Specific Aim 1: Quantify and characterize the parametric variation of cerebral response to delay, probability, and reward magnitude during decision making in MA dependent individuals vs Controls.
Specific Aim 2 : Quantify disruptions in cerebral connectivity as a factor underlying increased impulsivity in MA using functional correlation, diffusion-tensor imaging (DTI) and voxel based morphometry (VBM).
Specific Aim 3 : Investigate, in humans and rodents, the hypothesis that neuroimmune disruption of network connectivity contributes to impulsive choice in methamphetamine dependence METHODS: Forty-five actively using methamphetamine (MA) dependent individuals, 45 MA dependent patients in early (1 to 6 months) remission and 45 controls will be recruited from local residential treatment programs and by advertisement. Subjects will be evaluated with functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI) and voxel based morphometry (VBM) in order to identify the anatomical and functional networks that underlie impulsive choice. Component 9 will expose mice from two lines selected for high and low MA drinking (Component 9), to chronic MA administration, chronic administration followed by abstinence and saline vehicle (total of 120 mice) and then train them to perform an animal version of the delay discounting task. Component 9 will provide brains of these mice to this component for ex-vivo MRI scanning. We will perform parallel analyses in mouse and human brains. Measures of immune dysregulation and differential gene expression (from Component 8) will be investigated as factors responsible for disruption of decision networks in humans and in animals performing impulsivity tasks.
MA dependence has neuropsychiatric, economic and legal costs to individuals and communities. In particular, impulsivity in MA user may contribute both to the high legal cost associated with MA dependence and to the difficulty patients have maintaining abstinence. This project addresses critical aspects of impulsive choice in MA dependent individuals and has important implications for novel cognitive and pharmacological interventions.
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