Fig. 5

Optimized programming of DBS produces long-lasting effects. An example of GPe-DBS with population-specific neuromodulation that prolongs therapeutic benefits [199]. Both PV⁺ GPe and Lhx6⁺ GPe neurons receive excitatory inputs from STN to a similar degree. However, a distinction arises in their inhibition patterns originating from D1-SPN afferents. Lhx6⁺ GPe neurons experience proportionally greater inhibition from these afferents compared to PV⁺ GPe neurons. A highly precise electrical stimulation mode (175 Hz, 200 ms) with brief bursts is designed to bias towards antidromic activation of D1-SPNs, resulting in more potent inhibition of Lhx6⁺ GPe, while simultaneously exciting PV⁺ GPe neurons. Consequently, the firing rates of PV⁺ GPe neurons exceed those of Lhx6⁺ GPe neurons, which plays a crucial role in ameliorating bradykinesia in 6-OHDA-lesioned PD mice. Notably, these improvements persist long after stimulation. While the precise mechanism responsible for the extended therapeutic effects achieved through GPe-DBS with relative cell-specificity remains elusive, it is conceivable that this specific stimulation pattern bears similarities to certain forms of DBS, notably adaptive and coordinated reset DBS, both of which have shown the ability to produce enduring therapeutic benefits [191,192,193,194]