Fig. 4

Position-dependent therapeutic effects of DBS for PD. a Topologically determined position-dependent effects (exemplified by STN-DBS). In mice, the STN receives inputs from both the cortex and the GPe. These inputs exhibit a topographically graded organization, forming the hyperdirect and indirect pathways, respectively [150]. Furthermore, a topographical organization exists between the cortex and GPe. To elaborate, the posterolateral to anteromedial regions of the STN receive projections from various cortical areas, including sensorimotor, association, and limbic regions [136, 147, 148]. Within the STN, there is a distinct distribution of PV⁺ glutamatergic neurons, primarily clustered in the dorsolateral and middle regions. These neurons exhibit unique burst firing patterns and may contribute to excessive burst firing observed in PD [150]. Consequently, clinical benefits are typically observed when DBS electrodes are precisely positioned within the dorsolateral sensorimotor area [136,137,138,139]. b Neuronal population-determined position-dependent effects (exemplified by the PPN-DBS). The PPN is an integral component of the mesencephalic locomotor region, characterized by the spatial distribution of glutamatergic, GABAergic, and cholinergic neurons [159, 160]. Among these, glutamatergic neurons represent the major subpopulation. Activation of caudal glutamatergic neurons promotes locomotion [155, 162, 163], while their rostral counterparts induce locomotor arrest [162]. GABAergic neurons are slightly more concentrated in the rostral PPN [161] and tend to decrease the locomotor speed when activated [155, 163]. Cholinergic neurons outnumber GABAergic neurons, yet their influence on locomotion is less clear, with reported effects spanning from improvement to suppression of movement upon optogenetic activation [155, 163]. The specific distribution of these neuronal subpopulations likely underlies the rationale for targeting the caudal PPN as the optimal stimulation site [142,143,144,145]