Cell Tissue Res (2004) 318: 275–288 DOI 10.1007/s00441-004-0936-0 REVIEW Sorin Breit . Jörg B. Schulz . Alim-Louis Benabid Deep brain stimulation Received: 30 January 2004 / Accepted: 1 June 2004 / Published online: 19 August 2004 # Springer-Verlag 2004 Abstract During the last decade deep brain stimulation (DBS) has become a routine method for the treatment of advanced Parkinson’ s disease (PD), leading to striking improvements in motor function and quality of life of PD patients. It is associated with minimal morbidity. The rationale of targeting specific structures within basal ganglia such as the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) is strongly supported by the current knowledge of the basal ganglia pathophysiology, which is derived from extensive experi- mental work and which provides the theoretical basis for surgical therapy in PD. In particular, the STN has advanced to the worldwide most used target for DBS in the treatment of PD, due to the marked improvement of all cardinal symptoms of the disease. Moreover on-period dyskinesias are reduced in parallel with a marked reduc- tion of the equivalent daily levodopa dose following STN– DBS. The success of the therapy largely depends on the selection of the appropriate candidate patients and on the precise implantation of the stimulation electrode, which necessitates careful imaging-based pre-targeting and ex- tensive electrophysiological exploration of the target area. Despite the clinical success of the therapy, the fundamental mechanisms of high-frequency stimulation are still not fully elucidated. There is a large amount of evidence from experimental and clinical data that stimulation frequency represents a key factor with respect to clinical effect of DBS. Interestingly, high-frequency stimulation mimics the functional effects of ablation in various brain structures. The main hypotheses for the mechanism of high-frequen- cy stimulation are: (1) depolarization blocking of neuronal transmission through inactivation of voltage dependent ion-channels, (2) jamming of information by imposing an efferent stimulation-driven high-frequency pattern, (3) synaptic inhibition by stimulation of inhibitory afferents to the target nucleus, (4) synaptic failure by stimulation- induced neurotransmitter depletion. As the hyperactivity of the STN is considered a functional hallmark of PD and as there is experimental evidence for STN-mediated glutamatergic excitotoxicity on neurons of the substantia nigra pars compacta (SNc), STN–DBS might reduce glutamatergic drive, leading to neuroprotection. Further studies will be needed to elucidate if STN–DBS indeed provides a slow-down of disease progression. Keywords Deep brain stimulation . Basal ganglia . Subthalamic nucleus . Globus pallidus . Parkinson’ s disease History of surgical treatment and deep brain stimulation for Parkinson’s disease Surgical treatment for Parkinson’ s disease (PD) and other movement disorders was first introduced approximately 50 years ago by lesioning different functional targets within the basal ganglia. As the post-operative complications and morbidity were relatively high and the levodopa therapy emerged by the beginning of the 7th decade of the last century, surgical treatment for PD was almost completely abandoned. In the late 1980s and early 1990s a resurgence of new surgical techniques directed to new functional basal ganglia targets was observed. For the first time, the Grenoble group introduced high-frequency stimulation of the ventralis intermedius nucleus of the thalamus (Vim) to S. Breit (*) Department of General Neurology, Hertie Institute for Clinical Brain Research, Center of Neurology, University of Tübingen, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany e-mail: sorin.breit@uni-tuebingen.de Tel.: +49-7071-2982141 Fax: +49-7071-295260 S. Breit . J. B. Schulz Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, Center of Neurology, University of Tübingen, Tübingen, Germany A.-L. Benabid Department of Clinical and Biological Neurosciences, INSERM U-318, University of Grenoble, Grenoble, France