? The delivery of large molecular agents into the central nervous system (CNS) via the blood supply is often impossible as the blood brain barrier (BBB) protects the brain tissue from foreign molecules. The factors that determine penetration of substances from the blood to the CNS are lipid solubility, molecular size, and charge. The BBB prevents penetration of ionized water-soluble materials with molecular weight greater than 180 daltons. Thus most of the potential molecular imaging agents cannot reach the brain tissue via the blood supply. A technique that allows these agents to reach the brain tissue will open the door to new possibilities for the diagnosis and monitoring of brain disorders that currently cannot be performed. Laboratory experiments have shown that focused ultrasound beams can be used to noninvasively open the BBB in a highly localized tissue volume deep in the brain. While extensive research on the interaction with ultrasound and the CNS has been performed in animals, the clinical utilization of ultrasound in the brain has been seriously limited by the commonly accepted view that a piece of the skull bone must be removed for the ultra-sound beam to propagate into the brain. This additional procedure makes ultrasound treatments of the brain more complex, hazardous, and expensive. As a result, the effects of ultrasound in the brain have not been widely explored in clinical trials. We have demonstrated that highly focused ultrasound beams can be accurately delivered through an intact human skull noninvasively with a phased array of multiple transducers, thus eliminating the most significant barrier for using focused ultrasound in brain. The overall objective of this research is to combine our ability to deliver focused ultrasound through the intact skull and the method that allows us to use the ultrasound to open the BBB and to develop a device that can be used to open the BBB for molecular imaging agents. The device will be made MRI compatible so that it can be used to target specified anatomic locations in the brain. After the BBB is open, the molecular imaging agent can be injected, and the imaging can be performed using any imaging method. The system required to accurately focus and ultrasound beam is very complicated. While this complexity, as well as the need to shave the head, is acceptable for the targeted treatments, it makes the current system unrealistic for routine diagnostic imaging. The applicants' hypothesis is that the BBB opening can be performed with a much simpler system. Similarly, we estimate that the effect of human hair will most likely be reduced with our proposed approach. There is currently no date using the proposed ultrasound exposures for BBB opening. We propose to use the combined R21/R33 mechanisms to first establish the feasibility and then to develop a method for a relatively simple device to selectively open the BBB for molecular imaging. A successful implementation of this method will make many new molecular imaging approaches possible in brain. The development of even one such imaging method for routine clinical use would have a major impact on patient care. ? ?
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