Dissecting dopamine, salience and the risk of psychosis

Presentation First Author: 
Toby Winton-Brown

This study unpacks the concept of 'salience as invoked by Kapur and others in linking dopamine dysregulation to psychotic symptoms. Rather than relying on one-dimensional reward based conception of salience that has dominated studies so far it develops a multidimensional view. It sets out to then test this using fMRI and PET scanning in unmedicated subjects at high clinical risk for psychosis (UHR) in the neural setting of the MAM animal model of schizophrenia, that predicts abnormal hippocampal outputs drive striatal dopamine dysfunction in psychosis. We developed a factorial fMRI task with probes of Novelty Emotion and Reward. We found significant behavioral and fMRI main effects and interactions of each probe in a sample of 29 healthy controls, and significant departures from this in 29 matched UHR participants- overactivations to reward in the ventral pallidum and midbrain, and altered reward- emotion interactions in the ventral striatum and ACC-Insulae, or 'salience network. In half of the sample we also obtained 18-F-DOPA PET scans. The UHR group had altered relationships between ventral hippocampal activation to salient stimuli and striatal presynaptic dopamine synthesis compared to controls, consistent with the MAM model. These results resonate with the altered emotional and motivational states seen in early psychosis, and with cognitive models emphasizing emotions role in generating psychotic symptoms. They broaden our understanding of normal salience processing, and add support to aberrant salience psychosis models. Finally they support the MAM schizophrenia models prediction, that ventral hippocampal overdrive provokes striatal hyperdopaminergia, and point to new treatment targets.

Conference Name: 
Presentation Date: 
January, 2015
Additional Authors: 
Oliver Howes - Jonathan Roiser - James Stone - Christopher Chaddock - Alice Egerton - Nico Bunzeck - Emrah Düzel - Shitij Kapur - Philip McGuire
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