ULTRASOUND THERAPY DELIVERY THROUGH INTACT SKULL

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。对脑部疾病，如肿瘤、功能问题、血管畸形等进行侵入性干预是困难的，往往会扰乱周围的脑组织，并导致并发症和较长的恢复时间。此外，由于血脑屏障保护脑组织免受外来分子的侵害，通过血液供应输送治疗剂通常是不可能的。实验室实验表明，聚焦的超声波束可以无创地破坏深层组织，关闭血管，激活药物，打开血脑屏障，也许还可以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了普遍接受的观点的严重限制，这种技术需要移除一块颅骨，以便超声波束传播到大脑。这种额外的程序使脑部超声治疗变得更加复杂、危险和昂贵。因此，超声对脑部的治疗作用尚未在临床试验中得到广泛探索。这项拨款的假设是，经颅治疗性超声暴露可以通过优化的相控阵系统进行，而无需进行此类手术。在我们目前的资助中，我们已经证明了高度聚焦的治疗性超声光束可以无创地准确地通过完整的人类头骨。我们的研究结果表明，超声传输可以使用相控阵应用器来补偿由颅骨厚度和密度变化引起的波传播扭曲。此外，我们使用离体人类头骨证明，我们可以使用ct衍生的信息来预测校正波畸变所需的相移。在此资助期间，我们还开发了一种选择性打开血脑屏障（BBB）而不损害目标组织体积中的神经元的方法。同样，我们是第一个观察到大脑中超声波暴露可以诱导细胞凋亡的人。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. 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