Invasive interventions for brain disorders, such as tumors, functional problems, vascular malformations, etc., are difficult and often disturb surrounding brain tissue causing complications and long recovery times. In addition, delivery of therapeutic agents via the blood supply is almost impossible because of blood brain barrier protects the brain tissue from foreign molecules. Laboratory experiments have shown that focused ultrasound beams can noninvasively destroy deep tissue, close blood vessels, activate drugs, open the blood brain barrier, and perhaps increase the cell membrane permeability to molecules. However, the utilization of ultrasound in the brain has been seriously limited by the commonly accepted view that these therapeutic exposures would require a piece of the skull bone be removed to allow the ultrasound beam to propagate into the brain. This additional procedure makes ultrasound treatments of the brain more complex, hazardous, and expensive. As a result, the therapeutic effects of ultrasound in brain have not been widely explored in clinical trials. The applicants hypothesize that transcranial therapeutic ultrasound exposures could be delivered without surgery by an optimized ultrasound phased array system. In this system the phased array would assure a therapeutically acceptable concentration of ultrasound at the focal site while emitting a low enough intensity at the skull to make the exposure in the bone harmless. In preliminary experiments, the applicants described demonstrating that highly focused therapeutic ultrasound beams can be delivered through the skull noninvasively. Results show that the ultrasound delivery can be done most effectively using phased array applicators that take into account the phase shifts introduced by thickness variations in the skull. The study plans calls for: 1. First, to theoretically and experimentally optimize the phased array and energy delivery; 2. Second, to create computer models of the skull using modern imaging techniques; 3. Third, to test and improve these models using ex vivo human skull samples and in vivo animal models; 4. Fourth, to develop and test online MRI monitoring of cavitation events during high pressure amplitude sonifications; 5. Fifth, to investigate the optimal sonication parameters to produce the desired physiologic or histologic end points using in vivo rabbit brain studies; and 6. Finally, to integrate a complete phased array system and the controlling hardware and software with an MRI scanner and test and optimize the system for testing the feasibility of the proposed therapy. The transcranial delivery of ultrasound will have a major impact making existing surgeries much less invasive and allowing new therapies to be developed for the brain. A successful implementation of even one of these possible therapies to routing clinical practice could have a major impact on patient care.
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