This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Invasive interventions for brain disorders, such as tumors, functional problems, vascular malformations etc., are difficult and often disturb surrounding brain tissue and result in complications and long recovery times. In addition, the delivery of therapeutic agents via the blood supply is often impossible because the 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 this technique requires the removal of a piece of the skull bone 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 the brain have not been widely explored in clinical trials. The hypothesis of this grant has been that transcranial therapeutic ultrasound exposures can be delivered without such surgery with an optimized phased array system. During our current grant we have demonstrated that highly focused therapeutic ultrasound beams can be accurately delivered through an intact human skull noninvasively. Our results show that the ultrasound delivery can be done using phased array applicators that compensate for the wave propagation distortions introduced by thickness and density variations in the skull. Furthermore, we demonstrated using ex vivo human skulls that we can use CT-derived information to predict the phase shifts required for correcting the wave distortion. We have also developed during this grant period a method to selectively open the blood brain barrier (BBB) without damaging the neurons in the targeted tissue volume. Similarly, we were the first to observe that apoptosis can be induced by ultrasound exposures in the brain. These two biological endpoints extend the therapeutic possibilities of this techni
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