Brain cells

[Jonathan Edwards]

In the context of the recent interest in eccentric medium spiny neurons I thought it might be interesting to have a general thread on brain cells, as a background to working out what they might be doing in ME/CFS.

The way the genetic data are pointing to particular brain regions and cells is fascinating and I am sure worth pursuing. However, brain cell networks are hideously complicated and it may be wise to step back regularly to consider the bigger picture.

Involvement of brain cells also worries some members who fear that things might get sucked in to psychology. I don't think there is any need for that worry but it may be worth airing some thoughts around it. The mind/body interaction model is garbage, but the reasons why may again be complicated.

I am minded to make two posts, one about each issue, as soon as I can get to them. The first is a simple one about connections.

 

[Jonathan Edwards]

It struck me, looking at the links between genes and eccentric MSN cells, that we have to remember that everything a brain cell does is in the context of interaction with other cells. Each cell has two interaction compartments - dendrite input and axon output. (There are exceptions and variations but this is the usual.) So genes in cell M may be used to build input receptors to take messages from cells a,b,c,d and e or they may be used to produce transmitter machinery to send messages to ells r,s,t and u. Cells tend to be classified by their output transmitters, I think, but their input transmitters may be quite different.

Things are complicated because on average a brain cell has input synapses from about 10,000 ther cells and has axon branches going to about 10,000 other cells. A lot of the 10,000 in each case may be cells fairly close together in one functional module but a minority are likely to go, maybe as feedback, to a wide range of areas. Single mouse claustrum cells have axons that have branches going to every part of the cortex, if I remember Christof Koch's paper correctly.

And although neurobiologists tend to think of functions occurring in small brain areas - nuclei or gyri specialised for faces, colour, memory of place etc., in a way the function always involves a connection across brain, even if we just consider the axon domain (which in man could be a litre of brain for one pico- or femto-litre cell body).

I don't think this makes things impossible, although it may partly explain why even now nobody knows where the initial problem is in Parkinson's that leads to cell drop out in substantia nigra.

The one thing that does belong to the individual cell is its computation - what decision it makes, if you like. That computation is electrical and so genes may not be so relevant. The big problem for neuroscience is that we have no way of modelling these computations well enough to make any useful predictions.

If a cell seems to be doing something relevant to an illness - like prohibiting movement actions giving a sense of weakness or fatigue - then that presumably relates to its computing and so seems a useful clue. On the other hand the same function would not seem to help explain nausea or painfulness of light and sound. But we are not expecting the story to be easy I don't think. Moreover, my gut feeling is that if something is going wrong with brain cells it will involve more than one lot of cells getting into a confusion. I don't think we are expecting just loss of one cell type - which seems to be the easy explanation for narcolepsy. I think a brain aspect of ME/CFS is likely to involve potentially entirely reversible cross-talk between several cell types.

 

[hotblack]

Nothing useful to add atm other than to say something like fluctuating crosstalk within specific neural cell groups subjectively feels like a lot better explanation for a lot of my experiences than other theories. Not to say this is the whole explanation of course. More a few different loops in different places interacting in different ways depending upon genetic predisposition and random chance.

 

[Utsikt]

Which methods are currently available to measure what’s going on in the brain? It would be useful to know to be able to determine if a hypothesis is testable or not.

I know we can image various aspects, but those seem very high level and I’m not sure it would be easy to make any sense of them in terms of pathology.

The exception might be tracer studies where we can get a feel for how one particular thing varies between people with ME/CFS and others.

Can we measure some of the chemicals inside the brain without invasive methods? Maybe by proxy through metabolites.

And how can we measure the input/output to/from the brain? Would we have to look at nerves in the rest of body? I’m assuming there are also other ways to get signals into the brain through chemicals.

 

[Jonathan Edwards]

Which methods are currently available to measure what’s going on in the brain?

At a cellular level, I am not sure. Google tells me that UCL is a 'powerhouse' for neuroscience technology so presumably there are great people to talk to down the road. The only problem is that I can't make sense of half the stuff they have on their websites. James may know more.

I think the way forward is a bit hard to decipher at present but with enough people thinking about it, who knows where we might get to?

 

[mariovitali]

I wonder if synapses are simply downstream symptom amplifiers of impaired vesicle and ER-golgi trafficking :

https://pmc.ncbi.nlm.nih.gov/articles/PMC12183288/

 

[Utsikt]

I wonder if synapses are simply downstream symptom amplifiers of impaired vesicle and ER-golgi trafficking :

https://pmc.ncbi.nlm.nih.gov/articles/PMC12183288/

The abstract talks about neurodegeneration and impaired neurodeveloment, which I don’t think we have observed in ME/CFS yet.

Do they mention other potential effects that might fit ME/CFS?

 

[duncan]

What does Syphilis do to brain cells universally? As opposed to what can it do to brain cells. For instance, tertiary vs secondary syphilis.

Maybe looking hard at a fairly known brain infection might be a decent starting point.

It needn't be an infection. Brain cancer might approximate some severe ME/CFS cases.

Or parasite instances. Or mold or fungus..

Or countless viral.

What do they have in common other than brain physical trauma - that might not readily reveal that trauma?

 

[mariovitali]

The abstract talks about neurodegeneration and impaired neurodeveloment, which I don’t think we have observed in ME/CFS yet.

Do they mention other potential effects that might fit ME/CFS?

Good question. I wanted to show that there is a direct association with synapse function and vesicle trafficking and ER-Golgi trafficking (which DecodeME genes identified )

 

[Jonathan Edwards]

I wonder if synapses are simply downstream symptom amplifiers of impaired vesicle and ER-golgi trafficking :

I think the relevance of synapse-related genes is simply that it points us to neurons, maybe of certain types. No need to be more specific than that. But, like Utsikt, I don't see evidence of impairment of vesicle traffic in what we know about ME/CFS. That review seems to be a promotional Frontiers article by vesicle traffic workers. The abstract is pretty vague so I haven't delved further.

 

[Jonathan Edwards]

What do they have in common other than brain physical trauma - that might not readily reveal that trauma?

They kill cells, generally, and you can see dead cells on pathology. We don't see that in ME/CFS. And each infection tends to kill different sorts of cells in different areas in domains of different shapes and sizes. So I don't see anything common to infections likely to be of any help in ME/CFS. If anything the message seems to be that ME/CFS sn't like a brain infection.

 

[Jonathan Edwards]

I wanted to show that there is a direct association with synapse function and vesicle trafficking and ER-Golgi trafficking (which DecodeME genes identified )

I agree that that is a useful link to make. Synapse-related genes point us to brain cells. Vesicle traffic genes may get ignored because they may not point us to any particular cell. But they are also consistent with pointing to a neural signalling problem. A gene variant might 'impair' vesicle traffic in a way that amplified a synaptic signalling problem? But presumably not enough to be noticeable before illness struck. I am not sure what process that would impair transport further would provide a way of explaining illness onset.

 

[mariovitali]

I think the relevance of synapse-related genes is simply that it points us to neurons, maybe of certain types. No need to be more specific than that. But, like Utsikt, I don't see evidence of impairment of vesicle traffic in what we know about ME/CFS. That review seems to be a promotional Frontiers article by vesicle traffic workers. The abstract is pretty vague so I haven't delved further.

Agreed, we do not have direct evidence but we do have convergent evidence given DecodeME and work by Hanson et. al on extracellular vesicles after exertion.

Perhaps my impression is incorrect but if it is suggested that neurons are responsible for all the various symptoms of ME/CFS, I think that this is a far more stretched hypothesis let alone talking about existing evidence.

 

[Jonathan Edwards]

Agreed, we do not have direct evidence but we do have convergent evidence given DecodeME and work by Hanson et. al on extracellular vesicles after exertion.

I am not sure that content of vesicles in blood (assuming that is what the Hanson paper is about) would have anything to do with intracellular traffic? I don't know enough about the biology of these things but I worry that vesicles are just trendy at the moment.

if it is suggested that neurons are responsible for all the various symptoms of ME/CFS, I think that this is a far more stretched hypothesis let alone talking about existing evidence.

I don't see it that way. Pretty much all symptoms are brain mediated in the end. In ME/CFS we have a serious shortage of evidence of any antecedent causes in other tissues. All we really have is the link to infections suggesting hidden antecedent immune pathways are operating.
Several ME/CFS symptoms seem to arise directly in brain - brain fog and light sensitivity. Those of us who wrote a review on theory options in 2016 in Fatigue and Biomedicine came up with brain and immune system as the most likely contenders before any genes came up. My experience with working out disease pathways is that it is all about finding the one hypothesis that survives all the negative data. It is the existing negative evidence that is so powerful. Apart from anything systems other than brain and immune do not seem to have sufficiently complex regulation over long periods to explain the long term dynamics of ME/CFS, which can go up and down unpredictably over weeks, months or years.

 

[mariovitali]

I am not sure that content of vesicles in blood (assuming that is what the Hanson paper is about) would have anything to do with intracellular traffic? I don't know enough about the biology of these things but I worry that vesicles are just trendy at the moment.

I think it would be better to say that if one does not know enough about these concepts , they should not dismiss them so easily

I don't see it that way. Pretty much all symptoms are brain mediated in the end. In ME/CFS we have a serious shortage of evidence of any antecedent causes in other tissues.

"Pretty much all symptoms are brain mediated in the end". This is a statement that requires validation from the scientific community. If there is convergence from scientists on this one then we agree. Do we have convergence?

All we really have is the link to infections suggesting hidden antecedent immune pathways are operating.

I do not believe that ME/CFS is strictly initiated by infections, we have evidence for this : https://me-pedia.org/wiki/Organophosphate

Several ME/CFS symptoms seem to arise directly in brain - brain fog and light sensitivity.

Regarding light sensitivity. I have a number of patients ( I myself is one of them) who's light sensitivity was significantly minimised when they took TUDCA . Do you believe that this should be further investigated?

Those of us who wrote a review on theory options in 2016 in Fatigue and Biomedicine came up with brain and immune system as the most likely contenders before any genes came up. My experience with working out disease pathways is that it is all about finding the one hypothesis that survives all the negative data. It is the existing negative evidence that is so powerful. Apart from anything systems other than brain and immune do not seem to have sufficiently complex regulation over long periods to explain the long term dynamics of ME/CFS, which can go up and down unpredictably over weeks, months or years.

So, you are effectively leaving out metabolism in your 2016 theory. Isn't this quite a big part of human body function? Do we know everything about immunometabolic interactions, enough to leave metabolism out of the picture ?

Let's assume that eccentric medium spiny neurons are a key aspect of ME/CFS. My question is : what can we do about them, for example are we looking to increase or decrease glutamate metabolism in the brain ? Do we know what to do with eMSNs and the fact that they were found to be important ?

 

[SNT Gatchaman]

I think the relevance of synapse-related genes is simply that it points us to neurons, maybe of certain types.

Not exclusively. They could equally be pointing us to immune cells.

Eg Systems-level transcriptomic analysis reveals synapse-related gene dysregulation in peripheral leukocytes of MDD patients (2026) —

we investigated whether peripheral leukocytes exhibit transcriptional changes in genes annotated to synaptic processes, molecular functions typically associated with neurons but also possibly implicated in immune cell biology. A meta-analysis of transcriptomic data from 3072 individuals identified […] 73 whose known functions are linked to synaptic biology. Among them, functional enrichment analysis indicated synapse-related metaDEGs (48 downregulated, 25 upregulated) involved in synaptic vesicle cycling, neurotransmitter signaling, synaptic assembly, and neurogenesis. Linear discriminant analysis (LDA) identified 18 of these genes that robustly distinguished MDD patients from healthy controls across independent datasets. Notably, we identified metaDEGs shared between leukocytes and brain regions associated with MDD, indicating that genes traditionally linked to neuronal pathways are also expressed in immune cells

 

[Jonathan Edwards]

I think it would be better to say that if one does not know enough about these concepts , they should not dismiss them so easily

Nobody is dismissing anything @mariovitali. I am just focusing on the leads we do have.
And over the years I have found that reviews of trendy topics are usually blind alleys - statistically speaking.

I do not believe that ME/CFS is strictly initiated by infections, we have evidence for this : https://me-pedia.org/wiki/Organophosphate

Sure, but I was not saying that immune responses must be involved - that was a concession awayf rom just brain. And we are learning that immune cells respond to a lot of 'danger chemicals' beyond microorganisms.

Regarding light sensitivity. I have a number of patients ( I myself is one of them) who's light sensitivity was significantly minimised when they took TUDCA . Do you believe that this should be further investigated?

Possibly but there are all sorts of stores about what people think makes them better, including mindfulness and standing on bits of paper.

So, you are effectively leaving out metabolism in your 2016 theory. Isn't this quite a big part of human body function?

I don't understand that suggestion. Whatever cells are involved we can call whatever is going wrong metabolic in a local sense. So, no, no way am I leaving out metabolism. We did not have a 2016 theory. We were suggesting that it was reasonable to focus on areas where regulation is very complex over time. So something like loss of pancreatic islet cells wouldn't be a very likely explanation. We were focusing at a higher regulatory level and identifying systems that might fit that. Whatever the problems were in those systems would produce metabolic shifts - maybe in B cells or brains cells or macrophages, but we wouldn't expect generalised metabolic shifts to tell us much.

My question is : what can we do about them, for example are we looking to increase or decrease glutamate metabolism in the brain ?

I don't think we have any idea what to do yet. I don't think it will be a simple question of something being down so treating it by putting it back up a bit. My experience with RA is that you have to build a way more complicated model. But it might turn out that shifting one of the neurotransmitters might allow baance to be restored. I think the chances are much better than for something like Parkinson's or narcolepsy where there seems to be irreversible cell loss.

 

[Jonathan Edwards]

Not exclusively. They could equally be pointing us to immune cells.

I don't think we are expecting all synapse-related genes to be only involved in synapses. The collation of data that forestglip and ME/CFSSB have been doing has become interesting because so many pointers converge not just on synapses but on local brain areas.

My guess is that if genes are expressed in several cell types then they don't really 'point' usefully.

 

[neophyte32]

Nobody is dismissing anything @mariovitali. I am just focusing on the leads we do have.
And over the years I have found that reviews of trendy topics are usually blind alleys - statistically speaking.


Sure, but I was not saying that immune responses must be involved - that was a concession awayf rom just brain. And we are learning that immune cells respond to a lot of 'danger chemicals' beyond microorganisms.


Possibly but there are all sorts of stores about what people think makes them better, including mindfulness and standing on bits of paper.



I don't understand that suggestion. Whatever cells are involved we can call whatever is going wrong metabolic in a local sense. So, no, no way am I leaving out metabolism. We did not have a 2016 theory. We were suggesting that it was reasonable to focus on areas where regulation is very complex over time. So something like loss of pancreatic islet cells wouldn't be a very likely explanation. We were focusing at a higher regulatory level and identifying systems that might fit that. Whatever the problems were in those systems would produce metabolic shifts - maybe in B cells or brains cells or macrophages, but we wouldn't expect generalised metabolic shifts to tell us much.



I don't think we have any idea what to do yet. I don't think it will be a simple question of something being down so treating it by putting it back up a bit. My experience with RA is that you have to build a way more complicated model. But it might turn out that shifting one of the neurotransmitters might allow baance to be restored. I think the chances are much better than for something like Parkinson's or narcolepsy where there seems to be irreversible cell loss.

But are we sure that there is no cell loss in severe/very severe cases?

 

[Timko]

I am following the discussion with great enthusiasm. One big question that comes to my layman’s mind is: if everything points to the brain, how could this explain symptoms like tender lymph nodes or post-nasal drip? For other symptoms like PEM, fatigue, or myalgia, I can make the connection. Or am I thinking in too symplistic terms?