PROJECT SUMMARY/ABSTRACT Mindfulness-Based Stress Reduction (MBSR) has demonstrated efficacy for Generalized Anxiety Disorder (GAD), yet there remains a major knowledge gap about its neural mechanisms. Neuroimaging studies thus far have mostly focused on the impact of MBSR on structural and resting-state brain changes, and these studies have been predominantly conducted in healthy participants. Core features of GAD, such as ruminative worry, represent dysfunctional emotion regulation strategies that increase bias towards future threat. MBSR success is associated with improved emotion regulation, enhanced attention to the present moment, and non-judgmental acceptance of internal and external cues. Our primary aim is to elucidate neural mechanisms that drive response to MBSR in patients with generalized anxiety disorder (GAD), and to examine the degree to which sex differences in MBSR response are explained by sex differences in these mechanisms. Our overarching hypothesis is that MBSR enhances ‘top-down’ learning and memory capacities that are broad and impact ‘top-down’ as well as ‘instinctual’ abilities (bottom-up) to regulate fear and emotions. We will first study the functional activation of brain regions associated with the fear extinction network (ventromedial prefrontal cortex (vmPFC), hippocampus, and amygdala) as a specific probe of the ‘instinctual’ type of emotion regulation. Second, we will use a novel analytic approach to examine large-scale functional connectivity as a marker of neural plasticity changes (pre- and post- MBSR) trial-by-trial during fear extinction learning across the entire brain, focusing analyses on the default mode network (DMN), frontoparietal network (FPN), and ventral attention network (VAN). Next, we will examine sex differences in MBSR-induced neural changes and their relationship to sex differences in clinical GAD response. Finally, we will use a novel statistical approach to explore whether baseline neural measures can predict MBSR- induced neural changes and clinical symptom reduction to identify likely MBSR responders. Participants will undergo a standardized 2-day fear conditioning and extinction paradigm in the fMRI scanner before and after MBSR or stress education (SE) with primary clinical outcomes at endpoint and 3 month follow-up. This study’s objectives are aligned with NCCIH’s PA-18-323: Fundamental Science Research on Mind and Body Approaches by studying MBSR’s neural mechanism of action and sex differences in patients with generalized anxiety disorder (GAD), a prevalent condition often seen in primary care for whom MBSR efficacy is established. This study will deploy rigorous scientific methods with a time and attention control intervention to enable isolation of MBSR’s mechanistic impact on brain regions involved in emotion regulation and clinical response. The unique combination of a focus on a classic anxiety condition with established emotion regulation difficulties implicating target neural...