Our research is built around five research themes. These comprise three pillars of research on clinically-defined conditions (epilepsy, autism spectrum disorder and schizophrenia) and two transverse activities underpinned by cutting edge technology platforms. The aim is to dissolve the boundaries currently existing between the clinical entities by utilising behavioural and cognitive models, functional imaging, genetic linkage analysis and analogous genetic modelling in order to provide a clearer understanding of common versus distinct disease mechanisms. This integration of pure research and clinical neuroscience will provide positive translational outcomes for the field of neurodevelopmental disorders and add to the basic body of knowledge at the same time.
Over one per cent of the population has epilepsy and more than fifty per cent of these patients develop their first seizure in childhood. In addition, many other genetically determined developmental anomalies often present with onset of seizures in late adolescence or adult life, which suggests that specific developmental abnormalities may precede most epilepsies. The aim of this research programme is to shed light on the mechanisms underlying human epilepsies, from specific cellular defects to network abnormalities.
Autism Spectrum Disorder
A panoply of genetic alterations causes ASD and related intellectual disabilities, but the disease mechanisms underlying these conditions are not well understood. One important question is whether different gene mutations disrupt similar processes (i.e., impact on a final common pathway) during brain development. The aim of this research programme is to link clinical observations with a better understanding of the cellular and neural network alterations caused by specific mutations in ASD.
Schizophrenia is associated with severe behavioural and cognitive deficits, and extensive changes in brain structure and function. Two of the most consistent neuropathological findings are alterations in the prefrontal cortex, hippocampus and adjacent medial temporal lobe structures, and elevated presynaptic dopamine function in the striatum. The aim of this programme is to provide new insights into the neurobiology of schizophrenia by combining imaging studies in humans with mechanistic studies in mouse models.
Common Genetic Mechanisms in Neurodevelopmental Disorders
Although some specific genetic variations predispose specific neurodevelopmental disorders, there are many susceptibility genes associated with more than one disorder. Almost without exception, copy number variations (CNVs) associated with one neurodevelopmental disorder have been found linked to others. This feature of multiple complex neurodevelopmental disorders sharing genetic aetiology has also been observed at the level of individual gene mutations. This suggests a number of common biological mechanisms, but also hints at the potential for environmental factors to be having prominent influence in the clinical outcomes for individual patients. Consequently, we seek to integrate our clinical research in order to identify common disease mechanisms. Common features in which we have a particular interest are gene-environment interactions and disrupted cognition, though we are not limiting ourselves to these. Genome editing
in animal models and human-derived neurons will help us elucidate the specific contribution of gene mutations to disease.
Understanding Functional Variation in Neurodevelopmental Disorders
Macroscopic structural abnormalities associated with neurodevelopmental disorders have been documented for centuries. In more recent times, a considerable catalogue of microscopic structural and even synaptic variation has been built using modern imaging techniques. However there is a far smaller body of knowledge about variations in functional activity. We seek to develop new imaging techniques and to refine existing ones to build an open access dataset of comparative functional imaging data at micro-, meso- and macro-scales. Through the identification of neurobiological phenotypes, functional and behavioural, the neurobiological correlates of neurodevelopmental disorders should become illuminated. Our functional imaging platform
has been built for this purpose.