According to the aberrant salience proposal, reward processing abnormality, specifically erroneous reward prediction error (RPE) signaling due to stimulus-independent release of dopamine, underlies delusions in schizophrenia. However, no studies to date have examined RPE-associated brain activations in relation to this symptom.

Seventy-eight patients with a DSM-5 diagnosis of schizophrenia/schizoaffective disorder and 43 healthy individuals underwent fMRI while they performed a probabilistic monetary reward task designed to generate a measure of RPE. Ratings of delusions and referentiality were made in the patients.

Using whole-brain, voxel-based analysis, schizophrenia patients showed only minor differences in RPE-associated activation compared to healthy controls. Within the patient group, however, severity of delusions was inversely associated with RPE-associated activation in areas including the caudate nucleus, the thalamus and the left pallidum, as well as the lateral frontal cortex bilaterally, the pre- and postcentral gyrus and supplementary motor area, the middle cingulate gyrus, and parts of the temporal and parietal cortex. A broadly similar pattern of association was seen for referentiality.

According to this study, while patients with schizophrenia as a group do not show marked alterations in RPE signaling, delusions and referentiality are associated with reduced activation in parts of the prefrontal cortex and the basal ganglia, though not specifically the ventral striatum. The direction of the changes is on the face of it contrary to that predicted by aberrant salience theory.

A leading theory of the negative symptoms of schizophrenia is that they reflect reduced responsiveness to rewarding stimuli. This proposal has been linked to abnormal (reduced) dopamine function in the disorder, because phasic release of dopamine is known to code for reward prediction error (RPE). Nevertheless, few functional imaging studies have examined if patients with negative symptoms show reduced RPE-associated activations.

Matched groups of DSM-5 schizophrenia patients with high negative symptom scores (HNS, N = 27) or absent negative symptoms (ANS, N = 27) and healthy controls (HC, N = 30) underwent fMRI scanning while they performed a probabilistic monetary reward task designed to generate a measure of RPE.

In the HC, whole-brain analysis revealed that RPE was positively associated with activation in the ventral striatum, the putamen, and areas of the lateral prefrontal cortex and orbitofrontal cortex, among other regions. Group comparison revealed no activation differences between the healthy controls and the ANS patients. However, compared to the ANS patients, the HNS patients showed regions of significantly reduced activation in the left ventrolateral and dorsolateral prefrontal cortex, and in the right lingual and fusiform gyrus. HNS and ANS patients showed no activation differences in ventral striatal or midbrain regions-of-interest (ROIs), but the HNS patients showed reduced activation in a left orbitofrontal cortex ROI.

The findings do not suggest that a generalized reduction of RPE signalling underlies negative symptoms. Instead, they point to a more circumscribed dysfunction in the lateral frontal and possibly the orbitofrontal cortex.