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  • Review Article
  • Published:

Translational principles of deep brain stimulation

Nature Reviews Neuroscience volume 8, pages 623–635 (2007)Cite this article

Key Points

  • Deep brain stimulation (DBS) has shown remarkable therapeutic benefits for patients with otherwise treatment-resistant movement and affective disorders, such as chronic pain, Parkinson's disease, tremor and dystonia. Yet the precise mechanisms of action for DBS remain uncertain. Here we give an up-to-date overview of the principles of DBS, its neural mechanisms and its potential future applications.

  • DBS directly changes brain activity in a controlled manner and, unlike those of lesioning techniques, its effects are reversible. Furthermore, DBS is the only neurosurgical technique that allows blinded studies. New targets for DBS have been discovered through the use of translational research, and in particular through highly successful rodent and primate models of movement disorders.

  • DBS of both the normal and the diseased brain fundamentally depends on a number of parameters, including the physiological properties of the brain tissue, which may change with disease state, the stimulation parameters, including amplitude and temporal characteristics, and the geometric configuration of the electrode and the surrounding tissue.

  • In vivo neurophysiological recordings of activity from a deep brain electrode in one brain region, made while stimulating another brain region, have shown that DBS modulates the pathological oscillatory activity between brain regions.

  • Results from animal experiments have also shown that DBS appears to elicit neurotransmitter release in downstream brain structures, although there is conflicting evidence from human studies.

  • Functional neuroimaging methods can be used to elucidate the whole-brain responses elicited by DBS, and on the whole they have confirmed the findings from recordings in other animals. However, methods such as functional MRI should be used with extreme caution, as they entail significant risks to the patient. Owing to its non-invasive nature and high spatial and temporal resolution, magnetoencepholography (MEG) is currently one of the most promising techniques for elucidating the neural mechanisms affected by DBS.

  • On balance, the evidence so far suggests that the most likely mode of action for DBS is through stimulation-induced modulation of brain activity, where the modulation comes about through the local effects of the DBS electrode on the neural activity in the DBS target, which is passed on to mono- and poly-synaptic network connections.

  • Future applications of DBS include finding more effective brain targets and delivering individualized closed-loop demand-driven stimulation. It will also be important to develop robust translational models of affective disorders. Overall, combining DBS with whole-brain neuroimaging methods like MEG has the makings of a powerful and sophisticated tool for unravelling the fundamental mechanisms of normal and abnormal human brain function.

Abstract

Deep brain stimulation (DBS) has shown remarkable therapeutic benefits for patients with otherwise treatment-resistant movement and affective disorders. This technique is not only clinically useful, but it can also provide new insights into fundamental brain functions through direct manipulation of both local and distributed brain networks in many different species. In particular, DBS can be used in conjunction with non-invasive neuroimaging methods such as magnetoencephalography to map the fundamental mechanisms of normal and abnormal oscillatory synchronization that underlie human brain function. The precise mechanisms of action for DBS remain uncertain, but here we give an up-to-date overview of the principles of DBS, its neural mechanisms and its potential future applications.

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Figure 1: Electrophysiological principles of deep brain stimulation (DBS).
Figure 2: Neurophysiological recordings of deep brain stimulation (DBS).
Figure 3: Neuroimaging scan of deep brain stimulation (DBS).
Figure 4: Finding new deep brain stimulation (DBS) targets for the treatment of movement and affective disorders.

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References

  1. Fritsch, G. & Hitzig, E. Über die elektrische Erregbarkeit des Grosshirns. Arch. Anat. Physiol. 37, 300–332 (1870).

    Google Scholar 

  2. Gildenberg, P. L. Evolution of neuromodulation. Stereotact. Funct. Neurosurg. 83, 71–79 (2005). A good historical overview of neuromodulation.

    Article  Google Scholar 

  3. Owen, S. L., Green, A. L., Stein, J. F. & Aziz, T. Z. Deep brain stimulation for the alleviation of post-stroke neuropathic pain. Pain 120, 202–206 (2006).

    Article  Google Scholar 

  4. Marchand, S., Kupers, R. C., Bushnell, M. C. & Duncan, G. H. Analgesic and placebo effects of thalamic stimulation. Pain 105, 481–488 (2003).

    Article  Google Scholar 

  5. Bittar, R. G. et al. Deep brain stimulation for movement disorders and pain. J. Clin. Neurosci. 12, 457–463 (2005).

    Article  Google Scholar 

  6. Krack, P. et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease. N. Engl. J. Med. 349, 1925–1934 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Koller, W. C., Lyons, K. E., Wilkinson, S. B. & Pahwa, R. Efficacy of unilateral deep brain stimulation of the VIM nucleus of the thalamus for essential head tremor. Mov. Disord. 14, 847–850 (1999).

    Article  CAS  Google Scholar 

  8. Rehncrona, S. et al. Long-term efficacy of thalamic deep brain stimulation for tremor: double-blind assessments. Mov. Disord. 18, 163–170 (2003).

    Article  Google Scholar 

  9. Vidailhet, M. et al. Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N. Engl. J. Med. 352, 459–467 (2005).

    Article  CAS  Google Scholar 

  10. Ranck, J. B. Jr. Which elements are excited in electrical stimulation of mammalian central nervous system: a review. Brain Res. 98, 417–440 (1975). Excellent review of the underlying principles of electrical stimulation of neural tissue.

    Article  Google Scholar 

  11. McIntyre, C. C., Mori, S., Sherman, D. L., Thakor, N. V. & Vitek, J. L. Electric field and stimulating influence generated by deep brain stimulation of the subthalamic nucleus. Clin. Neurophysiol. 115, 589–595 (2004).

    Article  Google Scholar 

  12. Holsheimer, J., Demeulemeester, H., Nuttin, B. & de Sutter, P. Identification of the target neuronal elements in electrical deep brain stimulation. Eur. J. Neurosci. 12, 4573–4577 (2000).

    CAS  PubMed  Google Scholar 

  13. Nowak, L. G. & Bullier, J. Axons, but not cell bodies, are activated by electrical stimulation in cortical gray matter. II. Evidence from selective inactivation of cell bodies and axon initial segments. Exp. Brain Res. 118, 489–500 (1998).

    Article  CAS  Google Scholar 

  14. Volkmann, J., Herzog, J., Kopper, F. & Deuschl, G. Introduction to the programming of deep brain stimulators. Mov. Disord. 17, S181–S187 (2002).

    Article  Google Scholar 

  15. 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). Review of the potential neural mechanisms for DBS, with evidence from neurophysiology and computer modelling.

    Article  Google Scholar 

  16. 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  Google Scholar 

  17. Anderson, M. E., Postupna, N. & Ruffo, M. Effects of high-frequency stimulation in the internal globus pallidus on the activity of thalamic neurons in the awake monkey. J. Neurophysiol. 89, 1150–1160 (2003).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Pralong, E. et al. Effect of deep brain stimulation of GPI on neuronal activity of the thalamic nucleus ventralis oralis in a dystonic patient. Neurophysiol. Clin. 33, 169–173 (2003).

    Article  Google Scholar 

  20. Brown, P. et al. Effects of stimulation of the subthalamic area on oscillatory pallidal activity in Parkinson's disease. Exp. Neurol. 188, 480–490 (2004). Provided an important demonstration that DBS can modulate pathological oscillatory activity between the cortex and the basal ganglia.

    Article  Google Scholar 

  21. 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).

    Article  CAS  Google Scholar 

  22. Boulet, S. et al. Subthalamic stimulation-induced forelimb dyskinesias are linked to an increase in glutamate levels in the substantia nigra pars reticulata. J. Neurosci. 26, 10768–10776 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Hershey, T. et al. Cortical and subcortical blood flow effects of subthalamic nucleus stimulation in PD. Neurology 61, 816–821 (2003).

    Article  CAS  Google Scholar 

  25. Kringelbach, M. L. et al. Deep brain stimulation for chronic pain investigated with magnetoencephalography. Neuroreport 18, 223–228 (2007).

    Article  Google Scholar 

  26. Kringelbach, M. L. et al. Deep brain stimulation and chronic pain mapped with MEG. Soc. Neurosci. Abstr. 782.1 (2006). Provided the first demonstration of the feasibility of using MEG to map the whole-brain effects of DBS.

  27. Perlmutter, J. S. & Mink, J. W. Deep brain stimulation. Annu. Rev. Neurosci. 29, 229–257 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Beal, M. F. Experimental models of Parkinson's disease. Nature Rev. Neurosci. 2, 325–334 (2001).

    Article  CAS  Google Scholar 

  29. 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).

    Article  CAS  Google Scholar 

  30. Maurice, N., Thierry, A. M., Glowinski, J. & Deniau, J. M. Spontaneous and evoked activity of substantia nigra pars reticulata neurons during high-frequency stimulation of the subthalamic nucleus. J. Neurosci. 23, 9929–9936 (2003).

    Article  CAS  Google Scholar 

  31. Degos, B. et al. Neuroleptic-induced catalepsy: electrophysiological mechanisms of functional recovery induced by high-frequency stimulation of the subthalamic nucleus. J. Neurosci. 25, 7687–7696 (2005).

    Article  CAS  Google Scholar 

  32. Kita, H., Tachibana, Y., Nambu, A. & Chiken, S. Balance of monosynaptic excitatory and disynaptic inhibitory responses of the globus pallidus induced after stimulation of the subthalamic nucleus in the monkey. J. Neurosci. 25, 8611–8619 (2005).

    Article  CAS  Google Scholar 

  33. Filali, M., Hutchison, W. D., Palter, V. N., Lozano, A. M. & Dostrovsky, J. O. Stimulation-induced inhibition of neuronal firing in human subthalamic nucleus. Exp. Brain Res. 156, 274–281 (2004).

    Article  Google Scholar 

  34. Brown, P. et al. Dopamine dependency of oscillations between subthalamic nucleus and pallidum in Parkinson's disease. J. Neurosci. 21, 1033–1038 (2001).

    Article  CAS  Google Scholar 

  35. 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).

    Article  Google Scholar 

  36. Windels, F. et al. Influence of the frequency parameter on extracellular glutamate and γ-aminobutyric acid in substantia nigra and globus pallidus during electrical stimulation of subthalamic nucleus in rats. J. Neurosci. Res. 72, 259–267 (2003).

    Article  CAS  Google Scholar 

  37. Windels, F., Carcenac, C., Poupard, A. & Savasta, M. Pallidal origin of GABA release within the substantia nigra pars reticulata during high-frequency stimulation of the subthalamic nucleus. J. Neurosci. 25, 5079–5086 (2005).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  39. Hilker, R. et al. Deep brain stimulation of the subthalamic nucleus does not increase the striatal dopamine concentration in parkinsonian humans. Mov. Disord. 18, 41–48 (2003).

    Article  Google Scholar 

  40. Meissner, W. et al. Deep brain stimulation of subthalamic neurons increases striatal dopamine metabolism and induces contralateral circling in freely moving 6-hydroxydopamine-lesioned rats. Neurosci. Lett. 328, 105–108 (2002).

    Article  CAS  Google Scholar 

  41. Lauritzen, M. Reading vascular changes in brain imaging: is dendritic calcium the key? Nature Rev. Neurosci. 6, 77–85 (2005).

    Article  CAS  Google Scholar 

  42. Logothetis, N. K. & Wandell, B. A. Interpreting the BOLD signal. Annu. Rev. Physiol. 66, 735–769 (2004).

    Article  CAS  Google Scholar 

  43. Rezai, A. R. et al. Thalamic stimulation and functional magnetic resonance imaging: localization of cortical and subcortical activation with implanted electrodes. Technical note. J. Neurosurg. 90, 583–590 (1999).

    Article  CAS  Google Scholar 

  44. Uitti, R. J. et al. Magnetic resonance imaging and deep brain stimulation. Neurosurgery 51, 1423–1428 (2002).

    Article  Google Scholar 

  45. Sakatani, K., Katayama, Y., Yamamoto, T. & Suzuki, S. Changes in cerebral blood oxygenation of the frontal lobe induced by direct electrical stimulation of thalamus and globus pallidus: a near infrared spectroscopy study. J. Neurol. Neurosurg. Psychiatr. 67, 769–773 (1999).

    Article  CAS  Google Scholar 

  46. Georgi, J. C., Stippich, C., Tronnier, V. M. & Heiland, S. Active deep brain stimulation during MRI: a feasibility study. Magn. Reson. Med. 51, 380–388 (2004).

    Article  Google Scholar 

  47. Stefurak, T. et al. Deep brain stimulation for Parkinson's disease dissociates mood and motor circuits: a functional MRI case study. Mov. Disord. 18, 1508–1516 (2003).

    Article  Google Scholar 

  48. Hilker, R. et al. Subthalamic nucleus stimulation restores glucose metabolism in associative and limbic cortices and in cerebellum: evidence from a FDG–PET study in advanced Parkinson's disease. J. Cereb. Blood Flow Metab. 24, 7–16 (2004).

    Article  CAS  Google Scholar 

  49. Fukuda, M. et al. Networks mediating the clinical effects of pallidal brain stimulation for Parkinson's disease: a PET study of resting-state glucose metabolism. Brain 124, 1601–1609 (2001).

    Article  CAS  Google Scholar 

  50. May, A. et al. Hypothalamic deep brain stimulation in positron emission tomography. J. Neurosci. 26, 3589–3593 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  52. Hämäläinen, M., Hari, R., Ilmoniemi, R. J. & Knuutila, J. Magnetoencephalography — theory, instrumentation, and applications to noninvasive studies of the working human brain. Rev. Mod. Phys. 65, 1–93 (1993).

    Article  Google Scholar 

  53. Van Veen, B. D., van Drongelen, W., Yuchtman, M. & Suzuki, A. Localization of brain electrical activity via linearly constrained minimum variance spatial filtering. IEEE Trans. Biomed. Eng. 44, 867–880 (1997).

    Article  CAS  Google Scholar 

  54. Hillebrand, A. & Barnes, G. R. A quantitative assessment of the sensitivity of whole-head MEG to activity in the adult human cortex. Neuroimage 16, 638–650 (2002).

    Article  CAS  Google Scholar 

  55. Ioannides, A. A. et al. MEG tomography of human cortex and brainstem activity in waking and REM sleep saccades. Cereb. Cortex 14, 56–72 (2004).

    Article  PubMed  Google Scholar 

  56. Kringelbach, M. L. The orbitofrontal cortex: linking reward to hedonic experience. Nature Rev. Neurosci. 6, 691–702 (2005).

    Article  CAS  Google Scholar 

  57. Ray, N. J. et al. Using magnetoencephalography to investigate deep brain stimulation for cluster headache. Biomed. Imaging Interv. J. 4 Mar 2007 (doi:10.2349/biij.3.1.e25).

  58. Schnitzler, A. & Gross, J. Normal and pathological oscillatory communication in the brain. Nature Rev. Neurosci. 6, 285–296 (2005).

    Article  CAS  Google Scholar 

  59. Vitek, J. L. Mechanisms of deep brain stimulation: excitation or inhibition. Mov. Disord. 17, S69–S72 (2002).

    Article  Google Scholar 

  60. Beurrier, C., Bioulac, B., Audin, J. & Hammond, C. High-frequency stimulation produces a transient blockade of voltage-gated currents in subthalamic neurons. J. Neurophysiol. 85, 1351–1356 (2001).

    Article  CAS  Google Scholar 

  61. McIntyre, C. C., Grill, W. M., Sherman, D. L. & Thakor, N. V. Cellular effects of deep brain stimulation: model-based analysis of activation and inhibition. J. Neurophysiol. 91, 1457–1469 (2004).

    Article  Google Scholar 

  62. Urbano, F. J., Leznik, E. & Llinas, R. R. Cortical activation patterns evoked by afferent axons stimuli at different frequencies: an in vitro voltage sensitive dye imaging study. Thalamus Relat. Syst. 1, 371–378 (2002).

    Article  Google Scholar 

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

    Article  Google Scholar 

  64. Burns, R. S. et al. A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc. Natl Acad. Sci. USA 80, 4546–4550 (1983). Provided the first demonstration of the highly sucessful MPTP animal model of Parkinson's disease.

    Article  CAS  Google Scholar 

  65. Langston, J. W., Ballard, P., Tetrud, J. W. & Irwin, I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219, 979–980 (1983).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  67. 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). Together with reference 66, this classic study showed that lesions of the STN alleviate the symptoms of parkinsonian MPTP-treated monkeys.

    Article  CAS  Google Scholar 

  68. Limousin, P. et al. Effect of parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 345, 91–95 (1995). One of the first studies to demonstrate that DBS of the STN can help human patients.

    Article  CAS  Google Scholar 

  69. Voon, V., Moro, E., Saint-Cyr, J. A., Lozano, A. M. & Lang, A. E. Psychiatric symptoms following surgery for Parkinson's disease with an emphasis on subthalamic stimulation. Adv. Neurol. 96, 130–147 (2005).

    PubMed  Google Scholar 

  70. Pahwa, R., Wilkinson, S. B., Overman, J. & Lyons, K. E. Preoperative clinical predictors of response to bilateral subthalamic stimulation in patients with Parkinson's disease. Stereotact. Funct. Neurosurg. 83, 80–83 (2005).

    Article  Google Scholar 

  71. Matsumura, M. The pedunculopontine tegmental nucleus and experimental parkinsonism. A review. J. Neurol. 252, IV5–IV12 (2005).

    Article  Google Scholar 

  72. Garcia-Rill, E., Houser, C. R., Skinner, R. D., Smith, W. & Woodward, D. J. Locomotion-inducing sites in the vicinity of the pedunculopontine nucleus. Brain Res. Bull. 18, 731–738 (1987).

    Article  CAS  Google Scholar 

  73. Mogenson, G. J. & Wu, M. Differential effects on locomotor activity of injections of procaine into mediodorsal thalamus and pedunculopontine nucleus. Brain Res. Bull. 20, 241–246 (1988).

    Article  CAS  Google Scholar 

  74. Brudzynski, S. M., Houghton, P. E., Brownlee, R. D. & Mogenson, G. J. Involvement of neuronal cell bodies of the mesencephalic locomotor region in the initiation of locomotor activity of freely behaving rats. Brain Res. Bull. 16, 377–381 (1986).

    Article  CAS  Google Scholar 

  75. Crossman, A. R., Mitchell, I. J. & Sambrook, M. A. Regional brain uptake of 2-deoxyglucose in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the macaque monkey. Neuropharmacology 24, 587–591 (1985).

    Article  CAS  Google Scholar 

  76. Munro-Davies, L., Winter, J., Aziz, T. Z. & Stein, J. Kainate acid lesions of the pedunculopontine region in the normal behaving primate. Mov. Disord. 16, 150–151 (2001).

    Article  CAS  Google Scholar 

  77. Aziz, T. Z., Davies, L., Stein, J. & France, S. The role of descending basal ganglia connections to the brain stem in parkinsonian akinesia. Br. J. Neurosurg. 12, 245–249 (1998).

    Article  CAS  Google Scholar 

  78. Kojima, J. et al. Excitotoxic lesions of the pedunculopontine tegmental nucleus produce contralateral hemiparkinsonism in the monkey. Neurosci. Lett. 226, 111–114 (1997).

    Article  CAS  Google Scholar 

  79. Nandi, D., Aziz, T. Z., Giladi, N., Winter, J. & Stein, J. F. Reversal of akinesia in experimental parkinsonism by GABA antagonist microinjections in the pedunculopontine nucleus. Brain 125, 2418–2430 (2002). Exciting study that shows that microinjection of bicuculline into the PPN of parkinsonian MPTP-treated primates results in significant improvement of akinesia.

    Article  Google Scholar 

  80. Nandi, D., Liu, X., Winter, J. L., Aziz, T. Z. & Stein, J. F. Deep brain stimulation of the pedunculopontine region in the normal non-human primate. J. Clin. Neurosci. 9, 170–174 (2002).

    Article  Google Scholar 

  81. Jenkinson, N., Nandi, D., Miall, R. C., Stein, J. F. & Aziz, T. Z. Pedunculopontine nucleus stimulation improves akinesia in a Parkinsonian monkey. Neuroreport 15, 2621–2624 (2004). First study to demonstrate that DBS in the PPN of parkinsonian MPTP-treated monkeys can alleviate akinesia.

    Article  Google Scholar 

  82. Mazzone, P. et al. Implantation of human pedunculopontine nucleus: a safe and clinically relevant target in Parkinson's disease. Neuroreport 16, 1877–1881 (2005). One of the first studies to show that low frequency DBS in the human PPN helps with the symptoms of Parkinson's disease.

    Article  Google Scholar 

  83. Plaha, P. & Gill, S. G. Bilateral deep brain stimulation of the pedunculopontine nucleus for idiopathic Parkinson's disease. Neuroreport 16, 1883–1887 (2005). One of the first studies to show that DBS in the human PPN helps with gait disturbance and postural instability in Parkinson's disease.

    Article  Google Scholar 

  84. Stefani, A. et al. Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson's disease. Brain 130, 1596–1607 (2007).

    Article  Google Scholar 

  85. Berridge, K. C. Food reward: brain substrates of wanting and liking. Neurosci. Biobehav. Rev. 20, 1–25 (1996).

    Article  CAS  Google Scholar 

  86. Heath, R. G. Psychiatry. Annu. Rev. Med. 5, 223–236 (1954).

    Article  CAS  Google Scholar 

  87. Olds, J. & Milner, P. Positive reinforcement produced by electrical stimulation of the septal area and other regions of rat brain. J. Comp. Physiol. Psychol. 47, 419–427 (1954).

    Article  CAS  PubMed  Google Scholar 

  88. Cardinal, R. N., Parkinson, J. A., Hall, J. & Everitt, B. J. Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex. Neurosci. Biobehav. Rev. 26, 321–352 (2002).

    Article  PubMed  Google Scholar 

  89. Robbins, T. W. & Everitt, B. J. Limbic–striatal memory systems and drug addiction. Neurobiol. Learn. Mem. 78, 625–636 (2002).

    Article  CAS  Google Scholar 

  90. Peciña, S., Smith, K. S. & Berridge, K. C. Hedonic hot spots in the brain. Neuroscientist 12, 500–511 (2006).

    Article  Google Scholar 

  91. Schlaepfer, T. E. et al. Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology 11 Apr 2007 (doi: 10.1038/sj.npp.1301408). Provided an exciting demonstration that DBS of the nucleus accumbens alleviates anhedonia in treatment-resistant depression.

  92. Krack, P. et al. Mirthful laughter induced by subthalamic nucleus stimulation. Mov. Disord. 16, 867–875 (2001).

    Article  CAS  PubMed  Google Scholar 

  93. Bejjani, B. P. et al. Transient acute depression induced by high-frequency deep-brain stimulation. N. Engl. J. Med. 340, 1476–1480 (1999).

    Article  CAS  PubMed  Google Scholar 

  94. Temel, Y. et al. Deep brain stimulation of the thalamus can influence penile erection. Int. J. Impot. Res. 16, 91–94 (2004).

    Article  CAS  Google Scholar 

  95. Cummings, J. L. Depression and Parkinson's disease: a review. Am. J. Psychiatry 149, 443–454 (1992).

    Article  CAS  Google Scholar 

  96. Steckler, T., Inglis, W., Winn, P. & Sahgal, A. The pedunculopontine tegmental nucleus: a role in cognitive processes? Brain Res. Brain Res. Rev. 19, 298–318 (1994).

    Article  CAS  Google Scholar 

  97. Tass, P. A. et al. Obsessive–compulsive disorder: development of demand-controlled deep brain stimulation with methods from stochastic phase resetting. Neuropsychopharmacology 28, S27–S34 (2003).

    Article  Google Scholar 

  98. Tsubokawa, T. et al. Deep-brain stimulation in a persistent vegetative state: follow-up results and criteria for selection of candidates. Brain Inj. 4, 315–327 (1990).

    Article  CAS  Google Scholar 

  99. Fahn, S. & Elton, R. L. in Recent Developments in Parkinson's Disease. Vol. 2 (eds Fahn, S., Marsden, C. D., Goldstein, M. & Calne, D. B.) 153 (Macmillan Publishers Ltd, New York, 1987).

    Google Scholar 

  100. Siegfried, J. & Lippitz, B. Bilateral chronic electrostimulation of ventroposterolateral pallidum: a new therapeutic approach for alleviating all parkinsonian symptoms. Neurosurgery 35, 1126–1129 (1994).

    Article  CAS  Google Scholar 

  101. Benabid, A. L. et al. Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J. Neurosurg. 84, 203–214 (1996).

    Article  CAS  Google Scholar 

  102. Jenkinson, N., Nandi, D., Aziz, T. Z. & Stein, J. F. Pedunculopontine nucleus: a new target for deep brain stimulation for akinesia. Neuroreport 16, 1875–1876 (2005).

    Article  Google Scholar 

  103. Jenkinson, N., Nandi, D., Oram, R., Stein, J. F. & Aziz, T. Z. Pedunculopontine nucleus electric stimulation alleviates akinesia independently of dopaminergic mechanisms. Neuroreport 17, 639–641 (2006).

    Article  Google Scholar 

  104. Kumar, R., Dagher, A., Hutchison, W. D., Lang, A. E. & Lozano, A. M. Globus pallidus deep brain stimulation for generalized dystonia: clinical and PET investigation. Neurology 53, 871–874 (1999).

    Article  CAS  Google Scholar 

  105. Bittar, R. G. et al. Deep brain stimulation for generalised dystonia and spasmodic torticollis. J. Clin. Neurosci. 12, 12–16 (2005).

    Article  Google Scholar 

  106. Krauss, J. K., Yianni, J., Loher, T. J. & Aziz, T. Z. Deep brain stimulation for dystonia. J. Clin. Neurophysiol. 21, 18–30 (2004).

    Article  Google Scholar 

  107. Hassler, R. The influence of stimulations and coagulations in the human thalamus on the tremor at rest and its physiopathologic mechanism. Proc. Sec. Int. Cong. Neuropathol. 2, 637–642 (1955).

    Google Scholar 

  108. Lenz, F. A. et al. Single unit analysis of the human ventral thalamic nuclear group. Tremor-related activity in functionally identified cells. Brain 117, 531–543 (1994).

    Article  Google Scholar 

  109. Krack, P., Pollak, P., Limousin, P., Benazzouz, A. & Benabid, A. L. Stimulation of subthalamic nucleus alleviates tremor in Parkinson's disease. Lancet 350, 1675 (1997).

    Article  CAS  Google Scholar 

  110. Schuurman, P. R. et al. A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N. Engl. J. Med. 342, 461–468 (2000).

    Article  CAS  Google Scholar 

  111. Sydow, O., Thobois, S., Alesch, F. & Speelman, J. D. Multicentre European study of thalamic stimulation in essential tremor: a six year follow up. J. Neurol. Neurosurg. Psychiatr. 74, 1387–1391 (2003).

    Article  CAS  Google Scholar 

  112. Temel, Y., Blokland, A., Steinbusch, H. W. & Visser-Vandewalle, V. The functional role of the subthalamic nucleus in cognitive and limbic circuits. Prog. Neurobiol. 76, 393–413 (2005). An important review of the role of the STN not only in movement but also in affective processes.

    Article  CAS  Google Scholar 

  113. Pool, J. L., Clark, W. D., Hudson, P. & Lombardo, M. in Hypothalamic–Hypophysial Interrelationships (eds Fields, W. S., Guillemin, R. & Carton, C. A.) 114–124 (Charles C. Thomas Ltd, Illinois USA, 1956).

    Google Scholar 

  114. Mazars, G., Roge, R. & Mazars, Y. Results of the stimulation of the spinothalamic fasciculus and their bearing on the physiopathology of pain. Rev. Prat. 103, 136–138 (1960).

    CAS  Google Scholar 

  115. Hosobuchi, Y., Adams, J. E. & Rutkin, B. Chronic thalamic stimulation for the control of facial anesthesia dolorosa. Arch. Neurol. 29, 158–161 (1973). First successful use of chronic stimulation of the somatosensory thalamus for the treatment of denervation facial pain, anesthesia dolorosa.

    Article  CAS  Google Scholar 

  116. Mazars, G., Merienne, L. & Ciolocca, C. Intermittent analgesic thalamic stimulation. Preliminary note. Rev. Neurol. (Paris) 128, 273–279 (1973).

    CAS  Google Scholar 

  117. Hosobuchi, Y., Adams, J. E. & Linchitz, R. Pain relief by electrical stimulation of the central gray matter in humans and its reversal by naloxone. Science 197, 183–186 (1977).

    Article  CAS  Google Scholar 

  118. Richardson, D. E. & Akil, H. Long term results of periventricular gray self-stimulation. Neurosurgery 1, 199–202 (1977).

    Article  CAS  Google Scholar 

  119. Richardson, D. E. & Akil, H. Pain reduction by electrical brain stimulation in man. Part 1: acute administration in periaqueductal and periventricular sites. J. Neurosurg. 47, 178–183 (1977).

    Article  CAS  Google Scholar 

  120. Richardson, D. E. & Akil, H. Pain reduction by electrical brain stimulation in man. Part 2: chronic self-administration in the periventricular gray matter. J. Neurosurg. 47, 184–194 (1977).

    Article  CAS  Google Scholar 

  121. Coffey, R. J. Deep brain stimulation for chronic pain: results of two multicenter trials and a structured review. Pain Med. 2, 183–192 (2001).

    Article  CAS  Google Scholar 

  122. Hamani, C. et al. Deep brain stimulation for chronic neuropathic pain: long-term outcome and the incidence of insertional effect. Pain 125, 188–196 (2006).

    Article  Google Scholar 

  123. Krauss, J. K., Pohle, T., Weigel, R. & Burgunder, J. M. Deep brain stimulation of the centre median-parafascicular complex in patients with movement disorders. J. Neurol. Neurosurg. Psychiatr. 72, 546–548 (2002).

    Article  CAS  Google Scholar 

  124. Tronnier, V. M. in Deep Brain Stimulation (ed. Simpson, B. A.) 211–236 (Elsevier, Amsterdam, 2003).

    Google Scholar 

  125. Nandi, D., Aziz, T., Carter, H. & Stein, J. Thalamic field potentials in chronic central pain treated by periventricular gray stimulation — a series of eight cases. Pain 101, 97–107 (2003).

    Article  Google Scholar 

  126. Owen, S. L. F. et al. Deep brain stimulation for neuropathic pain. Neuromodulation 9, 100–106 (2006).

    Article  Google Scholar 

  127. Green, A. L., Owen, S. L., Davies, P., Moir, L. & Aziz, T. Z. Deep brain stimulation for neuropathic cephalalgia. Cephalalgia 26, 561–567 (2006).

    Article  CAS  Google Scholar 

  128. Bittar, R. G., Otero, S., Carter, H. & Aziz, T. Z. Deep brain stimulation for phantom limb pain. J. Clin. Neurosci. 12, 399–404 (2005).

    Article  Google Scholar 

  129. Franzini, A., Ferroli, P., Leone, M. & Broggi, G. Stimulation of the posterior hypothalamus for treatment of chronic intractable cluster headaches: first reported series. Neurosurgery 52, 1095–1099; discussion 1099–101 (2003).

    PubMed  Google Scholar 

  130. Leone, M., Franzini, A., Broggi, G., May, A. & Bussone, G. Long-term follow-up of bilateral hypothalamic stimulation for intractable cluster headache. Brain 127, 2259–2264 (2004).

    Article  CAS  Google Scholar 

  131. Andy, O. J. & Jurko, F. Thalamic stimulation effects on reactive depression. Appl. Neurophysiol. 50, 324–329 (1987).

    CAS  PubMed  Google Scholar 

  132. Jimenez, F. et al. A patient with a resistant major depression disorder treated with deep brain stimulation in the inferior thalamic peduncle. Neurosurgery 57, 585–593 (2005).

    Article  Google Scholar 

  133. Nuttin, B. J. et al. Long-term electrical capsular stimulation in patients with obsessive–compulsive disorder. Neurosurgery 52, 1263–1272 (2003).

    Article  Google Scholar 

  134. Visser-Vandewalle, V. et al. Chronic bilateral thalamic stimulation: a new therapeutic approach in intractable Tourette syndrome. Report of three cases. J. Neurosurg. 99, 1094–1100 (2003).

    Article  Google Scholar 

  135. Ackermans, L. et al. Deep brain stimulation in Tourette's syndrome: two targets? Mov. Disord. 21, 709–713 (2006).

    Article  Google Scholar 

  136. Beric, A. et al. Complications of deep brain stimulation surgery. Stereotact. Funct. Neurosurg. 77, 73–78 (2001).

    Article  CAS  Google Scholar 

  137. Hariz, M. I. Complications of deep brain stimulation surgery. Mov. Disord. 17, S162–S166 (2002).

    Article  Google Scholar 

  138. Bejjani, B. P. et al. Aggressive behavior induced by intraoperative stimulation in the triangle of Sano. Neurology 59, 1425–1427 (2002).

    Article  CAS  Google Scholar 

  139. Kulisevsky, J. et al. Mania following deep brain stimulation for Parkinson's disease. Neurology 59, 1421–1424 (2002).

    Article  CAS  Google Scholar 

  140. Nowak, L. G. & Bullier, J. Axons, but not cell bodies, are activated by electrical stimulation in cortical gray matter. I. Evidence from chronaxie measurements. Exp. Brain Res. 118, 477–488 (1998).

    Article  CAS  Google Scholar 

  141. Miocinovic, S. et al. Stereotactic neurosurgical planning, recording, and visualization for deep brain stimulation in non-human primates. J. Neurosci. Methods 162, 32–41 (2007).

    Article  Google Scholar 

  142. Hammond, C., Bergman, H. & Brown, P. Pathological synchronization in Parkinson's disease: networks, models and treatments. Trends Neurosci. 25 May 2007 (doi:10.1016/j.tins.2007.05.004).

  143. Bartholow, R. Experimental investigations into the functions of the human brain. Am. J. Med. Sci. 67, 305–313 (1874).

    Article  Google Scholar 

  144. Horsley, V. & Clarke, R. H. The structure and functions of the cerebellum examined by a new method. Brain 31, 45–124 (1908). A classic study that pioneered the stereotaxic frame (for animal use), which has since become central to the neurosurgical procedures for DBS.

    Article  Google Scholar 

  145. Spiegel, E. A., Wycis, H. T., Marks, M. & Lee, A. J. Stereotaxic apparatus for operations on the human brain. Science 106, 349–350 (1947). First study to adapt the stereotaxic frame for human use.

    Article  CAS  Google Scholar 

  146. Hassler, R., Riechert, T., Mundinger, F., Umbach, W. & Ganglberger, J. A. Physiological observations in stereotaxic operations in extrapyramidal motor disturbances. Brain 83, 337–350 (1960).

    Article  CAS  Google Scholar 

  147. Bechtereva, N. P., Bondartchuk, A. N. & Smirnov, V. M. Therapeutic electrostimulations of the deep brain structures. Vopr. Neirokhir. 1, 7–12 (1972).

    Google Scholar 

  148. Cooper, I. S. Effect of chronic stimulation of anterior cerebellum on neurological disease. Lancet 1, 206 (1973).

    Article  CAS  Google Scholar 

  149. Cooper, I. S., Riklan, M., Amin, I., Waltz, J. M. & Cullinan, T. Chronic cerebellar stimulation in cerebral palsy. Neurology 26, 744–753 (1976).

    Article  CAS  Google Scholar 

  150. Brice, J. & McLellan, L. Suppression of intention tremor by contingent deep-brain stimulation. Lancet 1, 1221–1222 (1980).

    Article  CAS  Google Scholar 

  151. Merienne, L. & Mazars, G. Treatment of various dyskinesias by intermittent thalamic stimulation. Neurochirurgie 28, 201–206 (1982).

    CAS  PubMed  Google Scholar 

  152. 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 

  153. Benabid, A. L. et al. Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 337, 403–406 (1991).

    Article  CAS  Google Scholar 

  154. Siegfried, J. & Lippitz, B. Chronic electrical stimulation of the VL-VPL complex and of the pallidum in the treatment of movement disorders: personal experience since 1982. Stereotact. Funct. Neurosurg. 62, 71–75 (1994).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors were funded by the Medical Research Council, the Norman Collisson Foundation, TrygFonden Charitable Foundation and the Charles Wolfson Charitable Trust.

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Authors and Affiliations

  1. Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JX, UK

    Morten L. Kringelbach

  2. Department of Physiology, University of Oxford, Anatomy and Genetics, Oxford, OX1 3PT, UK

    Morten L. Kringelbach, Ned Jenkinson, Sarah L.F. Owen & Tipu Z. Aziz

  3. University of Aarhus, Centre for Functionally Integrative Neuroscience (CFIN), Aarhus, Denmark

    Morten L. Kringelbach

  4. Nuffield Department of Surgery, John Radcliffe Hospital, Oxford, OX3 9DU, UK

    Ned Jenkinson & Tipu Z. Aziz

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  1. Morten L. Kringelbach
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  2. Ned Jenkinson
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  4. Tipu Z. Aziz
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Correspondence to Morten L. Kringelbach or Tipu Z. Aziz.

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Supplementary information

Supplementary information S1 (movie)

This clip shows the effects of deep brain stimulation of the pedunculopontine nucleus in a patient with Parkinson's disease. (Clip courtesy of P. Silburn, T. Coyne and R. Wilcox). (WMV 2064 kb)

Supplementary information S2 (movie)

This clip shows the effects of deep brain stimulation of the internal globus pallidus in a patient with dystonia. (WMV 561 kb)

Supplementary information S3 (movie)

This clip shows the effects of deep brain stimulation in the periventricular/periaqueductal grey in a patient with chronic pain in a phantom limb. (WMV 897 kb)

Supplementary information S4 (movie)

This clip shows the effects of deep brain stimulation of the subthalamic nucleus on tremor in a patient with Parkinson's disease. (WMV 2070 kb)

Related links

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DATABASES

OMIM

Parkinson's disease

FURTHER INFORMATION

Tipu Z. Aziz's lab's homepage

Morten Kringelbach's homepage

Glossary

Dystonia

A movement disorder that leads to involuntary sustained muscle contractions, causing distorted posturing of the foot, leg or arm.

Neural elements

The cell body, myelinated axons, dendrites and supporting glial cells.

Bradykinesia

The slowing of, and difficulty in initiating, movement that is characteristic of Parkinson's disease.

Frequency band

Neural oscillations have been classified into different frequency bands: delta (1–3 Hz), theta (4–7 Hz), alpha (8–13 Hz), beta (14–30 Hz), gamma (30–80 Hz), fast (80–200 Hz) and ultra fast (200–600 Hz).

Open-loop stimulator

An open-loop stimulator is a simple type of non-feedback controller whereby the input into the brain region is determined using only the current behavioural state and a model of the system.

6-hydroxydopamine

(6-OHDA). The first agent used to model Parkinson's disease. Injection of 6-OHDA into the substantia nigra causes it to selectively accumulate in dopamine neurons, and then kill them as a result of toxicity that is thought to involve the generation of free radicals. 6-OHDA can produce non-specific damage to other neurons.

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

(MPTP). A neurotoxin that causes degeneration of dopaminergic neurons in the substantia nigra and hence is used to study the pathophysiology of Parkinson's disease.

Local field potential

(LFP). The extracellular voltage fluctuations that reflect the sum of events in the dendrites of a local neuronal population.

Positron emission tomography

(PET). A medical imaging technique that uses injected radiolabelled tracer compounds, in conjunction with mathematical reconstruction methods, to produce a three-dimensional image, or map, of functional processes in the body (such as glucose metabolism, blood flow or receptor distributions).

Magnetic resonance imaging

(MRI). A non-invasive method used to obtain images of living tissue. It uses radio-frequency pulses and magnetic field gradients; the principle of nuclear magnetic resonance is used to reconstruct images of tissue characteristics (for example, proton density or water diffusion parameters).

Blood-oxygen-level-dependent signal

(BOLD signal). Local changes in the proportion of oxygenated blood in the brain, as measured by functional MRI. This proportion changes in response to neural activity, therefore the BOLD signal, or haemodynamic response, indicates the location and magnitude of neural activity.

Diffusion tensor imaging

(DTI). A technique based on MRI developed in the mid-1990s in which the diffusion constants of water molecules are measured along many (>six) orientations and diffusion anisotropy is characterized. It is used to visualize the location, orientation and anisotropy of the brain's white-matter tracts, and is sensitive to the directional parameters of water diffusion in the brain.

Essential tremor

The most common neurological movement disorder. Symptoms include involuntary rhythmic movements of the limbs, head or neck.

Magnetoencephalography

(MEG). A non-invasive neuroimaging technique that detects the changing magnetic fields associated with brain activity on the timescale of milliseconds.

Beamforming method

A signal processing technique that uses receptor arrays to detect signals (for example, in MEG). These techniques can be used to determine the brain sources of signals measured from SQUIDS.

Antidromic impulse

Conduction opposite the normal, orthodromic direction, whereby an action potential moves from the starting point of the depolarization towards the axons of the neuron.

Lenticular fasciculus

The output pathway of the basal ganglia that originates in the globus pallidus and terminates in the thalamus.

(14C)2-deoxyglucose

A glucose analogue that is used in imaging techniques carried out on experimental animals in order to estimate the level of neural activity in specific brain regions. The (14C)2-deoxyglucose is administered to the animals and subsequently taken up and trapped by active neurons.

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Kringelbach, M., Jenkinson, N., Owen, S. et al. Translational principles of deep brain stimulation. Nat Rev Neurosci 8, 623–635 (2007). https://doi.org/10.1038/nrn2196

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