Addiction is linked to faulty decision-making (1, 2), which may reflect maladaptive strategies in evaluation of rewards. When performing gambling tasks, methamphetamine-dependent individuals exhibit greater risk-taking than healthy control subjects in order to increase the size of rewards (3). On choices that involve the time when a reward is received, however, they prefer smaller, sooner rewards over larger, later ones (4, 5). While these observations indicate that task contingencies influence the subjective valence of reward, the neural mechanisms by which this influence is exerted are not known. The Neuroanatomical Model of Decision-making (6) postulates that dopaminergic afferents from the ventral tegmental area to the nucleus accumbens signal the occurrence of motivationally salient events, and that ventral tegmental area projections to the striatum and prefrontal cortex modulate the expression of subsequent behavior. Building on this model, the Impaired Response Inhibition and Salience Attribution model of addiction (7) posits that repeated drug use leads to adaptations in frontal white matter (8) and in glutamatatergic projections from the prefrontal cortex to the striatum (9), resulting in deficits in decision-making. The proposed work aims to extend our understanding of faulty decision-making processes in MA-dependent individuals, while investigating the potential contributions of deficits in evaluation of reward and associated neural circuitry. Two tasks will be used to examine the influence of different contingencies on decision-making in healthy and MA-dependent individuals. Relationships between performance on these tasks and the structural and functional integrity of regions implicated in the Neuroanatomical Model of Decision-making will be tested with functional MRI (fMRI) and diffusion tensor imaging (DTI). Responses during decision-making under risk, reward or delay will be examined using the Delay Discounting Task (DDT) (10) and the Balloon Analog Risk Task (BART) (11). The BART presents options to take risk in order to increase reward size, or to cash out and retain smaller rewards. Using the BART with fMRI, a goal of the study is to relate the proclivity for risk-taking and temporal discounting to brain function, and to examine differences in neural activation during risk-taking between groups. As performance deficits may also reflect reduced integrity of white matter connecting regions involved in the evaluation of reward, we will examine the extent to which white matter tracts connecting the striatum and prefrontal cortex modulate neural activity and performance on the BART and DDT. Behavioral approaches are the main treatments for MA abuse, but neural deficits that can affect their success are not well delineated. Knowledge of how different contingencies affect neural function subserving decision- making, and the structural connectivity that supports these functions in MA-dependent individuals may lead to a better understanding of MA dependence, and may help improve treatment for this disorder.

Public Health Relevance

Methamphetamine-dependent (MA) individuals show marked cognitive disturbances, including maladaptive decision making (12). Poor decision-making in MA-dependent individuals promote continued drug use (2) and interferes with treatment, particularly when cognitive behavioral approaches are used. This study aims to provide insight to the mechanisms of decision-making in MA-dependent individuals by examining behavior, associated neural activity, and connections between brain regions that are involved in decision-making functions. This knowledge may provide help in the design and implementation of rational therapies.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Predoctoral Individual National Research Service Award (F31)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-F02A-J (20))
Program Officer
Bjork, James M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Morales, A M; Kohno, M; Robertson, C L et al. (2015) Gray-matter volume, midbrain dopamine D2/D3 receptors and drug craving in methamphetamine users. Mol Psychiatry 20:764-71
Dean, Andy C; Kohno, Milky; Morales, Angelica M et al. (2015) Denial in methamphetamine users: Associations with cognition and functional connectivity in brain. Drug Alcohol Depend 151:84-91
London, Edythe D; Kohno, Milky; Morales, Angelica M et al. (2015) Chronic methamphetamine abuse and corticostriatal deficits revealed by neuroimaging. Brain Res 1628:174-85
Kohno, Milky; Ghahremani, Dara G; Morales, Angelica M et al. (2015) Risk-taking behavior: dopamine D2/D3 receptors, feedback, and frontolimbic activity. Cereb Cortex 25:236-45
Kohno, Milky; Morales, Angelica M; Ghahremani, Dara G et al. (2014) Risky decision making, prefrontal cortex, and mesocorticolimbic functional connectivity in methamphetamine dependence. JAMA Psychiatry 71:812-20
Dean, Andy C; Kohno, Milky; Hellemann, Gerhard et al. (2014) Childhood maltreatment and amygdala connectivity in methamphetamine dependence: a pilot study. Brain Behav 4:867-76
Morales, Angelica M; Ghahremani, Dara; Kohno, Milky et al. (2014) Cigarette exposure, dependence, and craving are related to insula thickness in young adult smokers. Neuropsychopharmacology 39:1816-22