Risky decision making, prefrontal cortex, and mesocorticolimbic functional connectivity in methamphetamine dependence.

Deficits in decision-making have been linked with addiction, and likely contribute to addiction vulnerability and to the maintenance and severity of dependence1–5. Chronic methamphetamine use is associated with abnormalities in the neural circuits involved in risky decision-making6–9, including structural and functional deficits in the prefrontal cortex (PFC) and striatum10–12, and in striatal dopaminergic markers13–17. Little is known, however, about the links between these observations and problems with decision-making. The mesocorticolimbic system, originating in the midbrain ventral tegmental area (VTA) and projecting to the nucleus accumbens, amygdala, hippocampus and medial PFC18, substantially influences goal-directed behaviors, and pathological drug-seeking behavior may result from drug-induced changes in this circuitry18, 19. Studies using resting-state functional connectivity (RSFC) to assess temporal correlations of spontaneous regional activity when participants are at rest20 have identified abnormalities in connectivity between nodes of the mesocorticolimbic system in cocaine and opiate users18. However, PFC and striatal dysfunction during risky decision-making by substance-dependent individuals21 has not been linked directly to network activity, nor has it yet been examined in methamphetamine users. We therefore used RSFC and task-based fMRI to clarify how circuit-level abnormalities may influence adaptive decision-making in methamphetamine users. Functional magnetic resonance imaging (fMRI) was paired with the Balloon Analogue Risk Task (BART)22, which presents sequential choices – pumping a balloon to increase monetary gains while risking loss, or cashing out to retain earnings. Using a parametric modulation analysis, we tested for differences between methamphetamine-dependent and control subjects in modulation of right dorsolateral prefrontal cortex (rDLPFC) and striatal activation by risk and potential reward (both indexed by pump number) during decision-making. As chronic methamphetamine users exhibit ventral striatal hyper-responsivity to reward23 but rDLPFC hypoactivity during decision-making24, 25, we expected them to display greater modulation of striatal activation by pump number during risky decision-making but less modulation in the rDLPFC, and to earn less on the BART than controls. RSFC was assessed with seeds in the midbrain, because of its dopaminergic projections to limbic and cortical regions, and in rDLPFC, which exhibits risk-sensitivity while participants perform the BART7, 9, 26, 27. Because stimulants produce adaptations in the mesolimbic dopamine system, which are thought to underlie psychomotor sensitization in animals28–30, it was expected that midbrain RSFC would be greater in methamphetamine users than in controls. Finally, because adaptations in mesolimbic and prefrontal cortical regions are thought to underlie addiction-related cognitive deficits31–34, the relationship between task-based activation and connectivity within mesocorticolimbic (midbrain seed) and corticostriatal circuits (rDLPFC seed) was tested. It was expected that modulation of rDLPFC activation would be positively related to rDLPFC RSFC in controls and negatively related to midbrain RSFC in methamphetamine users. Negative association of midbrain RSFC with modulation of rDLPFC activation would suggest that mesolimbic circuit dysfunction promotes maladaptive decision-making in methamphetamine users. As faulty decision-making is a target for addiction therapies, understanding its determinants might facilitate the development of more effective interventions.