, Volume 5, Issue 1, pp 14–25 | Cite as

Mechanisms of deep brain stimulation in movement disorders as revealed by changes in stimulus frequency

  • Merrill J. Birdno
  • Warren M. GrillEmail author
Review Article


Deep brain stimulation (DBS) is an established treatment for symptoms in movement disorders and is under investigation for symptom management in persons with psychiatric disorders and epilepsy. Nevertheless, there remains disagreement regarding the physiological mechanisms responsible for the actions of DBS, and this lack of understanding impedes both the design of DBS systems for treating novel diseases and the effective tuning of current DBS systems. Currently available data indicate that effective DBS overrides pathological bursts, low frequency oscillations, synchronization, and disrupted firing patterns present in movement disorders, and replaces them with more regularized firing. Although it is likely that the specific mechanism(s) by which DBS exerts its effects varies between diseases and target nuclei, the overriding of pathological activity appears to be ubiquitous. This review provides an overview of changes in motor symptoms with changes in DBS frequency and highlights parallels between the changes in motor symptoms and the changes in cellular activity that appear to underlic the motor symptoms.

Key Words

Electrical stimulation high-frequency stimulation movement disorders basal ganglia thalamus midbrain 


  1. 1.
    Gross RE, Lozano AM. Advances in neurostimulation for movement disorders. Neurol Res 2000;22:247–258.PubMedGoogle Scholar
  2. 2.
    Krauss JK, Yianni J, Loher TJ, Aziz TZ. Deep brain stimulation for dystonia. J Clin Neurophysiol 2004;21:18–30.CrossRefPubMedGoogle Scholar
  3. 3.
    Benabid AL, Pollak P, Gervason C, et al. Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 1991;337:403–406.CrossRefPubMedGoogle Scholar
  4. 4.
    McIntyre CC, Savasta M, Kerkerian-Le Goff L, Vitek JL. Uncovering the mechanism(s) of action of deep brain stimulation: activation, inhibition, or both. Clin Neurophysiol 2004;115:1239–1248.CrossRefPubMedGoogle Scholar
  5. 5.
    Grill WM, McIntyre CC. Extracellular excitation of central neurons: implications for the mechanisms of deep brain stimulation. Thalamus Relat Syst 2001;1:269–277.Google Scholar
  6. 6.
    Kuncel AM, Grill WM. Selection of stimulus parameters for deep brain stimulation. Clin Neurophysiol 2004;115:2431–2441.CrossRefPubMedGoogle Scholar
  7. 7.
    Benabid AL, Koudsic A, Benazzouz A, et al. Subthalamic stimulation for Parkinson’s disease. Arch Med Res 2000;31:282–289.CrossRefPubMedGoogle Scholar
  8. 8.
    Hodaic M, Wennberg RA, Dostrovsky JO, Lozano AM. Chronic anterior thalamus stimulation for intractable epilepsy. Epilepsia 2002;43:603–608.CrossRefGoogle Scholar
  9. 9.
    Gross RE. Deep brain stimulation in the treatment of neurological and psychiatric disease. Expert Rev Neurother 2004;4: 465–478.CrossRefPubMedGoogle Scholar
  10. 10.
    Nuttin BJ, Gabriels L, van Kuyck K, Cosyns P. Electrical stimulation of the anterior limbs of the internal capsules in patients with severe obsessive-compulsive disorder: anecdotal reports. Neurosurg Clin N Am 2003;14: 267–274.CrossRefPubMedGoogle Scholar
  11. 11.
    Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation for treatment-resistant depression. Neuron 2005;45:651–660.CrossRefPubMedGoogle Scholar
  12. 12.
    Dostrovsky JO, Lozano AM. Mechanisms of deep brain stimulation. Mov Disord 2002;17(suppl 3): S63–68.CrossRefPubMedGoogle Scholar
  13. 13.
    Moro E, Esselink RJ, Xie J, Hommel M, Benabid AL, Pollak P. The impact on Parkinson’s disease of electrical parameter settings in STN stimulation. Neurology 2002;59:706–713.PubMedGoogle Scholar
  14. 14.
    Fogelson N, Kuhn AA, Silberstein P, et al. Frequency dependent effects of subthalamic nucleus stimulation in Parkinson’s disease. Neurosci Lett 2005;382:5–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Timmermann L, Wojtecki L, Gross J, et al. Ten-Hertz stimulation of subthalamic nucleus deteriorates motor symptoms in Parkinson’s disease. Mov Disord 2004;19:1328–1333.CrossRefPubMedGoogle Scholar
  16. 16.
    Grill WM, Snyder AN, Miocinovic S. Deep brain stimulation creates an informational lesion of the stimulated nucleus. Neuroreport 2004;15:1137–1140.CrossRefPubMedGoogle Scholar
  17. 17.
    Ushe M, Mink JW, Revilla FJ, et al. Effect of stimulation frequency on tremor suppression in essential tremor. Mov Disord 2004;19:1163–1168.CrossRefPubMedGoogle Scholar
  18. 18.
    Kuncel AM, Cooper SE, Wolgamuth BR, et al. Clinical response to varying the stimulus parameters in deep brain stimulation for essential tremor. Mov Disord 2006;21:1920–1928.CrossRefPubMedGoogle Scholar
  19. 19.
    Welter ML, Houeto JL, Bonnet AM, et al. Effects of high-frequency stimulation on subthalamic neuronal activity in parkinsonian patients. Arch Neurol 2004;61:89–96.CrossRefPubMedGoogle Scholar
  20. 20.
    Foffani G, Ardolino G, Egidi M, Caputo E, Bossi B, Mori A. Subthalamic oscillatory activities at beta or higher frequency do not change after high-frequency DBS in Parkinson’s disease. Brain Res Bull 2006;69:123–130.CrossRefPubMedGoogle Scholar
  21. 21.
    Dostrovsky JO, Levy R, Wu JP, Hutchison WD, Tasker RR, Lozano AM. Microstimulation-induced inhibition of neuronal firing in human globus pallidus. J Neurophysiol 2000;84:570–574.PubMedGoogle Scholar
  22. 22.
    Meissner W, Leblois A, Hansel D, Bioulac B, Gross CE, Benazzouz A, et al. Subthalamic high frequency stimulation resets subthalamic firing and reduces abnormal oscillations. Brain 2005;128: 2372–2382.CrossRefPubMedGoogle Scholar
  23. 23.
    McIntyre CC, Grill WM, Sherman DL, Thakor NV. Cellular effects of deep brain stimulation: model-based analysis of activation and inhibition. J Neurophysiol 2004;91:1457–1469.CrossRefPubMedGoogle Scholar
  24. 24.
    Anderson TR, Hu B, Iremonger K, Kiss ZH. Selective attenuation of afferent synaptic transmission as a mechanism of thalamic deep brain stimulation-induced tremor arrest. J Neurosci 2006;26:841–850.CrossRefPubMedGoogle Scholar
  25. 25.
    Beurrier C, Bioulac B, Audin J, Hammond C. High-frequency stimulation produces a transient blockade of voltage-gated currents in subthalamic neurons. J Neurophysiol 2001;85:1351–1356.PubMedGoogle Scholar
  26. 26.
    Anderson ME, 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 2003;89:1150–1160.CrossRefPubMedGoogle Scholar
  27. 27.
    Hashimoto T, Elder CM, Okun MS, Patrick SK, Vitek JL. Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons. J Neurosci 2003;23:1916–1923.PubMedGoogle Scholar
  28. 28.
    Hershey T, Revilla FJ, Wemle AR, et al. Cortical and subcortical blood flow effects of subthalamic nucleus stimulation in PD. Neurology 2003;61:816–821.PubMedGoogle Scholar
  29. 29.
    Zhao YB, Sun BM, Li DY, Wang QS. Effects of bilateral subthalamic nucleus stimulation on resting-state cerebral glucose metabolism in advanced Parkinson’s disease. Chin Med J (Engl) 2004;117:1304–1308.Google Scholar
  30. 30.
    Windeis 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 2005;25:5079–5086.CrossRefGoogle Scholar
  31. 31.
    Nowak LG, Bullier J. Axons, but not cell bodies, are activated by electrical stimulation in cortical gray matter. I. Evidence from chronaxic measurements. Exp Brain Res 1998;118:477–488.CrossRefPubMedGoogle Scholar
  32. 32.
    Nowak LG, 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 1998;118:489–500.CrossRefPubMedGoogle Scholar
  33. 33.
    Benabid AL, Wallace B, Mitrofanis J, et al. A putative generalized model of the effects and mechanism of action of high frequency electrical stimulation of the central nervous system. Acta Neurol Belg 2005;105:149–157.PubMedGoogle Scholar
  34. 34.
    Xia R, Berger F, Piallat B, Benabid AL. Alteration of hormone and neurotransmitter production in cultured cells by high and low frequency electrical stimulation. Acta Neurochir (Wien) 2007;149:67–73; discussion 73.CrossRefGoogle Scholar
  35. 35.
    Urbano FJ, Leznik E, Llinas RR. Cortical activation patterns evoked by afferent axons stimuli at different frequencies: an in vitro voltage-sensitive dye imaging study. Thalamus Relat Syst 2002;1:371.Google Scholar
  36. 36.
    Garcia L, Audin J, D’Alessandro G, Bioulac B, Hammond C. Dual effect of high-frequency stimulation on subthalamic neuron activity. J Neurosci 2003;23:8743–8751.PubMedGoogle Scholar
  37. 37.
    Degos B, Deniau J-M, Thierry A-M, Glowinski J, Pezard L, Maurice N. Neuroleptic-induced catalepsy: electrophysiological mechanisms of functional recovery induced by high-frequency stimulation of the subthalamic nucleus. J. Neurosci. 2005;25:7687–7696.CrossRefPubMedGoogle Scholar
  38. 38.
    Jech R, Urgosik D, Tintera J, et al. Functional magnetic resonance imaging during deep brain stimulation: a pilot study in four patients with Parkinson’s disease. Mov Disord 2001;16:1126–1132.CrossRefPubMedGoogle Scholar
  39. 39.
    Phillips MD, Baker KB, Lowe MJ, et al. Parkinson disease: pattern of functional MR imaging activation during deep brain stimulation of subthalamic nucleus—initial experience. Radiology 2006;239:209–216.CrossRefPubMedGoogle Scholar
  40. 40.
    Windeis F, Bruet N, Poupard A, Feuerstein C, Bertrand A, Savasta M. Influence of the frequency parameter on extracellular glutamate and gamma-aminobutyric acid in substantia nigra and globus pallidus during electrical stimulation of subthalamic nucleus in rats. J Neurosci Res 2003;72:259–267.CrossRefGoogle Scholar
  41. 41.
    Gale JT, Amimovin R, Williams ZM, Flaherty AW, Eskandar EN. From symphony to cacophony: Pathophysiology of the human basal ganglia in Parkinson disease. Neurosci Biobehav Rev [Epub ahead of print] Apr 25 2007.Google Scholar
  42. 42.
    Bergman H, Wichmann T, Karmon B, DeLong MR. The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism. J Neurophysiol 1994;72:507–520.PubMedGoogle Scholar
  43. 43.
    Hammond C, Bergman H, Brown P. Pathological synchronization in Parkinson’s disease: networks, models and treatments. Trends Neurosci 2007;30:357–364.CrossRefPubMedGoogle Scholar
  44. 44.
    Brown P, Oliviero A, Mazzone P, Insola A, Tonali P, Di Lazzaro V. Dopamine dependency of oscillations between subthalamic nucleus and pallidum in Parkinson’s disease. J Neurosci 2001;21: 1033–1038.PubMedGoogle Scholar
  45. 45.
    Vitek JL, Chockkan V, Zhang JY, et al. Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus. Ann Neurol 1999;46:22–35.CrossRefPubMedGoogle Scholar
  46. 46.
    Levy R, Ashby P, Hutchison WD, Lang AE, Lozano AM, Dostrovsky JO. Dependence of subthalamic nucleus oscillations on movement and dopamine in Parkinson’s disease. Brain 2002;125:1196–1209.CrossRefPubMedGoogle Scholar
  47. 47.
    Tang JK, Moro E, Lozano AM, et al. Firing rates of pallidal neurons are similar in Huntington’s and Parkinson’s disease patients. Exp Brain Res 2005;166:230–236.CrossRefPubMedGoogle Scholar
  48. 48.
    Nini A, Feingold A, Slovin H, Bergman H. Neurons in the globus pallidus do not show correlated activity in the normal monkey, but phase-locked oscillations appear in the MPTP model of parkinsonism. J Neurophysiol 1995;74: 1800–1805.PubMedGoogle Scholar
  49. 49.
    Bergman H, Feingold A, Nini A, et al. Physiological aspects of information processing in the basal ganglia of normal and parkinsonian primates. Trends Neurosci 1998;21:32–38.CrossRefPubMedGoogle Scholar
  50. 50.
    Deuschl G, Raethjen J, Lindemann M, Krack P. The pathophysiology of tremor. Muscle Nerve 2001;24:716–735.CrossRefPubMedGoogle Scholar
  51. 51.
    Silberstein P, Oliviero A, Di Lazzaro V, Insola A, Mazzone P, Brown P. Oscillatory pallidal local field potential activity inversely correlates with limb dyskinesias in Parkinson’s disease. Exp Neurol 2005;194:523–529.CrossRefPubMedGoogle Scholar
  52. 52.
    Wichmann T, Bergman H, Starr PA, Subramanian T, Watts RL, DeLong MR. Comparison of MPTP-induced changes in spontaneous neuronal discharge in the internal pallidal segment and in the substantia nigra pars reticulata in primates. Exp Brain Res 1999;125:397–409.CrossRefPubMedGoogle Scholar
  53. 53.
    Amimovin R, Williams ZM, Cosgrove GR, Eskandar EN. Visually guided movements suppress subthalamic oscillations in Parkinson’s disease patients. J Neurosci 2004;24:11302–11306.CrossRefGoogle Scholar
  54. 54.
    Magnin M, Morel A, Jeanmonod D. Single-unit analysis of the pallidum, thalamus and subthalamic nucleus in parkinsonian patients. Neuroscience 2000;96:549–564.CrossRefPubMedGoogle Scholar
  55. 55.
    Albin RL, Young AB, Penney JB. The functional anatomy of basal ganglia disorders. Trends Neurosci 1989;12:366–375.CrossRefPubMedGoogle Scholar
  56. 56.
    DeLong MR. Primate models of movement disorders of basal ganglia origin. Trends Neurosci 1990;13:281–285.CrossRefPubMedGoogle Scholar
  57. 57.
    Wichmann T, DeLong MR. Pathophysiology of Parkinson’s disease: the MPTP primate model of the human disorder. Ann N Y Acad Sci 2003;991:199–213.CrossRefPubMedGoogle Scholar
  58. 58.
    Rossi L, Foffani G, Marceglia S, Bracchi F, Barbieri S, Priori A. An electronic device for artefact suppression in human local field potential recordings during deep brain stimulation. J Neural Eng 2007;4: 96–106.CrossRefPubMedGoogle Scholar
  59. 59.
    Llinas RR, Ribary U, Jeanmonod D, Kronberg E, Mitra PP. Thalamocortical dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography. Proc Natl Acad Sci U S A 1999;96: 15222–15227.CrossRefPubMedGoogle Scholar
  60. 60.
    Brown P, Mazzone P, Oliviero A, et al. Effects of stimulation of the subthalamic area on oscillatory pallidal activity in Parkinson’s disease. Exp Neurol 2004;188:480–490.CrossRefPubMedGoogle Scholar
  61. 61.
    Wingeier B, Tcheng T, Koop MM, Hill BC, Heit G, Bronte-Stewart HM. Intra-operative STN DBS attenuates the prominent beta rhythm in the STN in Parkinson’s disease. Exp Neurol 2006;197: 244–251.CrossRefPubMedGoogle Scholar
  62. 62.
    Birdno MJ, Cooper SE, Rezai AR, Grill WM. Pulse-to-pulse changes in the frequency of deep brain stimulation affect tremor and modeled neuronal activity. J Neurophysiol 2007;98:1675–1684.CrossRefPubMedGoogle Scholar
  63. 63.
    Garcia L, D’Alessandro G, Femagut PO, Bioulac B, Hammond C. Impact of high-frequency stimulation parameters on the pattern of discharge of subthalamic neurons. J Neurophysiol 2005;94:3662–3669.CrossRefPubMedGoogle Scholar
  64. 64.
    Lee DC, Grill WM. Differential effects of electric field distribution on the activation of CNS neurons. Presented at the Annual Fall Meeting of the Biomedical Engineering Society; Program No. 915; October 16, 2004; Philadelphia, Pennsylvania.Google Scholar
  65. 65.
    Dorval AD, Russo GS, Hashimoto T, Xu W, Vitek JL, Grill WM. Subthalamic high-frequency stimulation regularizes pallidal and thalamic neural activity. Soc Neurosci 2005; Program No. 331.7.2005 (abstract).Google Scholar
  66. 66.
    Bar-Gad I, Elias S, Vaadia E, Bergman H. Complex locking rather than complete cessation of neuronal activity in the globus pallidus of a l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primate in response to pallidal microstimulation. J Neurosci 2004;24:7410–7419.CrossRefPubMedGoogle Scholar
  67. 67.
    Zhang J, Russo GS, Mewes K, Rye DB, Vitek JL. Lesions in monkey globus pallidus extemus exacerbate parkinsonian symptoms. Exp Neurol 2006;199:446–453.CrossRefPubMedGoogle Scholar
  68. 68.
    Vitek JL, Hashimoto T, Peoples J, DeLong MR, Bakay RA. Acute stimulation in the external segment of the globus pallidus improves parkinsonian motor signs. Mov Disord 2004;19:907–915.CrossRefPubMedGoogle Scholar
  69. 69.
    Meissner W, Guigoni C, Cirilli L, et al. Impact of chronic subthalamic high-frequency stimulation on metabolic basal ganglia activity: a 2-deoxyglucose uptake and cytochrome oxidase mRNA study in a macaque model of Parkinson’s disease. Eur J Neurosci 2007;25:1492–1500.CrossRefPubMedGoogle Scholar
  70. 70.
    Kuncel AM, Cooper SE, Wolgamuth BR, Grill WM. Amplitude- and frequency-dependent changes in neuronal regularity parallel changes in tremor with thalamic deep brain stimulation. IEEE Trans Neural Syst Rehabil Eng 2007;15: 190–197.CrossRefPubMedGoogle Scholar
  71. 71.
    Babadi B. Bursting as an effective relay mode in a minimal thalamic model. J Comput Neurosci 2005;18:229–243.CrossRefPubMedGoogle Scholar
  72. 72.
    Person AL, Perkel DJ. Unitary IPSPs drive precise thalamic spiking in a circuit required for learning. Neuron 2005;46:129–140.CrossRefPubMedGoogle Scholar
  73. 73.
    Schlag J, Villablanca J. A quantitative study of temporal and spatial response patterns in a thalamic cell population electrically stimulated. Brain Res 1968;8:255–270.CrossRefPubMedGoogle Scholar
  74. 74.
    McIntyre CC, Grill WM. Extracellular stimulation of central neurons: influence of stimulus waveform and frequency on neuronal output. J Neurophysiol 2002;88:1592–1604.PubMedGoogle Scholar
  75. 75.
    Rubin JE, Terman D. High frequency stimulation of the subthalamic nucleus eliminates pathological thalamic rhythmicity in a computational model. J Comput Neurosci 2004;16:211–235.CrossRefPubMedGoogle Scholar
  76. 76.
    Bevan MD, Magill PJ, Hallworth NE, Bolam JP, Wilson CJ. Regulation of the timing and pattern of action potential generation in rat subthalamic neurons in vitro by GABA-A IPSPs. J Neurophysiol 2002;87:1348–1362.PubMedGoogle Scholar
  77. 77.
    Hallworth NE, Bevan MD. Globus pallidus neurons dynamically regulate the activity pattern of subthalamic nucleus neurons through the frequency-dependent activation of postsynaptic GABAA and GABAB receptors. J Neurosci 2005;25:6304–6315.CrossRefPubMedGoogle Scholar
  78. 78.
    Stefani A, Lozano AM, Peppe A, et al. Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson’s disease. Brain 2007;130:1596–1607.CrossRefPubMedGoogle Scholar
  79. 79.
    Moro E, Lang AE, Strafella AP, et al. Bilateral globus pallidus stimulation for Huntington’s disease. Ann Neurol 2004;56:290–294.CrossRefPubMedGoogle Scholar
  80. 80.
    Hebb MO, Garcia R, Gaudet P, Mendez IM. Bilateral stimulation of the globus pallidus internus to treat choreathetosis in Huntington’s disease: technical case report. Neurosurgery 2006;58:E383; discussion E383.CrossRefPubMedGoogle Scholar
  81. 81.
    Alterman RL, Shils JL, Miravite J, Tagliati M. Lower stimulation frequency can enhance tolerability and efficacy of pallidal deep brain stimulation for dystonia. Mov Disord 2007;22:366–368.CrossRefPubMedGoogle Scholar
  82. 82.
    Kumar R, Dagher A, Hutchison WD, Lang AE, Lozano AM. Globus pallidus deep brain stimulation for generalized dystonia: clinical and PET investigation. Neurology 1999;53:871–874.PubMedGoogle Scholar
  83. 83.
    Mazzone P, Lozano A, Stanzione P, et al. Implantation of human pedunculopontine nucleus: a safe and clinically relevant target in Parkinson’s disease. Neuroreport 2005;16:1877–1881.CrossRefPubMedGoogle Scholar
  84. 84.
    Gomez-Gallego M, Fernandez-Villalba E, Femandez-Barreiro A, Herrero MT. Changes in the neuronal activity in the pedunculopontine nucleus in chronic MPTP-treated primates: an in situ hybridization study of cytochrome oxidase subunit I, choline acetyl transferase and substance P mRNA expression. J Neural Transm 2007;114:319–326.CrossRefPubMedGoogle Scholar
  85. 85.
    Starr PA, Rau GM, Davis V, et al. Spontaneous pallidal neuronal activity in human dystonia: comparison with Parkinson’s disease and normal macaque. J Neurophysiol 2005;93:3165–3176.CrossRefPubMedGoogle Scholar
  86. 86.
    Tang JK, Moro E, Mahant N, et al. Neuronal firing rates and patterns in the globus pallidus internus of patients with cervical dystonia differ from those with Parkinson’s disease. J Neurophysiol 2007;98:720–729.CrossRefPubMedGoogle Scholar
  87. 87.
    Wei XF, Grill WM. Current density distributions, field distributions and impedance analysis of segmented deep brain stimulation electrodes. J Neural Eng 2005;2:139–147.CrossRefPubMedGoogle Scholar
  88. 88.
    Feng XJ, Greenwald B, Rabitz H, Shea-Brown E, Kosut R. Toward closed-loop optimization of deep brain stimulation for Parkinson’s disease: concepts and lessons from a computational model. J Neural Eng 2007;4:L14–21.CrossRefPubMedGoogle Scholar

Copyright information

© Springer New York 2008

Authors and Affiliations

  1. 1.Department of Biomedical EngineeringDuke UniversityDurham

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