Clinical Trial at Brighton/Sussex Hospital

[A.B.]

He also co-authored a study on neuropsychiatric symptoms in FM patients, so not really.

@Woolie what do you think about this conclusion?

In a patient population vulnerable to neuropsychiatric symptoms, we found that dissociative experiences are fully mediated by symptoms of orthostatic intolerance. This is also the first study, to our knowledge, to explore dissociation and orthostatic intolerance in the context of fibromyalgia. Moreover, dissociation and brain-fog appear closely linked and are frequently reported by both patients with fibromyalgia and those with PoTS. Our observations are consistent with the hypothesised basis to dissociative symptoms in abnormalities in self-representation and internal agency linked to autonomic control and interoceptive prediction, revealed by subjective symptoms of orthostatic intolerance. This study suggests possibilities for recognition and treatment of neuropsychiatric symptoms.

Is this a weird way of saying "poor blood flow to brain causes cognitive symptoms"?

 

[Marco]

This could be an interesting study.

Personally, if I were doing it; I'd be interested in how induced immune activation might impact on a comprehensive array of autonomic measures on the basis that immune activation via HMGB1 mediated microglial activation in the paraventricular nucleus of the hypothalamus results in autonomic dysfunction (at least in a rat model of hypertension) :

http://ajpheart.physiology.org/content/309/7/H1115

If they want to look at 'psychology' perhaps they might look at anxiety levels. Anxiety can be induced by systemic inflammation and alleviated by cox-2 inhibition (again potentially via attenuating microglial activation).

https://elifesciences.org/articles/14137

If induced immune activation results in impaired autonomic dysfunction and increased 'mood' disorders in PWME might cox-2 inhibition alleviate them? - Nowt to do with 'psychology'.

 

[Valentijn]

This is part of a letter in response to a pay-walled letter authored by Eccles and Harrison:

Eccles et al note that joint hypermobility is commonly associated
with psychiatric, anxiety and psychosomatic presentations.(1)

 

[user9876]

These brain changes aren't necessarily what determines how ill you feel.

Another question is does how ill you feel relate to how ill you are? From observations of one or two people when really ill they would not 'feel' ill because they are to ill for that. But the feeling of being ill happens on getting a bit better. To put it another way feelings of being ill take energy when very ill I see conscious thought reducing but as energy increases then the energy for such thoughts increases. I'm not sure I'm making sense but I would like to separate out different concepts of reports of 'feeling ill' to actual levels of illness. If we talk about observing mental states through oxygen usage in neurons (which I think is what fMRI does?) then we may observe different things?

 

[user9876]

To just add a bit about psychology. As I see it Harrison is not doing psychology because he is trying to explain symptoms entirely on the basis of neurophysiological events as observed from outside. Psychology tries to explain symptoms on the basis of concepts like 'emotions' or 'peer pressure' or 'rational thought' which derive from our shared inner experiences. Harrison would not want to invoke concepts of that sort as causes. He wants to replace them with something measurable - physiology.

A strong insular response IS a bodily difference, just as much as a strong LPS receptor response.

Isn't psychology really about studying mental representations and processes (or is that cognitive science). fMRI seems like a tool to look at regions of activation (oxygen usage) hence it seems to tie to mental representations/processes. Stimuli causing differences (whether external interactions, internal though processes as mental representations/activation transform, or biological signals) don't really get measured do they?

 

[Jo Best]

Firstly, I am worried that we do not actually know whether Neil has anything to do with the study on this thread or whether typhoid vaccine studies have anything to do with it either. Maybe they do but it sounds as if we may be confusing two completely different projects. It is possible that Neil wants to test typhoid vaccine on PWME to see if they have an increased or prolonged response but I have not heard that. Exercise testing is reasonable since it would illuminate the PEM phenomenon and has been suggested by many groups.

There may be different studies (perhaps one is still in the planning stage) but the study that's the subject of this thread involves giving pwme the vaccine, as indicated in the patient info pdf.
ETA: at least that's how I would interpret it if I were thinking of taking part.

Study Visit Two -
 A qualified doctor will give you the injection of typhoid (Typhim Vi) vaccine or placebo (saline injection) into the deltoid muscle of your upper arm. Although the doctor will know whether you received the typhoid vaccine or the saline injection neither you nor the other researchers will be told. This is to prevent knowledge of which injection you were given influencing your or the researcher’s behaviour. We will then ask you to rest whilst the injection takes effect.

Study Visit Three -
On the third study visit one of our team members will meet you at the reception desk. Exactly the same procedure will be followed as your second visit, only you will be given typhoid vaccine or placebo depending on the injection that you were given during your previous visit. Again, you will not know which you received on each occasion until you have completed your participation. Visits 2 and 3 will happen after visit 1 and will be approx. 2 weeks apart.

 

[Woolie]

@Woolie what do you think about this conclusion?

In a patient population vulnerable to neuropsychiatric symptoms, we found that dissociative experiences are fully mediated by symptoms of orthostatic intolerance. This is also the first study, to our knowledge, to explore dissociation and orthostatic intolerance in the context of fibromyalgia. Moreover, dissociation and brain-fog appear closely linked and are frequently reported by both patients with fibromyalgia and those with PoTS. Our observations are consistent with the hypothesised basis to dissociative symptoms in abnormalities in self-representation and internal agency linked to autonomic control and interoceptive prediction, revealed by subjective symptoms of orthostatic intolerance. This study suggests possibilities for recognition and treatment of neuropsychiatric symptoms.

Is this a weird way of saying "poor blood flow to brain causes cognitive symptoms"?

There's not a lot to go on there (only the Abstract has been published), but I think it might actually be quite tame. I think they might be trying to say that orthostatic intolerance causes various subjective experiences which include dissociative ones (the feeling of being somehow detached from your self, and your actions).

 

[Woolie]

Isn't psychology really about studying mental representations and processes (or is that cognitive science). fMRI seems like a tool to look at regions of activation (oxygen usage) hence it seems to tie to mental representations/processes. Stimuli causing differences (whether external interactions, internal though processes as mental representations/activation transform, or biological signals) don't really get measured do they?

No, you are right. fMRI is a tool that is primarily used to study the neural signature of mental processes, in order to learn more about the mental processes themselves. It does not measure the source of the stimuli. But of course you need to document this too to make any sense out of the results.

No point trying to study the brain regions engaged in recognising different types of visual stimuli without knowing which kind stimuli the person was actually viewing at the time.

To be complete, there are some other ways you can use fMRI that don't involve making inferences about mental function (you can use it to localise a function, for example prior to neurosurgery, or use it with brain damaged populations to examine plasticity - the extent to which different circuits can take over after one is damaged). But mostly, its about making inferences about mental functions.

 

[Woolie]

Firstly, I am worried that we do not actually know whether Neil has anything to do with the study on this thread or whether typhoid vaccine studies have anything to do with it either

Yes, they appear to be part of the research programme that Harrison describes in the talk above. He refers to it the typhoid pre- post-study as one of his planned projects, mentions Sussex.

 

[Sidereal]

I would just say that I agree with what Woolie has written. fMRI is psychology. One thing that we psychologists bump up against all the time is this widespread misunderstanding among laypeople that psychology is some unscientific claptrap where people sit around all day in a 1960s-style cafe talking about emotions and the id.

Granted, listening to the likes of White one would be excused for dismissing the entire discipline as worthless but even the BPS school has moved on from the brutal stupidity of the 1980s and 1990s level of analysis to a more modern couching of these 'false illness beliefs' in the language of 2000s cognitive neuroscience, hence all the buzzwords about interoceptive networks, insula, basal ganglia etc. which is why you have people like Harrison getting grant money now and people like White are retiring. But it's still false illness beliefs in the sense that the brain thinks the body is sick because its activity in certain areas is altered. You can describe the same phenomenon using different language.

Modern psychology is not Freud, ok? It attempts to understand mental phenomena at all levels of analysis, like peeling the layers of an onion, ranging from basic physiology and all the way through to social phenomena. In my time we had to learn brain anatomy, physiology, neuropsychopharmacology, neuropsychology, neuroimaging techniques etc. in addition to all the woollier bits that the man on the street thinks is 'psychology' like personality, intelligence, emotions, psychopathology etc.

I have a doctorate in the general area that Harrison has been researching so I think this entitles me to an opinion. I had a look at some of his publications last year when we were discussing this. There is nothing of value to be learned from this work. We have known for 30 years that people with 'emotional disorders' like depression have an abnormal reactivity to bacterial endotoxin and that there are immunological alterations of unknown aetiology or significance in these patients. More recently we have found out that immune modulating drugs can improve neurovegetative symptoms of depression. Countless groups have previously demonstrated, using neuroimaging techniques, that areas like the basal ganglia, insula, the DLPFC and anterior cingulate show altered patterns of blood flow / activation and neuropsychological tests tapping into areas underpinning frontal-executive function show decrements in performance compared to controls.

Again, all of this is psychology.

He thinks ME/CFS can be understood at this level of analysis, that altered brain activation is responsible for the symptoms, not that altered brain activity is the result of say an antibody somewhere in the periphery or some sort of generalised metabolic dysfunction. He is entitled to his opinion, for which he has no evidence, and we are entitled to dismiss it. IF there is an antibody, then why waste money studying how the brain responds to being sick? In neuropsychiatric lupus people show altered brain activity but no sane person would argue that this causes the disease.

 

[Jo Best]

It seems the main focus of this study is fibromyalgia and that ME/CFS participants are a comparison group for the symptoms of pain and fatigue (that could explain why it's wholly funded by Arthritis Research UK).

From the summary: "The aim of this study is to understand how the body and brain affect each other to cause pain and fatigue in fibromyalgia." https://www.ukctg.nihr.ac.uk/trials/trial-details/trial-details?trialId=38659

The exclusion criteria for patient participants is: major neurological illness

Presumably these researchers don't regard it as 'major' but ME is classified as neurological.

 

[NelliePledge]

A good way of finding the causal claim in psych/behaviorual/brain research is to ask what sort of intervention the researchers would hypothesise would lead to the greatest relief.

I do not think I did that. I gave a summary people could understand, which I thought was very fair to the central ideas, then my own assessment.

thanks Woolie this did help me understand - I had watched the presentation and from a total non scientist point of view I really couldnt get my head round why this research needed to be done.

Are they saying that this degree of brain activation in this particular area of the brain is particular to ME so would demonstrate someone had ME?

if that isnt the aim I dont think there's any mention of how the research would help patients - what might be done to reduce the brain activation once theyve shown its there

sorry if these are stupid questions or have already been covered having a foggy day today

 

[Dolphin]

I have a recollection that Dr. Neil Harrison discusses planning to use a vaccination to look at the effects of inflammation in one of these videos. It might be of interest to you or others as I think he might be involved in this research.

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

For what it is worth:

ME Association CMRC 2017 conference report:

16. Dr Neil Harrison – Brighton and Sussex Medical School

Dr Harrison spoke about the role of neuroimaging in ME/CFS and two new research studies that he is involved with – both of which are about to start recruiting in the Brighton and Sussex area.

The first is on the neurobiology of post-exertional fatigue and is being funded by the MRC. The study is using MRI scans to investigate the core symptom of post-exertional malaise in 20 people with ME/CFS and 20 healthy controls. This will involve blood testing for immune system changes and MRI imaging (to see what happens in the brain) before and 24 hours after an exercise challenge.

The second study, which is involves rheumatologist Professor Kevin Davies, is being funded by Arthritis Research UK. This will be focusing on pain and whether there is an exaggerated response following an inflammatory (i.e. typhoid vaccine) and autonomic nervous system challenge.

Dr Harrison also covered:
▪ the role of what is called ‘sick behavior’ (the natural physiological response to acute infection that involves fatigue, cognitive impairment, withdrawal, anorexia, and increased pain sensitivity),
▪ the role of the vagus nerve (during immune system activation),
▪ what happens when cytokines enter the central nervous system (during an acute episode of virus or vaccine induced immune system activation),
▪ microglial activation following immune system challenges, and,
▪ the possible role of specific centres in the brain – like the insula cortex and substantia nigra – in symptom development in ME/CFS.

This was an excellent presentation on a very complex area of neuroscience – so the video is well worth watching if you are interested in this topic.

More information: ME Association report from 2015 CMRC conference on the MRC funded study into PEM
Dr Neil Harrison – video presentation

 

[andyguitar]

The problem with these type of research projects is that they put together all sorts of different people with a range of symptoms. Pain and fatigue. What does it mean?

 

[Jo Best]

IIMEC10 (10th Invest in ME Conference) 2015 - http://investinme.eu/IIMEC10.shtml#

Honorary Consultant Neuropsychiatrist, Brighton & Sussex Medical School, UK

Dr Harrison's' work in the laboratory focuses on understanding how infection or inflammation in the body interacts with the brain. For most these symptoms are usually short lived and relatively mild. However, when the immune system is activated for long periods, such as in people suffering from rheumatoid arthritis, they can become extremely debilitating or even life-threatening. Understanding how the immune system interacts with the brain is a crucial first step that will form the foundations for future development of novel therapies targeting these common and disabling symptoms. Most of his studies utilise a combination of functional brain imaging (e.g. fMRI, FDG-PET, EEG, polysomnography), experimental models of inflammation, custom cognitive tasks and diverse measures of peripheral immune status.

Immune brain communication and relationship to inflammation induced fatigue were discussed by Neil Harrison (Sussex, UK). He outlined the symptoms associated with sickness behavior and listed the behavioural changes that occur to protect the body. He explained how cytokines injected into rodents led to symptoms of sickness behavior. Humans given high doses of interferon-α to treat Hepatitis C also develop sickness behavior and often experience severe fatigue. There is immune-brain communication via a number of pathways, and in particular via the vagus nerve. The microglia are also activated leading to brain inflammation. http://investinme.eu/Documents/IIMEC10/IIMEC10 Conference Report.pdf

 

[anni66]

There's not a lot to go on there (only the Abstract has been published), but I think it might actually be quite tame. I think they might be trying to say that orthostatic intolerance causes various subjective experiences which include dissociative ones (the feeling of being somehow detached from your self, and your actions).

I have to confess not a lot of knowledge in this area, but to a layperson it sounds the other way around. That brain function is the cause . Oh to find the autoimmune antibodies / bacteria/ toxins .....

 

[Woolie]

I have to confess not a lot of knowledge in this area, but to a layperson it sounds the other way around. That brain function is the cause . Oh to find the autoimmune antibodies / bacteria/ toxins .....

I looked over it again, and you might be right, @anni66. Its really hard to make out from what's published (just th Abstract). The are saying the basis of dissociative symptoms is:

abnormalities in self-representation and internal agency linked to autonomic control and interoceptive prediction.

Its hard to know if they are saying the autonomic control problems are the cause, and its not clear what causal role the interoceptive prediction part plays.

Its so badly expressed.

 

[anni66]

I looked over it again, and you might be right, @anni66. Its really hard to make out from what's published (just th Abstract). The are saying the basis of dissociative symptoms is:

Its hard to know if they are saying the autonomic control problems are the cause, and its not clear what causal role the interoceptive prediction part plays.

Its so badly expressed.

We live in an age of grey fuzzy buzzwords which have different meanings to different people

 

[Woolie]

I had a look at Neil Harrison's bio. There is some great work there. @Jonathan Edwards is right that some of this stuff really expands our understanding of the relationship between inflammation and mood. Harrison worked with Hugo Critchley (for his PhD I think), who I reckon is totally brilliant.

Most of Harrison's really good work is with Critchley. Some of his independent efforts are less impressive. He recently published an article on 'psychogenic' amnesia which I thought was lacking in critical insight. I'll talk about it if people are interested.

I still don't think any of the work Harrison is proposing at the moment will benefit CFS patients, either directly or indirectly. It also has the potential to be misused by the 'central sensitisation' crew, among others.

 

[Valentijn]

I had a look at Neil Harrison's bio. There is some great work there.

Google Scholar gives a lot of less impressive results, if looking for fibromyalgia, hypermobility, or psychosomatic terms.