First of my commentaries on the RC Conference.
This is on the new neuroimaging research.
These are a bit delayed because I think it's helpful to think about content of more detailed summaries.
Overall, this was another very enjoyable, stimulating and well attended biomedical research conference. Much of the content was on neurology with plenary sessions on neuropathology and autonomic dysfunction and a two hour workshop on neuropathology - where I have never been with so many colleagues from neurology, neuroradiology, and neuropathology sitting round a table (along with Prof Jose Montoya) discussing the neurobiology of ME/CFS for two hours!
POST-EXERTIONAL MALAISE (PEM) IN ME/CFS: MRC ANNOUNCES NEW NEUROIMAGING RESEARCH
Dr Charles Shepherd comments on post exertional malaise (PEM) and the new Medical Research Council (MRC) funded neuroimaging study that was announced at the Research Collaborative Conference in Newcastle on Tuesday 13th October
WHAT IS 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
In some respects, PEM is an illness within an illness
WHAT CAUSES PEM?
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
EXISTING RESEARCH INTO PEM
The MEA regards PEM as a research priority. Consequently, the MEA Ramsay Research Fund been funding two research studies in this area:
1 Professor Jo Nijs et al in Brussels and Belgium have been looking at the role of autonomic dysfunction in PEM, in particular the parasympathetic response to exercise. Professor Nijs presented some of the unpublished results to this study during the plenary session on autonomic nervous system dysfunction at the RC Conference. The autonomic nervous system - which is not under conscious control, hence the name - has its control centres in the brain. Through a network of sympathetic and parasympathetic nerves it passes messages to heart, blood vessels, bowel and bladder to regulate (by speeding up or slowing down) a wide range of body functions.
2 Dr Amolak Bansal et al at St Helier Hospital, Surrey have been looking at what happens to immune function before and after a cognitive challenge (completed) and an exercise challenge (not yet done).
So we already have some clues from these and other studies to indicate that the immune system and autonomic nervous system are involved in PEM
THE MISSING LINK?
But what might be happening elsewhere in the brain?
There is a growing consensus that ME/CFS may be an illness that is triggered by infection, which then causes the release of cytokines - immune system chemicals that produce flu like feelings, pain and malaise following any infection. This normal acute immune system response, which is unfortunately known as sickness behaviour/response, then continues in the form of low level immune system activity, continued cytokine production, and activation of immune cells in the brain called microglia. This is a model of causation involving on-going low level neuroinflammation which is supported by a recent Japanese PET neuroimaging study by Nakatomi et al:
http://www.ncbi.nlm.nih.gov/pubmed/24665088
And if there is already low level immune system activation, linked to activation of the microglia/low level neuroinflammation, could an exercise challenge with cytokine production, exacerbate the existing microglial activation and cause an increase in symptoms?
From a theoretical point of view, exercise can stimulate cytokine production (ie IL1, IL6 and TNF) and people with ME/CFS show an exaggerated immune response to exercise:
http://www.medizin.uni-tuebingen.de/transfusionsmedizin/institut/eir/content/2014/94/article.pdf
So, in theory, the answer is yes.....
THE NEW RESEARCH:
What has not been done so far in the investigation of PEM is to look at what happens to brain networks before and after an exercise challenge in ME/CFS - which is where this new study fits in
Dr Mark Edwards, a neurologist at the Motor Neurosciences and Movement Disorders Unit, UCL Institute of Neurology,
Dr Neil Harrison from the University of Sussex, who has already shown how acute inflammatory and infective challenges (e.g. following vaccination with typhoid vaccine:
http://www.nature.com/npp/journal/v40/n4/full/npp2014222a.html or during interferon treatment for hepatitis) can cause activation in parts of the brain and
Dr James Kilner at University College London, will be carrying out this study.
20 people with ME/CFS and 20 age and sex matched controls will have a baseline functional MRI scan and blood samples (for immune system activation measurements) taken
They will then have a specialised exercise challenge to induce PEM
There will also be a fairly difficult cognitive challenge using what is known as the Stroop test
24 hours later the scans and blood tests will be repeated
In relation to the fMRI scans, they will be looking in particular for evidence of activation in key brain structures such as the dorsal insula
Overall, I believe this is a very sound and welcome piece of research that should help to increase our understanding of what is happening in the brain in PEM.
Thanks are also due to Professor Hugh Perry, a member of the RC Board and Chair of the Neurosciences Board at the MRC, for his determination to see high quality research into the neuropathology of ME/CFS taking place
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Transcript of the presentation from Dr Edwards prepared by Russell Fleming:
https://docs.google.com/document/d/1f3FsqRgzLiah_mbMi1j7nDoUih5auUf8VJv03kjnsUQ/mobilebasic?pli=1
Comments from Professor Jonathan Edwards on the Phoenix Rising Forum discussion on the RC conference:
Now we know what we are talking about. It looks brilliant to me. Neil is superb and he clearly has a big input. It is all about inflammatory and neural pathways and specifically about PEM so all that stuff about Oxford criteria can go in the bin. Presumably they will even correlate findings with the degree of PEM. This is proper science. They have even thought of the confounding problems of what people will be thinking because they are in an experiment - and will control for that be switching around the order of events.
I think this is a seriously important move forward in the science. The right people are focusing in on the most likely place to find some clues. And the cytokines and things will be measured as well it sounds like. It fits with the point made on both sides of the Atlantic that we should be studying people during PEM and looking at the abnormal response to exercise rather than just looking at PWME at any old time.
With this and the people connecting to David Brooks repeating the Japanese PET study I think there is the best chance yet of actually pinning down what is going wrong in the ME brain.I think this is a seriously important move forward in the science. The right people are focusing in on the most likely place to find some clues. And the cytokines and things will be measured as well it sounds like. It fits with the point made on both sides of the Atlantic that we should be studying people during PEM and looking at the abnormal response to exercise rather than just looking at PWME at any old time.With this and the people connecting to David Brooks repeating the Japanese PET study I think there is the best chance yet of actually pinning down what is going wrong in the ME brain.And there is no suggestion that this is money pinched from the ME pot. Edwards and Harrison got this grant through the open application system. There was no special pleading, no internal politics. It would have gone up against applications for MS or Alzheimer's or whatever. ME has actually become a fashionable disease to study I suspect. I would double the £600,000 personally.Full discussion here:
http://forums.phoenixrising.me/index.php?threads%2Fuk-research-collaborative-conference-in-newcastle-13th-14th-october.36515%2Fpage-19#post-651365
Dr Charles Shepherd
Hon Medical Adviser, MEABoard member of the UK Research Collaborative
16 October 2015
The MEA funded 4 medical students to attend the RC conference. We also helped to fund the cost of bringing two overseas speakers - Oysten Fluge and Jo Nijs - to the conference.
Ends