Trajectory of Brain Structure and Function before and after the Onset of Psychosis: a Longitudinal Multicentre Study

Lead Research Organisation: King's College London
Department Name: Neuroimaging

Abstract

Psychotic disorders such as schizophrenia are disabling and relatively common conditions. They usually begin in early adulthood, and are chronic illnesses. Treatment can partially reduce some of the symptoms, but is not curative. These disorders are preceded by an 'at risk mental state' (ARMS). People in this state have a 30% risk of developing psychosis. However, at present, it is not possible to predict which individual with an ARMS will go on to develop psychosis and which will not. The aim of my study is to test whether measuring the structure and function of the brain with Magnetic Resonance Imaging (MRI) scanning in people with an ARMS can help clinicians to predict who will later become ill. In order to do this, I will put together a large number of scans collected from several different research centres in Europe and Australia. People with an ARMS who take part in the study will be scanned when they first contact support clinics, and then again after 3 months, 12 months and 24 months. I will use the information in the scans to test whether the way the brain changes over time is different in people who will later develop psychosis compared to people who do not. There is evidence to suggest that specific regions of the brain called the hippocampus, insula and lateral ventricles change in volume close to the time-point that a psychotic illness starts. However it is not known exactly when these changes occur and if they happen before or after the beginning of psychosis. From the MRI scans I will be able to discover exactly when these changes occur. One popular theory of schizophrenia proposes that a region of the brain called the hippocampus becomes abnormally active and then causes problems in regulating another region of the brain called the striatum which is important in symptoms of psychosis. I will test this theory by using the MRI scans to measure the activity of the hippocampus compared to activity in the striatum.

Technical Summary

The aim of this study is to characterise the trajectory of brain structure and function before and after the onset of psychosis. Specifically I will examine changes in the volume of the insula, hippocampus and lateral ventricles and test the hypothesis associated with the theory of Tony Grace that functional connectivity between these regions increases prior to psychosis. A secondary aim is to predict who will develop psychosis by applying machine learning techniques to the longitudinal data. The fellowship is to fund longitudinal MRI scans of subjects with an at risk mental state (ARMS), 25-30% of whom are expected to develop psychosis within 2 years of contacting medical services. The baseline MRI scans are already being collected as part of the EU-GEI project. However there were no plans in the original study to do subsequent scanning. My proposal aims to capitalise on this ARMS sample, which is an order of magnitude larger than any examined in previous studies. Scanning will be completed at 7 centres which each have ARMS clinics and a 3T MRI scanner. ARMS subjects will be scanned at the point of transition and 12 and 24 months after transition; those who do not transition to psychosis and healthy controls will be scanned 3, 12 and 24 months after the baseline scan. Analysis of the structural MRI data will be conducted with FreeSurfer and software developed by my collaborator Paul Thompson and resting state fMRI data will be analysed with FSL MELODIC. I will use support vector machines to predict psychosis transition from the imaging and clinical data which would have immediate translational benefits. Changes in brain structure and function before psychosis raises the intriguing possibility that future therapies may be able to arrest these changes. Charactering the trajectory of these changes would indicate which regions of the brain are first affected, and establish a reference point to compare the effects of preventative treatment strategies.

Planned Impact

The key problem in the clinical management of people who present with prodromal signs of psychosis is that it is impossible to predict which individuals will go on to develop a psychotic disorder and which will not. As a result, potentially preventative clinical interventions have to be applied to all subjects, even though only about 30% will subsequently become psychotic. A successful algorithm which correctly identifies the latter subgroup would have an immediate translational benefit, as preventative treatment could then be targeted to those who need it most. This would permit a more efficient use of clinical resources and would be more ethically acceptable. The findings may thus significantly improve the clinical management of people at high risk of psychosis, particularly in terms of preventative interventions.

A less direct, but equally important impact will result from an improved understanding of the mechanisms underlying the onset of psychotic disorders. This is fundamental to the development of new treatments for psychosis, especially in its early phase. Our poor understanding of the pathophysiology of psychosis has been a key factor in the failure to produce new treatments.

Mental health charities and public health bodies would be able to use the results of this research to reduce the stigma of psychosis by publicising that physical changes in the brain are associated with the development of psychosis (similar to neurological illnesses). They could also use the findings to foster a culture of prevention in mental health, educating the public to recognise the symptoms of an at risk mental state and if necessary contact appropriate medical services.

The cost of schizophrenia to the economy in England has been estimated at 6.7 billion pounds a year (Mangalore & Knapp 2007). A significant portion of this cost is related to delays in diagnosis and if early diagnosis could be achieved by the findings in this study, the financial burden of schizophrenia and other psychosis disorders to the economy would be lessened. In addition, as the research is European wide the findings from this study are likely to impact on mental health policy of the wider European community rather than the UK alone.

References
Mangalore R, Knapp M (2007) Cost of schizophrenia in England.J Ment Health Policy Econ.10(1):23-41.

Publications

10 25 50
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Antoniades M (2018) Verbal learning and hippocampal dysfunction in schizophrenia: A meta-analysis. in Neuroscience and biobehavioral reviews

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Brunton S (2015) A voxel-based morphometry comparison of the 3.0T ADNI-1 and ADNI-2 volumetric MRI protocols. in International journal of geriatric psychiatry

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European Network Of National Networks Studying Gene-Environment Interactions In Schizophrenia (EU-GEI) (2014) Identifying gene-environment interactions in schizophrenia: contemporary challenges for integrated, large-scale investigations. in Schizophrenia bulletin

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Gabay AS (2014) The Ultimatum Game and the brain: a meta-analysis of neuroimaging studies. in Neuroscience and biobehavioral reviews

 
Description Changing Clinical Practice in OASIS clinic
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
 
Description EC FP7 Grant
Amount € 689,032 (EUR)
Funding ID 603196 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 02/2014 
End 01/2020
 
Description HARMONY: Predictors and Mechanisms of Conversion to Psychosis
Amount £93,309 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 07/2016 
End 06/2018
 
Description KCL 2014/15 Conference Fund Grant for my PhD student
Amount £300 (GBP)
Organisation King's College London 
Sector Academic/University
Country United Kingdom
Start 11/2014 
End 11/2014
 
Description Quantitative MRI and cognitive measures in patients with Alzheimer's Disease before and after Table Tennis
Amount £20,874 (GBP)
Organisation Bounce Alzheimer's Therapy (BAT) Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2016 
End 05/2017
 
Description Jim Van Os, EU-GEI 
Organisation Maastricht University (UM)
Department European Graduate School of Neuroscience
Country Netherlands 
Sector Academic/University 
PI Contribution I have coordinated a work package of the EU-GEI (EU gene environment interactions) project which is an EU FP7 funded study into the causes of psychosis. The PI of the project is Prof Jim van Os who I have asked to be a collaborator on this fellowship.
Collaborator Contribution EU-GEI funded the baseline scans which I will be using as a comparison to the follow-up scans collected during my fellowship.
Impact Approximately 90 individuals with an At Risk Mental State have been assessed at the Institute of Psychiatry using funds provided by this collaboration led by Prof Jim van Os
Start Year 2010
 
Description MRC Fellowship Network 
Organisation Free University of Amsterdam
Country Netherlands 
Sector Academic/University 
PI Contribution Using this MRC Fellowship I have been able to fund the recruitment and MRI scanning of participants with a high risk of developing psychosis in a number of specialist clinics around the world.
Collaborator Contribution My partners in Europe and Australia will be transferring the MRI data as part of my fellowship. These centres will be collecting genetic data, and extensive clinical information regarding psychopathology, demographics and cognition.
Impact This collaboration will allow me to significantly increase the sample size of individuals with an at risk mental state. The collaboration involves PhD students, clinicians, and MRI technicians.
Start Year 2012
 
Description MRC Fellowship Network 
Organisation Free University of Amsterdam
Country Netherlands 
Sector Academic/University 
PI Contribution Using this MRC Fellowship I have been able to fund the recruitment and MRI scanning of participants with a high risk of developing psychosis in a number of specialist clinics around the world.
Collaborator Contribution My partners in Europe and Australia will be transferring the MRI data as part of my fellowship. These centres will be collecting genetic data, and extensive clinical information regarding psychopathology, demographics and cognition.
Impact This collaboration will allow me to significantly increase the sample size of individuals with an at risk mental state. The collaboration involves PhD students, clinicians, and MRI technicians.
Start Year 2012
 
Description MRC Fellowship Network 
Organisation University Psychiatric Clinics Basel
Country Switzerland 
Sector Academic/University 
PI Contribution Using this MRC Fellowship I have been able to fund the recruitment and MRI scanning of participants with a high risk of developing psychosis in a number of specialist clinics around the world.
Collaborator Contribution My partners in Europe and Australia will be transferring the MRI data as part of my fellowship. These centres will be collecting genetic data, and extensive clinical information regarding psychopathology, demographics and cognition.
Impact This collaboration will allow me to significantly increase the sample size of individuals with an at risk mental state. The collaboration involves PhD students, clinicians, and MRI technicians.
Start Year 2012
 
Description MRC Fellowship Network 
Organisation University of Melbourne
Department Department of Psychiatry
Country Australia 
Sector Academic/University 
PI Contribution Using this MRC Fellowship I have been able to fund the recruitment and MRI scanning of participants with a high risk of developing psychosis in a number of specialist clinics around the world.
Collaborator Contribution My partners in Europe and Australia will be transferring the MRI data as part of my fellowship. These centres will be collecting genetic data, and extensive clinical information regarding psychopathology, demographics and cognition.
Impact This collaboration will allow me to significantly increase the sample size of individuals with an at risk mental state. The collaboration involves PhD students, clinicians, and MRI technicians.
Start Year 2012
 
Description Tyrone Cannon, Yale 
Organisation Yale University
Country United States 
Sector Academic/University 
PI Contribution For this MRC fellowship I am collaborating with Professor Tyrone Cannon who is Principle Investigator of the North American Prodromal Longitudinal Study (NAPLS). I am setting up the same MRI scanning sequences as the NAPLS study so we the potential to share and pool data in the future.
Collaborator Contribution Professor Tyrone Cannon has sent me the MRI parameters used in the NAPLS study.
Impact Parameters for structural MRI data have been implemented in all collaborating sites. MRI parameters for resting state fMRI scans are currently being agreed on.
Start Year 2012