Project Summary/Abstract The exact mechanisms by which light stroking and deep pressure – components of massage therapy – induce pleasantness and pain modulation are not understood. Given the frequent use of massage therapy for relaxation and pain relief, and the need for complementary tools for chronic pain, there is a critical need to study the mechanisms of specific forms of affective touch. Our long-term goal is to elucidate the mechanisms by which manual therapies induce pleasant relaxation and pain relief. Our overall objectives in this application are to (1) Determine the extent to which A- and C-fibers contribute to affective effects of gentle stroking, 2) Determine the extent to which A- and C-fibers contribute to affective effects of deep pressure, and 3) Determine the contribution of C-fibers to neural mechanisms of touch-induced pleasantness and pain modulation. We will also (Exploratory) use machine learning to identify individual contributions of C-tactile (CT) fibers to neural mechanisms of touch pleasantness and pain modulation, and the association of interoceptive sensibility with CT effects. Our central hypothesis is that A-fibers are necessary but not sufficient for the pleasantness of gentle stroking and unnecessary for its pain reduction, but are necessary and sufficient for the pleasantness and pain reduction of deep pressure. Further, we hypothesize that left anterior insula and anterior cingulate cortex activation will predict CT contributions to modulation of pain by touch. We will conduct a two session within-subject study in healthy adult volunteers to test the effects of A- and C-fiber blockade on the pleasantness and pain modulation induced by slow stroking (N = 24) and deep pressure (N = 24). We will then test effects of A-fiber blockade on brain mechanisms of pain modulation during fMRI, and relationships between CT contributions and touch pleasantness, pain modulation, and interoceptive sensibility (N = 36). Effects of CT inputs on heart rate variability will comprise a secondary outcome. Upon successful completion of the proposed research, we expect to have identified the role of A- and C-fibers in the pathways and major effects of affective touch. This contribution is expected to be significant because it will define the pathways for two major forms of affective touch and their effects on pain, providing reliable information about non-invasive measures for pain control and potential targets for noninvasive neuromodulation of pain. Further, this project is innovative because it explores a novel affective touch pathway, applies a novel method to causally test afferent pathways for affective touch, and uses machine learning to explore individual differences in the contributions of CTs to neural mechanisms for affective touch. Our proposed project seeks to elucidate pathways for two major forms of affective touch commonly engaged by massage. This research will have a positive impact by opening new horizons for mechan...