Dr Neil Harrison: Webinar on neuroimaging (MRI, fMRI, SPECT and PET scans

[charles shepherd]

Webinar 80:

ME & diagnosis

In this webinar Dr. Harrison talks about:

Present and future possibilities and technologies
What is an MRI and what is an fMRI?
SPECT- & PET-scans
Other hopeful possibilities
Do you expect a breakthrough in research on ME?

 

[Sasha]

This is the latest in a series of interviews with Dr Harrison - the full list is here:

https://www.youtube.com/user/WetenschapvMEcvsVer/videos

 

[Justin30]

I am really interested in PET and SPECT and for a portion of ME patients this will show the problems....

I hope that they maybe able to use this technology for Dyautonomia seen in ME and maybe it might shed some light in that area as well.

 

[Scarecrow]

Do you expect a breakthrough in research on ME?

He was doing so well up to this point but it was disappointing that he got a case of foot in mouth and talked about ME in terms of changes in behaviour:

This is a very interesting question what's happening with research in ME and I think my answer to this is very much yes. I think the develops that I've seen in research funding within the UK and the number of groups that are getting involved in investigating the physiology in ME I think are very good signs that we should be hopeful of breakthroughs in ME research in the coming years. So, for example, the work again, as I've talked about before, of Andrew Lloyd in Australia I think really is very interesting, looking at how previously healthy individuals respond to acute infections and how that changes their behaviour, even after this infection apparently has resolved.

So I think this and a number of other groups' work around the world looking at ME I would be very hopeful that over coming years there could be a number of very useful and insightful breakthroughs into the basis of ME.

There's no doubt that ME does change your behaviour but that isn't the principal issue, rather it's the symptoms that cause your behaviour to change. Today, I'm exhibiting a great deal of sitting-on-the-sofa behaviour because two days ago I did some painting (decorating not artistic) and now I feel like I've been kicked in the head, which nicely illustrates what Harrison is studying. I don't get any sense that he is psychobabbling but it's a lazy use of language that bothers me in a way that talking about 'sickness behaviour' wouldn't have.

Neil Harrison is involved in the MRC funded neuroimaging study that Mark Edwards announced at the CMRC conference last year. There's a quick overview on the ME Association website here. Note that CCC will be used for patient selection:

This was followed by an important research funding announcement from the Medical Research Council relating to a new functional neuroimaging study (fMRI) study that should help to increase our understanding of what causes the most important clinical and diagnosis feature of ME/CFS: post-exertional malaise (PEM).

Post-exertional malaise (PEM), or post-exertional symptom exacerbation, describes a delayed and significant exacerbation of ME/CFS symptoms that always follows physical activity and often follows cognitive activity. PEM is a highly characteristic clinical and diagnostic feature of ME/CFS. And in some respects, PEM is an illness within an illness

The cause of PEM remains uncertain. However, clues are starting to emerge. So gaining a better understanding of the underlying pathophysiological mechanisms involved could help to improve at least one aspect of ME/CFS management

Researchers involved in this study include Dr Mark Edwards, a neurologist from University College London, Dr Neil Harrison, from the University of Sussex and who reported on cytokine-mediated neuroinflammation at the 2014 conference and Dr James Kilner (Institute of Neurology, Imperial College, London). Dr Edwards outlined the background and key points to this research:

On the first day, 20 people with Canadian criteria defined ME/CFS and 20 aged and sex matched controls will have a baseline fMRI scan and blood samples taken. They will then have an exercise challenge to induce PEM.

On the second day, the fMRI scans and blood tests will be repeated.

More details on this study can be found on the MEA website coverage of the conference:
www.meassociation.org.uk/2015/10/post-exertional-malaise-in-mecfs-medical-research-council-announces-new-neuroimaging-research-16-october-2015/

 

[Sasha]

He was doing so well up to this point but it was disappointing that he got a case of foot in mouth and talked about ME in terms of changes in behaviour [...]

There's no doubt that ME does change your behaviour but that isn't the principal issue, rather it's the symptoms that cause your behaviour to change. Today, I'm exhibiting a great deal of sitting-on-the-sofa behaviour because two days ago I did some painting (decorating not artistic) and now I feel like I've been kicked in the head, which nicely illustrates what Harrison is studying. I don't get any sense that he is psychobabbling but it's a lazy use of language that bothers me in a way that talking about 'sickness behaviour' wouldn't have.

I was watching this through the filter of concerns that came up on another thread last year about whether he could be a member of the biopsychosocial school in biomedical clothing and, apart from that single use of the word "behaviour", these videos reassured me. There's a point in one of videos where he's asked whether he thinks ME/CFS is psychological and he clearly says he doesn't think so and that the best evidence for that, from his point of view, is the Lloyd (Dubbo?) studies that show that about 20% of people get ME-like symptoms after a range of different infections, including EBV.

I think a psychobabbler would say that 20% of people get weird fears of exercise (the PACE view is that people might have an acute illness but then they're back to normal except that they're now deconditioned and frightened of activity because they now get a bit more tired and stiff than usual when they try to increase their activity).

I wondered if he said "behaviour" because that's the consistently observable phenomenon where many other markers have been inconsistent (otherwise we'd have a biomarker by now) or because he was using it as shorthand for "sickness behaviour", as you suggest. Like you, I didn't get any sense that he was talking about behaviour as a result of psychological issues.

It seemed clear to me from these videos that he thinks there's some sort of chronic inflammatory process going on in the brain, which he's keen to investigate with PET, MRI, fMRI, MR-spectroscopy and so on - and that inflammation causes "sickness behaviour" (an unfortunate term, but a technical term to refer to biology-driven, adaptive changes in animals' behaviour when they're sick).

 

[Sasha]

At the first day (yesterday) of the IiME biomedical research colloquium, Dr Harrison was presenting in this section:

Biomarkers: 2 Imaging

• Immune-Brain Communication and Relationship to Inflammation and Cohort Selection Challenges Dr Neil Harrison, Sussex University, UK
• Neuroimaging in Clinical Practice in ME tbc
• Chaired Discussion Neuroimaging in ME Research Professor Jonathan Edwards, UCL, UK

 

[Sasha]

I don't know if transcripts are available of these talks, BTW - they have Dutch subtitles and I wonder if they started off with an English transcript that they then translated. A transcript would be very handy (not suggesting that anyone else here does it - just that if transcripts already exist, it would be good to have them posted by WvP.

 

[Justin30]

I like that he is investigating the brain as is younger......I would personally like to see him in contact with Dr Byron Hyde about PET and SPECT Scans.

When ME was first described it was primarily Neurological as to why itvwas labelled that way by the WHO.

Broad definitions and Neuroimaging of people that present with high degrees of Neuro issues should be subjected to these Scans and then repeat on others with different symptom clusters.

I truly believe ME got burried in CFS along with a batch of other diseases as well as disease stages.

 

[Scarecrow]

This is the latest in a series of interviews with Dr Harrison - the full list is here:

https://www.youtube.com/user/WetenschapvMEcvsVer/videos

These were well worth a watch. There are seven clips of which the one Charles posted is (currently?) the final one.

My previous criticism was definitely undeserved. It just goes to show how dangerous it can be to take things out of context.

It is rather ironic, though, that he is such a fan of Lloyd, who appears to have gone over to the dark side in recent years.

 

[Effi]

I don't know if transcripts are available of these talks, BTW - they have Dutch subtitles and I wonder if they started off with an English transcript that they then translated. A transcript would be very handy (not suggesting that anyone else here does it - just that if transcripts already exist, it would be good to have them posted by WvP.

There's a transcript in Dutch (translation from English spoken text) on the local patient website. I ran it through google translate (that's a bit upside down, isn't it? ). Hope it helps?

Transcript College 81: ME and diagnosis

Web lecture by Dr. Neil Harrison, broadcast on May 31, 2016

Opportunities and Technologies: Now And In The Future

How can we in the future develop better diagnostic tools for ME? At present, there are a number of different possibilities. We have been working on MRI scans, and the development of new sequences that are hopefully susceptible to inflammation in the brains. This work is still at an early stage. However, we have already used a pair of sequences that are potentially susceptible to inflammation in the brains.

There is also the work from Japan, indicating that inflammation in the brains of ME patientscan be determined with PET. This is very interesting and should be further developed. What has been shown in particular, is that a PET scan that is sensitive to the activation of the microglia, the brain immune cells, may be an accurate tool for the diagnosis of ME. At this time, it has only been done in nine patients, but if future studies confirm this, then this may in fact become an important diagnostic technique for ME.

What Is An MRI And what is an fMRI?

What is MRI? MRI stands for magnetic resonance imaging. This is a technique in which the human body is being imaged. We use it, in particular, for the brains. MRI can do very much. It does not deliver one kind of image, but you can have all sorts of physiological changes in the brains display it. You can use it, for example, in order to examine the anatomy, or the size of various areas of the brain. You can also use it to look at changes in the chemistry of the brains.

With MR spectroscopy you can examine various chemical substances in the brains, but also, for example, the blood flow and various other parameters: temperature, pH-value in the brains. Thus, it is a versatile technique for the examination of brain structure and function.

fMRI is an MR technique, and with it you can especially see the brain. How brains react to different stimuli? With fMRI you measure small differences in blood flow that occur when a brain region is activated, and this way we can create activation cards through which we can investigate how the brain changes with different conditions.

SPECT and PET Scans


In SPECT and PET scans, radioactive substances are used to check the function of different brain parts. For example, the patient is given an injection of a radioactive tracer, and then looks at the decay of the radioactive substance in the course of time. With these scans we can highlight a chemical substance with a radioactive substance and see all kinds of functions in the brains.

For example, looking at specific receptors for serotonin and dopamine. You can also view the function of microglia with the scans. We may use certain chemicals or drugs in the PET scans that attach to the microglia when activated, but not when they are at rest. Thus, PET and SPECT are very useful tools to look at a variety of brain functions.


Other Hopeful Possibilities

I think that the PET scan and a PET scan of the microglia, is a promising technique to see inflammation in the brains. The problem is that this technique is very expensive, works with radiation and is quite difficult to work with. A number of research groups, including mine, are trying to develop MRI techniques that can show inflammation in the brains.

At present, there are already some encouraging data. We have published results which indicate that certain types of MRI scans are sensitive to brain inflammation. It should be mentioned that this research is still in progress and in the coming years should be further developed.

You expect A Breakthrough In The Search For ME?

This is a very interesting question. What's happening in ME research? My answer is a resounding yes. I think the trends I see in research funding in the UK, and the number of research that deals with the physiology of ME, are hopeful signs of a breakthrough in research into ME in the coming years.

For example, I find the work of Andrew Lloyd in Australia, of which I spoke earlier, very interesting, when you see how previously healthy individuals respond to acute infections and how their behavior will change even after the infection has seemingly disappeared. This work - and the work of other groups in the world who conduct research into ME - makes me hopeful that in the coming years there will be some useful breakthroughs that will provide more insight into the illness ME.

 

[Snowdrop]

These were well worth a watch. There are seven clips of which the one Charles posted is (currently?) the final one.

My previous criticism was definitely undeserved. It just goes to show how dangerous it can be to take things out of context.

It is rather ironic, though, that he is such a fan of Lloyd, who appears to have gone over to the dark side in recent years.

I confess, the more time passes and new information/potential research trials is/are presented the more confused I am as to who represents what view. To some extent at least. Maybe some people themselves are waffling (genuinely) in their own mind. It's pretty clear by now that the BPS people feel the need to concede the point of a biologic trigger that begins the illness. From there it seems one can believe any number of combination biology and mind constructs.

The idea of sickness behaviour wasn't generated for ME I know but it seems to me that over the time papers have been written on ME by the BPS people the language and wording has gone into what I call stealth mode which makes talking about this illness more difficult because now there is no clear meaning to be derived from the words used.

There's more to say but I'm struggling right now and that's all I can manage.

 

[Scarecrow]

There's a transcript in Dutch (translation from English spoken text) on the local patient website. I ran it through google translate (that's a bit upside down, isn't it? ). Hope it helps?

Thanks for pointing us to the transcripts. I'm just putting them through the translator and will post them one by one. [Edit: this transcript is now verbatim in English.]

So my name's Neil Harrison. I am an academic psychiatrist from the University of Sussex in the United Kingdom.

What type of research do you do?
So the type of research that I do really looks at how inflammation, or activation of the immune system, changes our behaviour. So, for example, the way that we think, the way that we feel, the way that we are able to process complex information. I do that in a number of different ways. So some of these studies involve healthy young volunteers that are given an inflammatory process. So I deliberately inflame them with a very mild inflammatory challenge and then look at how that changes their behaviour, how that changes their mood and how it changes things like memory function.

Models of inflammation
So what I mean by models of inflammation is that we have experimental ways of inducing mild inflammation in otherwise healthy individuals. So one of the things that we do is we use just a standard clinical typhoid vaccination. We get healthy individuals and we vaccinate them with typhoid vaccine and then we monitor their immune and inflammatory response over the next three, four, five hours.

How does this relate to ME?
So how does this work relate to ME? This is a very interesting question. What I do is look at normal responses to an inflammatory challenge both in healthy individuals and is that a very high percentage of individuals with ME describe having an acute infective challenge prior to the onset of symptoms. So I think though this isn't an exact, perfect model, I think it is quite a nice model to use to look at how our body and our brains respond to an acute inflammatory challenge.

 

[Scarecrow]

Note: part of this didn't translate, so I'll come back to edit this when I view the clip. Love the first translation of PEM [as post exertional slump] - I may use it in future. [Transcript now edited to verbatim English]

How do you measure fatigue?
So how do we measure fatigue? Fatigue I think is quite a challenging concept, and we measure it in a number of different ways. So at the simplest level we use a number of different questionnaires. For example, ask people to record on a simple, what we call a visual analogue scale, how much fatigue they're experiencing. And this means placing a mark on a line between no fatigue and extreme fatigue. We do a number of other things as well. We use some much more complex questionnaires to try to dissect the effects on different components of fatigue. And we also look at things like sleepiness, or the propensity to fall asleep, which is often confused or conflated with fatigue.

Does fatigue have different components?
Does fatigue have different components? Yes, it clearly does, and I think this is part of the challenge of working in the field of fatigue. For example, many people will describe, will mean different things by fatigue. So, for example, a subjective feeling, a feeling of tiredness. Other people may describe fatigue when what they really mean is feelings of tiredness or feeling like they are sleepy. Other people will relate it to physical fatigue. So, for example, an inability to perform motor actions in contrast to performing cognitive actions. So, yes, fatigue has many different components and I think that is one of the real challenges of work in this field.

Is there consensus about the word fatigue in psychoneuroimmunology?
Is there consensus in my field of psychoneuroimmunlogy? The answer is unfortunately 'no'. There are a number of different ways of measuring fatigue. For example, some of the methods I've just talked about with questionnaires. But it's also known that inflammation can change sleep propensities. We know that inflammation can cause bits of the brain to enter a sleep-like state. So within my field in PNI research, there isn't a true consensus about how we measure fatigue. And again, this remains a big challenge for the field.

Isn't fatigue an over-exposed topic in ME research?
Yes, I think this is an interesting question. Has too much emphasis been place on fatigue in ME research? I think the answer, perhaps, is yes. However, the reason I have tended to focus on fatigue is because we have a very nice potential model to look at how fatigue is represented within the brain. How is it possible that inflammation acts on the brain to change things like fatigue?

One of the other issues within my field is that inflammation induces acute fatigue. However, there's been very little research looking at things like. for example, post exertional malaise, which is another key feature in ME.

Difference between fatigue and PEM
So how do fatigue and post exertional malaise relate to one another? And, again, I think this is a very interesting question. Fatigue is conceptualised as a subjective feeling, the feeling of fatigue, also physiological fatigue. So, for example, an inability to perform as well or at such high level because of fatigue of muscles and also the related concept of tiredness, so sleep propensity. In contrast post exertional malaise is if you like a more complex phenomenon: the experience of many symptoms including fatigue after an exercise challenge or exertion, sometimes of really quite mild exertion.

So even thought the two concepts relate together, they are somewhat different. However, at the moment, my research is really focussed on fatigue itself with an aim of potentially in the future using what we know about that try and understand post exertional malaise.

 

[Scarecrow]

There isn't a transcript for 77. I may insert one later.

General effects of inflammation on the brain
So how does inflammation generally affect the brain? It's surprising that inflammation, even quite mild inflammation, can have quite marked effects on the brain. So in the studies that we use typhoid vaccination. This is a really mild inflammatory challenge yet we see really quite marked changes in brain function. So we see, for example, changes in the metabolism of the brain, how much glucose it's using. We look at various other measures, how it responds to particular challenges.

And other groups have also shown that particular immune cells within the brain appear to change their function. So inflammation, even quite mild inflammation, can have quite rapid and quite dramatic effects on brain function.

More specific effects of inflammation on the brain
So more specifically, inflammation can induce a number of different cognitive changes. So, for example, we and other groups have shown that inflammation can induce even in healthy individuals a mild reduction in mood within about two to three hours of becoming inflamed and interestingly this seems to change the function of part of the brain in fact called the subgenual cingulate region that we know is implicated in depression. So inflammation can change the function of the bit of the brain that we know is involved in depression.

Other areas as well, for example, inflammation can change memory performance. So a number of groups including my own have shown that even mild inflammation can impair our memory. This is a very subtle effect but it seems to do it through changing the function of the part of the brain, the hippocampus or the parahippocampus, that are involved in normal memory function.

We've also shown that inflammation can affect a number of other different brain regions. So, for example, the basal ganglia that are involved in complex cognition and also complex motor movements are also affected by inflammation.

The insula and the basal ganglia
The insula and the basal ganglia are two parts of the brain that have been repeatedly noted to respond to respond to inflammation and appear to have an important role in how inflammation induces fatigue but also impairs motivation.

So, for example, the insula cortex is a part of the brain that is believed to represent the physiological state of our body. So, for example, heart rate, the state of our lungs and of all of the other internal organs. It also seems to be able to represent the inflammatory state of our body. So if our immune system is activated, then we see an increase in activity within the insula. And interestingly those people that active insula most following inflammation are the ones that experience most fatigue.

The basal ganglia is a related region and this is an area that we know from many, many studies is involved in motivation. So, how we respond to rewards and other motivational behaviours and a number of studies have shown that inflammation also changes the responsivity of the basal ganglia, the ventral striatum in particular, to reward. So it seems that inflammation changes the way that we respond to rewards, makes rewarding, things we normally enjoy doing less enjoyable.

 

[Sasha]

It would be good to provide these to the guy who runs the site so he can post them there - I don't know if his contact details are there.

 

[Scarecrow]

Parts of the brain associated with ME
So which parts of the brain are implicated in ME? This is quite a challenging question because there have been quite a large number of different brain regions associated with ME on brain imaging studies.

So one of the most common findings or the most reported finding is quite widespread changes in white matter, and this is the part of the brain that connects different brain regions. There have been also a number of other studies looking, for example, at the role of the basal ganglia, in particular, the ventral striatum and Andrew Miller, a scientist workng in Atlanta, has suggested that the ventral striatum of the basal ganglia respond differently to rewards in people who have ME respond.

So there are quite a large number of different brain regions that have been associated with ME. However, I would say that there need to be a lot more studies done to really try to identify whether any of these are common across individuals with ME.

Connection brain - immune system
So how do the brain and the immune system communicate? This is a very interesting and also quite a difficult question to answer mainly because there are a number of quite different ways that the immune system and brain communicate.

One of the perhaps most important ways is the autonomic nervous system. So these are the nerves that communicate between the brain and the internal organs. They are responsible for controlling heart rate, controlling some degree of control of our intestines, our gut. But also they respond to changes within those organs. So our brain can sense when these different organs change in their function. And they're also very sensitive to inflammation. So if our bodies become inflamed, the autonomic nerves sense this and can communicate this directly to the brain.

There are a number of other ways also that the immune system can communicate with the brain. One is that these proteins produced by the immune system can act directly on the brain, in particular regions of the brain. They can also change the vasculature, so the blood vessels in the brain, resulting in an inflammatory response within the brain itself.

Connection brain - gastrointestinal tract
This is a very interesting question. How do the gastrointestinal tract and the brain communicate? Now even though this isn't work that I've personally been doing, there are a number of groups around the world with a very active interest in how the gut communicates with the brain and in particular, how what's called the microbiome, so the millions and billions of bacteria that we all have within our guts, how that impacts on human function and behaviour. And there have been a lot of very interesting studies beginning to emerge that would suggest that the bacteria within our guts can change a number of things, including our propensity to put on weight, to be overweight, as well as numerous other aspects of human behaviour. So this is a rapidly emerging field that I think will see some very exciting new developments in the coming years.

Cognitions and priming
So this is an interesting concept, and it really addresses the question of how we believe the brain may function. So there are a number of prominent theories that suggests that the brain is a predictive machine. It predicts what it expects to happen in the world and compares that to what is happening in the world. And a simple example of this could be catching a ball. In real time we place our hand in space where we think it needs to be and our brains get feedback from the hand to say where it truly is in space. And this needs to happen, if you like, in real time. In order to catch a ball, we need to be able to compare where we expect our hand to be with the feedback from where the hand actually is.

And similar ideas have been applied to, for example, the relationship between inflammation and fatigue. Our brain predicts a certain amount of inflammation within our body, and then compares that to the signal that is coming in and if there's a mismatch between those two signals, that could be perceived as fatigue.

So these are some ideas that we are currently looking at to see whether those individuals that experience the most fatigue or even chronic fatigue, have a big mismatch between absolute levels and levels predicted within the brain.

Strongest arguments that ME is not a mental illness ['psychic condition' on the slide]
Again this is an important question. What of all of the evidence out there do I think is most supportive of ME not being a psychic or psychological condition? And I think for me that some of the most compelling data comes from a group from Andrew Lloyd in Australia. They've done really beautiful work looking at what happens to otherwise healthy individuals after they get an infection. And they've done this in hundreds of different patients and they've been able to capture them pretty much as soon as they develop an infection and then follow them up for six months to a year. And what this group has shown is that, firstly, in otherwise previously healthy individuals, about twenty percent of them after an infection with things like Epstein Barr and also rarer infections like Ross River virus develop chronic disabling fatigue and that's associated with cognitive impairments, chronic headaches and in many cases also on going muscle aches.

So I think this is really exciting and important data that suggests even in a previously healthy group of individuals, about twenty percent of them will develop chronic fatigue syndrome or ME-like symptoms six months after having one of a number of different infections. So I think this is really powerful evidence that a wide range of different infections can induce chronic fatigue and cognitive symptoms.

 

[Scarecrow]

It would be good to provide these to the guy who runs the site so he can post them there - I don't know if his contact details are there.

The only missing transcript in Dutch is for 77. Instead there is a Q&A session which I haven't read properly yet but here's a link:
https://translate.google.co.uk/tran...odule-ME_CVS_docs-viewpub-tid-1-pid-1537.html

After I've put up the rest of the translations, I'll go back through them all and amend them to a verbatim form. (Might take several days, though).

 

[Scarecrow]

General effects of inflammation on the body
So within the body, inflammation has a number of different effects. It can induce redness around any point of infection or inflammation, and also at the same time a certain tenderness. So, whenever we get an infection or inflammation within the body, we notice that it becomes red and quite tender around that region. That can equally apply to things like muscles, if there's inflammation within a muscle it can become inflamed, it can become tender to the touch and then also painful to use. And one also tends to see a loss of function. So if there's inflammation within a particular organ in the body, it becomes more difficult to use that organ. So, for example, within muscles, When muscles, the muscle becomes weaker.

General effects of inflammation on the brain and relation to feelings of fatigue
So inflammation also has a number, quite a large number, of different effects on the brain. Perhaps one of the most obvious ones and ones that we've known about for many, many years, is that when we get an infection, our body temperature increases and that is an effect that's governed by an effect of inflammation on the brain. So the hypothalamus, a particular part of the brain that regulates body temperature senses inflammation, proteins induced by the immune system, and resets our body temperature to a slightly higher level.

Inflammation also has a number of other actions on the brain. For example, the reduction in appetite and the reduction in desire to drink are also effects that are controlled to some degree by the brain: so when we become infected and inflamed, and this inflammation reduces our desire to eat and to drink.

But inflammation also has a number of other very interesting effects on our behaviour. So, for example, when we become inflamed, we typically experience a light reduction in mood, perhaps even a degree of irritability but we also experience things like subjective feelings of fatigue, difficulty concentrating, difficulty focusing and also a slight reduction in our memory performance.

Other aspects inflammation can also impair are social behaviours, we tend to isolate ourselves more if we become infected and inflamed, and don't want to socialise or to perform, I guess, more novelty seeking type behaviours.

These symptoms as a cluster are known as sickness behaviours and we all experience them whenever we get any infection like the flu, for example.

Different responses to an inflammation in ME
So again I think this is a very interesting question and currently I think the answer to that is poorly understood and this is something that we are currently actively looking at.

So the question is whether somebody with ME responds differently to an inflammatory challenge to someone who doesn't have ME and I think there could be a few different answers to this and that's what we are currently looking at. But one could be that perhaps people with ME have a more aggressive inflammatory response to an inflammatory challenge in the blood or in the periphery or it could be that their response is exactly the same as somebody who doesn't have ME. And then the question would arise, well, are there differences within the way their brain processes that inflammatory challenge. So, for example, does their brain respond more aggressively or in a more, in a greater manner, to an inflammatory challenge than somebody who doesn't have ME?

So at the moment, I think that's a very good question, it's something we are looking at. There is no answer at the moment but hopefully there will be within the next year or two when we look specifically at this question.

Different effects of inflammation
So do all infections have the same effects on the body and on the brain? And again, this is an area of emerging research that, looking at our own research and other groups, there do seem to be some differences in the way that, for example, viral infections or bacterial infections or models of these different types of infection affect the brain. It's quite unclear why this is the case, but it seems that some of the proteins that are activated by different types of infection may have slightly different effects on the brain. So this is an area that we're currently researching, really trying to address are particular parts more sensitive to some types of infection or inflammation compared to others.

Interferon
So what is interferon? Interferon is a cytokine, it's a protein that our bodies naturally produce whenever we become infected and in particular when we become infected by viruses.

There are a number of different types of interferon, but one that is particularly interesting is interferon alpha. And this is also used therapeutically to help treat patients with chronic hepatitis C. And if it's used in combination with other drugs can actually cure quite a high percentage of people with chronic hepatitis C.

However what it also does is that it induces quite severe cognitive and mood changes when it's given to patients. And perhaps one in four to one in three patients who's given interferon alpha chronically develops depression. So it's very clear that by activating the immune system with interferon, we can induce depression, severe fatigue, and a number of other cognitive difficulties in previously relatively healthy individuals.

And just on this point, another interesting phenomenon is that these patients who are treated with chronic interferon, even though their hepatitis C may be cured, there's a percentage of them who go on to experience chronic fatigue chronic cognitive impairment even after the treatment is over.

So again this is potentially a very good model to look at the long term effects of activating the immune system. Why is it that symptoms of fatigue and cognitive impairment persist even after the immune activation ceases?

 

[Scarecrow]

ME patients and inflammation: the differences
Again, there's been quite a lot of research looking at the inflammatory profile or the immune profile in people or in patients with ME. And again the picture that emerges is that there may be some changes in immune activity. For example, a cell called natural killer cells, their function has been observed to be reduced in people with ME. There's also some suggestion that other cells, like T cells, may have altered activity in people with ME. But over all, there doesn't seem to be convincing evidence of elevated inflammatory cytokines in patients with ME. And that has been somewhat of a puzzle, in the literature to date. Why is that inflammatory cytokines are not persistently raised in individuals with ME?

Evidence of inflammation in the blood after the infection is gone
So what about after naturalistic infections, do we see evidence of increased inflammation in the blood after naturalistic infections? And again, the answer is quite interesting, and again this draws on the work of Andrew Lloyd in Sydney in Australia. But what he's shown is individuals that have natural infections with Epstein-Barr virus or other viruses or bacteria show an initial inflammatory response as would be expected.

However, within a few weeks to months, evidence of inflammation within the blood returns to normal. And what's very interesting is that this inflammation returns to normal even in people who have persistent symptoms of chronic fatigue, cognitive impairment and a range of other symptoms like headaches. So it suggests it possible to have persistence of these symptoms after an infection, even when the inflammation or signs of inflammation in the blood return to normal.

Evidence of effect of inflammation in the brain after an infection
So again this is another very interesting question. So what happens in the brains of people after they've had a naturalistic infection? Is there any evidence of increased inflammation in their brain after naturalistic infection? And unfortunately the answer to that question is currently unknown.

However, what is known now and has been very recently shown is that if you take a previously healthy individual and you inflame them, you can see increase in activity in immune cells within the brain, cells called microglia, within three to four hours of an acute inflammatory episode. Now, we don't know how long this activation remains high, but it could be that those individuals that experience on going chronic symptoms after an infection could have increased inflammation in their brain after this inflammatory challenge. And further evidence that I think is quite interesting is the data from patients with ME who have been shown to have increased microglial activation in their brain suggesting that may be this could be what one would anticipate to see after a chronic infection.

Evidence of brain inflammation in ME
So is there any evidence of brain inflammation in ME? Until recently, that would have been a quite a difficult question to answer. However, last year there was some work from a Japanese group using PET imaging, which is a type of imaging using a marker for activation of brain immune cells, so microglia. And what this group has shown is that there does seem to be increased activation of these brain immune cells in patients with ME.

Now, I think this is very exciting research, but one should bear in mind it's only in a very small population at the moment, it's only nine patients with ME were investigated. So this is work that really needs to be further explored.

Microglia and their function
So what are microglial cells? Well, microglia are the main immune cell in the brain and their really unusual cells in that their appearance is quite different from macrophages, their equivalent cell within the blood.

Now these cells within the brain until recently were considered largely to be there to mop up damage. So if cells are killed within the brain, it was believed that their principal role was to help remove debris within the brain.

However within the last five, ten years it's become increasingly clear that these microglial cells likely have very many interesting functions, even within the healthy brain. So there's data suggesting that these microglial cells may play a role in the development of the brain, so how neurons change their connections with one another, a process called dendritic pruning, and also a role in how we learn.

So at the moment, evidence is emerging quite rapidly that these immune cells within the brain probably have very important roles, even in the healthy brain, and in functions such as memory and learning. So this is a field that is rapidly developing, exploring exactly how broad the functions of these cells are.

Present and future possibilities and technologies
So where are we going to go or where may we go in the future to develop better diagnostic tools for ME? At the moment, a number of different possibilities exist. So we have done some work with MRI imaging, developing new sequences that we hope will be sensitive to inflammation within the brain. Currently this work is extremely early. However, we have used a couple of different sequences that we think may be sensitive to inflammation within the brain.

Also the work from Japan, suggesting that PET may be used to identify inflammation in the brains of patients with ME I think is very interesting and work that needs to be developed but essentially what this has shown is that PET imaging that is sensitive to the activation of microglia, these brain immune cells, may be a sensitive tool in diagnosing patients with ME. At the moment, this data's only been acquired in nine patients but of future studies suggest a consistent signal then this could be quite a powerful technique to aid in the diagnosis of patients with ME.

What is an MRI and what is an fMRI?
So what is MRI? MRI stands for magnetic resonance imaging. It's a technique for imaging the human body. In particular, we use it for imaging the human brain.

Now MRI is incredibly powerful. It's not just one type of image, one can image all sorts of different physiological changes within the brain. So, for example, one can use to look at differences in anatomy, differences in the size of different brain regions. One can also use it to look at differences in the chemistry of the brain. So something called MR spectroscopy can look at changes in different brain chemicals.

It can also be used, for example, to look at differences in blood flow and a huge range of other parameters - temperature, pH - within the brains.

So it's a very diverse technology for investigating brain structure and also brain function.

Now, fMRI is again, it's an MR technique that looks specifically at function within the brain. So how is it that the brain responds to different challenges? And it measures, actually, slight differences in blood flow that occur when a brain region is activated, and can produce these activation maps that we can use to look at how the brain function changes from one condition to another.

SPECT and PET Scans
So SPECT scans and PET scans use radioactive tracers to look at the function of different parts of the brain.

So, for example, one needs to inject a patient with a tracer and then look at how that tracer, it's a radioactive tracer, and look at how that tracer decays over the course of time. And what one can do with these scans is tag different chemicals with these radioactive tracers and then look at all sorts of different functions within the brains. So, for example, look at particular receptors for things like serotonin or dopamine. One can also use them for looking at microglial function.
So there are certain chemicals or drugs that can be used in PET scans that we know bind to microglia when they become activated, but not when they are in a resting state. So PET and SPECT are again very useful tools for looking at a diversity of brain function.

Other hopeful possibilities
So I think PET imaging and a PET imaging of microglia could be a very hopeful technology to look at inflammation within the brain. The problems with this technology are though it's very expensive, it involves radiation and it's quite challenging to work with. So a number of groups, including my own, are looking to see whether we can develop MRI techniques to identify inflammation within the brain.

At the moment, some of the data is quite hopeful. We've published some data to suggest that some types of MRI imaging are sensitive to brain inflammation. However, I would caution that this work is very much on going and needs to be further developed over the next few years.

Do you expect a breakthrough in research on ME?
This is a very interesting question. What's happening with research in ME? And I think my answer to this is very much yes. I think the developments that I've seen in research funding within the UK, and the number of groups that are getting involved in investigating the physiology in ME, I think are very good signs that we should hopeful of breakthroughs in ME research in the coming years.

So, for example, the work again, as I've talked about before, of Andrew Lloyd in Australia I think really is very interesting, looking at how previously healthy individuals respond to acute infections and how that changes their behaviour, even after this infection apparently has resolved.

So I think this and a number of other groups' work around the world looking at ME I would be very hopeful that over coming years there could be a number of very useful and insightful breakthroughs into the basis of ME.

 

[duncan]

Under Cognitions and Priming, he notes: "Our brains predict a degree of inflammation in the body and compare this to the signal that arrives. If these two signals do not match, it could be felt as fatigue. These are the things we are currently looking to see whether there is in those who experienced the most fatigue or chronic fatigue, a large difference between absolute levels and levels predicted by the brain."

"Then the question would be whether there is a difference in the way their brains processing inflammatory stimulus."

He seems to be suggesting pwME are interpreting things that aren't real. Maybe I am expressing that poorly. Regardless, these are potentially loaded observations.

He leaves me concerned.