UK Research Collaborative Conference in Newcastle: 13th - 14th October

[SOC]

But there seems to be more money flowing from American wealth into the hands of researchers. Again I could be wrong.

I'd say that's about right. The US is funding the vast majority of the non-BPS ME research, mostly through US philanthropy, but also a bit of government funding as well. The US is even funding the UK's biobank, IIRC, not the UK government or UK philanthropists. My tax dollars at work.

 

[Woolie]

Mark Edwards' idea of predictive coding (as described in his hysteria paper) is very much in line with Wessley/White thinking. There is a precipitating factor e.g your leg gets hurt. Your brain comes to expect pain in your leg and predicts that there is pain. When there is no longer pain, there is discordance between what is expected and what is happening. The brain doesn't like this and so, rather than adjust the expectation from 'there is pain' to 'there is no pain', somehow the brain registers pain. This creates concordance.

The person then assumes that they have a physical illness causing the pain and this strengthens the expectation of pain (and therefore the perception of pain). He claims that that there is evidence that people with poor learning styles (ie leaping to conclusions) are more prone to this type of problem happening.

He has hypothesised that CFS works by the same mechanism; a precipitating illness (eg a viral infection) leads the brain to expect to feel fatigue, muscle pain and more. When the illness is over, there is concordance gain if these illness sensation continue to be registered.

My post explaining the M. Edwards' idea was unnecessary: I just read through all the previous posts and @Hutan already had it exactly right. Where do all you guys get off on being more perceptive than the actual neuroscientists that work in this field?

But just for fun, to reveal the true idea behind Edwards' words, try substituting "person" or "mind" for "brain", and see how that reads. Brains are physical entities, they contain neurons capable to transmitting signals. Those neuron can fire in certain patterns, and can modify their interconnections through their activity. But its the person (or if you like, our mind) that does the expecting, the experiencing of pain and the adjusting of movement plans. These are mental processes, not brain functions. The brain is just the physical substrate.

How does it sound now?

Mark Edwards' idea of predictive coding (as described in his hysteria paper) is very much in line with Wessley/White thinking. There is a precipitating factor e.g your leg gets hurt. You come to expect pain in your leg and you predict that there is pain. When there is no longer pain, there is discordance between what is expected and what is happening. You don't like this and so, rather than adjust the expectation from 'there is pain' to 'there is no pain', somehow you register pain. This creates concordance.

The person then assumes that they have a physical illness causing the pain and this strengthens the expectation of pain (and therefore the perception of pain). He claims that that there is evidence that people with poor learning styles (ie leaping to conclusions) are more prone to this type of problem happening.

He has hypothesised that CFS works by the same mechanism; a precipitating illness (eg a viral infection) leads you to expect to feel fatigue, muscle pain and more. When the illness is over, there is concordance gain if these illness sensation continue to be registered.

Isn't that a great technique for cutting through the neuro-BS?

(Okay, I get that making "the brain" responsible allows for the possibility that some of this stuff is unconscious. But why not just say "this could occur outside of the person's awareness"?)

 

[SOC]

But why not just say "this could occur outside of the person's awareness"?)

Because they've gotten so deeply into obfuscating what they really mean that they can't even say the simplest things in a straight-forward manner. It's all about deliberately confusing people about what they're doing through lies and deceit -- which sounds like a serious personality problem to me.

 

[Woolie]

Mark Edwards hypothesis is that if there is continued activation of this part of the brain in the absence of known peripheral makers of inflammation, then the conclusion is that the brain must be activated in the absence of such. This leads to his existing theories about top-down regulation errors, or perhaps feedback loops localised that part of the interoception system (similar to these sorts of theories about chronic-pain). Thus such a finding could cause additional resistance against researching peripheral causes and treatments, in favor of brain focused treatments. Cognitive therapy, but also psychoactive drugs. The problem for us that so many psychoactive drugs have already been tested (and in genuine efforts - by researchers such as Natelson) and failed to provide evidence of efficacy.

All of this is speculative - because I expect, like all the brain imaging studies we've already seen: although 'statistically significant' associations may be found, these associations will lack both sensitivity and specificity for this disease.

Spot on, @Snow Leopard!

Sorry, I know I'm late in contributing, but have now read M Edwards' presentation transcript. Here's my interpretation of it:

Most of us heave heard about somatisation. Its supposed to be about experiencing distress in the form of bodily sensations and misinterpreting these sensations as signs of illness. Most of us consider it to be the biggest cop-out in medical science when it comes to illnesses we don't yet understand, right?

Well, it has recently been suggested that interoceptive network is the neural substrate that is responsible for somatisation. I think this is the basic idea that Edwards et al plan to study. Models of the function of this network are a bit more sophisticated than the basic somatisation idea (they emphasise that this network makes active predictions when evaluating incoming sensations, and that it can also itself cause chemical/physiological changes within the body, which can further exacerbate the problem). But the underlying concept is still much the same.

According to recent articles like this one (warning: hard read!):

"... interoceptive predictions … are the brain’s best hypothesis, based on past experiences, as to the cause of current sensations… interoceptive perception is largely a construction of beliefs that are kept in check by the actual state of the body (rather than vice versa).

However… aberrant interoceptive predictions can lead to chronic physical burdens that result in various mental and physical illnesses — particularly disorders of mood, appetite and metabolism."

According to this perspective, abnormal cytokine production isn't a cause of depression, its the other way around. It all starts in the brain. First of all, the interoceptive network starts malfunctioning: it keeps erroneously predicting that there is stress. So there is increased production of cortisol, which in turn is supposed to activate pro-inflammatory cytokines (I don't know how this works, I thought increases in cortisol actually suppressed the production of some cytokines, but I guess not my area). A whole aberrant feedback loop is created.

"in a bid to ultimately reduce prediction error, limbic visceromotor cortices begin guiding the body towards a constellation of sickness behaviours associated with fatigue and negative affect that are designed to reduce activity and energy expenditure."

My guess is that Edwards et al are hoping PEM is correlated with changes in this interoceptive network. Notice that the ideas above allow for the possibility that the whole decoupling thing might take a while to progress to "sickness behaviour". I think Dr. Edwards mentioned this delay in his talk, so I think that's where he might be going with this.

Okay, now how do people feel about the value of this work? Is this a new spin on the old somatization idea? Or is it a new hypothesis about what causes our illness that leads to actual new effective treatments?

 

[Bob]

Why is this mindset so deeply embedded in the UK? This might be a question worth exploring to figure out how to shake it loose.

I think it's to do with our medical system. It is a very standardised and centralized system, and unfortunately the BPS school have managed to monopolize it because of a lack of knowledge about the illness or treatment for it. And there was a void for them to fill because of a lack of interest from other specialities.

The customer doesn't pay here, so we are disempowered to a degree and have to rely on processes within the system in order to challenge anything, rather than being able to take our custom elsewhere. We could potentially pay privately but it rarely happens. Because we don't pay, the system is centralised and we don't have a number of specialists who have set up on their own like e.g. Peterson in the states or Hyde in Canada.

I'm a great fan of the NHS; If you get heart disease or cancer in the UK, or any range of illnesses, then the health service is usually amazing and offers a world-class service. But it doesn't allow for innovative or intensive individualized investigations, because the doctors can't charge anyone for it. The family doctors get funded a flat rate per patient. They will do a range of blood tests but they won't do extensive testing or offer experimental or innovative treatments.

The specialists in other fields (e.g. neurologists) who work within hospitals don't want to know about us because our tests come back normal so they decide that we don't fall within their specialty.

If there's ever an 'evidence-based' treatment for ME, then it will be available to all of us for free. We just need a breakthrough. Or a biomarker would be a good starting point.

 

[Sidereal]

So there is increased production of cortisol, which in turn is supposed to activate pro-inflammatory cytokines (I don't know how this works, I thought increases in cortisol actually suppressed the production of some cytokines, but I guess not my area). A whole aberrant feedback loop is created.

Not my area of research either but from the literature I've read they have posited that in chronic stress states you end up with glucocorticoid resistance which then allows for chronically elevated cytokines to exist despite high cortisol.

 

[user9876]

Spot on, @Snow Leopard!

Sorry, I know I'm late in contributing, but have now read M Edwards' presentation transcript. Here's my interpretation of it:

Most of us heave heard about somatisation. Its supposed to be about experiencing distress in the form of bodily sensations and misinterpreting these sensations as signs of illness. Most of us consider it to be the biggest cop-out in medical science when it comes to illnesses we don't yet understand, right?

Well, it has recently been suggested that interoceptive network is the neural substrate that is responsible for somatisation. I think this is the basic idea that Edwards et al plan to study. Models of the function of this network are a bit more sophisticated than the basic somatisation idea (they emphasise that this network makes active predictions when evaluating incoming sensations, and that it can also itself cause chemical/physiological changes within the body, which can further exacerbate the problem). But the underlying concept is still much the same.

According to recent articles like this one (warning: hard read!):



According to this perspective, abnormal cytokine production isn't a cause of depression, its the other way around. It all starts in the brain. First of all, the interoceptive network starts malfunctioning: it keeps erroneously predicting that there is stress. So there is increased production of cortisol, which in turn is supposed to activate pro-inflammatory cytokines (I don't know how this works, I thought increases in cortisol actually suppressed the production of some cytokines, but I guess not my area). A whole aberrant feedback loop is created.
?

I could believe that a disfunction in part of the brain could cause feedback looks and strange even chaotic effects within other systems within the body. But to be a useful theory we would need:
1) To have a better specified hypothesis.
2) To be clear about supporting evidence. I'm not convinced that looking at activation patterns in part of the brain could tell us that. An fMRI scan basically says oxygen is being used in a region and therefore the brain is doing some work in that region. So an activation in a perceptual or control part of the brain may be as a result of processing signals that something is wrong in the body or taking part in an active loop. Timing information could be interesting but I feel could also be misleading. What perhaps is interesting is other scans that suggest microglia activation in parts of the brain.
3) Have some idea of cause and effect. That is would would be causing such disfunction. The psychiatrists theory would be bad thoughts cause this disfunction but other (more sensible) theories would have the microglia activation or antibodies binding to receptors or even limited blood flow in the brain as a route to the disfunction. I'm not sure how fMRI scans would help here. The question is what experiment could you devise to disambiguate different theories. My guess is they should fit into existing evidence (although it all needs much more replication).

I do tend to think that ME is some sort of control system failure whether this is due to the inability to control blood flow through capillaries, issues with the control of energy production or the control of the body via low level brain functions. Part of the reason it has that feel to me is the fluctuations and that people do have remissions without showing permanent organ damage.

 

[Valentijn]

Is this a new spin on the old somatization idea? Or is it a new hypothesis about what causes our illness that leads to actual new effective treatments?

It's still pretty stupid. There is still an unassailable pre-existing conclusion ("CBT is the cure") where people are trying to work backwards to find an explanation for that conclusion.

That isn't science. It's persuasive creative writing with a pseudo-experiment thrown in. They will never accept any finding which challenges their conclusion. They will always find a way to "prove" that wrong-thinking is the cause, even if it's patently absurd to suggest that such wrong-thinking could cause so many involuntary symptoms, especially when asleep.

How do expectations cause swollen lymph nodes? How do they cause fevers? Or blood pressure dysregulation which only manifests when upright? Do they suggest we have orthostatic hysteria? How do expectations cause obviously involuntary muscle twitching and spasms - where the limb isn't moving but the muscle is visibly jumping in a manner which no one can deliberately replicate?

It's all completely absurd. They'd might as well suggest that we can change our hair color with our expectations, or grow extra limbs. It's complete science fiction.

 

[Snow Leopard]

My guess is that Edwards et al are hoping PEM is correlated with changes in this interoceptive network. Notice that the ideas above allow for the possibility that the whole decoupling thing might take a while to progress to "sickness behaviour". I think Dr. Edwards mentioned this delay in his talk, so I think that's where he might be going with this.

Okay, now how do people feel about the value of this work? Is this a new spin on the old somatization idea? Or is it a new hypothesis about what causes our illness that leads to actual new effective treatments?

Very interesting thoughts.

My main question is how would research prove such directionality, e.g. brain->body, rather than body->brain.

Rather than merely falling back to the argument from ignorance - (e.g. we can't find what is causing the problems in the body, therefore the brain must be in error.)

This comes back to the main criticism of the bio-psycho-social model: the fact that there are no plausible/demonstrated bio-psycho-social models of illness. The directionality of the feedback systems is never established.

This is a necessary question to answer because there are practical and ethical questions involved - otherwise you end up using wrongly targeted treatments, e.g. antidepressants for depression that is non-endogenous. Or psychoactive drugs for conditions that are primarily peripheral in nature.

 

[Jonathan Edwards]

Very interesting thoughts.

My main question is how would research prove such directionality, e.g. brain->body, rather than body->brain.

That seems to be a central question. I have reservations about fMRI being able to pick up what is needed but if it is looking at central brain areas like basal ganglia and brain stem then it is unlikely just to be reflecting conscious thinking. (I think the signal in the typhoid study was basal ganglia.) I think there is a reasonable chance that some headway can be made with the question.

If people with PEM can be shown to have a particular signal in central brain during PEM which they did not have before and which is not present in healthy controls but maybe looks like something seen in people just after typhoid vaccination then I think that would be a huge step forward. It might even be a diagnostic test. As far as I know, when people are actively thinking 'beliefs' in the sense of conscious ideas about oneself or the world there are no changes in central brain on fMRI. If there are changes they are likely to be in medial prefrontal cortex where thoughts about oneself and ones relation to the world seem to give signals. If the study shows a signal in basal ganglia and the researchers say 'look there is the false belief operating' I think it would fairly rapidly become clear with further research in cognitive science units that this was not a belief in the personal sense. @Woolie makes an interesting point about replacing the word brain with 'person' but I think there are complications to that, which I may come back to in another post.

So if it becomes possible to show objectively the brain registering PEM then if at the same time peripheral mediators are measured it becomes possible to refute certain body>brain options. If blood lactate is normal in a study where people say they are having PEM it may seem a bit subjective. But if blood lactate is consistently normal when fMRI shows brain changes of PEM during the symptoms then it is reasonable to conclude that lactate is not the mediator. That does not exclude cellular level interferon signals in muscle signalling to the brain via sensory nerves without any rise in plasma interferon but at least it reduces the possibilities by one. And that tends to be how one moves forward in pathophysiological research - crossing off options until one is left with very few possibilities.

And of course an objective measure of PEM in the brain would be the perfect tool for showing that CBT has no effect if indeed it has no effect. After CBT patients may say they have much less PEM to please the therapist but if the fMRI after exercise still shows PEM changes the cover is blown. Equally for rituximab - either it will change the fMRI signal during PEM or it will not

 

[Sasha]

I think this is a new comment on the research by @charles shepherd:

http://www.meassociation.org.uk/201...es-new-neuroimaging-research-16-october-2015/

 

[Snow Leopard]

That seems to be a central question. I have reservations about fMRI being able to pick up what is needed but if it is looking at central brain areas like basal ganglia and brain stem then it is unlikely just to be reflecting conscious thinking. (I think the signal in the typhoid study was basal ganglia.) I think there is a reasonable chance that some headway can be made with the question.

No, the studies in question were investigating the dorsal insula.

There is a lot of discussion/speculation on the roles that the insula plays between interoceptive awareness, motor control and emotional experience as a result of bodily sensations.
https://en.wikipedia.org/wiki/Insular_cortex

Also, the Dorsal insula has shown to be active during attentional tasks.

"Dissociable large-scale networks anchored in the right anterior insula subserve affective experience and attention" http://www.sciencedirect.com/science/article/pii/S1053811912001899

"Pain and emotion in the insular cortex: evidence for functional reorganization in major depression." http://www.ncbi.nlm.nih.gov/pubmed/22503725

This shift of emotion-related responses to the dorsal insula, i.e., where pain-processing takes place in healthy subjects, may play a role in "emotional allodynia" - a notion that individuals with MDD experience pain in response to stimuli that are normally not painful.

Several recent studies have focused on the dorsal insula and its role in chronic pain.
"The dorsal posterior insula subserves a fundamental role in human pain" http://www.nature.com/neuro/journal/v18/n4/full/nn.3969.html

And lastly, the Neil Harrison study (open access): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885492/

At best, what the study will find is a non-specific marker that is associated with pain or fatigue from a variety of potential conditions.

 

[charles shepherd]

MEA summary of this important MRC funding announcement at the conference is now up on our website:

http://www.meassociation.org.uk/201...es-new-neuroimaging-research-16-october-2015/

One of the the next aspects I want to cover is the section on the use of antiviral drugs, valganciclovir in particular, that formed a key part of the opening presentation from Professor Jose Montoya in the Plenery Session on Neuropathology.

Professor Montoya also joined us for the two hour Workshop on Neuropathology on Tuesday afternoon

 

[A.B.]

If an individual suffers from maladaptive interoception, shouldn't it be easy to test this by giving them painful electro shocks until they start to feel pain even when there is no current?

 

[Jonathan Edwards]

But just for fun, to reveal the true idea behind Edwards' words, try substituting "person" or "mind" for "brain", and see how that reads. Brains are physical entities, they contain neurons capable to transmitting signals. Those neuron can fire in certain patterns, and can modify their interconnections through their activity. But its the person (or if you like, our mind) that does the expecting, the experiencing of pain and the adjusting of movement plans. These are mental processes, not brain functions. The brain is just the physical substrate.

What intrigues me is that behind all this discussion is a very real distinction between two ways of looking at an illness - psychological or physical - but almost everybody is getting the distinction wrong because of universal false assumptions about the brain-mind relation. The psychiatrists and neurologists are the worst criminals because they should know better, but the way out of the muddle is not so easy.

The psychiatrists will say to your proposal, Woolie, that you are a Cartesian dualist (i.e following Descartes) and that there is no difference between brain and mind. Everything is physical, even if it can also be described as mental in some cases. But they would be wrong about you being Cartesian. Descartes did not say that it is the person that expects or experiences or adjust movement plans. He said it was something sitting in a very small part of the brain (the pineal) that was in addition to the brain, body and indeed person. And if one is going to have a purely physical account, as neurologists say they insist on, then one has to have something like what Descartes proposed. Whatever experiences pain must be some very small part of a brain that receives pain signals. A person includes a liver and toenails and finger bones and a hypothalamus and cerebellum, none of which are involved in experiencing pain. If we are trying to understand a mechanism within the confines of the whole body, as we are, then person is not a helpful term. It is a purely social term. Equally, adjustments to movements will be produced by very small parts of the brain probably in the pre-motor cortex, not a person.

But, strangely enough, the neurologists actually believe in this overall person as well. They think that experience is a function of a total brain activity, and movement planning too. They deny that there is anywhere that gets the pain signals and feels them or any particular place that causes the movement.

Descartes probably got one thing right and one thing wrong. What he got right is that experience of pain must occur in some very small part of the brain that receives signals that mean pain. What he got wrong is the idea that there is only one of these places. Present day neuroscientists having actually got this the wrong way around. They think Descartes was wrong about there being anywhere that gets pain signals. But they think he was right to think there was only one experience of pain. Brain structure actually tells us that there must be thousands of experiences of pain all at the same time - at least to make any physical sense.

This may all sound very philosophical and obscure, not to mention weird and creepy. But as I see it it is just getting the neurobiology right. And unless people like Mark Edwards start thinking in the right neurobiological framework their theories will continue to be impossible to make sense of in a physical framework. On the other hand going outside a physical framework is no good - it is the mentalist approach we all want to avoid.

My suspicion is that the key distinction to make is between brain loops occurring at levels such as pituitary and hypothalamus and reticular activating system in brain stem, that 'learn' and 'expect' in much the way the immune system does and brain loops occurring in the areas of cortex that learn and expect in the popular sense.

From what I hear from PWME I find it quite hard to believe that ME is simply a brain loop of either sort. I think there must be some input from peripheral signals from tissues. However, I am not sure. My wife suffered an illness due to an antimalarial drug that left her weighing 6 stone on a drip feed unable to move out of bed. Her body was entirely normal and even her brain was entirely structurally normal on MRI scan. But she got completely better by treatment for brain loops. As indicated in my previous post, I see Mark Edwards's research proposal as something that may help us to unravel what is going on whether it is a brain or an immune loop. I think his previous theoretical models have problems but now that there are neuroscientists engaging in ME research who have as little time for biopsychosocial theories as people on PR do I think whatever results emerge are going to be subjected to very detailed critique - not least on PR - and the truth will become apparent.

 

[Snow Leopard]

If an individual suffers from maladaptive interoception, shouldn't it be easy to test this by giving them painful electro shocks until they start to feel pain even when there is no current?

The theory is that (eg pain conditions), that they are over sensitive to low level signals (rather than zero) and indeed there are studies showing reduced pain thresholds in various groups, though I think these sorts of studies can easily be biased.

 

[user9876]

So if it becomes possible to show objectively the brain registering PEM then if at the same time peripheral mediators are measured it becomes possible to refute certain body>brain options. If blood lactate is normal in a study where people say they are having PEM it may seem a bit subjective. But if blood lactate is consistently normal when fMRI shows brain changes of PEM during the symptoms then it is reasonable to conclude that lactate is not the mediator. That does not exclude cellular level interferon signals in muscle signalling to the brain via sensory nerves without any rise in plasma interferon but at least it reduces the possibilities by one. And that tends to be how one moves forward in pathophysiological research - crossing off options until one is left with very few possibilities.

I can see the point of an experiment that says we have this set of readings and certain brain activation, perform a task to bring on PEM and then see which readings have changed if the brain activation has changed. It could threshold out if the brain is already activated prior to the task which may happen if the trip to the scanner is hard. The question then comes as to what set of readings are taken, at what times and I would also not we shouldn't expect a linear response to changes. I would feel happier if the set of readings were taken over time without PEM as well to understand the natural variation. I can see it could be used to rule out certain things with the caveat that there could still be local effects which I can see is useful.

Do you have an idea of what the set of readings he is planning to take? Or what you think would be a reasonable/interesting set?

And of course an objective measure of PEM in the brain would be the perfect tool for showing that CBT has no effect if indeed it has no effect. After CBT patients may say they have much less PEM to please the therapist but if the fMRI after exercise still shows PEM changes the cover is blown. Equally for rituximab - either it will change the fMRI signal during PEM or it will not

Since he is in UCL could tests be done on patients from any Rituximab trial there.

 

[Jonathan Edwards]

No, the studies in question were investigating the dorsal insula.

OK, that's important. Insula is much more difficult to interpret, I agree.

 

[Jonathan Edwards]

I can see the point of an experiment that says we have this set of readings and certain brain activation, perform a task to bring on PEM and then see which readings have changed if the brain activation has changed. It could threshold out if the brain is already activated prior to the task which may happen if the trip to the scanner is hard. The question then comes as to what set of readings are taken, at what times and I would also not we shouldn't expect a linear response to changes. I would feel happier if the set of readings were taken over time without PEM as well to understand the natural variation. I can see it could be used to rule out certain things with the caveat that there could still be local effects which I can see is useful.

Do you have an idea of what the set of readings he is planning to take? Or what you think would be a reasonable/interesting set?



Since he is in UCL could tests be done on patients from any Rituximab trial there.

I do not know the details planned. I think we are a long way off seeing an objective endpoint based on fMRI but if something was found that could be replicated by other groups it would make sense.

 

[user9876]

The psychiatrists will say to your proposal, Woolie, that you are a Cartesian dualist (i.e following Descartes) and that there is no difference between brain and mind. Everything is physical, even if it can also be described as mental in some cases.

There are different ways you can observe the system. You can observe it in terms of neurons firing or in terms of outputs that in some way capture thoughts (spoken or written words, actions, movements). The issue to me is how we go about tying the two sets of observations together and we seem a very long way off understanding the relationships although I've not kept up with research in that area.

However, I am not sure. My wife suffered an illness due to an antimalarial drug that left her weighing 6 stone on a drip feed unable to move out of bed. Her body was entirely normal and even her brain was entirely structurally normal on MRI scan. But she got completely better by treatment for brain loops.

This brings in another physical area of whether it is enough to understand firing of neurons or whether chemicals or other substances either temporarily change the effects of neurons or permanently change connections. When my wife was on one particular antibiotic she became very confused and quite paranoid but the effect went when the drug was changed (not sure of the time lag). Such changes seem just to add a huge amount of complexity when trying to understand the system.