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.

Insights into the mechanisms of deep brain stimulation

Key Points

  • Deep brain stimulation (DBS) is a well-established functional neurosurgical technique that is used to treat a variety of neurological disorders, but the mechanisms underpinning its therapeutic efficacy remain unclear

  • As DBS was first used in Parkinson disease (PD), much of our current understanding of this technique stems from PD-related studies; however, insights have also been gained from other conditions, including dystonia, intractable pain and psychiatric disorders

  • The time course and patterns of symptom improvement vary considerably among conditions that are treatable by DBS

  • Initial views on the mechanisms of DBS were based on the classic 'rate model', in which the motor symptoms of PD were attributed to altered neuronal firing rates in the basal ganglia

  • Recent observations indicate that DBS acts through multifactorial mechanisms, including immediate neuromodulatory effects, synaptic plasticity, and long-term neuronal reorganization

  • In light of this complexity, a change in the terminology from deep brain 'stimulation' to deep brain 'neuromodulation' is proposed

Abstract

Despite long-term and widespread use of deep brain stimulation (DBS) in a variety of neurological conditions, the underlying mechanisms of action have been elusive. Growing evidence suggests that DBS acts through multimodal mechanisms that are not limited to inhibition and excitation of basal ganglia circuits. DBS also seems to act over variable time spans — for example, the effects on tremor are immediate, whereas the effects on dystonia emerge over several weeks — suggesting that large networks are targeted. Studies reviewing the use of DBS in pain and obsessive–compulsive disorder have demonstrated direct involvement of axonal fibres rather than grey matter. In this Review, we draw on clinical and experimental data to examine the various hypotheses that have been put forward to explain the effects of DBS. In agreement with several other experts, we suggest that the term 'deep brain stimulation' warrants modification. A potentially more accurate term is 'deep brain neuromodulation', as the mode of action spans an array of therapeutic effects over a variable period of time, and is not just limited to 'stimulation' of the basal ganglia brain centres. Terms such as 'electrical neuro-network modulation' may be useful for applications in which deep brain structures are not the primary target.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Timing of the effects of deep brain stimulation.

References

  1. National Institute for Health and Care Excellence. Deep brain stimulation for Parkinson's disease. NICE https://www.nice.org.uk/guidance/ipg19 (2003).

  2. 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 

  3. Pollack, P., Gaio, J. M. & Perret, J. Parkinson's disease and parkinsonian syndromes. Rev. Prat. 39, 647–651 (in French) (1989).

    CAS  PubMed  Google Scholar 

  4. Albin, R. L., Young, A. B. & Penney, J. B. The functional anatomy of basal ganglia disorders. Trends Neurosci. 12, 366–375 (1989).

    CAS  Article  Google Scholar 

  5. Wichmann, T., DeLong, M. R., Guridi, J. & Obeso, J. A. Milestones in research on the pathophysiology of Parkinson's disease. Mov. Disord. 26, 1032–1041 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  6. Magill, P. J., Bolam, J. P. & Bevan, M. D. Dopamine regulates the impact of the cerebral cortex on the subthalamic nucleus–globus pallidus network. Neuroscience 106, 313–330 (2001).

    CAS  PubMed  Article  Google Scholar 

  7. Soares, J. et al. Role of external pallidal segment in primate parkinsonism: comparison of the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism and lesions of the external pallidal segment. J. Neurosci. 24, 6417–6426 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Weinberger, M. et al. Beta oscillatory activity in the subthalamic nucleus and its relation to dopaminergic response in Parkinson's disease. J. Neurophysiol. 96, 3248–3256 (2006).

    PubMed  Article  Google Scholar 

  9. Sharott, A. et al. Activity parameters of subthalamic nucleus neurons selectively predict motor symptom severity in Parkinson's disease. J. Neurosci. 34, 6273–6285 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. DeLong, M. & Wichmann, T. Deep brain stimulation for movement and other neurologic disorders. Ann. NY Acad. Sci. 1265, 1–8 (2012).

    PubMed  Article  Google Scholar 

  11. Deffains, M. et al. Subthalamic, not striatal, activity correlates with basal ganglia downstream activity in normal and parkinsonian monkeys. eLife 5, 4854 (2016).

    Article  CAS  Google Scholar 

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

    PubMed  PubMed Central  Article  Google Scholar 

  13. Little, S. et al. Adaptive deep brain stimulation in advanced Parkinson disease. Ann. Neurol. 74, 449–457 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  14. de Hemptinne, C. et al. Therapeutic deep brain stimulation reduces cortical phase–amplitude coupling in Parkinson's disease. Nat. Neurosci. 18, 779–786 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Berardelli, A., Rothwell, J. C., Hallett, M. & Thompson, P. D. The pathophysiology of primary dystonia. Brain 121, 1195–1212 (1998).

    PubMed  Article  Google Scholar 

  16. Tisch, S. et al. Pallidal stimulation modifies after-effects of paired associative stimulation on motor cortex excitability in primary generalised dystonia. Exp. Neurol. 206, 80–85 (2007).

    PubMed  Article  Google Scholar 

  17. Krauss, J. K., Yianni, J., Loher, T. J. & Aziz, T. Z. Deep brain stimulation for dystonia. J. Clin. Neurophysiol. 21, 18 (2004).

    PubMed  Article  Google Scholar 

  18. Wu, D., Wang, S., Stein, J. F., Aziz, T. Z. & Green, A. L. Reciprocal interactions between the human thalamus and periaqueductal gray may be important for pain perception. Exp. Brain Res. 232, 527–534 (2014).

    PubMed  Article  Google Scholar 

  19. Boccard, S. G., Pereira, E. A. & Aziz, T. Z. Deep brain stimulation for chronic pain. J. Clin. Neurosci. 22, 1537–1543 (2015).

    PubMed  Article  Google Scholar 

  20. Pereira, E. A. et al. Elevated gamma band power in humans receiving naloxone suggests dorsal periaqueductal and periventricular gray deep brain stimulation produced analgesia is opioid mediated. Exp. Neurol. 239, 248–255 (2013).

    CAS  PubMed  Article  Google Scholar 

  21. Knyazev, G. G. EEG delta oscillations as a correlate of basic homeostatic and motivational processes. Neurosci. Biobehav. Rev. 36, 677–695 (2012).

    PubMed  Article  Google Scholar 

  22. 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).

    CAS  PubMed  Article  Google Scholar 

  23. Abelson, J. L. et al. Deep brain stimulation for refractory obsessive–compulsive disorder. Biol. Psychiatry 57, 510–516 (2005).

    PubMed  Article  Google Scholar 

  24. Anderson, D. & Ahmed, A. Treatment of patients with intractable obsessive–compulsive disorder with anterior capsular stimulation. J. Neurosurg. 98, 1104–1108 (2003).

    PubMed  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

  26. Huff, W. et al. Unilateral deep brain stimulation of the nucleus accumbens in patients with treatment-resistant obsessive–compulsive disorder: outcomes after one year. Clin. Neurol. Neurosurg. 112, 137–143 (2010).

    PubMed  Article  Google Scholar 

  27. Lavano, A. et al. Deep brain stimulation for treatment-resistant depression: review of the literature. Brain Disord. Ther. 4, 168 (2015).

    Google Scholar 

  28. 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).

    PubMed  Article  Google Scholar 

  29. Figee, M. et al. Deep brain stimulation induces striatal dopamine release in obsessive–compulsive disorder. Biol. Psychiatry 75, 647–652 (2014).

    CAS  PubMed  Article  Google Scholar 

  30. Galvan, A., Devergnas, A. & Wichmann, T. Alterations in neuronal activity in basal ganglia–thalamocortical circuits in the parkinsonian state. Front. Neuroanat. 9, 5 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. Min, H.-K. et al. Deep brain stimulation induces BOLD activation in motor and non-motor networks: an fMRI comparison study of STN and EN/GPi DBS in large animals. Neuroimage 63, 1408–1420 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  32. Lozano, A. M. & Hallett, M. Preface. Discovery of electricity. Handb. Clin. Neurol. 116, ix–x (2013).

    CAS  PubMed  Article  Google Scholar 

  33. Arsenault, D. et al. A novel combinational approach of microstimulation and bioluminescence imaging to study the mechanisms of action of cerebral electrical stimulation in mice. J. Physiol. 593, 2257–2278 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Martic´-Kehl, M. I., Schibli, R. & Schubiger, P. A. Can animal data predict human outcome? Problems and pitfalls of translational animal research. Eur. J. Nucl. Med. Mol. Imag. 39, 1492–1496 (2012).

    Article  Google Scholar 

  35. Stein, E. & Bar-Gad, I. Beta oscillations in the cortico-basal ganglia loop during parkinsonism. Exp. Neurol. 245, 52–59 (2013).

    PubMed  Article  Google Scholar 

  36. Beck, M. H. et al. Short- and long-term dopamine depletion causes enhanced beta oscillations in the cortico-basal ganglia loop of parkinsonian rats. Exp. Neurol. 286, 124–136 (2016).

    CAS  PubMed  Article  Google Scholar 

  37. Pahapill, P. A. et al. Tremor arrest with thalamic microinjections of muscimol in patients with essential tremor. Ann. Neurol. 46, 249–252 (2001).

    Article  Google Scholar 

  38. Benazzouz, A. et al. Effect of high-frequency stimulation of the subthalamic nucleus on the neuronal activities of the substantia nigra pars reticulata and ventrolateral nucleus of the thalamus in the rat. Neuroscience 99, 289–295 (2000).

    CAS  PubMed  Article  Google Scholar 

  39. Dostrovsky, J. O. et al. Microstimulation-induced inhibition of neuronal firing in human globus pallidus. J. Neurophysiol. 84, 570–574 (2000).

    CAS  PubMed  Article  Google Scholar 

  40. Montgomery, E. B. Jr. Effect of subthalamic nucleus stimulation patterns on motor performance in Parkinson's disease. Parkinsonism Relat. Disord. 11, 167–171 (2005).

    PubMed  Article  Google Scholar 

  41. Montgomery, E. B. Jr & Gale, J. T. Mechanisms of action of deep brain stimulation (DBS). Neurosci. Biobehav. Rev. 32, 388–407 (2008).

    PubMed  Article  Google Scholar 

  42. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Stefani, A. et al. Subthalamic stimulation activates internal pallidus: evidence from cGMP microdialysis in PD patients. Ann. Neurol. 57, 448–452 (2005).

    PubMed  Article  Google Scholar 

  44. Montgomery, E. B. Jr. Effects of GPi stimulation on human thalamic neuronal activity. Clin. Neurophysiol. 117, 2691–2702 (2006).

    PubMed  Article  Google Scholar 

  45. Windels, F. et al. Effects of high frequency stimulation of subthalamic nucleus on extracellular glutamate and GABA in substantia nigra and globus pallidus in the normal rat. Eur. J. Neurosci. 12, 4141–4146 (2000).

    CAS  PubMed  Article  Google Scholar 

  46. Perlmutter, J. S. et al. Blood flow responses to deep brain stimulation of thalamus. Neurology 58, 1388–1394 (2002).

    CAS  PubMed  Article  Google Scholar 

  47. Lanotte, M. M. et al. Deep brain stimulation of the subthalamic nucleus: anatomical, neurophysiological, and outcome correlations with the effects of stimulation. J. Neurol. Neurosurg. Psychiatry 72, 53–58 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Vitek, J. L., Hashimoto, T., Peoples, J., DeLong, M. R. & Bakay, R. A. Acute stimulation in the external segment of the globus pallidus improves parkinsonian motor signs. Mov. Disord. 19, 907–915 (2004).

    PubMed  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

  50. Jech, R. et al. Functional magnetic resonance imaging during deep brain stimulation: a pilot study in four patients with Parkinson's disease. Mov. Disord. 16, 1126–1132 (2001).

    CAS  PubMed  Article  Google Scholar 

  51. Knight, E. J. et al. Motor and nonmotor circuitry activation induced by subthalamic nucleus deep brain stimulation in patients with Parkinson disease. Mayo Clin. Proc. 90, 773–785 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  52. Vitek, J. L. et al. Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus. Ann. Neurol. 46, 22–35 (1999).

    CAS  PubMed  Article  Google Scholar 

  53. Benabid, A. L., Benazzous, A. & Pollak, P. Mechanisms of deep brain stimulation. Mov. Disord. 17, S73–S74 (2002).

    PubMed  Article  Google Scholar 

  54. 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).

    PubMed  Article  Google Scholar 

  55. Rizzone, M. et al. Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: effects ofvariation in stimulation parameters. J. Neurol. Neurosurg. Psychiatry. 71, 215–219 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Gale, J. T. Basis of Periodic Activities in the Basal Ganglia–Thalamic–Cortical System of the Rhesus Macaque (Kent State Univ., 2004).

    Google Scholar 

  57. Wingeier, B. et al. Intra-operative STN DBS attenuates the prominent beta rhythm in the STN in Parkinson's disease. Exp. Neurol. 197, 244–251 (2006).

    PubMed  Article  Google Scholar 

  58. Kühn, A. A. et al. Increased beta activity in dystonia patients after drug-induced dopamine deficiency. Exp. Neurol. 214, 140–143 (2008).

    PubMed  Article  CAS  Google Scholar 

  59. Bronte-Stewart, H. et al. The STN beta-band profile in Parkinson's disease is stationary and shows prolonged attenuation after deep brain stimulation. Exp. Neurol. 215, 20–28 (2009).

    CAS  PubMed  Article  Google Scholar 

  60. Zaidel, A., Spivak, A., Grieb, B., Bergman, H. & Israel, Z. Subthalamic span of beta oscillations predicts deep brain stimulation efficacy for patients with Parkinson's disease. Brain 133, 2007–2021 (2010).

    PubMed  Article  Google Scholar 

  61. Giannicola, G. et al. The effects of levodopa and ongoing deep brain stimulation on subthalamic beta oscillations in Parkinson's disease. Exp. Neurol. 226, 120–127 (2010).

    CAS  PubMed  Article  Google Scholar 

  62. Eusebio, A. et al. Deep brain stimulation can suppress pathological synchronisation in parkinsonian patients. J. Neurol. Neurosurg. Psychiatry 82, 569–573 (2011).

    CAS  PubMed  Article  Google Scholar 

  63. Davidson, C. M., de Paor, A. M. & Lowery, M. M. Application of describing function analysis to a model of deep brain stimulation. IEEE Trans. Biomed. Eng. 61, 957–965 (2014).

    PubMed  Article  Google Scholar 

  64. McIntyre, C. C., Chaturvedi, A., Shamir, R. R. & Lempka, S. F. Engineering the next generation of clinical deep brain stimulation technology. Brain Stimul. 8, 21–26 (2015).

    PubMed  Article  Google Scholar 

  65. Quinn, E. J. et al. Beta oscillations in freely moving Parkinson's subjects are attenuated during deep brain stimulation. Mov. Disord. 30, 1750–1758 (2015).

    PubMed  Article  Google Scholar 

  66. Hamilton, N. B. & Attwell, D. Do astrocytes really exocytose neurotransmitters? Nat. Rev. Neurosci. 11, 227–238 (2010).

    CAS  PubMed  Article  Google Scholar 

  67. Vedam-Mai, V. et al. Deep brain stimulation and the role of astrocytes. Mol. Psychiatry 17, 124–131 (2011).

    PubMed  Article  Google Scholar 

  68. Fenoy, A. J., Goetz, L., Chabardes, S. & Xia, Y. Deep brain stimulation: are astrocytes a key driver behind the scene? CNS Neurosci. Ther. 20, 191–201 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Tawfik, V. L. et al. Deep brain stimulation results in local glutamate and adenosine release: investigation into the role of astrocytes. Neurosurgery 67, 367–375 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  70. Bekar, L. et al. Adenosine is crucial for deep brain stimulation mediated attenuation of tremor. Nat. Med. 14, 75–80 (2014).

    Article  CAS  Google Scholar 

  71. Wallace, B. A. et al. Survival of midbrain dopaminergic cells after lesion or deep brain stimulation of the subthalamic nucleus in MPTP-treated monkeys. Brain 130, 2129–2145 (2007).

    PubMed  Article  Google Scholar 

  72. Ho, D. X., Tan, Y. C., Tan, J., Too, H. P. & Ng, W. H. High-frequency stimulation of the globus pallidus interna nucleus modulates GFRα1 gene expression in the basal ganglia. J. Clin. Neurosci. 21, 657–660 (2014).

    CAS  PubMed  Article  Google Scholar 

  73. Herrington, T. M., Cheng, J. J. & Eskandar, E. N. Mechanisms of deep brain stimulation. J. Neurophysiol. 115, 19–38 (2016).

    CAS  PubMed  Article  Google Scholar 

  74. Jahanshahi, A., Schönfeld, L.-M., Lemmens, E., Hendrix, S. & Temel, Y. In vitro and in vivo neuronal electrotaxis: a potential mechanism for restoration? Mol. Neurobiol 49, 1005–1016 (2014).

    CAS  PubMed  Article  Google Scholar 

  75. Kádár, E. et al. High-frequency stimulation of the ventrolateral thalamus regulates gene expression in hippocampus, motor cortex and caudate–putamen. Brain Res. 1391, 1–13 (2011).

    PubMed  Article  CAS  Google Scholar 

  76. Vedam-Mai, V. et al. Increased precursor cell proliferation after deep brain stimulation for Parkinson's disease: a human study. PLoS ONE 9, e88770 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. Vedam-Mai, V., Baradaran-Shoraka, M., Reynolds, B. A. & Okun, M. S. Tissue response to deep brain stimulation and microlesion: a comparative study. Neuromodulation 19, 451–458 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  78. Wolz, M. et al. Immediate effects of deep brain stimulation of the subthalamic nucleus on nonmotor symptoms in Parkinson's disease. Parkinsonism Relat. Disord. 18, 994–997 (2012).

    PubMed  Article  Google Scholar 

  79. Okun, M. S. & Oyama, G. Mechanism of action for deep brain stimulation and electrical neuro-network modulation (ENM) [Japanese]. Rinsho Shinkeigaku 53, 691–694 (2013).

    PubMed  Article  Google Scholar 

  80. Rowland, N. C. et al. Combining cell transplants or gene therapy with deep brain stimulation for Parkinson's disease. Mov. Disord. 30, 190–195 (2014).

    PubMed  Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

P.R., H.B. and I.U. researched data for the article. K.A. and P.R. discussed the content. K.A, P.R. and I.U. wrote the article. K. A., H.B. and I.U. reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Keyoumars Ashkan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ashkan, K., Rogers, P., Bergman, H. et al. Insights into the mechanisms of deep brain stimulation. Nat Rev Neurol 13, 548–554 (2017). https://doi.org/10.1038/nrneurol.2017.105

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2017.105

Further reading

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