PROJECT SUMMARY Patients with refractory chronic pain typically do not respond to traditional analgesics or weak opioids as these agents do not directly address the cause for their pain. Many chronic pain patients do not achieve satisfactory pain relief even with evidence-based treatment, or they do not tolerate effective doses because of adverse side effects. Deep brain stimulation (DBS) is already an established treatment for intractable movement disorders and epilepsy, and recent advancements in the fields of pain neurophysiology and biotechnology may facilitate the use of DBS as a nonpharmacological therapy for refractory chronic pain. In the first stage of the proposed project, we will enroll 12 subjects with refractory neuropathic pain to an inpatient clinical trial for insular brain mapping with acute stimulation and neurophysiological brain monitoring. Electrodes for stimulating and recording will be implanted stereotactically along the anterior-posterior axis of the insular cortex. Subjects with positive analgesic effects during acute insular stimulation in the first stage of the proposed project will continue to the second stage, which will consist of a randomized, sham-stimulation-controlled, double-blinded, cross-over clinical trial of chronic insular DBS with the purpose of obtaining safety and efficacy data for this procedure. Furthermore, we aim to develop neurophysiological biomarkers of pain by studying changes in neural activity. Safety data, effect size, and insular stimulation parameters obtained from this research will be used in the design of subsequent clinical trials. The neurophysiological pain biomarkers identified in this project will also aid the development of a novel, closed-loop insular DBS system, as well as new diagnostic/prognostic measures for managing chronic pain. If proven to be safe and effective, insular DBS will offer a much needed non-pharmacological treatment option for patients suffering from refractory chronic pain.