Previous studies investigating feedback-driven reinforcement learning in patients with schizophrenia have provided mixed results. In this study, we explored the clinical predictors of reward and punishment learning using a probabilistic classification learning task. Patients with schizophrenia (n=40) performed similarly to healthy controls (n=30) on the classification learning task. However, more severe negative and general symptoms were associated with lower reward-learning performance, whereas poorer general psychosocial functioning was correlated with both lower reward- and punishment-learning performances. Multiple linear regression analyses indicated that general psychosocial functioning was the only significant predictor of reinforcement learning performance when education, antipsychotic dose, and positive, negative and general symptoms were included in the analysis. These results suggest a close relationship between reinforcement learning and general psychosocial functioning in schizophrenia.

To better understand the cognitive component of the deficit syndrome in schizophrenia in which patients display negative symptoms including apathy, social withdrawal and lack of affect, we studied patients learning a sequence chaining task previously used with Parkinson's and aMCI patients (Shohamy et al, 2005; Nagy et al, 2007). Participants navigated a cartoon character through a sequence of four rooms by learning to choose the open door from three colored doors in each room. In the training phase, each stimulus leading to reward (open door in each room) was trained via feedback until the complete sequence was learned. In the probe phase, the decision-making context was manipulated so that, in a given room, there appeared a door which was correct in another room as well as the door that was correct in that room. In our previous papers, we argued that the training phase is predominantly related to basal ganglia circuits while the context-dependent probe phase requires intact medial-temporal lobe functioning. In the current study, both deficit and non-deficit patients (that is, those who display only positive but not negative symptoms) were similarly impaired on the probe phase compared with controls. However, the training phase was only compromised in deficit patients. In particular, more severe negative symptoms were associated with more errors on the training phase. Executive functions were unrelated to performance on this sequence learning task. These results suggest that the deficit syndrome in schizophrenia is associated with prominently impaired stimulus-response reinforcement learning, which may indicate abnormal functioning of basal ganglia circuits.

Weickert, T., Goldberg, T., Callicott, Q. C., Apud, J., Das, S., Zoltick, B., Egan, M., Meeter, M., Myers, C., Gluck, M., Weinberger, D., & Mattay, V. (2009). Neural correlates of probabilistic category learning in patients with schizophrenia. Journal of Neuroscience. 29(4). 1244-1254.

Forty patients with schizophrenia receiving antipsychotic medication and 25 healthy participants were assessed on interleaved blocks of probabilistic category learning and control tasks while undergoing functional magnetic resonance imaging. Based on analyses of the patients and healthy adults matched on learning and performance, a minority of patients with schizophrenia achieve successful probabilistic category learning and performance levels through differential activation of a circumscribed neural network which suggests a compensatory mechanism in patients showing successful learning. In particular, we found greater caudate and dorsolateral prefrontal cortex activity in the healthy adults and greater activation in a more rostral region of the dorsolateral prefrontal, cingulate, parahippocampal and parietal cortex in patients. These results suggest that successful probabilistic category learning can occur in the absence of normal frontal-striatal function.

Farkas, M., Polgar, P., Kelemen, O., Rethelyi, J., Bitter, I., Myers, C. E., Gluck, M. A., & Keri, S. (2008). Associative learning in deficit and non-deficit schizophrenia. Neuroreport. 19(1), 55-58

We studied feedback-guided associative learning and acquired equivalence in schizophrenia patients who were subtyped as being deficit (showing negative symptoms) or non-deficit (not showing negative symptoms). Acquired equivalence learning, which depends on the medial temporal lobe, was impaired in both subtypes. In contrast, feedback-guided associative learning, which depends on basal ganglia function, was impaired only in the deficit patients. This suggests that the enduring negative symptoms in deficit schizophrenia may be related to decreased response to cognitive feedback and deficient basal ganglia function.

Kéri, S., Nagy, O., Kelemen, O., Myers, C. E, & Gluck, M. A. (2005). Dissociation between medial temporal and basal ganglia memory systems in schizophrenia. Schizophrenia Research. 77. 321-328.

Basal ganglia and medial temporal lobe dependent learning was studied in patients with schizophrenia using a two-phase acquired equivalence task in which prior training to treat two stimuli as equivalent increases generalization between them (Myers et al, 2003). Patients with schizophrenia showed a selective deficit on stimulus generalization, whereas initial stimulus-response learning was spared. However, errors during the initial stimulus-response learning was correlated with daily dose of chlorpromazine-equivalent antipsychotics. This is the first study to show that patients with schizophrenia exhibit deficits in medial-temporal-dependent learning, but not during basal-ganglia-dependent learning, within a single task. High-dose first generation antipsychotics may disrupt basal-ganglia-dependent learning by blocking dopaminergic neurotransmission in the nigro-striatal system.