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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    213—Amphetamine and Related Drugs: Neural Mechanisms of Addiction

    Sunday, November 10, 2013, 1:00 pm - 4:00 pm

    213.04: Relationship betweem mesolimbic resting-state functional connectivity and prefrontal activation during decision-making in methamphetamine dependence

    Location: 23A

    1Neurosci. Interdepartmental Program, 2Dept. of Psychiatry and Biobehavioral Sci., UCLA, Los Angeles, CA

    Abstract Body: Frontostriatal and mesolimbic circuitry mediate risky decision-making, and dysfunction in these circuits has been associated with addiction. This study, therefore, compared frontostriatal activation during risky decision-making between methamphetamine dependent (MA) and healthy control (HC) subjects, and tested whether this activation was related to intrinsic functional connectivity of the mesolimbic and frontostriatal networks.
    Methods: Functional magnetic resonance imaging (fMRI) was paired with the Balloon Analogue Risk Task (BART) to measure frontostriatal activation in 24 MA and 27 healthy participants during risky decision-making. In the BART, participants can pump a virtual balloon to increase potential monetary reward or cash out to receive accumulated reward; each pump presents greater risk and potential reward (indexed by pump number). A parametric design was used to test for a linear relationship between pump number and activation during balloon pumps. Resting-state functional connectivity (RSFC) was measured in a subset of participants (18 HC/15 MA). For RSFC analysis, separate whole-brain voxel-wise correlations were computed for the time-courses of midbrain and DLPFC. Parameter estimates (GLM β-values) of modulation of DLPFC activation by pump number were entered in whole-brain seed-based RSFC analyses to test the relationships between RSFC and modulation of DLPFC activation during the BART.
    Results: The HC group exhibited greater modulation of DLPFC activation by pump number and less modulation of ventral striatal activation than the MA group. Mesolimbic RSFC was greater in the MA than HC group and negatively related with task-based modulation of DLPFC activation in the MA group. There were no group differences in frontostriatal RSFC; however, frontostriatal RSFC was positively correlated with task-based DLPFC activation in the HC group (all p’s < 0.05).
    Conclusion: In the MA group, resting-state activity of the mesolimbic network and the relationship between mesolimbic RSFC and DLPFC modulation of activation during risk-taking suggest that abnormal activation patterns during decision-making may reflect loss of prefrontal control due to mesolimbic hyperactivity. The relationship between DLPFC modulation of activation and frontostriatal RSFC in the HC group suggests that greater intrinsic frontostriatal connectivity enhances inhibition of reward-driven responses through DLPFC activation during decision-making. These findings provide new information about the relationships between frontostriatal and mesolimbic connectivity and dysfunctional patterns of neural activation during risky decision-making.

    Lay Language Summary: Heightened activity in the brain’s reward circuitry may contribute to maladaptive decision-making by stimulant abusers. We show that methamphetamine users have high naturally occurring (or resting) activity in the brain’s reward network and that this influences brain activation during risky decision-making.When making risky choices, the frontal cortex, a region important for decision-making, was less sensitive to levels of risk in methamphetamine users than in healthy comparison participants, but methamphetamine users exhibited hyperactivity in the brain’s reward pathway even in the absence of rewarding stimuli. In the stimulant users, this high level of resting activity in the brain’s reward network was related to the blunted response of the prefrontal cortex during risky decision-making.
    As cognitive impairments (e.g., poor decision making ability) associated with stimulant dependence interfere with treatment and contribute to maintaining addiction, our findings have both clinical and neuroscientific implications. Physical changes in the wiring of the brain’s reward circuit have been shown in animals exposed to drugs, and our results may reflect these plastic changes in human drug dependence. We show that the heightened activity of the reward pathway in addicted individuals in turn affects decision-making and related brain activation. An understanding of this relationship may enhance the effectiveness of current behavioral treatments.
    We measured brain activation using functional magnetic imaging (fMRI), which provides an indirect measure of changes in neuronal activity. Two types of measurements were taken: one while participants performed a decision-making task involving monetary risk, called the Balloon Analogue Risk Task (BART), and another while they rested in the MRI scanner with their eyes open (Resting-state fMRI). In the BART, participants pump a virtual balloon to earn $0.25 per pump. While each balloon pump offers an opportunity for additional earnings, it also increases the risk of the balloon exploding, which leads to loss of accumulated earnings. Participants may avoid the risk of a balloon explosion by cashing out and retaining the accumulated earnings.
    During risky decision-making, healthy control participants had greater activation in the dorsolateral prefrontal cortex, a region important for cognitive functions, such as short-term memory and probability assessment, when compared to the stimulant users. In contrast, the stimulant users showed greater activation in the nucleus accumbens, a brain region that is activated when participants are exposed to rewarding stimuli and during drug use.
    Resting-state fMRI is used to investigate networks of brain regions that are intrinsically active independent of cognitive tasks. In the resting state, the stimulant users showed greater intrinsic activity than healthy controls in the mesolimbic network, which is thought to be the brain’s “reward network” and is activated by pleasurable stimuli. In drug addiction, mesolimbic network activity has been linked with drug craving and drug-seeking behavior.
    We also observed that stimulant users with elevated activation in the brain’s reward network had less activation in the executive control regions (i.e. dorsolateral prefrontal cortex) during decision-making. The results suggest that the hyperactivity of the brain’s reward network compromises the ability of the prefrontal cortex to exert control during decision making and to make adaptive choices.
    This study helps clarify the biological underpinnings and network interactions of risky decision-making in human drug dependence. We present evidence for abnormalities in brain networks associated with addiction and show how these differences affect prefrontal activation during risky decision-making. The examination of deficits in brain activation in concert with spontaneous brain activity may reveal individual profiles that could be useful for developing individualized treatment. In addition, if cognitive therapies can re-wire the reward network of the addicted brain, they may promote adaptive choices by enhancing the dorsolateral prefrontal involvement during decision-making.