Our findings demonstrate abnormal responses to reward prediction error in the midbrain and key target regions (striatum, hippocampus, cingulate, insula) in patients with psychosis. They provide direct empirical support for a model of psychosis, which invokes abnormal dopamine-dependent motivational salience as a key underlying disturbance. While patients successfully learnt the required contingencies, suggesting that their abnormal brain responses were not secondary to impaired task performance, these disrupted neural responses were accompanied by significant behavioural differences, notably, a tendency to show rapid reaction times even to stimuli that predicted neutral feedback. Previous reinforcement learning experiments using paradigms similar to ours have reported faster reaction times in response to rewarding stimuli than neutral stimuli: this phenomenon has been termed ‘reinforcement related speeding’.21,23,27
Such reinforcement related speeding is attributed to the anticipation of a potential reward on such trials leading to enhanced motivation and hence faster responding. In our study, both patients and controls were significantly faster on reward trials than neutral trials, in accordance with previous data, but the difference
between latencies on reward and neutral trials was attenuated in patients. Patients were significantly faster than controls on neutral trials, consistent with the theory that they found such trials inappropriately motivationally significant. It is not unprecedented that psychosis patients perform rapidly on cognitive tests—it has been previously been shown that deluded patients are faster than controls when making decisions during probabilistic reasoning tasks.33
Our results suggest that, at the behavioural level, psychotic patients are failing to make the distinction between events that are motivationally salient (that is, in this case, signalling a potential for reward) and those that are not. This maladaptive behaviour is consistent with their abnormal midbrain activations. Here, patients failed to show the normal differential response to rewarding and neutral prediction error related activity. In controls, the distinction was reflected in the responses to a number of regions—midbrain, striatum, cingulate, insula—that have been previously implicated in reward processing in both human30,34,35
and animal studies.13
Furthermore, reward processing/reward prediction error are mediated by dopamine in both humans23,36,37
We suggest that the midbrain activations in controls, and its aberration in individuals with psychosis, is related to dopamine activity, though we acknowledge that this experimental design only provides indirect evidence in this regard.
While the results from the neuroimaging analysis show very striking differences between groups, the behavioural differences were more subtle; this may reflect the increased sensitivity of functional MRI compared with behavioural analysis. In fact, controls chose the high probability stimulus more often than patients (this difference was not statistically significant). Perhaps, on a more difficult reward learning test, there would have been more pronounced behavioural differences between groups in choice behaviour; this area demands further empirical investigation in future studies.
Some of the patients were taking atypical antipsychotic dopamine receptor anatagonist medication. However, there are several reasons why the group differences we observed are unlikely to be secondary to medication: the midbrain VTA/substantia nigra group differences remained significant when the analysis was restricted to unmedicated patients; our analysis did not reveal any effect of medication on brain activity in patients taking antipsychotics, and a previous study by Juckel and colleagues39
provided evidence that atypical antipsychotics, rather than inducing abnormal brain responses, in fact normalize physiological responses to reward expectation in schizophrenia.
Although several previous authors have hypothesized that dysfunctional dopamine-mediated reinforcement processing is implicated in the pathology of psychotic illnesses,10,11,19,40-43
few empirical studies have addressed the issue. To our knowledge, this is the first study to examine brain reward prediction error in any psychiatric or neurological disorder. In a reward anticipation task that robustly elicits ventral striatal signal change, patients with schizophrenia displayed abnormal ventral striatal activation compared with controls, though this study did not study learning or examine prediction error.44
Previous behavioural studies have demonstrated disturbances in the classic dopamine-dependent associative learning processes of Kamin blocking and latent inhibition in early psychosis.45
More recent evidence for a model of disrupted error-dependent learning in psychosis comes from Corlett and colleagues,46
who showed that right prefrontal prediction error signal during causal learning predicts subsequent vulnerability to the psychotogenic effects of ketamine in healthy volunteers. Our study provides subtle behavioural and more prominent physiological evidence of reinforcement learning abnormality in psychosis, a psychological process that, it is theorised, is important in both the positive and negative symptoms in schizophrenia and other psychotic disorders.