Methamphetamine (MA) dependence is associated with deficits in markers of fronto-striatal function. Current data suggest that a variety of behavioral impairments, including diminished capacity for response inhibition accompany this frontostriatal dysfunction. Deficits in response inhibition may compromise treatment outcomes, and contribute to the unusually rapid progression of addiction to MA. Knowledge of the circuitry that mediates response inhibition and its impairment in MA-dependent individuals may help guide the development of innovative therapeutic approaches. We will use the Stop-Signal and the Probabilistic Reversal Learning Tasks to measure response inhibition, and will assess functional and structural integrity of cortical and striatal brain regions thought to mediate performance on these tasks. We will pair functional magnetic resonance imaging (fMRI) with these tests of inhibitory control, indirectly assessing neural activity from the change in magnetic resonance signal: Control and MA-dependent (7-15 days abstinent) research subjects will be tested after administration of placebo and of 200 mg modafinil (counterbalanced). Modafinil improves response inhibition in healthy subjects and those with ADHD, and a clinical trial has indicated that modafinil may reduce cocaine self- administration by dependent subjects. Structural MRI will be used to address hypotheses regarding gray matter volume in cortical (e.g., inferior frontal gyrus, orbitofrontal cortex) and striatal regions. Our study aims to help define the cognitive resources available to MA-dependent clients entering treatment, and to clarify the neural bases for deficits in response inhibition. We expect that performance measures of response inhibition will be associated with activity in the inferior frontal cortex, ventral striatum, and orbitofrontal cortex in both groups, with MA users having poorer performance and less task-related activity in these regions than the controls, and that modafinil will improve performance with corresponding effects on signal change in frontostriatal regions. We also predict that MA abusers will exhibit deficits in gray matter volumes of the inferior frontal gyrus, orbitofrontal cortex, and in the striatum, and that these deficits will be inversely related to performance on tests of inhibitory control and associated brain activity assessed with fMRI.
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