MRI-guided focused ultrasound thalamotomy reduced hand tremor in patients with essential tremor. Side effects included sensory and gait disturbances. (Funded by InSightec and others; ClinicalTrials.gov number, NCT01827904.).

The clinical use of deep brain stimulation (DBS) is among the most important advances in the clinical neurosciences in the past two decades. As a surgical tool, DBS can directly measure pathological brain activity and can deliver adjustable stimulation for therapeutic effect in neurological and psychiatric disorders correlated with dysfunctional circuitry. The development of DBS has opened new opportunities to access and interrogate malfunctioning brain circuits and to test the therapeutic potential of regulating the output of these circuits in a broad range of disorders. Despite the success and rapid adoption of DBS, crucial questions remain, including which brain areas should be targeted and in which patients. This Review considers how DBS has facilitated advances in our understanding of how circuit malfunction can lead to brain disorders and outlines the key unmet challenges and future directions in the DBS field. Determining the next steps in DBS science will help to define the future role of this technology in the development of novel therapeutics for the most challenging disorders affecting the human brain.

Competing interestsJ. K. K. is a consultant for Medtronic and Boston Scientific. P. B. is a consultant for Medtronic. W. M. G. is the Director, Chief Scientific Officer and share owner of Deep Brain Innovations, LLC. He also receives royalty payments for licensed patents on temporal patterns of deep brain stimulation. M. I. H. has received travel expenses and honoraria from Boston Scientific for speaking at meetings. A. H. was supported by the German Research Council (DFG grant 410169619) and reports lecture fees from Medtronic and Boston Scientific unrelated to the present work. P. A. T. works as a consultant for Boston Scientific Neuromodulation. J. V. works as a consultant to Boston Scientific, Medtronic, and Newronika and has received honoraria for lectures from Boston Scientific and Medtronic as well as research grants from Boston Scientific and Medtronic. A. M. L. has served as a consultant for Boston Scientific, Medtronic, Aleva, and Abbott and is a co-founder of Functional Neuromodulation. All other authors declare no competing interests. Peer review informationNature Reviews Neurology thanks V. Visser-Vandewalle and Y. Temel for their contribution to the peer review of this work. Publisher's noteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

We developed a method for the efficient generation of functional dopaminergic (DA) neurons from human embryonic stem cells (hESCs) on a large scale. The most unique feature of this method is the generation of homogeneous spherical neural masses (SNMs) from the hESC-derived neural precursors. These SNMs provide several advantages: (i) they can be passaged for a long time without losing their differentiation capability into DA neurons; (ii) they can be coaxed into DA neurons at much higher efficiency than that from previous reports (86% tyrosine hydroxylase-positive neurons/total neurons); (iii) the induction of DA neurons from SNMs only takes 14 days; and (iv) no feeder cells are required during differentiation. These advantages allowed us to obtain a large number of DA neurons within a short time period and minimized potential contamination of unwanted cells or pathogens coming from the feeder layer. The highly efficient differentiation may not only enhance the efficacy of the cell therapy but also reduce the potential tumor formation from the undifferentiated residual hESCs. In line with this effect, we have never observed any tumor formation from the transplanted animals used in our study. When grafted into a parkinsonian rat model, the hESC-derived DA neurons elicited clear behavioral recovery in three behavioral tests. In summary, our study paves the way for the large-scale generation of purer and functional DA neurons for future clinical applications.is a neurodegenerative disorder characterized by progressive and selective loss of dopaminergic (DA) neurons in the midbrain substantia nigra (1). Currently, the prevailing strategy for the treatment of PD is pharmacological. However, pharmacological treatment with L-DOPA works initially, but over time, the effectiveness of L-DOPA wanes and side effects develop (2). An alternative approach may be the transplantation of DA-synthesizing cells. One source of DA-synthesizing cells is embryonic stem cells (ESCs). ESCs are pluripotent and capable of self-renewal (3-5). For the purpose of applying the ESCs to PD, many researchers have tried to develop protocols by which ESCs from some species can differentiate into DA neuronal phenotypes (6-11). Although some progress has been made in the generation of DA neurons from human ESCs (hESCs) (12-22), there are still many technical improvements to be made before the application of hESCs to treat PD. Examples include increasing the purity of DA neurons, supplying a sufficient quantity of DA neurons for clinical applications, decreasing tumor formation after transplantation, and clearly demonstrating the functionality of hESC-derived DA neurons in a parkinsonian animal model.Here, we introduce a method that allows us to differentiate hESCs into functional tyrosine hydroxylase-positive (TH ϩ ) neurons up to near 86% of the total hESC-derived neurons, which is the highest purity ever reported. Achieving high efficiency of DA neuronal derivation is an important issue in cell therapy, because it would not only increase the effica...