Clinical Trial at Brighton/Sussex Hospital

[ladycatlover]

2) "Dr Alastair Miller
...
He is Chair of the British Association for Chronic Fatigue Syndrome and ME (BACME) and Principal Medical Advisor for Action for ME (AfME)."
[My bold]

He was "Clinical Champion" here in Liverpool some years ago. I went to a talk he gave on CFS, I think it might have been in the University Bookshop. He sounded very reasonable until you thought about what he was saying. I suspect he was disappointed that most of the audience were patients rather than students or medics. Actually looking back I think it might have been organised by the local (university) chapter of Quackwatch. Sorry, memory fails me, but I wasn't impressed by the talk or the question session.

 

[Londinium]

Possibly a dim question (I know very little about FM), but anybody have an idea as to why it's being funded by Arthritis Research UK? Would FM fall into their sphere? Would they normally be funding research into ME?

 

[Invisible Woman]

I believe they originally cofunded some research as many patients with arthritis - especially rheumatoid arthritis - suffer a lot with fatigue.

FM is often treated in rheumatology depts as is rheumatoid arthritis.

 

[Orla]

He was "Clinical Champion" here in Liverpool some years ago. I went to a talk he gave on CFS, I think it might have been in the University Bookshop. He sounded very reasonable until you thought about what he was saying. I suspect he was disappointed that most of the audience were patients rather than students or medics. Actually looking back I think it might have been organised by the local (university) chapter of Quackwatch. Sorry, memory fails me, but I wasn't impressed by the talk or the question session.

Edit: I don't think he has anything to do with this study, just an advisor to the Sussex group

A little more info on Alastair Miller http://forums.phoenixrising.me/inde...iser-dr-miller-who-promotes-cbt-and-get.3846/

and the handbook the clinic was using under his leadership http://forums.phoenixrising.me/inde...liverpool-cf-cfs-clinic-patient-handout.3066/

 

[NelliePledge]

Dr Neil Harrison talked about the study at CMRC

 

[Woolie]

@Woolie is our expert.

@A.B., I looked over the proposal, the typhoid vaccination and blood samples part seems like it might produce some interesting results for us (for example, PwMEs might exhibit an exaggerated immune response to the vaccination). But the trade is that much of the rest of the study seems to be about Psychology.

I cannot underestimate how important it is to realise that functional imaging is in fact Psychology. Functional activity in the brain (fMRI) is used to draw conclusions about how we are processing, interpreting or reacting to things or how we are feeling emotionally. This type of approach - fMRI - is almost never used to identify physiological or other brain abnormalities, you use entirely different methods to study these things.

fMRI is Psychology. I can't stress this enough. I'm a cognitive neuroscientist and active researcher in the field, so feel very well qualified to make this statement.

There are a few other hints that a psychological spin may be placed on the data:

Finally, we will take a small sample of your hair to look for long term sings (sic) of activation of the “fight and flight” nervous system. Fibromyalgia and ME/Chronic Fatigue syndrome have been associated with an altered response to stress and a way to measure this is by studying the levels of the stress hormone, cortisol, in your hair

There are also hints that the tilt table procedure is being used to simulate something akin to psychological stress (references to inducing the “fight or flight” system).

The decision of those that take part is whether you think the vaccination and blood tests part of the study is valuable enough to override the other parts of the study, which are almost certainly going to be used to make psychological arguments.

 

[Woolie]

Dr Neil Harrison talked about the study at CMRC

I also watched the presentation, @NelliePledge. In this talk, Harrison talks a lot about the insula, which responds to changes in bodily states, like inflammation, cold. He argues that people who feel really sick from the flu are those who display the strongest insula response. The implication he is making is that there's no bodily difference between the mildly iil and the really ill people, its a difference in their brain's reaction to the physiological changes, indexed by the insula activation.

He thinks the insula is a big part of the 'interoceptive pathway' and is important in generating our subjective experience of fatigue, pain.

Then he talks about the 'psychomotor slowing' associated with acute infection. He thinks this has a different neural basis, its associated with the substantial nigra (in the midbrain).

He then goes on to talk about a study where he induced fatigue using interferon in normals. They found no changes in the insula, but big changes in basal ganglia activity (not what they hoped for). The magnitude of these changes predicts the degree of subsequent fatigue over the next few days.

He goes on to outline a framework where the insula/interoceptive network is part of the subjective experience of pain/fatigue and the basal ganglia are part of the motivational aspects of the experience (sickness behaviour, etc)

He talks about a planned study where he's going to do an exercise challenge with PwMEs. He's going to do imaging before and after the challenge. He predicts greater activation of the insula/interoceptive pathway.

The Sussex study is going to look not at an exercise challenge, but at an inflammatory challenge. That's the typhoid vaccine we've been talking about here.

I have to go now, but will pop back later to add a few of my own insights.

 

[Woolie]

...continuing....

The material in this talk is all organised around one central idea: that the degree to which you feel ill or in pain, and the degree to which you alter your behaviour because of this, is all down to the way your "brain" responds.

I found there was a logical flaw in the causal reasoning. The various studies Harrison presented all showed that various brain changes were associated with changes in how severe people's symptoms were. But this does not demonstrate causation. These brain changes aren't necessarily what determines how ill you feel. It could be they are responses to changes happening elsewhere in the body, in other systems, and it is these changes that control the brain responses, that in turn signal how severely ill you feel.

Or it could be that the brain changes are an attempt to compensate in some way for the impaired functioning happening elsewhere in the body. So again, the more ill you feel, the bigger the brain changes will be, but in this case, they play no causal role at all. The finding of changes in basal ganglia activity certainly fits with this idea.

To me, it is the same sort of argument that the psychosocial researchers have been making for years, and with the same fundamental flaw: if we can't find any markers that predict symptom severity, then it must all be down to patients' perceptions.

 

[Valentijn]

As far as I know the typhoid vaccine studies are on healthy people. I think it was probably a confusion to think it was going to be given to PWME. The idea of typhoid vaccine was to simulate the immune response that might cause malaise and look at neural mediation.

The decision of those that take part is whether you think the vaccination and blood tests part of the study is valuable enough to override the other parts of the study, which are almost certainly going to be used to make psychological arguments.

I expect the vaccine response is also part of the psychological study. Questionnaires (primarily psych) are given afterwards. But based on their past work, it sounds like any increased responses in patients would be somehow spun as being an indication of a brain or stress dysfunction.

By they way, any idea how long an immune response to the typhoid vaccination takes? Patients are only there for 2.5-4 hours per visit, with no post-visit testing, aside from whatever happens during the next visit in relation to a different procedure.

 

[boombachi]

@Woolie thank you for explaining this cmrc presentation in a way that even I understand. I saw the presentation and the only thing I got from it is that fatigue can have different sources so why base a study of cfs on another fatiguing illness that could have a completely different mechanism?

Your point about the brain changes not being the root cause is an important one and it still amazes me that people clever enough to get through medical school or achieve phds still miss this point. Confusing correlation with causation is another one that seemingly very intelligent people do in many areas of research (government policy seems often to be based on this kind of research but that may be intentional).

In your research as a cognitive neuroscientist, have you a theory about why these blind spots exist?

 

[Jonathan Edwards]

By they way, any idea how long an immune response to the typhoid vaccination takes? Patients are only there for 2.5-4 hours per visit, with no post-visit testing, aside from whatever happens during the next visit in relation to a different procedure.

They are not studying an immune response They are studying the immediate response to lipopolysaccharide or 'endotoxin', which is a prominent component of typhoid vaccine and is why typhoid vaccine makes people feel much iller than most vaccines - immediately. The endotoxin reaction through CD14/LPS receptor takes about 15-20 minutes to start up and tends to peak in the first hour.

 

[Jonathan Edwards]

functional imaging is in fact Psychology.

Firstly, I am worried that we do not actually know whether Neil has anything to do with the study on this thread or whether typhoid vaccine studies have anything to do with it either. Maybe they do but it sounds as if we may be confusing two completely different projects. It is possible that Neil wants to test typhoid vaccine on PWME to see if they have an increased or prolonged response but I have not heard that. Exercise testing is reasonable since it would illuminate the PEM phenomenon and has been suggested by many groups.

I actually disagree with the suggestion that fMRI is psychology. I have spent several periods of half an hour or so talking to Neil in detail about his views and the purpose of his studies. He is studying brain physiology in the context of noxious insults like typhoid vaccine. He has absolutely no preconceptions about causality of the sort you are suggesting. We discussed in detail various possibilities about the insult findings actually being an artefact of the experimental context. He is totally aware of these sorts of methodological issues.

Moreover, I have no problem with the idea that it is the brain response that matters. If autoantibodies are affecting brain cell responses then looking for increased brain responses to stimuli that might mediate symptoms is very good science. In lupus autoantibodies are responsible for people feeling fatigued. We pretty much know that. And it is very likely that the mechanism involves central signals rather than any effects on muscles - which are not found.

After all, sensitivity to light, which is part of ME, pretty much has to be an increased brain response because the eye itself is in fact an extension of the brain up to the skin, not a separate organ on the end of a nerve. Even if autoantibodies or some other factor do affect muscles or lungs or cardiovascular receptors it looks to me that we have to accept that the same factor is having a direct effect on brain responses. Ockham's razor would say that the simpler story is that it is all a matter of brain responses. That may not turn out right but it is an entirely legitimate scientific approach.

I think we do a disservice to ourselves, if we are genuinely trying to understand ME, if we dismiss people like Neil Harrison as blinkered. He understands all the caveats involved and has the courage to do well thought out science.

 

[user9876]

Actually looking back I think it might have been organised by the local (university) chapter of Quackwatch.

Is that a group at the university that gets quacks to speak so people can watch them?

 

[user9876]

He argues that people who feel really sick from the flu are those who display the strongest insula response. The implication he is making is that there's no bodily difference between the mildly iil and the really ill people, its a difference in their brain's reaction to the physiological changes, indexed by the insula activation.

That implies people have a consistent response to a illness. I.e. that the same person is always very ill with the flu. I don't think that is the case but it is up to him to demonstrate that.

 

[Jonathan Edwards]

To just add a bit about psychology. As I see it Harrison is not doing psychology because he is trying to explain symptoms entirely on the basis of neurophysiological events as observed from outside. Psychology tries to explain symptoms on the basis of concepts like 'emotions' or 'peer pressure' or 'rational thought' which derive from our shared inner experiences. Harrison would not want to invoke concepts of that sort as causes. He wants to replace them with something measurable - physiology.

A strong insular response IS a bodily difference, just as much as a strong LPS receptor response.

 

[Valentijn]

Firstly, I am worried that we do not actually know whether Neil has anything to do with the study on this thread or whether typhoid vaccine studies have anything to do with it either.

The pdf linked on the prior page talks about the Typhoid vaccine a lot. Neil Harrison is mentioned as being involved in the project on Dr Jessica Eccles' staff research page.

And it is very likely that the mechanism involves central signals rather than any effects on muscles - which are not found.

Central nerve signals and/or processing aren't a good explanation for localized muscle twitching shortly after overusing a muscle. It happens to me very predictably, and is a common ME symptom. Nor does it account for specific muscles completely failing to respond when badly overused.

Theories of central causation only work if ignoring patients and their symptoms. I don't doubt that there is brain involvement, but it seems to be an effect of muscle dysfunction, not a cause of it.

 

[A.B.]

The pdf linked on the prior page talks about the Typhoid vaccine a lot. Neil Harrison is mentioned as being involved in the project on Dr Jessica Eccles staff research page.

Okay, maybe there is hope after all.

 

[Cheshire]

I actually disagree with the suggestion that fMRI is psychology.

fMRI is just a tool, saying "it is psychology" is maybe too strong.
But I agree with @Woolie that there seems to be a trend in psychology to use it to prove a pre-conceived theory. And whatever they will find is used in a "your thoughts/emotions are changing the way your brain behave and then it creates your symptoms" frame.

But I'd like to be proven wrong; maybe there are (or will be) flawless fMRIs studies made.

In the meantime, I think we are justified to be very defiant.

 

[Valentijn]

Okay, maybe there is hope after all.

He also co-authored a study on neuropsychiatric symptoms in FM patients, so not really.

He's actually done quite a few studies involving the psychologization of FM and hypermobility patients.

 

[Woolie]

To just add a bit about psychology. As I see it Harrison is not doing psychology because he is trying to explain symptoms entirely on the basis of neurophysiological events as observed from outside. Psychology tries to explain symptoms on the basis of concepts like 'emotions' or 'peer pressure' or 'rational thought' which derive from our shared inner experiences. Harrison would not want to invoke concepts of that sort as causes. He wants to replace them with something measurable - physiology.

You need to look past the level of terminology that is used and look at the causal claims that are being made.

The claim being implied in Harrison's presentation was very much that chronic pain, fatigue are all down to differences in the way people perceive and/or respond to bodily stimuli. Yes, it is expressed in terms of the 'interoceptive network' and such like. So yes, the level of description is a bit different from what you're used to in Psychology. You have to get used to translating from one level to another. But follow the causation trail, and then you will find the core thesis.

It is true that when most people think 'Psychology', they think of only a subset of mental processes that have something to do with thoughts and feelings that are (at least potentially) accessible to conscious awareness. And there is certainly no implication here that any of this is accessible to conscious awareness. But then as a Psychologist, I would define Psychology very much more broadly, to include everything beneath awareness - all the mental processes that go into perceiving, moving, retrieving, predicting, controlling, motivating, etc.

f autoantibodies are affecting brain cell responses

No, I think you misunderstand. The claim is not that these brain responses are downstream effects of abnormalities happening elsewhere. The claim is that the brain is playing a primary causal role - to the extent that if we could alter the brain's activity, we could reverse the symptoms.

A good way of finding the causal claim in psych/behaviorual/brain research is to ask what sort of intervention the researchers would hypothesise would lead to the greatest relief.

I think we do a disservice to ourselves, if we are genuinely trying to understand ME, if we dismiss people like Neil Harrison as blinkered. He understands all the caveats involved and has the courage to do well thought out science.

I do not think I did that. I gave a summary people could understand, which I thought was very fair to the central ideas, then my own assessment. It is my view that this line of research is probably a dead end in terms of understanding and treating CFS. Just as it is your view that some biomedical approaches are probably a dead end.