Gulf War Illness (/CFS): two subgroups in response to exercise challenge?

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Simon McGrath examines the latest research publication from Professor Baraniuk and Dr Rayhan


An fMRI image showing activation of brain areas during a cognitive test. From the PLoS One paper


Exercise challenge is fast the becoming THE key method when studying illnesses characterised by Post Exertional Malaise, such as Gulf War Illness (GWI) and ME/CFS. A paper just published looks at how exercise affects pain, cognitive performance, heart rate and brain functioning in patients with GWI. These patients also happened to meet the criteria for CFS, albeit only based on questionnaire diagnosis, making this study particularly interesting from an ME/CFS perspective.

Professor James Baraniuk and his colleague Dr Rakib Rayhan actually used a repeat challenge, with bicycle exercise on successive days, and looked for differences between 28 GWI patients and 10 controls, both before exercise and after. What they found was...initially, not much, it seems.

Pain was higher at baseline in GWI patients, as expected given that pain is one of the symptoms of GWI. And it appears that pain for GWI patients got worse after exercise, unlike controls. But they didn't find the expected drop off in performance on the exercise bike at the second test (this fits with the latest results for CFS patients presented by Christopher Snell at the FDA workshop). And cognitive performance didn't deteriorate after exercise (it was already low) - and brain functioning wasn't so different either. Overall, increase in heart rate on standing (POTS) was unaffected by exercise too.


Detective work pays off


Dr Rakib Rayhan

The study looked like a disappointment, until Rakib Rayhan did some digging through the data and noticed a marked difference amongst GWI patients. One subgroup (of 10 patients) showed tachycardia on standing (POTS) after exercise, while the remainder, 18, did not. The tachycardia patients, dubbed START for "Stress Test Associated Reversible Tachycardia", also had much higher levels of anxiety and other problems such as gastrointestinal symptoms. The other GWI subgroup, labelled STOPP (with the PP standing for 'Phantom Perception' of pain), had an increase in pain after exercise compared with controls. However, the STOPP group pain increase doesn't appear to be significantly different from START, and I suspect the label was chosen mainly because it makes a snappy acronym :) (though see below for some fMRI evidence that extra 'pain' regions are activated in STOPP patients).

What made these START and STOPP groups so interesting was that when they re-analysed the fMRI data they found the two groups had very different brain activation patterns during cognitive testing, and the patterns changed in a different way for each subgroup after exercise. For controls, the expected brain areas assoicated with working memory lit up during pre-exercise memory testing, but GWI patients activated these areas and aditional ones too (a similar phenomenon has been seen in CFS patients); it's possible that GWI patients needed to use more brain areas to get the same job done. Intriguingly, START and STOPP groups activated different additional areas. After exercise, there was less activation in the brain of controls as well as GWI patients, and bizarrely no activation in the START group.


Try a version of the working memory test used in this study


Intriguingly, for the STOPP group, the additional regions lighting up in response to cognitive exercise increased are play important roles in processing pain perception. Before exercise the extra activity was in the bilateral anterior insula, after exercise it was the medial frontal gyrus. However, these regions have functions other than pain perception too so their activation may not relate to pain perception.

Rayhan and Baraniuk also looked at brain structure, and found lower volumes of grey and white matter in certain regions compared with controls - again the pattern was different for START and STOPP patients.

The researchers theorise that these differences in post-exercise tachycardia, brain functioning and brain structure mark out two distinct phenotypes. Which is amazing as originally they'd thought the tachycardia testing wouldn't go anywhere: "I thought this would be a waste of the nursing staff's time," said James Baraniuk, adding that they did not expect the veterans to be different from the control group – or for there to be subgroups within the veterans. Instead, "It became a fundamental way of splitting the two veteran groups".


Except...

Other experts are less convinced, noting that most of the subjects in the Georgetown study were self-selected and that their number was relatively small: 28 veterans with symptoms and 10 participants without symptoms. For the START subgroup, the comparison was between 10 controls and 10 patients and findings on such small samples can prove unreliable. Also, the authors say the bizarre finding of no brain activation during cognitive testing post-exercise may be an artefact of their method - but presumably some of the other findings could be artefacts too. The results need verifying.
Dr Drew A Helmer, director of the Department of Veterans Affairs’ War-Related Illness and Injury Study Center, called the Georgetown studies “very preliminary” but also “a very important step forward.”

Replication (as always) is key

The authors themselves emphasise the need for replication and validation, and they are hoping to get funding for a replication study on a new sample of patients. Given Dr Helmer's comments on the potential importance of the findings, perhaps his Department will fund the work. The results from this will give a far clearer picture of whether or not there are indeed two types of GWI patients - if there are, it could prove very important indeed, as they note:

Identifying biomarkers such as these for phenotypic designation is one way to begin untangling the pathophysiological and molecular mechanisms underlying idiopathic disease states such as Gulf War Illness.

Those idiopathic illnesses, of course, include ME/CFS.

Update on the replication study, and relevance to CFS, from Dr Rakib Rayhan on Monday 1 July:

We are hopeful that this leads to a replication study in the near future. Ideally, we would like a very large sample of controls and GWI subjects for greater power and validation of current findings. Due to the overlap in symptomology, we feel that this protocol of brain scans before and after exercise perturbation holds tremendous promise to possibly try to understand central nervous system mechanisms in CFS.



Simon McGrath tweets about ME/CFS Research Follow @sjmnotes




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Comments

Also, it is hard to express my irritation with STOPP "Stress Test Occurring Phantom Perception".

First of all, they operationalized it into "tender point exams." That's all it is. Those are controversial as to what they even represent.

Maybe in the study it was meant to represent changes in pain threshold. Yeah maybe it does. Maybe it doesn't. But then you call it "Stress Test Occurring Pain Threshold Decrease"--look, it almost spells STOP.

What the heck is a "phantom perception"? Translation: the observer gets to decide if the subject has "real" pain or not. (Newsflash: the word "pain" means a subjective perception, unless you are a behaviorist/solipsist).

The observer apparently then gets to decide if the subject has "real" injury (for example, if exercise causes injury to nerves) or not. Instead of, you know, studying the subject to look for injury.

The term seems to evoke "phantom limb pain."

Phantom limb pain is pain, not a phantom. The limb is the phantom, not the pain. The pain exists in the nervous system.

People who, for example, actually have limbs, do not have phantom limb pain, nor phantom pain, they have limb pain.

You could have "phantom pain" if a disembodied soul had pain. Then you could surmise that "pain" does not "exist in the nervous system" but was instead, for sure, "phantom pain."

Disgusting.
 
I think the two-day exercise test is so important because it demonstrates that THERE EXIST people whose VO2 max drops on the second day. Because of this, you could consider PEM to be a clinical entity in itself. Everything I read up until this (Snell waffling) seems consistent with that.

--PEM defined that way might be unique to people who seem to have something wrong with them but do not have another disease label other than Fukuda etc. Thus: a new clinical entity.
--PEM defined that way might turn out to be a symptom shared by some/all CFS people with (say) MS and/or cardiomyopathy and/or ALS or who knows. This would be evidence for something severely wrong with CFS people and would suggest what it might be.
--PEM defined that way is evidence that people with PEM will be made worse or killed by exercise. That is most definitely a treatment suggestion.

It would work best for our purposes if someone simply divided people into two groups-- those whose VO2 max falls on second day and those who don't, and then study the first group.

Simon, would it be possible for you to write a summary from this perspective?
Welcome to the forum, Heidi

I will be blogging on the new Snell paper shortly, which will hopefully help.

However, the VO2max effect itself is probably of limited value. First, those willing to undertake a double VO2 max test are probably unrepresentative of CFS patients as a whole. And the effect is quite small, so it looks like there is a lot of overlap between healthy controls and CFS patients.

Wheras the reduced power output, and efficiency at Ventilatory Threshold on Day 2 test might be altogether more important. Still picking my way through a fairly detailed paper so not sure yet.
 
Welcome to the forum, Heidi

I will be blogging on the new Snell paper shortly, which will hopefully help.

However, the VO2max effect itself is probably of limited value. First, those willing to undertake a double VO2 max test are probably unrepresentative of CFS patients as a whole. And the effect is quite small, so it looks like there is a lot of overlap between healthy controls and CFS patients.

Wheras the reduced power output, and efficiency at Ventilatory Threshold on Day 2 test might be altogether more important. Still picking my way through a fairly detailed paper so not sure yet.
I, for one, am eagerly awaiting your blog on this paper. :)
 
I think the two-day exercise test is so important because it demonstrates that THERE EXIST people whose VO2 max drops on the second day. Because of this, you could consider PEM to be a clinical entity in itself. Everything I read up until this (Snell waffling) seems consistent with that.

--PEM defined that way might be unique to people who seem to have something wrong with them but do not have another disease label other than Fukuda etc. Thus: a new clinical entity.
--PEM defined that way might turn out to be a symptom shared by some/all CFS people with (say) MS and/or cardiomyopathy and/or ALS or who knows. This would be evidence for something severely wrong with CFS people and would suggest what it might be.
--PEM defined that way is evidence that people with PEM will be made worse or killed by exercise. That is most definitely a treatment suggestion.

It would work best for our purposes if someone simply divided people into two groups-- those whose VO2 max falls on second day and those who don't, and then study the first group.

Simon, would it be possible for you to write a summary from this perspective?
Welcome to the forum, Heidi

I will be blogging on the new Snell paper shortly, which will hopefully help.

However, the VO2max effect itself is probably of limited value. First, those willing to undertake a double VO2 max test are probably unrepresentative of CFS patients as a whole. And the effect is quite small, so it looks like there is a lot of overlap between healthy controls and CFS patients.

Wheras the reduced power output, and efficiency at Ventilatory Threshold on Day 2 test might be altogether more important. Still picking my way through a fairly detailed paper so not sure yet.
Thanks for the welcome, the clarification, and of course for reporting on these papers.

I am astonished that the VO2 max thing was not what I thought. Wow. So nothing is ever simple after all... I hope that my surmise/assumption/guess will be true--that some second-day tests are so messed-up that PEM can be characterized from them. And I hope that something simple can be made from that.

Really appreciate your analyses, Simon.