Abstract
Deep brain stimulation (DBS) and lesioning are two surgical techniques used in the treatment of advanced Parkinson’s disease (PD) in patients whose symptoms are not well controlled by drugs, or who experience dyskinesias as a side effect of medications. Although these treatments have been widely practiced, the mechanisms behind DBS and lesioning are still not well understood. The subthalamic nucleus (STN) and globus pallidus pars interna (GPi) are two common targets for both DBS and lesioning. Previous studies have indicated that DBS not only affects local cells within the target, but also passing axons within neighboring regions. Using a computational model of the basal ganglia-thalamic network, we studied the relative contributions of activation and silencing of local cells (LCs) and fibers of passage (FOPs) to changes in the accuracy of information transmission through the thalamus (thalamic fidelity), which is correlated with the effectiveness of DBS. Activation of both LCs and FOPs during STN and GPi-DBS were beneficial to the outcome of stimulation. During STN and GPi lesioning, effects of silencing LCs and FOPs were different between the two types of lesioning. For STN lesioning, silencing GPi FOPs mainly contributed to its effectiveness, while silencing only STN LCs did not improve thalamic fidelity. In contrast, silencing both GPi LCs and GPe FOPs during GPi lesioning contributed to improvements in thalamic fidelity. Thus, two distinct mechanisms produced comparable improvements in thalamic function: driving the output of the basal ganglia to produce tonic inhibition and silencing the output of the basal ganglia to produce tonic disinhibition. These results show the importance of considering effects of activating or silencing fibers passing close to the nucleus when deciding upon a target location for DBS or lesioning.
Similar content being viewed by others
References
Afsharpour, S. (1985). Light microscopic analysis of Golgi-impregnated rat subthalamic neurons. Journal of Computational Neurology, 236(1), 1–13.
Alvarez, L., Macias, R., Pavón, N., López, G., Rodríguez-Oroz, M. C., Rodríguez, R., et al. (2009). Therapeutic efficacy of unilateral subthalamotomy in Parkinson’s disease: results in 89 patients followed for up to 36 months. Journal of Neurology, Neurosurgery, and Psychiatry, 80(9), 979–985.
Aziz, T. Z., Peggs, D., Sambrook, M. A., & Crossman, A. R. (1991). Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate. Movement Disorders, 6(4), 288–292.
Baker, K. B., Lee, J. Y., Mavinkurve, G., Russo, G. S., Walter, B., DeLong, M. R., et al. (2010). Somatotopic organization in the internal segment of the globus pallidus in Parkinson’s disease. Experimental Neurology, 2, 219–225.
Bejjani, B., Damier, P., Arnulf, I., Bonnet, A. M., Vidailhet, M., Dormont, D., et al. (1997). Pallidal stimulation for Parkinson’s disease: two targets? Neurology, 49, 1564–1569.
Begman, H., Wichmann, T., & DeLong, M. R. (1990). Reversal of experimental parkinsonism by lesions of the STN. Science, 249, 1436–1438.
Bergman, H., Wichmann, T., Karmon, B., & DeLong, M. R. (1994). The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism. Journal of Neurophysiology, 72, 507–520.
Bergman, H., Feingold, A., Nini, A., Raz, A., Slovin, H., Abeles, M., et al. (1998). Physiological aspects of information processing in the basal ganglia of normal and parkinsonian primates. Trends in Neuroscience, 21, 32–28.
Benazzouz, A., Breit, S., Koudsie, A., Pollak, P., Krack, P., & Benabid, A. L. (2002). Intraoperative microrecordings of the subthalamic nucleus in Parkinson’s disease. Movement Disorders, 17(Suppl 3), S145–S149.
Beurrier, C., Congar, P., Bioulac, B., & Hammond, C. (1999). Subthalamic nucleus neurons switch from single-spike activity to burst-firing mode. Journal of Neuroscience, 19, 599–609.
Bevan, M. D., & Wilson, C. J. (1999). Mechanisms underlying spontaneous oscillation and rhythmic firing in rat subthalamic neurons. Journal of Neuroscience, 19(17), 7617–7628.
Birdno, M. J., & Grill, W. M. (2008). Mechanisms of deep brain stimulation in movement disorders as revealed by changes in stimulus frequency. Neurotherapeutics, 5(1), 14–25. Review.
Boraud, T., Bezard, E., Guehl, D., Bioulac, B., & Gross, C. (1998). Effects of L-DOPA on neuronal activity of the globus pallidus externalis (GPe) and globus pallidus internalis (GPi) in the MPTP-treated monkey. Brain Research, 787, 157–160.
Brown, P., Oliviero, A., Mazzone, P., Insola, A., Tonali, P., & Di Lazzaro, V. (2001). Dopamine dependency of oscillations between subthalamic nucleus and pallidum in Parkinson’s disease. Journal of Neuroscience, 21, 1033–1038.
Butson, C. R., Cooper, S. E., Henderson, J. M., Wolgamuth, B., & McIntyre, C. C. (2010). Probabilistic analysis of activation volumes generated during deep brain stimulation. NeuroImage, 54(3), 2096–2104.
Carpenter, M. B., Whittier, J. R., & Mettler, F. A. (1950). Analysis of choreoid hyperkinesia in the Rhesus monkey; surgical and pharmacological analysis of hyperkinesia resulting from lesions in the subthalamic nucleus of Luys. The Journal of Comparative Neurology, 92(3), 293–331.
Chang, J. W., Yang, J. S., Jeon, M. F., Lee, B. H., & Chung, S. S. (2003). Effect of subthalamic lesion with kainic acid on the neuronal activities of the basal ganglia of rat parkinsonian models with 6-hydroxydopamine. Acta Neurochirurgica. Supplement, 87, 163–168.
Coban, A., Hanagasi, H. A., Karamursel, S., & Barlas, O. (2009). Comparison of unilateral pallidotomy and subthalamotomy findings in advanced idiopathic Parkinson’s disease. British Journal of Neurosurgery, 23(1), 23–29.
Cooper, A. J., & Stanford, I. M. (2000). Electrophysiological and morphological characteristics of three subtypes of rat globus pallidus neurone in vitro. The Journal of Physiology, 527(Pt 2), 291–304.
Costa, R. M., Lin, S. C., Sotnikova, T. D., Cyr, M., Gainetdinov, R. R., Caron, M. G., et al. (2006). Rapid alterations in corticostriatal ensemble coordination during acute dopamine-dependent motor dysfunction. Neuron, 52, 359–369.
Destexhe, A., Neubig, M., Ulrich, D., & Huguenard, J. (1998). Dendritic low-threshold calcium currents in thalamic relay cells. Journal of Neuroscience, 18(10), 3574–3588.
Dorval, A. D., Russo, G. S., Hashimoto, T., Xu, W., Grill, W. M., & Vitek, J. L. (2009). Deep brain stimulation reduces neuronal entropy in the MPTP-primate model of Parkinson’s disease. Journal of Neurophysiology, 100, 2807–2818.
Dorval, A. D., Kuncel, A. M., Birdno, M. J., Turner, D. A., & Grill, W. M. (2010). Deep brain stimulation alleviates parkinsonian bradykinesia by regularizing pallidal activity. Journal of Neurophysiology, 801.
Eusebio, A., Chen, C. C., Lu, C. S., Lee, S. T., Tsai, C. H., Limousin, P., et al. (2008). Effects of low-frequency stimulation of the subthalamic nucleus on movement in Parkinson’s disease. Experimental Neurology, 209, 125–130.
Feng, X. J., Shea-Brown, E., Greenwald, B., Kosut, R., & Rabitz, H. (2007). Optimal deep brain stimulation of the subthalamic nucleus–a computational study. Journal of Computational Neuroscience, 23(3), 265–282.
Fogelson, N., Kühn, A. A., Silberstein, P., Limousin, P. D., Hariz, M., Trottenberg, T., et al. (2005). Frequency dependent effects of subthalamic nucleus stimulation in Parkinson’s disease. Neuroscience Letters, 382, 5–9.
Garcia, L., D’Alessandro, G., Fernagut, P. O., Bioulac, B., & Hammond, C. (2005). Impact of high-frequency stimulation parameters on the pattern of discharge of subthalamic neurons. Journal of Neurophysiology, 94, 3662–3669.
Godinho, F., Thobois, S., Magnin, M., Guenot, M., Polo, G., Benatru, I., et al. (2006). Subthalamic nucleus stimulation in Parkinson’s disease: anatomical and electrophysiological localization of active contacts. Journal of Neurology, 253, 1347–1355.
Grill, W. M., Snyder, A. N., & Miocinovic, S. (2004). Deep brain stimulation creates an informational lesion of the stimulated nucleus. Neuroreport, 15, 1137–1140.
Gross, R. E. (2008). What happened to posteroventral pallidotomy for Parkinson’s disease and dystonia? Neurotherapeutics, 5(2), 281–293.
Guo, Y., Rubin, J. E., McIntyre, C. C., Vitek, J. L., & Terman, D. (2008). Thalamocortical relay fidelity varies across subthalamic nucleus deep brain stimulation protocols in a data-driven computation model. Journal of Neurophysiology, 99, 1477–1492.
Hahn, P. J., Hashimoto, T., Russo, G. S., Xu, W., Miocinovic, S., Mcintyre, C., et al. (2008). Pallidal burst activity during therapeutic deep brain stimulation. Experimental Neurology, 211, 243–251.
Hahn, P. J., & McIntyre, C. C. (2010). Modeling shifts in the rate and pattern of subthalamopallidal network activity during deep brain stimulation. Journal of Computational Neuroscience, 28, 425–441.
Hallworth, N., Wilson, C., & Bevan, M. (2003). Apamin-sensitive small conductance calcium-activated potassium channels, through their selective coupling to voltage-gated calcium channels, are critical determinants of the precision, pace, and pattern of action potential generation in rat. Journal of Neuroscience, 23, 7525–7542.
Hamel, W., Fietzek, U., Morsnowski, A., Schrader, B., Herzog, J., Weinert, D., et al. (2003). Deep brain stimulation of the subthalamic nucleus in Parkinson’s disease: evaluation of active electrode contacts. Journal of Neurology, Neurosurgery, and Psychiatry, 74, 1036–1046.
Hashimoto, T., Elder, C. M., Okun, M. S., Patrick, S. K., & Vitek, J. L. (2003). Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons. Journal of Neuroscience, 23, 1916–1923.
Hassini, O. K., Mouroux, M., & Feger, J. (1996). Increased subthalamic neuronal activity after nigral dopaminergic lesion independent of disinhibition via the globus pallidus. Neuroscience, 72, 105–115.
Jahnsen, H., & Llinas, R. (1984). Electrophysiological properties of guinea-pig thalamic neurones: an in vitro study. The Journal of Physiology, 349, 205–226.
Johnsen, E. L., Sunde, N., Mogensen, P. H., & Ostergaard, K. (2010). MRI verified STN stimulation site—gait improvement and clinical outcome. European Journal of Neurology, 17, 746–753.
Johnson, M. D., & McIntyre, C. C. (2008). Quantifying the neural elements activated and inhibited by globus pallidus deep brain stimulation. Journal of Neurophysiology, 100, 2549–2563.
Kita, H., & Kitai, S. T. (1991). Intracellular study of rat globus pallidus neurons: membrane properties and responses to neostriatal, subthalamic and nigral stimulation. Brain Research, 564, 296–305.
Kita, H., & Kita, T. (2011). Role of striatum in the pause and burst generation in the globus pallidus of 6-OHDA-treated rats. Frontiers in Systems Neuroscience, 5, 1–11.
Kleiner-Fisman, G., Lozano, A., Moro, E., Poon, Y. Y., & Lang, A. E. (2010). Long-term effect of unilateral pallidotomy on levodopa-induced dyskinesia. Movment Disorders, 25(10), 1496–1498.
Krack, P., Pollak, P., Limousin, P., Hoffmann, D., Benazzouz, A., Le Bas, J. F., et al. (1998). Opposite motor effects of pallidal stimulation in Parkinson’s disease. Annals of Neurology, 43, 180–192.
Kuncel, A. M., & Grill, W. M. (2004) Selection of stimulus parameters for deep brain stimulation. Clinical Neurophysiology, 115(11), 2431–2441.
Levy, R., Hutchison, W. D., Lozano, A. M., & Dostrovsky, J. O. (2000). High-frequency synchronization of neuronal activity in the subthalamic nucleus of parkinsonian patients with limb tremor. Journal of Neuroscience, 20, 7766–7775.
Levy, R., Ashby, P., Hutchison, W. D., Lang, A. E., Lozano, A. M., & Dostrovsky, J. O. (2002). Dependence of subthalamic nucleus oscillations on movement and dopamine in Parkinson’s disease. Brain, 125, 1196–1209.
Magill, P. J., Bolam, J. P., & Bevan, M. D. (2001). Dopamine regulates the impact of the cerebral cortex on the subthalamic nucleus globus pallidus network. Neuroscience, 106, 313–330.
Magnin, M., Morel, A., & Jeanmonod, D. (2000). Single-unit analysis of the pallidum, thalamus and subthalamic nucleus in parkinsonian patients. Neuroscience, 96, 549–564.
Mallet, N., Pogosyan, A., Márton, L. F., Bolam, P. B. J., Peter, B., & Magill, P. J. (2008). Parkinsonian beta oscillations in the external globus pallidus and their relationship with subthalamic nucleus activity. Journal of Neuroscience, 28, 14245–14258.
McIntyre, C. C., Grill, W. M., Sherman, D. L., & Thakor, N. V. (2004). Cellular effects of deep brain stimulation: model-based analysis of activation and inhibition. Journal of Neurophysiology, 91, 1457–1469.
McIntyre, C. C., & Hahn, P. J. (2009). Network perspectives on the mechanisms of deep brain stimulation. Neurobiology of Disease, 38(3), 329–337.
Miocinovic, S., Parent, M., Butson, C. R., Hahn, P. J., Russo, G. S., Vitek, J. L., et al. (2006). Computational analysis of subthalamic nucleus and lenticular fasciulus activation during therapeutic deep brain stimulation. Journal of Neurophysiology, 96, 1569–1580.
Moro, E., Esselink, R. J., Xie, J., Hommel, M., Benabid, A. L., & Pollak, P. (2002). The impact on Parkinson’s disease of electrical parameter settings in STN stimulation. Neurology, 59, 706–713.
Moro, E., Lozano, A. M., Pollak, P., Agid, Y., Rehncrona, S., Volkmann, J., et al. (2010). Long-term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson’s disease. Movement Disorders, 25, 578–586.
Montgomery, E. B., Jr. (2005). Effect of subthalamic nucleus stimulation patterns on motor performance in Parkinson’s disease. Parkinsonism & Related Disorders, 11, 167–171.
Nambu, A., & Llinas, R. (1994). Electrophysiology of globus pallidus neurons in vitro. Journal of Neurophysiology, 72, 1127–1139.
Nishio, M., Korematsu, K., Yoshioka, S., Nagai, Y., Maruo, T., Ushio, Y., et al. (2009). Long-term suppression of tremor by deep brain stimulation of the ventral intermediate nucleus of the thalamus combined with pallidotomy in hemiparkinsonian patients. Journal of Clinical Neuroscience, 16(11), 1489–1491.
Obwegeser, A. A., Uitti, R. J., Lucas, J. A., Witte, R. J., Turk, M. F., Galiano, K., et al. (2008). Correlation of outcome to neurosurgical lesions: confirmation of a new method using data after microelectrode-guided pallidotomy. British Journal of Neurosurgery, 22(5), 654–662.
Okun, M. S., & Vitek, J. L. (2004). Lesion therapy for Parkinson’s disease and other movement disorders: update and controversies. Movement Disorders, 19(4), 375–389.
Parent, A., Sato, F., Wu, Y., Gauthier, J., Lévesque, M., & Parent, M. (2000). Organization of the basal ganglia: the importance of axonal collateralization. Trends in Neuroscience, 10(Suppl), S20–S27.
Parent, M., Lévesque, M., & Parent, A. (2001). Two types of projection neurons in the internal pallidum of primates: single-axon tracing and three-dimensional reconstruction. The Journal of Comparative Neurology, 439, 162–175.
Parent, M., & Parent, A. (2004). The pallidofugal motor fiber system in primates. Parkinsonism & Related Disorders, 10, 203–211.
Patel, N. K., Heywood, P., O’Sullivan, K., McCarter, R., Love, S., & Gill, S. S. (2003). Unilateral subthalamotomy in the treatment of Parkinson’s disease. Brain, 126(Pt 5), 1136–1145.
Pirini, M., Rocchi, L., Sensi, M., & Chiari, L. (2009). A computational modelling approach to investigate different targets in deep brain stimulation for Parkinson’s disease. Journal of Computational Neuroscience, 26(1), 91–107.
Plenz, D., & Kital, S. T. (1999). A basal ganglia pacemaker formed by the subthalamic nucleus and external globus pallidus. Nature, 400, 677–682.
Pollo, C., Vingerhoets, F., Pralong, E., Ghika, J., Maeder, P., Meuli, R., et al. (2007). Localization of electrodes in the subthalamic nucleus on magnetic resonance imaging. Journal of Neurosurgery, 106, 36–44.
Rubin, J. E., & Terman, D. (2004). High frequency stimulation of the subthalamic nucleus eliminates pathological thalamic rhythmicity in a computational model. Journal of Computational Neuroscience, 16, 211–235.
Sato, F., Lavallée, P., Lévesque, M., & Parent, A. (2000). Single-axon tracing study of neurons of the external segment of the globus pallidus in primate. The Journal of Comparative Neurology, 417, 17–31.
Smith, Y., Bevan, M. D., Shink, E., & Bolam, J. P. (1998). Microcircuitry of the direct and indirect pathways of the basal ganglia. Neuroscience, 86, 353–387.
Stanford, I. M. (2003) Independent Neuronal Oscillators of the Rat Globus Pallidus. Journal of Neurophysiology, 89, 1713–1717.
St George, R. J., Nutt, J. G., Burchiel, K. J., & Horak, F. B. (2010). A meta-regression of the long-term effects of deep brain stimulation on balance and gait in PD. Neurology, 75(14), 1292–1299.
Steigerwald, F., Pötter, M., Herzog, J., Pinsker, M., Kopper, F., Mehdorn, H., et al. (2008). Neuronal activity of the human subthalamic nucleus in the parkinsonian and nonparkinsonian state. Journal of Neurophysiology, 100, 2515–2524.
Su, P. C., Tseng, H. M., Liu, H. M., Yen, R. F., & Liou, H. H. (2002). Subthalamotomy for advanced Parkinson disease. Journal of Neurosurgery, 97(3), 598–606.
Tarsy, D. (2009). Does subthalamotomy have a place in the treatment of Parkinson’s disease? Journal of Neurology, Neurosurgery and Psychiatry, 80(9), 939–940.
Terman, D., Rubin, J. E., Yew, A. C., & Wilson, C. J. (2002). Activity patterns in a model for the subthalamopallidal network of the basal ganglia. Journal of Neuroscience, 22, 2963–2976.
Timmermann, L., Wojtecki, L., Gross, J., Lehrke, R., Voges, J., Maarouf, M., et al. (2004). Ten-hertz stimulation of subthalamic nucleus deteriorates motor symptoms in Parkinson’s disease. Movement Disorders, 19, 1328–1333.
Voges, J., Volkmann, J., Allert, N., Lehrke, R., Koulousakis, A., Freund, H. J., et al. (2002). Bilateral high-frequency stimulation in the subthalamic nucleus for the treatment of Parkinson disease: correlation of therapeutic effect with anatomical electrode position. Journal of Neurosurgery, 96, 269–279.
Weaver, F. M., Follett, K., Stern, M., Hur, K., Harris, C., Marks, W. J., Jr., et al. (2009). Bilateral deep brain stimulation vs best medical therapy for patients with advanced parkinson disease: a randomized controlled trial. JAMA, 301, 63–73.
Wilson, C. J., Weyrick, A., Terman, D., Hallworth, N. E., & Bevan, M. D. (2004). A model of reverse spike frequency adaptation and repetitive firing of subthalamic nucleus neurons. Journal of Neurophysiology, 91, 1963–1980.
Wilson, C. L., Cash, D., Galley, K., Chapman, H., Lacey, M. G., & Stanford, I. M. (2006). Subthalamic nucleus neurones in slices from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice show irregular, dopamine-reversible firing pattern changes, but without synchronous activity. Neuroscience, 143, 565–572.
Wichmann, T., Bergman, H., & DeLong, M. R. (1994). 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. Journal of Neurophysiology, 72, 521–530.
Wichmann, T., & Soares, J. (2006). Neuronal firing before and after burst discharges in the monkey basal ganglia is predictably patterned in the normal state and altered in parkinsonism. Journal of Neurophysiology, 95, 2120–2133.
Xu, W., Russo, G. S., Hashimoto, T., Zhang, J., & Vitek, J. L. (2008). Subthalamic nucleus stimulation modulates thalamic neuronal activity. Journal of Neuroscience, 28, 11916–11924.
Yelnik, J., Damier, P., Demeret, S., Gervais, D., Bardinet, E., Bejjani, B. P., et al. (2003). Localization of stimulating electrodes in patients with Parkinson disease by using a three-dimensional atlas-magnetic resonance imaging coregistration method. Journal of Neurosurgery, 99, 89–99.
Yokoyama, T., Ando, N., Sugiyama, K., Akamine, S., & Namba, H. (2006). Relationship of stimulation site location within the subthalamic nucleus region to clinical effects on parkinsonian symptoms. Stereotactic and Functional Neurosurgery, 84(4), 70–175.
Zonenshayn, M., Sterio, D., Kelly, P. J., Rezai, A. R., & Beric, A. (2004). Location of the active contact within the subthalamic nucleus (STN) in the treatment of idiopathic Parkinson’s disease. Surgical Neurology, 62, 216–226.
Author information
Authors and Affiliations
Corresponding author
Additional information
Action Editor: Gaute T. Einevoll
This work was supported in part by a grant from the US National Institutes of Health (NIH R01 NS040894) and in part by Singapore A*STAR BS-PhD National Science Scholarship.
Appendix A
Appendix A
Here we describe the equations and parameters used for each cell type and for the synaptic connections. All potentials have the unit of mV, conductances have the unit of mS/cm2, currents have unit of uA/cm2, and time constants have unit of msec. For all cell models the membrane capacitance is 1 uF/cm2.
Membrane potentials (v) of the TH cells were governed by the equations:
Membrane potentials (v) of the STN cells were governed by the equations:
GPe and GPi cells were modeled similarly. Membrane potentials (v) of the GP cells were governed by the equations:
Rights and permissions
About this article
Cite this article
So, R.Q., Kent, A.R. & Grill, W.M. Relative contributions of local cell and passing fiber activation and silencing to changes in thalamic fidelity during deep brain stimulation and lesioning: a computational modeling study. J Comput Neurosci 32, 499–519 (2012). https://doi.org/10.1007/s10827-011-0366-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10827-011-0366-4