巴金森氏症（Parkinson's disease，PD）是一種常見的退化性神經疾病，患者黑質緻密部腦區（substantia nigra pars compacta，SNc）多巴胺神經元退化甚至死亡，導致多巴胺分泌大量減少，造成黑質和紋狀體間神經路徑（nigrostriatal pathway）的運動調節功能喪失。對於藥物治療已無法起到良好效果的晚期重症巴金森氏症患者，腦深層電刺激（deep brain stimulation，DBS）是目前最為行之有效的替代療法，大部分患者接受視丘下核（subthalamic nucleus，STN）的腦深層電刺激治療後都可以有效控制自主運動、改善基本生活品質，但腦深層電刺激的治療機制目前仍不明確。我們對正常大鼠及巴金森氏症大鼠施予視丘下核的連續高頻電刺激並利用c-Fos蛋白作為神經細胞活化的標記物，通過免疫組織化學染色法和免疫螢光染色法觀察比較視丘下核腦深層電刺激對運動皮質中細胞活化的影響，進而探討視丘下核腦深層電刺激的治療機制。我們發現巴金森氏症大鼠接受視丘下核腦深層電刺激後在刺激側同側運動皮質第5層會出現一群c-Fos染色強度高且顆粒大的c-Fos蛋白強陽性細胞（gaint c-Fos positive cell），並且這種c-Fos蛋白強陽性細胞基本上僅出現在巴金森氏症大鼠對受損側同側施予電刺激的情況中。我的研究結果顯示大多數這種c-Fos蛋白強陽性細胞是會將神經纖維投射至視丘下核的PT型神經元（pyramidal tract type neuron），可經視丘下核腦深層電刺激在軸突上產生逆向傳導而活化。我們推測視丘下核腦深層電刺激的療效正是通過直接刺激電極周圍PT型神經元的軸突產生逆向傳導、進而活化多個運動相關腦區和神經訊號傳遞路徑達成的。

Parkinson's disease (PD) is a common neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), thereby leading to severe deprivation of dopaminergic input from SNc to the striatum. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective medical therapy in alleviating motor symptoms in moderate to sever PD patients. However, the mechanism of how DBS works remains unclear. In this study, I used c-Fos immunocytochemical staining to identify the motor cortex neurons whose activity were changed after STN-DBS and then characterized those cells exhibiting STN-DBS-dependent changes in their activities. I observed a group of larger and dark c-Fos positive cells (gaint c-Fos positive cell) in the layer Vb of the ipsilateral motor cortex after ipsilateral STN-DBS in PD rats, while similar neurons were not found in normal rats subjected to STN-DBS or in PD rats subjected to contralateral STN-DBS. The results of double-staining with the antibodies of c-Fos and of NeuN, GABA or SMI 32 indicated that most of the giant c-Fos positive cells were pyramidal tract type (PT-type) neurons whose descending axons could send out collaterals to and innervate STN. On the basis of my data, I propose that STN-DBS antidromically excited afferent axons which originated from the PT-type neuron and the therapeutic effects of STN-DBS may be due to, at least partly, by the activation of these afferent axons.

Benabid, A. L. (2003). "Deep brain stimulation for Parkinson's disease." Curr Opin Neurobiol 13(6): 696-706.
Benabid, A. L., Chabardes, S., Mitrofanis, J. and Pollak, P. (2009). "Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson's disease." Lancet Neurol 8(1): 67-81.
Bjorklund, A. and Dunnett, S. B. (2007). "Dopamine neuron systems in the brain: an update." Trends Neurosci 30(5): 194-202.
Bosch, C., Mailly, P., Degos, B., Deniau, J. M. and Venance, L. (2012). "Preservation of the hyperdirect pathway of basal ganglia in a rodent brain slice." Neuroscience 215: 31-41.
Byblow, W. D., Coxon, J. P., Stinear, C. M., Fleming, M. K., Williams, G., Muller, J. F. M. and Ziemann, U. (2007). "Functional connectivity between secondary and primary motor areas underlying hand-foot coordination." Journal of Neurophysiology 98(1): 414-422.
Carron, R., Chaillet, A., Filipchuk, A., Pasillas-Lepine, W. and Hammond, C. (2013). "Closing the loop of deep brain stimulation." Front Syst Neurosci 7: 112.
Chakravarthy, V. S., Joseph, D. and Bapi, R. S. (2010). "What do the basal ganglia do? A modeling perspective." Biological Cybernetics 103(3): 237-253.
Chiken, S. and Nambu, A. (2013). "High-frequency pallidal stimulation disrupts information flow through the pallidum by GABAergic inhibition." J Neurosci 33(6): 2268-2280.
Chiken, S. and Nambu, A. (2014). "Disrupting neuronal transmission: mechanism of DBS?" Front Syst Neurosci 8: 33.
Chomiak, T. and Hu, B. (2007). "Axonal and somatic filtering of antidromically evoked cortical excitation by simulated deep brain stimulation in rat brain." Journal of Physiology-London 579(2): 403-412.
Cirelli, C. and Tononi, G. (2000). "On the functional significance of c-fos induction during the sleep-waking cycle." Sleep 23(4): 453-469.
Degos, B., Deniau, J. M., Chavez, M. and Maurice, N. (2013). "Subthalamic nucleus high-frequency stimulation restores altered electrophysiological properties of cortical neurons in parkinsonian rat." PLoS One 8(12): e83608.
Deumens, R., Blokland, A. and Prickaerts, J. (2002). "Modeling Parkinson's disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway." Exp Neurol 175(2): 303-317.
Deuschl, G., Schade-Brittinger, C., Krack, P., Volkmann, J., Schafer, H., Botzel, K., Daniels, C., Deutschlander, A., Dillmann, U., Eisner, W., Gruber, D., Hamel, W., Herzog, J., Hilker, R., Klebe, S., Kloss, M., Koy, J., Krause, M., Kupsch, A., Lorenz, D., Lorenzl, S., Mehdorn, H. M., Moringlane, J. R., Oertel, W., Pinsker, M. O., Reichmann, H., Reuss, A., Schneider, G. H., Schnitzler, A., Steude, U., Sturm, V., Timmermann, L., Tronnier, V., Trottenberg, T., Wojtecki, L., Wolf, E., Poewe, W. and Voges, J. (2006). "A randomized trial of deep-brain stimulation for Parkinson's disease." N Engl J Med 355(9): 896-908.
Finlay, C. J., Duty, S. and Vernon, A. C. (2014). "Brain morphometry and the neurobiology of levodopa-induced dyskinesias: current knowledge and future potential for translational pre-clinical neuroimaging studies." Front Neurol 5: 95.
Glinka, Y., Gassen, M. and Youdim, M. B. H. (1997). "Mechanism of 6-hydroxydopamine neurotoxicity." Journal of Neural Transmission-Supplement(50): 55-66.
Gradinaru, V., Mogri, M., Thompson, K. R., Henderson, J. M. and Deisseroth, K. (2009). "Optical Deconstruction of Parkinsonian Neural Circuitry." Science 324(5925): 354-359.
Groenewegen, H. J. (2003). "The basal ganglia and motor control." Neural Plast 10(1-2): 107-120.
Hamani, C., Saint-Cyr, J. A., Fraser, J., Kaplitt, M. and Lozano, A. M. (2004). "The subthalamic nucleus in the context of movement disorders." Brain 127: 4-20.
Hashimoto, T., Elder, C. M., Okun, M. S., Patrick, S. K. and Vitek, J. L. (2003). "Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons." Journal of Neuroscience 23(5): 1916-1923.
Hauser, R. A., McDermott, M. P. and Messing, S. (2006). "Factors associated with the development of motor fluctuations and dyskinesias in Parkinson disease." Arch Neurol 63(12): 1756-1760.
He, Z., Jiang, Y. X., Xu, H. M., Jiang, H., Jia, W. T., Sun, P. and Xie, J. X. (2014). "High frequency stimulation of subthalamic nucleus results in behavioral recovery by increasing striatal dopamine release in 6-hydroxydopamine lesioned rat." Behavioural Brain Research 263: 108-114.
Hooks, B. M., Mao, T. Y., Gutnisky, D. A., Yamawaki, N., Svoboda, K. and Shepherd, G. M. G. (2013). "Organization of Cortical and Thalamic Input to Pyramidal Neurons in Mouse Motor Cortex." Journal of Neuroscience 33(2): 748-760.
Iravani, M. M. and Jenner, P. (2011). "Mechanisms underlying the onset and expression of levodopa-induced dyskinesia and their pharmacological manipulation." Journal of Neural Transmission 118(12): 1661-1690.
Jankovic, J. (2008). "Parkinson's disease: clinical features and diagnosis." J Neurol Neurosurg Psychiatry 79(4): 368-376.
Kahlig, K. M., Binda, F., Khoshbouei, H., Blakely, R. D., McMahon, D. G., Javitch, J. A. and Galli, A. (2005). "Amphetamine induces dopamine efflux through a dopamine transporter channel." Proceedings of the National Academy of Sciences of the United States of America 102(9): 3495-3500.
Khoshbouei, H., Sen, N., Guptaroy, B., Johnson, L., Lund, D., Gnegy, M. E., Galli, A. and Javitch, J. A. (2004). "N-terminal phosphorylation of the dopamine transporter is required for amphetamine-induced efflux." Plos Biology 2(3): 387-393.
Kim, S. W., Jang, Y. J., Chang, J. W. and Hwang, O. (2003). "Degeneration of the nigrostriatal pathway and induction of motor deficit by tetrahydrobiopterin: an in vivo model relevant to Parkinson's disease." Neurobiol Dis 13(2): 167-176.
Kita, T. and Kita, H. (2012). "The Subthalamic Nucleus Is One of Multiple Innervation Sites for Long-Range Corticofugal Axons: A Single-Axon Tracing Study in the Rat." Journal of Neuroscience 32(17): 5990-5999.
Kovacs, K. J. (2008). "Measurement of immediate-early gene activation-c-fos and beyond." Journal of Neuroendocrinology 20(6): 665-672.
Lang, A. E. and Lees, A. (2002). "Management of Parkinson's disease: An evidence-based review." Movement Disorders 17: I-I.
Lei, W., Jiao, Y., Del Mar, N. and Reiner, A. (2004). "Evidence for differential cortical input to direct pathway versus indirect pathway striatal projection neurons in rats." J Neurosci 24(38): 8289-8299.
Li, Q., Ke, Y., Chan, D. C., Qian, Z. M., Yung, K. K., Ko, H., Arbuthnott, G. W. and Yung, W. H. (2012). "Therapeutic deep brain stimulation in Parkinsonian rats directly influences motor cortex." Neuron 76(5): 1030-1041.
Li, S., Arbuthnott, G. W., Jutras, M. J., Goldberg, J. A. and Jaeger, D. (2007). "Resonant antidromic cortical circuit activation as a consequence of high-frequency subthalamic deep-brain stimulation." J Neurophysiol 98(6): 3525-3537.
Limousin, P., Krack, P., Pollak, P., Benazzouz, A., Ardouin, C., Hoffmann, D. and Benabid, A. L. (1998). "Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease." N Engl J Med 339(16): 1105-1111.
Lindenbach, D. and Bishop, C. (2013). "Critical involvement of the motor cortex in the pathophysiology and treatment of Parkinson's disease." Neurosci Biobehav Rev 37(10 Pt 2): 2737-2750.
Mathai, A. and Smith, Y. (2011). "The corticostriatal and corticosubthalamic pathways: two entries, one target. So what?" Front Syst Neurosci 5: 64.
McIntyre, C. C., Savasta, M., Walter, B. L. and Vitek, J. L. (2004). "How does deep brain stimulation work? Present understanding and future questions." J Clin Neurophysiol 21(1): 40-50.
Moran, A., Stein, E., Tischler, H., Belelovsky, K. and Bar-Gad, I. (2011). "Dynamic stereotypic responses of Basal Ganglia neurons to subthalamic nucleus high-frequency stimulation in the parkinsonian primate." Front Syst Neurosci 5: 21.
Nambu, A., Takada, M., Inase, M. and Tokuno, H. (1996). "Dual somatotopical representations in the primate subthalamic nucleus: evidence for ordered but reversed body-map transformations from the primary motor cortex and the supplementary motor area." J Neurosci 16(8): 2671-2683.
Nambu, A., Tokuno, H., Hamada, I., Kita, H., Imanishi, M., Akazawa, T., Ikeuchi, Y. and Hasegawa, N. (2000). "Excitatory cortical inputs to pallidal neurons via the subthalamic nucleus in the monkey." J Neurophysiol 84(1): 289-300.
Nambu, A., Tokuno, H. and Takada, M. (2002). "Functional significance of the cortico-subthalamo-pallidal 'hyperdirect' pathway." Neurosci Res 43(2): 111-117.
Okun, M. S., Fernandez, H. H., Wu, S. S., Kirsch-Darrow, L., Bowers, D., Bova, F., Suelter, M., Jacobson, C. E. t., Wang, X., Gordon, C. W., Jr., Zeilman, P., Romrell, J., Martin, P., Ward, H., Rodriguez, R. L. and Foote, K. D. (2009). "Cognition and mood in Parkinson's disease in subthalamic nucleus versus globus pallidus interna deep brain stimulation: the COMPARE trial." Ann Neurol 65(5): 586-595.
Okun, M. S. and Foote, K. D. (2010). "Parkinson's disease DBS: what, when, who and why? The time has come to tailor DBS targets." Expert Rev Neurother 10(12): 1847-1857.
Olanow, C. W. and Tatton, W. G. (1999). "Etiology and pathogenesis of Parkinson's disease." Annu Rev Neurosci 22: 123-144.
Pringsheim, T., Jette, N., Frolkis, A. and Steeves, T. D. (2014). "The prevalence of Parkinson's disease: A systematic review and meta-analysis." Mov Disord.
Qiu, M. H., Chen, M. C., Huang, Z. L. and Lu, J. (2014). "Neuronal activity (c-Fos) delineating interactions of the cerebral cortex and basal ganglia." Frontiers in Neuroanatomy 8.
Reiner, A., Jiao, Y., Del Mar, N., Laverghetta, A. V. and Lei, W. L. (2003). "Differential morphology of pyramidal tract-type and intratelencephalically projecting-type corticostriatal neurons and their intrastriatal terminals in rats." Journal of Comparative Neurology 457(4): 420-440.
Rezai, A. R., Machado, A. G., Deogaonkar, M., Azmi, H., Kubu, C. and Boulis, N. M. (2008). "Surgery for movement disorders." Neurosurgery 62 Suppl 2: 809-838; discussion 838-809.
Rodriguez-Pallares, J., Parga, J. A., Munoz, A., Rey, P., Guerra, A. J. and Labandeira-Garcia, J. L. (2007). "Mechanism of 6-hydroxydopamine neurotoxicity: the role of NADPH oxidase and microglial activation in 6-hydroxydopamine-induced degeneration of dopaminergic neurons." Journal of Neurochemistry 103(1): 145-156.
Romito, L. M. and Albanese, A. (2010). "Dopaminergic therapy and subthalamic stimulation in Parkinson's disease: a review of 5-year reports." Journal of Neurology 257: S298-S304.
Shehab, S., D'Souza, C., Ljubisavljevic, M. and Redgrave, P. (2014). "High-Frequency Electrical Stimulation of the Subthalamic Nucleus Excites Target Structures in a Model Using C-Fos Immunohistochemistry." Neuroscience 270: 212-225.
Shin, D. S., Samoilova, M., Cotic, M., Zhang, L., Brotchie, J. M. and Carlen, P. L. (2007). "High frequency stimulation or elevated K+ depresses neuronal activity in the rat entopeduncular nucleus." Neuroscience 149(1): 68-86.
Smith, M. A., Banerjee, S., Gold, P. W. and Glowa, J. (1992). "Induction of c-fos mRNA in rat brain by conditioned and unconditioned stressors." Brain Res 578(1-2): 135-141.
Vitek, J. L. (2008). "Deep brain stimulation: how does it work?" Cleve Clin J Med 75 Suppl 2: S59-65.
Voelker, C. C., Garin, N., Taylor, J. S., Gahwiler, B. H., Hornung, J. P. and Molnar, Z. (2004). "Selective neurofilament (SMI-32, FNP-7 and N200) expression in subpopulations of layer V pyramidal neurons in vivo and in vitro." Cereb Cortex 14(11): 1276-1286.
Windels, F., Carcenac, C., Poupard, A. and Savasta, M. (2005). "Pallidal origin of GABA release within the substantia nigra pars reticulata during high-frequency stimulation of the subthalamic nucleus." Journal of Neuroscience 25(20): 5079-5086.
Zwartjes, D. G., Heida, T., Feirabend, H. K., Janssen, M. L., Visser-Vandewalle, V., Martens, H. C. and Veltink, P. H. (2012). "Motor cortex stimulation for Parkinson's disease: a modelling study." J Neural Eng 9(5): 056005.