Study shows why exercise magnifies exhaustion for cfs patients

[Marco]

I think we're being a little unfair to the researchers. As @Sherlock said they did use quantitative sensory testing which appears to be a standard measure in neuropathic pain conditions for reasons as described in this paper on thermal hyperalgesia in complex regional pain syndrome :

http://www.painphysicianjournal.com/2014/january/2014;17;71-79.pdf

They also state :

"Our findings provide indirect evidence for significant contributions of peripheral tissues to the increased exercise related fatigue in CFS patients consistent with sensitization of fatigue pathways"

I'm not sure that this form of testing can rule out central hypersensitivity as it is still subjective (but then so is tone detection threshold testing in standard hearing tests) but their statement about the contribution of peripheral tissues suggests that central sensitization isn't the main thrust of their conclusions (at least as stated in the abstract).

 

[Snow Leopard]

Btw, they also did do:

Mechanical and heat hyperalgesia were assessed by quantitative sensory testing (QST).

which is from the abstract:
http://www.ncbi.nlm.nih.gov/pubmed/25659069

http://www.ncbi.nlm.nih.gov/pubmed/12795516

Abstract
Quantitative sensory testing is a reliable way of assessing large and small sensory nerve fiber function. Sensory deficits may be quantified and the data used in parametric statistical analysis in research studies and drug trials. It is an important addition to the neurophysiologic armamentarium, because conventional sensory nerve conduction tests only the large fibers. QST is a psychophysical test and lacks the objectivity of NCS. The results are subject to changes owing to distraction, boredom, mental fatigue, drowsiness, or confusion. When patients are consciously or unconsciously biased toward an abnormal QST result, no psychophysical testing can reliably distinguish these patients from those with organic disease. QST tests the integrity of the entire sensory neuraxis and is of no localizing value. Dysfunction of the peripheral nerves or central nervous system may give rise to abnormalities in QST. As is true for other neurophysiologic tests, QST results should always be interpreted in light of the patient's clinical presentation. Quantitative sensory testing has been shown to be reasonably reproducible over a period of days or weeks in normal subjects. Because longitudinal QST studies of patients in drug trials are usually performed over a period of several months to a few years, reproducibility studies on the placebo-control group should be included. For individual patients, more studies are needed to determine the maximum allowable difference between two QSTs that can be attributed to experimental error. The reproducibility of thermal thresholds may not be as good as that of vibration threshold. Different commercially available QST instruments have different specifications (thermode size, stimulus characteristics), testing protocols, algorithms, and normal values. Only QST instruments and their corresponding methodologies that have been shown to be reproducible should be used for research and patient care. The data in the literature do not allow conclusions regarding the superiority of any QST instruments. The future of QST is promising; however, many factors can affect QST results. As is true for other neurophysiologic tests, QST is susceptible to many extraneous factors and to misuse when not properly interpreted by the clinician.

QST hardly fills me with confidence.

To me, this (cuff study) is just another cheap study to pad someones academic CV, nothing more.

 

[biophile]

They should have measured the metabolite levels in the arm before speculating about central sensitivity etc. For all we know the patients' metabolite levels were much higher than normal, which IIRC, has been found by other research groups.

 

[Sherlock]

QST hardly fills me with confidence.

To me, this (cuff study) is just another cheap study to pad someones academic CV, nothing more.

It's one small step in the process of understanding what is wrong with muscle in CFS/ME. The cost was very likely minimal, as they probably used whatever equipment they had on hand - the lead author is a pain doctor and it's a good guess that QST is something he uses in his practice. The didn't use specialized restriction equipment which is commercially sold, they just used a normal BP cuff.

They expanded on the work that's been done by Alan Light, as Alex has mentioned.

That might be a central point in the discussion contained in the full paper.


Did you really expect this little, inexpensive study to answer every possible question and be totally unassailable? Have you ever been one to complain that there is insufficient funding for ME/CFS but now complain about inexpensive studies?

 

[Sherlock]

They should have measured the metabolite levels in the arm before speculating about central sensitivity etc.

Invasive lab testing will likely (or at least hopefully) follow at some point. Let's all just imagine that there's not a psychologist involved in the study, and not throw the baby out with the bathwater. What remains is a focus on physiological differences in CFS muscle.

For all we know the patients' metabolite levels were much higher than normal, which IIRC, has been found by other research groups.

That is what I see as the central point. If the metabolites are mainly acids, then how simple it is to try to counter that with simple baking soda or something similar - which is precisely what is done out in the world in normals who are aiming for athletic performance improvements. There is also a very long thread in the PEM forum that centers on baking soda, where some people just try it and some get benefit.

I've also seen some here get a benefit from ribose. IIRC, ribose is also used as a Tx in myoadenylate deaminase deficiency. So there's another easy, fairly inexpensive something for people to try without waiting for definitive studies and getting left behind.

 

[Sherlock]

I do find [a BP cuff] a lot more uncomfortable than it ever was when well.

I did at first, too. Since I started out with sudden onset hypertension and orthostatic hypotension, I was measuring my BP a lot. Unexpectedly, the pain decreased in fairly short order and the feeling became normal again. Maybe after repeated use the cuff was squeezing out something, and that something was composed of the same molecules that restricting blood flow peri-exercise is keeping in.

The mere fact that Kaatsu (flow restriction) training seems to work is a surprise, and understanding why it works might lead to a benefit in CFS. Kaatsu might be something like a mirror image of CFS.

(Kaatsu is used e.g. for burn victims or elderly who can't exercise normally. By restricting flow, they get a benefit in maintaining or possibly increasing muscle mass even while using very light weight.)

 

[Valentijn]

Invasive lab testing will likely (or at least hopefully) follow at some point. Let's all just imagine that there's not a psychologist involved in the study, and not throw the baby out with the bathwater. What remains is a focus on physiological differences in CFS muscle.

Getting blood drawn is hardly invasive.

And the problem isn't so much the psychologist, but rather the psychological spin which has been heavily applied with no basis. And then there's the problem of not being clear about how weak and unsupported those hypotheses are, with the suggestion that the present study somehow supports them when it does no such thing.

Frankly, it was a rather useless study, and a waste of someone's funds, time, and hand-clenching exertion. The only thing concrete which came out if it is that fatigued patients are more fatigued - and I'm pretty sure that's already universally accepted. The "research" is looking like a flimsy excuse for someone to espouse his grand (and baseless) theories, nothing more.

 

[Sherlock]

Getting blood drawn is hardly invasive.

Piercing the skin is not invasive?

And the problem isn't so much the psychologist, as is the psychological spin which has been heavily applied with no basis. And then there's the problem of not being clear about how weak and unsupported those hypotheses are, with the suggesting that the present study somehow supports them when it does no such thing.

Frankly, it was a rather useless study, and a waste of someone's funds, time, and hand-clenching exertion.

baby/bathwater

 

[Valentijn]

Piercing the skin is not invasive

Not really. My rose bush does it on a regular basis, and I can't say I find it to be at all inconvenient or somehow harmful. And if you only want to nitpick, perhaps you shouldn't use "invasive" to sound as if you mean something which is indeed harmful or burdensome.

baby/bathwater

Care to elaborate on what this study contributes? All I can see is 1) Patients with fatigue report more fatigue when exercising isolated muscles. This hasn't been in contention, ever. And 2) Psychological pet theories of central sensitization. Completely baseless and random in respect to the current study.

 

[Sherlock]

Not really. My rose bush does it on a regular basis, and I can't say I find it to be at all inconvenient or somehow harmful. And if you only want to nitpick, perhaps you shouldn't use "invasive" to sound as if you mean something which is indeed harmful or burdensome.

No, nitpicking is objecting to my use of the word invasive - when I had used the phrase invasive lab testing to talk about more expensive further study, in reply to "They should have measured the metabolite levels in the arm".

Care to elaborate on what this study contributes?

I've already elaborated - except for mentioning that IIRC they measured periodically (every 30 sec?) and found that scores increased over time, with them speculating that was due to metabolites increasing over time in the restricted arm.

All I can see is 1) Patients with fatigue report more fatigue when exercising isolated muscles. This hasn't been in contention, ever.

No, the comparison was between the restricted arm, with metabolites backing up in the muscle, and the non-restricted arm. Perhaps you are not aware of the background of blood flow restriction, aka Kaatsu.

Btw there is also a background to using grip strength, which has also been used IIRC in very elderly e.g. as a predictor of mortality. This study did not materialize out of thin air.

And 2) Psychological pet theories of central sensitization. Completely baseless and random in respect to the current study.

I'm somewhat aware of why so many have a strong resentment to anything mentioning psychology or exercise. That does not mean that any study using exercise should be reflexively mocked and rejected. Baby/bathwater.

 

[Bob]

I might have misunderstood some of it - it's difficult to understand their exact methodology and intentions from the abstract - but, in case it helps anyone, my rudimentary understanding of this study is as follows...

They asked patients to carry out a hand-grip exercise, at 50% of peak capacity, and afterwards they used a blood pressure monitoring cuff to restrict blood flow to and from the arm, for 5 mins. Then they assessed the level of fatigue. Then they did the same with the patients' other arm but without using the cuff after exercise.

They found that the patients experienced more fatigue than the controls who didn't have CFS. And they also found that fatigue in the uncuffed arm was lower than that reported for the cuffed arm.

The aim of this study seems to be to demonstrate that CFS patients have sensitized fatigue and pain pathways to the brain, and have higher levels of fatigue and pain in reaction to normal levels of metabolites. I can't see any information with regards to why the fatigue and pain pathways might be sensitized. The news article seems to be suggesting that their hypothesis is that the neural pathways are sensitized rather than any suggestion of a maladaptive subjective interpretation of normal sensations.

The working hypothesis of the study seems to be rather simplistic and simply intends to demonstrate that metabolites cause fatigue, and by trapping the metabolites in the arm with the cuff, this hypothetical model can be demonstrated because the metabolites continue to exert an effect after the exercise has finished. It's not clear if they actually assessed the levels of metabolites or whether they simply made an assumption about them. They seem to be making rather a lot of assumptions, and the study and conclusions are based on assumptions.

Without measuring the metabolites, I'm at a loss to understand value of the study. All it really tells us is that CFS patients experience increased fatigue after exercise.

I don't understand exactly how they measured fatigue. It says they used self-report measures and quantitative sensory testing (QST), which has been discussed above. I've not read up on the details of QST, but it seems to be a fairly subjective measure, judging from the abstract that @Snow Leopard has posted above.

The article says: "Researchers focused on the role of muscle metabolites, including lactic acid and adenosine triphosphate, or ATP, in the disease. The study has demonstrated for the first time that these substances, released when a person exercises his or her muscles, seem to activate these neural pathways."

Again, is not clear if they actually measured any of these.

The abstract says: "As no specific metabolic alterations have been identified in CFS patients we hypothesized that sensitized fatigue pathways become activated during exercise corresponding with increased fatigue."

Again, if they didn't measure the metabolites then this is just an assumption; The levels of metabolites could have been higher in the CFS patients then controls.

So the suggestion seems to be that normal levels of metabolites have an abnormal effect in CFS patients because of sensitized neural pathways. But there is no indication that they actually measured the metabolites in this study.

I'm not sure how the cuff was supposed to demonstrate anything in relation to metabolites. Surely the neural pathways are sensitized with or without the cuffs, if the hypothesis holds true? An increase of fatigue after exertion would demonstrate the same issues with or without the cuff.

I can't work out what this refers to, but the news article also says: "“What we have shown now, that has never been shown before in humans, is that muscle metabolites can induce fatigue in healthy people as well as patients who already have fatigue,” said Dr. Roland Staud.."

The abstract concludes: "Our findings provide indirect evidence for significant contributions of peripheral tissues to the increased exercise related fatigue in CFS patients consistent with sensitization of fatigue pathways. Future interventions that reduce sensitization of fatigue pathways in CFS patients may be of therapeutic benefit."

The news article says: "Next, Staud plans to explore treatment interventions and to conduct brain-imaging studies of patients with SEID."

If we are generous to the motives of the investigators, then it seems they are attempting to demonstrate that fatigue originates in the neural pathways and comes about due to faulty neural pathways. i.e. a biomedically based dysfunction of the neural pathways.

The nature of the proposed treatments will be telling. If they intend to trial drugs that have an effect on the neurological pathways then that will tell us a lot about their intentions and motivations, but if they intend to use psychological interventions to supposedly reduce over-sensitive pathways then that also tells us a lot.

Really we need to read the full paper to make sense of it, but I'm not excited by it. It looks like an exceptionally simple study that a school child could design and implement. And, if we ignore all of the assumptions, all it tells us is that fatigued individuals experience more fatigue than non fatigued individuals.

 

[Sherlock]

There seems to be overlap in posting here, @Bob, so I'll just pick out one point that hasn't been explicitly addressed yet:

The abstract says: "As no specific metabolic alterations have been identified in CFS patients we hypothesized that sensitized fatigue pathways become activated during exercise corresponding with increased fatigue."

I'd guess that they are saying that no metabolic alterations have been found at rest (which claim has been disputed here), so they wanted to look post-exercise and wanted to look for something only sensory. I personally don't think that any claim about effects being only and entirely sensory is correct - since I have been more prone to muscle tears at times.

Their line of research might lead to identifying non-sensory CFS-specific differences regardless of what they are currently thinking. So I welcome it. I have been surprised that there aren't tons of CFS post-exertion muscle biopsy studies. There are lots of post exercise biopsy studies done in normals, such as at McMasters U. in Canada.

They didn't measure an increase in metabolites this time, but I'd guess that their references show exactly that occurring from flow restriction - probably from Japan where Kaatsu is researched. Yes, the methodology must seem strange if not aware of the background.

Btw, the statement about ATP seems like a mistake that the press officer made, since ATP is reduced, not increased in exercise.

And this one:

I can't work out what this refers to, but the news article also says: "“What we have shown now, that has never been shown before in humans, is that muscle metabolites can induce fatigue in healthy people as well as patients who already have fatigue,” said Dr. Roland Staud.."

It probably happens that previously no one cared about measuring fatigue in normals from flow restriction.

That part would indeed fall into the category of being obvious - but it fits with the type of statements that I see researchers make, as if part of a public relations approach guided by a PR officer, with an eye to getting more funding and dressing up the reputation of the institution. Saying "for the first time" is supposed to be impressive, while saying "we replicated" would be the opposite.

 

[Sherlock]

Two quick things before I have to go:
a) no one sedentary should try this, since that's a risk factor for VTE
b) any effects from occlusion, good or bad, might be from hypoxia instead of metabolites; or from both; or from some unknown other thing - unless recent research has cleared that up

c.1) checking myocytes for contents involves muscle biopsy, which is done in the same way as getting Arctic core samples (ouch) - which is better than the less used way of cutting open the skin and then using alligator forceps (double ouch)
c.2) a quizzical thing about Kaatsu: occluding the upper arm, which does not occlude flow to/from the chest muscle, still affects the chest muscle somehow