Long-Lasting Electrophysiological After-Effects of High-Frequency Stimulation in the Globus Pallidus: Human and Rodent Slice Studies.

Deep-brain stimulation (DBS) of the globus pallidus pars interna (GPi) is a highly effective therapy for movement disorders, yet its mechanism of action remains controversial. Inhibition of local neurons because of release of GABA from afferents to the GPi is a proposed mechanism in patients. Yet, high-frequency stimulation (HFS) produces prolonged membrane depolarization mediated by cholinergic neurotransmission in endopeduncular nucleus (EP, GPi equivalent in rodent) neurons. We applied HFS while recording neuronal firing from an adjacent electrode during microelectrode mapping of GPi in awake patients (both male and female) with Parkinson disease (PD) and dystonia. Aside from after-suppression and no change in neuronal firing, high-frequency microstimulation induced after-facilitation in 38% (26/69) of GPi neurons. In neurons displaying after-facilitation, 10 s HFS led to an immediate decrease of bursting in PD, but not dystonia patients. Moreover, the changes of bursting patterns in neurons with after-suppression or no change after HFS, were similar in both patient groups. To explore the mechanisms responsible, we applied HFS in EP brain slices from rats of either sex. As in humans, HFS in EP induced two subtypes of after-excitation: excitation or excitation with late inhibition. Pharmacological experiments determined that the excitation subtype, induced by lower charge density, was dependent on glutamatergic transmission. HFS with higher charge density induced excitation with late inhibition, which involved cholinergic modulation. Therefore HFS with different charge density may affect the local neurons through multiple synaptic mechanisms. The cholinergic system plays a role in mediating the after-facilitatory effects in GPi neurons, and because of their modulatory nature, may provide a basis for both the immediate and delayed effects of GPi-DBS. We propose a new model to explain the mechanisms of DBS in GPi.SIGNIFICANCE STATEMENT Deep-brain stimulation (DBS) in the globus pallidus pars interna (GPi) improves Parkinson disease (PD) and dystonia, yet its mechanisms in GPi remain controversial. Inhibition has been previously described and thought to indicate activation of GABAergic synaptic terminals, which dominate in GPi. Here we report that 10 s high-frequency microstimulation induced after-facilitation of neural firing in a substantial proportion of GPi neurons in humans. The neurons with after-facilitation, also immediately reduced their bursting activities after high-frequency stimulation in PD, but not dystonia patients. Based on these data and further animal experiments, a mechanistic hypothesis involving glutamatergic, GABAergic, and cholinergic synaptic transmission is proposed to explain both short- and longer-term therapeutic effects of DBS in GPi.