Non-invasive ultrasonic neuromodulation of neuronal excitability for treatment of epilepsy
Non-invasive ultrasonic neuromodulation of neuronal excitability for treatment of epilepsy
复制标题
无创超声神经调节神经元兴奋性治疗癫痫
DOI：
10.7150/thno.40520
复制
发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Zheng, Hairong
中科院分区：
文献类型：
--
作者：
Lin, Zhengrong;Meng, Long;Zheng, Hairong
无创低强度脉冲超声已被用于直接神经调制。然而，其范围和不同的神经系统疾病的有效性尚未完全阐明。研究方法：我们使用电生理学、免疫组织化学和行为测试的多种方法作为非人灵长类癫痫模型和人癫痫组织中的潜在癫痫治疗。将频率为750 kHz、声压为0.35 MPa（空间峰值脉冲平均强度，ISPPA = 2.02 W/cm 2）的低强度脉冲超声输送到5只青霉素诱导癫痫猴模型的致癫痫灶。采用频率为28 MHz、声压为0.13MPa（ISPPA = 465 mW/cm ~ 2）、与膜片钳系统兼容的超声神经调制系统刺激15例癫痫患者脑片。结果如下：低强度脉冲超声治疗30 min后，16 h癫痫发作次数（假手术组：107.7 ± 1.2，超声组：66.0 ± 7.9，P < 0.01）和每小时癫痫发作次数（假手术组：15.6 ± 1.2，超声组：9.6 ± 1.5，P < 0.05）均明显减少。在离体癫痫患者活检标本中研究了低强度脉冲超声治疗的疗效和潜在机制。超声刺激可以抑制癫痫样活动，效率超过65%，这可能是由于通过增加局部抑制性神经元的活动来调节兴奋-抑制性（E/I）突触输入的平衡。结论：在此，我们首次证明了低强度脉冲超声改善了非人灵长类癫痫模型的电生理活动和行为结果，并抑制了人类癫痫切片神经元的癫痫样活动。该研究为无创低强度脉冲超声刺激治疗癫痫的潜在临床应用提供了证据。
Non-invasive low-intensity pulsed ultrasound has been employed for direct neuro-modulation. However, its range and effectiveness for different neurological disorders have not been fully elucidated. Methods: We used multiple approaches of electrophysiology, immunohistochemistry, and behavioral tests as potential epilepsy treatments in non-human primate model of epilepsy and human epileptic tissues. Low-intensity pulsed ultrasound with a frequency of 750 kHz and acoustic pressure of 0.35 MPa (the spatial peak pulse average intensity, ISPPA = 2.02 W/cm2) were delivered to the epileptogenic foci in five penicillin-induced epileptic monkey models. An ultrasound neuro-modulation system with a frequency of 28 MHz and acoustic pressure of 0.13 MPa (ISPPA = 465 mW/cm2) compatible with patch-clamp systems was used to stimulate the brain slices prepared from fifteen patients with epilepsy. Results: After 30 min of low-intensity pulsed ultrasound treatment, total seizure count for 16 hours (sham group: 107.7 ± 1.2, ultrasound group: 66.0 ± 7.9, P < 0.01) and seizure frequency per hour (sham group: 15.6 ± 1.2, ultrasound group: 9.6 ± 1.5, P < 0.05) were significantly reduced. The therapeutic efficacy and underlying potential mechanism of low-intensity pulsed ultrasound treatment were studied in biopsy specimens from epileptic patients in vitro. Ultrasound stimulation could inhibit epileptiform activities with an efficiency exceeding 65%, potentially due to adjusting the balance of excitatory-inhibitory (E/I) synaptic inputs by the increased activity of local inhibitory neurons. Conclusion: Herein, we demonstrated for the first time that low-intensity pulsed ultrasound improves electrophysiological activities and behavioral outcomes in a non-human primate model of epilepsy and suppresses epileptiform activities of neurons from human epileptic slices. The study provides evidence for the potential clinical use of non-invasive low-intensity pulsed ultrasound stimulation for epilepsy treatment.