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1 R01 DA016663-01A1 (Paulus, Martin)            04/01/04 - 03/31/09:

Neurobiology of Transition to Stimulant Dependence

Stimulant use and dependence are important problems among young adults in the U.S.  It has been suggested that an imbalance between motivational drives for novel experiences and inhibitory control systems could predispose to impulsive and risk-taking behaviors. Decision-making, risk-taking, and error processing are inter-related processes that are important for every-day functioning and have been implicated in subjects with substance dependence.  Functional neuroimaging studies have shown that decision-making is critically dependent on the activation of inferior prefrontal cortex, ventromedial and ventrolateral frontal cortex, anterior cingulate, insula, and parietal cortex.  Our main goal is to identify differences in brain processes and their underlying neural activation patterns between young adults  who use stimulants and are at risk for transition to stimulant dependence and matched comparison subjects.  We will use risk-taking decision-making paradigms during functional magnetic resonance imaging (fMRI) to determine the activation patterns related to risk-taking, decision-making, and error processing. 

The specific aims are:

1. We will contrast brain functioning during risk-taking decision-making using fMRI in subjects who recently used stimulants (i.e. are at higher risk for developing stimulant dependence) and in subjects who have never used stimulants. 

2. We will evaluate the relationship between risk-taking decision-making tasks and the fMRI activation pattern at baseline and the future development of stimulant dependence in stimulant-using subjects. 

The hypotheses are that stimulant using subjects, relative to subjects who have never taken stimulants, will show more risk-taking behavior during decision-making paradigms and will show less activation of brain areas that are critical for error processing, including the anterior cingulate, insula, inferior prefrontal and medial prefrontal cortex.  Moreover, it is hypothesized that subjects who develop dependence relative to those who do not show more rigid stimulus-bond decision-making and less activation in the posterior parietal cortex. 

Testing these hypotheses will advance the neurobiology of substance dependence by (1) identifying the neural substrates that may differentiate stimulant using versus non-using subjects; (2) relating behavioral characteristics during risk-taking decision-making in stimulant using subjects to patterns of brain activation; (3) identifying patterns of brain activation that are predictive of transition to stimulant dependence.

1 R01 DA018307-01A1 (Paulus, Martin)            10/01/05 - 09/30/09:

Stimulant Dependence: Neural Mechanisms of Relapse

Stimulant dependence is an important problem in the U.S and relapse is a frequent and complex phenomenon that occurs within one year in more than 50% of people with stimulant dependence who seek treatment.  Yet the cognitive and neural mechanisms that underlie relapse are not well understood but may be closely related to basic decision-making processes.  This proposal builds on work that has been accomplished in a previous R21 aimed to determine the neural substrates that underlie decision-making dysfunctions in treatment seeking methamphetamine dependent subjects.  We have begun to assemble a decision-making model that combines cognitive mechanisms and underlying neural substrate activation patterns in healthy volunteers and methamphetamine dependent subjects. 

This proposal focuses on examining three candidate mechanisms, i.e. trend detection, error processing, and risk-taking to probe three important components of the decision-making circuitry: (1) inferior prefrontal cortex (ventromedial and ventrolateral prefrontal cortex), (2) anterior cingulate and inferior parietal lobule, and (3) anterior insula and posterior parietal cortex.  Our preliminary data indicate that neural substrate activation patterns during decision-making tests may provide a sensitive indicator for the propensity to relapse. 

Now, we will compare decision-making characteristics and neural substrate activation patterns in methamphetamine dependent and cocaine dependent with those of normal comparison subjects to extend our finding from methamphetamine.  Second, we will follow both methamphetamine and cocaine dependent subjects using a comprehensive assessment of important relapse factors to address the following specific aims: (1) To examine three candidate mechanisms and determine the specificity and characteristics of decision-making dysfunctions in stimulant and cocaine dependent subjects. (2) To determine which altered candidate mechanism and which neural substrate activation patterns underlying decision-making best predict susceptibility to relapse in methamphetamine and cocaine dependent subjects. 

This project will link systems neuroscience with clinical research in substance use disorders thereby providing cognitive neuroscience and neuroimaging insights into dysfunctions associated with substance use disorders, and develop tools for improving clinical care in substance use disorders.

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last edited: 07/28/2007