UK CFS/M.E. Research Collaborative Science Conference Day One, Part Two 13th Oct 2015

Transcript of presentation by Dr Mark Edwards featuring new research ‘Imaging the Neural Correlates of Post-Exertional Malaise in CFS/ME’

By Russell Fleming (@Firestormmer)

Stephen Holgate:

...Mark Edwards’ is a new grant that Hugh Perry brought to our attention that had been awarded by the neuroscience and mental health board of the MRC very recently, so Hugh I think asked Mark if he would be kind enough to come up here at really quite short notice he’s come to tell us what his plans are and what his research is about. So thank you very much indeed Mark for coming and we’re kicking you off, we’ll put you in the centre here and ask you questions afterwards, and then we’ll let you go.

Mark Edwards:

It’s a great pleasure to be here. Thanks very much indeed for the introduction. I wasn’t actually going to talk about how I got involved in this area but I thought it might be relevant.

I am a neurologist and working in the field of movement disorders [sound problems] and working in specialist movement disorders clinic about 20% of the people coming to those clinics had symptoms which didn’t really fit into categories like Parkinson’s disease and so on, and people didn’t really know what was wrong with them. They might use those terrible words that should be banned from textbooks ‘medically unexplained symptoms’. And I got interested in what was wrong with those people.

Predominant models were either there was nothing wrong at all or that based on a particular interpretation of a Freudian model of how psychiatric problems converted [?] into physical symptoms. What I saw was just a lot of people who had very significant disabilities and no explanation for what was wrong.

My approach to that – which is a complex area of medicine – was just really to try and think about mechanism and to concentrate on thinking about how symptoms might be being produced in the brain and starting from that point is a much easier and a much better place to start from than from a particular idea about why it might have happened.

Because what we know about any medical condition really is that why things might happen is always very very complex and it is often different in different people and it is often difficult to know. In fact most of our ways of explaining what is going on with mental problems and in treating them is about thinking about how the brain might go wrong [sound problems].

So, this took me into a way of thinking about neurological symptoms and symptoms in general which sparked an interest in thinking about fatigue and chronic fatigue syndrome.

I want to talk to you about a project which is part of a MRC grant which is based on that idea about thinking about mechanism first of all. Think about mechanism for key symptoms and maybe if we understand more about mechanism we’d be able to understand a little bit more about treatment.

This is a collaborative project – I just wanted to point that out – it’s not me on my own, there are a number of people involved in this sphere, particularly Neil Harrison who may have spoken at one of these events before [he did in 2014 – see my twitter feed for details]. Neil is a neuropsychiatrist working for the University of Sussex and has a particular interest in the interaction between the immune system and the brain. James Kilner who is a former colleague at UCL [university college London] who is interested in motor-neuroscience, and, from the department of sports medicine, Dr Anne Brice, and also the Sussex ME Association who have been particularly helpful talking about this project and helping to get it off the ground.

This is the symptom we were thinking about when we were designing this project – post-exertional malaise. We can’t say post-exertional fatigue because it is something more than that. It is a key symptom in CFS/ME and it comes with a range of different phenomena – physical phenomena – relating to pain, to weakness, to fatigue and also cognitive phenomena like cognitive slowing, fogginess etc. And there is this interesting phenomenon that at least for some people it has this slightly delayed onset; so somebody might have a period of exertion one day and then the next day all of this hits in a very big way.

So it is a key symptom, essentially a key mechanism that is going on. Thinking about that symptom, are there any models out there from what we know about how the brain works in different conditions that might allow a little more information about that.

Well there is a key model and that’s that this range of symptoms I am talking about – this post-exertional malaise – is similar to something which is usually called a ‘sickness response’.

A sickness response is a set of symptoms similar to what I have just said, which occur in lots and lots of different species like humans when they have an acute inflammatory response, when they have an acute infective response.

That seems like a reasonable model, so if we knew what was happening with the symptoms [sound problems]. And importantly this sickness response is something where there has been quite a lot of work done, particularly by Neil Harrison, looking at the network of brain structures which seems to generate these symptoms.

Just to tell you a little bit about that, I am going to talk about studies that Neil did in healthy people giving them typhoid vaccinations. When we give typhoid vaccinations – a live vaccine – it gives people routinely a sickness response, a sort of flu-like response.

And what Neil did was give this type of vaccination to healthy people and then put them in a scanner and look at patterns of brain activation. What you see routinely is activation of a particular brain structure which is called the insula, going across all these different scans using different techniques, and activation in this structure of course seems to be related to how strongly people perceive these symptoms that are happening.

This is something where you can do further work in actually tracking a network of structures which seem to be involved in taking information from the body and sending it to the brain and this structure this insula being particular important in processing this information it is getting and generating the symptoms that people experience.

And this is something called the interoceptive network – the network of brain structures which lets us take information from the body and lets us interpret that saying what’s going on in our own body.

There are some questions which come from this and using that previous research, and one question is what happens to these networks – which seem to be involved in acute inflammation and infective response generating this whole group of symptoms – what happens to that network when people with CFS/ME are experiencing an exacerbation of symptoms, are experiencing post-exertional malaise?

And there is a secondary question which is whether the changes that people with CFS might get in this network in response to post-exertional malaise, are they the same as what people are getting when you give them an acute inflammatory challenge or an acute infective challenge? Or maybe they are different? And those similarities and differences would be useful and interesting in understanding a little bit more about the mechanism of these important symptoms.

And, this is a study which hasn’t started yet so I am going to tell you briefly what the plan is, we are going to get a group of people who have CFS and a group of healthy and age-matched controls, and we’re also going to incorporate data from a number of studies that Neil has done in the past looking at people experiencing acute inflammation and response say to typhoid vaccination, and also at a group of patients who have for example rheumatoid arthritis or Hepatitis C who have had immune challenges like interferon [?] who have developed chronic symptoms.

The plan is to do a baseline scan where people have an fMRI scanner and use a technique that allows us to map this activity that I was talking about, this interoceptive network, we are also going to take some blood samples to look at immune activation as well.

And then we are going to do a specialised exercise protocol which is defined on the basis of their own person’s heart rate and their own person’s exercise abilities, so something that we are hoping that across people who might have a variety of people with different severity of symptoms, we might get them to do a similar amount of exertion. And then, 24 hours later, they come back again and repeat the study.

So this is going to allow us to look at what the neural correlates are – what the patterns of brain activation are – particularly in these structures when people are experiencing post-exertional malaise. We are also going to be able to look at different aspects of activation of immune system by blood samples that we have taken as well.

So that is the plan for the study at the moment, and I’d just like to finish by saying thank you to the people who designed the study with me and also thank you to this research collaborative and to the MRC as well.

Holgate:

I think what this illustrates and we are going to see it in the next few talks as well, how important it is to study the complexities of a disease condition like chronic fatigue syndrome by using other disease models to help understand the complexity, and I think this is one of the great things the collaborative is encouraging now is trying to suck people into the area who are in other areas like you were [Mark Edwards] but then coming in and studying it using these new technologies to enable us to get a grasp of a least one component of a very complicated group of conditions and I think this is very exciting.

And the fact the Neurosciences Board funded this, I mean the competition would have been incredibly high to get something like this through, I mean you have no idea what you would be competing against, is amazing and I think you deserve a lot of credit for doing that because I know how hard it must have been to got that support.

Now, we do have some questions because Mark is going to pop off back to Sussex.

Question from audience [I haven’t transcribed questions]

Edwards Replied: I think what you just said shows an important point, I suppose I am trying to take a slightly one-step-back view of saying we have a symptom which is commonly reported it is fairly consistently reported across a group of people, and we have a network of brain structures which we know are typically activated when people experience that symptom but in a context of an acute infection or an acute inflammation, and so the interest for me is to see whether the pattern of activation which you get in those people who have an acute inflammation or infection, is that the same as what is happening in people with CFS because they are experiencing the same sort of thing, or is it something different? And it is possible to see whether the way in which that system activates might be different and that might give you a better idea about mechanism. And it also might give you a better idea that there might be different groups of people that have CFS/ME and they are going to respond in a different way. It is not going to tell you about ammonia in the brain though I am afraid but it is looking at it from a different level of description so I think it is possible to... the important thing in research into complex conditions is to look at lots of different possible levels of description, so you can look at things on a biochemical level, you can also look at the level of systems neurology which is what this is, and you can look at the level of societal experience. But they are all valued, equally valued.

Question from audience

Edwards Replied: They are not. I should have said. There are some people [in the study] who are going to have exercise and scanning first and then they are going to have... [A concern was expressed I think about the effect of all the testing on ‘stamina’ or a person’s apprehension regarding scans and presumably the effect this might have on outcomes, and so they will seek to vary the order in which participants do the various parts of the study. They were referring to one of Edwards’s slides].

Holgate: Just on the point – just going back to this [the slide under discussion] with these new technologies it would be quite nice to revisit some of the old ideas as well, it doesn’t mean they were wrong but it means that if we have another handle on the process it might give insight into connectivity between the metabolism for example that you were describing, and obviously the functional changes that you [are studying?].

Question from audience

Edwards Replied: It’s a very good question and I would have to defer to someone who is not here – Professor Neil Harrison – who is the person who is going to be looking at that. He has a lot of experience in looking at cytokines for example and response to immune challenge and there is a panel and [sound problems] is part of that.

Holgate: We had a talk this morning that very much addressed some of that and it would be interesting to see whether you are sharing the same biological markers.

Question from audience: Would you be performing the fMRI scans during mental exertion or not?

Edwards Replied: Yes. So the paradigm that has been used previously in Neil’s [research?] has been using the Stroop Task which is a standard cognitive task where you have to pick words that might be a different colour – so there might be the word Green but it is blue in colour and you have to tell what the colour is as well as the word. It is a quite a difficult cognitive task so that is what we will use as the activation task in the scans and we are doing that at somebody’s baseline and post-exertional.

Holgate: Well I think we’d all like to wish you every success and like to get you back again in a year or two with the answer...

Audience member: So long as it is the right one! [Laughter]

Holgate: Thank you very much for coming.