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Theranostics 2020; 10(12):5514-5526. doi:10.7150/thno.40520 This issue Cite

Research Paper

Non-invasive ultrasonic neuromodulation of neuronal excitability for treatment of epilepsy

Zhengrong Lin^1,5*, Long Meng^1,2,5*, Junjie Zou^1,3*, Wei Zhou^1,5, Xiaowei Huang^1,5, Shan Xue³, Tianyuan Bian¹, Tifei Yuan⁴, Lili Niu^1,2,5✉, Yanwu Guo^3✉, Hairong Zheng^1,2✉

1. Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China, 518055.
2. CAS Key Laboratory of Health Informatics, Shenzhen Institutes of Advanced Technology, Shenzhen, China, 518055.
3. The National Key Clinic Specialty; The Engineering Technology Research Center of Education Ministry of China; Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration; Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China, 510282.
4. Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, China, 200030.
5. Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, China, 510515
*These authors contributed equally to this work.

✉ Corresponding author: E-mail: ll.niuac.cn; eguoyanwucom; hr.zhengac.cn

Abstract

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, I_SPPA = 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 (I_SPPA = 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.

Keywords: pulsed ultrasound treatment, epilepsy, electrophysiological activities

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