Abnormal reward prediction-error signalling in antipsychotic naive individuals with first-episode psychosis or clinical risk for psychosis

Abstract

Ongoing research suggests preliminary, though not entirely consistent, evidence of neural abnormalities in signalling prediction errors in schizophrenia. Supporting theories suggest mechanistic links between the disruption of these processes and the generation of psychotic symptoms. However, it is unknown at what stage in the pathogenesis of psychosis these impairments in prediction-error signalling develop. One major confound in prior studies is the use of medicated patients with strongly varying disease durations. Our study aims to investigate the involvement of the meso-cortico-striatal circuitry during reward prediction-error signalling in earliest stages of psychosis. We studied patients with first-episode psychosis (FEP) and help-seeking individuals at-risk for psychosis due to sub-threshold prodromal psychotic symptoms. Patients with either FEP (n = 14), or at-risk for developing psychosis (n = 30), and healthy volunteers (n = 39) performed a reinforcement learning task during fMRI scanning. ANOVA revealed significant (p < 0.05 family-wise error corrected) prediction-error signalling differences between groups in the dopaminergic midbrain and right middle frontal gyrus (dorsolateral prefrontal cortex, DLPFC). FEP patients showed disrupted reward prediction-error signalling compared to controls in both regions. At-risk patients showed intermediate activation in the midbrain that significantly differed from controls and from FEP patients, but DLPFC activation that did not differ from controls. Our study confirms that FEP patients have abnormal meso-cortical signalling of reward-prediction errors, whereas reward-prediction-error dysfunction in the at-risk patients appears to show a more nuanced pattern of activation with a degree of midbrain impairment but preserved cortical function.

Fig. 1

Behavioural task. a The three different trial types and feedback probabilities. b The experimental task, including trial timing

Fig. 2

Trial performance: percentage of “correct” (high-likelihood) choices stratified by trial type and participant group. Error bars are ± 1 SE

Fig. 3

Group differences in region of interest analysis of activation associated with reward prediction-error signal (p < 0.05 FWE-corrected) across the three groups (controls, first-episode psychosis and at-risk patients) in the midbrain ventral tegmental area (right panel, z = −12), and right middle gyrus/dorsolateral prefrontal cortex (left panel, z = 22). Colour bar depicts corrected voxel p-value from 0.001 (yellow) to 0.05 (red)

Fig. 4

Bar chart shows the mean prediction-error contrast values (termed contrast of parameter estimates, or COPEs in FSL) according to the group, extracted from the significant clusters determined by FSL randomised ANOVA results. The contrast values (COPEs) are derived from the contrast between Reward win and Bivalent win, which constitute the reward prediction error. Error bars show ± 1 SE; a.u. arbitrary units. *p < 0.05