Neuromelanin MRI: A tool for non-invasive investigation of dopaminergic abnormalities in adolescent substance use. - PROJECT SUMMARY/ ABSTRACT Chronic substance use is associated reduced mesolimbic and nigrostriatal dopamine function. Despite having a central role in research and applied models of Substance Use Disorders (SUDs), very little is known about the etiopathogenesis of altered dopamine function, especially in youth that engage in high-risk substance use. For instance, it is fundamentally unclear in humans whether altered dopamine function precedes or follows from substance use, differs by sex, or triggers neurodevelopmental changes (e.g., altered maturation in reward circuit). The primary obstacles are that 1.) Positron Emission Tomography (PET) imaging cannot be utilized in pediatric populations to study early changes in dopamine function, and 2.) there is no developmentally- appropriate alternative imaging method. Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) provides a quantitative index of cumulative NM accumulation, which corresponds to lifetime biosynthesis rate in dopamine-producing midbrain neurons. Unlike PET imaging, NM-MRI does not involve radiation exposure and is therefore suitable for longitudinal investigations in youth to track pathophysiology of dopamine function during the earliest stages of SUDs. In our studies, we have found that midbrain NM-MRI signal in 20-24 year- olds is positively correlated with lifetime exposure to alcohol and marijuana, as well as with self-report markers of reward function (n=149). This corroborates etiological theories of increased dopamine function early in course of SUDs, yet the origin of increased NM accumulation is unclear given the age of the cohort. This R01 application is the next step of this novel program of research. We now propose to collect NM-MRI in a new cohort of 300 15-16 year-olds, an age group on the cusp of transitioning from substance naïve to habitual users. Then, we will collect two additional NM-MRI sessions over a year apart, a period in youth when they vary naturally in frequency and intensity of substance use. This longitudinal project will test developmentally- informative bi-directional hypotheses about the association between NM accumulation (a proxy for DA biosynthesis) and adolescent substance use over a period of 36 months. Further, it will clarify whether pediatric NM accumulation indexes pediatric reward function, tracks changes in pediatric reward function following substance use, corresponds to activity in functional brain connectivity networks, and is moderated by sex differences. These fundamental translational and neurodevelopmental questions about DA function cannot be answered by PET imaging in a pediatric cohort. NM-MRI is poised to revolutionize translational science of SUDs by enabling a suite of developmentally informative investigations.
