Treating pain in sickle cell disease by means of focused ultrasound neuromodulation

镰状细胞病(SCD)困扰着全球数百万人的慢性和急性疼痛。剧烈的疼痛可以 SCD从婴儿期开始，并在整个生命周期中逐渐严重。患者经常需要复发 住院、长期使用大剂量阿片类药物和生活质量差。慢性阿片类药物的使用与 副作用包括服药过量和死亡。开发无毒、不上瘾、 治疗SCD疼痛的非药物疗法。我们建议开发一种新型的经颅聚焦 超声(TFUS)技术，具有改进的空间靶向能力用于疼痛治疗，并进一步集成 使用非侵入性电生理源成像(ESI)功能跟踪超声目标。我们 建议开发和测试一种新型的无创ESI引导的闭环式tFUS设备，以实现安全和有效的 治疗SCD中的疼痛。我们将使用现有的SCD疼痛指示的动物模型来解决 建议的tFUS设备。我们建议的工作包括开发用于疼痛治疗的新型tFUS设备和 建立其治疗人源化小鼠SCD疼痛的有效性，并进行安全性评价和面向设计 在更大的动物身上扩大规模。具体目标为：目标1：研制tFUS疼痛神经调节器 管理层。我们将开发一种可操作的tFUS疼痛治疗设备，识别实用的换能器 横向分辨率优于2 mm的随机阵列换能器的特性 用于tFUS靶向的轴向分辨率大于3 mm。目标2：评估tFUS效果并优化刺激 SCD小鼠模型的参数。我们将获得有效的tFUS参数知识，以减少SCD 疼痛，并将达到至少1小时的持久治疗效果。目的3：动物体内ESI信息的闭环式tFUS 模型及其安全性评价。TFUS系统将被充分开发和评估用于疼痛管理 具有空间精度优于5 mm的ESI波束跟踪能力。TFUS系统的规格将 最后确定，包括输入和输出参数。拟议项目的圆满完成 承诺开发一种变革性的、非侵入性的经颅聚焦超声设备，以有效和 安全地治疗镰状细胞病中的疼痛。这种非药物止痛疗法将非常有益。 对于SCD患者来说，因为往往是终生疼痛。

Sickle cell disease (SCD) afflicts millions of people worldwide with chronic and acute pain. Intense pain can start during infancy and increase in severity throughout life in SCD. Patients often require recurrent hospitalization, long-term use of high-dose opioids and live a poor quality of life. Chronic opioid use is associated with side-effects including overdose and death. There is an unmet need to develop non-toxic, non-addictive, non-pharmacologic therapies to treat pain in SCD. We propose to develop a novel transcranial focused ultrasound (tFUS) technology with improved spatial targeting capability for pain treatment, and further integrating with non-invasive electrophysiological source imaging (ESI) for functionally tracking the ultrasound target. We propose to develop, and test a novel noninvasive ESI-guided closed-loop tFUS device, for safely and effectively treating pain in SCD. We will use an existing animal model for SCD pain indication to be addressed by the proposed tFUS device. Our proposed work involves developing novel tFUS device for pain treatment and establishing its effectiveness for treating SCD pain in humanized mice, and safety evaluation and design-oriented scaling up in larger animals. The specific aims are: Aim 1: Developing tFUS neuromodulation device for pain management. We will develop an operational tFUS device for pain treatment, identifying practical transducer characteristics of the random array transducer that can achieve better than 2 mm lateral resolution and better than 3 mm axial resolution for tFUS targeting. Aim 2: Evaluating tFUS effectiveness and optimizing stimulation parameters in SCD mice model. We will obtain the knowledge of effective tFUS parameters in reducing the SCD pain and will achieve at-least 1 hour long lasting treatment effect. Aim 3: ESI-informed closed-loop tFUS in animal models and its safety evaluation. The tFUS system will be fully developed and evaluated for pain management with ESI beam tracking capability with spatial accuracy better than 5 mm. Specifications of the tFUS system will be finalized, including the input and output parameters. The successful completion of the proposed project promises to develop a transformative, noninvasive transcranial focused ultrasound device for effectively and safely treating pain in sickle cell disease. Such non-pharmacologic analgesic therapy would be highly beneficial for SCD patients because of the often life-long pain.