ABSTRACT Chronic pain is a major public health problem. An estimated 100 million Americans have experienced chronic pain producing significant economic and social burden. Pharmacological treatments frequently require the use of opioids resulting in a major epidemic of abuse in the United States. New, non-addicting treatments for pain are critically needed. Neuromodulation with low intensity focused ultrasound (LIFU) may provide a non- pharmacological treatment for chronic pain. The enormous potential of LIFU stems from the ability to focus ultrasound through the intact skull to a millimeter-sized focal spot size anywhere in the brain. One promising target to treat chronic pain is the insular cortex. Multiple lines of evidence support the involvement of the insula in abnormal pain modulation or central sensitization and pain chronicity. Unfortunately, the insula lies deep to the cortex and contains small discrete sub-regions making non-invasive access difficult. Preliminary data demonstrates that LIFU can target individual sub-regions of the insula non-invasively to inhibit laser-evoked potentials as well as reduce subjective report of pain in humans. It is the purpose of this proposal to investigate the causal influence of LIFU to sub-regions of the insula on brain activity and behavior related to central sensitization in healthy human volunteers and fibromyalgia patients. This is important as central sensitization is a shared characteristic of many chronic pain conditions. It is the long-term goal of this project to advance LIFU as a human pain management tool to enhance the health and reduce suffering in those with chronic pain.