A bimodal closed-loop neuromodulation implant integrated with ultraflexible probes to treat epilepsy

Gen Li; Ye Tian; Luyue Jiang; Shuang Jin; Yifei Ye; Yunxiao Lu; Haoyang Su; Yingkang Yang; Xiaoling Wei; Zhitao Zhou; Tiger H Tao; Liuyang Sun

doi:10.1016/j.bios.2024.117071

A bimodal closed-loop neuromodulation implant integrated with ultraflexible probes to treat epilepsy

Biosens Bioelectron. 2024 Dec 16:271:117071. doi: 10.1016/j.bios.2024.117071. Online ahead of print.

Authors

Gen Li¹, Ye Tian¹, Luyue Jiang², Shuang Jin², Yifei Ye², Yunxiao Lu², Haoyang Su³, Yingkang Yang³, Xiaoling Wei⁴, Zhitao Zhou⁴, Tiger H Tao⁵, Liuyang Sun⁶

Affiliations

¹ 2020 X-Lab, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China; State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; School of Graduate Study, University of Chinese Academy of Sciences, Beijing, 100049, China.
² 2020 X-Lab, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China.
³ 2020 X-Lab, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China; State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China.
⁴ Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China; State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China.
⁵ 2020 X-Lab, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China; State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; School of Graduate Study, University of Chinese Academy of Sciences, Beijing, 100049, China; Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China; Guangdong Institute of Intelligence Science and Technology, Hengqin, Zhuhai, Guangdong, 519031, China; Tianqiao and Chrissy Chen Institute for Translational Research, Shanghai, 200020, China. Electronic address: [email protected].
⁶ 2020 X-Lab, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China; State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; School of Graduate Study, University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: [email protected].

PMID: 39709654
DOI: 10.1016/j.bios.2024.117071

Abstract

Anti-seizure medications and deep brain stimulation are widely used therapies to treat seizures; however, both face limitations such as resistance and the unpredictable nature of seizures. Recent advancements, including responsive neural stimulation and on-demand drug release, have been developed to address these challenges. However, a gap remains, as electrical stimulation provides only transient effects while medication has a delayed onset. To bridge this gap, we developed a Bimodal Closed-loop Neurostimulation Implant System that integrates real-time neural recording, immediate electrical stimulation, and on-demand drug release to achieve more effective seizure suppression. This dual-modality system combines rapid electrical intervention with sustained pharmacological treatment to provide comprehensive seizure control. An embedded platform powered by a Long Short-Term Memory network detects seizures and autonomously triggers these interventions. In vivo studies in an epileptic mouse model revealed that electrical stimulation achieved rapid seizure suppression, terminating 75.16% of seizures, with 90% of episodes suppressed within 10 s. The subcutaneous drug capsule provided additional control, with an onset of action approximately 15 min after release. The dual-modality approach bridged the gap between immediate and delayed intervention, stabilizing neural activity and reducing seizure recurrence. Furthermore, we confirmed the long-term viability of neurons, observing no significant changes in morphology or signal quality following stimulation and drug release. These results suggest that the system offers rapid, stable, and minimally invasive seizure control, making it a promising therapeutic tool for epilepsy. By bridging the gap between electrical effects and delayed pharmacological action, the system presents a novel approach to epilepsy management.

Keywords: Closed-loop neuromodulation; Controlled subcutaneous drug delivery; Electrical stimulation; Ultra-flexible neural probe.