DESCRIPTION (provided by applicant): This application describes a focused 3-year training plan that will enable me, a psychologist with background in functional magnetic resonance imaging (fMRI) of cocaine addiction, to initiate clinical neuroscience research employing tools from neuroeconomics, an emerging field that combines neuroscience and economics to understand how people or the brain make decisions. Supervised by neuroeconomics (Dr. Glimcher) and addiction (Dr. Ross) experts, the current proposal aims to test how craving might bias addicted individuals' decisions toward drug use and away from other courses of action. Craving is the intense desire for a specific drug and is thought to increase behavioral indices of its subjective value (SV). The underlying mechanism of this influence, however, has not been determined. The overlap in the neural circuits that represent craving and those involved in the computation and comparison of SVs when making a choice, such as the striatum and ventromedial prefrontal cortex, raises the possibility that craving might bias decisions towards the drug by increasing neural activity in this circuit specifically associated with the drug's SV. n alternative view stemming from research on incidental emotions suggests that craving could also influence decisions by nonspecific effects in this circuit, such that mood states that accompany craving or perhaps craving itself, might modify category- independent SVs (those related as well as unrelated to the drug of choice). To test which of these mechanisms is at play and its underlying neurobiological basis, opioid users undergoing a detoxification program, in whom craving and mood states are expected to be particularly variable, will first complete repeated testing sessions where they will rate their level of craving and mood, provide physiological measures of arousal, and make hypothetical decisions on tasks designed to establish the SV of drug-related (e.g., different amounts of the drug, drug paraphernalia) and drug-unrelated items (e.g., consumer goods such as event tickets, DVDs, accessories, etc. and food). This design will allow for testing the specificity of craving's influence on SVs [as compare with other mood states and as a function of the types of items being evaluated (drug-related, drug-unrelated)]. Detoxified subjects will then complete fMRI following experimentally induced craving or a neutral condition in a randomized, crossover design. During fMRI, subjects will perform a novel "hybrid" decision making task that intersperses craving (symptom-capture) and similar decision (cognitive-task-based) trials. Given that craving will be manipulated directly, ths latter component will allow for testing, in a causal manner, how real-time craving influences neural signals that track the two types of SVs. If successful, results of this proposal may help advance our understanding of drug addiction by linking a specific neural computation to the occurrence of a specific symptom. Results may also help identify new therapeutic targets (drug-related SVs and their neural correlates) amenable to pharmacological and behavioral interventions and inform treatment development aimed at reversing the specific decision biases caused by fluctuations in craving.

PUBLIC HEALTH RELEVANCE: Craving is one of the most reported symptoms experienced by individuals in treatment, reported by 66% of those with opioid use disorders alone1. If successful, this study will have uncovered a previously unknown biological indicator of how craving works to bias decisions toward drugs in addicted individuals. Studies can then use this indicator as a target of treatment, perhaps ultimately culminating in the implementation of interventions to reverse the specific decision biases induced by craving and thus improve treatment outcomes.