Eccentric medium spiny neuron (eMSN)

[Jonathan Edwards]

It is interesting to me that nobody seems very bothered about the idea that ME/CFS might involve 'dysautonomia' in the sense of failure of regulation within the autonomic nervous system yet once we start talking about the brain some people get a bit emotional. The brain events involved here are very similar to, if not actually part of, the autonomic system in that they are involuntary and probably occurring around the hypothalamus and striatum where autonomic events are co-ordinated.

And if the problem is at the microstructural level of synaptic tuning it is perhaps more likely to be reversible by a treatment than if there is permanent cell death, as in Parkinson's disease or rheumatoid arthritis. We just need to think out of all the old boxes.

 

[N_Dina]

About software malfunction analogy: I do understand Dr Edwards is using it here differently, but this metaphor of “hardware being ok, just software malfunctioning” has been widely used by doctors psychologising ME/CFS and long COVID. In my case a neurologist told me that implying I have “central sensitization” issue and depression after COVID and should be treated with CBT and antidepressants.

 

[duncan]

The brain events involved here

It would be helpful if you would be specific about what you mean about "brain events". Very specific, without invoking analogies.

 

[Jonathan Edwards]

About software malfunction analogy: I do understand Dr Edwards is using it here differently, but this metaphor of “hardware being ok, just software malfunctioning” has been widely used by doctors psychologising ME/CFS and long COVID. In my case a neurologist told me that implying I have “central sensitization” issue and depression after COVID and should be treated with CBT and antidepressants.

Sure, this is the standard narrative.

But in science one cannot afford to be put off by other people's mistakes or motives. It may turn out that Dr Michael Sharpe's study of prolactin responses to buspirone will be a key to understanding the disease.

We may end up saying to the psychiatrists "You very nearly solved this but because of muddle-headed thinking and seriously bad study methodology you screwed up totally."

People with ME/CFS do have central sensitisation in physiologic terms. It is the interpretation put on it that goes wrong.

 

[Jonathan Edwards]

It would be helpful if you would be specific about what you mean about "brain events". Very specific, without invoking analogies.

That's easy. Post synaptic integration of synaptic potentials leading to neuronal firing. That is the only type of event of real interest. For some cells these events are known to us as conscious experiences and in that sense 'mental'. For lots of other cells they are only known to those cells.

 

[V.R.T.]

It is interesting to me that nobody seems very bothered about the idea that ME/CFS might involve 'dysautonomia' in the sense of failure of regulation within the autonomic nervous system yet once we start talking about the brain some people get a bit emotional. The brain events involved here are very similar to, if not actually part of, the autonomic system in that they are involuntary and probably occurring around the hypothalamus and striatum where autonomic events are co-ordinated.

And if the problem is at the microstructural level of synaptic tuning it is perhaps more likely to be reversible by a treatment than if there is permanent cell death, as in Parkinson's disease or rheumatoid arthritis. We just need to think out of all the old boxes.

The idea of an illness involving the brain doesn't make me emotional. I am certain MECFS involves the brain. The idea of an illness that is exclusively contained to the brain and is therefore much harder to devise treatment for than say, an immune brain loop driven by gamma delta t cells, does.

Much of the hope that keeps me going is predicated on the idea that we could figure out what is wrong soon and potentially very quickly thereafter (in scientific terms) find effective treatment.

I know youve said you don't see much of a difference and a brain solution may be just as close/treatable, but I think about how little we know about the brain compared to the immune system and how ineffective and not based in concrete biology the drugs we have for e.g. depression are, and I begin to hear the word 'forever'.

I don't think I am alone in feeling this way.

 

[neophyte32]

It is interesting to me that nobody seems very bothered about the idea that ME/CFS might involve 'dysautonomia' in the sense of failure of regulation within the autonomic nervous system yet once we start talking about the brain some people get a bit emotional. The brain events involved here are very similar to, if not actually part of, the autonomic system in that they are involuntary and probably occurring around the hypothalamus and striatum where autonomic events are co-ordinated.

And if the problem is at the microstructural level of synaptic tuning it is perhaps more likely to be reversible by a treatment than if there is permanent cell death, as in Parkinson's disease or rheumatoid arthritis. We just need to think out of all the old boxes.

I think many find it frightening to realize that research into the brain aspects of ME/CFS is still in its infancy; we are starting almost from scratch.

Daratumumab represented a goal for many severely ill patients who are in excruciating pain every single minute. Now, assuming your intuition is correct, we are heading in a completely different direction—without any guarantee of the outcome—where a handful of researchers will be working on little-known neurons... In short, we know these brain regions are difficult to analyze without funding, and the technology itself may even be inadequate.

And then there is the question of treatment... a new molecule, and so on. I think many people are in despair, Professor. Especially when you consider that 98% of researchers will continue to focus on immunity, autoantibodies, mitochondria...

 

[V.R.T.]

(I also don't think my personal apprehension about the implications of a brain only loop invalidates my point about MECFS SB's bias towards the brain only theory, even if I regret the tone in which I made it. I don't think the idea that there is very possibly an immune element to the MECFS signalling loop is entirely based on feelings or wishes.)

 

[Simon M]

OK, but invoking long term relapse is to me a key part of what makes the PEM concept distinct - and others seem to take that view.

As usual, I'd like to see some data to back that up. We know that PEM is very common, it's why we all pace. But relapses are not, otherwise we would all be severe. When I said like to see some data , I suspect that it's the usual story that there is none, and for something is important to this as this, we need to do more than rely on a consensus view, because that doesn't have a good track record.

My analogies are not intended to be close parallels, just indicators that when it comes to nerve networks all sorts of long er term shifts are recognised even if we have no real understanding of the mechanics.

That still sounds a little like, "then magic happens". Many things are possible. That's why I was asking if there are any examples of things as dramatic as a relapse, with major long-term functional loss happening in other illnesses where the biological mechanism is understood and similar to the ideas being proposed here.

Because of the evidence presented here, we are working on the basis that eccentric medium spiny neurons are important, I'd like to see how that connects to such long-term changes. From what I had understood, the striatum and eMSN play a role in deciding what to pay attention to, which seems different.

In other words, I'd like to see the same level of explanations or attempted explanations applying to relapse as to other aspects of ME/CFS. And simply saying PEM and relapses are the same thing seems too easy.

These are exciting times because we finally have some good data and smart people working on interpreting them. It's also exciting because we have Sequence ME data to look forward to, which should provide a much clearer picture, possibly simply confirmation of things that have been figured out here. And I'd like to see relapses being explicitly included in the work because they're impact is dramatic and life changing

 

[Axel]

If symptoms very similar to those experienced during flu or following a concussion can occur in the absence of any sign of immune system activity, does this not call into question our understanding of what is actually at stake during an infection or an accident?

It may well be, after all, that the known signaling molecules play a secondary role in all cases.

 

[ME/CFS Science Blog]

I'd like to see relapses being explicitly included in the work because they're impact is dramatic and life changing

Can I ask why you would put so much emphasis on relapses?

I know it was a prominent feature in old ME descriptions but not sure if they are an essential aspect of ME/CFS. Is there data showing that relapses are characteristic of ME/CFS compared to other diseases?

 

[N_Dina]

Sure, this is the standard narrative.

But in science one cannot afford to be put off by other people's mistakes or motives. It may turn out that Dr Michael Sharpe's study of prolactin responses to buspirone will be a key to understanding the disease.

We may end up saying to the psychiatrists "You very nearly solved this but because of muddle-headed thinking and seriously bad study methodology you screwed up totally."

People with ME/CFS do have central sensitisation in physiologic terms. It is the interpretation put on it that goes wrong.

As a patient, I am scared that using biopsychosocial lobby vernacular would just feed their beliefs in brain retraining effectiveness and whatever other options of ME treatment they have on their minds. Language does matter in this political issue in my opinion.

 

[Jonathan Edwards]

The idea of an illness involving the brain doesn't make me emotional. I am certain MECFS involves the brain. The idea of an illness that is exclusively contained to the brain and is therefore much harder to devise treatment for than say, an immune brain loop driven by gamma delta t cells, does.

I understand that position. But I am not dismissing a role for T cells and I don't think EM/CFS Science Blog would either. The relevant T cells might be fairly normal though, just with the capability to get a brain loop set up. Taking away the T cells might still abolish the problem. I think whatever model we end up with it will be multilayered.

I think about how little we know about the brain compared to the immune system and how ineffective and not based in concrete biology the drugs we have for e.g. depression are, and I begin to hear the word 'forever'.

And I understand that too. But if a brain loop contributes then it is surely best to find it rather than pretend it isn't possible.

 

[Jonathan Edwards]

As usual, I'd like to see some data to back that up.

This seems to me just an issue of terminology. Members constantly emphasise that PEM can involve a major step down in function long term. How is that different from 'relapse'? I am personally not that much of a fan of the focus on PEM as a term and think long term relapse is much more important but I find it difficult to see what the distinction really is.

 

[Jonathan Edwards]

That's why I was asking if there are any examples of things as dramatic as a relapse, with major long-term functional loss happening in other illnesses where the biological mechanism is understood and similar to the ideas being proposed here.

There are other examples that are known to be brain problems, even if we are not any further forward than ME/XCFS in knowing exactly what is going on. My wife's reaction to malarone is always in my mind. She ended up unable to move or eat, like someone with severe ME/CFS but in a different way.

 

[V.R.T.]

I think it's great we're looking at the brain and I would be the first to dismiss anyone who insisted on an 'immune only' pathology that doesn't affect the brain/CNS,

I'm not saying brain only is impossible. I'm just not sure it's the most logical conclusion from the evidence we have.

if a brain loop contributes then it is surely best to find it rather than pretend it isn't possible.

I wasn't pretending it isn't possible, as you can clearly see from the above quotes.

I understand that position. But I am not dismissing a role for T cells and I don't think EM/CFS Science Blog would either. The relevant T cells might be fairly normal though, just with the capability to get a brain loop set up. Taking away the T cells might still abolish the problem. I think whatever model we end up with it will be multilayered.

Yes that's fair enough. I suppose it is just a rough landing from all the hope of last year to where we seem to be now. Maybe there will still turn out to be an immune aspect that is easy to address. I certaintly think we need some small clinical trials to probe whether there is.

I want to get to the answer, whatever it is. I just worry we're dismissing the immune aspect rather rapidly and prematurely.

 

[Jonathan Edwards]

If symptoms very similar to those experienced during flu or following a concussion can occur in the absence of any sign of immune system activity, does this not call into question our understanding of what is actually at stake during an infection or an accident?

I am not sure. We have known for years that a lot of these feelings are just the way the hypothalamus interprets some cytokine or neural signal inputs. You can produce the feeling of having flu without any immune activation just by injecting a cytokine. In one volunteer cytokine study I think some people were left on life support the response was so bad.

 

[V.R.T.]

The relevant T cells might be fairly normal though, just with the capability to get a brain loop set up. Taking away the T cells might still abolish the problem

Are you thinking here about T cells in the DRG and similar places?

 

[mariovitali]

It is interesting to me that nobody seems very bothered about the idea that ME/CFS might involve 'dysautonomia' in the sense of failure of regulation within the autonomic nervous system yet once we start talking about the brain some people get a bit emotional. The brain events involved here are very similar to, if not actually part of, the autonomic system in that they are involuntary and probably occurring around the hypothalamus and striatum where autonomic events are co-ordinated.

And if the problem is at the microstructural level of synaptic tuning it is perhaps more likely to be reversible by a treatment than if there is permanent cell death, as in Parkinson's disease or rheumatoid arthritis. We just need to think out of all the old boxes.

It is interesting to me that we are looking for a single point of failure in a polygenic disease.

 

[SugarSquared]

As a patient, I am scared that using biopsychosocial lobby vernacular would just feed their beliefs in brain retraining effectiveness and whatever other options of ME treatment they have on their minds. Language does matter in this political issue in my opinion.

It is definitely something worthy of being afraid of, but I don’t think it is something that we can close ourselves off from either.

The current trend is for people to use neuroplasticity. That is a genuine scientific term that has meaning, but they co-opt it to then sell treatment that is entirely run by the patient and is basically CBT and meditation with some extra fluff. These people also love talking about the vagus nerve and lymphatic fluid. I have a hard time hearing about biology without wincing because of how these people misuse it.

The psychosomatic people are going to use whatever biology terms they can get their hands on to sound more legitimate. It doesn’t matter how complex the neurobiology is, they will use it to their own gain. If we focus so much on making sure that the way we talk cannot be corrupted by them, we are giving them too much thought and letting them meddle in our conversations.

We may have something that resembles central sensation or neurons misfiring without any further damage. The difference between what the psychosomatic folk believe and the biomedical truth is how the owner is put on the patient and how they are treated. At the end of the day, no matter how the psychosomatic people spin it, they believe the illness is in our hands and so is treatment. It will be, as you said earlier, CBT, and antidepressants, maybe some physiotherapy too. When we have a better biological understanding, even if it is solely a signalling error, we will have medication that treats this and not be told to work through our emotions. People will be able to recognize that it is not something we fabricated and not something we can get out of ourselves.

Apologies for the long rant. It may seem outsized to what you wrote, but this is just a general feeling that I’ve had building up and not something directed solely at what you said.