tripped up as others did over some of the assumptions about ME/CFS.
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We’re so used to seeing the same assumptions and ideas being repeated that it’s probably not surprising there can be a bit of a ‘here we go again’ reading some things. I know I find myself doing it and try to remember those new to the topic don’t have the years of experiences we have. It makes me think about what may be another useful thing for the forum (or website) a ‘common ideas’ or ‘common theories’ section. Maybe something we could get different people to contribute to and could help newcomers. Although I guess mepedia does a bit of this and also it could be counterproductive by stopping debate if someone can bring an old idea with a new twist.

Trish said:
I hope the author might join us here to discuss and develop their ideas and, importantly, how they might be tested.
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Absolutely. It would be great to have people join in the wider community and discussion.
 
Hello all, I am the author of the article. Just created an account to participate in the discussion.

Firstly, thanks for the feedback. Addressed the ungrounded assumptions mentioned above, which were likely all wrong on my part. I am very new to ME/CFS and know probably much less than all of you do about the disease. Nonetheless, I still find the setpoint hypothesis worth considering. The idea for it just came a couple of weeks ago, did not know that or whether it was raised before.

Was just talking to a colleague yesterday (neurologist) and he said that most people he sees with ME/CFS are of the baseline anxious/depressive type. So I replaced the "Type A people are more likely to contract it" (which was criticised above) with "Being depressed or anxious at baseline (before contracting ME/CFS) is a risk factor for the disease, possibly because depression and anxiety are linked to higher levels of neuroinflammation and/or reduced levels of neuroplasticity, which presumably makes it easier for ME/CFS to take hold." Not sure whether that is correct or not but the data seems to suggest something along the lines.

Personally, I am interested in many fields of medicine (desmolysium.com is my blog) and my only point of contact with ME/CFS is a couple of friends and aquaintances (incl. one of my very good friends) who got it after COVID and are suffering to this day. So, I tried to help them as best as I could with the limited information available. I shared some of the things here: From Severe Long-COVID to Ironman Training in 18 Months
 
desmolysium said:
Firstly, thanks for the feedback. Addressed the ungrounded assumptions mentioned above, which were likely all wrong on my part. I am very new to ME/CFS and know probably much less than all of you do about the disease. Nonetheless, I still find the setpoint hypothesis worth considering. The idea for it just came a couple of weeks ago, did not know that or whether it was raised before.
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Nice to have you here.

We have been digging away at this together here for about ten years now. It is always good to get a fresh mind interested. The re-setting idea is familiar but worthy of any new version. There probably isn't any neuro-inflammation in ME/CFS but there does seem to be a suggestion from genetics that synaptic events may be involved.
 
desmolysium said:
Was just talking to a colleague yesterday (neurologist) and he said that most people he sees with ME/CFS are of the baseline anxious/depressive type.
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Hello, welcome.
This idea of anxious / depressive / perfectionist types is based on outdated psychological research ideas. But common misconception among neurologists who mostly don’t know much about ME/CFS and like to throw out these ideas as facts!
 
Hi @desmolysium, thanks for your interest in ME/CFS.

A couple of us have been discussing epigenetic changes in the brain in relation to a recent autopsy study presentation (data not published yet). The thread may be of interest to you:
J

Thread 'Loss of CRH neurons and other neural changes in ME/CFS autopsy study - University of Amsterdam'


  • All in all, the HPA axis with the dramatic reduction of CRH-producing neurons in the hypothalamus, a shutdown of the pituitary, and lower cortisol levels found appeared to be pretty much of a wreck in these autopsied patients.
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desmolysium said:
Not sure whether that is correct or not but the data seems to suggest something along the lines.
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It's a narrative that has been around in ME/CFS for a long time. There's plenty of evidence to the contrary, most recently Leonard Jason's prospective post-EBV study that found no predictive association with baseline anxiety, depression or coping.

Once we know the disease mechanism it may be possible to understand how it contributes to disease in some cases. At our current level of understanding, though, I tend to find that speculating on the role of depression/anxiety/pre-existing mental illness does more harm than good.


I was part of the IMPACC consortium that did longitudinal tracking of people hospitalized with SARS-CoV-2. One of the papers from the group (which I wasn't an author on) looked at acute-phase viral load and long term outcome:
www.nature.com

Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study - Nature Communications

Post-acute sequelae of SARS-CoV-2 (PASC) is still not well understood. Here the authors provide patient reported outcomes from 590 hospitalized COVID-19 patients and show association of PASC with higher respiratory SARS-CoV-2 load and circulating antibody titers, and in some an elevation in...
www.nature.com www.nature.com
From Fig S4:
1772561308790.png
These plots show qPCR measurements for viral load. The groups there are recovered/minimally affected (MIN), primarily physical deficit (PHYS), primarily cognitive deficit (COG), and physical + cognitive deficit (MLT). The MLT group is the one with functional assessment scores closest to typical ME/CFS cases (with the caveat that a couple people in that group had pre-existing cardiac conditions). From what I remember, this serological data was pretty consistent with nasal swab and antibody titer trends.

Viral load was significantly higher at hospital admission for ppts who went on to have a post-COVID functional deficit, but you can see it's a small difference with a lot of overlap. There's a slight difference at ~day 14, mostly driven by a few outliers. In general, it seems like the people who went on to get LC did not have higher viral titers for much longer than people who recovered--though it may have been an additional risk factor for a handful of cases. Some caveats, obviously, with this being on all hospitalized patients
 
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Welcome desmolysium, it's great to be able to chat with you directly.

desmolysium said:
Nonetheless, I still find the setpoint hypothesis worth considering.
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The comparison with an obesity set-point has occurred to me too and I do find it compelling. The way my system seems to claw back any temporary improvement I have does make it feel like that's my body's new idea of normal.

desmolysium said:
most people he sees with ME/CFS are of the baseline anxious/depressive type
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As it sounds like you're finding out in rapid time, there's an endless wellspring of (sometimes contradictory) theories about how personality traits, mood states and/or stress could play into the illness. We humans seem to love making connections between psychology and ill health, and from what I can see we've done this in one form or another for every major disease, before we understood its biological causes, at which point we suddenly decide personality plays a much smaller role (@ME/CFS Science Blog has some lovely posts on various examples here).

In theory these could be interesting questions, however in practice much of the research turns out to be very poor quality once you dig into it (for instance, many of the questionnaires assessing depression ask vague questions about fatigue and pain so that anyone ill in any way is likely to score highly, another example is our recent thread on a truly awful endometriosis paper). Additionally, on a personal level, many people with ME/CFS end up feeling like every aspect of their personalities has being picked over as possibly contributing to their illness by friends, family, doctors and of course, inevitably, ourselves. It ends up as this unfalsifiable hypothesis floating in the background.

Ok. That's the end of my whole spiel on that aspect.


I had not heard of epigenetic editing before so that was very interesting. Appreciate you taking an interest and sharing your thoughts!
 
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Braganca said:
Hello, welcome.
This idea of anxious / depressive / perfectionist types is based on outdated psychological research ideas. But common misconception among neurologists who mostly don’t know much about ME/CFS and like to throw out these ideas as facts!
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Also I can kind of see why doctors might think they're seeing 'anxiety' when a patient is breathing erratically or seems to be distracted or finding it hard to organise their words, when actually it's physical distress and/or cognitive impairment. Or they think they're seeing 'depression' when it's actually exhaustion.
 
Great to have you here @desmolysium and thanks for joining! I hope you’re able to stick around and get involved.

There’s some really interesting ideas coming out of some of the genetics studies as well as research by a few other groups and I’m sure people be happy to point you in the right direction if you’re interested. Some of the researchers responsible also take part in discussions here and it would be great to have your input too.
 
I agree @Eleanor that there is a lot of misinterpretation of what’s going on by some doctors. My experiences have certainly been miles away from the clinical depression I experienced some years prior to ME/CFS.

Something I’ve been interested in recently is he link between interferon and glutamine/glutamate which could be be an interesting angle to explain some symptoms of physical and mental fatigue as well mood changes though (see some discussion here).
 
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