ME/CFS as a biological information processing problem

[jnmaciuch]

No, cholinesterase is the one mentioned in all the recipes but Thioflavine T binds in grooves of lots of oligomers as far as I can see. The segments are linear, wiggly and shortish (and there are dots that would do for end on). The staining does not seem to be picking up main nerve trunks but we don't know how the pictures were selected.

Sorry, I’m having a bit of trouble understanding what you mean here. Which oligomers are you suggesting? To me it seems linear only insofar as it is following the boundaries between cells in the extracellular space (plus many dots in the cytosol itself, which would not be nerves)

 

[Jonathan Edwards]

To me it seems linear only insofar as it is following the boundaries between cells in the extracellular space (plus many dots in the cytosol itself, which would not be nerves)

I don't think the linear streaks can be between cells. They wiggle both with and across the matrix as nerves will and stop and start abruptly as they would if segments of nerves. The dots in between muscle fibres would fit fine for narrow nerve endings I think. If there was staining between cells then at certain angles of cut you would get reticular patterns around the matrix (end on) and there isn't any. In some areas the linear streaks are too densely packed to be tiny vessels. I don't see how this can be anything but nerve cells. I have asked around histopathologists and not had any other suggestions.

 

[Jonathan Edwards]

In one micrograph there is what looks like an arteriole with linear wiggles going perpendicular to the wall structure and matrix. As far as I know the only structure that would do anything like tha would be a nerve. Everything else in a vessel wall is flattened in the direction of the wall. If this wiggle was between cells it would have to be in some curious isolated tubular channel between cells going perpendicular - and as far as I know that has to be nerve cells and no such channels exist.

 

[rapidboson]

Does Pregabalin helping makes sense if we think there is some sort of action stimulating neurons when they shouldn’t? So drugs which tamps down the activity or makes it less likely can help with at least part of the problem?

To me it makes sense if we frame my bro-science hypothesis ("strong LTP circuits are more vulnerable to dysfunction in ME than lesser potentiated ones") somewhat like this. Very high-level hypothesis:

I believe strongly LTP synapses release more glutamate per spike compared to lesser potentiated synapses.

1. If some immunological signal causes astrocyte dysfunction/stress, it could lead to failure to remove glutamate from synaptic cleft adequately or excessive glutamate release from astrocytes (gliotransmission).
2. This might cause glutamate spillover to extrasynaptic NMDA receptors or neighboring synapses.
3. Extrasynaptic NMDAR activation may transiently cause tonic depolarization of the neuron and/or cause long-term depression which might transiently cause noise in signal transmission?
4. Once the immunological insult has resolved and astrocytes work properly again, the neural signalling should recover.
5. Potentially, repeated insults (repeated PEM?) would favor LTD (by extrasynaptic NMDAR) of the originally LTP circuit and cause long-term worsening of the condition?

Pregabalin would reduce glutamate release presynaptically, potentially mitigating this transient glutamate spillover.

Another idea: Strongly long-term potentiated neural circuits have a higher metabolic demand. If there is some sort of mitochondrial dysfunction, the mitochondria might not be able to keep up with energy demand of this LTP synapse/circuit. Less potentiated circuit needs less energy, thus dysfunction of the circuit only happens at even lower mitochondrial output.

 

[jnmaciuch]

I am not sure what new information Wust is using to exclude the possibility of nerve fibers in his brief answers to me.

If there was staining between cells then at certain angles of cut you would get reticular patterns around the matrix (end on) and there isn't any.

Does this completely preclude the possibility of free-floating aggregated mtDNA?

 

[chillier]

In one micrograph there is what looks like an arteriole with linear wiggles going perpendicular to the wall structure and matrix. As far as I know the only structure that would do anything like tha would be a nerve. Everything else in a vessel wall is flattened in the direction of the wall. If this wiggle was between cells it would have to be in some curious isolated tubular channel between cells going perpendicular - and as far as I know that has to be nerve cells and no such channels exist.

But why would the number of what they call amyloid deposits and what you think must be nerve cells increase in the day after their exercise challenge.

 

[Jonathan Edwards]

But why would the number of what they call amyloid deposits and what you think must be nerve cells increase in the day after their exercise challenge.

Either way I have absolutely no idea.
But remember that these are muscle biopsies, which are notorious for sampling problems.
I have seen just as puzzling results many times before.

The staining isn't amyloid of any known form so it is rather likely to be a red herring. It might be something unexpected and fascinating. But without knowing what, that is hard to judge.

 

[Jonathan Edwards]

Does this completely preclude the possibility of free-floating aggregated mtDNA?

Yes, absolutely. There is no way that free floating aggregated DNA would produce linear structures perpendicular to matrix and cell layering. In the 1980s I spent many hours sectioning and staining free floating aggregated DNA - when it was known as haematoxyphilic fibrinoid rather than some fancy new name now given by people who never read the German nineteenth century literature!!

 

[jnmaciuch]

Yes, absolutely. There is no way that free floating aggregated DNA would produce linear structures perpendicular to matrix and cell layering. In the 1980s I spent many hours sectioning and staining free floating aggregated DNA - when it was known as haematoxyphilic fibrinoid rather than some fancy new name now given by people who never read the German nineteenth century literature!!

The only thing that wouldn’t make sense to me then is the few points scattered inside the cytosol of muscle cells. Granted it’s only a few points, but some are at the same intensity as the signal in the matrix so I don’t feel like I can completely write them off. Given the lack of specificity of Thioflavin T I think it’s actually very likely that it may be staining multiple different things in those images.

I’m still interested in the question of mtDNA as it would be in line with several other features both in Rob Wust’s paper and more broadly. Though if it is being released during activity and binding to cGAS-STING or NLRP3, this time point might be too late to see it.

 

[EndME]

But why would the number of what they call amyloid deposits and what you think must be nerve cells increase in the day after their exercise challenge.

I think @LarsSG analysis showed quite nicely that there might be no increases following the exercise challenge and that sampling problems might be driving those differences.

 

[JemPD]

I'm scannin the thread for bits i understand, which is currently approx 1 sentence in 500 . However of the bits that did catch my eye, just wanted to chip these in, JIC

For some to me still inconceivable reason, low to medium doses of gabapentinoids (say 75-150 mg pregabalin) do wonders to my cognitive dysfunction most of the times. It feels like the "pressure" in my forehead is somehow relieved and I can start thinking straight again.

Does Pregalbin helping makes sense if we think there is some sort of action stimulating neurons when they shouldn’t?

you likely aware of this but Cognitive inprovment with PRegablin/Gabapentin is entirely contrary to some peoples experiences of it though. MAkes me feel much better bodily, but the brain fog, the congintive suymptoms get much worse for me, 'drunk doesnt even begin to cover it.

 

[JemPD]

Another one of my pet questions.

It's based on experience of doing more activity than I have capacity for, and ending up so wired-but-tired that I can't sleep at all. There's no PEM the next day, and I feel pretty okay by ME/CFS standards. I usually sleep on the second night and wake on day 3 with hard-hitting PEM.

If I did manage to sleep the first night, the PEM would start on day 2.

It's been consistent for half a century, and I've never heard a plausible explanation for why PEM caused by physical activity doesn't begin until I've slept. Not even if I've pushed myself so far over my limit that I don't sleep for four consecutive nights (that happened more than once when I was working ).

This is exactly, exactly my experience, I am sick of attempting to explain it to carers who cannot grasp it. MAssive over exert on monday, looks fine tuesday wed, better than usual even & why were you awake at5am after such a 'tiring' day. then when they expect me to be recovering, they arrive to find me in severe PEM. "isnt it weird" they say.

 

[Kitty]

"isnt it weird" they say.

It IS weird, but it wouldn't be hard to grasp if people just listened.

If sleep were a luxury you could do without, like massages or sunbathing, I'd never do it. It makes me feel so crap that I have to spend time every day recovering from it.

The effect of being awake for one night varies between making no difference at all and giving me a gain in function. Physical function only improves a bit, but the cognitive side really benefits. Sometimes I seem to have 50% more clarity of thought and ability to remember stuff.

It's rare for short term insomnia to make me feel worse, to the extent that I used to wonder why healthy people make such a fuss about it. I got ill so many years ago that I can't remember a time when it made me feel awful in the way that they do.

 

[JemPD]

It IS weird, but it wouldn't be hard to grasp if people just listened.

If sleep were a luxury you could do without, like massages or sunbathing, I'd never do it. It makes me feel so crap that I have to spend time every day recovering from it.

The effect of being awake for one night varies between making no difference at all and giving me a gain in function. Physical function only improves a bit, but the cognitive side really benefits. Sometimes I seem to have 50% more clarity of thought and ability to remember stuff.

It's rare for short term insomnia to make me feel worse, to the extent that I used to wonder why healthy people make such a fuss about it. I got ill so many years ago that I can't remember a time when it made me feel awful in the way that they do.

Yes i can relate to this. Although the gain for me only comes if i also have emotionally induced stress hormone surge like anger or fear/anxiety - which always makes me feel so much sharper.

 

[bobbler]

This is exactly, exactly my experience, I am sick of attempting to explain it to carers who cannot grasp it. MAssive over exert on monday, looks fine tuesday wed, better than usual even & why were you awake at5am after such a 'tiring' day. then when they expect me to be recovering, they arrive to find me in severe PEM. "isnt it weird" they say.

Agree that at least sometimes (I can do it less now as more ill) I thought that pushing thru PEM sort of delayed the boom starting (I was kidding myself I think, and going into that is another long one and certainly the function was more autopilot/not that same deep thinking and could have seemingly complex conversations but would dodge direct questions eg particularly s direct question on what my symptoms do would be impossible to think thru, as would if writing an essay trying to lace/join up thoughts across papers I read, tho I could comment on one individual bit of a paper at a time in a kind of micro fashion, and with mistakes but feeling ok because the moving etc distracted from the pain/body wanting to concertina into a heap feeling, or I’d just not wake up etc)

I relate to your feelin awful and not sleeping and in this situation I want to add in a specific muscle/body pain type I need help with the adjective for - it’s like an extreme form of everything being ‘pinched’ both in the muscle and feeling overall fit all of them but also in the how much I can open/flex anything. I say pinchy because it isn’t burn or sting or stab etc (all of which I get so I can differentiate this other specific one) . An example being pinchy wrists which are common in me to ache round the joint but my hands and on top would now be really pinchy and just my posture of feeling folded and pinchy - anyone else?


This wasn’t the only sensation/pain I suffer at these times (I have a lot of them) but I think it seems to be one a bit more unique that comes in and out on top and is related to threshold and then not getting rest soon enough and yes pinchy is the best my brain can think of for the type/category/style of pain but it downplays how unpleasant it is.

 

[rapidboson]

I'm scannin the thread for bits i understand, which is currently approx 1 sentence in 500 . However of the bits that did catch my eye, just wanted to chip these in, JIC
you likely aware of this but Cognitive inprovment with PRegablin/Gabapentin is entirely contrary to some peoples experiences of it though. MAkes me feel much better bodily, but the brain fog, the congintive suymptoms get much worse for me, 'drunk doesnt even begin to cover it.

That happens with common doses for me as well, they must be small enough to not reach some sort of threshold that makes everything worse for me! Do you have any experience with that? Maybe in your case 25 mg or even less?

I feel like what's often discussed are doses used for neuropathic pain, those are higher than what I'm talking about (plus I'm a 100 kg male, so my doses are generally higher than average).

 

[Jonathan Edwards]

The only thing that wouldn’t make sense to me then is the few points scattered inside the cytosol of muscle cells.

You have to remember that single dots on fluorescence nearly always include a proportion of artifactual signals (binding to dust or aggregates in the reagent). In the two pictures I have on file I don't see any significant signal in muscle cells. In the image without a vessel there are no dots within muscle cells. All the signals are between muscle cells. They are mostly dots but about 10% are short linear segments. That indicates they are almost certainly all sections of linear structures (taking into account the likely section thickness to be ~3micron). In the other picture there are about three dots the look to be inside muscle cells but (a) they look to me a slightly different hue, suggesting maybe artefact and (b) muscle cells can have peripheral invaginations that may not be apparent in terms of the background staining that shows us 'edge' here.

To me the muscle cells are pristine clean of stain.

 

[JemPD]

Do you have any experience with that? Maybe in your case 25 mg or even less?

it started making me feel stoned immediately, even at 25mg for pregabalin, & 100 for gabapentin (which is the smallest dose - gabapentin doses are huge in comparison! 3600 is max daily dose for pain)

 

[rapidboson]

it started making me feel stoned immediately, even at 25mg for pregabalin, & 100 for gabapentin (which is the smallest dose - gabapentin doses are huge in comparison! 3600 is max daily dose for pain)

Hm, I guess I'm either just much less sensitive or we're just too different.
To me there's a massive difference (positively) for brainfog on low doses. As you rightly mentioned, I believe it's an inverted U shaped dose-response curve and higher doses make me feel drunk/high/stoned.
I really wonder if even lower doses, say 5-10 mg would make a difference to more sensitive people.
Following the rule of thumb of 6:1, 100 mg gabapentin would be equivalent to around 17 mg pregabalin, but not sure if it scales well.

 

[Creekside]

Cytokines mostly act locally but there must be systemic signals for fever and malaise.

I was under the impression that circulating cytokines trigger glial cells, which in turn cause "flu-like symptoms".