Effects of longer-term pallidal stimulation on the severity of dystonia in a phenotypic animal model

Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an established therapy for drug-intractable dystonia, a severe movement disorder. As shown by previous studies, short-term (three hours) DBS of the entopeduncular nucleus (EPN, the homologue of the GPi in rodents) improved dystonia in dt^sz mutant hamsters, a genetic animal model of paroxysmal dystonia. However, DBS in dystonia patients is thought to alter long-term plasticity during prolonged DBS accompanied with delayed improvement of dystonia. Therefore, it is important to investigate the mechanisms of long-term stimulation. In the present study, we examined the effects of prolonged bilateral pallidal (EPN) DBS (130 Hz, 60 μs, 50 μA) over ten days on the severity of dystonia by using an innovative implantable DBS device. Electrode implantation alone reduced the severity of dystonia in mutant hamsters (post-OP vs. pre-OP). In comparison to post-OP data, the severity of dystonia remained unchanged after two days of pallidal DBS (postOp-d37-On). However, during continuous DBS the severity slowly decreased. After ten days of DBS, the severity was significantly reduced compared to both pre-DBS (postOP-d35) and postOp-d37-ON, while the severity scores did not differ in age-matched sham-stimulated dt^sz hamsters. Notably, in the DBS group three out of 13 animals did not respond to pallidal DBS. Thus, the present data highlight individual variability and temporal differences in the response to DBS in this model, paralleling observations in patients. Therefore, the dt^sz hamster model is highly suitable for investigating the mechanisms of DBS within the pathological network.