输出电压对聚焦超声经颅开放血脑屏障有效性及安全性的影响

Effect of output voltage on efficacy and safety of blood-brain barrier opening via transcranial focused ultrasound

摘要:

目的 采用现有聚焦超声（FUS）治疗系统，固定基础频率等其他参数，探索输出电压对FUS经颅开放血脑屏障（BBB）有效性及安全性的影响，筛选出合适的输出电压幅值。方法 将SPF级雄性昆明小鼠（8～9周龄）随机分为0 mV组、100 mV组、200 mV组、500 mV组和1 200 mV组，尾静脉注射微泡后给予FUS辐照（Bregma-2.7 mm，lateral+2.5 mm），再经尾静脉注入伊文思蓝（EB），4 h后取材，用脑组织的EB含量表征FUS经颅开放BBB的有效性指标，用HE染色探查安全性。结果 0 mV组小鼠BBB未开放。各组小鼠脑组织EB含量比较，差异有统计学意义（P <0.05），且随着输出电压升高，脑组织EB含量显著升高（P <0.05）。0 mV组和100 mV、200 mV组小鼠大脑受超声辐照区域脑组织正常，均无红细胞渗出；500 mV组、1200 mV组小鼠大脑超声作用区域脑组织有不同程度红细胞渗出。结论 当FUS基础频率为1 MHz，脉宽10 ms，总辐照时间120 s，脉冲重复频率为1 Hz，SonoVue^?六氟化硫微泡剂量2.5 μL/g的情况下，输出电压为200 mV可经颅、高效、安全地开放BBB，是较为合适的输出电压幅值。

Abstract:

Objective To explore the influence of output voltage on efficacy and safety of blood-brain barrier (BBB) opening with focused ultrasound (FUS) by keeping other parameters like base frequency unchanged, thus screening out the appropriate value of output voltage.Methods SPF male KM mice (8 to 9 weeks old) were randomly divided into 0 mV group, 100 mV group, 200 mV group, 500 mV group and 1,200 mV group. FUS exposure was given (Bregma -2.7 mm, lateral + 2.5 mm) after injections of microbubbles into the tail veins, followed by injections of Evans blue (EB) via the tail veins. The brain samples were collected 4 h later. The content of EB in brain was used to indicate the efficacy of BBB opening, and H&E staining was used to investigate the safety.Results The BBB of mice in the 0 mV group stayed unopen, and the content of EB in brain was different among the groups (P < 0.05). With the increase in the output voltage, the content of EB in brain was elevated (P < 0.05). The brain tissues exposed to FUS were normal in the 0 mV, 100 mV and 200 mV groups, where no red blood cell exudation was observed. There were different degrees of red blood cell exudation in the brain parenchyma exposed to FUS of mice in the 500 mV group and 1,200 mV group.Conclusions Under the conditions of 1 MHz of base frequency, 10 ms of burst duration, 120 s of total exposure time, 1 Hz of pulse repetition frequency, and 2.5 μL/g of microbubbles, the BBB can be opened effectively and safely via transcranial FUS when the output voltage is set to 200 mV.