PROJECT SUMMARY/ABSTRACT Essential tremor (ET) is a debilitating, common movement disorder, with prevalence as high as 4% of the population. ET is often disabling, with reduced ability to write, eat, or drink. People with the disorder often curtail their social interactions because of embarrassment and are at risk for depression. There are medical therapies that can reduce symptoms, but many patients have tremor that is not responsive to medical treatment. Deep brain stimulation can work well, but many patients are not candidates for surgery or would prefer a non-surgical option. MR-guided Focused Ultrasound (MRgFUS) is a minimally invasive method of treating ET that works in patients who are refractory to medical therapy. Focused ultrasound (FUS) delivers acoustic energy that focally heats lesions to ablative temperatures of greater than 60C. The combination of FUS with MRI guidance (MRgFUS) enables precisely localized tissue ablation, monitored by real-time MR thermometry. Transcranial MRgFUS has been used to treat ET with significant and durable reduction in symptoms. Through our clinical experience, we have identified several critical areas where improved treatment monitoring could dramatically increase safety and effectiveness. The overall goal of this project is to provide comprehensive MRI feedback for transcranial focused ultrasound to improve the safety, efficiency and efficacy of treatment. Our specific aims are the following: Aim 1: Develop real-time volumetric thermometry techniques to monitor thermal treatment. MRgFUS treatments are currently monitored using a 2D pulse sequence for temperature mapping. During ablation, the treatment can only be monitored in a plane, and the location of peak temperature rise can occur outside of the plane. In this aim, we will develop new methods for real-time volumetric MR thermometry and validate these techniques in pre-clinical and volunteer studies. Aim 2: Develop methods to monitor unintended heating of the brain and skull. The skull absorbs energy from the applied ultrasound, which results in heating of the skull and the nearby soft tissue, including the brain. There is currently no direct monitoring of this heating, and the required wait time between sonications is only estimated using simple models. In this aim, we will develop new, rapid, 3D ultrashort-echo-time methods for monitoring skull temperature changes combined with whole-brain volumetric thermometry and test these methods in studies of patients undergoing FUS treatment for ET. Aim 3: Develop real-time treatment monitoring techniques to give early assessment of viability. Critical MR moni- toring functions include visualizing the lesion as it is created. We hypothesize that diffusion-weighted imaging can capture clinically useful lesion contrast at early time points. In this aim, we will develop and validate new methods for diffusion imaging in the challenging environment of a FUS transducer and test these methods in studies of patients. This research will fundamentally improve the treatment of essential tremor using MRgFUS, thereby advancing a tech- nology that can have a significant impact on the treatment of these patients.

PROJECT NARRATIVE Essential tremor is a debilitating disease with prevalence as high as 4% of the population. MR-guided focused ultra- sound (MRgFUS) is a promising new minimally invasive treatment for essential tremor, in which sound waves are focused to a specific region of the brain while the temperature of the brain is monitored by MRI. Through our clinical experience we have identified several opportunities to improve the safety and efficacy of treatment through more thorough and precise treatment monitoring. This research project will develop and validate these new imaging methods for improved guidance of MRgFUS of essential tremor.