Fair, but ascribing channelopathies to neurology seems almost capricious. How did they pull that off? Some PP researchers like Tawil did have genetic references - as we also do now. If those researchers can stake a claim, maybe we should be doing the same.
Brain cells
- Thread starter Jonathan Edwards
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Yes, I was referring only to the negative symptoms: lack of concentration and a somewhat simplified intellectual life. But one may argue, as a neurologist once told me, that these symptoms are nonspecific and could be present in any pathology of the brain.
Jonathan Edwards
Senior Member (Voting Rights)
I thought the genetic findings for channelopathies were directly linkable to the ion channel defects. We don't have anything quite like that for ME/CFS.
Some, but only some. ETA: And how did they shoehorn that into neurology?
We have more than what we did before DecodeME.
Utsikt
Senior Member (Voting Rights)
«Symptoms» are subjective, so they have to involve the brain because that’s where the me(s) that perceives is located. If it’s objectively measurable it’s called a sign.
It hasn’t been done more extensively for ME/CFS because it’s very expensive and requires investments over many years. I hope DecodeME and SequenceME will be the thing that gives people the push to get brainbanks set up. Perhaps the Germans could do it with their decade of funding.
neophyte32
Senior Member (Voting Rights)
Wasn't it in the Netherlands that 10 brains were autopsied? Weren't there supposed to be more?
Actually, it seems to me that it's a priority. Autopsies of the brains of severely ill MECFS patients. Doing 50 to 100 seems essential.
The Germans are rushing towards autoimmunity research, the Americans with Polybio are receiving a lot of funding for viral persistence when they should be focusing on neuroscience and SequencEM.
We have Fluge and Mella who are already doing excellent work on Daratumumab. But Carmen Scheibenbogen doesn't seem to want to change her strategy...
This is great analogy. I have a similar one. I think of ME/CFS like a car’s “limp mode” program. When relevant sensors are activated, indicating a certain category of problem, limp mode turns on. The car will still run and drive, but horsepower, speed, features are greatly limited to protect the car from damage like the engine overheating. So, it’s a rough cost/benefit compromise intended to get you home slowly, while protecting the vehicle from further damage.
In some cases, limp mode activates for some minor reason, like a bad sensor or broken wire, and the car would have actually been safe to drive at full speed. I think we are stuck in limp mode, likely due to an obscure, undiscovered, signal.
Utsikt
Senior Member (Voting Rights)
I don’t know how many they planned for originally.
I agree it would be very useful to have more autopsies, preferably of all severities.
ScoutB
Senior Member (Voting Rights)
They plan to do more (I think I remember mention of 50?). The issue is their throughput is pretty low so they were planning to do this over the span of like 10 years or something. I wonder if all the interest in their results might encourage extra resources being spent to speed things up...
neophyte32
Senior Member (Voting Rights)
10 years !!! My god... Leaving patients in critical condition for years is criminal, especially since research can progress so quickly with MECFS. Imagine if the disease were potentially reversible? All that wasted time.
Jonathan Edwards
Senior Member (Voting Rights)
Yes, I think we need those numbers. And it would be good to see the results sooner than eems to be scheduled at present.
Hoopoe
Senior Member (Voting Rights)
I would like to know what role eccentric medium spiny neurons play a role in recovery from exertion, restorative sleep, and things like that.
I don't know much about the brain and would like to satisfy my curiosity. How would you go about checking whether there is a connection like this?
I don't know much about the brain and would like to satisfy my curiosity. How would you go about checking whether there is a connection like this?
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ScoutB
Senior Member (Voting Rights)
I happened to be looking at this study, Cerebellar Excitability Regulates Physical Fatigue Perception, which says:
The claim seems to be: if you repeat a motor task a bunch, the internal feeling of it getting harder and harder might be in part do to the cerebellum sending an inhibitory signal to the rest of the brain. (I've only skimmed their paper so far though.)
I've been reading about the cerebellum since it came up in @paolo's analysis as the brain region with the smallest p-value. This is kind of surprising because the cerebellum is weird: it's small, relatively isolated from the rest of the brain and traditionally thought of as basically a calculator for precise physical movements. It contains half our neurons in its small volume, these neurons are arranged in a very regular way, and have a unique operation:
wikipedia said:
Everything is being compared to AI these days but the analogy might actually be somewhat reasonable here:
(supervised learning = where an algorithm learns to map input data to a specific output based on example input-output pairs.)
Anyway, now I'm wondering if the cerebellum could be providing computational services/fine-tuning other internal processes that are just less obvious from the outside than movement, i.e. autonomic, immune responses, or deciding the internal perceptions that are provided to the 'diver' of the car? (Just spit-balling because it's interesting to think about. Don't know if this is even a reasonable idea.)
Another study in rats claims that lesioning part of the cerebellum lead to immune changes: Cerebellar interposed nucleus lesions suppress lymphocyte function in rats. Again, I have only skimmed, and an obvious first question is: is this unique to the cerebellum or would you expect this kind of thing from any brain lesion?
This post is getting way too long so I'll stop there, but I find this kind of fascinating
Eddie
Senior Member (Voting Rights)
But what is the rational for separating thinking out from everything else. Thinking is mental but so is seeing and feeing and pain and everything else that exists. It is fair to say that thinking has different causal factors at play. But psychiatry often claims to know that casual factors are certain types of other experiences in the mind. I think it is reasonable to assume that brain fog has the same cause as the other symptoms in ME/CFS so why say that is mental but not fatigue or pain when those too are mental experiences?
A brain is a collection of experiences that exists within our mind. We assume that those experience refer to a collection of indivisible units that we call matter in that there must be some casual connection between it and the idea. Whether we go down the route that matter exists in our minds or as its own experience, the distinction between mind and non mind isn't experience and not experience. It is a matter of categorization types of experiences by the ways in which they impact on us.
Psychiatry seems to have decided that certain diseases are caused by the experience of certain neurons or minds like ours and not the experiences of those things that are matter. It seems clear to me how matter could cause changes in the mind as the structure of the matter is required for the existence of the mind. But I am not sure what it means for a disease to be caused by the mind. Clearly the experiences of neurons can impact on the experiences of other neurons. But since matter is also required, matter and mind seem too intertwined to separate out causes in the way psychiatry tires to do. It is not clear to me how it would be possible to determine that the cause of some experience was the mind alone or even what that really means.
The other problem with psychiatry is the idea of blame. Since psychiatric disease exists in some ill defined category of mind, it is easy to say that one has some level of control or choice in regards to their disease. If you are the conscious agent in control over your mind, then it is easy to say you must have some responsibility (even if there are many other minds to blame too). But even if we could separate out the cause as being mind, I still don't agree that there is any meaningful choice. While I am prepared to concede that there are choices presented to an individual, one must "choose" what they desire and what they desire is not a choice. A Choice requires a motivation, as otherwise there need not be a choice. And I think that desire in the broadest sense is the only real motivation that exists.
Jonathan Edwards
Senior Member (Voting Rights)
I agree, hence the scare quotes. It is all a terrible muddle, as you know. The main need is to find a way of talking about it all that does not give people the heebie-jeebies (or have them sent to people who don't understand evidence)
I think I disagree, technically. Our brains represent brains in our minds in our experiences. As you say, to make any sense of life we have to assume that something other than the experience at the time is being represented. Matter is passé. We should have an experience-centred event ontology, I agree, but this is getting off topic I think. Rarefaction, maybe?
Well, if 'mind', like 'matter' and 'me' and 'knowledge' and 'the truth' (rather than truth) are bogus concepts in the first place, as they are, then hardly surprising we don't know what it means.
The BPS idea of mind-matter interaction is so metaphysically naive it is a complete joke, as I think you are saying. So, yes.
Ravn
Senior Member (Voting Rights)
Let’s say we’re looking for a mechanism no one has thought about yet and one that involves some very poorly understood cell types like the ones that recently popped up on our radar, e.g. eMSN or splatter neurons
How can we get a clearer picture? Who might already have relevant info? What sort of additional research would be most informative? Who could do it? Etc
Eddie
Senior Member (Voting Rights)
I'm trying to sort out my own muddle, relating concepts to happenings in the brains isn't easy but it is interesting.
I think we agree on what "things" are, just not my most precise wording. I might have a different perspective on which neuron "your" experience relates to at different times but that's a side point.
Tying this back to ME/CFS, for the 98% of the brain that you wouldn't classify as mind, how are those computations being done? Presumably they are also being done by neurons. Is it still occurring as a wave in the neuronal membrane just with fewer relations to other inputs? Or are there other ways of performing computation within a neuron? If we know possible ways in which the computations get disrupted maybe there is some way to find a molecule that can be used as a imaging tracer.
Jonathan Edwards
Senior Member (Voting Rights)
I think we keep talking about it here and I think quite likely if there are scientists with bright suggestions to add they will get to hear. In the past I would talk to colleagues I see during weekly meetings but sadly weekly meetings don't occur much in medical faculties in the UK now - certainly not at UCL. It is quite spooky. We have some medical problems at home but once they are sorted I hope to contact other people as soon as I can.
I think we might get input from all sorts of directions - UCL has a huge neuroscience network = but at the moment I am a bit baffled as to what is likely to be most productive.
Jonathan Edwards
Senior Member (Voting Rights)
All brain computations occur in individual neurons separately but large banks of neurons are sent signals encoding the same scenario and the 'answer' will depend on which cells fire first. Nobody has good data on how these computations work in vivo. Most neurons, at whatever stage, can take in about 100 signals at various synapses out of a total input capacity of maybe 10,000 synapses before they fire.
Nobody knows what determines firing. For decades there was a default theory that signals just add up until they hit a threashold ("integrate and fire") but nobody ever thought this was the right answer and since 2010 there has been evidence that it is not. Koch and Segev showed that a giant locust neuron that recognises a predator coming nearer, computes with a math more like multilication than addition. Newer stuff from Aru and others suggests that some cells have two input domains and firing depends on how well the patterns of inputs in the two domains match - which mathematically is subtraction.
There probably is no wave in the membrane. Dendritic integration f electrical potentials is quite different from the Hodgkin Huxley travelling wave in the axon. Completely different dynamics.
The only real handle we have at present is that we know which transmitters different cells use and that some of these are excitatory and some inhibitory of membrane depolarisation, over various time scales. That means that if we are dealing with cells using complex pattern subtraction we don't have ways of predicting how specific rogue loops could form, butit may mean that we can make more general predictions sufficient to point to a treatment avenue.