ULTRASOUND THERAPY DELIVERY THROUGH INTACT SKULL

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 项目摘要 针对脑部疾病（如肿瘤、功能问题、血管畸形等）的侵入性干预，是困难的，并且经常干扰周围的脑组织，导致并发症和长的恢复时间。此外，通过血液供应递送治疗剂通常是不可能的，因为血脑屏障保护脑组织免受外来分子的影响。实验室实验表明，聚焦超声波束可以非侵入性地破坏深层组织，关闭血管，激活药物，打开血脑屏障，并可能增加细胞膜对分子的渗透性。然而，超声波在大脑中的应用受到普遍接受的观点的严重限制，该观点认为该技术需要去除一块颅骨以允许超声波束传播到大脑中。这种额外的程序使得大脑的超声治疗更加复杂，危险和昂贵。因此，超声在大脑中的治疗效果尚未在临床试验中得到广泛探索。 这项资助的假设是，经颅治疗性超声照射可以在没有手术的情况下通过优化的相控阵系统进行。在我们目前的资助期间，我们已经证明了高度聚焦的治疗性超声波束可以准确地通过一个完整的人类颅骨非侵入性地传递。我们的研究结果表明，超声输送可以使用相控阵探头，补偿在颅骨中的厚度和密度的变化所引入的波传播失真。此外，我们证明了使用离体人类头骨，我们可以使用CT衍生的信息来预测校正波失真所需的相移。在此期间，我们还开发了一种选择性打开血脑屏障（BBB）而不损伤靶组织体积中的神经元的方法。同样，我们是第一个观察到细胞凋亡可以诱导超声波暴露在大脑中。这两个生物学终点扩展了该技术的治疗可能性。

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. Project Summary 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 technique.