Motivational processing, Mesolimbic and Mesostriatal Function in Neuropsychiatric Disease

Lead Research Organisation: University of Cambridge
Department Name: Psychiatry

Abstract

Motivation and the response to rewarding events are adversely affected in many psychiatric and neurological illnesses: many patients with psychosis or Parkinson‘s Disease (PD) are de-motivated and experience apathy. Also, patients with some illnesses, such young adults with psychosis, seem to be over motivated by irrelevant information, which they seem to find captivating. This can also happen in patients with PD, possibly secondary to medication. But very little is known about the precise cause of these motivational abnormalities at the brain level. One reason is why few studies have even tried to investigate these processes in patients is because, until very recently, the techniques and methods to study brain motivational processes in patients were underdeveloped. Recent advances in (a) MRI brain imaging, and (b) basic understanding of reward and motivational processing, have meant that the time is now ripe to study how these processes are affected in psychiatric and neurological illness. I will study patients with psychosis, and PD, and examine to what extent their apathy and psychotic symptoms can be related to abnormalities in motivational and reward processing systems. Greater understanding will be helpful to patients, will enable better use of existing treatments and could help develop new treatments.

Technical Summary

Whilst a wealth of studies in animals and healthy humans have recently characterized brain responses whilst learning about or anticipating reward (and strongly implicating dopamine neurons in these processes, as well as in the related construct of incentive salience), this progress has yet to be translated into advances in understanding deficits in motivation, reward and salience processing in patients. This is in spite of the fact that disrupted motivation and abnormal responses to rewards are strongly implicated in a number of neurological and psychiatric disorders, including Parkinson‘s Disease (PD) and psychotic illness. However, recent neuroimaging experiments (by myself and others) have shown that it is possible and instructive to study brain activity in patients whilst they learn about, and respond to, rewards, indicating that there is now a opportunity for a translational approach to further the understanding of how incentive salience and reward prediction are be disturbed in illness.

I will study the emergence of psychosis through complementary studies extending my previous work on reward prediction and salience processing in psychotic illness. I will characterize brain responses to reward in unmedicated patients with mild psychotic symptoms (young adults with attenuated psychotic symptoms or prodromal symptoms). I anticipate they will show similar pathophysiological disruptions whilst learning about salient events as do patients with established psychotic illness. I will use the same psychological paradigms to study PD patients with and without psychotic symptoms (between 20-40% of PD patients report some level of psychotic symptoms), to see if the same pattern of brain activity is tied to psychosis in a different clinical context. I will also study motivational deficits in PD and attenuated psychosis using specific tasks, and I will relate functional brain abnormalities here to severity of symptoms such as apathy; in this way I will examine if therere common brain deficits in reward related regions in patients with differing conditions, each of which involve motivational deficits.

These experiments will demonstrate how reward and salience signals affect choice behaviour and brain response, and how this differs in health and in disease. The results will show whether there are abnormalities in brain or behavioural responses to salient stimuli in psychosis and Parkinson‘s Disease, and how these relate to symptoms. Such increased understanding will be of direct benefit to patients and their families in terms of patient education, could lead to better use of existing treatments and will help in developing new treatments.

Publications

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Arrondo G (2015) Hedonic and disgust taste perception in borderline personality disorder and depression. in The British journal of psychiatry : the journal of mental science

 
Guideline Title PSYCHOSIS AND SCHIZOPHRENIA IN CHILDREN AND YOUNG PEOPLE RECOGNITION AND MANAGEMENT
Description Citation in NICE guidelines
Geographic Reach National 
Policy Influence Type Citation in clinical guidelines
URL http://www.nice.org.uk/CG155
 
Description Grant for early career researcher
Amount £77,000 (GBP)
Organisation University of Cambridge 
Sector Academic/University
Country United Kingdom
Start 10/2013 
End 05/2015
 
Description Research Capacity Development Award
Amount £84,650 (GBP)
Organisation Cambridgeshire and Peterborough NHS Foundation Trust 
Sector Public
Country United Kingdom
Start 04/2015 
End 03/2017
 
Description Addictor 
Organisation Cambridge Cognition Ltd
Country United Kingdom 
Sector Private 
PI Contribution Jointly wrote a successful grant application to Finnish Academy and Canadian Institutes of Health Research and started a project to examine mechanisms underpinning risk for addiction
Collaborator Contribution Jointly wrote a successful grant application to Finnish Academy and Canadian Institutes of Health Research and started a project to examine mechanisms underpinning risk for addiction
Impact over £1 million equivalent funding held at University of Toronto and University of Oulu.
Start Year 2009
 
Description Addictor 
Organisation University of Toronto
Department Department of Psychiatry
Country Canada 
Sector Academic/University 
PI Contribution Jointly wrote a successful grant application to Finnish Academy and Canadian Institutes of Health Research and started a project to examine mechanisms underpinning risk for addiction
Collaborator Contribution Jointly wrote a successful grant application to Finnish Academy and Canadian Institutes of Health Research and started a project to examine mechanisms underpinning risk for addiction
Impact over £1 million equivalent funding held at University of Toronto and University of Oulu.
Start Year 2009
 
Description Arterial Spin Labelling Research 
Organisation University of Ulm
Department Clinic for Psychiatry
Country Germany 
Sector Academic/University 
PI Contribution Piloting of novel MRI sequences. Collaboration with Dr Roberto Viviani, Ulm University, Germany
Collaborator Contribution Provision of technical expertise
Impact Multidisciplinary: psychiatry & physics
Start Year 2009
 
Description EDIE-II MRC funded trial: (G0500264) 
Organisation University of Manchester
Department School of Medicine Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution I managed the Cambridge site of this multicentre trial
Collaborator Contribution Greater understanding of the clinical phenomenon of the psychosis prodrome, and greater understanding of its natural history and response to treatment. I have also learned how to run a clinical trial which influences my future research plans.
Impact Initial trial publication describing the study published this year. Primary results currently under review. Disciplines involved are clinical psychology, psychiatry, statistics, health economics. psychotherapy.
Start Year 2007
 
Description Ongoing Collaboration with my fellowship mentor 
Organisation University of Cambridge
Department Department of Psychiatry
Country United Kingdom 
Sector Academic/University 
PI Contribution I continue to collaborate my mentor and former supervisor and his team, prodiving advice on data analysis and interpretation.
Collaborator Contribution Intellectual input in terms of hypothesis testing and hypothesis development
Impact This collaboration influences most of my work, and directly led to 4 publications 2009-2010.
 
Description Partnership with Oulu University, Finland 
Organisation University of Oulu
Department Biocenter Oulu
Country Finland 
Sector Academic/University 
PI Contribution I led a new strand of data-analysis as part of a longstanding birth cohort study (Northern Finalnd Birth Cohort Study 1966).
Collaborator Contribution Collaborators provided raw data that had already been collected for different purposes, which enabled my team and I to perfrom novel analyses.
Impact This resulted in 5 peer reviewed 2009-2010 publications in which I am a co-author (one as senior author), and I have several senior author papers in preparation from this collaboration.
 
Description UNSW 
Organisation Neuroscience Research Australia
Country Australia 
Sector Academic/University 
PI Contribution Jointly wrote a successful application to access a valuable clinical research resource: the Australian Schizophrenia Research Bank
Collaborator Contribution Jointly wrote a successful application to access a valuable clinical research resource: the Australian Schizophrenia Research Bank
Impact We were awarded permission to access data on several hundred schizophrenia patients and controls, including genetic and phenotype profiling and MRI brain scans
Start Year 2012
 
Description UNSW 
Organisation University of New South Wales
Department School of Psychiatry
Country Australia 
Sector Academic/University 
PI Contribution Jointly wrote a successful application to access a valuable clinical research resource: the Australian Schizophrenia Research Bank
Collaborator Contribution Jointly wrote a successful application to access a valuable clinical research resource: the Australian Schizophrenia Research Bank
Impact We were awarded permission to access data on several hundred schizophrenia patients and controls, including genetic and phenotype profiling and MRI brain scans
Start Year 2012
 
Title Consultancy for NHS choices website 
Description NHS choices website, psychosis section. I provided consultancy for this website, resulting in significant changes of content. 
Type Management of Diseases and Conditions
Current Stage Of Development Wide-scale adoption
Year Development Stage Completed 2012
Development Status Under active development/distribution
Impact NHS choices website, psychosis section. I provided consultancy for this website, resulting in significant changes of content. 
 
Description BBC radio cambridgeshire interview 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact BBC local radio interview to disseminate research findings
Year(s) Of Engagement Activity 2015
 
Description Extended interview with Cambridge TV 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Interview with local TV station to disseminate to public research outcomes and their importance.
Year(s) Of Engagement Activity 2015
URL http://www.cambridge-tv.co.uk/dr-graham-murray-adhd/
 
Description Media coverage 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Dissemination of research findings through press release, covered by a variety of medical media.

Emails and calls received for information
Year(s) Of Engagement Activity 2014
URL http://www.cam.ac.uk/research/news/antipsychotic-drugs-linked-to-slight-decrease-in-brain-volume
 
Description Media coverage of publication - radio, TV and print interviews 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact I was interviewed for several UK and foreign newspapers, several radio stations and TV shows.

There was widespread coverage in international media.
Year(s) Of Engagement Activity 2009,2015
 
Description Podcast for charity MQ 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Third sector organisations
Results and Impact Podcast completed regarding work I presented at a conference. Accessed 73 times within 1 month.
Year(s) Of Engagement Activity 2017
URL https://soundcloud.com/user-181734274/graham-murray
 
Description Public multimedia arts and education event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Primary Audience Public/other audiences
Results and Impact over 240 members of the public attended a multimedia event that took place under the auspices of the Cambridge University Science Festival initiative. It was a collaboration between a mental health charity and University of Cambridge.

The event was covered in the Today program on radio 4, as well as in local media. Audience feedback data showed that 85 % of the audience had learnt something new about current scientific research into the brain and mind, and 75% had changed their perception of people with Mental Health issues.
Year(s) Of Engagement Activity 2011
 
Description Public talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Public/other audiences
Results and Impact 80 members of the public attended a co-operative venture between Cambridge University and a local mental health charity, situated in a Cambridge cafe. This multi-media event involved exerts from a modern opera written and performed by mental health service users, installation art, and talks by myself and other mental health/neuroscience researchers.

Ongoing collaboration between Cambridge University and local mental health services users and mental health charity.
Year(s) Of Engagement Activity 2010