Neurobiological factors underlying the onset of psychosis. (360G-Wellcome-091667_Z_10_Z)

Dysfunction of the medial temporal lobe (MTL) and of the subcortical dopamine system are key pathophysiological features of psychosis. Animal models propose that psychosis develops as a result of MTL dysfunction driving subcortical dopaminergic hyperactivity through glutamatergic projections to the striatum. MTL, glutamate and dopamine function can all be measured in patients with psychosis using neuroimaging techniques, but to date they have largely been studied separately. A key objective of t he present proposal is to combine functional MRI, MR spectroscopy and PET in the same individual, so that the relationship between these pathophysiological factors can be examined directly. We will do this in subjects with an At Risk Mental State, who have a 20-45% risk of developing psychosis within 2 years. After scanning, the sample will be followed up clinically to determine which of the subjects subsequently becomes psychotic. This will clarify the extent to which these pathophysiological f actors, and their interaction, are critical to the onset of illness. A further objective is to assess whether these neuroimaging measures can be used in a clinical setting to predict which individuals will later develop psychosis.