This R21 application proposes to develop a novel way of measuring brain function after smoking marijuana that combines Functional Magnetic Resonance Imaging (fMRI) and Near Infrared Spectroscopy (NIRS). Background: Marijuana remains the most commonly used illicit drug in the U.S., but we do not to date understand the full spectrum of its reinforcing effects. Advanced brain imaging techniques such as PET, SPECT, EEG and MRI have been used to explore the acute and chronic effects of marijuana, but each of these techniques has limitations that preclude its use in some situations or populations. Recently, we have developed a device that allows individuals to smoke marijuana during functional magnetic resonance imaging (fMRI) and have successfully correlated fMRI data with subjective reports of behavioral states such as high, and physiological responses. The merger of fMRI with behavior during smoking is an important breakthrough in our knowledge of the spatial and temporal patterns of brain activity changes during marijuana use. This knowledge will be crucial for the development of rational and effective treatments for marijuana dependence. Significance: However, there are three important issues that need to be addressed to maximize the utility of fMRI.. First, perception of pleasurable drug effects is subjective, and is modulated by mood. Subjects must remain immobile in a confined space for up to two hours and these conditions can be unnatural for some people, and most likely affect their perception of what would otherwise be a rewarding experience. Second, BOLD fMRI only gives information about deoxy-hemoglobin changes, not changes in oxy-hemoglobin or blood flow. Third, a major confound in brain fMRI is distortion and signal loss around regions of discontinuous magnetic susceptibility, specifically air-tissue interfaces. Also, there is considerable motion artifact. NIRS offers an ideal companion method for studying frontal brain activity changes that addresses all of these concerns. NIRS is a method for making local measurements of cortical blood oxygenation and flow, which are closely coupled to neural activity. While its spatial resolution is lower than fMRI, and it is limited to regions near the cortical surface, its temporal resolution is significantly better than fMRI. These qualities make it well suited to enhancing the data acquired with fMRI. Specific Aims: In this proposal, we will: 1) develop and optimize an fMRI compatible depth sensitive NIRS imaging probe for the study of frontal areas; 2) Compare frontal activations measured concurrently during marijuana smoking using NIRS and BOLD fMRI, and 3) compare NIRS activation in response to marijuana smoking inside the fMRI scanner to activation in a natural setting. This study will pave the way for using brain imaging in vulnerable populations like children and pregnant women. This project aims to develop and validate an extremely safe, low-cost, non-invasive method for measuring the brain changes that occur during marijuana smoking. This study will pave the way for using brain imaging in vulnerable populations like children and pregnant women, and will provide a better understanding of the reinforcing effects of this drug. This understanding is a necessary step in developing strategies and therapies for reducing marijuana use and abuse. [unreadable] [unreadable] [unreadable]