Project Abstract/Summary Despite research been potential benefits of mindfulness meditation to various clinical disorders and an increase in interest in in recent years, the basic mechanisms of meditation are stil l not fully known. Synaptic changes have proposed as a plausible hypothesis for the potential benefits of meditationas synapses are important for behavioral and cognitive functioning. The proposed research project applies novel molecular neuroimaging methods to directly investigate synapses in experienced meditators (EM) by using positron emission tomography (PET) imaging with our newly developed synaptic density tracer, 11C-UCB-J. This tracer binds to the synaptic vesicle glycoprotein 2A or SV2A, an essential vesicle membrane protein expressed in virtually all synapses. This proposal examines, for the first time, whether synaptic density differences occurs in EM in vivo. The study will perform a detailed comparison between 20 EM subjects and 20 control subjects over 2 years. Our primary objective is to characterize the distribution of 11C-UCB-J in brain areas implicated in experienced meditators compared to non-meditative controls (Aim 1). We hypothesize that there will be a magnitude and regional pattern of higher synaptic density in EM subjects involving brain areas including the including the insula, amygdala, posterior cingulate cortex, middle and superior frontal sulci and the prefrontal cortex. We will also examine if potential differences in synaptic density relates to structural and functional MRI data as determined by voxel based morphometry and resting-state functional connectivity in the primary regions-of- interest in the brain. EM subjects will be recruited from current and past research projects of the Co-I and consultant as well as local word of mouth and advertisements to the meditation communities. Inclusion/exclusion criteria will be the same for both groups and will include medical and psychiatric examination (including ECG and laboratory studies) to determine study eligibility. Subjects eligible to participate will receive an anatomical MRI for co- registration (and partial volume corrections) and a High Resolution Research Tomography (HRRT) PET scan with the radiotracer11C-UCB-J. This project will further our understanding by allowing, for the first time, in-vivo estimation of synaptic density of experienced meditators. This is an important development in meditation research for several reasons. It will be the first study to directly examine a plausible mechanism of meditation's effects, synaptic differences in associated brain regions, which needs to be established. Secondly, the current results will be compared to structural and functional MRIs, testing whether there is molecular evidence of synaptic differences as a solid underpinning of other imaging work. Lastly, the ability to assess synaptic density in vivo would be of high utility in future studies using meditative techniques that are focused on clinical po...