PROJECT SUMMARY Head and neck cancer is particularly susceptible to nocioceptive and neuropathic pains because it is dense with sensitive anatomic structures and richly innervated by the nervous system. In fact, head and neck cancer, estimated as the ninth most common cancer and cause of cancer mortality, is associated with the highest prevalence of pain. These craniocervical pains are particularly difficult for three reasons. Firstly, medical therapy often wanes in effect and/or high doses are required with cognitive side effects. Secondly, surgical options are limited by the cephalad extent in the neural axis. Lastly, cancer and its terminal stages are difficult for invasive surgery or implanted devices that require intensive management. Patients and their oncologists seek pain relief that is easy, safe, and without cognitive side effects. Transcranial MRI-guided focused ultrasound (FUS) is a new stereotactic modality capable of delivering high intensity energy through the intact human skull with submillimeter precision. Our initial experience with FUS targeted the ventrolateral thalamus for essential tremor and Parkinson?s disease, eventually leading to FDA approvals. Cancer pain is an ideal indication to consider stereotactic ablation as the disease burden limits the options. A minimally invasive, transcranial option to treat refractory cancer pain would be welcomed by patients ? avoiding opioid medications, open surgery, and device implantation. This exploratory clinical trial (already approved by the FDA under IDE#G180222) will target both the spinothalamic and spinoreticular pain circuits by performing unilateral FUS mesencephalotomy, a historically effective procedure for cancer pain but limited by the accuracy of its era. The primary aim of this study is to assess the safety and preliminary effectiveness in six head and neck cancer patients with opioid-resistant pain. Additionally, we will investigate the potential mechanism of pain relief as the mesencephalotomy target involves the confluence of the ascending and descending pain systems. Aims 2 and 3 will investigate these systems with electrophysiology specific for the spinothalamic tract and carfentanil PET imaging that measures the brain?s endogenous opioids.