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

[JemPD]

When I have flu I don't actually have a choice. I collapse shivering if I try to do anything vigorous.

No and neither does an severe ME sufferer, the comparison you're making with your own experience, is an accurate comparison to my own experience. But the words you used initially were about 'wanting' to get on the bike - thats what i was responding to. I was saying that as a person with ME what you are prepared to try to do, is different. Nobody who is severely affected*** and in PEM could possibly get on an exercise bike and pedal & complete a successful CPET, that is well established i think, thats why only mild/moderate participants can ever be involved in these studies.

But my point was exactly this - that to overcome feeling so ill you need to be in a very particular mental state supported by adrenaline and cortisol and goodness knows what and that may matter.

For sure


*** as i understand 'severely affected' to mean

 

[Mij]

Maybe not. Maybe there are different types of PEM.

Cognitive PEM comes on within a few hours and resolves after I lie down for an hour, physical PEM is delayed in my case and takes days or more depending how much I went over. But one does affect the other so they're related.

 

[duncan]

Cognitive PEM comes on within a few hours and resolves after I lie down for an hour, physical PEM is delayed in my case and takes days or more depending how much I went over.

That is pretty much my experience as well. Except cognitive can last longer if I've concentrated/focused longer or thought harder, e.g. employed more complex reasoning. But it's pretty quick. Emotion triggers can be even faster and can last longer. Physical typically are delayed about 48 hours.

All of that is generally speaking. Nothing is cast in concrete except some sort of exertion is involved.

It's too complex. The logic escapes me. I've read all the rules of thumb, and I've found they are all fallible to one degree or another.

So maybe it's good they are focusing on physical by extreme. Something just seems incongruous, though.

 

[Medfeb]

That sounds a bit weird. I thought the post of doing it twice was to show a difference?

Yes, but the very first time she tested an ME patient, she was expecting to see reproducibility because that's how it is in other conditions. The fact that it was not in ME patients is what made her wonder if it was her equipment.

 

[rvallee]

But how would metabolites come into PEM caused through mental exertion?

That would be my preferred way, frankly. An exercise challenge has too many factors involved, while a cognitive challenges massively reduces the impact of unrelated factors, especially low physical fitness.

Not everyone has cognitive PEM but when we do it's as abrupt and significant as with any physical exertion. There's a lot of untapped potential there. And an exercise bike doesn't really jive well with an MRI machine, neither does movement. A cognitive exertion challenge allows the use of every type of imaging, including fMRI.

In the end I'm sure this is mostly about energy utilisation and there's no reason why the energy demand on muscles should be fundamentally different from cognitive exertion. It's still all about powering metabolic processes.

 

[Jonathan Edwards]

Yes, but the very first time she tested an ME patient, she was expecting to see reproducibility because that's how it is in other conditions. The fact that it was not in ME patients is what made her wonder if it was her equipment.

Are you sure? It seems to me a bit odd to do a CPET two days running to show reproducibility. I would expect in the context of ME to leave it for a week or two at least before trying again. I thought it was a deliberate attempt to demonstrate fatiguability - which after all was supposed to be the hallmark of ME.

 

[Kitty]

I heard yesterday that my wife's cousin has an app linked to a sensor in her ski boots that tells her how good her turning technique is in terms of edging the ski and weight alignment.

I get similar info from my swim app. It's important for me because if my technique, speed, and efficiency drop off, I know that it might be better to skip the next planned session because I'm on a downward slope (I'll get me coat ).

So not only potentially important for research, but for management too. Many moderately affected patients describe how clumsy they become in PEM, and I've read descriptions of different breathing and heart rate patterns too. I don't know whether a wrist-worn sensor can pick up breathing patterns, but I'm certain it could pick up poorly controlled and erratic movement, and also any different heart rate patterns (I literally get a breakdown of my average heart rate per lap of the pool—not that I need to know, but it's there). It can also capture walking speed and speed of ascent of stairs for those who can still do that.

So lots of potential, although I don't underestimate the challenge of working out which types of movement to capture, and which devices could be included. The actual coding would probably be less of a problem once those decisions were made.

 

[Hoopoe]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1280928/

For me, the progressive deterioration described as occurring in patients enrolled in a daily walking program in the paper above, is closer than a CPET in approximating what happens in daily life. It's a constant process of finding the right balance between doing more and doing less. Marked deterioration from one day to the next is uncommon because I tend to avoid situations that trigger it. I do tend to deteriorate faster than the patients in this study though.

Karl Morten has done a metabolomic analysis of patients enrolled in a GET programme and while he didn't publish the findings (presumably due to a lack of control group), he did describe them in one of his talks and if I remember right at the end of the GET program there was a "depletion of central energy metabolism" or something close to these words.

 

[Medfeb]

Are you sure? It seems to me a bit odd to do a CPET two days running to show reproducibility. I would expect in the context of ME to leave it for a week or two at least before trying again. I thought it was a deliberate attempt to demonstrate fatiguability - which after all was supposed to be the hallmark of ME.

Sorry for not being clearer. My understanding is that based on studies showing reproducibility with other diseases, she had expected to see it also be reproducible with ME and when it was not, questioned whether her equipment was broken.

But perhaps the core question is what initially led Keller, Snell, Van Ness, Stevens, and others to try the 2 day format? Was it experience and observations on an Ampligen study where they did 2 CPETs two weeks apart and then did a third test if the first two differed by more than 10%. I don't know if those findings were reported

Or maybe also their own experience with pwME who did not get better with exercise clinically?

Edited to add - the paper above also referenced 3 studies in 1990, 1997, and 2000 by other researchers who they said reported reduced peak oxygen consumption

 

[Hutan]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1280928/

For me, the progressive deterioration described as occurring in patients enrolled in a daily walking program in the paper above, is closer than a CPET in approximating what happens in daily life.

That's an interesting paper strategist. I've made a thread for it here:
Time course of exercise induced alterations in daily activity in CFS, 2005, Black and McCully

And maybe the breathing was dysfunctional of the first test and not on the second and so ventilation threshold occurred at lower work rate?

For me, that's more possible. For the first time, I stood by the side of the road for 15 minutes waiting to be picked up and didn't feel well from standing that long in the cold; I didn't know what the procedure would be or how hard the test would be; I was meeting new people. It's possible that there was adrenalin and cortisol etc that made my performance better the first time. It's possible that something like that, the stress of finding the clinic for example, might apply to more people with ME/CFS than me. But it seems unlikely that an idea of 'the stress of a novel experience' in the first test causing an abnormally good test result really accounts for what seems to be a fairly consistent result of the drop in performance in the second test. As @Medfeb has pointed out, people with other diseases haven't shown that pattern, and they too would surely be subject to the same 'stress of a novel experience' and the concern about the effect of the test.

I go out of my way to be sceptical because it is the way to get debate going and I am happy to believe that there is some consistent finding on the 2day CPET of relevance to what is going on in ME.

For sure, being skeptical and picking apart assumptions is helpful in finding out what is true. I'm still not completely sure that the lower performance on second test is a true finding - there is so much scope for the data being messy, with levels of activity before and during the test not being controlled.

Different breathing patterns on the second test perhaps might be the cause of the drop in performance on the second test without a psychological cause. An increase in a metabolic process that is part of the disease as a result of previous exertion might cause a change in breathing upon subsequent exertion. And that change in breathing might contribute to the lower performance.

I think we need to find out if/how changes in breathing could influence a CPET outcome, and if there is any evidence that people with ME/CFS have shown this change in breathing.

 

[Snow Leopard]

Maybe not. Maybe there are different types of PEM.

Many people with ME/CFS report PEM due to mental/emotional exertion to be different from that of physical exertion.

And maybe the breathing was dysfunctional of the first test and not on the second and so ventilation threshold occurred at lower work rate?

We know that isn't the case because it would show up in the graphs when compared (and we've had more than a handful of different research groups perform the studies - so someone would have spotted it). I've also done the test myself and I know that doesn't make sense in my experience.

The ventliatory threshold is not merely a breathing phenomena - metabolism, muscle drive, motor unit recruitment patterns and ventliatory drive are all intimately entwined through feedback loops and fatigubility plays a strong role. It is far more interesting than most people initially think.

You could not fake the pattern by trying to deliberately hyperventilating at some point (in fact you will have difficulty trying to do that as the breathing will not be under voluntary control at this level of intensity).

 

[Jonathan Edwards]

We know that isn't the case because it would show up in the graphs when compared

I don't follow that. If it shows up on the graphs as the result that we see then it does.
I realise things are complicated but as far as I can see at the moment it is possible that increased ventilation occurs at a lower work rate in the second CPET for PWME because of some inhibition of that increase from involuntary neural mechanisms in the first test that do not apply in the second. The person would be completely unaware that tis was going on. People are unaware that they don't breathe as much as they should during sporting activities when learning, for instance, which is why sports trainers pay attention to deliberate breathing control.

I am not suggesting anyone is faking anything, but rather that the change from test one to test two is neurally mediated rather than anything to do with disordered metabolism. Which seems to fit with what you say here (below) and also in the bit Hutan quoted from you from before.

The ventliatory threshold is not merely a breathing phenomena - metabolism, muscle drive, motor unit recruitment patterns and ventliatory drive are all intimately entwined through feedback loops and fatigubility plays a strong role. It is far more interesting than most people initially think.

 

[Snow Leopard]

I don't follow that. If it shows up on the graphs as the result that we see then it does.

I'm talking about the VE/VO2 and VE/VCO2 slopes, not the VT1 (gas exchange threshold). It would be obvious to anyone looking at the graphs.

Another correlate of the VT1 is also a non-linear increase of rated perceived exertion (Borg scale) in terms of muscle effort that precedes or is even independent of rated perceived exertion of breathing.

There are also mechanical and electrical (measuring non-linear shifts in twitch frequencies) fatigue thresholds at around this point.

I realise things are complicated but as far as I can see at the moment it is possible that increased ventilation occurs at a lower work rate in the second CPET for PWME because of some inhibition of that increase from involuntary neural mechanisms in the first test that do not apply in the second.

The problem with your hypothesis is that it contradicts what we already know about the relationship between motor drive and ventilation and effort (upstream of the motor cortex).
We know that during intense exercise, ventilatory drive is coupled to the effort signal (upstream of the motor cortex). We also know that feedback from peripheral afferents are critical in maintaining the appropriate excitability of the motor cortex - experimentally, when these afferents are blocked in humans, there is minimal central fatigue, motor cortex excitability remains high, but the ventilatory drive is insufficient leading to increased peripheral fatigue due to metabolic factors.

This is why also mitochondrial myopathies, muscular dystrophies etc all show the same pattern as ME/CFS patients - high central fatigue, rather than peripheral fatigue on supramaximal twitch interpolation nerve studies. Stimulation of peripheral afferents causes central fatigue which prevents unusual peripheral fatigue. Something that was not recognised in those 1980s/90s studies is that supramaximal twitches predominately rely on anerobic metabolism are too short to measure disturbances of sustained oxidative metabolism, and are only responsive to increased physical blockade of the nerve junctions or glycogen depletion.

 

[Jonathan Edwards]

I'm talking about the VE/VO2 and VE/VCO2 slopes, not the VT1 (gas exchange threshold). It would be obvious to anyone looking at the graphs.

Can you explain that in plain English. What would be obvious?

The problem with your hypothesis is that it contradicts what we already know about the relationship between motor drive and ventilation and effort (upstream of the motor cortex).

Surely we only 'know' about what happens in standard situations with healthy controls, which might not happen for all sorts of reasons with patients?

 

[Snow Leopard]

Can you explain that in plain English. What would be obvious?

Ve is the volume of air that enters the lungs over a given period of time (typically a minute).
VO2 is the volume of oxygen consumed
VCO2 is the volume of carbon dioxide output.

Here is an example of ventilatory equivalent plots used to determine the ventilatory thresholds (in this case, VE/VO2 and VE/CO2 plotted against workrate):
https://www.researchgate.net/figure...rbon-dioxide-VE-VCO2-and-their_fig2_355851633

If there is a disturbance in minute ventilation relative to workrate then this will raise or lower the points on the graph and this could easily be compared from day 1 to day 2 as well as against the sedentary controls. If there was a glaring difference, it would be published, similar to all of the chronic heart-failure patient papers showing a difference.

In fact, as an example Dane Cook's recently published single day CPET study showed that VE versus workrate was the same in patients and controls.

The change that is observed in the 2 day studies is the difference in slope around the VT1. This, at least in my view is a critical hint to what could be going wrong.

Also carefully note (in the above graph) that there is approximate isocapnia between the two ventilatory thresholds (between the gas exchange threshold-VT1 and the respiratory compensation point-VT2) - this means the increase in ventilation past VT1 is very close to what is needed, at least for the athletic participant in this example.



Further reading for others following along:
https://me-pedia.org/wiki/Two-day_cardiopulmonary_exercise_test

 

[Hoopoe]

This is why also mitochondrial myopathies, muscular dystrophies etc all show the same pattern as ME/CFS patients - high central fatigue, rather than peripheral fatigue on supramaximal twitch interpolation nerve studies. Stimulation of peripheral afferents causes central fatigue which prevents unusual peripheral fatigue. Something that was not recognised in those 1980s/90s studies is that supramaximal twitches predominately rely on anerobic metabolism are too short to measure disturbances of sustained oxidative metabolism, and are only responsive to increased physical blockade of the nerve junctions or glycogen depletion.

Regarding sustained metabolism. I've been doing walks with other people and one clearly observable difference is that I don't have the same stamina as others, even people who are 30+ years olders and have their own health problems. In comparison to people who are significantly older than me, my walking speed is initially faster and I'm stronger as would be expected. This advantage is maintained for some time but then fatigue appears relatively quickly and affects my walking speed, gait, and I start getting more orthostatic symptoms. Afterwards I tend to get quite hungry and may have to lie down, or even take a nap just to recover and feel okay again.

In comparison to people of my age, my initial speed and strength is about the same, maybe slightly reduced and the difference in stamina is more pronounced.

That I tend to get hungry and eating helps somewhat to me suggests that this might be a problem with low fuel reserves. I'm not sure this problem would be as clearly visible on an exercise stress test because the test doesn't last as long as my walks and the intensity of exercise is higher and it's done while sitting which might matter as this reduces orthostatic stress somewhat.

 

[Snow Leopard]

Regarding sustained metabolism. I've been doing walks with other people and one clearly observable difference is that I don't have the same stamina as others, even people who are 30+ years olders and have their own health problems.

A key point that sadly needs to be repeatedly stated, is that this difference in stamina is not explained by differences in cardiovascular fitness. It is not and should not be compared to an unfit person pushing themselves!!!!!

When I did the 2 day CPET, I had above average VO2Peak for my age on the first day, yet my stamina is woeful compared to my peers.

 

[Hoopoe]

Has medical science developed tests of stamina? By stamina I mean the ability to keep doing an activity for longer periods of time with limited decline in performance or discomfort.

 

[Sean]

Best I can tell volition/drive is not impaired or pathological in ME. What is impaired or pathological is the consequences of engaging it, of putting it into action.

The urge to be active and involved in life is not diminished, but the capacity to do so is, often to the point of being non-existent.

Patients learn the hard way that they can do things, but pay a very high physiological price for it.

 

[Michelle]

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.

It's still a very blunt tool but I have been using an old-school pedometer clipped to my underwear for about 8 years now and it seems to be a measure of not only how *many* steps I'm taking, but *how* I'm taking them. When I first started using the pedometer, I noticed that on days when I felt better, my step counts almost doubled even though my activity level hadn't really altered. Baffled, I started paying attention to the step counts throughout the day as I did activities (I usually only look at my pedometer once a day before going to sleep). What I found was that a higher number of steps were recorded for the same activity (say, walking from my bedroom to the kitchen) on days when I felt better than on days when I felt worse. On my bad days I tended to shuffle and many of those steps appeared to not get picked up on my pedometer, while on my good less horrible days I was actually taking more of a stride and the pedometer seemed to pick those steps up more. I don't know how typical that is. I'm on the severe end (my baseline has been about 500 steps/day; I've been completely homebound and mostly bedbound since 2011).

A complicating wrinkle has been that since Nov 2020, I've started having a lot of muscle spasming and atrophy in my legs. In the past, when my step counts have dropped below 250, my flu-like malaise symptoms have been so bad that I've not been able to be very verbal. Yet since 11/20, I routinely have days below 150 (even 100) where I can still chat with my partner on Hangouts for an hour or two and the flu-like symptoms don't feel especially worse; I just feel a bit more tired. I'm being referred to a neurologist.