Functional Somatic Syndromes" (ME/CFS/FM, etc.) As Serious As other Medical Conditions

[Onslow]

Which are mediated (biologically) how? (rhetorical question)

I assume when you say "rhetorical" you're assuming there is no plausible mechanism. If so, I would suggest you have a look at Noakes and Boksem's reviews. It has been shown that in athletes, psychological factors significantly influence fatigue, which appears to be through connections between the insular cortex and the motor cortex. Also, animal experiments have shown that psychological factors significantly influence whether activity takes place (only taking place if the benefits outweigh the costs). The brain regions responsible have direct control over the HPA axis and ANS.

And if you look at Ben-Zvi (2009) and Gupta (2007) you'll see they predict that there is a state where the HPA axis can get stuck in an abnormal state. Cort wrote a story about this back in 2014 (quoting Broderick).

I'm surprised that anyone cares about effect sizes when there is no control. As Neuroskeptic said when specifically asked about this: generally that's meaningless. That's why you need a control. Within-group D = natural improvement + regression to the mean + placebo effect + real effect. Real effect is generally only a small % of the within group effect, only a placebo controlled study can reveal that.

There were two groups: UK and NL, which had extremely different effect sizes (0.33 vs 0.99). That's certainly worth looking into.

The key is to use a combination of objective measures, including fitness testing, actigraphy, neuropsychological testing and to set composite measures of improvement (eg if step count is normal, then improvement on that is not required). Jonathan Edwards had some stuff to say about how outcome measures could be improved (and how composite measures are sometimes used in other trials for other medical conditions - even when it means the end result seems less impressive). But actigraphy is more than step count and the patterns (eg day to day variation and intensity of exercise are much more revealing than total step count).

But studies show that actigraphy results are not significantly different between CFS and control groups, so it doesn't look like it would be a useful measure. We really need to wait until there is an agreed biomarker. Perhaps something like measuring R-R after exercise.

So when doing less psychologically demanding activities, we answer differently on questionnaires. That's great, but it doesn't mean that person's physical health has improved.

I'm not sure what you mean by "psychologically demanding". They certainly weren't less mentally demanding. Perhaps a better term would be "psychologically damaging". Everyone should avoid psychologically damaging activities, especially CFS patients (and recovered patients).

I agree that we definitely need a definitive measure of recovery, but that isn't available yet. In the absence of that, questionnaires are about the best we have.

Are you skeptical that people can recover? Or skeptical that people can recover from exercise or psychological treatment?

 

[Snow Leopard]

I assume when you say "rhetorical" you're assuming there is no plausible mechanism. If so, I would suggest you have a look at Noakes and Boksem's reviews. It has been shown that in athletes, psychological factors significantly influence fatigue, which appears to be through connections between the insular cortex and the motor cortex. Also, animal experiments have shown that psychological factors significantly influence whether activity takes place (only taking place if the benefits outweigh the costs). The brain regions responsible have direct control over the HPA axis and ANS.

I'm assuming that no one has shown a credible mechanism yet.

By the way, I know a few ultraendurance athletes, and well, I don't think much of Noakes...

Both Noakes and Boksem are vague on how the feedback mechanisms are invoked. Oh look, some brain studies pointing to all sorts of places in the brain. Studies which lack specificity, sensitivity. I'm not much impressed.

But there is a key difference, in that in a healthy person, the fatigue is only invoked after physical activity and resulting peripheral signals "anticipatory fatigue" - the resulting reduction in drive may well be lower due to psychological reasons eg. you don't want to work as hard because it hurts. But then the signal goes away in a day or two at most and the person is able to work hard again.

This is not the same as the experience of fatigue in ME & CFS.

But if a ME & CFS (with PEM) person starts to push, they hit the wall quickly - not just a sensation of fatigue, but vascular sensations and a strong reduction in motor potential, no matter how hard I push. It is an experience I never had experienced when I used to go on long runs or bike rides before I became ill - I always had far more endurance than my peers when I was a child. And ME & CFS patients take far longer to recover.

If you are arguing that there are feedback looks leading to persistent fatigue signals (an interesting hypothesis), leading to involuntary reduction in motor potential when hitting the wall as described above, then how and where does the issue occur? I mean what is the evidence that the amplification of the signal occurs in the brain, rather than at an afferent nerve?

Also, how does it account for the kinetics and directionality of PEM - and physical activity causing (delayed) mental fatigue, but not the other way around (eg doing an exam doesn't make my legs hurt more).

And if you look at Ben-Zvi (2009) and Gupta (2007) you'll see they predict that there is a state where the HPA axis can get stuck in an abnormal state. Cort wrote a story about this back in 2014 (quoting Broderick).

Yes, I remember writing a comment on the Ben-Zvi (2009) atticle, back in 2011.
There are also other similar papers written on PTSD. They are interesting papers, but well, a key fact of all of them is that none of them actually match the observations of GR expression or affinity or require peak ACTH and CRH levels that are much higher than physiologically possible. This is also why I explicitly mentioned earlier that studies need to measure more than just cortisol - so we can develop realistic models.

There were two groups: UK and NL, which had extremely different effect sizes (0.33 vs 0.99). That's certainly worth looking into.

I've read that paper and there is nothing much of value in it.

But studies show that actigraphy results are not significantly different between CFS and control groups, so it doesn't look like it would be a useful measure. We really need to wait until there is an agreed biomarker. Perhaps something like measuring R-R after exercise.

No, studies consistently show differences in activity patterns between patients and controls.

http://onlinelibrary.wiley.com/doi/10.1002/art.20779/full
http://www.sciencedirect.com/science/article/pii/S0022399900001975
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC555551/
http://www.archives-pmr.org/article/S0003-9993(11)00417-5/abstract
http://www.ncbi.nlm.nih.gov/pubmed/9447571

It is true that patients who participate in such studies (on the milder end of the scale) seem to have similar activity levels to sedentary controls, but the activity patterns still tend to be different. Different enough to measure on an intervention trial anyway.
Also, the above studies show, on the contrary to what is sometimes suggested in the literature, that a large majority of patients do not have a "boom-bust" activity cycle that maintains their fatigue.

I agree that we definitely need a definitive measure of recovery, but that isn't available yet. In the absence of that, questionnaires are about the best we have.

Questionnaires are worthless measures of improvement where a major consequence of the therapy is to bias how one would answer on a questionnaire.

Are you skeptical that people can recover? Or skeptical that people can recover from exercise or psychological treatment?

I'm not saying that recovery is not possible, I'm saying it has never been convincingly demonstrated as a result of psychological therapies, using the same standards of evidence we would have for drug trials.

 

[Onslow]

I'm assuming that no one has shown a credible mechanism yet.

Actually, quite a few people have...that is what I was discussing above. The proposed mechanism is that CFS is due to chronic stress that the person is unable to resolve, and it is a protection mechanism to protect the organism.

http://www.ncbi.nlm.nih.gov/pubmed/15950390

As well as the science being plausible, it also appears to fit the patients (i.e. what causes the illness, and what causes recovery).

By the way, I know a few ultraendurance athletes, and well, I don't think much of Noakes...

How so?

Both Noakes and Boksem are vague on how the feedback mechanisms are invoked. Oh look, some brain studies pointing to all sorts of places in the brain. Studies which lack specificity, sensitivity. I'm not much impressed.

You're not easily impressed

I see it as similar to the science behind depression. We only have a vague idea of how depression is caused in the brain. Previously it was thought to be lack of serotonin, but now we know that isn't the case. It's all quite vague and a lot of the drugs are no better than placebo. Brain studies have shown a few regions that might be responsible (such as the prefrontal cortex), but overall we don't really know very much.

But there is a key difference, in that in a healthy person, the fatigue is only invoked after physical activity and resulting peripheral signals "anticipatory fatigue" - the resulting reduction in drive may well be lower due to psychological reasons eg. you don't want to work as hard because it hurts. But then the signal goes away in a day or two at most and the person is able to work hard again.

This is not the same as the experience of fatigue in ME & CFS.

But if a ME & CFS (with PEM) person starts to push, they hit the wall quickly - not just a sensation of fatigue, but vascular sensations and a strong reduction in motor potential, no matter how hard I push. It is an experience I never had experienced when I used to go on long runs or bike rides before I became ill - I always had far more endurance than my peers when I was a child. And ME & CFS patients take far longer to recover.

Yes, I'm well aware of the experience of fatigue in CFS vs healthy people.

The theory is that the anticipatory fatigue sensation is being generated all the time in CFS, because the brain still thinks that there is negative stress that cannot be overcome, and it is better to force the body to rest.

If you are arguing that there are feedback looks leading to persistent fatigue signals (an interesting hypothesis), leading to involuntary reduction in motor potential when hitting the wall as described above, then how and where does the issue occur? I mean what is the evidence that the amplification of the signal occurs in the brain, rather than at an afferent nerve?

To be honest I doubt we will ever get to that level of evidence. Do we have that level of evidence for depression? Perhaps in 50 or 100 years, but right now we're very far away from it. However, according to a study referenced by Noakes:

More recently the same group (Hilty et al., 2011b) found evidence for increased communication between the mid/anterior insular and the motor cortex during fatiguing exercise indicating “a fatigue-induced increase in communication between these regions”

So if you're interested, it might be worth looking at that study to see what the exact communication is between the insular cortex and motor cortex.

However, I don't think we do need to know the exact mechanisms to build a model of CFS. There are quite a few "black box" systems in the physical world where we don't know exactly what is going on inside them, but we can build a working model by looking at the inputs and outputs.

Also, how does it account for the kinetics and directionality of PEM - and physical activity causing (delayed) mental fatigue, but not the other way around (eg doing an exam doesn't make my legs hurt more).

Is that actually the case? Most patients report increased symptoms after cognitive effort. In my own case both physical and mental effort generated symptoms of both mental and physical fatigue. I can't find any study looking at whether mental tasks create physical fatigue.

It is true that patients who participate in such studies (on the milder end of the scale) seem to have similar activity levels to sedentary controls, but the activity patterns still tend to be different. Different enough to measure on an intervention trial anyway.

Yes, it does look like peak activity might be a useful measure.

Questionnaires are worthless measures of improvement where a major consequence of the therapy is to bias how one would answer on a questionnaire.

That is a particularly pessimistic viewpoint, and it wouldn't appear to apply to GET.

I'm not saying that recovery is not possible, I'm saying it has never been convincingly demonstrated as a result of psychological therapies, using the same standards of evidence we would have for drug trials.

Agreed, there definitely seems to be room for improvement, and future trials will hopefully show more convincing effectiveness.

 

[Snow Leopard]

The theory is that the anticipatory fatigue sensation is being generated all the time in CFS, because the brain still thinks that there is negative stress that cannot be overcome, and it is better to force the body to rest.

That is not a theory, nor even a hypothesis, it's a vague statement that has not specific testable consequences.

To be honest I doubt we will ever get to that level of evidence. Do we have that level of evidence for depression? Perhaps in 50 or 100 years, but right now we're very far away from it.

If we continue to believe BS hypotheses with no evidence, then we'll never get there. If we actually try to dig deeper and find the truth, then we might.

However, I don't think we do need to know the exact mechanisms to build a model of CFS. There are quite a few "black box" systems in the physical world where we don't know exactly what is going on inside them, but we can build a working model by looking at the inputs and outputs.

If such models have high predictive specificity, and sensitivity, then yes we could presume that correlation = causation with such a model. But that is not the case with any of the models I have seen trying to explain "functional somatic syndromes".

Is that actually the case? Most patients report increased symptoms after cognitive effort. In my own case both physical and mental effort generated symptoms of both mental and physical fatigue. I can't find any study looking at whether mental tasks create physical fatigue.

Sure, patients commonly report increased cognitive (or sleep) related symptoms after cognitive effort.

That is a particularly pessimistic viewpoint, and it wouldn't appear to apply to GET.

It most definitely does apply to "GET".

Let me put it this way: studies show that neither fitness, nor activity levels increase as a result of GET. Studies trying to explain why there would be such a counter-intuitive finding, proposed cognitive factors (which of course affect how people answer questionnaires). In studies conducted by UK or NL psychiatrists, there was a strong cognitive therapy element to their GET.

Graded exercise also has strong therapist effects (on subjective questionnaires), to the point that GET alone without the therapist effect has a null effect: http://dynamic-med.biomedcentral.com/articles/10.1186/1476-5918-4-3

You're not easily impressed

You become less easily impressed after the first thousand (or two) papers you read. On that note, I think this discussion has run its course.