Yiming Chen1  · Wenxu Tang2  · Yifan Wang1,3  · Ya Gao1,3  · Jiaqi Hu2,4  · Yixuan Lu2  · Long Meng5  · Hairong Zheng5  · Yi Feng6  · Liming Cheng3  · Wenyong Fan3  · Qian Cheng1,3,7  · Lei Xue2,8

1 Institute of Acoustics, School of Physics Science and Engineering, Tongji University, Shanghai 200092, China 

2 State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Physiology and Neurobiology, School of Life Sciences, Fudan University, Shanghai 200438, China 

3 Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of the Ministry of Education, Department of Orthopedics, School of Medicine, Tongji Hospital afliated to Tongji University, Tongji University, Shanghai 200065, China 

4 Center for Rehabilitation Medicine, Department of Pain Management, Zhejiang Provincial People’s Hospital, Afliated People’s Hospital, Hangzhou Medical College, Hangzhou 310014, China 

5 Paul C. Lauterbur Research Center for Biomedical Imaging, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China 

6 Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China 

7 Frontiers Science Center for Intelligent Autonomous Systems, Shanghai 201210, China 

8 Research Institute of Intelligent Complex Systems, Fudan University, Shanghai 200433, China

Abstract

Ultrasound neuromodulation shows promise for treating neurological disorders, but the underlying mechanisms remain unclear. Here, we developed an integrated surface acoustic wave (SAW) ultrasound chip enabling simultaneous electrophysiological recording and Ca²⁺ imaging of cultured hippocampal neurons to investigate neuronal excitability and synaptic transmission during ultrasound stimulation. This study revealed, for the first time, three distinct neuronal response patterns induced by SAW ultrasound: an immediate response showing rapid activation, a delayed response exhibiting facilitation after several minutes, and a non-response maintaining baseline activity. Ultrasound stimulation increased action potential firing, enhanced excitatory postsynaptic currents, and elevated intracellular Ca²⁺ levels. These effects were dependent on extracellular Ca²⁺ influx and primarily dominated by L-type Ca²⁺ channels. Our findings suggest that individual neurons exhibit heterogeneous responses to SAW ultrasound stimulation based on their intracellular Ca²⁺ levels and L-type Ca²⁺ channel activity. This integrated approach provides new insights into the cellular mechanisms of ultrasound neuromodulation while highlighting the potential of SAW technology for precise, cell-type-specific neural control.

Keywords

Surface Acoustic Wave; Ultrasound Neuromodulation; Neuronal Excitability; Synaptic Transmission; Calcium Signaling

[SpringerLink]