A New fMRI Method to Measure Substantia Nigra Signaling During Reward Processing

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 DESCRIPTION (provided by applicant): Substance abuse and related conditions are complex, common, and costly disorders. A better understanding of the neural mechanisms giving rise to these conditions may yield valuable clues for the development of new and more effective treatments. While we now know in broad terms that dopamine and its regulation of reward processing are involved in the pathogenesis of substance abuse, there is still much to learn about the details of how dopaminergic mechanisms of reward processing may be subverted and lead to addiction, particularly in human models. The midbrain dopaminergic nuclei are among the most important structures regulating dopamine function because they store and release the majority of dopamine in the brain. Thus, the availability of a flexible, widely available, non-invasive means of measuring their signaling during reward processing in humans could prove to be useful in elucidating dopaminergic mechanisms. However, these nuclei are very difficult to image due to their small size and location. We have recently developed a new, simple, yet precise high resolution fMRI method for measuring the signal from one of the major dopaminergic nuclei, the substantial nigra, a structure that is now recognized to play an important role in reward related processes closely associated with substance abuse and addiction. Using the well-known fact that its high iron content renders the nigra as a distinct region of hypointensity on fMRI volumes, we will use a unique set of image processing steps that have been optimized to localize and distinguish nigra from nearby structures directly on task images. We will then be able to derive estimates of task evoked fMRI signal from as well as verify the localization of significant activity within the nigra. We propose validating this method for use in substance abuse research by testing the hypothesis that it can measure reward processing related nigral signaling. We will scan a sample of healthy young adults while they complete a reward processing task that has been well validated as a driver of reward associated nigral dopamine signaling in humans. We will then compare nigral signal during reward vs. non-reward trials, as well as verify that significant reward activity occurs within the nigra. The successful completion of this project will provide preliminary confirmation of a new fMRI method for measuring dopamine function that may be useful in in vivo human models of substance abuse. In addition, it will alllow the PI to obtain valuable experience in substance abuse research that may enable him to obtain more extensive grants and conduct further research in this field.