Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Deep brain stimulation: current challenges and future directions

Abstract

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.

Key points

  • Deep brain stimulation (DBS) is opening new therapeutic possibilities for neurological and psychiatric disorders.

  • DBS is enabling neuroscientists to obtain direct measures of cellular activity and to probe the function of neural circuits.

  • The delivery of DBS at precise locations and the wide range of stimulation parameters available enable unprecedented temporal and spatial control of brain circuits.

  • The mechanisms of action of DBS at the cell, molecular and systems level are poorly understood and much work remains to be done.

  • The ethical issues presented by the application of DBS in new patient populations and for new indications require careful consideration.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Deep brain stimulation mechanisms.

Similar content being viewed by others

References

  1. Lozano, A. M. & Lipsman, N. Probing and regulating dysfunctional circuits using deep brain stimulation. Neuron 77, 406–424 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Kuhn, A. A. et al. High-frequency stimulation of the subthalamic nucleus suppresses oscillatory beta activity in patients with Parkinson’s disease in parallel with improvement in motor performance. J. Neurosci. 28, 6165–6173 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lipsman, N. et al. Subcallosal cingulate deep brain stimulation for treatment-refractory anorexia nervosa: a phase 1 pilot trial. Lancet 381, 1361–1370 (2013).

    Article  PubMed  Google Scholar 

  4. Laxton, A. W. et al. A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease. Ann. Neurol. 68, 521–534 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Ballanger, B. et al. Cerebral blood flow changes induced by pedunculopontine nucleus stimulation in patients with advanced Parkinson’s disease: a [(15)O] H2O PET study. Hum. Brain Mapp. 30, 3901–3909 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Nuttin, B. et al. Consensus on guidelines for stereotactic neurosurgery for psychiatric disorders. J. Neurol. Neurosurg. Psychiatry 85, 1003–1008 (2014).

    Article  PubMed  Google Scholar 

  7. Schuepbach, W. M. et al. Neurostimulation for Parkinson’s disease with early motor complications. N. Engl. J. Med. 368, 610–622 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Follett, K. A. et al. Pallidal versus subthalamic deep-brain stimulation for Parkinson’s disease. N. Engl. J. Med. 362, 2077–2091 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Eisenstein, S. A. et al. Acute changes in mood induced by subthalamic deep brain stimulation in Parkinson disease are modulated by psychiatric diagnosis. Brain Stimul. 7, 701–708 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Merola, A. et al. Impulse control behaviors and subthalamic deep brain stimulation in Parkinson disease. J. Neurol. 264, 40–48 (2017).

    Article  CAS  PubMed  Google Scholar 

  11. Ashkan, K., Rogers, P., Bergman, H. & Ughratdar, I. Insights into the mechanisms of deep brain stimulation. Nat. Rev. Neurol. 13, 548–554 (2017).

    Article  PubMed  Google Scholar 

  12. McIntyre, C. C. & Anderson, R. W. Deep brain stimulation mechanisms: the control of network activity via neurochemistry modulation. J. Neurochem. 139 (Suppl. 1), 338–345 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Groome, J. R. The voltage sensor module in sodium channels. Handb. Exp. Pharmacol. 221, 7–31 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. Bucher, D. & Goaillard, J. M. Beyond faithful conduction: short-term dynamics, neuromodulation, and long-term regulation of spike propagation in the axon. Prog. Neurobiol. 94, 307–346 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Miocinovic, S. et al. Computational analysis of subthalamic nucleus and lenticular fasciculus activation during therapeutic deep brain stimulation. J. Neurophysiol. 96, 1569–1580 (2006).

    Article  PubMed  Google Scholar 

  16. Llinas, R. R., Leznik, E. & Urbano, F. J. Temporal binding via cortical coincidence detection of specific and nonspecific thalamocortical inputs: a voltage-dependent dye-imaging study in mouse brain slices. Proc. Natl Acad. Sci. USA 99, 449–454 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rosenbaum, R. et al. Axonal and synaptic failure suppress the transfer of firing rate oscillations, synchrony and information during high frequency deep brain stimulation. Neurobiol. Dis. 62, 86–99 (2014).

    Article  PubMed  Google Scholar 

  18. Lindner, B., Gangloff, D., Longtin, A. & Lewis, J. E. Broadband coding with dynamic synapses. J. Neurosci. 29, 2076–2088 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Montgomery, E. B. Jr & Baker, K. B. Mechanisms of deep brain stimulation and future technical developments. Neurol. Res. 22, 259–266 (2000).

    Article  PubMed  Google Scholar 

  20. Grill, W. M., Snyder, A. N. & Miocinovic, S. Deep brain stimulation creates an informational lesion of the stimulated nucleus. Neuroreport 15, 1137–1140 (2004).

    Article  PubMed  Google Scholar 

  21. Agnesi, F., Johnson, M. D. & Vitek, J. L. Deep brain stimulation: how does it work? Handb. Clin. Neurol. 116, 39–54 (2013).

    Article  PubMed  Google Scholar 

  22. Zimnik, A. J., Nora, G. J., Desmurget, M. & Turner, R. S. Movement-related discharge in the macaque globus pallidus during high-frequency stimulation of the subthalamic nucleus. J. Neurosci. 35, 3978–3989 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wichmann, T. & DeLong, M. R. Deep brain stimulation for movement disorders of basal ganglia origin: restoring function or functionality? Neurotherapeutics 13, 264–283 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Rivlin-Etzion, M., Elias, S., Heimer, G. & Bergman, H. Computational physiology of the basal ganglia in Parkinson’s disease. Prog. Brain Res. 183, 259–273 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Cagnan, H. et al. Frequency-selectivity of a thalamocortical relay neuron during Parkinson’s disease and deep brain stimulation: a computational study. Eur. J. Neurosci. 30, 1306–1317 (2009).

    Article  PubMed  Google Scholar 

  26. Guo, Y., Rubin, J. E., McIntyre, C. C., Vitek, J. L. & Terman, D. Thalamocortical relay fidelity varies across subthalamic nucleus deep brain stimulation protocols in a data-driven computational model. J. Neurophysiol. 99, 1477–1492 (2008).

    Article  PubMed  Google Scholar 

  27. Moran, A., Stein, E., Tischler, H. & Bar-Gad, I. Decoupling neuronal oscillations during subthalamic nucleus stimulation in the parkinsonian primate. Neurobiol. Dis. 45, 583–590 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Rubin, J. E. & Terman, D. High frequency stimulation of the subthalamic nucleus eliminates pathological thalamic rhythmicity in a computational model. J. Comput. Neurosci. 16, 211–235 (2004).

    Article  Google Scholar 

  29. Eusebio, A. et al. Resonance in subthalamo-cortical circuits in Parkinson’s disease. Brain 132, 2139–2150 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Hahn, G., Bujan, A. F., Fregnac, Y., Aertsen, A. & Kumar, A. Communication through resonance in spiking neuronal networks. PLOS Comput. Biol. 10, e1003811 (2014).

    Article  CAS  Google Scholar 

  31. Wilson, C. J., Beverlin, B. II & Netoff, T. Chaotic desynchronization as the therapeutic mechanism of deep brain stimulation. Front. Syst. Neurosci. 5, 50 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Guridi, J. & Alegre, M. Oscillatory activity in the basal ganglia and deep brain stimulation. Mov. Disord. 32, 64–69 (2017).

    Article  PubMed  Google Scholar 

  33. Tass, P. A. & Majtanik, M. Long-term anti-kindling effects of desynchronizing brain stimulation: a theoretical study. Biol. Cybern. 94, 58–66 (2006).

    Article  PubMed  Google Scholar 

  34. Gondard, E. et al. Rapid modulation of protein expression in the rat hippocampus following deep brain stimulation of the fornix. Brain Stimul. 8, 1058–1064 (2015).

    Article  PubMed  Google Scholar 

  35. International Basal Ganglia Society. The Basal Ganglia II: Structure and Function: Current Concepts (eds Carpenter, M. B. & Jayaraman, A.) (Plenum Press, 1987).

  36. Aziz, T. Z., Peggs, D., Sambrook, M. A. & Crossman, A. R. Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate. Mov. Disord. 6, 288–292 (1991).

    Article  CAS  PubMed  Google Scholar 

  37. Bergman, H., Wichmann, T. & DeLong, M. R. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 249, 1436–1438 (1990).

    Article  CAS  PubMed  Google Scholar 

  38. Benabid, A. L., Pollak, P., Louveau, A., Henry, S. & de Rougemont, J. Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Appl. Neurophysiol. 50, 344–346 (1987).

    CAS  PubMed  Google Scholar 

  39. Benazzouz, A., Gross, C., Feger, J., Boraud, T. & Bioulac, B. Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys. Eur. J. Neurosci. 5, 382–389 (1993).

    Article  CAS  PubMed  Google Scholar 

  40. Mirski, M. A. & Ferrendelli, J. A. Interruption of the mammillothalamic tract prevents seizures in guinea pigs. Science 226, 72–74 (1984).

    Article  CAS  PubMed  Google Scholar 

  41. Mirski, M. A. & Fisher, R. S. Electrical stimulation of the mammillary nuclei increases seizure threshold to pentylenetetrazol in rats. Epilepsia 35, 1309–1316 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. Mirski, M. A., Rossell, L. A., Terry, J. B. & Fisher, R. S. Anticonvulsant effect of anterior thalamic high frequency electrical stimulation in the rat. Epilepsy Res. 28, 89–100 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Fisher, R. et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 51, 899–908 (2010).

    Article  PubMed  Google Scholar 

  44. Devergnas, A. et al. The subcortical hidden side of focal motor seizures: evidence from micro-recordings and local field potentials. Brain 135, 2263–2276 (2012).

    Article  PubMed  Google Scholar 

  45. Hamani, C. & Temel, Y. Deep brain stimulation for psychiatric disease: contributions and validity of animal models. Sci. Transl Med. 4, 142rv148 (2012).

    Article  Google Scholar 

  46. Morishita, T., Fayad, S. M., Higuchi, M. A., Nestor, K. A. & Foote, K. D. Deep brain stimulation for treatment-resistant depression: systematic review of clinical outcomes. Neurotherapeutics 11, 475–484 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lim, L. W. et al. Electrical stimulation alleviates depressive-like behaviors of rats: investigation of brain targets and potential mechanisms. Transl Psychiatry 5, e535 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mayberg, H. S. Limbic-cortical dysregulation: a proposed model of depression. J. Neuropsychiatry Clin. Neurosci. 9, 471–481 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Mayberg, H. S. et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am. J. Psychiatry 156, 675–682 (1999).

    CAS  PubMed  Google Scholar 

  50. Baup, N. et al. High-frequency stimulation of the anterior subthalamic nucleus reduces stereotyped behaviors in primates. J. Neurosci. 28, 8785–8788 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tan, S. K. et al. A combined in vivo neurochemical and electrophysiological analysis of the effect of high-frequency stimulation of the subthalamic nucleus on 5-HT transmission. Exp. Neurol. 233, 145–153 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Temel, Y. et al. Inhibition of 5-HT neuron activity and induction of depressive-like behavior by high-frequency stimulation of the subthalamic nucleus. Proc. Natl Acad. Sci. USA 104, 17087–17092 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Janssen, M. L. et al. Cortico-subthalamic inputs from the motor, limbic, and associative areas in normal and dopamine-depleted rats are not fully segregated. Brain Struct. Funct. 222, 2473–2485 (2016).

    Article  PubMed  CAS  Google Scholar 

  54. Temel, Y. & Jahanshahi, A. Neuroscience. Treating brain disorders with neuromodulation. Science 347, 1418–1419 (2015).

    Article  PubMed  Google Scholar 

  55. Jourdain, V. A. & Schechtmann, G. Health economics and surgical treatment for Parkinson’s disease in a world perspective: results from an international survey. Stereotact. Funct. Neurosurg. 92, 71–79 (2014).

    Article  PubMed  Google Scholar 

  56. Youngerman, B. E., Chan, A. K., Mikell, C. B., McKhann, G. M. & Sheth, S. A. A decade of emerging indications: deep brain stimulation in the United States. J. Neurosurg. 125, 461–471 (2016).

    Article  PubMed  Google Scholar 

  57. Ineichen, C. & Christen, M. Analyzing 7000 texts on deep brain stimulation: what do they tell us? Front. Integr. Neurosci. 9, 52 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Schnurman, Z. & Kondziolka, D. Evaluating innovation. Part 1: the concept of progressive scholarly acceptance. J. Neurosurg. 124, 207–211 (2016).

    Article  PubMed  Google Scholar 

  59. Deuschl, G. et al. Stimulation of the subthalamic nucleus at an earlier disease stage of Parkinson’s disease: concept and standards of the EARLYSTIM-study. Parkinsonism Relat. Disord. 19, 56–61 (2013).

    Article  PubMed  Google Scholar 

  60. Odekerken, V. J. et al. GPi versus STN deep brain stimulation for Parkinson disease: three-year follow-up. Neurology 86, 755–761 (2016).

    Article  CAS  PubMed  Google Scholar 

  61. Rizzone, M. G. et al. Long-term outcome of subthalamic nucleus DBS in Parkinson’s disease: from the advanced phase towards the late stage of the disease? Parkinsonism Relat. Disord. 20, 376–381 (2014).

    Article  CAS  PubMed  Google Scholar 

  62. Rodriguez-Oroz, M. C., Moro, E. & Krack, P. Long-term outcomes of surgical therapies for Parkinson’s disease. Mov. Disord. 27, 1718–1728 (2012).

    Article  PubMed  Google Scholar 

  63. Fasano, A. & Lang, A. E. Unfreezing of gait in patients with Parkinson’s disease. Lancet Neurol. 14, 675–677 (2015).

    Article  PubMed  Google Scholar 

  64. Hamani, C. et al. Pedunculopontine nucleus region deep brain stimulation in Parkinson disease: surgical anatomy and terminology. Stereotact. Funct. Neurosurg. 94, 298–306 (2016).

    Article  PubMed  Google Scholar 

  65. Hacker, M. L. et al. Deep brain stimulation may reduce the relative risk of clinically important worsening in early stage Parkinson’s disease. Parkinsonism Relat. Disord. 21, 1177–1183 (2015).

    Article  PubMed  Google Scholar 

  66. DeLong, M. R. et al. Effect of advancing age on outcomes of deep brain stimulation for Parkinson disease. JAMA Neurol. 71, 1290–1295 (2014).

    Article  PubMed  Google Scholar 

  67. Krauss, J. K., Pohle, T., Weber, S., Ozdoba, C. & Burgunder, J. M. Bilateral stimulation of globus pallidus internus for treatment of cervical dystonia. Lancet 354, 837–838 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Volkmann, J. et al. Pallidal neurostimulation in patients with medication-refractory cervical dystonia: a randomised, sham-controlled trial. Lancet Neurol. 13, 875–884 (2014).

    Article  PubMed  Google Scholar 

  69. Kupsch, A. et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N. Engl. J. Med. 355, 1978–1990 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Andrews, C., Aviles-Olmos, I., Hariz, M. & Foltynie, T. Which patients with dystonia benefit from deep brain stimulation? A metaregression of individual patient outcomes. J. Neurol. Neurosurg. Psychiatry 81, 1383–1389 (2010).

    Article  PubMed  Google Scholar 

  71. Isaias, I. U. et al. Factors predicting protracted improvement after pallidal DBS for primary dystonia: the role of age and disease duration. J. Neurol. 258, 1469–1476 (2011).

    Article  PubMed  Google Scholar 

  72. Lumsden, D. E. et al. Proportion of life lived with dystonia inversely correlates with response to pallidal deep brain stimulation in both primary and secondary childhood dystonia. Dev. Med. Child Neurol. 55, 567–574 (2013).

    Article  PubMed  Google Scholar 

  73. Panov, F. et al. Pallidal deep brain stimulation for DYT6 dystonia. J. Neurol. Neurosurg. Psychiatry 83, 182–187 (2012).

    Article  PubMed  Google Scholar 

  74. Jinnah, H. A. et al. Deep brain stimulation for dystonia: a novel perspective on the value of genetic testing. J. Neural Transm. (Vienna) 124, 417–430 (2017).

    Article  CAS  Google Scholar 

  75. Moro, E. et al. Efficacy of pallidal stimulation in isolated dystonia: a systematic review and meta-analysis. Eur. J. Neurol. 24, 552–560 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Blahak, C. et al. Micrographia induced by pallidal DBS for segmental dystonia: a subtle sign of hypokinesia? J. Neural Transm. (Vienna) 118, 549–553 (2011).

    Article  Google Scholar 

  77. Schrader, C. et al. GPi-DBS may induce a hypokinetic gait disorder with freezing of gait in patients with dystonia. Neurology 77, 483–488 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Ostrem, J. L. et al. Subthalamic nucleus deep brain stimulation in primary cervical dystonia. Neurology 76, 870–878 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Loher, T. J., Pohle, T. & Krauss, J. K. Functional stereotactic surgery for treatment of cervical dystonia: review of the experience from the lesional era. Stereotact. Funct. Neurosurg. 82, 1–13 (2004).

    Article  PubMed  Google Scholar 

  80. Pauls, K. A. et al. Deep brain stimulation in the ventrolateral thalamus/subthalamic area in dystonia with head tremor. Mov. Disord. 29, 953–959 (2014).

    Article  PubMed  Google Scholar 

  81. Ruge, D. et al. Deep brain stimulation effects in dystonia: time course of electrophysiological changes in early treatment. Mov. Disord. 26, 1913–1921 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Grips, E. et al. Patterns of reoccurrence of segmental dystonia after discontinuation of deep brain stimulation. J. Neurol. Neurosurg. Psychiatry 78, 318–320 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Cif, L. et al. The influence of deep brain stimulation intensity and duration on symptoms evolution in an OFF stimulation dystonia study. Brain Stimul. 6, 500–505 (2013).

    Article  PubMed  Google Scholar 

  84. Vidailhet, M., Grabli, D. & Roze, E. Pathophysiology of dystonia. Curr. Opin. Neurol. 22, 406–413 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Gimeno, H. & Lin, J. P. The International Classification of Functioning (ICF) to evaluate deep brain stimulation neuromodulation in childhood dystonia-hyperkinesia informs future clinical & research priorities in a multidisciplinary model of care. Eur. J. Paediatr. Neurol. 21, 147–167 (2017).

    Article  PubMed  Google Scholar 

  86. Austin, A., Lin, J. P., Selway, R., Ashkan, K. & Owen, T. What parents think and feel about deep brain stimulation in paediatric secondary dystonia including cerebral palsy: a qualitative study of parental decision-making. Eur. J. Paediatr. Neurol. 21, 185–192 (2017).

    Article  PubMed  Google Scholar 

  87. Hariz, M. I. et al. Multicentre European study of thalamic stimulation for parkinsonian tremor: a 6 year follow-up. J. Neurol. Neurosurg. Psychiatry 79, 694–699 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Schuurman, P. R., Bosch, D. A., Merkus, M. P. & Speelman, J. D. Long-term follow-up of thalamic stimulation versus thalamotomy for tremor suppression. Mov. Disord. 23, 1146–1153 (2008).

    Article  PubMed  Google Scholar 

  89. Elias, W. J. et al. A randomized trial of focused ultrasound thalamotomy for essential tremor. N. Engl. J. Med. 375, 730–739 (2016).

    Article  PubMed  Google Scholar 

  90. Oliveria, S. F. et al. Safety and efficacy of dual-lead thalamic deep brain stimulation for patients with treatment-refractory multiple sclerosis tremor: a single-centre, randomised, single-blind, pilot trial. Lancet Neurol. 16, 691–700 (2017).

    Article  PubMed  Google Scholar 

  91. Vandewalle, V., van der Linden, C., Groenewegen, H. J. & Caemaert, J. Stereotactic treatment of Gilles de la Tourette syndrome by high frequency stimulation of thalamus. Lancet 353, 724 (1999).

    Article  CAS  PubMed  Google Scholar 

  92. Baldermann, J. C. et al. Deep brain stimulation for Tourette-syndrome: a systematic review and meta-analysis. Brain Stimul. 9, 296–304 (2016).

    Article  PubMed  Google Scholar 

  93. Welter, M. L. et al. Anterior pallidal deep brain stimulation for Tourette’s syndrome: a randomised, double-blind, controlled trial. Lancet Neurol. 16, 610–619 (2017).

    Article  PubMed  Google Scholar 

  94. Levy, R., Deer, T. R. & Henderson, J. Intracranial neurostimulation for pain control: a review. Pain Physician 13, 157–165 (2010).

    PubMed  Google Scholar 

  95. Boccard, S. G., Pereira, E. A., Moir, L., Aziz, T. Z. & Green, A. L. Long-term outcomes of deep brain stimulation for neuropathic pain. Neurosurgery 72, 221–230; discussion 231 (2013).

    Article  PubMed  Google Scholar 

  96. Boccard, S. G. J. et al. Long-term results of deep brain stimulation of the anterior cingulate cortex for neuropathic pain. World Neurosurg. 106, 625–637 (2017).

    Article  PubMed  Google Scholar 

  97. Velasco, F. et al. Deep brain stimulation for treatment of the epilepsies: the centromedian thalamic target. Acta Neurochir. Suppl. 97, 337–342 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Salanova, V. et al. Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy. Neurology 84, 1017–1025 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Jobst, B. C. et al. Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas. Epilepsia 58, 1005–1014 (2017).

    Article  PubMed  Google Scholar 

  100. Eitan, R. et al. One year double blind study of high versus low frequency subcallosal cingulate stimulation for depression. J. Psychiatr. Res. 96, 124–134 (2018).

    Article  PubMed  Google Scholar 

  101. Blair-West, G. W., Cantor, C. H., Mellsop, G. W. & Eyeson-Annan, M. L. Lifetime suicide risk in major depression: sex and age determinants. J. Affect. Disord. 55, 171–178 (1999).

    Article  CAS  Google Scholar 

  102. Whiteford, H. A. et al. Estimating remission from untreated major depression: a systematic review and meta-analysis. Psychol. Med. 43, 1569–1585 (2013).

    Article  CAS  PubMed  Google Scholar 

  103. Hamani, C. et al. The subcallosal cingulate gyrus in the context of major depression. Biol. Psychiatry 69, 301–308 (2011).

    Article  PubMed  Google Scholar 

  104. Mayberg, H. S. et al. Deep brain stimulation for treatment-resistant depression. Neuron 45, 651–660 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Aouizerate, B. et al. Deep brain stimulation of the ventral caudate nucleus in the treatment of obsessive-compulsive disorder and major depression. Case report. J. Neurosurg. 101, 682–686 (2004).

    PubMed  Google Scholar 

  106. Sartorius, A. et al. Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient. Biol. Psychiatry 67, e9–e11 (2010).

    Article  PubMed  Google Scholar 

  107. Coenen, V. A., Panksepp, J., Hurwitz, T. A., Urbach, H. & Madler, B. Human medial forebrain bundle (MFB) and anterior thalamic radiation (ATR): imaging of two major subcortical pathways and the dynamic balance of opposite affects in understanding depression. J. Neuropsychiatry Clin. Neurosci. 24, 223–236 (2012).

    Article  PubMed  Google Scholar 

  108. Kennedy, S. H. et al. Deep brain stimulation for treatment-resistant depression: follow-up after 3 to 6 years. Am. J. Psychiatry 168, 502–510 (2011).

    Article  PubMed  Google Scholar 

  109. Holtzheimer, P. E. et al. Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. Lancet Psychiatry 4, 839–849 (2017).

    Article  PubMed  Google Scholar 

  110. Dougherty, D. D. et al. A randomized sham-controlled trial of deep brain stimulation of the ventral capsule/ventral striatum for chronic treatment-resistant depression. Biol. Psychiatry 78, 240–248 (2015).

    Article  PubMed  Google Scholar 

  111. Bewernick, B. & Schlaepfer, T. E. Update on neuromodulation for treatment-resistant depression. F1000Res 4, 1389 (2015).

    Article  Google Scholar 

  112. Gippert, S. M. et al. Deep brain stimulation for bipolar disorder-review and outlook. CNS Spectrums 22, 254–257 (2017).

    Article  PubMed  Google Scholar 

  113. Nuttin, B., Cosyns, P., Demeulemeester, H., Gybels, J. & Meyerson, B. Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder. Lancet 354, 1526 (1999).

    Article  CAS  PubMed  Google Scholar 

  114. Denys, D. et al. Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder. Arch. Gen. Psychiatry 67, 1061–1068 (2010).

    Article  PubMed  Google Scholar 

  115. Greenberg, B. D. et al. Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience. Mol. Psychiatry 15, 64–79 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Sturm, V. et al. The nucleus accumbens: a target for deep brain stimulation in obsessive-compulsive- and anxiety-disorders. J. Chem. Neuroanat. 26, 293–299 (2003).

    Article  PubMed  Google Scholar 

  117. Raymaekers, S. et al. Long-term electrical stimulation of bed nucleus of stria terminalis for obsessive-compulsive disorder. Mol. Psychiatry 22, 931–934 (2017).

    Article  CAS  PubMed  Google Scholar 

  118. Mallet, L. et al. Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. N. Engl. J. Med. 359, 2121–2134 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. Bewernick, B. H. et al. Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol. Psychiatry 67, 110–116 (2010).

    Article  PubMed  Google Scholar 

  120. Malone, D. A. Jr et al. Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol. Psychiatry 65, 267–275 (2009).

    Article  PubMed  Google Scholar 

  121. Coenen, V. A. et al. The medial forebrain bundle as a target for deep brain stimulation for obsessive-compulsive disorder. CNS Spectr. 22, 282–289 (2017).

    Article  PubMed  Google Scholar 

  122. Lipsman, N. et al. Deep brain stimulation of the subcallosal cingulate for treatment-refractory anorexia nervosa: 1 year follow-up of an open-label trial. Lancet Psychiatry 4, 285–294 (2017).

    Article  PubMed  Google Scholar 

  123. Kuhn, J. et al. Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer’s dementia. Mol. Psychiatry 20, 353–360 (2015).

    Article  CAS  PubMed  Google Scholar 

  124. Lozano, A. M. et al. A phase II study of fornix deep brain stimulation in mild Alzheimer’s disease. J. Alzheimers Dis. 54, 777–787 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Pilitsis, J. G. et al. 124 low-back pain relief with a new 32-contact surgical lead and neural targeting algorithm. Neurosurgery 63 (Suppl. 1), 151 (2016).

    Article  Google Scholar 

  126. Sun, F. T. & Morrell, M. J. Closed-loop neurostimulation: the clinical experience. Neurotherapeutics 11, 553–563 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Deer, T. et al. Prospective, multicenter, randomized, double-blinded, partial crossover study to assess the safety and efficacy of the novel neuromodulation system in the treatment of patients with chronic pain of peripheral nerve origin. Neuromodulation 19, 91–100 (2016).

    Article  PubMed  Google Scholar 

  128. Schlaepfer, T. E. & Fins, J. J. Deep brain stimulation and the neuroethics of responsible publishing: when one is not enough. JAMA 303, 775–776 (2010).

    Article  CAS  PubMed  Google Scholar 

  129. Hamani, C. et al. Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Ann. Neurol. 63, 119–123 (2008).

    Article  PubMed  Google Scholar 

  130. Synofzik, M., Fins, J. J. & Schlaepfer, T. E. A neuromodulation experience registry for deep brain stimulation studies in psychiatric research: rationale and recommendations for implementation. Brain Stimul. 5, 653–655 (2012).

    Article  PubMed  Google Scholar 

  131. Fins, J. J. et al. Ethical guidance for the management of conflicts of interest for researchers, engineers and clinicians engaged in the development of therapeutic deep brain stimulation. J. Neural Eng. 8, 033001 (2011).

    Article  PubMed  Google Scholar 

  132. Rabins, P. et al. Scientific and ethical issues related to deep brain stimulation for disorders of mood, behavior, and thought. Arch. Gen. Psychiatry 66, 931–937 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Benazzouz, A. & Hallett, M. Mechanism of action of deep brain stimulation. Neurology 55, S13–S16 (2000).

    CAS  PubMed  Google Scholar 

  134. Jensen, A. L. & Durand, D. M. High frequency stimulation can block axonal conduction. Exp. Neurol. 220, 57–70 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Hashimoto, T., Elder, C. M., Okun, M. S., Patrick, S. K. & Vitek, J. L. Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons. J. Neurosci. 23, 1916–1923 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. McIntyre, C. C., Savasta, M., Kerkerian-Le Goff, L. & Vitek, J. L. Uncovering the mechanism(s) of action of deep brain stimulation: activation, inhibition, or both. Clin. Neurophysiol. 115, 1239–1248 (2004).

    Article  PubMed  Google Scholar 

  137. Urbano, F. J., Rosato-Siri, M. D. & Uchitel, O. D. Calcium channels involved in neurotransmitter release at adult, neonatal and P/Q-type deficient neuromuscular junctions. Mol. Membr. Biol. 19, 293–300 (2002).

    Article  CAS  PubMed  Google Scholar 

  138. Wichmann, T., Bergman, H. & DeLong, M. R. The primate subthalamic nucleus. III. Changes in motor behavior and neuronal activity in the internal pallidum induced by subthalamic inactivation in the MPTP model of parkinsonism. J. Neurophysiol. 72, 521–530 (1994).

    Article  CAS  PubMed  Google Scholar 

  139. Temel, Y. et al. Motor and cognitive improvement by deep brain stimulation in a transgenic rat model of Huntington’s disease. Neurosci. Lett. 406, 138–141 (2006).

    Article  CAS  PubMed  Google Scholar 

  140. van Kuyck, K., Brak, K., Das, J., Rizopoulos, D. & Nuttin, B. Comparative study of the effects of electrical stimulation in the nucleus accumbens, the mediodorsal thalamic nucleus and the bed nucleus of the stria terminalis in rats with schedule-induced polydipsia. Brain Res. 27, 93–99 (2008).

    Article  CAS  Google Scholar 

  141. Hamani, C. et al. Deep brain stimulation reverses anhedonic-like behavior in a chronic model of depression: role of serotonin and brain derived neurotrophic factor. Biol. Psychiatry 71, 30–35 (2012).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the World Society for Stereotactic and Functional Neurosurgery. It was coordinated together with the Research Committee of the World Society for Stereotactic and Functional Neurosurgery.

Review criteria

With the growing interest in deep brain stimulation (DBS) and its worldwide use, the leadership of the World Society for Stereotactic and Functional Neurosurgery (WSSFN) decided to address the manifold unanswered questions and unmet needs in this rapidly expanding field. To achieve this goal, the WSSFN produced this Review to outline the contemporary discussions, the challenges and the future directions in this area on the basis of a dedicated workshop, which was held 9–11 March 2017. The objective of the workshop was to identify the most pressing current and emerging challenges and unmet needs in the DBS field. Participants from different disciplines were chosen on the basis of their special expertise in neuroscience, neurology, neurosurgery or psychiatry. Specific sections were assigned to two experts, respectively, and the assembled text was then discussed by the whole group during an intensive 2.5-day workshop. Discussion centred around several key topics, including the current clinical status of DBS, the role of preclinical models, emerging science surrounding DBS mechanisms and the role of DBS in motor and non-motor conditions. Additional topics included the ethical challenges surrounding the application of DBS in neurology and psychiatry as well as emerging trends and future directions of the field. The manuscript then underwent several modifications over the next few months until consensus with regard to both relevance and content was reached among the authors.

Author information

Authors and Affiliations

Authors

Contributions

All authors researched data for the article, contributed substantially to discussion of content, contributed to writing of the manuscript and undertook review and/or editing of the manuscript before submission. A.M.L., N.L. and J.K.K. provided overall guidance and oversight of the group writing and review process.

Corresponding author

Correspondence to Andres M. Lozano.

Ethics declarations

Competing interests

A.M.L. is a consultant to Medtronic, Abbott (formerly St. Jude) and Boston Scientific and is Scientific Director of Functional Neuromodulation. H.B. has received honoraria for speaking from AlphaOmega, Medtronic and Boston Scientific and research support from the Magnet Program of the Israel Ministry of Economics. P.B. has received honoraria for speaking from Medtronic and Boston Scientific. S.C. is a consultant for Boston Scientific and for Medtronic and has received financial support from Medtronic for preclinical research purposes in the field of deep brain stimulation (DBS). K.M. has chaired advisory boards for studies of DBS for obsessive–compulsive disorder sponsored by Medtronic and has received travel and accommodation support to attend meetings from Medtronic and Abbott. C.C.M. is a paid consultant for Boston Scientific Neuromodulation and Kernel as well as a shareholder in the following companies: Surgical Information Sciences, Inc.; Autonomic Technologies, Inc.; Cardionomic, Inc.; Enspire DBS, Inc.; and Neuros Medical, Inc. T.S. has received limited research support for three investigator-initiated studies from Medtronic. M.S. owns stock in General Electric. J.V. receives grants and personal fees from Boston Scientific and is a consultant and paid speaker for Medtronic. J.K.K. is a consultant to Medtronic and Boston Scientific; has received fees for speaking from Abbott; is a past and honorary president of the European Society for Stereotactic and Functional Neurosurgery; and is a past president of the World Society for Stereotactic and Functional Neurosurgery. The other authors have no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lozano, A.M., Lipsman, N., Bergman, H. et al. Deep brain stimulation: current challenges and future directions. Nat Rev Neurol 15, 148–160 (2019). https://doi.org/10.1038/s41582-018-0128-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41582-018-0128-2

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing