Upconversion-Based Remote Deep Brain Modulation for Therapeutic Dissection of Parkinson's Disease

High frequency deep brain stimulation (DBS) is widely used for improving motor capability in patients with Parkinson's disease (PD). Here, an upconversion-based strategy is described for remote deep brain modulation, which is an all-optical solution for treating PD in rodent animals without any tethering interferences. It is demonstrated that both high frequency stimulation and inhibition of subthalamic nucleus (STN), can improve the motor function of Hemi-Parkinsonian rodent models, potentially providing a specific and flexible therapeutic alternative for treating PD. A multi-modal approach is further taken that combines optogenetics and electrophysiology recording, and found that high frequency optogenetic inhibition of STN work similarly as high frequency activation to rescue the pathologic electrical activity in the motor cortex and restore the motor deficiency in Hemi-Parkinsonian rodents. It is also shown that indirect inhibitory modification of entopeduncular nucleus (EP) within the basal ganglia system, which is induced by either STN inhibition or activation, plays a critical role in the STN-DBS induced therapeutic effects in the Hemi-Parkinsonian animals. These results provide first experimental evidence supporting a working principle of STN-DBS by disruption of anterograde signal transmission along the indirect pathway of basal ganglia, and can be instructive for future clinical treatment of PD with DBS. #x000A9; 2025 The Author(s). Advanced Therapeutics published by Wiley-VCH GmbH.