We have therefore termed such stimulation “closed-loop” stimulation. We demonstrate that in the MPTP-treated primate,

closed-loop stimulation of the GPi based on the ongoing activity in M1 is more efficient in alleviating parkinsonian motor symptoms than the standard continuous (open-loop) high-frequency BYL719 order GPi DBS paradigm. Furthermore, closed-loop DBS is also accompanied by a greater reduction in oscillatory activity in both the pallidum and the primary motor cortex as compared with standard DBS. The current study could therefore serve as a “proof of concept” for the utilization of closed-loop stimulation paradigms in the treatment of brain disorders in general and PD in particular. In addition, our results suggest that the role of the oscillatory activity of cortico-basal ganglia loops is more significant selleck screening library than that of the changes in their discharge rate with regards to the generation of akinesia, the main motor symptom of Parkinson’s disease.

Thus, this study also provides an insight into the underlying pathophysiology of PD and indications for the future directions of closed-loop DBS research and utilization. Previous models of the corticobasal ganglia networks have emphasized the role of changes in discharge rate of the BG neurons in the generation of PD symptoms (Albin et al., 1989 and Bergman et al., 1990), a view that is now considered to be incomplete (Hammond et al., 2007 and Wichmann and DeLong, 2006). Indeed, the application of both the standard DBS and GPtrain|M1 closed-loop stimulation resulted in improvement of the primates’ motor deficits (Figure 5A), which coincided with a reduction in the pallidal discharge rate (Figure 6B). However, this improvement also coincided with a reduction in oscillatory activity (Figures 7C and 7D). While the reduction in oscillatory activity was limited to double-tremor

frequency oscillations during standard DBS application, it also occurred at tremor frequency in the closed-loop GPtrain|M1 paradigm. Furthermore, the reduction in GPi double-tremor frequency oscillatory activity was more pronounced during the application of the GPtrain|M1 not paradigm (Figure 7D). Notably, the pallidal oscillatory activity was not correlated to the pallidal discharge rate either before or during the application of standard DBS and closed-loop GPtrain|M1, which is suggestive of independent mechanisms behind the two phenomena (Figures S6 and S7). These results are in line with a recent report indicating that independent mechanisms may underlie the burst discharges and oscillatory activity of most GPi neurons in human PD patients (Chan et al., 2011). These findings therefore suggest, in agreement with other recent studies (Eusebio and Brown, 2007, Hammond et al., 2007, Kühn et al., 2009, Tass et al., 2010, Vitek, 2008, Weinberger et al., 2009, Wichmann and DeLong, 2006 and Zaidel et al.