EDITORIAL. Special Feature: Deep Brain Stimulation

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2 EDITORIAL Special Feature: Deep Brain Stimulation Didier Pinault Inserm u666, Pathophysiology and Psychopathology of Schizophrenia, IFR37, Faculty of Medicine, University of Strasbourg, Strasbourg, France Tel: +33 (0) Fax: +33 (0) Deep brain electrical stimulation (DBS) has evolved as a surgical treatment when drug therapy no longer provides relief from symptoms accompanying severe neurological and psychiatric disorders. The pioneering, seminal work of Alim-Louis Benabid and his colleagues has demonstrated the efficacy of DBS in patients with advanced Parkinson s disease (PD; Benabid et al., 1987, 1991). DBS is now used to treat a wider range of chronic brain disorders in patients resistant to pharmacological mono- and polytherapies, including epilepsy, dystonia, obsessive compulsive disorders, pain, depression and Gilles de la Tourette syndrome. It is also used to improve the condition of brain-injured patients in a vegetative or minimally conscious state. In PD patients, DBS involves the implantation of a multi-contact electrode designed to deliver highfrequency electrical current pulses to the subthalamic nucleus (STN; Fig 1). They are generated thanks to a miniature electronic device combined with a battery, which are implanted subcutaneously. 3D imaging techniques have considerably improved the accuracy of implantations into deep brain regions (Miocinovic et al., 2007). Although DBS can be an effective symptomatic therapy, it is often accompanied by adverse effects. Insert Figure 1 This Special Feature of EJN consists of reviews by world experts conducting basic and clinical researches on DBS. As several of the reviews in this Special Feature point out, our understanding of the neuronal mechanisms mediating the diverse effects of DBS, while growing rapidly, has remained 1

3 limited. The authors therefore emphatically emphasize the importance of research, specifically in order to address key questions, including: What are the most effective anatomical targets and stimulation parameters for DBS therapy? What are the neuronal mechanisms underlying DBS effects, and what type of information can be deduced from studying animal models? What is the minimal number of neuronal elements that may be stimulated to generate therapeutic efficacy? What are the relative contributions of stimulation-induced electric fields and lesions, and of the intensive care of patients treated with DBS? Is DBS more effective when applied to white or grey matter? Can DBS influence cerebral rhythms, brain state, consciousness and emotions? Can DBS enhance cognitive functions? Can DBS provide symptomatic relief for patients with severe psychiatric disorders? Overview of the Special Feature In the first article, Morten Kringelbach and colleagues review basic principles and mechanisms underlying DBS effects. They stress the importance of translational research to improve and refine the use of therapeutic DBS against severe motor and affective disorders. Focusing on the potential benefits of DBS for patients with affective disorders, these authors discuss how effects on network activity might alleviate disabling symptoms such as anhedonia. Jean-Michel Deniau and colleagues review basic principles of DBS, basal ganglia physiology, and the rodent model of PD. They show that STN stimulation induces multiple, local and distant effects (via ortho- and antidromic activation), generating inhibition as well as excitation and impacting on the oscillatory properties of thalamocortical (TC) networks. The authors further emphasize the importance of increasing our understanding of the anatomical properties of the circuits stimulated by DBS, in order to identify effective targets for therapeutic DBS. Anne Spieles-Engemann and colleagues discuss the predictive validity of the effects of STN stimulation in 6-OHDA-lesioned rats, a major model of PD. They emphasize the necessity of studying long-term effects of STN DBS in animal models, notably to identify confounding effects of lesions caused by the 2

4 implanted electrodes. Furthermore, they stress the importance of studying potential neuroprotective effects of DBS in the STN. Finally, these authors provide convincing arguments for applying a clinicallike approach in well-established rodent models of neurological disorders, offering a most favorable preclinical experimental platform. Romulo Fuentes and colleagues have developed spinal cord stimulation in rodent models of PD as a less invasive neurosurgical procedure than conventional DBS in the STN. This procedure is thought to activate ascending pathways reaching brainstem, thalamic nuclei and the cerebral cortex. The thalamic nuclei that are most strongly activated upon spinal cord stimulation differ from those activated by STN DBS. Unexpectedly, however, both strategies appear to provide comparable outcomes. Clement Hamani and Jose Nobrega review encouraging clinical and fundamental findings on DBS against depression, highlighting the involvement of cortical/limbic-striatal-pallidal-thalamic circuits. Although the homology of prefrontal cortical regions across phylogeny remains controversial, the authors carefully emphasize features relevant for the translation of data from animal models to patients. William Haynes and Luc Mallet discuss the application of DBS to obsessive-compulsive disorders (OCD). About 25% of OCD patients present severe intractable symptoms. In PD patients with OCD comorbidity, STN high-frequency DBS has been observed to reduce their compulsions and obsessions. The authors present the theory of a dysfunctional basal ganglia-thalamocortical loop and its associative and limbic components, which may include promising targets for DBS. Interestingly, in rodent models based on dopaminergic D2/D3 receptors hyperactivity, STN DBS induces a reproducible but transient reduction of compulsive symptoms without affecting locomotion. Marwan Hariz and Mary Robertson critically review all published studies on the use of DBS against Gilles de la Tourette Syndrome (GTS) in nine different brain targets in the thalamus, basal ganglia and cortical white matter. They state Only two studies on very few patients fulfill some of the evidencebased criteria. The authors further stress that these empirical experiences reflect the complexity of the neural mechanisms underlying GTS. In severe GTS patients that are refractory to pharmaco-therapies, DBS appears promising if applied by experienced neurosurgeons working in GTS clinic centers. Sudhin Shah and Nicholas Schiff review a history of efforts regarding the use of thalamic DBS in severely brain-injured patients, with the aim to improve their cognitive abilities. They point out several 3

5 potential, short-term and long-term plastic mechanisms in cortico-striatopallidal-thalamocortical and corticothalamic networks, which might underlie such DBS-induced pro-cognitive action. Intrathalamic DBS is inspired by Moruzzi and Magoun s (1949) conceptualization of ascending activating systems. Takamitsu Yamamoto and colleagues convincingly demonstrate the importance of electrophysiological criteria, obtained by recording the EEG and evoked responses, to select patients in a vegetative state (VS) for DBS therapy. Such VS patients (21 out of 107) were stimulated in the mesencephalic reticular formation or in the centromedian/parafascicularis nucleus complex and followed for over 10 years. Eight of these patients recovered from VS and were able to respond to verbal commands. These authors approach likewise is informed by Moruzzi and Magoun s theory (1949). Indeed, in VS patients TC functions are more disturbed than brainstem functions, and TC systems are central in maintaining consciousness. DBS elicits an arousal response immediately after the beginning of the stimulation but recovery from VS is not observed before 4 months along with an intensive care follow up. The authors stress that the DBS-related recovery should be accompanied by a specific neuro-rehabilitation program for facilitate the recovery of motor function. Finally, Jens Clausen highlights ethical concerns about the growing use of DBS as a symptomatic treatment. Ethical issues arise at all stages, even during the neurosurgical implantation of the stimulating electrode. Also, it is important to take into account familial and social aspects, which are stimulating and thus important for the overall well-being of the patient. Clausen also points out that the therapeutic as well as the adverse effects of DBS may be influenced by variables associated with the quality of the intensive care. The therapeutic uses of DBS presently are studied intensively. Clinical studies in Parkinson s and Alzheimer s diseases are underway ( Technical developments are sought to minimize or circumvent current problems of DBS, notably the risks associated with invasive procedures, lesions caused by electrode implantation, and non-specific stimulation of axons en passage. Noninvasive approaches include transcranial magnetic resonance-guided high-intensity focused ultrasound beams for non-invasive brain neurosurgery (Martin et al., 2009). With this approach, targeted lesions are safely and reliably achieved in fully awaked patients, with minimal risk of bleeding and free of collateral damages to non-targeted structures. Another possibility, currently at the stage of preclinical research, is light DBS, an integrated fiber optic and optogenetic technology that allows stimulation of the axonal 4

6 and/or somatodendritic compartments of a selected neuronal population expressing light sensitive channels upon viral transfection (Aravanis et al., 2007; Gradinaru et al., 2009; Zhang et al., 2007). As a result, light DBS is hoped to generate patterns of neural activity that alleviate the symptoms of neurological diseases. ACKNOWLEDGEMENTS I sincerely thank all the scientists, clinicians and colleagues who contributed excellently to this Special Feature on DBS. This Special Feature would not have been possible without the support by Neurex ( which has generously helped us organizing the 2010 European workshop on DBS ( I would also like to acknowledge all colleagues who have significantly contributed to research on DBS, and especially those who have not been quoted here. 5

7 REFERENCES Aravanis,A.M., Wang,L.P., Zhang,F., Meltzer,L.A., Mogri,M.Z., Schneider,M.B. & Deisseroth,K. (2007) An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology. J.Neural Eng, 4, S143-S156. Benabid,A.L., Pollak,P., Gervason,C., Hoffmann,D., Gao,D.M., Hommel,M., Perret,J.E. & de Rougemont,J. (1991) Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet, 337, Benabid,A.L., Pollak,P., Louveau,A., Henry,S. & de Rougemont,J. (1987) Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Appl.Neurophysiol., 50, Gradinaru,V., Mogri,M., Thompson,K.R., Henderson,J.M. & Deisseroth,K. (2009) Optical deconstruction of parkinsonian neural circuitry. Science, 324, Martin,E., Jeanmonod,D., Morel,A., Zadicario,E. & Werner,B. (2009) High-intensity focused ultrasound for noninvasive functional neurosurgery. Ann.Neurol., 66, Miocinovic,S., Zhang,J., Xu,W., Russo,G.S., Vitek,J.L. & McIntyre,C.C. (2007) Stereotactic neurosurgical planning, recording, and visualization for deep brain stimulation in non-human primates. J.Neurosci.Methods, 162, Moruzzi,G. & Magoun,H.W. (1949) Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol. 1: Zhang,F., Aravanis,A.M., Adamantidis,A., de Lecea,L. & Deisseroth,K. (2007) Circuit-breakers: optical technologies for probing neural signals and systems. Nat.Rev.Neurosci., 8,

8 FIGURE LEGENDS FIG. 1. Stereotaxic insertion of an electrode for therapeutic, electrical deep brain stimulation in a patient with end-stage Parkinson's disease. The DBS electrode is introduced in the brain using a micromanipulator (on the top) guided by a high-resolution neuronavigator. GNU Free Documentation License. 7