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

[charles shepherd]

That seems to be a central question. I have reservations about fMRI being able to pick up what is needed but if it is looking at central brain areas like basal ganglia and brain stem then it is unlikely just to be reflecting conscious thinking. (I think the signal in the typhoid study was basal ganglia.) I think there is a reasonable chance that some headway can be made with the question.

If people with PEM can be shown to have a particular signal in central brain during PEM which they did not have before and which is not present in healthy controls but maybe looks like something seen in people just after typhoid vaccination then I think that would be a huge step forward. It might even be a diagnostic test. As far as I know, when people are actively thinking 'beliefs' in the sense of conscious ideas about oneself or the world there are no changes in central brain on fMRI. If there are changes they are likely to be in medial prefrontal cortex where thoughts about oneself and ones relation to the world seem to give signals. If the study shows a signal in basal ganglia and the researchers say 'look there is the false belief operating' I think it would fairly rapidly become clear with further research in cognitive science units that this was not a belief in the personal sense. @Woolie makes an interesting point about replacing the word brain with 'person' but I think there are complications to that, which I may come back to in another post.

So if it becomes possible to show objectively the brain registering PEM then if at the same time peripheral mediators are measured it becomes possible to refute certain body>brain options. If blood lactate is normal in a study where people say they are having PEM it may seem a bit subjective. But if blood lactate is consistently normal when fMRI shows brain changes of PEM during the symptoms then it is reasonable to conclude that lactate is not the mediator. That does not exclude cellular level interferon signals in muscle signalling to the brain via sensory nerves without any rise in plasma interferon but at least it reduces the possibilities by one. And that tends to be how one moves forward in pathophysiological research - crossing off options until one is left with very few possibilities.

And of course an objective measure of PEM in the brain would be the perfect tool for showing that CBT has no effect if indeed it has no effect. After CBT patients may say they have much less PEM to please the therapist but if the fMRI after exercise still shows PEM changes the cover is blown. Equally for rituximab - either it will change the fMRI signal during PEM or it will not

There is some interesting evidence from the dim and disrant past regarding the possible role of basal ganglia:

http://www.ncbi.nlm.nih.gov/pubmed/12598734

- which was carried out by my neurologist colleague, Dr Abhijit Chaudhuri

and in the brain stem:

http://www.ncbi.nlm.nih.gov/pubmed/8542261

in ME/CFS

The brain stem hypoperfusion abnormality from Durval Costa et al at the Middx Hospital was put forward as a diagnosic marker at the time and it is unfortunate that this single-photon emission tomography (SPECT) study has never been properly replicated

There was some interesting discussion on the possibility that these two anatomical regions are involved in ME/CFS during the neuropathology session and workshop at the UKRC conference

 

[user9876]

I do not know the details planned. I think we are a long way off seeing an objective endpoint based on fMRI but if something was found that could be replicated by other groups it would make sense.

I wasn't thinking of an fMRI end point but an exploration to see if there were changes before Rituximab and as people respond along with taking a set of measures/readings to compare to those without treatment. I was wondering if this would help understand what has changed and hence how it may be working?

 

[Snow Leopard]

From what I hear from PWME I find it quite hard to believe that ME is simply a brain loop of either sort. I think there must be some input from peripheral signals from tissues.

There is a genuine fear that a brain-loop centred theory will lead to stagnation in terms of finding treatments with strong efficacy/low side effects. Most examples of such treatments today are quite crude - from electroshock therapy to neurotransmitter modulating drugs. The rest are put in the too-hard basket.

There is some interesting evidence from the dim and distant past regarding the possible role of basal ganglia

Is the proposed study going to investigate these other regions too?

 

[Jonathan Edwards]

This brings in another physical area of whether it is enough to understand firing of neurons or whether chemicals or other substances either temporarily change the effects of neurons or permanently change connections. When my wife was on one particular antibiotic she became very confused and quite paranoid but the effect went when the drug was changed (not sure of the time lag). Such changes seem just to add a huge amount of complexity when trying to understand the system.

Agreed, we have touched on this in another context. Changes to connection patterns may be all that is needed and that does not show up directly on any known technique to date. It might show up indirectly in terms of responses to stimuli though.

 

[Sidereal]

There is some interesting evidence from the dim and disrant past regarding the possible role of basal ganglia:

http://www.ncbi.nlm.nih.gov/pubmed/12598734

- which was carried out by my neurologist colleague, Dr Abhijit Chaudhuri

There is an American study from last year using fMRI showing decreased activation in basal ganglia:

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098156

Compared to non-fatigued controls, patients with CFS exhibited significantly decreased activation in the right caudate (p = 0.01) and right globus pallidus (p = 0.02). Decreased activation in the right globus pallidus was significantly correlated with increased mental fatigue (r2 = 0.49, p = 0.001), general fatigue (r2 = 0.34, p = 0.01) and reduced activity (r2 = 0.29, p = 0.02) as measured by the Multidimensional Fatigue Inventory. No such relationships were found in control subjects. These data suggest that symptoms of fatigue in CFS subjects were associated with reduced responsivity of the basal ganglia, possibly involving the disruption of projections from the globus pallidus to thalamic and cortical networks.

 

[charles shepherd]

There is an American study from last year using fMRI showing decreased activation in basal ganglia:

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098156

Thanks - I should have included this one as it also supports a role for basal ganglia:

Abstract
Reduced basal ganglia function has been associated with fatigue in neurologic disorders, as well as in patients exposed to chronic immune stimulation.

Patients with chronic fatigue syndrome (CFS) have been shown to exhibit symptoms suggestive of decreased basal ganglia function including psychomotor slowing, which in turn was correlated with fatigue. In addition, CFS patients have been found to exhibit increased markers of immune activation.

In order to directly test the hypothesis of decreased basal ganglia function in CFS, we used functional magnetic resonance imaging to examine neural activation in the basal ganglia to a reward-processing (monetary gambling) task in a community sample of 59 male and female subjects, including 18 patients diagnosed with CFS according to 1994 CDC criteria and 41 non-fatigued healthy controls. For each subject, the average effect of winning vs. losing during the gambling task in regions of interest (ROI) corresponding to the caudate nucleus, putamen, and globus pallidus was extracted for group comparisons and correlational analyses.

Compared to non-fatigued controls, patients with CFS exhibited significantly decreased activation in the right caudate (p = 0.01) and right globus pallidus (p = 0.02). Decreased activation in the right globus pallidus was significantly correlated with increased mental fatigue (r2 = 0.49, p = 0.001), general fatigue (r2 = 0.34, p = 0.01) and reduced activity (r2 = 0.29, p = 0.02) as measured by the Multidimensional Fatigue Inventory. No such relationships were found in control subjects.

These data suggest that symptoms of fatigue in CFS subjects were associated with reduced responsivity of the basal ganglia, possibly involving the disruption of projections from the globus pallidus to thalamic and cortical networks.

 

[Large Donner]

In the cases of meningitis and encephalitis once its said the original virus has cleared are there diagnostic tests which explain long term illness?

I was just wondering, in order to put this in to context for Edwards study and similar studies that presumably start from the premise of no active or current infection or inflammation in ME and what a downstream fMRI could say about cause or effects of symptoms. Presumably the starting notion is that there is no nerve damage present which seems somewhat flawed.

I know for a fact that "non epeleptic seizures" is a problematic notion now because higher Tesla magnet MRIs are proving to find many more lesions in that patient group that where said not to be present in the standard 1.5 MRI Tesla tests.

It seems quite clear now that a "lack of epileptic lesions" is a problematic call to make whilst one continues using old tools because "that's the scan that everyone else gets".

Actually even in MS they are now claiming that the lesions present do not correlate with understanding or predicting symptoms. Yet there is not the attempt to push for the notion of a "functional disorder" to anything like the same extent as there is in ME.

Wouldn't it make much more sense to spend this MRC money on 3 Tesla and even up to 7 Tesla MRI scans instead of the bog standard 1.5 magnet field instead of the downstream effects of ........ on a functional MRI?

 

[Simon]

This appears to be the key Neil Harrison study (from 2009) using typhoid vaccine to provoke inflammation and sickness response. So I guess this is the core methodology they will use, typhoid for healthy controls, compared with exercise challenge for mecfs patients. Guess being the operative word. Or maybe it's patients vs healthy on the exercise challenge - he mentioned they have historical data for other groups, so perhaps they will use historical data to look at the typhoid inflammation challenge.

Neural Origins of Human Sickness in Interoceptive Responses to Inflammation

Abstract
Background
Inflammation is associated with psychological, emotional, and behavioral disturbance, known as sickness behavior. Inflammatory cytokines are implicated in coordinating this central motivational reorientation accompanying peripheral immunologic responses to pathogens. Studies in rodents suggest an afferent interoceptive neural mechanism, although comparable data in humans are lacking.

Methods
In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Profile of Mood State questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed a high-demand color word Stroop task during functional magnetic resonance imaging. Blood samples were performed at baseline and immediately after scanning.

Results
Typhoid but not placebo injection produced a robust inflammatory response indexed by increased circulating interleukin-6 accompanied by a significant increase in fatigue, confusion, and impaired concentration at 3 hours.

Performance of the Stroop task under inflammation activated brain regions encoding representations of internal bodily state.

Spatial and temporal characteristics of this response are consistent with interoceptive information flow via afferent autonomic fibers.

During performance of this task, activity within interoceptive brain regions also predicted individual differences in inflammation-associated but not placebo-associated fatigue and confusion.

Maintenance of cognitive performance, despite inflammation-associated fatigue, led to recruitment of additional prefrontal cortical regions.


Conclusions
These findings suggest that peripheral infection selectively influences central nervous system function to generate core symptoms of sickness and reorient basic motivational states.
--------------------------------------

Certainly looks very interesting.

Maintenance of cognitive performance, despite inflammation-associated fatigue, led to recruitment of additional prefrontal cortical regions.

That rings a bell, I dimly remember a CFS study that found although patients matched controls on cognitive performance, they need to use more brain areas to get the job done.

I think the study is well worth doing, it could help illuminate what's happennig in mecfs, and this Neil Harrison paper does provide a very interesting experimental approach.

My concern is that if they don't find inflammation in response to exercise there will be a jump to a conclusion that there is no problem in the periphery (as others have said) and an interpretation in line with that favoured by Mark Edwards for Functional Neurological symptoms. Now, maybe that would be the right conclusion, but I'd want it to be based on positive evidence, not the absence of a spike in inflammatory cytokines.

 

[A.B.]

Speaking of expectations and beliefs: people with ME/CFS commonly report underestimating, sometimes severely, their capacity to exert themselves. It's not just other people that underestimate how sick we are, we ourselves tend to underestimate it.

Theories that we have come to expect symptoms and fill them in when they're absent don't seem to make any sense if one observes what is actually happening.

I'm also not sure how maladaptive interoception is supposed to develop in patients with gradual onset, which are a substantial portion.

 

[Simon]

George Davey Smith talk is now on youtube, but the audio quality is 'not ideal'

 

[Snowdrop]

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.

First I'd like to just insert the comment again that I too think that the NHS does some things brilliantly. When my daughter was an undergrad at Durham she had to have an operation to remove a neurofibroma. This was done at Newcastle and she had nothing but good things to say about the actual medical experience (they booked her while she was doing exams so she rebooked her surgery--that was a bureaucratic nightmare--but that's something else). But even if a biomarker is found I fear that there will still be a colossal battle for those in the UK. After all what if the biomarker is discovered by US researchers. How much validity will it be given since the powerful psychiatric interests are capable of ignoring other good research. To me this is a political issue that needs to be aggressively addressed.

I don't understand all that is being said about M Edwards proposed research but even if it does find what it's looking for as J Edwards proposes I again don't see how that stops him and others from declaring CBT/GET efficacious. As Valentijn pointed out--that's where they start from and work backward from there. They've probably already mapped out the conclusions is my guess. My conclusion doesn't stem from any science obviously but from as SOC pointed out loads of previous experience.
And I'm not sure how the other two arms of his research (which is also on pain?) might be used to cross pollinate findings from the ME study. There are a lot of open ends here.

And as far as monies being spent how high up there is this kind of research on behalf of ME in terms of importance to pursue? Is it a potential biomarker? And if it does look like a biomarker given what J Edwards said about their conception of mind/body could it be spun to mean something other than how we would think of it?

I feel like I'm sounds rather negative here. Does anyone know how far in the future the results will be from this research?

Just read C Shepherd's message on the MEA site. So separate money. I just don't know what to say about the upbeat hopefulness except may it prove to be so.

 

[Jonathan Edwards]

Theories that we have come to expect symptoms and fill them in when they're absent don't seem to make any sense if one observes what is actually happening.

I'm also not sure how maladaptive interoception is supposed to develop in patients with gradual onset, which are a substantial portion.

I agree; I still do not see how this is supposed to work in the framework of Bayesian 'forward models' of perception. You should get the opposite effect. Moreover, my limited experience of post-EBV fatigue (6 months) was the opposite. There remain two distinct memories from 50 years ago fresh in my mind. The first was sweating and feeling sick after a minor attempt to go canoeing around 6 months after EB infection. I said to my mother how miserable I felt that I could not go out on the water with the others. She explained to me (she was an EB virologist) that this was common for about 6 months after being ill. The second memory is of being out in the open about two to three months later and running and suddenly thinking 'wow, I can do this; nothing is stopping me any more'. So the theory fails. When the bad input fails to arrive the response is not the same old misery but the opposite - an exaggerated feeling of wellness, enough to remember for a lifetime. That is what the Bayesian forward model should give you, just as you see the other train as going backwards when in fact it is your train that has started going forwards too slowly for you to feel.

Maybe the theory would say that my brain unlearned the bad expectations that had lingered on for 6 months. But I didn't do any graded exercise therapy. I just went out one day and found the malaise was gone. How would the theory deal with good patches and crashes in ME? i cannot get my head around it.

 

[lansbergen]

Maybe the theory would say that my brain unlearned the bad expectations that had lingered on for 6 months. But I didn't do any graded exercise therapy. I just went out one day and found the malaise was gone. How would the theory deal with good patches and crashes in ME? i cannot get my head around it.

It does not make sense.

 

[Sidereal]

Speaking of expectations and beliefs: people with ME/CFS commonly report underestimating, sometimes severely, their capacity to exert themselves. It's not just other people that underestimate how sick we are, we ourselves tend to underestimate it.

Theories that we have come to expect symptoms and fill them in when they're absent don't seem to make any sense if one observes what is actually happening.

I'm also not sure how maladaptive interoception is supposed to develop in patients with gradual onset, which are a substantial portion.

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.

 

[Sean]

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.

[snip]

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.

They can be maddeningly unpredictable.

 

[Sidereal]

But I didn't do any graded exercise therapy. I just went out one day and found the malaise was gone. How would the theory deal with good patches and crashes in ME? i cannot get my head around it.

Good post.

I would just add that the deconditioning hypothesis is also something I cannot wrap my head around. I've been living in a house with stairs for the past several months, having previously lived in apartments with no stairs. As a result, I now have to climb stairs many times a day so you would expect this new physical activity to gradually get easier over time as a result of re-conditioning. The reality is just the opposite - my ability to carry out this activity, or any other physical activity, is exactly the same as it was the day I moved in. On "normal" days I can go up and down many times with my regular levels of orthostatic intolerance and fatigue. Some days when I'm having a bad day I probably go down only once or twice because more than that will result in severe difficulties. No random spontaneous trips to make tea! Sad, pathetic really, how grotesquely disabling this disease is. On really bad days - very rare now - I cannot get to the kitchen at all because I won't be able to get back up the stairs so I have to stay upstairs all day and people have to bring me food (embarrassing and certainly not something I indulge in). On good days - even rarer - I can feel my legs being much "lighter" than normal, I naturally move much faster, I can get up and down easier and faster, no ataxia, less dizziness, no abnormal fears of activity, I naturally & spontaneously increase the number of times I go up and down without having to get psychotherapy to persuade me to do "graded" anything etc. The good days during which I do more "exercise" as a result of feeling better never lead to any sustained improvement in my condition. The day after a good day I am usually back to my baseline or below my baseline, it is never possible to implement any kind of graded programme of reconditioning. Good, bad and regular days alternate seemingly at random. The only time I am guaranteed to have three bad days in a row is if I exerted myself beyond the PEM threshold the day before so that part is not random and is entirely predictable like clockwork.

Just as they make these arguments about muscle / cardiovascular deconditioning, they make similar arguments about orthostatic intolerance and POTS being caused by bedrest. No way. A bad flare of OI when I'm stumbling around with dizziness and heart rate is going to 120+ gets better only after total bedrest for me. If I continue to do stuff, it only gets worse and worse. It's exactly the opposite of what they would predict. I just can't fathom how they can believe the things they do when patients have been telling them the opposite for years.

 

[A.B.]

I just can't fathom how they can believe the things they do when patients have been telling them the opposite for years.

I have been joking about how one should always do and believe the opposite of what they say. Either they're comically incapable of listening to patients, or they are listening very well but have decided that whatever it is we're doing and thinking must be making us sick, and that therefore patients should do the opposite of what they want.

 

[SOC]

Speaking of expectations and beliefs: people with ME/CFS commonly report underestimating, sometimes severely, their capacity to exert themselves. It's not just other people that underestimate how sick we are, we ourselves tend to underestimate it.

Theories that we have come to expect symptoms and fill them in when they're absent don't seem to make any sense if one observes what is actually happening.

I'm also not sure how maladaptive interoception is supposed to develop in patients with gradual onset, which are a substantial portion.

Exactly my thinking. This also doesn't explain variation in how much activity will cause PEM. It's not always the same degree of exertion that causes symptoms. Sometimes we don't get PEM when we expect to and other times, we get PEM when we don't expect to. How does that fit with the interoception theory?

Then there are the cases where people are able to do more before they PEM once they've received medical treatment -- OI meds, abx, antivirals, etc. One could suggest that there is some expectation of improvement, but that totally ignores the degree. How does interoception fit when we don't know if, or how much, improvement we'll get? What puts the "stop" on improvement? Does my brain decide (without my knowledge) that it's going to expect a certain amount of improvement, but only that much and not more?

If this hypothesis is true for ME symptoms (and those of a few other illnesses they can't explain), then why doesn't it apply equally to illnesses that are currently explained? Why aren't RA, or cancer, or influenza symptoms caused by the brain expecting bodily changes and then causing physical reactions that result in the expected symptoms? If it explains some illnesses with genuine physical changes, why wouldn't it explain all the others? If the hypothesis is sound, it should apply universally, not just to a few conditions the researcher selects.

Finally, how many of us had no idea whatsoever what symptoms to expect when we first became ill? I know I would never have expected the symptoms I have developed with this illness. Immune dysfunction, for example, was completely off my radar. I had no idea then that EBV, HHV6, CMV remain latent in the body, so I had no expectation they would reactivate. My assumed initiating viral infection was not particularly severe and I had every expectation of a normal recovery. The acute phase didn't last any longer than a normal flu, so my brain certainly couldn't have been trained to expect on-going symptoms. This whole "brain training" thing doesn't fit the majority of ME cases, as far as I can tell.

IMO, this abysmal science. Instead of looking at all the facts and trying to construct a hypothesis that fits all the facts (good science), they are starting with their conclusion and trying to bend the facts to fit the conclusion, ignoring any information that doesn't fit their conclusion (non-science).

 

[Dolphin]

There is an American study from last year using fMRI showing decreased activation in basal ganglia:

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098156

Unfortunately this uses the CDC's empiric criteria: 2.54% of the population including people who have primary major depressive disorder.
I'm afraid I think such studies have limited value regarding CFS.

 

[Sidereal]

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.