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Mechanisms of High Frequency Stimulation of the Subthalamic Nucleus in Parkinson's Disease: From Local to Distal Effects on the Basal Ganglia Network

1.1 Parkinson’s disease, basal ganglia and the value of the subthalamic nucleus as a treatment target Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting about 1% of adults over the age of 60 years (Samii et al., 2004). It is caused by a progressive loss of the dopaminergic neurons of the substantia nigra pars compacta (SNc) and of their axons, which project to the striatum (Ehringer & Hornykiewicz, 1960). Degeneration of the nigrostriatal pathway results in the development of the motor symptoms characteristic of the disease, including tremor, rigidity, postural abnormalities and bradykinesia. These cardinal signs of PD reflect striatal dopamine (DA) depletion, leading to the global disorganization of the activity of the basal ganglia (BG), a complex network of subcortical nuclei involved in the control and execution of motor behavior. According to the classical model of BG organization (Albin et al., 1989; Alexander et al., 1990; DeLong, 1990), the interruption of dopaminergic transmission induces an imbalance between the activity of the two striatal circuits, the so-called ‘direct’ and ‘indirect’ pathways (Fig. 1). The activity of the inhibitory striatal neurons projecting directly to the substantia nigra pars reticulata (SNr) and the globus pallidus internalis (GPi), the direct pathway, is decreased. Conversely, the activity of the inhibitory striatal neurons projecting to the globus pallidus externalis (GPe) is increased, disinhibiting the activity of the subthalamic nucleus (STN), which projects excitatory glutamatergic neurons to the SNr and the GPi (indirect pathway). As efferent neurons of the SNr and GPi are GABAergic and are tonically active, this increase in indirect pathway activity results in an increase in the inhibitory output from the BG output structures to the thalamus and the thalamocortical neurons. The resulting reduction of cortical activation accounts for some of the signs of PD, such as akinesia (Albin et al., 1989; Bolam et al., 2000; DeLong, 1990; Obeso et al., 2008; Parent & Hazrati, 1995a, b). Based on this model and the results of others studies demonstrating the key role of the STN in controlling movement (Kita & Kitai, 1987; Kitai & Deniau, 1981; Smith et al., 1998), it has been suggested that the abnormal glutamatergic hyperactivity observed in the STN in the parkinsonian state plays a critical role in the expression of motor symptoms (Bergman et al.,