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 [18F]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.

Ventral Striatal Dysfunction and Symptom Expression in Individuals With Schizotypal Personality Traits and Early Psychosis

“…Importantly, increased striatal activity during reward anticipation was mostly driven by positive symptoms, which is consistent with our previous study in unmedicated individuals atrisk for psychosis. 19 These findings are in line with studies showing a relation between positive symptoms and increased hemodynamic responses to reward-predicting cues 55 or neutral stimuli in the mesolimbic reward system 21,32,56,57 in individuals at-risk for psychosis and patients with psychotic disorders. In contrast, a recent study in unmedicated patients with schizophrenia has reported a negative association between VS activity during anticipation of wins and losses, ie, salience, with positive symptoms.…”

“…[15][16][17][18] Other studies including patients with broadly defined first-episode psychosis (not restricted to schizophrenia and schizophreniform disorder) or individuals at-risk for psychosis did not report any group differences, but focused more on the relationship with symptom expression. [19][20][21][22][23] This work supports the idea that on a group level reduced activation of the striatum may be more strongly related to schizophrenia or chronic forms of psychosis than to psychotic disorders in general. Importantly, these divergent findings highlight the importance of using dimensional approaches to investigate the neural basis of psychosis rather than restricting research to group differences.…”

“…19,53 At the group level, we found no differences between HCs and individuals with SPT or first-episode psychosis in VS activation, which is consistent with previous results in broadly defined FEP patients and individuals at-risk for psychosis. [19][20][21][22] In contrast, there is now meta-analytic support for reduced VS activation in patients with established schizophrenia, 24 but results on the individual study level are very inconsistent. 15,16,23,25,31,35,59,62,63 These mixed findings support the notion that striatal alterations in psychosis do not solely consist of hypo-activation but vary between different stages (early vs chronic) and different forms of psychosis (schizophrenia vs non-schizophrenia).…”

“…Based on previous studies discussed above, 19,21,23,25,35 we expected symptom expression but not group membership to be associated with aberrant ventral striatal activity during reward anticipation.…”

“…18 Concerning positive symptoms, the literature strongly suggests an association with diminished striatal activity to relevant stimuli in unmedicated first-episode psychosis patients and individuals at ultra-high risk, which is consistent with the aberrant salience model of psychosis. 15,21 However, on a meta-analytic level including studies with unmedicated and medicated patients the association of neural alterations during reward processing and positive symptoms is less clearly delineated. 24 Furthermore, the association between striatal dysfunction and depressive symptoms is well described within depressive disorders 28,29 but data are limited for schizophrenia.…”