Plasma metabolomics reveals disrupted response and recovery following maximal exercise in ME/CFS, Arnaud Germain, Maureen R. Hanson et al, 2022

[Ravn]

Some of the study findings are discussed in this video:

Originally posted by @Jaybee00 here https://www.s4me.info/threads/news-...disease-and-maureen-hanson.20339/#post-409538

 

[FMMM1]

I would argue that patients that, in theory, met the majority of those descriptions shouldn't have been able to take part in this study, and if they did then I'd query how ethical it was to allow them to do so.

Haven't read the study (or even the abstract) but my knee jerk reaction is that they could have selected using actimetry combined with a diagnosis of ME/CFS. There are probably plenty of studies which demonstrate how actimetry could be used e.g. Friedberg* and (didn't think I'd even quote this) the dreaded Knoop** who uses it to select participants. Also, OMF (Hanson is part of it) have expetise in actimetry.

*Friedberg F, Adamowicz J, Caikauskaite I, Seva V, Napoli A. Efficacy of two delivery modes of behavioral self-management in severe chronic fatigue syndrome. Fatigue: Biomedicine, Health and Behavior. 2016; 4(3):158-174

**https://www.s4me.info/threads/recov...gnosed-with-covid-19.16227/page-5#post-403544

 

[Mithriel]

I would have thought that anyone with ME who got PEM from the first maximal exercise would want to avoid a second one. If a feel lousy enough not to be able to carry on with normal daily activities I am pretty sure I wouldn't want to do an exercise test.

When Workwell did the first studies they commented that the controls complained on the second day but the ME patients "would have walked over burning coals to get proof they had a physical disease"

With ME you are always doing things you do not feel well enough to do. It is one of the worst things about it. When I was moderately ill I actually pushed myself more because now I am worse I look ill so people help me. You push through exhaustion and pain or you do not eat. People give up washing but need to struggle to a toilet.

There is also the adrenalin effect where you can do much more than normal.

The 2 day CPET testing shows that people with ME do not recover from exertion the way it happens in normal people and other diseases they have tested. Exertion causes something in people with ME which makes it impossible for them to exert to the same level the next day.

If PEM is anything it is a shorthand for whatever is going on in the body that accounts for this. It is not a separate symptom but a reflection of something that causes symptoms which can be different between people and within patients on different occasions.

 

[cassava7]

If I remember correctly, the clinical trial registration mentioned 90 patients and 90 controls. I presume the pandemic put a dent into the recruitment effort.

 

[Hutan]

Yes, Maureen Hansen says as much in that recent video. There are plans to continue on with recruitment up to the planned 90/90.

 

[Jonathan Edwards]

I continue to be very puzzle by all this CPET stuff. I would like to get to grips with it but fail every time because of the jargon.

How can feeling ill reduce ability to do work during a CPET without alteration in utilisation of metabolic pathways?

If you have pain you may have a reduced ability to do work without altering utilisation of metabolic pathways. You put effort into protecting painful parts, maybe by contracting opposing muscle groups to splint a joint rather than using the joint efficiently to push a peal or whatever.

Can you explain to me @Snow Leopard, in plain English terms exactly what the consistent fining is for 2nd day CPET in ME in terms of process. Is it that despite using the same amount of oxygen, less useful work is one (on the peals or whatever) or that less oxygen is used for a given heart rate or what? I find it very hard to understand how we can be sure this isn't just a nonspecific response to discomfort.

On a ramped exercise test, the level of performance is basically forced until the test ends - a voluntary reduction in effort cannot occur during the test.

This puzzles me too. How do we now a voluntary reduction does not occur? We know almost nothing of the mechanism of 'voluntary effort'. If I am on an exercise bike and someone asks me if I am doing maximum voluntary effort I don't think I can say. One can get somewhere near to a sense that instantaneously but over a period of many seconds all sorts of things modulate the sense of effort being maximal. Effort isn't actually something we have any way of measuring. And if you feel ill you are in a completely different mindset.

 

[Jonathan Edwards]

If PEM is anything it is a shorthand for whatever is going on in the body that accounts for this.

The trouble is that this screws up any scientific analysis.

PEM is a symptom pattern - as I understand it of feeling ill after exertion.
If we then want to use the same word to mean what causes PEM we get PEM causes PEM and that opens things up to confusion.

Maybe exertion releases some mediator X which give people a sense of PEM. Having a sense of PEM may generate signal Y which interferes with the ability to do work on a bicycle. So the second day PET does not tell us about X but about Y.

 

[Hutan]

If you have pain you may have a reduced ability to do work without altering utilisation of metabolic pathways. You put effort into protecting painful parts, maybe by contracting opposing muscle groups to splint a joint rather than using the joint efficiently to push a peal or whatever.

@Snow Leopard can give us the details of the physiology, but I just want to say that when I did my second CPET test, I did not feel worse at all, I felt better. (I was part of a study where there was a two day delay between tests - I had overt PEM on the night after the first test but was ok after that.) I think I felt better on the second test because I knew what I was doing. I didn't feel sore at all, I was not holding anything back, just pedalling through the various levels of resistance.

But, anyway, I still showed a substantial decrease in the work rate at the point of ventilatory threshold.

Ventilatory threshold (VT1) is the point when the ventilation (litres per minute of air) starts to increase faster than the consumption of oxygen (the VO2).



On the maximal effort, that isn't worked out by asking someone 'are you making a maximal effort?' One method is if the Respiratory Exchange Ratio (RER) is over 1.1. The RER is the ratio between the volume of CO2 being produced by the body and the amount of O2 being consumed. The value of this ratio indicates whether the body is operating aerobically or anaerobically. Given that it's a measure of physiology, it's objective. We've talked about ways to determine maximal effort on the forum before, I think another way is when the oxygen consumption peaks (ie you get to VO2max).

However, if you are looking at where the ventilatory threshold occurs, it's besides the point whether people made a maximal effort or not, because the ventilatory threshold happens well before getting to that point (50 to 80% of VO2max).

 

[Hutan]

Here's Snow Leopard explaining the issue of lowered work rate at the ventilatory threshold from another thread:

The consistent finding is reduced workload (usually measured in watts) at the first ventilatory threshold (VT1, sometimes known as the gas exchange threshold (GET)) between day 1 and day 2.

It is not influenced by voluntary factors as the workrate is fixed - the participant must put out the same amount of power at the same rate of increase, else the test is aborted.

All of this begs the question, what is the gas exchange threshold/why does it occur?

I'd first like to start by saying what it is not.

The VT1/GET is not a point at which the participant will suddenly feel out of breath. There is a second ventilatory threshold, known as the respiratory compensation point which occurs at around 90% of VO2Max where participants (including healthy athletes) start to hyperventilate to compensate for reduced blood PH. At this point, some participants may report feeling out of breath, but not all do. (also, COPD patients may report feeling out of breath at much lower levels of exertion)

The VT1/GET is not a point at which the muscles suddenly run out of oxidative/mitochondrial capacity, indeed it happens well below VO2Max.

The VT1/GET is not synonymous with an 'anerobic threshold', nor is it the same as a 'lactate threshold' which the point at which lactate accumulates significantly in the blood (and thus is additionally related to things like the kinetics of lactate transport).

The VT1/GET is an artefact of the ramped exercise protocol itself. Under uncontrolled exercise conditions, or controlled conditions where there is not a constant increase in workrate (examples include CPETs while fin-swimming), there may not be a clear transition point and the VT (or an anerobic threshold) is not a consequence of reaching a particular heart rate.

The VT1/GET is a non linearity of the graph when VO2 (Volume of O2 consumed) is plotted against VCO2 (Volume of CO2 exhaled). The VT1 can also be indicated using the ventilatory equivalent method, plotting VE/VO2 and VE/VCO2 on the same graph and noting the point where VE/VO2 increases significantly, while VE/VCO2 remains flat (where VE is minute ventilation).

The reason for this non-linearity has often been debated in an chicken or egg type manner. Is it primarily due to a non-linear increase in motor drive, or a shift in nonlinear shift in metabolic balance versus force output? I suggest both are necessary, since they inevitably lead to the other, causing the clear nonlinearity in the graph.

There is a transition in metabolic balance (from aerobic to non-aerobic metabolism) as higher threshold motor units are recruited, which have a lower balance of oxygen consumption versus force output due to physiological reasons (lower muscle fibre capillarisation, increased O2 diffusion distance etc.)

An aside, the ventilatory drive itself is ramped up in parallel with the increase motor drive (upstream of the motor cortex). Also note that autonomic responses (heart rate and blood pressure) lag behind and react to the change in ventilation. Additionally, note that there isn't a clear pattern of O2 Pulse (VO2/Heart rate) differences at VT1, suggesting that the observed differential between the two days likely isn't due to altered autonomic drive of the heart.

So why is there a reduction in workrate at VT1 between the two days in most ME/CFS patients (in 10+ studies), but not controls?

There are several possible answers:

-due to peripheral motor units being fatigued earlier (such as less optimal firing rates, less force output for a given motor drive) due to metabolic factors
-significantly altered muscle capillary blood flow leading to altered O2 kinetics
-due to stimulation of Group III/IV muscle afferents, which alters the balance between ventilatory drive and motor cortex excitability.
-the brain decided to completely re-wire it's afferent signals and bypass all of the normal feedback mechanisms that prevent this from happening for shits and giggles. (Note, the signalling of the fatigue related muscle afferents is much more complex than most other forms of pain and cannot be explained by typical pain central sensitisation models or experiments (in experiments, the phenomena is almost always transient, rather than chronic) as there are more systems involved - the proprioceptive system, the motor drive system (various supplementary areas), and the fatigue-related pain system - all of which have to fail, given the feedback between these systems that prevents things from going out of wack)

 

[FMMM1]

I recall Simon M, in a review of a previous metabolic study (by Hanson's group), writing something along the lines of --- we [this study] didn't find anything --- if we were to repeat this study then we'd introduce a stressor --- like exercise.

So they've now done that follow up study i.e. including exercise as a stressor. I just wonder if the forthcoming GWAS study might help to shed some light on the findings in this study e.g. if metabolic pathway X appears to be affected then do the results from the GWAS study suggest a problem and/or does it link to the findings of this metabolic study?

 

[Jonathan Edwards]

Here's Snow Leopard explaining the issue of lowered work rate at the ventilatory threshold from another thread:

OK I am beginning to remember half-understanding this. It seems that the change in work rate at ventilatory threshold could be affected by all sorts of shifts in neural control of the sort I was thinking of. So I am not sure why it should be interpreted as a metabolic phenomenon.

One of the things that worries me is what Mithriel mentioned. PWME go in to this test motivated by wanting to produce an abnormal result - maybe the second result to look different from the first. Knowing just how much frame of mind affects one's physical performance on the running track I wonder how problematic this is.

I am wondering whether if researchers are looking for metabolic shifts, rather than performance shifts, it would make more sense to study the sorts of level of activity that PWME engage in day to day and look at the metabolic profiles. As far as I can make out the only reason to use maximal exertion is in order to use work output as your outcome measure. If you are studying shifts in metabolism directly this would not seem to be necessary. Presumably metabolic shifts are only relevant to ME if they occur during normal daily activities for PWME.

 

[Mithriel]

One of the things that worries me is what Mithriel mentioned. PWME go in to this test motivated by wanting to produce an abnormal result - maybe the second result to look different from the first. Knowing just how much frame of mind affects one's physical performance on the running track I wonder how problematic this is

This is not anything worth worrying about. People with ME want a test that will give proof that something is going on to show they are not imaging they are ill. I doubt if it is possible for someone who has not experienced it to know how it feels to be made to doubt yourself for decades, there is no comparison with running performance. No matter how much you say to yourself it is wrong you are genuinely ill that worm of doubt is there all the time. We continually try to prove we are not slackers or hysterical. Other researchers have noticed this too, people doing standing tests for POTS have been amazed at the endurance of ME patients.

There is more likelihood of patients pushing themselves more on the second day. In fact patient stories often say they believed they did just as well until they were shown the results then they were surprised. It is not about performance it is about endurance and effort so it can't be compared to athletes.

if anything, controls are more likely to be fed up on the second day and not put so much effort in but they still achieve the same results as on day 1.

The trouble is that this screws up any scientific analysis.

PEM is a symptom pattern - as I understand it of feeling ill after exertion.
If we then want to use the same word to mean what causes PEM we get PEM causes PEM and that opens things up to confusion.

Maybe exertion releases some mediator X which give people a sense of PEM. Having a sense of PEM may generate signal Y which interferes with the ability to do work on a bicycle. So the second day PET does not tell us about X but about Y.

PEM was imposed on us as part of the criteria for CFS put in as a sop to the ME people who believed that exercise caused ME to flare up. None of the criteria were researched or laid down because of careful examination of patient experience.

We have been left with it as the best we have but I do not think it is accurate or very helpful as a concept. Exercise causes us damage and that damage has consequences for our health. To talk about a broken leg using the concept of "unable to load bear" and drawing a graph of recovery tells you something but much better to talk about the healing of the bone.

Asking whether a patient gets worse after exertion, particularly if it is delayed is only a way of separating out ME from other fatiguing illnesses so we can get at what the actual physiology of the disease is doing. The delay before PEM shows that exercise is causing damage long before it is expressed. That is the damage we need to work out.

Though CPET testing has shown a deficit exists it is not ideal and can't even be necessary as damage must occur in usual daily living. It is not ethical to exercise patients to exhaustion but patients volunteer knowing the risks. The psychology people refuse to accept exercise is damaging so they do not accept any risk exists. Another way ME research is screwed up.

 

[Hoopoe]

Some thoughts on the CPET.

I agree that the CPET might not be a good test because it doesn't replicate exactly what happens in daily life. Usually what causes crashes for me is not things that resemble a CPET, but more doing too much over a day or several with inadequate rest. It's almost never a single instance of exercise until exhaustion.

I haven't really been able to figure out what aspects of exertion contribute the most to crashes. The narrative that it has to do with intensity of exercise (as per the advice sometimes given "don't exceed a certain heart rate") doesn't seem to be true for me

 

[Jonathan Edwards]

This is not anything worth worrying about.

From what you say it seems there might be a big difference in mental state between patients and controls. And in hormonal responses over the 48 hour period and so on. Cortisol levels are likely to behave very differently, as well as adrenaline. Vagal control of respiration might well differ. And so on.

 

[Mithriel]

Such things may affect metabolites but people are sent for single CPET tests every day and the results are taken as evidence of heart disease or lung disease with no one worrying about their mental state. The protocols for annual testing of Cystic Fibrosis patients does not say anything about mental attitude or hormone levels.

There is no good reason for people with ME to have their mental state or willingness to do the test properly doubted.

 

[Jonathan Edwards]

There is no good reason for people with ME to have their mental state or willingness to do the test properly doubted.

It is isn't a matter of doubting willingness to do the test properly. It is recognising that if you are feeling ill you may be in a mental state that affects repeated tests differently from healthy controls. And if you are worried that you will not be believed that may well affect mental state too.

The end point for standard cardiac and lung patients is something quite different - simple capacity to do work I guess. The ME findings appear to depend on a complicated relation between ventilatory rate changes and measured work.

If there is a reproducible difference between PWME and controls then it is likely to reflect what is going on in ME in some way but I am concerned that there is confusion about the way changes should be interpreted.

 

[Kitty]

I am wondering whether if researchers are looking for metabolic shifts, rather than performance shifts, it would make more sense to study the sorts of level of activity that PWME engage in day to day and look at the metabolic profiles.

Given that the vast majority of the PEM experienced by patients is induced by daily living activities, this makes sense to me.

I still think it would be worthwhile investing in the development of an app that could capture ME-specific data from commonly used devices such as sports watches. For instance, my swimming app crunches data from my watch in such a way that it not only distinguishes reliably between several different pull strokes, but also measures how far each pull moves me forward. It must therefore be pretty straightforward to pick up basic information such as whether or not someone's moving their arms (indicating activity rather than complete rest) even if they're sitting or lying down.The app is more important than the source device, because it can be tailored to process info in ways that might not be of interest to any other type of user.

 

[Medfeb]

It is isn't a matter of doubting willingness to do the test properly. It is recognising that if you are feeling ill you may be in a mental state that affects repeated tests differently from healthy controls. And if you are worried that you will not be believed that may well affect mental state too.

My understanding is that repeat CPET tests are reproducible (have low variablility) in healthy people, in a number of chronic conditions (reportedly includes for cardiovascular disease, lung disease, end-stage renal disease, pulmonary arterial hypertension and cystic fibrosis) and in deconditioned people. But this is not the case with ME which fails to reproduce on subsequent tests. Presumably some of those patients with other chronic illnesses also feel ill.

Given they are measuring physiological parameters, with one being RER (ratio of VCO2/VO2) to demonstrate maximal effort, I wouldn't think mental state would affect physiological measures only in ME but not in those other chronic conditions.

 

[Hutan]

One of the things that worries me is what Mithriel mentioned. PWME go in to this test motivated by wanting to produce an abnormal result - maybe the second result to look different from the first. Knowing just how much frame of mind affects one's physical performance on the running track I wonder how problematic this is.

It's a reasonable concern. We have talked about ways that the CPET finding might be actively or unconsciously manipulated on the forum. From memory, the concern was about VO2 max and more about researchers stopping people with ME/CFS too early out of an abundance of caution, or perhaps wanting to 'help' the patient get an abnormal test result. For example, an RER of 1.1 might be reached, but a high VO2max might have been reached if the person had been allowed to continue with the test a bit longer. That problem doesn't apply to measurements at the ventilatory threshold.

I suppose it is conceivable that something about a person's breathing might affect when ventilatory threshold occurs and might be altered by a person's psychological state; I can't remember if we have talked about that on the forum. We are getting off-topic though. This thread would be a good place to continue talking about that idea:
2 Day CPET discussion - is it evidence that GET is harmful, and is it a biomarker?

As far as I can make out the only reason to use maximal exertion is in order to use work output as your outcome measure.

The approach in this study is not a great way to correlate metabolites with PEM, because the test alone might not induce PEM, or might not induce it at the same time the blood testing is done. It is a reasonable way to see if changes in metabolites correlate with the change in CPET performance, which is very interesting, but they didn't tell us about the change in CPET performance.

As we've mentioned elsewhere, there is the good day, bad day approach, where blood samples are taken when a person with ME/CFS feels particularly good and particularly bad. That's slightly different, it's looking to see if metabolites might be correlated with and potentially explain symptom load (and essentially PEM).

 

[Sean]

We have talked about ways that the CPET finding might be actively or unconsciously manipulated on the forum.

Do you mean:

We have talked on the forum about ways that the CPET finding might be actively or unconsciously manipulated.