Studies of human psycho-physiological responses to visceral pain.

Lead Research Organisation: Queen Mary, University of London
Department Name: Unlisted

Abstract

Nature of proposed research: while pain is a common human experience, our tolerance to it varies. This is because factors that influence pain perception such as life experiences, mental state and our genes, differ between individuals. Furthermore, when we perceive pain different parts of the nervous system are activated. These include nerves that carry pain signals from the body to the brain, control organ function e.g. heart and gut, and those that control the secretion of hormones such as cortisol that help combat stress.
In our preliminary studies, we induced pain by blowing up a balloon in the healthy human oeosphagus (gullet) while we measured the activity of nerves that control the heart. We demonstrated that the activity of the vagus nerve which slows down the heart increased in some subjects and decreased in others. Interestingly, subjects who showed an increase in activity were in general more anxious and worried than those who showed a decrease in activity. These results suggest that two distinct populations exist in the way they respond to pain. We now want to carry out studies in a larger number of subjects to determine how prevalent the two types of responses to pain are and also to determine whether a particular response in an individual is reproducible over time. Furthermore we want to determine whether the hormonal response (cortisol levels) to stress is different in the two types of individuals and whether they also differ in the degree to which their oesophagus becomes sensitive after injury with acid. Finally we want to determine if patients who have chronic pain arising from the oesophagus but in whom no cause can be identified also demonstrate the same two types of response to pain as healthy subjects. We will also determine whether individuals who behave differently to pain do so because they have different genes from others.
Prospective outcomes: we anticipate that this research will improve our understanding of why individuals differ in their response to pain and also whether certain individuals are more likely to developing chronic pain conditions.
Expected benefit to human health: if certain individuals are more at risk of developing chronic pain then treatment strategies can be developed based on the reasons leading to this increase in risk, and preventative measures can then be taken to protect these individuals from environmental influences that may predispose them to the development of chronic pain conditions.

Technical Summary

Background: Pain perception depends on the interaction between the psychological state and trait of the individual with physiological responses in the Autonomic Nervous System (ANS) and the Hypothalamic Pituitary Axis (HPA). Our preliminary healthy subject studies suggest that two distinct ANS responses to visceral pain occur. Subjects with an increase in Cardiac Vagal Tone (CVT) have more pain-susceptible psychological traits (group A) compared with those who show a decrease in CVT (group B). Primary aim: to determine the prevalence and stability of the psychophysiological response to visceral pain in health. General hypothesis: there will be phenotypic differences in the psychophysiolgical response to visceral pain and these phenotypes will respond differently to psychophysiological stress and to transient oesophageal injury/inflammation. Similar phenotypes will exist in patients with chronic oesophageal pain.
Questions to be addressed:
1. What is the prevalence and stability of the psycho-physiological phenotypes to visceral pain?
2. Do these psycho-physiological phenotypes differ:
a. in their ANS and HPA response to psychological and physiological stress?
b. in the magnitude of central sensitisation to transient injury?
c. in their cortical processing of sensation?
3. Do similar psycho-physiological phenotypes exist in patients with chronic oesophageal pain as in the healthy population?
Methods: study 1: in healthy subjects prevalence and stability of group A and B psychophysiolgical response to visceral pain will be assessed over time. Study 2: In groups A and B the: a) effect of physiological (35% CO2 inhalation) and psychological stress (Trier Social Stress Task) b) the magnitude of secondary allodyina to oesophageal acidification and c) the cortical response (using Magnetoencephalography) to psychological and sensitising stimuli will be assessed. Study 3: In patients with Non cardiac chest pain, the prevalence of psychophysiological profiles identified in healthy subjects will be assessed.
Outcome: these studies will lead to identification of risk factors for the development of chronic pain.

Publications

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Farmer AD (2014) Psychophysiological responses to visceral and somatic pain in functional chest pain identify clinically relevant pain clusters. in Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society

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Farmer AD (2016) Vagus nerve stimulation in clinical practice. in British journal of hospital medicine (London, England : 2005)

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Farmer AD (2017) The Role of Esophageal Hypersensitivity in Functional Esophageal Disorders. in Journal of clinical gastroenterology

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Farmer AD (2014) It's a gut feeling: how the gut microbiota affects the state of mind. in The Journal of physiology

 
Title Gut Feelings 
Description Leslie Hill and Helen Paris are two artists who after discussion with me and my research group about our research funded by the MRC developed a stage performance called "what are gut feelings?" (Autobiology). The also created a film called 'The moment I saw you I knew I could love you'. This film is also based on the concept of 'gut feelings'. They also created a Gut Feelings Trilogy DVD includes: full length documentation of the performance the moment I saw you I knew I could love you; the film Sea Swallow'd by Curious and Andrew Kotting; interviews on 'Autobiology' workshops - in which Curious worked with 56 artists across the UK using 'gut feelings' to generate text, performance, video and installation work; and a special bonus track on the creative process in making the performance and film. 
Type Of Art Film/Video/Animation 
Year Produced 2010 
Impact The performances, DVD and Films have reached a large audience about the importance of gut feelings and how these are generated. The film Sea Swallow'd by Curious and Andrew Kotting was shown at Chelsea Theatre 
URL http://www.placelessness.com/
 
Description Brain imaging guidelines for visceral pain
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact The guidelines provide information on optimal methods for functional brain imaging of visceral pain.
 
Description CLINICAL GUIDELINES FOR IBS
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact These guidelines were commissioned by the BSG were publisHed in GUT which is one of the major gastroenterology journals. These quidelines are used internationally for the management of Irritable Bowel Syndrome patients
 
Description Co Lead for the International Association For the Study of Pain's Global Year Programme against Visceral Pain
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact Provided information and education about different types of visceral pain in health and disease and this led to 1st world congress on visceral pain in Amsterdam in 2013
 
Description Education Committee of UEG
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
Impact As a member of the education committee of the united European Gastroenterology Federation I have influenced policy regarding education across Europe in particualar related to Neurogastroenterology and Motility. This has led to development of workshops; international conferences etc which has disseminated best practice guidelines to trainees and gastroenterologists across Europe.
 
Description International Association for the Study of Pain - Chair Special Interest Group for Abdominal and Pelvic Pain
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact In this role I am in charge of organising educational activities for abdominal and visceral pain and am participating in the IASPs Global Year in Pain Education. This will include webinars and development of written material. I am also organising the educational activities around visceral and abdominal pain for the forthcoming World Pain Congress in Boston USA in September 2018 and The World Congress of Abdominal and Pelvic Pain in London in 2019. In these congresses we will be disseminating new classification criteria for visceral pain developed as part of WHO-ICD 11 visceral pain new codes development. I am also in the process of writing a review article for 'Pain Reports' on the new WHO 11 pain classification which will have a world wide impact.
 
Description Member and lead for education for European Society of Neurogastroenterology and Motility
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
Impact Involved in designing educational platforms for trainees and gastroenterologists across Europe
 
Guideline Title Functional oesophageal disorders
Description ROME CRITERIA FOR FUNCTIONAL GUT DISORDERS
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
URL http://www.romecriteria.org
 
Guideline Title ROME IV - Oesophageal Disorders
Description ROME IV Criteria for Functional Oesophageal Disorders
Geographic Reach South America 
Policy Influence Type Citation in clinical guidelines
Impact I was first author of a paper on Functional oesophageal disorders which describes the new classification criteria for these disorders and provides best practice guidelines. I wrote the classification of a new category called 'Reflux Hypersensitivity' in this manuscript. The new criteria will now be used in the diagnosis of functional oesophageal disorders worldwide and these criteria will be mandatory for clinical trials in these conditions
URL https://www.sciencedirect.com/science/article/pii/S0016508516001785?via%3Dihub
 
Description Butterfield Awards for UK-Japan collaboration in medical research and public health practice
Amount £22,500 (GBP)
Organisation The Great Britain Sasakawa Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2013 
End 01/2015
 
Description CLINICAL RESEARCH FELLOWSHIP
Amount £60,000 (GBP)
Organisation Barts Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2017 
End 11/2018
 
Description INNOVATIVE MEDICINES INITIATIVE
Amount € 2,000,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 09/2018 
End 08/2021
 
Description Large Grants Scheme
Amount £459,956 (GBP)
Organisation Barts Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2013 
End 08/2013
 
Description MRC Translational Medicine Grant
Amount £535,200 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2009 
End 08/2011
 
Description NeuroGut- European Training in Neural Regulation of Intestinal Function; FP7-PEOPLE-2013-ITN. Marie Curie Actions- Initial Training Networks (ITN)
Amount € 3,600,000 (EUR)
Funding ID 607652 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 09/2014 
End 08/2017
 
Description PHD STUDENTSHIP
Amount £75,000 (GBP)
Organisation Bowel & Cancer Research 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2018 
End 03/2021
 
Description PROGRAMME GRANT
Amount £2,233,960 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 02/2018 
End 02/2021
 
Description Project grant
Amount £50,000 (GBP)
Organisation Bowel & Cancer Research 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2011 
End 01/2013
 
Description Lueven Collaboration 
Organisation University of Leuven
Country Belgium 
Sector Academic/University 
PI Contribution We got a joint grant from University of Leuven to study the effect of deep breathing on Pain We are co supervising 2 PhD students based in dept of psychology at University of Leuven
Collaborator Contribution I was co-applicant on grant application. 2 PhD students were funded. One of the students will spend 1 year of her training in our dept.
Impact Not yet - The students have now submitted their protocols for ethics and are awaiting outcomes and research should start very soon.
Start Year 2015
 
Description Maastricht Collaboration 
Organisation Maastricht University (UM)
Country Netherlands 
Sector Academic/University 
PI Contribution We have provided expertise and training
Collaborator Contribution Provided research fellow for 6 months to visit our department
Impact Working of collaborative projects which should lead to publications and EU grants
Start Year 2014
 
Title Transcutaneous Vagal Nerve Stimulation for managing oesophageal hypersensitivity 
Description We are using a commercially available device to non-invasively stimulate the vagus nerve to determine its efficacy in a model of health human acid induced oesophageal hypersensitivity. The study is now nearing completion 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2018
Development Status Under active development/distribution
Impact Depending on final results the intervention may have an impact on treatment of mild to moderate visceral pain non-pharmacologically. 
 
Description Meet the investigator meetings 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Our medical School through has an active dissemination programme for local school children. This allows particular scheme allows investigators to speak to school children about their reserach programme in lay language to inform and encourage children about medical research

One student and one teacher went on to undertake work experience in our department as a direct result of my talk
Year(s) Of Engagement Activity 2009
 
Description PATIENT EDUCATION 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact patients were educated about the causes and management of IBS. Which generated a lot of discussion. There were a lot of interactive sessions and group work to which I contributed.

Similar activities are planned for each year and will take place around the country and I will be involved in these.
Year(s) Of Engagement Activity 2012
 
Description Patient engagement - Irritable Bowel Syndrome (IBS) Nework UK and Ehlers Danlos Syndrome (EDS) UK and Bart Health Cardiovascular Patient Support Group 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact All activities were associated with discussions with patients and I informed them of resources and facilities that are available to them for optimal management of their conditions.

- The EDS UK have funded a research nurse to support EDS patients that are referred to my clinic
- Referrals of EDS patients have increased
- We have used feed back give by patients during the Lets Talk Hearts Seminar in a grant application related to the treatment of non cardiac chest pain
Year(s) Of Engagement Activity 2013,2014
 
Description Television Programme 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Television medical journalist Dr Michael Mosely visited our lab and shot a whole day of interviews with my clinical research fellows Dr Adam Farmer who was appointed on a MRC grant. Dr Mosely participated in the research study as a volunteer. This was then presented in a BB4 documentary programme about novel research programmes about different parts of the gut in particular how the brain and the gut communicate.

Greater public awareness of our programme which led to quite a few enquiries from patients about our research.
Year(s) Of Engagement Activity 2012
 
Description work experience 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact during work experience of student from local school and teacher they were given explanation and were shown experiments related to this grant.

student has decided to persue a career in medicine
Year(s) Of Engagement Activity 2009
 
Description work experience 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact as mentioned for other grants, we regularly host students and on one occasion even a teacher from a local and regional school for work experience and the work being conducted on the current grant was explained to them.

student has decided to study medicine
Year(s) Of Engagement Activity 2009,2010,2011,2012,2013
 
Description work experience 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact One teacher and one student from local school did work experience where they were able to see reserach being carried out on projects relevant to the MRC funded project.

The student has decided to study medicine
Year(s) Of Engagement Activity 2009