This project focuses on understanding the cognitive and neural mechanisms by which mindfulness training (MT) results in positive behavioral change and enhanced psychological well-being. Although MT is rapidly gaining in popularity as a life-style intervention, there are still critical gaps in our understanding of its primary mechanism of action. Current theoretical frameworks suggest that MT operates by improving attentional control, emotional regulation, and self-awareness capabilities, potentially by targeting neuroplastic brain mechanisms of executive control. This suggests an important role for cognitive neuroscience research, but current work is still in its infancy, and subject to a number of well-recognized methodological and conceptual limitations. The proposed project aims to systematically remedy these limitations of prior MT research, by leveraging the unique opportunities offered by the Human Connectome Project (HCP), and our own on-going NIH R01-funded research. A key feature of the project is the use of a randomized, longitudinal discordant twin design, in which monozygotic (MZ; identical) twin pairs will be recruited, with one co-twin randomly assigned to the MT condition (mindfulness-based stress reduction, or MBSR; the most-validated and standardized form of MT instruction) and the other serving as a (wait-list) control. Each co-twin will undergo extensive behavioral and MRI neuroimaging assessments in a pre/post fashion, before and after the MT (or no-contact control) intervention, to test for specific MT-related effects. The discordant twin design, though never previously employed in an MT context, is widely recognized as one of the strongest for causal inference, since it avoids many of the challenges and confounds associated with inadequately matched control groups, and enables twin-pair focused analyses, which greatly increase statistical power. We will use this design to investigate theoretically-focused hypotheses that stem from our guiding framework regarding the neural mechanisms of cognitive control. Specifically, using a newly developed cognitive control task battery, we will test the counter-intuitive hypothesis that MT is produces an enhancement in the neural mechanism and circuits associated with reactive (rather than proactive) control. An additional subset of MZ twin participants will undergo retesting with the original HCP protocol, in order to provide a comprehensive assessment and comparison of MT effect sizes across multiple domains of cognitive and brain function. Success in this project will have high relevance for public health, by providing innovative experimental tools and a novel theoretical framework from which to empirically evaluate and better understand the potential impact of MT programs as lifestyle interventions for enhancing psychological well-being in healthy populations.