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

[Large Donner]

I think some or many of us here are in the dire situation we are in because we grossly underestimated how ill we were in the early stages of the illness (especially those of us with gradual onset where there was no clear demarcation line between well and ill) and we continued to push and push ourselves at a time when bedrest might have given the best prognosis.

My experience is incongruent with what Mr Edwards is proposing as the mechanism behind functional neurological symptoms. I have experienced situations where I've had, say, 700 bad days in a row with lots of soul-destroying symptoms causing inability to do anything and then a single "good day" comes along when my symptoms are still present but greatly diminished for no obvious reason. Despite all previous evidence to the contrary, I immediately start to think how this could be the beginning of an upward trend, I become optimistic about the illness going away and start imagining totally unrealistic scenarios about how I'm going to be able to go back to work soon etc. And then of course the next day I wake up with symptoms back to square one and I feel extremely foolish for underestimating this ME thing.

Careful the psychs will say this is "Biopolar exertion". 700 bad days and a 1 good day cycle. They can measure that on fMRIs ya know!!!

 

[Large Donner]

The other thing that struck me about Mr Edwards' cogitations is this notion that functional neurological symptoms must be caused by beliefs because they reflect lay people's understanding of the functioning of the nervous system as opposed to what is known in the medical literature about anatomy and physiology. So in his presentation slides and Bayesian hysteria paper he gives an example of a type of functional blindness where the patient develops tunnel vision which is inconsistent with the laws of optics but consistent with Joe Shmoe's intuitions / naive beliefs about the workings of the eye and the brain. In the ME/CFS field we have been subjected to similar hypotheses put forward by some psychiatrists and persons who are B.A. in English Lit and Sociology graduates but who have for some reason decided to write book chapters about ME and who have argued that this illness exists only as an expression of cultural memes / mass hysteria, that without cultural contagion this condition wouldn't exist. But when you think about it, that can't be so. The cardinal symptom of this disease--PEM--which is experienced by millions of people across the world, many of whom had this before media coverage, the internet and support groups is in no way in line with lay people's beliefs about the effects of exertion or the timing of those effects (for some of us with ME, we feel alright while doing the actual activity and the crash/exacerbation of all symptoms starts 24-48 hours AFTER the activity). The immune and autonomic symptoms of PEM are not consistent with what humans believe about exercise, nor is PEM part of any normal human experience or any human language. Only if you are uneducated about ME/CFS and you think this illness is about constant exhaustion or tiredness can you believe that beliefs could cause this illness. In reality this very important key symptom totally defies belief and seems totally alien and improbable. Most of us here struggled for years to make sense of what was happening to us, to understand the causal relationship with exertion that happened a day or more ago, had never met anyone who had ever experienced such a thing, had no language to describe our experience and when we did try to explain it to family or doctors all we got were blank stares and abuse.

If I could give 100 likes to this post I would.

 

[Sidereal]

Careful the psychs will say this is "Biopolar exertion". 700 bad days and a 1 good day cycle. They can measure that on fMRIs ya know!!!

 

[Woolie]

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

@Jonathan Edwards, if you really did believe brain and mind are exactly the same thing, completely synonymous, you would have no problem with my exercise. According to that framework, all I have done is to paraphase.

But in no framework are the terms synonymous. They refer to different levels of description. I substituted one term for the other to show how the message changes.

This is not dualism; this is being clear not to confuse levels of explanation in a way that obfiscates.

In their first lecture, I tell my third year Cognitive Neuroscience students to always consider which term they use in any sentence. We have a level of explanation that is the brain. It has structural properties, functional properties (effective connectivity, resting state connectivity). It has processes: neural activity, modification of connectivity properties through repeated firing, etc).

The mind is a higher level of description again, describes the products of brain activity at the next level of abstraction: its domain is mental processes, feelings, experiences, action plans. One should avoid saying "my brain thinks" any more than "my body walks". You think, you walk: the brain, body, feet are the lower-level systems that make it possible.

This is all pedantry in class, perhaps. But I do think the common trend to substitute brain when you mean mind or person perpetuates misconceptions and can be used to mislead. Compare: "My brain made me do it" to "I did it". Notice how the first allows the user to plead lower responsibility.

Now compare: "My brain is incorrectly processing afferent signs as indicators of illness, and is reacting inapproapriately." to "I am misinterpreting normal bodily signals as signs of illness and catastrophizing". They describe the same phenomenon - at different levels of description - but is clear that the first will offend patients less.

 

[Woolie]

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?

Yea, but you can bet, @A.B., but that somewhere in there, there'll be a "psychologically unstable" clause, that says people who are anxious depressed, introverted, personality disordered, somatisers, etc. are going to be more prone to this than "normal" people.

 

[Large Donner]

Edwards is claiming they will use CCC to look at the issue of PEM in PWME.

Isn't his premise that there is no active/ongoing infection or inflammation in PWME?

If so what does the CCC say about infection, chronic infections, inflammation and other issues like swollen lymph nodes sore throats having to be present?

I cant remember all the stipulations of CCC.

 

[alex3619]

this is being clear not to confuse levels of explanation in a way that obfiscates.

Quite so. This is a tricky point. Its why I talk about emergent behaviour. You could speak about why someone behaves based on quantum, or subatomic, atomic, chemical, biological or psychological levels. Its just silly and totally impractical to research something at one level rather than one that is more appropriate. So behaviour is grounded in sensory processes and brain function, but that goes all the way down to quantum theory if you want it to.

That is why I claim that mind is a label for what is happening. Its not some independent thing. Its just a different description. Mind as the classicists would have it, does not exist. What we call mind is so much more convenient though than talking about detailed functioning and inputs and outputs of the brain, though of course it can be researched like that. Its why I can never quite give up using the term "mind". I do try to use "brain" where applicable though.

 

[user9876]

@Jonathan Edwards, Ii you really did believe brain and mind are exactly the same thing, completely synonymous, you would have no problem with my exercise. According to that framework, all I have done is to paraphase.

But in no framework are the terms synonymous. They refer to different levels of description. I substituted one term for the other to show how the message changes.

This is not dualism; this is being clear not to confuse levels of explanation in a way that obfiscates.

In their first lecture, I tell my third year Cognitive Neuroscience students to always consider which term they use in any sentence. We have a level of explanation that is the brain. It has structural properties, functional properties (effective connectivity, resting state connectivity). It has processes: neural activity, modification of connectivity properties through repeated firing, etc).

The mind is a higher level of description again, describes the products of brain activity at the next level of abstraction: its domain is mental processes, feelings, experiences, action plans. One should avoid saying "my brain thinks" any more than "my body walks". You think, you walk: the brain, body, feet are the lower-level systems that make it possible.

This is all pedantry in class, perhaps. But I do think the common trend to substitute brain when you mean mind or person perpetuates misconceptions and can be used to mislead. Compare: "My brain made me do it" to "I did it". Notice how the first allows the user to plead lower responsibility.

Now compare: "My brain is incorrectly processing afferent signs as indicators of illness, and is reacting inapproapriately." to "I am misinterpreting normal bodily signals as signs of illness and catastrophizing". They describe the same phenomenon - at different levels of description - but is clear that the first will offend patients less.

If mind is effect and brain is physical then don't we need some way of saying what mental processes are automatic or where thoughts are not explicit but that could be said to have an overall affect on cognition. For example, language processing is pretty automatic yet infringes on conscious thought - I was particularly thinking of the conversion from sentence structure into an internal mental representation but has an impact on what we understand others saying.

I guess I would argue that it is not sufficient to talk of mind or brain but proposals should be made in terms of specific neurological things or mental processes.

 

[charles shepherd]

Will there be a Phoenix Rising article, or summary of this conference (of the biomedical stuff, I don't care about the babble) ? I found the stream impossible to follow due to sound qualities.

I am preparing (with a heavy cold caught somewhere in Newcastle!) a fairly detailed report on the RC conference - currently about 3,000 words - for the MEA.

The section on the new MRC funded neuroimaging study from Edwards et al has already been released.

I don't normally produce instant comment on conferences and prefer to take a bit of time afterwards to reflect and produce a detailed summary that covers the whole meeting…...

 

[Jonathan Edwards]

@Woolie, @alex3619, @Snow Leopard, @user9876 and anyone interested.
I am going to try to open a thread on General ME/CFS discussion on 'Mind/Brain and ME theorising' to avoid getting too off topic here. Not that these issues are not important to discussion of the content of the CMRC meeting but they probably need some separate focusing.

 

[charles shepherd]

The potential irony is that today I was at the inaugural meeting of EMERG (European ME Research Group), which was just such a workshop, except at a pan-European level. Moreover the UK side is spearheaded by the Biobank group set up with the help of AfME - and their representative was in London, not Newcastle!! IiME still seem to be a little ahead in this game. But I very much hope that in the longer term everyone will be pulling in the same direction.

I am not in a position to report anything specific back from EMERG but no doubt IiME will make an announcement. It was a very practical businesslike meeting focussing on specifics of cross-European collaboration. There was consensus on pretty much everything and there were no prima donnas. This may go down as a rather peculiar day in the history of ME research but I think entirely positive - different routes need to be worked through. Bigger funding organisations are being drawn in to the discussion through such different routes and that must be good.

Hi Jonathan

I think I ought to clarify that members of the ME/CFS Biobank team were in both London and Newcastle last week

In addition, in Newcastle, we had four members of the Biobank Steering Group and Erinna Bowman had a poster stand explaining the work of the UK ME/CFS Biobank

We also had handouts for everyone attending explaining that the next phase is to open up the biobank to researchers who want to make use of the blood samples that have been collected from over 500 participants so far

The ME/CFS Biobank was established with joint equal funding from AfME, MEA, MERUK and a private MEA donor

The MEA Ramsay Research Fund has agreed to act as sole funder for the next two years work - at a cost of around £80,000 - which will enable us to start supplying samples to the research community

This is the section on the ME/CFS Biobank that I am writing in my RC conference report:

Over lunch (on Tuesday) we had an opportunity to visit the wide ranging exhibition of poster research, including one presented by Erinna Bowman from the ME/CFS Biobank.

This described the work of the ME/CFS Biobank – which is now being funded by the MEA Ramsay Research Fund - and what has been achieved so far in relation to blood sample collection.

This includes over 25,000 samples/aliquots from over 500 participants.

The three groups comprise of:

(a) people with ME/CFS (diagnosed by a physician and compliant with Fukuda and Canadian criteria and compliance available for four other diagnostic criteria) including a cohort with severe ME/CFS and samples that are being collected longitudinally at 6 monthly intervals,

(b) healthy controls and

(c) a further cohort of people with multiple sclerosis.

Figures at July 2015: 245 ME/CFs cases; 101 healthy controls; 44 with MS = 22,500 aliquots

The blood samples comprise of whole blood; serum, plasma, RBCs, PBMCs, blood for RNA extraction.

Associated data available includes:

(a) baseline standard Laboratory tests to exclude other causes of fatigue,

(b) detailed clinical data and symptom assessment,

(c) demographic information

(e) standardized instruments of fatigue severity and functional impairment.

The ME/CFS Biobank aims to open for the supply of samples to research groups in early 2016.

Fees, which are currently being calculated, will be based on cost recovery only.

Researchers who wish to register an interest in sample supply should do so via: mecfsbiobank@LSHTM.ac.uk

ME/CFS Biobank website:

http://www.lshtm.ac.uk/itd/crd/research/cure-me/ukmecfsbiobank/


CS

(Chair of UK ME/CFS Biobank Steering Group)

 

[Cheshire]

This is all pedantry in class, perhaps. But I do think the common trend to substitute brain when you mean mind or person perpetuates misconceptions and can be used to mislead. Compare: "My brain made me do it" to "I did it". Notice how the first allows the user to plead lower responsibility.

Now compare: "My brain is incorrectly processing afferent signs as indicators of illness, and is reacting inapproapriately." to "I am misinterpreting normal bodily signals as signs of illness and catastrophizing". They describe the same phenomenon - at different levels of description - but is clear that the first will offend patients less.

I agree it's important not to offend patients, but I've got a problem with the "what's less offensive to patients" stance. It's what Stone et al. were trying to achieve in the paper about the numbers needed to offend (a nice way to tell a "truth" disturbing to patients). I think what should be aimed at is not is it offensive or not, but is this statement correct or not.
So in those two ways of explaining things, what facts allow to back up every theory, according to the available evidence, is one more probable? I'd behappy to see any convincing evidence to support the misinterpretation hypothesis.

(I hope it's clear, cause I'm really foggy (or my brain is?)

 

[Jonathan Edwards]

Hi Jonathan

I think I ought to clarify that members of the ME/CFS Biobank team were in both London and Newcastle last week

Yes, thanks for the detail, Charles. I think we are agreed that what was good about last week was exactly this - that however much there may be different venues and umbrellas in ME research in the UK the important people were represented in all of them!!

I did not mean to leave out MEA as a funder of the Biobank. I think I only mentioned AfME because they had been mentioned in a previous comment and I was trying to indicate that everyone was everywhere. I would have liked to get to Newcastle as well but had too much on to do both meetings that week. I am very pleased to see the Biobank getting exposure there with Erinna's poster etc. I look forward to meeting up at the next steering committee meeting.

 

[K22]

I think the MRC have rolled a clever ball. We have nearly 27 pages largely hypothetically discussing a small probably £200,000 study, so all focus is on the crumb not that we have, for yet another year as lives waste, been only given a crumb by a uk tax payer funded research society who should be doing/giving far more. Whilst Holgate talks big data Ron Davis, for his wasting away son, is DOING big data research with plans to do a grand project. At least the severe in the uk have that as a beacon of hope.

 

[charles shepherd]

I think the MRC have rolled a clever ball. We have nearly 27 pages largely hypothetically discussing a small probably £200,000 study, so all focus is on the crumb not that we have, for yet another year as lives waste, been only given a crumb by a uk tax payer funded research society who should be doing/giving far more. Whilst Holgate talks big data Ron Davis, for his wasting away son, is DOING big data research with plans to do a grand project. At least the severe in the uk have that as a beacon of hope.

I think this discussion on the 2015 RC conference is getting bogged down on just one important presentation on the new PEM neuroimaging study. There were around 25 presentations + workshops + posters at this meeting. I will post below my MEA summary of the presentation from Prof Jose Montoya, which I think provides plenty of food for thought and discussion as well…..!

 

[charles shepherd]

TUESDAY MORNING: Conference Opening and Plenary Session on Neuropathology


PHOTO: Professor Stephen Holgate, Southampton University, opened the conference with some encouraging news about the Wellcome Trust (a major funder of medical research) and Arthritis Research UK (another research funder that is interested in some of the overlaps between inflammatory arthritis and ME/CFS) joining the collaborative and making a substantial financial contribution.


Professor Holgate referred to some of the key conclusions and recommendations relating to nomenclature, definition, and the need to make ME/CFS an inclusive diagnosis that were contained in the Institute of Medicine (IoM) report. He also welcomed the sometimes critical but constructive analysis of ME/CFS research contained in the National Institutes of Health Pathways to Prevention report.


Taking this forward in the form of a ‘Grand Challenge’, Professor Holgate set out a number of research priorities which all the key stakeholders involved in research must now address:


· Agreeing on a case definition for ME/CFS


· Subgrouping (phenotyping in medical jargon) people who come under the ME/CFS umbrella in order to develop what is now referred to as personalized medicine. Professor Holgate compared the situation in ME/CFS to asthma, which used to be regarded as one homogenous disease with one basic cause and treatment. Asthma is now recognized to be a very heterogeneous condition that involves at least six different molecular and cellular pathways, with differing phenotypes responding (or not responding) to different forms of treatment (mast cell stabilization for example).


· Collecting and banking biological samples – blood, post-mortem tissue etc


· Identifying preventable and therapeutic targets for each subgroup


PHOTO: Professor Jose Montoya, Stanford University, USA, opened the first plenary session on neuropathology with an outstanding presentation that commenced with a one minute silent tribute to his close colleague Dr Martin Lerner, who had recently died. Martin Lerner had worked with Professor Montoya on a number of research studies, including the use of antiviral treatment.


Professor Montoya also referred to the impact of the Institute of Medicine (IoM) report and is a supporter of the new IoM diagnostic definition for ME/CFS (or systemic exertion intolerance disease/SEID as is being recommended in the report) because he believes that clinicians need a simple and accurate way of making a diagnosis and one that is better than is contained in the options – eg Canadian, Fukuda – that are currently available. Work from the Stanford group indicates that there is a strong (90%) concordance between Canadian, Fukuda and IoM definitions.


He then said that people with ME/CFS had been ignored and humiliated by the very people who were supposed to be helping them – the medical profession. In his own words….“I have a wish and a dream that medical and scientific research societies in the US will apologise to their ME/CFS patients”.


Turning to treatment, Professor Montoya described how the publication of a flawed clinical trial involving acyclovir had led to the view that ME/CFS was not caused by EBV infection and that antiviral drugs do not have any role in the treatment of ME/CFS. Despite this, he has been involved in a number of the clinical trials that have assessed the efficacy and safety of the antiviral drug valganciclovir. This is a treatment option – involving a lower dose than is normally used in other situations over a prolonged period of time, at least 6 months, possibly much longer - that he now uses for some ME/CFS patients with considerable success. In addition to antiviral activity and reduction of latent HHV-6 replication, he believes that this drug may have immunomodulatory effects in ME/CFS as well (as it can decrease the level of white blood cells called monocytes and reduce microglia activation in mice).


[CS note: During the discussion that followed I pointed out that here in the UK antiviral treatment is not recommended by NICE - so antiviral drugs are seldom used in ME/CFS and very little interest has been shown in further research or clinical trials involving antiviral treatment. The MEA has met with Roche, the pharmaceutical company that makes this drug, but we did not have any success in trying to set up a UK clinical trial. We clearly need an independent randomized placebo-controlled trial to assess the value of valganciclovir in ME/CFS.


Professor Montoya then described some of the other research that his multidisciplinary group at Stanford are carrying out on a large group of ME/CFS patients, along with healthy controls, with the help of a $5 million anonymous donation. In particular:


· Immune function studies which are looking at the response to infection with various organisms and the role of immune system chemicals called cytokines, and how the cytokine pattern changes over time (less or more than 3 years – the Hornig/Lipkin study), as well as daily fluctuations in cytokines relating to activity levels. To do so they can measure over 50 individual cytokines and have access to a cohort of around 200 ME/CFS patients and 400 controls. The Stanford group intend to examine the function and role of natural killer (NK) cells. A proposed research study will also involve a detailed study of the role of NK cell status and function in ME/CFS.


· Virology studies examining the role of latent herpes viruses including EBV and HHV-6 and how low NK function may be maintaining HHV-6 activation in ME/CFS. Professor Montoya also referred to research involving Torque viruses. Torque teno virus is considered to be a relatively new global marker of immune function and the more immunosuppression occurs, the higher the level of torque viruses. Professor Montoya pointed out that torque viruses have been found to be lower in ME/CFS – adding further support to the role of immune system activation in ME/CFS.


· Neuroimaging studies looking at both grey and white matter in the brain - one of which has used diffusion tensor imaging, an MRI based technique that can visualize location, orientation and anisotropy of white matter tracts in the brain. This study has recently been published and reported a very significant structural abnormality involving the right arcuate fasciculus. This structure contains fibres, which connect different areas of the brain. The fibres are thicker in ME/CFS than in healthy controls and the inference that nerve fibre transmission is therefore affected could turn out to be a diagnostic marker for ME/CFS.


· Genetic studies examining HLA characteristics in ME/CFS and a genetic predisposition to ME/CFS


Key references:


Immunology: cytokine status and illness duration


http://www.ncbi.nlm.nih.gov/pubmed/26079000


Neuroimaging: right arcuate fascicus abnormality


http://pubs.rsna.org/doi/abs/10.1148/radiol.14141079


Valganciclovir clinical trials:


Kogelnick 2006:

http://www.ncbi.nlm.nih.gov/pubmed/17276366


Lerner et al, 2002:

http://www.ncbi.nlm.nih.gov/pubmed/12582420


Lerner et al: 2004:

http://www.ncbi.nlm.nih.gov/pubmed/12582420


Montoya et al 2013:

http://www.ncbi.nlm.nih.gov/pubmed/23959519


Watt et al, 2012

http://www.ncbi.nlm.nih.gov/pubmed/23080504


Valganciclovir reduces inflammation in HIV:


http://hivandhepatitis.com/recent/2011/0426_2011_c.html


>> All patients treated with valganciclovir had undetectable CMV viral load after 8 weeks of treatment, while 44% of those in the placebo group still had detectable CMV. In addition, valganciclovir-treated participants had significantly greater reductions in CD8 T-cell activation (defined as CD38+HLA-DR+ marker profile) compared with placebo recipients at weeks 8 and 12 -- a reduction of about 20%. Patients in the valganciclovir arm also had reduced levels of high-sensitivity C-reactive protein (CRP), a blood biomarker of inflammation.


Virology: Torque viruses:


http://jid.oxfordjournals.org/content/early/2014/05/05/infdis.jiu210.full


YouTube video of opening remarks from Professor Stephen Holgate and presentation from Professor Jose Montoya:

 

[MeSci]

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.

As long as the cost-benefit sums are in our favour. There are patients who can't get drugs prescribed even if they will slow down their disease progression, prolong their lives or preserve their eyesight because NICE or other bodies decide that the cost-benefit calculations don't warrant them. It can be very distressing, and patients/parents/carers/supporters/friends/communities sometimes raise the funds to have the treatments abroad.

 

[Dolphin]

As long as the cost-benefit sums are in our favour. There are patients who can't get drugs prescribed even if they will slow down their disease progression, prolong their lives or preserve their eyesight because NICE or other bodies decide that the cost-benefit calculations don't warrant them. It can be very distressing, and patients/parents/carers/supporters/friends/communities raise the funds to have the treatments abroad.

In ME/CFS specifically, there could well be a "fight"/comparison between CBT/GET or a new treatment on which is better value for money.

 

[MeSci]

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.

When theorising about pain in ME, one needs to bear in mind that we suffer it to very varying degrees, some of us not at all. See this poll thread for example.

 

[Bob]

As long as the cost-benefit sums are in our favour. There are patients who can't get drugs prescribed even if they will slow down their disease progression, prolong their lives or preserve their eyesight because NICE or other bodies decide that the cost-benefit calculations don't warrant them. It can be very distressing, and patients/parents/carers/supporters/friends/communities raise the funds to have the treatments abroad.

I know it's distressing for those involved but my understanding is that the cost-benefit issues tend to be related to very expensive drugs that have borderline or minimal benefits. The NHS does provide plenty of expensive drugs. If rituximab helps half to two-thirds of patients then I can't imagine it being refused on cost grounds.