, 2007, Leblois et al., 2007, Lozano and Eltahawy, 2004, Tass et al., 2010, Vitek, 2002 and Weinberger et al., 2009). For instance, while the parkinsonian rest tremor occurs mainly at the 4–7 Hz frequency band, the oscillatory neuronal activity is observed in several characteristic frequency bands in both human PD patients (Hutchison et al., 2004) and animal models (Bergman et al., 1994 and Gubellini et al., 2009). Our study provides strong

support for the pathological Panobinostat mouse role of these oscillations, in that stimulation targeted directly at this activity (in a specific band, the double-tremor frequency band, approximately 9–15 Hz) provided greater alleviation of parkinsonian motor symptoms than standard DBS. The fact that M1-based closed-loop stimulation was the most successful in improving all the output parameters is perhaps not too surprising considering the central role of cortical discharge patterns in the pathophysiology of PD. M1 is one of the main components of the cortico-basal ganglia loops, and although the GPi (and the SNr) are the main output nuclei of the basal ganglia network, the M1 is the main output via the corticospinal and corticobrainstem tracts (Albin et al., 1989, Alexander et al., 1986, Alexander and Crutcher, 1990, Bergman et al., 1990 and Mink, 1996). Furthermore, M1′s direct projection to the STN (Nambu et al., 2000) makes it a perfect candidate to serve as a reference

structure in future closed-loop stimulation of the STN. The M1 has been implicated find more in many aspects of parkinsonian brain activity, such as oscillatory L-NAME HCl discharge and transient synchronization with pallidal activity (Cassim et al., 2002 and Goldberg et al., 2002). Such synchronization during epochs of double-tremor frequency oscillatory discharge could be the basis for the success of GPtrain|M1 when using 80 ms delays compared with the apparent ineffectiveness of other delays, as indicated by our preliminary studies (Figure 2 and Figure S1). A stimulus delivered to the GPi during an oscillatory burst synchronized to its double-tremor frequency

counterpart in M1 would disrupt this pathological activity of the pallidum and via the thalamus in M1 itself. On the other hand, when no such synchronization exists, the effect of GPtrain|M1 stimulation on the pallidal discharge would be less significant. Since GP stimulation could, in fact, activate efferent GPi axons while inhibiting their somata (Johnson and McIntyre, 2008), this mechanism could also explain the worsening of akinesia during GPtrain|GP application. Such activation of GPi efferent axons could in essence induce double-tremor frequency oscillations during GPtrain|GP stimulation by activating GPi targets 80 ms after a previous GPi spike/burst, even if the latter was originally independent of oscillatory activity. Most current models of the BG network assume competitive dynamic (Frank et al.

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