Prefrontal cortex fails to learn from reward prediction errors in alcohol dependence.

Patients suffering from addiction persist in consuming substances of abuse, despite negative consequences or absence of positive consequences. One potential explanation is that these patients are impaired at flexibly adapting their behavior to changes in reward contingencies. A key aspect of adaptive decision-making involves updating the value of behavioral options. This is thought to be mediated via a teaching signal expressed as a reward prediction error (PE) in the striatum. However, to exert control over adaptive behavior, value signals need to be broadcast to higher executive regions, such as prefrontal cortex. Here we used functional MRI and a reinforcement learning task to investigate the neural mechanisms underlying maladaptive behavior in human male alcohol-dependent patients. We show that in alcohol-dependent patients the expression of striatal PEs is intact. However, abnormal functional connectivity between striatum and dorsolateral prefrontal cortex (dlPFC) predicted impairments in learning and the magnitude of alcohol craving. These results are in line with reports of dlPFC structural abnormalities in substance dependence and highlight the importance of frontostriatal connectivity in addiction, and its pivotal role in adaptive updating of action values and behavioral regulation. Furthermore, they extend the scope of neurobiological deficits underlying addiction beyond the focus on the striatum.