We thank Dr. Igor Kagan and Dr. James Bonaiuto for the acquisition Metformin cost and processing of MR images, Dr. Bardia Behabadi for scientific discussion, Tessa Yao for editorial assistance, Kelsie Pejsa and Nicole Sammons for animal care, and Viktor Shcherbatyuk for technical assistance. “
“Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is now a recognized therapeutic option for Parkinson’s disease (PD) (Benabid et al., 1994; Benazzouz et al.,

1993; Deuschl et al., 2006; Obeso et al., 2001). However, the exact mechanism of action of STN-DBS is still not settled (Chang et al., 2008; Gubellini et al., 2009; Montgomery and Gale, 2008). Early studies favored an inhibitory action of DBS. Functional inactivation, like depolarizing block and depletion of transmitters, could produce a lesion-like effect in the STN (Beurrier et al., 2001; Garcia et al., 2003; Magariños-Ascone et al., 2002). Later studies suggested that DBS may exert an excitatory effect on neural elements and interferes

with the abnormal oscillatory and synchronized activities that are commonly found in the basal ganglia in Parkinsonism (Brown and Eusebio, 2008; Eusebio et al., 2011). In principle, DBS can directly activate a wide range of neuronal elements in STN and the surrounding area, including STN neuronal soma, axons of passage, and also the terminals MAPK inhibitor of descending fibers from the cortex to STN (Deniau et al., 2010; Lee et al., 2006; Li et al., 2007; McIntyre and Hahn, 2010; Miocinovic et al., 2006). By activating both afferent and efferent axons, STN-DBS can potentially generate widespread and heterogeneous effects at local and distal sites (Hammond et al., 2008; Hashimoto et al., 2003; Maurice et al., 2003). In fact, there are a number of studies in both human and animals suggesting that STN stimulation can evoke or modulate cortical activities, which may be beneficial to PD symptoms (Dejean et al., 2009; Fraix et al., 2008; Gradinaru mefexamide et al.,

2009; Kuriakose et al., 2010; Lehmkuhle et al., 2009). Thus, early experiments in patients undergoing implantation of STN electrodes demonstrated cortical evoked potentials that resembled antidromic activation from the electrodes (Ashby et al., 2001; MacKinnon et al., 2005). Later demonstration of resonant antidromic cortical circuit activation as a consequence of STN-DBS in anaesthetized rats (Li et al., 2007) was followed by demonstration that high frequency subthalamic stimulation in awake rats could release them from the akinesia that followed application of dopamine antagonists (Dejean et al., 2009). These studies along with others in different situations demonstrated that the subthalamic stimulation also disrupted the beta rhythms in the cortex in akinetic animals (Fraix et al., 2008; Kuriakose et al., 2010; Lehmkuhle et al., 2009).