Mapping Neurodevelopmental Trajectories for Adult Psychiatric Disorder: ALSPAC-MRI-II

The Avon Longitudinal Study of Parents and Children (ALSPAC) has shown that over 9% of 18 year olds have psychotic experiences (PEs) such as hallucinations and delusions, verified by trained psychologists and using strict criteria. When persistent, PEs increase the likelihood of a person developing psychotic disorders such as schizophrenia, other psychiatric conditions (eg depression) and poor psychosocial outcomes such as unemployment. PEs can sometimes recede as people pass from adolescence to adulthood but we don't know how changes in the brain, which continues to develop and mature through these years, underlie and affect PEs. Thanks to grants from the MRC, we have recently shown, using magnetic resonance imaging (MRI) brain scans, that at age 20+, individuals from ALSPAC with PEs have small changes in regional brain volumes, and global and local connectivity which cannot be ascribed to the consequences of having a psychiatric diagnosis or treatment with medication. We have also shown that individuals from ALSPAC who may be at a slightly increased risk of psychosis due to their genetic makeup (using a 'risk score' made out of the contribution of the many genes which when added together, are associated with a small but significantly increased risk of schizophrenia) also have subtle changes in brain thickness and volume.
Our objective is to re-scan these same individuals, numbering about 450 in total, at age 26 using the full range of MRI scanning techniques. This will enable us to test the hypothesis that persistent PEs are underpinned by anomalous pathways or trajectories of brain development and abnormalities in function, as compared with those without PEs and against their original baseline scans. Additional objectives are to plot changes in cognition (using IQ tests) that we expect might show some decline in those with persistent PEs. We will make use of the latest genetic risk score for schizophrenia from genome-wide association studies available in ALSPAC to examine the potential of our brain measures to be used as intermediate links between genes and clinical outcomes. Finally we will see if blood markers of inflammation which can act on the brain, measured in the same individuals when they were children and again when adults, might explain the brain changes we see on MRI.
We will use a powerful MRI brain scanner located in Cardiff to obtain detailed structural images and measures of grey and white matter volumes and a particular variant of scanning called diffusion MRI that quantifies the microscopic properties of white matter tracts - nature's wires - that connect together groups of brain cells. Functional MRI, which picks up those parts of the brain that are more active during a task, will be carried out while participants are trying to remember a sequence of letters and also while they are at rest (although their brains will still be working). This will help us to determine the degree of physiological compromise/compensation evident in the brain in those with PEs and structural changes. This will also help us look at how the different specialised parts of the brain are working together as a coherent unit.
This project will enable us to map the change in brain development in young people with and without potentially important psychotic experiences (PEs) taken from ALSPAC, one of the most well-studied epidemiological samples available to medical science. Because there is such a wealth of information available, it means that when we analyse the brain scans we can take into account lots of other factors that might otherwise obscure or falsely exaggerate the effects of PEs such as cannabis and alcohol misuse. The project as a whole has the potential to advance our understanding of the biological basis of psychotic and related disorders and to help guide the development of primary prevention and early intervention strategies in mental health care.

The Avon Longitudinal Study of Parents and Children (ALSPAC) has shown that 9% of 18 year olds have psychotic experiences (PEs) such as hallucinations and delusions. When persistent, PEs are a strong risk factor for psychotic disorders (eg schizophrenia) and poor psychosocial outcomes. We have recently shown that at age 20, individuals from ALSPAC with PEs have subtle changes in regional brain volumes, and global and local connectivity that cannot be ascribed to the consequences of psychiatric treatment. In a related study, we showed that ALSPAC participants selected on the basis of a high psychosis risk score (PRS) derived from GWAS data also had subtle brain changes.
Objectives: To re-scan the same individuals (n=450) at age 26 using multi-modal magnetic resonance imaging (MRI). We will test the hypothesis that persistent PEs are underpinned by anomalous trajectories of brain structural change and abnormalities in function, as compared with those without PEs and against their baseline scans. We will also plot changes in cognition and use the PRS to examine the potential of our brain measures as endophenotypes. Finally we will make use of blood-based inflammatory markers such as IL-6 taken in childhood and age 24, to examine their association with brain changes.
Measures: We will use 3-T MRI to obtain detailed structural images of grey/white matter volumes and microstructural MR imaging for white matter tracts. Functional MRI will be carried out during a working memory task and at rest to determine the degree of physiological compromise/compensation in relation to PEs, as well as functional integrity of core cognitive hubs.
This project will enable us to map neurodevelopmental changes in a well-studied epidemiological sample with PEs while adjusting for potential confounders. It has the potential to deliver important advances in our understanding of the biological basis of psychotic disorders and to inform primary prevention and early intervention strategies.

(Please see 'Pathways to Impact' statement (attached)).

Who will benefit from this research?
This research project is focused on questions that will have an impact beyond the academic environment, with beneficiaries including patients and their families, young people in the general population, clinical practitioners, policy-makers, and the wider population upon which much of the economic burden of psychosis falls.

Relevance of the research to these beneficiaries:
This project has the potential to deliver important advances in our understanding of the biological basis of psychotic and related disorders, and perhaps to inform the development of primary prevention and early intervention strategies, a key priority for the medical charities, the MRC and National Health Service.
Psychosis most commonly begins in late adolescence and early adulthood and hence it may have a devastating impact on an individuals life chances and productivity. It has been identified by the World Health Organisation as one of the major causes of disability worldwide and affects between 1% and 3% of the population.
Psychosis affects cognitive function and hence impacts on educational attainment and affects motivation and behaviour that in turn greatly reduces employment opportunities and earnings. Psychotic experiences interfere with relationships and so are associated with social isolation. The study is based on psychotic experiences and these are risk factors, not only for psychosis itself but suicidal behaviour, mood and anxiety disorders, substance misuse etc. These in turn are a huge burden on the NHS and society. Understanding the developmental origins of psychotic experiences may, in the longer term, lead to preventative strategies and new therapies.