Stimulant-dependent subjects show dysfunctions in decision-making similar to those seen in subjects with ventromedial prefrontal cortex lesions. Studies of drug craving, reward association, and decision-making have implicated dysfunctions of the dorsolateral and orbitofrontal cortex as a key neural substrate in subjects with stimulant dependence. Here, a functional magnetic resonance imaging (fMRI) study was carried out to determine the relationship between decision-making dysfunction and neural activation in different prefrontal areas. This investigation tested the behavioral hypothesis that methamphetamine-dependent subjects in early sustained remission show decision-making dysfunctions that are consistent with an increased reliance on stimulus-contingent response selection. It was hypothesized that these decision-making dysfunctions are due to differences in task-related activation in the dorsolateral and ventromedial prefrontal cortex. Ten methamphetamine-dependent subjects were compared with ten age-and education-matched controls performing a twochoice prediction task and a two-choice response task during a fMRI session. Response bias, latency, and mutual information measures assessing the underlying strategies of the decision-making sequences were obtained. First, methamphetamine-dependent subjects were more influenced by the immediately preceding outcome during the two-choice prediction task relative to normal comparison subjects. Second, methamphetamine-dependent subjects activated less dorsolateral prefrontal cortex (BA 9) and failed to activate ventromedial cortex (BA 10,11) The compulsive and nonadaptive nature of drug-taking behavior in substance-dependent subjects has led several investigators to hypothesize that subjects with substance dependence show a dysregulation of ventromedial or orbitofrontal cortex Rolls 2000; Volkow and Fowler 2000). Disruption of the orbitofrontal cortex via the striato-thalamo-orbitofrontal neural systems loop, which is critical for the assessment of stimulus-reward relationships, has been proposed as a key neural substrate underlying the neural systems dysregulation in substance dependence (Volkow and Fowler 2000). Specifically, the orbitofrontal cortex maintains a detailed representation of rewarding stimuli and updates the current reward value of a stimulus continually (O'Doherty et al. 2000). Therefore, the orbitofrontal cortex is critical for rapid stimulus-reinforcement association learning and the correction of these associations when reinforcement contingencies change (Rolls 2000). The combination of dorsolateral and orbitofrontal cortex dysregulation in substance-dependent subjects may affect three distinct behavioral functions : first, expectancy, which is based on the predictions of reward and observed probabilities of reinforcement with a stimulus; second, compulsion, which involves the repetitive application of a behavioral strategy despite the lack of association of reward with the stimulus; third, decision-making, which involves the balancing of expec...