帕金森氏症是常見的神經退化性疾病之ㄧ。帕金森氏症的成因是由於大腦調控自主運動功能的黑質緻密﹙SNc﹚中的多巴胺神經元退化，導致顫抖、動作遲緩或肌肉僵直等運動功能障礙。在早期的病程中，給予多巴胺的替代藥物是常見且有效的治療手段，但無法減緩多巴胺神經元損失的惡化。重複性經顱刺激﹙rTMS﹚及皮質電刺激﹙CES﹚的技術已被應用於神經性退化性疾病上，其神經可塑性的機制對於運動皮質的興奮性調節，被認為對帕金森氏症具有治療的潛力。在過去的研究當中顯示，由6-羥基多巴胺﹙6-OHDA﹚所誘發的單側帕金森氏症大鼠，在透過間歇性陣列式﹙iTBS﹚皮質電刺激後，對其喪失的運動功能具有改善效果。
為了探討陣列式脈衝刺激在帕金森氏症的運動功能上的機制，我們建立6-羥基多巴胺所誘發的慢性單側帕金森氏症大鼠，用以評估陣列式皮質電刺激在於阿朴嗎啡誘發之旋轉行為時的影響，並以滾輪測試及腦皮質電訊號觀測期病況的進程。在透過陣列式皮質電刺激介入的旋轉測試下，發現間歇性陣列式刺激對阿朴嗎啡誘發之旋轉有抑制的效果，相反地，連續性陣列式刺激﹙cTBS﹚則提升了整體的旋轉圈數。透過皮質腦電圖的觀測，發現一個約略30赫茲的貝塔頻帶在慢性單側帕金森氏症大鼠的患側皮質上，並可透過連續性陣列式的皮質電刺激對其進行抑制性的調節。
我們假設連續性陣列式皮質電刺激對於單側帕金森氏症的患側腦所產生的貝塔頻帶抑制效果，是透過運動皮質與丘腦下核的投射路徑影響丘腦下核的訊號抑制。實驗結果顯示，透過刺激運動皮質與丘腦下核的投射路徑，可用來調節帕金森氏症的運動功能以及丘腦下核的過度活化。其實驗結果驗證了在運動皮質上的陣列式刺激對於帕金森氏症的治療效果。

Parkinson’s disease (PD) is one of most neuron degenerative disorders that affects in 1% of the population resulting from the degeneration of the dopaminergic neurons of the substantia nigra pars compacta (SNc). The common symptoms are inability of controlling voluntary movements and disturbances of motor performance, such as tremor, frigidity, bradykinesia and gait movement. In the early stages of PD, substitutive dopaminergic therapy can improves motor symptoms significantly, but usually cannot slow down the progress of degeneration. In addition to the pharmacological treatment, various techniques such as repetitive Transcranial magnetic stimulation (rTMS) or cortical electrical stimulation (CES) have been developed for modulation cortical excitability through the plastic-like mechanisms, which are considered to having the therapeutic potential for the brain degenerative diseases such as PD. In our previously studies, 6-hydroxydopamine (6-OHDA) induced Hemiparkinsonian rats model has been used to investigate the gait performance after the modulation by CES with theta burst stimulation (TBS) protocol. The results showed that CES with intermittent TBS (iTBS) protocol could improve gait performance including stride length and speed in 6-OHDA-lesioned PD model rats. However, the therapeutic mechanisms of TBS on PD are still unclear. In this research, apomorphine-induced rotation and rota-rod test were performing to evaluate the motor function in hemiparkinsonian rat. In the result, the latency of fall of rota-rod gradually decreased after the lesion of 6-OHDA, the rotation also found to be increased as the progress of MFB lesion. For the CES-TBS, the total number of rotations decreased after the intervention of iTBS compared to the increased rotation induced by continuous TBS (cTBS). A 30 Hz band was observed in electrocorticography (ECoG) on 6-OHDA ipsilateral lesioned site. The 30 Hz band ECoG was suppressed after 30-minite of cTBS but not in iTBS. The suppression of beta band oscillation by cTBS may be mediated through M1-STN projection and be coupled with STN suppression. These findings agree with the hypothesis that M1-cTBS treatment can modulate parkinsonian behavior and STN hyperactivity through M1-STN projection. Our results support the idea that M1 could be a potential target for TBS therapy in PD.

Adkins-Muir, D. L., & Jones, T. A. (2003). Cortical electrical stimulation combined with rehabilitative training: enhanced functional recovery and dendritic plasticity following focal cortical ischemia in rats. Neurol Res, 25(8), 780-788. doi:10.1179/016164103771953853
Albin, R. L., Young, A. B., & Penney, J. B. (1995). The functional anatomy of disorders of the basal ganglia. Trends Neurosci, 18(2), 63-64.
Alexander, G. E., DeLong, M. R., & Strick, P. L. (1986). Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci, 9, 357-381. doi:10.1146/annurev.ne.09.030186.002041
Alm, P. A., & Dreimanis, K. (2013). Neuropathic pain: transcranial electric motor cortex stimulation using high frequency random noise. Case report of a novel treatment. J Pain Res, 6, 479-486. doi:10.2147/JPR.S44648
Aroniadou, V. A., & Keller, A. (1995). Mechanisms of LTP induction in rat motor cortex in vitro. Cereb Cortex, 5(4), 353-362.
Bamford, N. S., Zhang, H., Schmitz, Y., Wu, N. P., Cepeda, C., Levine, M. S., . . . Sulzer, D. (2004). Heterosynaptic dopamine neurotransmission selects sets of corticostriatal terminals. Neuron, 42(4), 653-663.
Barker, A. T., Jalinous, R., & Freeston, I. L. (1985). Non-invasive magnetic stimulation of human motor cortex. Lancet, 1(8437), 1106-1107.
Benninger, D. H., Berman, B. D., Houdayer, E., Pal, N., Luckenbaugh, D. A., Schneider, L., . . . Hallett, M. (2011). Intermittent theta-burst transcranial magnetic stimulation for treatment of Parkinson disease. Neurology, 76(7), 601-609. doi:10.1212/WNL.0b013e31820ce6bb
Bliss, T. V., & Lomo, T. (1973). Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol, 232(2), 331-356.
Braak, H., Del Tredici, K., Rub, U., de Vos, R. A., Jansen Steur, E. N., & Braak, E. (2003). Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging, 24(2), 197-211.
Braunewell, K. H., & Manahan-Vaughan, D. (2001). Long-term depression: a cellular basis for learning? Rev Neurosci, 12(2), 121-140.
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. The Journal of Neuroscience, 21(3), 1033.
Brown, P., & Williams, D. (2005). Basal ganglia local field potential activity: character and functional significance in the human. Clin Neurophysiol, 116(11), 2510-2519. doi:10.1016/j.clinph.2005.05.009
Bury, S. D., & Jones, T. A. (2002). Unilateral Sensorimotor Cortex Lesions in Adult Rats Facilitate Motor Skill Learning with the “Unaffected” Forelimb and Training-Induced Dendritic Structural Plasticity in the Motor Cortex. The Journal of Neuroscience, 22(19), 8597.
Calabresi, P., Pisani, A., Centonze, D., & Bernardi, G. (1997). Synaptic plasticity and physiological interactions between dopamine and glutamate in the striatum. Neurosci Biobehav Rev, 21(4), 519-523.
Cardenas-Morales, L., Nowak, D. A., Kammer, T., Wolf, R. C., & Schonfeldt-Lecuona, C. (2010). Mechanisms and applications of theta-burst rTMS on the human motor cortex. Brain Topogr, 22(4), 294-306. doi:10.1007/s10548-009-0084-7
Cassidy, M., Mazzone, P., Oliviero, A., Insola, A., Tonali, P., Di Lazzaro, V., & Brown, P. (2002). Movement-related changes in synchronization in the human basal ganglia. Brain, 125(Pt 6), 1235-1246.
Cepeda, C., Hurst, R. S., Altemus, K. L., Flores-Hernandez, J., Calvert, C. R., Jokel, E. S., . . . Levine, M. S. (2001). Facilitated glutamatergic transmission in the striatum of D2 dopamine receptor-deficient mice. J Neurophysiol, 85(2), 659-670. doi:10.1152/jn.2001.85.2.659
Chen, R., Cros, D., Curra, A., Di Lazzaro, V., Lefaucheur, J. P., Magistris, M. R., . . . Ziemann, U. (2008). The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol, 119(3), 504-532. doi:10.1016/j.clinph.2007.10.014
Chen, R., & Udupa, K. (2009). Measurement and modulation of plasticity of the motor system in humans using transcranial magnetic stimulation. Motor Control, 13(4), 442-453.
Chen, Y.-H., Kuo, T.-T., Kao, J.-H., Huang, E. Y.-K., Hsieh, T.-H., Chou, Y.-C., & Hoffer, B. J. (2018). Exercise Ameliorates Motor Deficits and Improves Dopaminergic Functions in the Rat Hemi-Parkinson’s Model. Scientific Reports, 8(1), 3973. doi:10.1038/s41598-018-22462-y
Degardin, A., Devos, D., Defebvre, L., Destee, A., Plomhause, L., Derambure, P., & Devanne, H. (2012). Effect of intermittent theta-burst stimulation on akinesia and sensorimotor integration in patients with Parkinson's disease. Eur J Neurosci, 36(5), 2669-2678. doi:10.1111/j.1460-9568.2012.08158.x
DeLong, M., & Wichmann, T. (2009). Update on models of basal ganglia function and dysfunction. Parkinsonism Relat Disord, 15 Suppl 3, S237-240. doi:10.1016/S1353-8020(09)70822-3
Duffau, H. (2006). Brain plasticity: from pathophysiological mechanisms to therapeutic applications. J Clin Neurosci, 13(9), 885-897. doi:10.1016/j.jocn.2005.11.045
Elahi, B., Elahi, B., & Chen, R. (2009). Effect of transcranial magnetic stimulation on Parkinson motor function--systematic review of controlled clinical trials. Mov Disord, 24(3), 357-363. doi:10.1002/mds.22364
Fagundes-Pereyra, W. J., Teixeira, M. J., Reyns, N., Touzet, G., Dantas, S., Laureau, E., & Blond, S. (2010). Motor cortex electric stimulation for the treatment of neuropathic pain. Arq Neuropsiquiatr, 68(6), 923-929.
Fasano, A., Piano, C., De Simone, C., Cioni, B., Di Giuda, D., Zinno, M., . . . Bentivoglio, A. R. (2008). High frequency extradural motor cortex stimulation transiently improves axial symptoms in a patient with Parkinson's disease. Mov Disord, 23(13), 1916-1919. doi:10.1002/mds.21977
Ghiglieri, V., Pendolino, V., Sgobio, C., Bagetta, V., Picconi, B., & Calabresi, P. (2012). Theta-burst stimulation and striatal plasticity in experimental parkinsonism. Exp Neurol, 236(2), 395-398. doi:10.1016/j.expneurol.2012.04.020
Gradinaru, V., Mogri, M., Thompson, K. R., Henderson, J. M., & Deisseroth, K. (2009). Optical deconstruction of parkinsonian neural circuitry. Science, 324(5925), 354-359. doi:10.1126/science.1167093
Haber, S. N. (2003). The primate basal ganglia: parallel and integrative networks. J Chem Neuroanat, 26(4), 317-330.
Hammond, C., Ammari, R., Bioulac, B., & Garcia, L. (2008). Latest view on the mechanism of action of deep brain stimulation. Mov Disord, 23(15), 2111-2121. doi:10.1002/mds.22120
Hernandez-Lopez, S., Tkatch, T., Perez-Garci, E., Galarraga, E., Bargas, J., Hamm, H., & Surmeier, D. J. (2000). D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLC[beta]1-IP3-calcineurin-signaling cascade. J Neurosci, 20(24), 8987-8995.
Hsieh, T. H., Huang, Y. Z., Rotenberg, A., Pascual-Leone, A., Chiang, Y. H., Wang, J. Y., & Chen, J. J. (2015). Functional Dopaminergic Neurons in Substantia Nigra are Required for Transcranial Magnetic Stimulation-Induced Motor Plasticity. Cereb Cortex, 25(7), 1806-1814. doi:10.1093/cercor/bht421
Huang, Y. Z., Edwards, M. J., Rounis, E., Bhatia, K. P., & Rothwell, J. C. (2005). Theta burst stimulation of the human motor cortex. Neuron, 45(2), 201-206. doi:10.1016/j.neuron.2004.12.033
Huang, Y. Z., Rothwell, J. C., Edwards, M. J., & Chen, R. S. (2008). Effect of physiological activity on an NMDA-dependent form of cortical plasticity in human. Cereb Cortex, 18(3), 563-570. doi:10.1093/cercor/bhm087
Huang, Y. Z., Rothwell, J. C., Lu, C. S., Chuang, W. L., & Chen, R. S. (2011). Abnormal bidirectional plasticity-like effects in Parkinson's disease. Brain, 134(Pt 8), 2312-2320. doi:10.1093/brain/awr158
Hummel, F. C., & Cohen, L. G. (2005). Drivers of brain plasticity. Curr Opin Neurol, 18(6), 667-674.
Kanno, M., Matsumoto, M., Togashi, H., Yoshioka, M., & Mano, Y. (2004). Effects of acute repetitive transcranial magnetic stimulation on dopamine release in the rat dorsolateral striatum. J Neurol Sci, 217(1), 73-81.
Keck, M. E., Welt, T., Muller, M. B., Erhardt, A., Ohl, F., Toschi, N., . . . Sillaber, I. (2002). Repetitive transcranial magnetic stimulation increases the release of dopamine in the mesolimbic and mesostriatal system. Neuropharmacology, 43(1), 101-109.
Kobayashi, M., & Pascual-Leone, A. (2003). Transcranial magnetic stimulation in neurology. Lancet Neurol, 2(3), 145-156.
Lang, A. E., & Lozano, A. M. (1998). Parkinson's disease. First of two parts. N Engl J Med, 339(15), 1044-1053. doi:10.1056/NEJM199810083391506
Lefaucheur, J. P. (2006). Repetitive transcranial magnetic stimulation (rTMS): insights into the treatment of Parkinson's disease by cortical stimulation. Neurophysiol Clin, 36(3), 125-133. doi:10.1016/j.neucli.2006.08.003
Lefaucheur, J. P., Drouot, X., Von Raison, F., Menard-Lefaucheur, I., Cesaro, P., & Nguyen, J. P. (2004). Improvement of motor performance and modulation of cortical excitability by repetitive transcranial magnetic stimulation of the motor cortex in Parkinson's disease. Clin Neurophysiol, 115(11), 2530-2541. doi:10.1016/j.clinph.2004.05.025
Lehmkuhle, M. J., Bhangoo, S. S., & Kipke, D. R. (2009). The Electrocorticogram Signal Can Be Modulated With Deep Brain Stimulation of the Subthalamic Nucleus in the Hemiparkinsonian Rat. Journal of Neurophysiology, 102(3), 1811-1820. doi:10.1152/jn.90844.2008
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(Pt 6), 1196-1209.
Mallet, N., Pogosyan, A., Sharott, A., Csicsvari, J., Bolam, J. P., Brown, P., & Magill, P. J. (2008). Disrupted dopamine transmission and the emergence of exaggerated beta oscillations in subthalamic nucleus and cerebral cortex. J Neurosci, 28(18), 4795-4806. doi:10.1523/JNEUROSCI.0123-08.2008
Metz, G. A., Tse, A., Ballermann, M., Smith, L. K., & Fouad, K. (2005). The unilateral 6-OHDA rat model of Parkinson's disease revisited: an electromyographic and behavioural analysis. Eur J Neurosci, 22(3), 735-744. doi:10.1111/j.1460-9568.2005.04238.x
Monville, C., Torres, E. M., & Dunnett, S. B. (2006). Comparison of incremental and accelerating protocols of the rotarod test for the assessment of motor deficits in the 6-OHDA model. J Neurosci Methods, 158(2), 219-223. doi:10.1016/j.jneumeth.2006.06.001
Nambu, A., Tokuno, H., & Takada, M. (2002). Functional significance of the cortico-subthalamo-pallidal 'hyperdirect' pathway. Neurosci Res, 43(2), 111-117.
Pascual-Leone, A., Tormos, J. M., Keenan, J., Tarazona, F., Canete, C., & Catala, M. D. (1998). Study and modulation of human cortical excitability with transcranial magnetic stimulation. J Clin Neurophysiol, 15(4), 333-343.
Pascual-Leone, A., Valls-Sole, J., Wassermann, E. M., & Hallett, M. (1994). Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain, 117 ( Pt 4), 847-858.
Picconi, B., Centonze, D., Hakansson, K., Bernardi, G., Greengard, P., Fisone, G., . . . Calabresi, P. (2003). Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia. Nat Neurosci, 6(5), 501-506. doi:10.1038/nn1040
Pilato, F., Profice, P., Ranieri, F., Capone, F., Di Iorio, R., Florio, L., & Di Lazzaro, V. (2012). Synaptic plasticity in neurodegenerative diseases evaluated and modulated by in vivo neurophysiological techniques. Mol Neurobiol, 46(3), 563-571. doi:10.1007/s12035-012-8302-9
Schrag, A., & Quinn, N. (2000). Dyskinesias and motor fluctuations in Parkinson's disease. A community-based study. Brain, 123 ( Pt 11), 2297-2305.
Schulz, R., Gerloff, C., & Hummel, F. C. (2013). Non-invasive brain stimulation in neurological diseases. Neuropharmacology, 64, 579-587. doi:10.1016/j.neuropharm.2012.05.016
Sharott, A., Magill, P. J., Harnack, D., Kupsch, A., Meissner, W., & Brown, P. (2005). Dopamine depletion increases the power and coherence of beta-oscillations in the cerebral cortex and subthalamic nucleus of the awake rat. Eur J Neurosci, 21(5), 1413-1422. doi:10.1111/j.1460-9568.2005.03973.x
Shirota, Y., Ohtsu, H., Hamada, M., Enomoto, H., Ugawa, Y., & Research Committee on r, T. M. S. T. o. P. s. D. (2013). Supplementary motor area stimulation for Parkinson disease: a randomized controlled study. Neurology, 80(15), 1400-1405. doi:10.1212/WNL.0b013e31828c2f66
Strafella, A. P., Paus, T., Fraraccio, M., & Dagher, A. (2003). Striatal dopamine release induced by repetitive transcranial magnetic stimulation of the human motor cortex. Brain, 126(Pt 12), 2609-2615. doi:10.1093/brain/awg268
Surmeier, D. J., Ding, J., Day, M., Wang, Z., & Shen, W. (2007). D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trends Neurosci, 30(5), 228-235. doi:10.1016/j.tins.2007.03.008
Tolwani, R. J., Jakowec, M. W., Petzinger, G. M., Green, S., & Waggie, K. (1999). Experimental models of Parkinson's disease: insights from many models. Lab Anim Sci, 49(4), 363-371.
Udupa, K., & Chen, R. (2013). Motor cortical plasticity in Parkinson's disease. Front Neurol, 4, 128. doi:10.3389/fneur.2013.00128
Xie, Y. F., Jackson, M. F., & Macdonald, J. F. (2013). Optogenetics and synaptic plasticity. Acta Pharmacol Sin, 34(11), 1381-1385. doi:10.1038/aps.2013.150
Zhuang, X., Mazzoni, P., & Kang, U. J. (2013). The role of neuroplasticity in dopaminergic therapy for Parkinson disease. Nat Rev Neurol, 9(5), 248-256. doi:10.1038/nrneurol.2013.57