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

[chillier]

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 agree! CA10 is also expressed in the brain of course

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.

I believe there are different mechanisms that can increase and decrease synapse connections over time in an activity dependent manner and they probably operate over different time scales. In this example of learning a skill it might rely more on long term potentiation perhaps.

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.

Yeah that could be right, and I'm thinking that other enduring abnormality could be could be related to synaptic scaling, another mechanism for changing the sensitivity of neurons to maintain homeostatic firing rates in the long run.

A large synapse loss event might be enough to (in a probabilistic way with risk increased perhaps by genetic background and if sleep related brain areas are affected) precipitate out a disease state where neurons become sensitised due to loss of input, enabling them to cause more synapse loss in an activity dependent fashion.

 

[chillier]

I think there is some evidence that CA10 could work in a way consistent with this. Tao 2019 argues that CA10 is secreted from cultured neurons in a way that is dependent on their firing rate (see fig S1). And Montoliu-Gaya 2021 argues that CA10 inhibits the addition of heparin sulfate onto neurexins, thereby inhibiting synapse formation/ stabilisation.

So a little mechanistic model:

1) sudden synapse loss event leads to input loss
2) after about 24 hours (time it takes for scaling to detect the neuron hasn't been firing much - also a PEM timeframe), scaling kicks in and the neuron becomes sensitised.
3) this produces simultaneously the inability to receive important information like a thought whilst also becoming hypersensitive to random stimuli like light and sound.
4) if neurons are also being driven to fire by activity (cognitive or physical) then increased CA10 is released from already sensitised neurons driving further synapse loss
5) synapse loss drives sensitisation after 24 hours leading the cycle to continue

In other words the temporal dynamics of the fluctuations, relapses, and PEM are mediated by two main factors: neurons firing and synapses recovering

 

[neophyte32]

If I understand your hypothesis correctly, the process unfolds as follows :
1 An initial loss or weakening of synaptic input reduces neuronal activity.

2 After approximately 24 hours, neurons compensate by becoming hypersensitive. This hypersensitivity makes normal sensory, cognitive, or physical stimuli overwhelming, while important signals may be processed less efficiently.

3 When these sensitized neurons are activated, they release more CA10. The increase in CA10 levels reduces the modification of neurexins by heparan sulfates, further weakening synapse formation or stability.

4 This additional synaptic loss triggers a new, delayed compensatory response of hypersensitivity.

5 Repeated cycles would progressively lower the activity threshold; this could explain post-exertional malaise (PEM) and in severe cases of ME/CFS why even minimal physical, cognitive, or sensory activity can lead to a major worsening of symptoms.

But why do many severe patients not recover, even when doing nothing ?

 

[marshtacky]

This is an interesting idea, but how quickly can synapses regenerate? I’m thinking of the reports of people having sudden remissions— going from severe to no symptoms, overnight sometimes. Could you physically regenerate 10% of your synapses that quickly and what would trigger it?

Could you have a “functional” loss of 10% or whatever of your synapses that perfectly mimics a physical loss? By functional loss, I mean not because of loss of the physical synaptic structures, but because of down regulation of transcriptional programs that are important for synaptic functioning? (which I think would be a confounding factor for the interpretation of the VMAT2 results, as well as any technique that targets membrane proteins). How could you distinguish between the two scenarios? Would you actually have to visualize the synapses in brain samples from autopsies using microscopy and compare them to control samples?

 

[Jonathan Edwards]

Could you have a “functional” loss of 10% or whatever of your synapses that perfectly mimics a physical loss?

My guess is that in ME/CFS we would not be thinking so much of loss of synapses. All that needs to be invoked is some form of silencing. My other main interest is in synaptic signal integration in the formation of mental images and other sensory phenomena. I think there is now strong evidence indicating that the contribution of a synapse is not just a certain amount of depolarisation of a dendritic tree to add up with others. It looks as if the pattern of synapses firing matters - which implies that synaptic function is dependent on how each synapse is 'tuned' in relation to the others, either by spatial positioning or by modification of the complex spine structure that each synapse has.

Modification/tuning of synapses is likely to occur by adding in or taking away structural proteins. This seems to be what CA10 is involved in. It controls neurexin attachment to synapses. I see the situation as a bit like the options open to the violinist for tuning or muting strings. Turn a little knob at the bridge and the G string tunes up a bit. Slip a mute on the bridge and all strings take on a different sound.

Jaan Aru has suggested that anaesthetics work by interfering with communication between patterns of signals in basal dendrite synapses and patterns in apical dendrite synapses. Such pattern comparisons are implicit in the 'predictive coding' idea of sensation being based on what has changed from what is expected.

Older members will be familiar with tuning a television image by turning the vertical hold knob. A slight shift will make the image break down. With MRI machines engineers can take weeks 'shimming up' the magnetic field pattern by tuning various parameters. My guess is that a neuron will only function usefully if it is well tuned in about 10,000 places. Fever, anaesthetics, alcohol and others things can detune. This would fit with the gradual loss of co-ordinated function in Alzheimer's with neurofibrillary tangles - the structural proteins that keep the synapses in the right relations get disrupted.

 

[marshtacky]

My guess is that in ME/CFS we would not be thinking so much of loss of synapses. All that needs to be invoked is some form of silencing

Yes, I think we’re getting at the same thing here, ie no need to invoke synaptic loss

Modification/tuning of synapses is likely to occur by adding in or taking away structural proteins.

Also an interesting idea— so if I understand you correctly, you’re proposing that in MECFS there could be a failure of synaptic tuning? Do you have any ideas on how you get from the initial immune insult to dysregulation of these tuning processes, but only in a small population?

For that matter, @chillier (or anyone interested in the hypothesis in the original post who wants to answer) how do we get from an initial immune insult like a virus to mass loss of synapses, but only in a small percentage? Or do you propose that everyone undergoes synaptic loss during an illness, but most can recover?

 

[marshtacky]

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.

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

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".

I can second (fourth?) the issues with playing instruments.. I played guitar for half my life before I got sick, and within a few months I could no longer manage even a short song. I couldn’t coordinate my fingers to hit the right notes, I just couldn’t…. Do anything right? And the effort that was required was enormous and left me utterly exhausted. I have the same problem with trying to type more than a few phrases (I’m dictating this right now). I also experienced the paradoxical decline in ability over time.

Sometimes I wonder if some or much of the fatigue is from a) my problems with coordination—both fine and gross motor coordination— requiring more effort to do the same task and b) more speculatively, problems with “coordination” in a different sense, problems with “coordinating” different parts of the brain. Famously music requires lots of cross talk between many many different regions of the brain, and it needs to happen fast. I wonder if the problems with music would point to an issue with those processes, which would probably lead us back to synapses.

 

[voner]

My other main interest is in synaptic signal integration in the formation of mental images and other sensory phenomena. I think there is now strong evidence indicating that the contribution of a synapse is not just a certain amount of depolarisation of a dendritic tree to add up with others. It looks as if the pattern of synapses firing matters - which implies that synaptic function is dependent on how each synapse is 'tuned' in relation to the others, either by spatial positioning or by modification of the complex spine structure that each synapse has.

Interesting and this sounds plausible. I’m curious in the case of mental images what do you think happens in somebody like me who has aphantasia (I have never seen a mental image in my life)? synapse signal loss? blockage? Or is it more mediated in the brain??

I’m not trying to derail the thread here, I’m curious is if this might give us any insights into synaptic signaling. I trust that the moderators will split this off into a different thread if necessary.

Also, How is the pattern of synaptic firing determined?

 

[Kitty]

I wonder if the problems with music would point to an issue with those processes, which would probably lead us back to synapses.

Either that, or music is an important but unacknowledged cause of ME/CFS? I got ill the year punk landed, and even I—with the same natural empathy for stringed instruments that I have for being a prawn—tried to play guitar.

But seriously, there is a poverty and unreliability of connection. I'm just not sure if it's different to what happens when bodies are otherwise engaged battling a virus, or being pregnant, or drunk, or sleep deprived.

 

[Jonathan Edwards]

I’m curious in the case of mental images what do you think happens in somebody like me who has aphantasia (I have never seen a mental image in my life.)? synapse signal loss? blockage?

Have you never had a dream?

 

[marshtacky]

Either that, or that music is an important but unacknowledged cause of ME/CFS? I got ill the year punk landed, and even I—with the same natural empathy for stringed instruments that I have for being a prawn—tried to play guitar.

But seriously, there is a poverty and unreliability of connection. I'm just not sure if it's different to what happens when bodies are otherwise engaged battling a virus, or being pregnant, or drunk, or sleep deprived.

Lol, fair enough!! you could also certainly argue the causation is reversed — actually I’m thinking that might be more plausible —that fatigue causes issues with coordination, timing, etc. Although that also raises some interesting questions . Sometimes we think of fatigue as being purely perception but usually people who are fatigued, such as from being sleep deprived, end up having issues with all of those things. When I was healthy if I played guitar for three hours by the end of the session, I might be making the same kind of mistakes that I now would make after one minute. How is that actually mediated in terms of brain processes?

Funny you mentioned the effect of being drunk— early on in my illness I told people it was literally like I was drunk. I told my roommate it was a good thing that I didn’t drive because if someone pulled me over, I would not pass a field sobriety test. Jokingly, I decided to “ walk the line” and was horrified to discover that I couldn’t take more than three steps without falling over.

(Ps: I meant to comment about this in another thread several weeks ago and I don’t remember what it was, but there was a conversation about potentially looking at the cerebellum and @Jonathan Edwards suggested that there weren’t common symptoms related to cerebellar functioning. I always assumed my problems with coordination were common, but am I wrong with that assumption? Before my symptoms became severe a neurologist diagnosed me with postviral cerebellar ataxia, and assured me it would go away— it didn’t, of course)

 

[Jonathan Edwards]

I’m curious in the case of mental images what do you think happens in somebody like me who has aphantasia (I have never seen a mental image in my life.)? synapse signal loss?

I am actually talking about 'images' in the sense of 'seeing something'. If you can see a tree then for my purposes you have a mental image of a tree.

 

[jnmaciuch]

In other words the temporal dynamics of the fluctuations, relapses, and PEM are mediated by two main factors: neurons firing and synapses recovering

I guess I struggle to see how this mechanism results in a symptom pattern that has substantial overlap between individuals (despite the individual variability in exact symptoms). A large proportion feel malaise akin to an actual infection during PEM. Many get swollen lymph nodes or post-nasal drip. There’s the “poisoned” feeling people talk about. GI issues flaring up.

If those particular symptoms were just central warning signs that happened anytime the body senses something is “off”, then that would make sense. You’d expect those common pathways to be among the most common ones “hit” when there’s a large neurological shake-up. So that fits with fatigue on its own, but not many of the other common symptoms that appear or worsen during PEM. Orthostatic intolerance does make sense with a neurological issue but it’s not really a commonly recognized symptom in stroke, traumatic injury, infections, etc. despite its prevalence in ME/CFS.

That’s part of the reason I’m more inclined towards actual immunological signaling since that’s exactly what you’d expect to see: when people get the same vaccine there’s definitely heterogeneity in the exact side effects an individual may experience, but there are some core common symptoms. But if the driving issue of ME/CFS is a random synapse loss, the resulting symptom profile seems less random than it actually should be.

Plus we’d still need to explain why certain viruses seem more likely to cause this issue than others despite the majority of common viruses (including the ones most associated with ME/CFS) having similarly low brain penetrance and ability to infect neurons/glial cells.

 

[voner]

Have you never had a dream?Neurexin

Yes, I dream and I have mental images when I dream, but outside of dreaming I have never seen a mental image. I can look at a tree, close my eyes and I never see an image of the tree or any tree or an image.

So you are talking about the process of vision when refering to "mental images"?

 

[Kitty]

you could also certainly argue the causation is reversed — actually I’m thinking that might be more plausible —that fatigue causes issues with coordination, timing, etc.

Yes, that's what I was thinking. Overstretched, fatigued, both—the space between the main OS telling you it's time to take a rest from ordinary stuff, and the launch of the backup that responds to stabby-looking types wielding knives.

The difficult bit is why the normal process of getting tired happens so soon after activity commences. Also, I suppose, why the backup spends the next day and a half keeping you primed for rooftop snipers, just because you carried on sitting up for ten minutes too long. After which you're actually attacked by a steamroller.

 

[Jonathan Edwards]

Many get swollen lymph nodes or post-nasal drip.

I agree that this is puzzling. But a thought occurred to me.

I don't think anyone has documented objective lymph node enlargement in ME/CFS. That may reflect medical laziness but it suggests that for most people with ME/CFS lymph nodes may be subjectively tender or uncomfortable but do not increase in size substantially. (Young adults often have a few persistently larger cervical nodes.)

It is still puzzling that lymph nodes should produce symptoms (and nasal mucosa) without some ongoing immunological stimulus.

However, I still remember that during EBV infection my symptoms from nodes and throat varied quite markedly during the day, as did fever. There are two cycles roughly 12 hour recognised (my mother was an EBV virologist.) You are good at two times during the day and bad in between. This presumably is driven by a central hypothalamus dependent mechanism.

So if the hypothalamus can impact 'immunological' symptoms that much over hours maybe it can impact them in PEM. As I get older I am pestered by a variety of peculiar painful problems. My feet are the worst. They become intolerably painful about an hour after going to bed but settle an hour later. When I wake I often have respiratory symptoms with catarrh that are gone after an hour. And since 2019, when my wife and I went to Peru, we have both had virus like symptoms coming and going every couple of weeks for no obvious reason.

The point being that I think we may be closer to the threshold for getting symptoms of this sort than is often recognised and the hypothalamus may be able to shift that threshold significantly. I am not satisfied that this is an adequate explanation but I do think we may need to keep options open.

 

[Jonathan Edwards]

So you are talking about the process of vision when refering to "mental images"?

Yes, in simple terms. To consciously see is to have a sense of a scene, which is an image being presented by some part of the brain to some other part. There are no images out in the world and none in the retina (a common misconception) but we are aware of manifest scenes and those are what i mean by images.

 

[Kitty]

A large proportion feel malaise akin to an actual infection during PEM. Many get swollen lymph nodes or post-nasal drip.

I read in the last few days, somewhere here (or linked from here), a sentence or two about 'immune' symptoms like this being triggered by some problem with sleep. It's driving me nuts that I can't remember where.

What I'd like to know is whether that bit of text actually suggests this could be a normal phenomenon rather than an odd feature of ME/CFS, or whether I just read too much in. Does anyone else remember?

 

[Kitty]

I don't think anyone has documented objective lymph node enlargement in ME/CFS.

I don't know, but the people who worked with me could see the swelling (and the streaming eyes and nose, and rapidly alternating facial flushing and draining), which I have to thank for rarely encountering disbelief. In severe PEM I look like death dug up as well as feeling like it.

 

[Jonathan Edwards]

I don't know, but the people who worked with me could see the swelling

Yes, but as a clinician one comes to recognise swollen nodes and SWOLLEN nodes. The former are within what the immune system is normally seen to do. They occur with colds and flu and EBV and for no obvious reason. Evidence of their presence can come and go. The trick is to distinguish them from the very large, woody or irregular nodes of lymphoma, cancer or TB.