A research paper by scientists at Peking University Third Hospital presented a study on the regulatory mechanisms of the ECS in the substantia nigra (SN) of PD rats following STN-DBS.
The research paper, published on Apr. 3, 2025 in the journal Cyborg and Bionic Systems.
Deep brain stimulation (DBS) is a neuromodulation therapy that has proven effective in treating medication-refractory neurological disorders like tremors, rigidity, and epilepsy, especially in Parkinson's disease (PD) patients. Subthalamic nucleus DBS (STN-DBS) has emerged as a frontline treatment to alleviate PD symptom. However, the therapeutic mechanisms remain incompletely understood, particularly regarding the extracellular space (ECS), a critical microenvironment where molecular diffusion and interstitial fluid (ISF) dynamics are essential for neural function. This study aims to explore the regulatory mechanisms of the ECS in the substantia nigra (SN) of PD rats following STN-DBS. "Our findings suggest that STN-DBS improves PD symptoms by modifying the ECS and enhancing ISF drainage in the SN regions." said the author Dan Du, a researcher at Peking University Third Hospital.
This study evaluates how STN-DBS modulates ECM components and ISF drainage in PD rat models, aiming to understand its remote effects in the SN. To evaluate whether STN-DBS can modulate ECS diffusion and drainage, researchers conducted quantitative measurements using a tracer-based magnetic resonance imaging. Our findings indicated that, compared to the PD group, STN-DBS treatment resulted in a decreased diffusion coefficient (D*), shorted half-life (T1/2), and increased clearance coefficient (k′) in the SN. To investigate the mechanisms underlying these changes in molecular diffusion, researchers employed enzyme-linked immunosorbent assay (ELISA), Western blotting (WB), and microdialysis techniques. The results revealed that STN-DBS led to an increase in hyaluronic acid content, elevated expression of excitatory amino acid transporter 2 (EAAT2), and a reduction in extracellular glutamate concentration. Additionally, to further elucidate the mechanisms influencing ISF drainage, researchers employed immunofluorescence and immunohistochemical techniques for staining aquaporin-4 (AQP-4) and α-synuclein. The results demonstrated that STN-DBS restored the expression of AQP-4 while decreasing the expression of α-synuclein. In conclusion, our findings suggest that STN-DBS improves PD symptoms by modifying the ECS and enhancing ISF drainage in the SN regions.
This article presented a thorough investigation into the modifications of ECS parameters in a rat model of PD, both preceding and subsequent to STN-DBS intervention. Research results compellingly demonstrate that STN-DBS exerts its therapeutic efficacy by regulating extracellular ECM constituents and enhancing ISF drainage, thereby improving the extracellular microenvironment and preserving dopaminergic neurons. These findings not only contribute to a deeper understanding of the mechanisms underlying STN-DBS in PD treatment but also provide a robust theoretical framework for its application. "Our Research results also open up new avenues for the exploration of therapeutic targets and the optimization of clinical protocols, holding promise for the development of more efficacious treatment strategies in the future." said Dan Du.
Authors of the paper include Dan Du, Wanyi Fu, Shaoyi Su, Xin Mao, Liu Yang, Meng Xu, Yi Yuan, Yajuan Gao, Ziyao Geng, Yanjing Chen, Mingming Zhao, Yu Fu, Feng Yin, and Hongbin Han.
This work was supported by the Major Program of the National Natural Science Foundation of China (62394314), the National Natural Science Foundation of China (62171003), the Major Program of the National Natural Science Foundation of China (62394313, 62394310), and the Clinical Cohort Construction Program of Peking University Third Hospital (BYSYDL2023014).
The paper, "Remote Regulation of Molecular Diffusion in Extracellular Space of Parkinson's Disease Rat Model by Subthalamic Nucleus Deep Brain Stimulation" was published in the journal Cyborg and Bionic Systems on Apr. 3, 2025, at DOI: 10.34133/cbsystems.0218.
