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The treatment of Parkinson's disease (PD) has been revolutionized by the introduction of deep brain stimulation (DBS) surgery, a procedure which allows delivering continuous current to brain targets. The first systematic application of DBS in PD dates back to 1987, when Benabid et al . targeted the thalamic ventral intermediate nucleus (Vim) for the treatment of tremor [1]. Since then, DBS has become an established treatment in PD and other movement disorders, and other brain structures, besides Vim, have been studied, that is, the subthalamic nucleus (STN) and the globus pallidus pars interna (GPi). It became evident that the stimulation of Vim allowed only the control of tremor, whereas subthalamic and pallidal stimulation also improved rigidity and bradykinesia. STN DBS has been shown to be superior to the best medical treatment in the control of motor fluctuations and dyskinesia, and in the improvement of quality of life [2,3]. Its effects have been shown to persist over many years [4]. Hence, the STN has become the most widely used DBS target.
Although STN stimulation represents a breakthrough in the treatment of PD, it does not satisfactorily improve the symptoms that do not respond to dopaminergic treatment, such as axial signs (postural instability, freezing of gait, posture abnormalities, dysarthria) and cognitive decline. These symptoms are the main source of disability for patients with advanced PD, the main burden for their caregivers and the main challenge to deal with for physicians. The pathogenesis of these symptoms appears to be complex and linked to the involvement of non-dopaminergic structures. Therefore, DBS of different new brain targets is under investigation.
In this review, we will focus on new experimental brain targets for PD, and specifically the pedunculopontine nucleus (PPN), the caudal zona incerta (cZi), the thalamic centromedian-parafascicular (CM-Pf)complex, the substantia nigra pars reticulate (SNr), and we will also discuss different therapeutic strategies, such as multi-target stimulation.
The pedunculopontine nucleus
The PPN is part of the so-called mesencephalic locomotor region, a functional area of the mesencephalon with a crucial role in locomotion [5]. Electrical stimulation of this area can induce controlled locomotion on a treadmill in decerebrated animals [6-9].
The PPN receives inputs from the cortex, the limbic system, the basal ganglia, the spinal cord and the brainstem, especially the...