Substantia nigra/ventral tegmental reward prediction error disruption in psychosis

Abstract

While dopamine systems have been implicated in the pathophysiology of schizophrenia and psychosis for many years, how dopamine dysfunction generates psychotic symptoms remains unknown. Recent theoretical interest has been directed at relating the known role of midbrain dopamine neurons in reinforcement learning, motivational salience and prediction error to explain the abnormal mental experience of psychosis. However, this theoretical model has yet to be explored empirically. To examine a link between psychotic experience, reward learning and dysfunction of the dopaminergic midbrain and associated target regions, we asked a group of first episode psychosis patients suffering from active positive symptoms and a group of healthy control participants to perform an instrumental reward conditioning experiment. We characterized neural responses using functional magnetic resonance imaging. We observed that patients with psychosis exhibit abnormal physiological responses associated with reward prediction error in the dopaminergic midbrain, striatum and limbic system, and we demonstrated subtle abnormalities in the ability of psychosis patients to discriminate between motivationally salient and neutral stimuli. This study provides the first evidence linking abnormal mesolimbic activity, reward learning and psychosis.

Figure 1

Experimental task. Subjects select either of two visual stimuli presented on a display screen, and subsequently observe the outcome—either a financial reward of 20 pence (shown on the top right of the figure), or neutral feedback (not shown here but shown in Supplementary Figure 1), or nothing.

Figure 2

Behavioural results. (a) Choice behaviour. Each group learnt to choose the high probability stimulus on reward trials, but there were no significant differences between groups. Error bars denote standard error of the mean and stars denote significant differences (P < 0.05). (b) Reaction time. The difference between reward and neutral trial latencies was less in psychosis patients compared to controls (Diagnosis by Valence interaction: F = 7.1, d.f. = 1, 23, P = 0.014), and patients responded more rapidly than control subjects to neutral stimuli (T = 3.3, P = 0.003). Error bars denote standard error of the mean and stars denote significant differences (P < 0.05).

Figure 3

fMRI results for analysis in entire sample. (a-c) Results of the contrast of prediction error on reward versus neutral trials in region of interest analysis. Effects significant at P < 0.05 FDR-corrected for multiple comparisons are shown in yellow and orange. (d) The a priori defined mesolimbic region of interest was composed of the union of the midbrain and ventral striatum, shown here in a maximum intensity projection.

Figure 4

Group differences. Regions in which there were group differences in the relationship between prediction error and brain response (in reward compared to neutral trials) are shown in yellow and red. (a) and (b) Region of interest analysis results in sagittal (a) and axial (b) sections, P < 0.05 FDR-corrected; (d) whole brain analysis results in coronal section (P < 0.05 FDR-corrected, cluster level 100). (c) Parameter estimates at 8, -22, -8 (right midbrain). The differing midbrain activations between the two groups appeared to be driven by a combination of patients’ attenuated responses to prediction error in reward trials together with patients’ augmented responses to prediction error in neutral trials. Error bars denote standard error of the mean.