A study I want someone to do: (as far as I know, a study has not been done on this) Group of patients. First measurement at a time when they are not in PEM Get them to overexert themselves cognitively Second measurement immediately after the exertion Third measurement during PEM time (should probably be done at whatever time the patient predicts they are likely to have PEM based on past experiences). Measuring: Neurotransmitter metabolites Any other metabolites potentially relevant to brain function Inflammation markers Brain scan to detect inflammation or microglial activation (OK, apparently this would be really expensive, so maybe not the brain scan)
As I've said before, this is the thing which most completely baffles me regarding this disease. What is it that goes on in my brain when I cognitively overexert (even by a small amount) that results in worsened cognition for a long time?! And if cognitively overexerting by a large amount, then permanently worsened cognition!
That would be interesting. I am very aware that cognition burns a lot of energy. Study often left me tired when I was healthy. Now it’s even more obvious.
https://www.nature.com/articles/s41598-017-15383-9 https://bmcneurosci.biomedcentral.com/articles/10.1186/s12868-019-0488-6 They excluded a lot from these papers even though they covered a lot of what you asked. They could be data mining or the results could be irrelevant, it is probably the second part. It is pretty hard to write a paper that is 90% negative results. When a healthy person exercises, signals from muscle damage reach the brain to reduce further injury. More of those signals reach the brain in CFS, but the same amount are produced. This means one of two things: a localized infection already exists in this part of the brain causing double the exertion sensation. Or, part of the brainstem is over-exposed in CFS patients. This a good idea, but very few researchers have the capacity to detect brain inflammation, maybe 5-10 in the United States. Japan is about 10 years ahead of CFS research, so no one can really duplicate Nakatomi's brain inflammation results. They do not cheat just to publishing anything, and have a single cohesive source of funding. You have to be skeptical of their research though, even as they explain in the symptoms in totality.
You might want to check out Jarred Younger's work. He's one of the OMF-funded scientists. He's focusing a lot on what he describes as brain inflammation. Here's his presentation at the OMF Symposium last year. I recall him describing evidence of activated microglia in patients in this talk. https://www.youtube.com/watch?v=8XrdSlpUQTE
These articles are physical exercise. I know that studies have been done on PEM from physical exertion. I want studies to be done on PEM from cognitive exertion.
One thing of interest for me is that for some any trigger of PEM produces a crossover of symptoms, that is cognitive over exertion can produce physical PEM symptoms and vice versa, whereas other suggest that they have distinct physical and cognitive symptoms dependent on the PEM trigger.
I think for me... a small to medium cognitive or physical overexertion will only produce cognitive or physical PEM respectively, but a really large overexertion will result in lots of different PEM symptoms.
(Sorry this is longish but hopefully not too confusing. A new thought.) I think this is a very sensible thing to want to study in principle. I suspect the problem is that these particular markers are not going to show anything. I do not know much about neurotransmitter metabolite levels but most of these things are resorbed locally and recycled as far as I know. CSF levels might change but even there I would be doubtful and it would be hard to measure. I don't think there will be any inflammation as such. I think the term 'inflammation marker' is often confusing. Cytokines and other signalling molecules can cause inflammation and can be produced in inflammation but they can also cause us to feel ill without there being any inflammation. When we have flu we feel terrible but there is little or no inflammation, just cytokine release affecting the hypothalamus. Drugs like ibuprofen block the hypothalamic response to cytokines and make us feel better. So I think it makes sense to look for cytokines but I would separate that from inflammation. Unfortunately, I doubt cytokines will show much. They are also hard to interpret because they get involved in so many processes at some point. I also do not think that microglial activation is going to occur in the activity PEM cycle. I suspect that microglial activation occurs when there is actual structural neuronal damage. It accumulates over time in degenerative brain conditions. Similarly I do not think brain scans will show anything in this time frame. That all sounds negative but what I think it means is that we need to find a way to identify what the continuing 'blockage' in the brain after mental exertion is (to use your term). I suspect it may be the sort of 'blockage' that builds up if normal people get no sleep. I think there must be some form of chemical change that occurs over a period of hours that can extend to days following brain cell usage. This is actually something I am interested in in my other area of study, which is conscious thought. I am interested in the idea that nerve cell activity is followed by non-covalent binding of proteins to the cytoskeletal core of cell dendrites in a way that changes the 'tuning' of the cell's responsiveness. The idea is a bit like a Xerox copier or now LASER printer. Electrical patterns 'write' a trace on to the cytoskeleton, just as the LASER writes a trace on to the printing plate. The trace normally lasts for a short while and is then cleaned away but maybe in ME the cleaning away is not working as it should Measuring this sort of effect chemically in working brains would be very hard. However, a thought has come to me. Various studies have tried to show defects in brain function in ME - in terms of visual responses or cognitive tasks etc. A problem here is that if PWME are feeling ghastly it may not be too surprising if they fail on cognitive tasks. Someone with flu might fail. 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.
What do you think would be useful measures to measure with and without cognitive PEM? 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.
On your point re microglial activation. Didn't Jarred Younger find this in ME? On your point re ibuprofen and cytokines and inflammation. That is interesting. Do you know whether turmeric or curcumin could have a similar effect? I am absolutely certain that for me personally this hugely improves my cognition. I have been assuming that it's due to its anti inflammatory properties, but am very open to other suggestions. (I'm reading your message in bits and replying in bits.)
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. 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.
I am not sure Younger had any data on microglial activation. My impression is that all his find gins so far are preliminary. The Japanese PET scan group found what looked like microglial activation. That needs confirming. I think it quite possible that over a period of years neural damage in ME might lead to microglial activation but it is not something I would expect to be detectable in the short term. I am pretty sure neither turmeric nor curcumin have any significant pharmacological effects on inflammation - or anything much. I think the popular belief that they have specific actions is just a popular belief. But they both stimulate the brain strongly through taste receptors and that may be enough to have a powerful effect. (Which in a sense is a pharmacological effect I guess.) It took me a long time to realise that much the most powerful analgesic, by a factor of about tenfold, is ice. If I hit my hand with a hammer or have a root canal problem or a feverish headache I can remove the pain often completely and instantly with temperature change. It does not last maybe but the effect is just as real as an injection of local anaesthetic. Flavours may have very powerful effects on brain function, including the hypothalamic centres that give us fever symptoms I suspect.
Ah, I must have gotten my researchers mixed up there. I take turmeric and curcumin in a capsule, so they don't taste of anything to me. It is not just a popular belief, various studies have found effects of curcumin in a few different illnesses.
I sometimes wonder whether PEM would make everything worse. Say, a study that first lets patients with ME and controls overexert themselves cognitively to induce PEM and then measure the consequences on purely physical tasks, the day after. There might be an effect that the cognitive task worsens physical performance in ME patients but not in controls. If I remember correctly there are some studies that tried the opposite, a cognitive task after an exercise test, but the results are contradictory.
Yes, here are a couple of reviews: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664031/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535097/
One issue you may run into is where you say 'not in PEM.' When is that, in the context of a study? I've tried to make this point to several researchers, and some seemed to get it, others not so much. If you have to travel to a site--travel anywhere, even across the street--for a study, you may not be 'in PEM,' but it's certainly not baseline. I suspect, especially for severe patients (those even capable of getting out of bed) that...just getting out of bed...produces some kind of ill effect. I certainly feel it. The amount of energy that goes into being able to simply walk out the front door is staggering, and not discussed enough in general, I don't think. Just a thought. Seems like what you're driving at is a good idea, but sometimes details affect these things in ways we may not always take into consideration.
