A study I want someone to do

[DokaGirl]

@Sarah94

If I'm sleep deprived my OI is worse.

PEM and cognitive functions for me: I have difficulty going through the motions of something I've done many, many times. I also have more memory problems.

PEM and physical function: my balance and coordination can be effected. After the first half of a 2 day CPET, I tripped three times on flat surfaces - this was in the space of about one hour.

I think another thing to measure after PEM is heart rate and BP. My HR stayed quite elevated - about 120 BPM for almost an hour after a short burst of exercise. I don't think this is normal - but maybe it is, although medic advice was to rest due to my elevated HR.

 

[Mij]

I didn't experience cognitive/processing decline for the first 11 years of illness, I was sharp as a knife, it was when I started improving and doing physical exercise (PEM over and over again) that my cognition declined. I didn't even realize this until a few years later.

 

[rvallee]

On the basis of what I am suggesting lack of sleep and PEM would not feel the same necessarily because feedback drives, which may well generate symptoms in both situations, may be at different levels of control. But it is interesting that you notice a difference.

Not the overall feel or sleepiness but I find a lot of similarity in the slow cognitive processing and dullness of thought. It's the mental equivalent of trying to do another set of weight lifting right after having done a maximum set, there's just no juice to initiate the action.

Lack of sleep tends to cause a sort of "buzz" as well, jitters I guess, that is quite similar to the type of "wired" buzz from PEM. It's distinct from anxiety, especially as there are usually little to no actual thoughts happening during.

I doubt unrefreshing sleep is a significant cause of ME but there are likely similarities in how it affects higher brain function, especially executive function. The brain is basically running all on automatic, things we know how to do without a thought are still accessible, though much slower, but anything that requires concentration is simply unavailable.

Although in addition to sleep it would likely be possible to cause that with excessive stimulation, like chaotic noise, movement and other distracting things, just overwhelming the brain in a sort of stimulus denial-of-service.

 

[Mij]

In general I sleep well and wake up feeling refreshed, so unrefreshing sleep has not altered my cognition.

 

[Marco]

But what if a blockage in nerve cell function actually meant that PWME retained things that healthy people did not? What if paradoxically the blockage left a trace that allowed a response that healthy brains could not make? It might be in terms of what neuropsychologists call 'masking' in visual experiments. Or imprinting with a subliminal stimulus.. In lots of experiments people are asked to respond to a picture having had various other visual stimuli flashed subconsciously either before or after so that the brain's response is distorted. Maybe in ME some of these effects might go on for longer?

It is just a speculation and it might well be wrong but it might just show something interesting. Everyone assumes that cognitive tests in ME should just show a deficit. But if there was a paradoxical extra or enhanced effect, however useless in practice, it could be a powerful clue to what is wrong.

Why don't we (the forum) put together an outline protocol for what such an experiment would look like. Perhaps someone might be interested in running it?

 

[beverlyhills]

Why don't we (the forum) put together an outline protocol for what such an experiment would look like. Perhaps someone might be interested in running it?

They already did in the studies I posted. Blood tests and lumbar punctures after the cognitive testing but before the exercise (regardless whether they published it - the default mode network study had CFS patients but they were not included in the manuscript). You would be able to interpolate differences in-group from that data.

If you are able to notice baseline differences, what purpose would repeated administrations serve? You might be able to show that CFS patients have an exponential loss vs. healthy patients or steeper linear loss. This is something than can be inferred from existing data, and even if it could not, pragmatically what is its usefulness to improve patient care?

I am not trying to dogpile a patient getting better - I am saying it already has been done, and the DoD shelled out many millions to do it.

 

[JemPD]

Re the OP @Sarah94 Great idea

I suspect it may be the sort of 'blockage' that builds up if normal people get no sleep.

Interesting suggestion re sleep deprivation... personally, having experienced both sleep deprivation and ME (both separately and together) it doesn't feel to me like a related thing... but feelings can be misleading of course.

FWIW thats the same for me... PEM & in fact ME in general has little in common with sleep deprivation for me. Sleep deprivation i experience as 'fatigue'... ME in general & particularly PEM feels like flu/virus/bacterial infection (without the sore throat/sinus/cough), the 2 things are a very different experience (but of course as already said that doesn't mean it cant be part of the same process). But that's why I detest the word fatigue so much. Yuppie flu is more accurate than CFS imo despite it's derogatory inference.
I do of course recognise that others with the same dx will have different experience. Perhaps it is just diff experience, perhaps entirely different pathology.

Drugs like ibuprofen block the hypothalamic response to cytokines and make us feel better.

Interestingly (lol to me!) ibuprofen I find pretty effective at reducing symptoms both during PEM & in general, but unfortunately because it reduces symptoms it makes pacing more difficult - it makes me feel as if i am less ill & therefore I do more, but it's just an illusion & the PEM just kicks in worse afterwards. Same as the effects of adrenaline/stress hormones - temporary relief but its only an illusion of being less ill, & behaving as if the illusion were real just worsens the PEM later - in accordance with the amount of over exertion performed whether cognitive or physical.

This is why I always thought the hypothesis that something was making the body 'believe' it had an infection when the infection had passed, held promise.
However the only time I ever experienced the cognitive problems in a comparative way was when I was stoned - too much cannabis - in my misspent youth!
Flu/virus/infection never made me forget what I just discussed, how many £4 items I could buy with £10, or how to make a cup of tea! so... I too heartily wish someone would study them in a more focussed way.

 

[Jonathan Edwards]

They already did in the studies I posted.

I think Marco was referring to the suggestion I had made in the post he quoted.
We need an experimental neuropsychologist. Maybe @Woolie would know?

 

[obeat]

As a junior doctor, I worked 24 to 36 hour shifts and I think that there are some similarities between sleep deprivation and PEM.
In both cases I would be aware of the increased cognitive effort required to carry out physical tasks. Writing up a drug chart was more difficult after a night with little sleep. I would have had a sore throat.

The difference is that 2 hours sleep after the shift was finished was restorative.

Perhaps the small amounts of sleep during a shift weren't deep enough ?

 

[Marco]

I think Marco was referring to the suggestion I had made in the post he quoted.
We need an experimental neuropsychologist. Maybe @Woolie would know?

Yes thanks Jonathan. I suspect thought an experiment like this would appear to be such an abtraction that it wouldn't be immediately apparent to PWME that it's relevant to their daily experience. Not a reason not to do it though. These can be pretty simple experiments to set up (using a PC rather than t-scope) and would (I believe) get to potentially the key problem.

 

[Jonathan Edwards]

These can be pretty simple experiments to set up (using a PC rather than t-scope) and would (I believe) get to potentially the key problem.

So maybe there might be a clue in the everyday experience of PWME? Is it possible that PWME recognise that certain sorts of memory, e.g. from yesterday's events, stick around longer than expected? Might visual images hang around longer - anything like that?

 

[Marco]

So maybe there might be a clue in the everyday experience of PWME? Is it possible that PWME recognise that certain sorts of memory, e.g. from yesterday's events, stick around longer than expected? Might visual images hang around longer - anything like that?

Yes there might. The challenge being to operationalise those experiences into an experimental design which will be to a greater or lesser extent an abstraction. One example which I'm sure you're familiar with is metacontrast masking which might show up some differences in temporal image processing but may not immediately appear to have implications for the experience of PEM.

 

[Hoopoe]

So maybe there might be a clue in the everyday experience of PWME? Is it possible that PWME recognise that certain sorts of memory, e.g. from yesterday's events, stick around longer than expected? Might visual images hang around longer - anything like that?

I can't think of anything that really stands out, except maybe a overstimulated feeling that prevents relaxation and presumably good sleep and seems to result from overexertion, with an increased chance to transition into a crash.

Initially I had severely disrupted sleep for no apaprent reason, in fact it preceded the onset of the illness. I slept for 8 hours without awakening but woke up feeling horribly bad. Over the years this improved. It tends to get worse again with more exertion but I usually don't reach the activity level required to really trigger this again. At least I think this is happening, I mostly don't have this kind of bad sleep anymore and even wake up with some spare energy on a regular basis.

PS After images from bright lights maybe last longer than normal but I don't know what's normal.

PPS my memories fades quickly and events from yesterday are often already hazy and lacking detail.

 

[Saz94]

So maybe there might be a clue in the everyday experience of PWME? Is it possible that PWME recognise that certain sorts of memory, e.g. from yesterday's events, stick around longer than expected? Might visual images hang around longer - anything like that?

Absolutely not in my experience. All the days have blurred into one and I could not tell you whether something happened yesterday or last week.

 

[It's M.E. Linda]

As a junior doctor, I worked 24 to 36 hour shifts and I think that there are some similarities between sleep deprivation and PEM.
In both cases I would be aware of the increased cognitive effort required to carry out physical tasks. Writing up a drug chart was more difficult after a night with little sleep. I would have had a sore throat.

The difference is that 2 hours sleep after the shift was finished was restorative.

Perhaps the small amounts of sleep during a shift weren't deep enough ?

Interesting.
If I wake with a sore throat (and as if Harry Potter’s Knight Bus has run me over), I absolutely know PEM has hit me. Says a lot about my (lack of ) ‘restorative sleep’.

 

[Woolie]

I think Marco was referring to the suggestion I had made in the post he quoted.
We need an experimental neuropsychologist. Maybe @Woolie would know?

@Jonathan Edwards, I'm guessing you're referring to the idea of doing some sort of masking study in PwME?

But what if a blockage in nerve cell function actually meant that PWME retained things that healthy people did not? What if paradoxically the blockage left a trace that allowed a response that healthy brains could not make? It might be in terms of what neuropsychologists call 'masking' in visual experiments. Or imprinting with a subliminal stimulus.. In lots of experiments people are asked to respond to a picture having had various other visual stimuli flashed subconsciously either before or after so that the brain's response is distorted. Maybe in ME some of these effects might go on for longer?

It is just a speculation and it might well be wrong but it might just show something interesting. Everyone assumes that cognitive tests in ME should just show a deficit. But if there was a paradoxical extra or enhanced effect, however useless in practice, it could be a powerful clue to what is wrong.

Masking is when you show someone a visual stimulus (like a printed word, let's say "cat") and then a fraction of a second afterwards, you show some meaningless image in the area where the word just appeared (say "XXXX"). The person is often unable to report that they saw a word at all. But you can show with response time tasks that they are nonetheless influenced by the word, For example, if you ask them to repeat the word "dog" shortly afterwards, they will be faster, compared to when they were presented with an unrelated word like "bed".

It isn't really a "neural" effect, its better understood as a feature of human cognitive functioning. We need quite a lot of exposure time for something to reach our awareness (a few hundred milliseconds). This is sometimes called "integration time". If we have less than that, we still process the stimulus to some extent - enough to influence how we respond to the very next stimulus - just not enough to report it. The effect doesn't last long. If you wait a second or so, then you won't see any sign that the person ever viewed the word cat at all.

Usually, a mask has to be shown within 150 milliseconds or so of a stimulus ("cat") to prevent us from "seeing" the stimulus. You might expect that any condition that slows cognition - including ME - that period could be a bit longer. This would be expected because "integration time" is slowed. It wouldn't necessarily mean that PwMEs are retaining a "trace" longer than healthies. It just means that they are processing the visual stimulus information more slowly.

The sort of thing neuropsychologists measure when they are studying perception - maybe with a tachistoscope! Effects of flash images on recall and choices maybe, but maybe something a bit different from the usual routine. We need an experimental neuropsychologist.

You don't need a tachistoscope any more. A simple Macbook will suffice. There are plenty of freeware programmes that can be used to present this sort of timed display.

If you want a cognitive task that would be sensitive to cognitive PEM, I wouldn't choose something as complex as masked priming, there are too many variables that could be responsible for any effect. I would choose a speeded task, something like responding to simple letters with a button press. You can vary the timing and other parameters in order to get measures of various things, such as sustained attention, response speed, etc.

I think response speed might be what you want, because speed is a sensitive measure, and because damage to the anterior cingulate results in a general slowing of response times. People think the anterior cingulate might function as an "interface" between the brain and the autonomic nervous system (ANS). It signals to the ANS when high performance of some kind is required, and the ANS responds by increasing heart rate variability, etc. If the task is a cognitive one, these changes will increase blood flow to the participating brain regions. I suspect that in ME, there might be a lack of responsiveness of this kind - due to problems outside of the central nervous system entirely - so the brain is not able to respond to cognitive challenges in the normal way.

So I'm saying in ME, the anterior cingulate is working fine, but the ANS/cardiovascular system cannot respond effectively. But the same tasks that are sensitive to anterior cingulate damage might also pick up the problems in PwME.

I think its interesting how PwMEs seem to vary in how much cognitive versus physical PEM they have. And its interesting that people say cognitive tasks generate cognitive PEM and physical tasks generate physical PEM. Still think, though, that ANS and cardiovascular variables like OI might be at the bottom of all that variation.

 

[Jonathan Edwards]

It isn't really a "neural" effect, its better understood as a feature of human cognitive functioning.

I appreciate your explanation is very helpful @Woolie but cognition is neural as far as I am concerned. I realise that I may be seen as a 'reductionist' biologist by some but in reality I am an anti-reductionist Leibnizian if one really wants to go in to metaphysics. (Like Leibniz and Descartes I see the phenomenal as primary, but this is getting off track.) In other words this is all nerve cells receiving and sending signals. Cognition is a word I have a deep suspicion of.

And I am actually not suggesting we look for some slowing or deficit or even with PEM particularly. I am suggesting that there is a failure to clear input data somewhere in neurons and that this may paradoxically lead to enhanced recall function, although it may show up in a very counterintuitive way. My reference to masks was just as an example of how neuropsychologists play around with recall. They are probably irrelevant. But they might just be in some odd way. Maybe neurons in ME retain the mask in a way other people do not or something odd. I want to turn the experimental routines on their heads.

Basically I am suggesting that we turn the paradigm upside down and look for things that ME neurons can do that normal neurons cannot. I am not suggesting that whatever it might be would be remotely useful but it might tell us what is going on. I suppose the crude analogy would be the ability of some autistic individuals to perform amazing mathematical tasks. There may be no mileage in it but it might be worth teasing out.

Basically I would argue that if there is 'slowing' there is prolonged retention of something. Just by physics. The information has to be there for longer in that particular computational pass. Or it is somewhere later than it would have been. That may leave nothing more to retrieve than in the quick version but in raw biophysical terms it might.

Another sort of related issue would be whether PWME are more difficult to anaesthetise. Again it would reflect a basic biophysical property of information retention.

 

[beverlyhills]

Stuart Johnson was a consultant studies that I referenced. He is a neuroscientist at Georgetown. The protocol is here.

The patients were quarantined, diet-controlled, had drug restrictions and I do not see how it would be helpful to know that repeated administrations would decrease cognitive reserve. It should be intuitive. Even under that environment you still have test timing confounds, even an MMSE is cognitive exertion. Plus the travel to the test site, plus the natural variability in cognitive function day to day.

This is definitely not restricted to CFS researchers, I am seeing more and more PhD units replicating to the point of plagiarism.

 

[Marco]

And I am actually not suggesting we look for some slowing or deficit or even with PEM particularly. I am suggesting that there is a failure to clear input data somewhere in neurons and that this may paradoxically lead to enhanced recall function, although it may show up in a very counterintuitive way.

Basically I would argue that if there is 'slowing' there is prolonged retention of something. Just by physics. The information has to be there for longer in that particular computational pass. Or it is somewhere later than it would have been.

How about, rather than prolonged retention of something, we have a situation of impaired filtering leading ultimately to an information processing blockage?

As an example (grossly simplified), suppose that transport (specifically reuptake) of glutamatergic neurotransmission is impaired. In response to sensory input, excitatory glutamate is released, crosses the synaptic cleft, binds to glutamate receptors causing neurons to fire transmitting the information and eventually glutamate is removed from the receptor (reuptake) for recycling. In normal circumstances salient sensory input causes repeated cycles of this process (or parallel signals? - I'm not up to date with the current literature) resulting in a stronger signal being passed to higher brain areas while irrelevant sensory input is 'suppressed' so no further signals are passed. These salient signals are consolidated as long term memories.

Assume then that PWME have a deficit in glutamatergic re-uptake. In normal circumstances the effects may be comparatively mild. Sensory input (salient and irrelevant) causes glutamate release and binding to post synaptic receptors as per normal but at an earlier than normal stage glutamatergic reuptake reaches a limit and glutamate receptors remain temporarily 'blocked' resulting in successive cycles of reinforcement of salient sensory input is 'blocked'. Glutamatergic neurotransmission is not blocked totally but the cycle is slowed. While this may not impact drastically on recall of salient memories it may reduce the contrast between them and irrelevant sensory input so PWME's memories may be 'messy'?

Under greater load (physical or mental exertion etc) resulting in increased demand on neurotransmission, reuptake may be overwhelmed leading to a prolonged state where receptors remain blocked with elevated glutamate in the synaptic cleft (or elevated extracellular glutamate). In this situation you would expect that information processing generally would be more significantly impaired. How long would this state take to clear?

Perhaps in an experimental situation PWME might recall more 'irrelevant' data compared to controls. There is some evidence for this :

As can be seen, for the CCFS patients as a whole, on the ERP measure there was no difference between them and healthy controls on the response amplitude (strength of response) to the target stimulus, while the overall CCFS response to the non-target stimulus was higher than that of healthy controls.

Sorry to link to my own blog but the original paper is hard to access : https://www.healthrising.org/blog/2...deficits-present-in-chronic-fatigue-syndrome/

.. and in a post PEM situation, information processing should be generally impaired?

 

[wastwater]

This was an autism spectrum study
http://eprints.whiterose.ac.uk/9830...a frequency in autism spectrum conditions.pdf
I wondered how those with M.E would perform