Behavioral and functional neuroimaging evidence for prefrontal dysfunction in methamphetamine-dependent subjects.

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 two-choice 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) during the two-choice prediction task compared with the two-choice response task. These results support the basic hypothesis that stimulant-dependent subjects exhibit fundamental cognitive deficits during decision-making that are consistent with both orbitofrontal and dorsolateral prefrontal dysfunction.