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

镰状细胞病（SCD）使全世界数百万人遭受慢性和急性疼痛。剧烈的疼痛可以 在婴儿期开始，并在SCD的整个生命过程中严重程度增加。患者经常需要反复 住院、长期使用高剂量阿片类药物和生活质量差。长期使用阿片类药物与 副作用包括用药过量和死亡开发无毒、不成瘾、 治疗SCD疼痛的非药物疗法。我们建议开发一种新的经颅聚焦 超声（tFUS）技术，具有改善的空间靶向能力，用于疼痛治疗，并进一步整合 与非侵入性电生理源成像（ESI）一起用于功能性地跟踪超声目标。我们 我建议开发和测试一种新型的无创ESI引导闭环tFUS设备，以安全有效地 治疗SCD中的疼痛。我们将使用现有的SCD疼痛适应症动物模型， tFUS装置。我们建议的工作包括开发新的tFUS设备用于疼痛治疗， 建立其在人源化小鼠中治疗SCD疼痛的有效性，并进行安全性评价和设计导向 在更大的动物中扩大。具体目标为：目标1：研制tFUS疼痛神经调节装置 管理我们将开发一种用于疼痛治疗的可操作的tFUS设备， 可以实现优于2mm的横向分辨率和更好的横向分辨率的随机阵列换能器的特性。 tFUS定位的轴向分辨率超过3 mm。目的2：评估tFUS有效性并优化刺激 SCD小鼠模型中的参数。我们将获得减少SCD的有效tFUS参数的知识 疼痛，并将达到至少1小时的持久治疗效果。目的3：动物中的ESI通知闭环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 包括输入和输出参数。成功完成拟议项目 承诺开发一种变革性的、非侵入性的经颅聚焦超声设备， 安全地治疗镰状细胞病的疼痛。这种非药物性镇痛治疗将是非常有益的 对于SCD患者来说，因为往往是终身的痛苦。

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.