ABSTRACT OF THE DISSERTATION
Methamphetamine (MA) abuse is associated with maladaptive decision-making, particularly when risk and reward are involved. Decision-making deficits are linked to impairments in the neural circuitry underlying cognitive control and the evaluation of reward, especially in dopaminergic brain regions that guide motivated behavior and prefrontal cortical (PFC) regions that modulate them.
However, the mechanism by which dopamine neurotransmission and frontostriatal activity are integrated to affect choices is unclear. MA-dependent individuals exhibit abnormal patterns of activation in the prefrontal cortex and striatum and deficits in markers of dopamine function (i.e., dopamine transporter and receptor availability, dopamine release, tyrosine hydroxylase). The concurrent examination of the dopamine system and brain activation during decision-making may provide a better understanding of the neural systems underlying cognitive appraisal of risk and reward and identify systems-level biomarkers for maladaptive decision-making in human drug dependence.
To understand the modulators of maladaptive decision-making, the two studies presented here examined the relationships between risky decision-making, brain function, striatal dopamine receptor availability and the intrinsic activity of the mesocorticolimbic network in MA-dependent and healthy control (HC) individuals.
The studies assessed brain activation while subjects performed the Balloon Analogue Risk Task (BART), using functional magnetic resonance imaging (fMRI). In study 1, the relationship between dopamine D2-type receptor availability and risky decision-making was tested. Sixty healthy research volunteers performed the BART while undergoing fMRI, and in a subset of participants, dopamine D2-type receptor availability was measured using F positron emission tomography (PET). The second study examined differences in risk-taking performance and associated activation between MA-dependent and healthy control groups and related differences to intrinsic brain activity of the mesolimbic system using resting-state fMRI.
Study 1 showed that the modulation of activation by level of risk in the dorsolateral prefrontal cortex (DLPFC) during risky decision-making was negatively correlated with striatal D2-type dopamine receptor availability and positively related to total amount earned on the BART. The decision to limit risk and cash out was associated with the modulation of activation in the ventral striatum, which was positively related to striatal D2-type dopamine receptor availability. In addition, both measures were negatively related to the number of risky choices following the choice to cash-out as well as to the total amount earned on the BART.
In study 2, the groups differed in the modulation of activation by levels of risk during risky decision-making where the MA-dependent subjects compared to controls exhibited greater modulation of activation in the ventral striatum while the healthy controls had greater modulation of activation in the DLPFC. MA-dependent subjects also exhibited greater intrinsic activity in the mesocorticolimbic network compared to healthy control subjects. Furthermore, the intrinsic activity of the mesocorticolimbic system was negatively related to the modulation of activation in the DLPFC during risky decision-making in the MA-dependent group. Despite the lack of group differences in resting-state connectivity of the corticostriatal circuit, healthy controls showed a positive relationship between the strength of functional connectivity between the DLPFC and striatum and the modulation of activation by levels of risk in the DLPFC during risky decision-making.
The results suggest that the enhanced sensitivity for potential reward and diminished cortical inhibition of reward-driven responses exhibited by MA-dependent subjects may result from the altered relationship between prefrontal cortical activation and functional connectivity of dopaminergic pathways. By combining positron emission tomography, task-based fMRI and resting-state fMRI, these studies help clarify the biological underpinnings and network interactions of risky decision-making in human drug dependence.