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.
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.
People |
ORCID iD |
Matthew Kempton (Principal Investigator / Fellow) |
Publications
Antoniades M
(2018)
Verbal learning and hippocampal dysfunction in schizophrenia: A meta-analysis.
in Neuroscience and biobehavioral reviews
Berendsen S
(2021)
Pre-training inter-rater reliability of clinical instruments in an international psychosis research project.
in Schizophrenia research
Bonoldi I
(2019)
Basic Self-Disturbances Related to Reduced Anterior Cingulate Volume in Subjects at Ultra-High Risk for Psychosis.
in Frontiers in psychiatry
Borsini A
(2020)
Characterizing anhedonia: A systematic review of neuroimaging across the subtypes of reward processing deficits in depression.
in Cognitive, affective & behavioral neuroscience
Bromis K
(2018)
Meta-Analysis of 89 Structural MRI Studies in Posttraumatic Stress Disorder and Comparison With Major Depressive Disorder
in American Journal of Psychiatry
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
Calem M
(2017)
Meta-analysis of associations between childhood adversity and hippocampus and amygdala volume in non-clinical and general population samples.
in NeuroImage. Clinical
Catalan A
(2022)
Relationship between jumping to conclusions and clinical outcomes in people at clinical high-risk for psychosis.
in Psychological medicine
Chester LA
(2023)
Influence of cannabis use on incidence of psychosis in people at clinical high risk.
in Psychiatry and clinical neurosciences
Ciufolini S
(2014)
HPA axis response to social stress is attenuated in schizophrenia but normal in depression: evidence from a meta-analysis of existing 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 | Brain Research Trust Travel Award |
Amount | £300 (GBP) |
Organisation | Brain Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2020 |
End | 05/2020 |
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 | £383,333 (GBP) |
Organisation | National Institutes of Health (NIH) |
Sector | Public |
Country | United States |
Start | 06/2016 |
End | 06/2019 |
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 | Mapping Neurodevelopmental Trajectories for Adult Psychiatric Disorder: ALSPAC-MRI-II |
Amount | £1,762,268 (GBP) |
Funding ID | MR/S003436/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2018 |
End | 09/2022 |
Description | Maximising sensitivity of structural MRI sequence for longitudinal clinical MRI studies (NIHR Maudsley Biomedical Research Centre internal award - Neuroimaging Theme) equiv scanning costs |
Amount | £19,656 (GBP) |
Organisation | South London and Maudsley (SLAM) NHS Foundation Trust |
Department | NIHR Maudsley Biomedical Research Centre |
Sector | Academic/University |
Country | United Kingdom |
Start | 01/2019 |
End | 12/2019 |
Description | Psychosis MRI Shared Data Resource (Psy-ShareD): Partnership Grant |
Amount | £454,000 (GBP) |
Funding ID | MR/X010651/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2023 |
End | 05/2025 |
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 |
Title | Open access human structural MRI data that can be used to determine the reliability of any MRI processing software |
Description | The dataset includes at total of 125 structural freely available MRI scans (1.3Gb) from 24 subjects who have given their consent for their neuroimaging, demographic and physiological data to be made freely available. Scans have have been 'defaced' to preserve anonymity. The dataset includes MRI scans of the brain from individuals scanned at multiple time points and on different scanners and is decribed in detail in the paper Reliability of structural MRI measurements: The effects of scan session, head tilt, inter-scan interval, acquisition sequence, FreeSurfer version and processing stream (https://doi.org/10.1016/j.neuroimage.2021.118751) |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | The data has led to publication in 2 papers and was picked up by a number of prominant twitter users eg |
URL | https://sites.google.com/view/pinstudy |
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 |
Description | Presentation at the first National Conference on Psychosis Prevention |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | I was one of a small number of speakers (approx 7) at the first National Conference on Psychosis Prevention. The conference was for clinicians in the UK treating those at risk of psychosis |
Year(s) Of Engagement Activity | 2023 |
URL | https://maudsleylearning.com/courses/national-conference-on-psychosis-prevention/ |