What would happen if you suddenly lost 10% of all synapses in the body?

[Jonathan Edwards]

My hunch is that if we are talking about synapse events the likely problem is some failure to 'tune-off' synapses that are unhelpful on a daily basis as the brain constantly re-adjusts to shifting environments and learns.

The question would then be why there are crashes. One thought is that retaining suboptimal synatic connections allows the action-decision/exertion accouting area to build networks that are not stable enough. I think in terms of putting out planks across ice to get to the other side and if the overlapping network of planks is not well enough constructed you suddenly find the plank under you levering up half of the network and the ice cracking through. Or constructing a sentence that you cannot finish because it was badly formed at the beginning.

The tuning-off process could still be there available if the system is allowed to settle without new inputs but it would require 'pacing' to ensure crashing did not re-occur.

 

[chillier]

Global randomness is not the same as an even distribution of synapse loss. Randomness produces patches and blotches at every order of magnitude, so I think it could look similar to the case with MS - but much more patchy perhaps.

on the other hand it's true me symptoms aren't generally restricted to one side/part like one eye or one leg

 

[Eleanor]

The example you give about being able to speedily do a crossword in the morning and it become a garbled mess a few hours later could be explained by redundancy of functions of sets of neurons. Imagine for a normal person different neuron sets are being used and tire out and pass the baton to other neuron sets to create a consistent ability to do crosswords all day long. In an ME person you've got some neurons that are up to the task but once they're tire out you're done for until they rest up a bit.

This chimes with something I experience a lot: being able to produce a sentence that's pretty coherent, but if the person I'm talking to didn't catch it and asks me to repeat it, I have real trouble doing that. Like the run of dominoes should have been reset and ready to re-topple but somehow it just isn't.

 

[V.R.T.]

This chimes with something I experience a lot: being able to produce a sentence that's pretty coherent, but if the person I'm talking to didn't catch it and asks me to repeat it, I have real trouble doing that. Like the run of dominoes should have been reset and ready to re-topple but somehow it just isn't.

And when I play the guitar, it isn't just that I get tired quickly or my arms hurt or i feel weird (though thats all true), it's that I am often markedly shitter and less able to play after playing a chord progression for a few minutes than I was at the start. Which isn't the way it's support to work.

When I was milder I would find myself making loads of uncharacteristic mistakes in jams or while recording at a mates house after we'd been playing for a while, when I should have been warmed up and raring to go.

 

[DHagen]

And when I play the guitar, it isn't just that I get tired quickly or my arms hurt or i feel weird (though thats all true), it's that I am often markedly shitter and less able to play after playing a chord progression for a few minutes than I was at the start. Which isn't the way it's support to work.

When I was milder I would find myself making loads of uncharacteristic mistakes in jams or while recording at a mates house after we'd been playing for a while, when I should have been warmed up and raring to go.

Yes! This is extremely familiar, both with specific regard to playing the guitar and to cognitively demanding activity more generally - there is no "warm up" period and practice does not bring improvement, both are detrimental. The best performance occurs at the very beginning, the starting point is the high from which things only deteriorate.

 

[SugarSquared]

Thanks @chillier for starting this thread. It's a really interesting idea. It feels tangible/salient.

I have a classic question: How would you prove this? Hopefully it's the kind of hypothesis you could study

 

[SugarSquared]

I spoke about this idea with my girlfriend, and she raised a rare case of a man found to be missing 90% of his brain. He was unaware of it and was living a normal life. It was only discovered when he weakness in his left leg and got an MRI to find the cause. (Here is a short CBC News article I read and here is the clinical picture published in the Lancet.) Her point for raising this is that the brain can be surprisingly adaptable and that 10% of synapses might not be enough to produce symptoms. I wonder if this brain abnormality was stable for most of this man's life, leading the brain to adapt, while our synapses change too often to adapt. Like, the parts that go missing/stop functioning are changing too frequently and as soon as our brain can try to adapt, a new part goes offline. And since it's not localized and stable, it doesn't resemble the MS symptoms and are instead the vague ones we get.

 

[Peter T]

Her point for raising this is that the brain can be surprisingly adaptable and that 10% of synapses might not be enough to produce symptoms.

The brains of young children are much more plastic, and developmentally it seems that parts of the young brain can take on different functions normally mediated by other parts, however the adult brain is not nearly as adaptable,

 

[ScoutB]

a man found to be missing 90% of his brain.

I do think this kind of example might help guide us. One thing to note to avoid confusion is that 'missing 90% of the brain' might be better stated as 'missing 90% of the volume.' i.e. The brain volume loss in hydrocephalus seems to be due in part to the neurons getting squished together rather than all being destroyed. In this and another case I read about researchers thought that the regular brain structures were intact, just very very physically distorted.

I think it does show that massive structural difference is not necessarily correlated with how disabling a problem in the brain is. The brain is doing all its work on a microscopic/synapse/neuron scale, so it seems natural that something going wrong may only be apparent if you take into account differences at that level.

 

[chillier]

I see your point, though the temporal dynamics are still quite different. What I observe in MS is a series of localized issues with onset correlating with lesion appearance, and which generally tend to stay bad until steroids are administered and a few days pass. If there's been permanent damage then the symptom is pretty constant for a much longer timeframe. The main thing that has ME/CFS-like temporal dynamics in MS is the fatigue/brain fog, which tend to appear in the majority of people with MS regardless of where their specific lesions are. So seems more likely that those specific symptoms have more to do with just the presence of an ongoing immune process somewhere in the brain.

But even so, like MS, MEcfs has generic universal symptoms like fatigue, and a massive array of odd specific symptoms.

The fatigue seems achievable by 'missingness' in the brain anywhere as in MS or stroke.

My biggest relapses have very often come with the emergence of a brand new symptom. My 2012 crash driven by brain fog, 2016 by numbness and twitching in my right hand, 2018 by insomnia, 2021 by GI issues. As time goes on with each dip and crash the older symptoms comeback more and more weakly but a new symptom sweeps in ferociously. I'm curious if others can relate to this.

My point being here that the parts of the brain / circuits affected could be anywhere and also change over time - but still produce the more common symptoms like fatigue.

In mecfs the missingness achieved by synapse loss rather than lesions or stroke, and with randomness of the location.


Also maybe 'location' might have a slightly different meaning in mecfs, more meaning particular networks of interconnected neurons that might span brain regions, rather than a chunk of neurons at this specific xyz coordinate in the head. Mecfs being about synapses rather than lesions I think could leave you with the redundancy of neuron sets that allow for fluctuations like I mentioned before. Even a disease like alzheimers with clear neurodegeneration still features good days and bad days.

 

[chillier]

I have a classic question: How would you prove this? Hopefully it's the kind of hypothesis you could study

Hmmm good question to be honest I'm not sure. I suppose brain scans with radiotracers for synapses could be interesting, but i don't feel like a negative result there would really be conclusive.

Maybe we're best placed trying to find a high penetrance rare variant from sequenceME or elsewhere and modelling it in mice. There we could do all sorts of phenotyping, stimulating neurons in the brain and so on.

There's other stuff in humans I think should be done in general like try and work out if DRG neurons are sensitised. Maybe there's clever physiology stuff that can be done like generating motor evoked potentials with magnetic stimulation to check how those brain circuits are working, but I dont know much about that and we'd need to be clear what specific questions we're asking.

 

[Sean]

Might have missed this in the thread, but how long do neurons take to regrow? Variable, depending on several factors?

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And when I play the guitar, it isn't just that I get tired quickly or my arms hurt or i feel weird (though thats all true), it's that I am often markedly shitter and less able to play after playing a chord progression for a few minutes than I was at the start. Which isn't the way it's support to work.

When I was milder I would find myself making loads of uncharacteristic mistakes in jams or while recording at a mates house after we'd been playing for a while, when I should have been warmed up and raring to go.

Yes! This is extremely familiar, both with specific regard to playing the guitar and to cognitively demanding activity more generally - there is no "warm up" period and practice does not bring improvement, both are detrimental. The best performance occurs at the very beginning, the starting point is the high from which things only deteriorate.

So much this.

One feature for me was that I frequently missed the moment to come in, to hit the entrance, even when I knew the music very well and knew what was coming. Used to drive me up the wall. Only reason it doesn't now is because I stopped playing 30 years ago when it all became too difficult, unrewarding, and depressing.

Some properly targeted music based measures could work well as part of a cognitive-sensory assessment.

 

[Clio]

Wouldn't the brain basically reconnecting itself each day (to explain the extreme variance from okayish to PEM to okayish) burn an insane amount of calories that could be measured?

How expensive is a synapse metabolically? Energy having to come from somewhere is the one rule disease can't break

 

[Kitty]

One feature for me was that I frequently missed the moment to come in, to hit the entrance, even when I knew the music very well and knew what was coming.

I sometimes have gaps where it feels as if I've gone completely offline for a split second, so I miss the beat. I know it's time to put my stuff away at that point because it's only going to get worse. I also have days where I just can't play, my brain's not working fast enough.

I seem to progress at fairly normal speed on learning instruments, though, and I'd say attention deficit probably holds me back at least as much as iffy ME/CFS processing. Being unable to focus on one thing for more than three seconds was a useful skill for a project manager, but it makes playing music with others hard work.

God only knows what my playing face looks like. I suspect "contemplating mass murder".

 

[Jonathan Edwards]

My point being here that the parts of the brain / circuits affected could be anywhere and also change over time - but still produce the more common symptoms like fatigue.

I think this may be a false analogy. In MS, RA, all sorts of conditions in brain or outside brain you get fatigue because the fatigue system is presented with things being wrong. Having blindness on the left side is likely to induce fatigue just because it messes so much with other body functions. In ME/CFS we see 'fatigue' without there being any obvious problem to feed into it. moreover, I think we see a quite different fatigue dynamic, which varies independently of any other problem.

It might of course be that there is a primary problem in ME/CFS somewhere we have not yet pinpointed, like dorsal root ganglion or nucleus caeruleus, with the fatigue system involved secondarily as for other things but my guess is that the odd temporal pattern of ME/CFS is telling us that the problem is in the fatigue system itself.

 

[chillier]

I think this may be a false analogy. In MS, RA, all sorts of conditions in brain or outside brain you get fatigue because the fatigue system is presented with things being wrong. Having blindness on the left side is likely to induce fatigue just because it messes so much with other body functions.

I don't think this conflicts with what I suggested. This just adds that the affected regions mediate the fatigue via a fatigue center that senses something wrong. I'm happy that it could maybe work like that. They could still be anywhere and change over time.

In ME/CFS we see 'fatigue' without there being any obvious problem to feed into it.

It might of course be that there is a primary problem in ME/CFS somewhere we have not yet pinpointed, like dorsal root ganglion or nucleus caeruleus, with the fatigue system involved secondarily...

If it could be a problem with changes in the sensitivity of drg neurons, then why not any myriad of other places or systems in the brain? It could be even more invisible to current assays than checking drg neurons would be i would guess.

Are you sure the fatigue is independent of any other problem? It always comes with loads of other symptoms and these vary.

 

[ScoutB]

I suppose brain scans with radiotracers for synapses could be interesting, but i don't feel like a negative result there would really be conclusive.

We have the one PET study of this suggesting there is synaptic loss in LC, though they haven’t published yet afaik, it’s just an abstract:

[18F]SynVes-T1 VT was reduced across all regions in 10 Long COVID compared to 23 healthy controls (P = 0.003).

A plausible interpretation for the reduction in [18F]SynVesT1 VT is that there is a generalized reduction in presynaptic nerve terminals across PFC and hippocampus, and the striatum in long COVID. Reductions in SV2A binding in brain regions participating in cognition are associated with cognitive decline in most neuropsychiatric illnesses.

On the other hand, it would be good to figure out if synaptic loss is a consequence of another problem. Eg if dopamine isn’t being released when and where it needs to be then maybe plasticity isn’t working properly (as was suggested earlier in this thread) and that’s led to a net loss of synapses.

Very much agree if we can get a mouse model out of sequenceME that seems like it could tell us a lot.

 

[Jonathan Edwards]

If it could be a problem with changes in the sensitivity of drg neurons, then why not any myriad of other places or systems in the brain? It could be even more invisible to current assays than checking drg neurons would be i would guess.

Yes, but we have various pointers to DRG - the old autopsy studies, the fact that they are the portal for most sensory entry and the expression of CA10 there, especially in muscle nociceptors. I admit that this fails to cover sound and light but they may have their versions of DRG in midbrain.

Are you sure the fatigue is independent of any other problem? It always comes with loads of other symptoms and these vary.

I don't think it is independent of other symptoms. As we all know, the term fatigue is very elusive. I am thinking of it as something often overlaid as a 'value' on more specific sensory data.

 

[jnmaciuch]

Even a disease like alzheimers with clear neurodegeneration still features good days and bad days.

It does have good days and bad days, though I’m not sure it can serve as an example here because we are very much in the dark as to what parts of Alzheimer’s are actually due to synapse loss vs. what is due to the poorly characterized process driving any structural neurodegeneration. For all we know the mechanism causing good-day-bad-day fluctuations is the same as in ME/CFS, and neither might have much to do with synapse connectivity. MS also has that ambiguity but at least with very focalized lesions you can draw a connection between clear obvious structural damage in one part of the brain and the appearance of specific symptoms.

The other thing to think about here is if we know that repetition actually builds and strengthens synaptic connections for things like manual skills, why this doesn’t seem to be the trick in ME/CFS. A family friend had a stroke and lost the ability to play tennis. Over time, and especially with repetition/practice, he regained his serve. In order for this to be a driving mechanism of ME/CFS, you need some way to explain why repeatedly doing a task doesnt make things easier in ME/CFS in a way that it clearly does when someone regains a skill after a stroke.

It only works as a chronic disease mechanism if initial synaptic loss drives further synaptic loss somehow, but we do have examples where that doesn’t seem to happen. So it can’t be synaptic loss alone, it would have to be synaptic loss plus some other enduring abnormality.

 

[duncan]

The other thing to think about here is if we know that repetition actually builds and strengthens synaptic connections for things like manual skills, why this doesn’t seem to be the trick in ME/CFS. A family friend had a stroke and lost the ability to play tennis. Over time, and especially with repetition/practice, he regained his serve. In order for this to be a driving mechanism of ME/CFS, you need some way to explain why repeatedly doing a task doesnt make things easier in ME/CFS in a way that it clearly does when someone regains a skill after a stroke.

It only works as a chronic disease mechanism if initial synaptic loss drives further synaptic loss somehow, but we do have examples where that doesn’t seem to happen. So it can’t be synaptic loss alone, it would have to be synaptic loss plus some other enduring abnormality.

Persistence.