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 The 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
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
Cullen AE
(2019)
Associations Between Non-neurological Autoimmune Disorders and Psychosis: A Meta-analysis.
in Biological psychiatry
Cullen AE
(2019)
Reply to: Odds and Risk Ratios: When They Are Similar and When They Are Not.
in Biological psychiatry
Dickens AM
(2021)
Dysregulated Lipid Metabolism Precedes Onset of Psychosis.
in Biological psychiatry
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
Fusar-Poli P
(2013)
Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies.
in Neuroscience and biobehavioral reviews
Fusar-Poli P
(2013)
Efficacy and safety of second-generation long-acting injections in schizophrenia: a meta-analysis of randomized-controlled trials.
in International clinical psychopharmacology
Gabay AS
(2014)
The Ultimatum Game and the brain: a meta-analysis of neuroimaging studies.
in Neuroscience and biobehavioral reviews
Gabay AS
(2015)
Facial affect processing deficits in schizophrenia: a meta-analysis of antipsychotic treatment effects.
in Journal of psychopharmacology (Oxford, England)
Gabay AS
(2019)
MDMA Increases Cooperation and Recruitment of Social Brain Areas When Playing Trustworthy Players in an Iterated Prisoner's Dilemma.
in The Journal of neuroscience : the official journal of the Society for Neuroscience
Goozée R
(2014)
A systematic review and meta-analysis of the effects of antipsychotic medications on regional cerebral blood flow (rCBF) in schizophrenia: association with response to treatment.
in Neuroscience and biobehavioral reviews
Guevara C
(2016)
Whole-Brain Atrophy Rate in Idiopathic Parkinson's Disease, Multiple System Atrophy, and Progressive Supranuclear Palsy.
in Parkinson's disease
Hedges EP
(2022)
Meta-analysis of longitudinal neurocognitive performance in people at clinical high-risk for psychosis.
in Psychological medicine
Hedges EP
(2022)
Verbal memory performance predicts remission and functional outcome in people at clinical high-risk for psychosis.
in Schizophrenia research. Cognition
Hermans KSFM
(2021)
Elucidating negative symptoms in the daily life of individuals in the early stages of psychosis.
in Psychological medicine
Hibar DP
(2018)
Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group.
in Molecular psychiatry
Hird E
(2023)
Speech Illusions in People at Clinical High Risk for Psychosis Linked to Clinical Outcome
in Schizophrenia Bulletin
Kempton MJ
(2015)
Speed of Psychosis Progression in People at Ultra-High Clinical Risk: A Complementary Meta-analysis.
in JAMA psychiatry
Kempton MJ
(2015)
How can neuroimaging facilitate the diagnosis and stratification of patients with psychosis?
in European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
Klippel A
(2017)
Modeling the Interplay Between Psychological Processes and Adverse, Stressful Contexts and Experiences in Pathways to Psychosis: An Experience Sampling Study.
in Schizophrenia bulletin
Kraan TC
(2018)
Child Maltreatment and Clinical Outcome in Individuals at Ultra-High Risk for Psychosis in the EU-GEI High Risk Study.
in Schizophrenia bulletin
Menghini-Müller S
(2019)
Gender differences of patients at-risk for psychosis regarding symptomatology, drug use, comorbidity and functioning - Results from the EU-GEI study.
in European psychiatry : the journal of the Association of European Psychiatrists
Menghini-Müller S
(2020)
Sex differences in cognitive functioning of patients at-risk for psychosis and healthy controls: Results from the European Gene-Environment Interactions study.
in European psychiatry : the journal of the Association of European Psychiatrists
Merritt K
(2016)
Nature of Glutamate Alterations in Schizophrenia: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies.
in JAMA psychiatry
Modinos G
(2013)
Molecular genetic gene-environment studies using candidate genes in schizophrenia: a systematic review.
in Schizophrenia research
Modinos G
(2020)
Association of Adverse Outcomes With Emotion Processing and Its Neural Substrate in Individuals at Clinical High Risk for Psychosis.
in JAMA psychiatry
Moura LM
(2016)
Age-effects in white matter using associated diffusion tensor imaging and magnetization transfer ratio during late childhood and early adolescence.
in Magnetic resonance imaging
Munafò MR
(2015)
Has analytical flexibility increased in imaging studies of bipolar disorder and major depression?
in Psychological medicine
Nicholson TR
(2014)
A structural MRI study of motor conversion disorder: evidence of reduction in thalamic volume.
in Journal of neurology, neurosurgery, and psychiatry
Ong HL
(2021)
Obsessive-Compulsive Symptoms and Other Symptoms of the At-risk Mental State for Psychosis: A Network Perspective.
in Schizophrenia bulletin
Paetzold I
(2021)
Momentary Manifestations of Negative Symptoms as Predictors of Clinical Outcomes in People at High Risk for Psychosis: Experience Sampling Study.
in JMIR mental health
Paetzold I
(2021)
Stress reactivity as a putative mechanism linking childhood trauma with clinical outcomes in individuals at ultra-high-risk for psychosis: Findings from the EU-GEI High Risk Study.
in Epidemiology and psychiatric sciences
Pezzoli S
(2018)
Meta-analysis of regional white matter volume in bipolar disorder with replication in an independent sample using coordinates, T-maps, and individual MRI data.
in Neuroscience and biobehavioral reviews
Pollak TA
(2021)
Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis.
in Molecular psychiatry
Postma MR
(2021)
Across the continuum: Associations between (fluctuations in) momentary self-esteem and psychotic experiences.
in Schizophrenia research
Reininghaus U
(2016)
Stress Sensitivity, Aberrant Salience, and Threat Anticipation in Early Psychosis: An Experience Sampling Study.
in Schizophrenia bulletin
Reininghaus U
(2016)
Psychological processes underlying the association between childhood trauma and psychosis in daily life: an experience sampling study.
in Psychological medicine
Reininghaus U
(2019)
Liberal Acceptance Bias, Momentary Aberrant Salience, and Psychosis: An Experimental Experience Sampling Study.
in Schizophrenia bulletin
Rosenzweig I
(2013)
Hippocampal hypertrophy and sleep apnea: a role for the ischemic preconditioning?
in PloS one
| 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 | 04/2020 |
| 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 | 07/2016 |
| 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 | 10/2018 |
| 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 | 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 | 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/ |