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Frontier studies on fatigue, autonomic nerve dysfunction, and sleep-rhythm disorder

Justin30

Senior Member
Messages
1,065
I think aspects of the problem are in the brain. Whether its primary or secondary is still unproven. The brain is very vulnerable to immune and metabolic effects, for example. These systems are all loops that point back to each other. Where is the start of a circle?

I agree I think this illness core comes from the brain and spinal cord as in true ME and is perpetuated and made worse by the malfunctioning of other bodily systems.

I just see it so rare that people get well.

Like POTS an infection hits and what does it mess up the autonomic nervouse system.

True ME was burried in CFS in my opinion.
 

lansbergen

Senior Member
Messages
2,512
If the attack is to strong than that would likely be damage then correct?.

Yes, but not all damage is irreverseble. Damage from an immune response is normal. Infected cells must be killed, removed and replaced by healthy cells. As long as there are still healthy stemcells in the body that can happen.

With the infection I suspect, damage to the neurons usely occurs decades after infection and there is presumptive evidence that it starts in the axons ends (synapse).

I am pretty sure in natural infection nose and mouth are entry places and then it travels alomg the cranial nerves to the brainstem. Another transmission route is via the intestine and the nervus vagus.

I think as long as the infection is only in the accessory cells (not the neurons) it can be halted.

When the accessory cells do not work correct the neurons cannot either.
 

Simon

Senior Member
Messages
3,789
Location
Monmouth, UK
I sound like a broken record, but again, I urge scepticism when it comes to "brain dysfunction" models of our illness. They suffer from many of the same problems as traditional psychological explanations.

The whole model is based on the premise that our fatigue arises entirely in the brain. The underlying reasoning is that "there's nothing wrong with the body, therefore it must be in the brain". Where have we heard that kind of faulty reasoning before?

This model also shares with its psychosomatic brethren an obsession with the symptom of fatigue, to the exclusion of all others. If you try to consider the full complement of symptoms that make up ME, brain dysfunction models start to look less and less impressive.

That may be how some people view the brain dysfunction model, but it is, or can be, a lot more sophisticated than that, with a clear implication of how research should probe the problem.

So the brain dysfunction model was one of several highlighted as useful in the paper by Jonathan Edwards and patients, including me:
The biological challenge of myalgic encephalomyelitis/chronic fatigue syndrome: a solvable problem - Fatigue: Biomedicine, Health & Behavior - Volume 4, Issue 2

Considering both the clinical picture itself (with widespread cognitive and other global problems such as pain and fatigue), and the likelihood that the chronic disease state may involve a complex regulatory system shifting to an abnormal equilibrium state, it is likely that the pathophysiology involves the central nervous system (CNS), plus or minus the immune system (both with complex regulatory dynamics) in some or all cases.
First off, there are several reasons to implicate the brain beyond fatigue - most notably cognitive problems and global problems such as pain. The sickness response too, which overlaps with (but does not mimic) mecfs is based in the brain, another reason to think the brain could play a central role. Note this isn't a 'we know it's not in the body, so it has t be in your head' view, it targets the brain for specific, positive reasons.

Even so, brain dysfunction is only one model we consider
There are many possible models, but three major categories of causal model appear of most interest:
  1. The brain is responding normally and symptoms are due to persistent signal input from peripheral tissues, such as cytokines or metabolites, based on persistent immune dysregulation (as in autoimmunity, for example, or, conceivably, low-grade infection).

  2. There is a persistent abnormality of ‘housekeeping’ processes in the brain, such as an increase in activation of microglia following an initial insult, which leads to distorted processing of peripheral signals including autonomic pathway activation.

In the first model, the brain plays a central role, but it's problems in the body that drive the illness (you mention this one later). In the second, it's problems in the brain that are primary.

Crucially, we argue that a good way to move research forward is to focus on the brain (whether it plays a primary or secondary role):
Brain imaging. Given the likely role of the CNS in the symptomatology, brain imaging has potential to provide direct evidence of pathophysiology. Although appropriate techniques may still be under development, both MRI and PET show promise.[27,28,39]
We could have mentioned spinal fluid studies too (eg immune, metabolomic).

It's very different from the biopsychosocial model, beyond saying what's in your head is likely to play a role: we specifically mean brain biology, as do many biomedical researchers, including Mady Hornig and Jarred Younger.

added: the point is, the brain dysfunction model is just a broad model (the brain could malfunction in many different ways, not just activated microglia). It will stay a model until there's hard evidence either way, but could be useful in guiding research. It's not intrinsically a hand-waving "well, it's not that so it must be this" kind of explanation, though some might choose to use it that way.

btw, you didn't sound like a broken record to me - you view had only just got through to me!
 
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Messages
3,263
@Simon, I've had debates about this with @Jonathan Edwards, and he remains adamant that brain research, as long as it is "good science", has a place in understanding our illness. Maybe it can. Maybe the brain's contribution can be modified in some way to help patients feel better. I'm sceptical, because sometimes even what looks like "good science" ends up being a reframing of psychological accounts.

The hard thing is navigating the terrain of cognitive neuoscience. Its so hard to tell which hypotheses are really offering something different, and which are just neuroscience instantiations of earlier, psychological models. I can pick it instinctively, but I do this sort of thing all day. I need to be able to produce a cheat sheet for everyone else.

Here it is - the neurobabble meter for brain studies of ME (studies that don't just report observation, but make suggestions about what those observations might mean).

1. Causal Role of the Brain in the Whole Illness

Is the brain dysfunction said to be the primary cause for the illness (either its original cause, or the reason for the illness being maintained over time)? Score 1 for this.

Or are the abnormalities seen as consequences of some other disease process? So brain is responding normally to messed up incoming information. Score 0 for this. Skip the other questions. Your total score is 0.

If causality is left as an open question, and various hypotheses are considered, score a 1 (this amount of hedging often indicates a psychological approach).

2. Reason for the brain dysfunction itself


What, in the authors' view, gave raise to the actual brain dysfunction? If it was "learned experience from a previous severe and prolonged illness", and it is hinted that such learned changes might be "unlearned", score 1. This is a psychological model, phrased in neuroscience terms.

If the dysfunction is said to have a direct, biological origin (dysfunction caused by long term effects of inflammation on brain function, actual tissue damage/ or irreversible loss of tissue), and it cannot be modified through learning, score 0. If you score 0 here, then you need not complete the other questions (insert a score of 0 for each one).

If left open, or not explained clearly, score a 1.

3. Nature of the brain regions whose functions are said to be affected?

Score a 1 if some or all of these regions are mentioned:
-insula, anterior cingulate (any part), basal ganglia, prefrontal cortex or orbitofrontal cortex
But few or none of these regions are mentioned:
- temporal lobes, occipital lobes, parietal lobes.

The first set of regions are often discussed in relation to psychiatric disturbances involving motivation, interpretation of pain and other bodily signals, anxiety etc. Genuine brain dysfucntion will affect both the first and the second group of regions most likely equally. If only the first set are mentioned (preodminantly or exclusively), the authors are subtly moving in the direction of a neuropsyhciatric model (a model based on impaired emotion, motivation, responseivess, disorted pain perception).

4. Reason why only a subset of persons with severe infections get ME


If this is not considered, score 1.
If it is suggested the "individual differences" come into play, score 1 (this is hinting at a psychological explanation)
If a good account is given, that doesn't appeal to personality factors or had waving "individudal differences", but rather emphasises biological variables (good luck finding one of those!). Score 0.

5. Other clues

Those with psychological views about ME are aware that patients don't like them, so they can be good at avoiding any statements that might say as much. So I think its reasonable to look beyond the study to find other evidence of their view.

Score 1 if there is no mention of any research that does not focus on brain or mind accounts of ME.
Score 1 if the only symptom discussed is fatigue, without even mention of others or justification for the focus on fatigue.
Score 1 if the researcher has made other statements in other work to suggest he/she believes psychological factors are at play in ME/CFS.

How did you score?

4-7: Disregard this study. Its psychobabble dressed up in neuroscience terminology
2-3: There are red alerts here. Not all may be as it seems. Treat with caution
0-1: This could well be good research that contributes new information.

EDIT: PS Simon, see thread on Neil Harrison's work for an example of a proposed brain study that Jonathan and I disagree on (his view, its good science; my view, its a new framework for describing an essentially psychosomatic view of the disease):
http://forums.phoenixrising.me/inde...ing-mri-fmri-spect-and-pet-scans.44961/page-4
 
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duncan

Senior Member
Messages
2,240
If this disease is centered in the brain, or directly involves the brain, then "dysfunction" is as misplaced as if one were to use it in describing brain cancer or an aneurysm or a broken skull that causes cerebral swelling and irreversible damage. Not one of these comparisons fits "dysfunction."

The very use of the word invites problems and is likely incorrect anyway, i.e. if our brains are involved, they could well be reacting appropriately to an unknown pathogen or stimulus.

Words that can apply to other organs or conditions can and will be dragooned by scientist-wannabees whose only recourse - since Science eludes them - is to manhandle and mutate language to conform with a narrative that serves their purposes.

This is our reality and we would be wise to adapt to it.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Misuse of terminology invites a medical game of whispers. The first doc uses it right, with caveats. The next forgets the caveats. The next who hears it then uses an alternative definition of the word. Finally we wind up with a doc who dismisses the claim because it does not make sense to them.

Of course there is also the issue that some researchers deliberately create this issue, so that they can publish using terminology with caveats, and then use public relations techniques to push things forward under alternative interpretations.

"Brain", "mind", "pain", "fatigue", "depression" are all abused words. Now we can add "normal" and "recovered". "On the path to recovery" is probably also abused, and I assert that "psychosomatic", "psychogenic" and modern variants incorporating words like "functional" are systematic abuse of terminology in most cases.
 
Messages
15,786
@Woolie - Thanks for the Neurobabble Detection Guide. I often struggle with the neurobabble papers simply because I don't understand enough about the brain to assess many of the claims being made. So I found this bit especially useful:
Score a 1 if some or all of these regions are mentioned:
-insula, anterior cingulate (any part), basal ganglia, prefrontal cortex or orbitofrontal cortex
But few or none of these regions are mentioned:
- temporal lobes, occipital lobes, parietal lobes.

The neurobabblers would claim that you can't argue with the data, which is supposedly showing whatever abnormalities in the emotional/crazy bits of the brain. But being a very distrusting individual, I wonder how subjective their interpretations are.

Are those areas of the brain really firmly associated with those functions? Are the scans interpreted by software or by neurobabblers themselves? My impression is that they have a huge amount of room for interpretation of scans, and can claim pretty much any abnormalities they want. Is this the case? And how plausible is it for outsider neuroimaging researchers to get access to the scans from published research to review the interpretation?
 
Messages
3,263
Are those areas of the brain really firmly associated with those functions? Are the scans interpreted by software or by neurobabblers themselves? My impression is that they have a huge amount of room for interpretation of scans, and can claim pretty much any abnormalities they want. Is this the case? And how plausible is it for outsider neuroimaging researchers to get access to the scans from published research to review the interpretation?
Good question, @Valentijn. The quick answer to this is no. Those areas do a whole lot of things, only some of which appear to be directly connected with motivation, control, perception of pain/bodily states, emotional processing. The prefrontal cortex is important for working memory, switching between tasks, inhibiting responses. The insula is important for all sorts of things, like planning and articulating speech. So you can't use "reverse' inference to say that if the insula cortex is overactivated, that a person is feeling emotional. It just doesn't work like that.

But you get to see a theme after a while in these psycho papers. They cherry pick the fucntions that suit them best. The observations are often shoehorned into the preferred account.

False positives are a whole different issue. But the short answer is yes, there are lots of these. Neuroimaging studies are notoriously unreplicable (and you thought only soft psychology was crap!).
 

Simon

Senior Member
Messages
3,789
Location
Monmouth, UK
3. Nature of the brain regions whose functions are said to be affected?

Score a 1 if some or all of these regions are mentioned:
-insula, anterior cingulate (any part), basal ganglia, prefrontal cortex or orbitofrontal cortex
But few or none of these regions are mentioned:
- temporal lobes, occipital lobes, parietal lobes.

... Genuine brain dysfucntion will affect both the first and the second group of regions most likely equally.
Is that really true? You probably know a ton more about the brain than I do, but my understanding is that networs of activity often span many regions ie function doesn't neatly map to geography, and there is a vast amount of variation. In particular, I wondered how safe it is to assume that a result is suspicious because those areas don't come out equal? But given my suspicion of MRI data in general (and the conflicting literature finding on mecfs), it probably doens't matter too much.

PS Simon, see thread on Neil Harrison's work for an example of a proposed brain study that Jonathan and I disagree on (his view, its good science; my view, its a new framework for describing an essentially psychosomatic view of the disease):
Yes, I saw at least some of that, though didn't realise that extended to a blanket concern over brain studies. I'm in two minds about that work. I have a lot of concerns about the views of Mark Edwards in particular, and how he might interpret any findings. (I spend a lot of time looking at Brian Walitt and am well aware of the lengths some will go to to disguise their real views.) On the other hand, I think testing the affect of exercise on the brain is a really interesting approach, and I'd love to see the results.

(Actually, I'm a big fan of stress-testing in general in mecfs. And the NIH intramural study is built around exercise testing and includes MRI scans too (as well as a ton of biological tests), so perhaps that will help cross-check this work.)

But that example sums things up for me: I happen to think there are many reasons to believe the brain is involved, as I outlined above, and while I'm aware of this issues around a kind of Biopsychosocial 2.0 theory that dresses itself in neurology, I continue to think brain studies are important.

I also share the concerns about brain scans and false positives. That's actually another reason to like the Neil Harrison work: it applies a biologically relevant scenario (exercise stress testing), and the fact this then uses intra- rather than inter-subject variation gives it more chance of a robust finding.

Plus, there are other ways to study the brain apart from standard brain scans eg the PET studies that have shown signs of activated microglia, and the brain flow work of Meadows and colleagues. Then there's spinal fluid work. I'm not sure these are so vulnerable to BPS 2.0 interpretations, but even if they are I don't want researchers to treat the brain as a no-go area for that reason - it might hold the key to solving my illness.
 
Messages
3,263
Is that really true? You probably know a ton more about the brain than I do, but my understanding is that networs of activity often span many regions ie function doesn't neatly map to geography, and there is a vast amount of variation. In particular, I wondered how safe it is to assume that a result is suspicious because those areas don't come out equal? But given my suspicion of MRI data in general (and the conflicting literature finding on mecfs), it probably doens't matter too much.
For some reason, I never saw your post, Simon. Sorry!

What you need to look out for are papers with a table of key differences, but some are discussed in detail (anterior cingulate, insula or the others on the list), and others are not. I challenge you to find a neuroimaging study of MECFS that actually finds key differences only in those areas mentioned and not in other areas. Most studies find differences in a wide array of regions. Yet the majority of these discuss only those regions that they have a plausible explanation for.