Neural and behavioral correlates of aberrant salience in individuals at risk for psychosis

Abstract

The "aberrant salience" model proposes that psychotic symptoms first emerge when chaotic brain dopamine transmission leads to the attribution of significance to stimuli that would normally be considered irrelevant. This is thought to occur during the prodromal phase of psychotic disorders, but this prediction has not been tested previously. In the present study, we tested this model in 18 healthy volunteers and 18 unmedicated individuals at ultra-high risk of psychosis. Subjects performed the Salience Attribution Test, which provides behavioral measures of adaptive and aberrant motivational salience, during functional magnetic resonance imaging to assess neural responses to relevant and irrelevant stimulus features. On a separate occasion, the same subjects were also studied with [(18)F]fluorodopa positron emission tomography to measure dopamine synthesis capacity. Individuals at ultra-high risk of psychosis were more likely to attribute motivational salience to irrelevant stimulus features (t(26.7) = 2.8, P = .008), and this bias was related to the severity of their delusion-like symptoms (r = .62, P = .008). Ventral striatal responses to irrelevant stimulus features were also correlated with delusion-like symptoms in the ultra-high risk group (r = .59, P = .017). Striatal dopamine synthesis capacity correlated negatively with hippocampal responses to irrelevant stimulus features in ultra-high risk individuals, but this relationship was positive in controls. These data are consistent with the hypothesis that aberrant salience processing underlies psychotic symptoms and involves functional alterations in the striatum, hippocampus, and the subcortical dopamine system.

Keywords: aberrant salience; dopamine; functional magnetic resonance imaging; positron emission tomography; psychosis; salience attribution test.

Figures

Fig. 1.

Behavioral data. Ultra-high risk (UHR) individuals exhibited (a) elevated explicit aberrant salience but (b) equivalent explicit adaptive salience relative to controls. (c) Explicit aberrant salience was positively correlated with delusion-like symptoms in the UHR group. Error bars indicate standard errors of the mean (SEM). VAS, Visual Analogue Scale; CAARMS, Comprehensive Assessment of At-Risk Mental State.

Fig. 2.

Aberrant neural reward prediction signals in UHR individuals. (a & b) The magnitude of aberrant salience attribution was positively correlated with ventral striatal response to irrelevant cue features (peak voxel: [x = –12; y = 18; z = –12]), with a significantly steeper slope [F(1,31) = 9.39, P = .004] in controls (r = .74, P < .001 [uncorrected]) than UHR subjects (r = .40, P = .11 [uncorrected]). (c) Aberrant reward prediction signals in the ventral striatum (peak voxel from the above analysis) correlated positively with the severity of delusion-like symptoms in the UHR group (r = .59, P = .017). Error bars indicate SEM.

Fig. 3.

Relationship between striatal dopamine levels and aberrant neural reward prediction signals. (a & b) In controls, aberrant reward prediction signals in the hippocampus (peak voxel: [x = 33; y = –36; z = –9]) correlated positively with 18F-DOPA Ki in the dorsal striatum (r = .65, P = .004 [uncorrected]), but the same relationship was negative in UHR individuals (r = –.52, P = .035 [uncorrected]).