大腦皮質陣發型刺激(TBS)可藉由長期增益及長期衰減的機制來調控運動可塑性並改善其運動表現，在一些運動障礙的神經疾病例如帕金森氏症，陣發性刺激具有非侵入性的治療潛力，在大鼠研究中經過重複性經顱磁刺激(rTMS)以及皮質電刺激(CES)的多種陣發型刺激模式，藉由動作誘發電位可反映出運動可塑性的變化，並且可觀察到動作誘發電位在陣發性刺激前後有顯著的變化，間歇性陣發型刺激(iTBS)使得動作誘發電位上升，而連續性陣發型刺激(cTBS)則使動作誘發電位下降，然而，皮質刺激的機制仍然尚未釐清，傳統的電刺激模式刺激所有種類的細胞，難以去區別陣發性刺激在特定神經迴路與神經可塑性的影響，為了瞭解陣發性刺激調節神經可塑性的細胞機制，利用光基因法專一性的表現光敏感性通道視紫紅質-2(ChR2)於興奮性榖胺酸神經細胞，剖析特定細胞種類的神經迴路，並使用自製的光電極結合光纖及不鏽鋼管來達到同時地執行光刺激以及訊號量測。並結合光刺激以及電刺激兩種刺激方式，藉由量測局部場電位來直接的分析大腦的活性並比較在電刺激陣發性刺激前後的變化，此外，藉由光基因的動物模式，探討專一性的光基因間歇性陣發型刺激(Opto-iTBS)於榖胺酸神經迴路，並比較其動作誘發電位在光基因間歇性陣發型刺激、皮質間歇性陣發型電刺激(CES-iTBS)及控制組的變化。在光基因及皮質電刺激的間歇性陣發型刺激皆可使得動作電位逐漸的上升，局部場電位在皮質間歇性陣發型電刺激則會稍微下降，而在光基因刺激則無顯著影響。
光基因刺激可幫助我們去了解陣發性刺激改善運動表現調控機制，並且可以藉由專一性的刺激特定神經迴路發展一個更有效的治療方式。

Cortical theta burst stimulation (TBS) has been shown to be able to modulate motor plasticity via long-term potentiation/depression (LTP/LTD) like-mechanism to enhance motor function. Studies on cortical TBS had shown potential in non-invasive therapy for motor deficit diseases such as Parkinson’s disease (PD) through repeat transcranial magnetic stimulation (rTMS) and focal cortical electrical stimulation (CES) in rats. Changes in motor-evoked potential (MEP) were measured to reflect motor plasticity before and after intervened intermittent (iTBS) and continuous (cTBS). MEPs were significantly enhanced immediately after iTBS and suppressed after cTBS. However, the mechanism of cortical stimulation was still unclear. The CES excited all types of neurons surrounding the electrode in cortex makes it difficult to differentiate the effect of TBS on specific neural circuit that involved motor plasticity and performance. In order to understand the cellular mechanism of TBS-modulated plasticity, optogenetics was used to dissect the cell-type specific neural circuit involved via expressed the light-sensitive channelrhodopsin-2 (ChR2) in the excitatory (glutamatergic) in corticostriatal projection. The optrode combining an optical fiber and stainless steel tube was fabricated to achieve optogenetic stimulation and in situ electrocorticography (ECoG) recording simultaneously. Combining the electrical and optogenetic stimulation, the acute effects of CES-TBS on cortical activity were analyzed from local field potentials (LFPs) in anesthetized rats. Furthermore, specific TBS on glutamatergic neuron circuits were studied by optogenetic TBS (Opto-TBS) to compare the time course change of MEP among opto-iTBS, CES-iTBS and sham group. Both of the opto- and CES-iTBS would progressively increase MEP amplitude. However, the local field potentials were only mildly decrease after CES-iTBS, or no evident effect in opto-iTBS scheme. Optogenetic stimulation provides a unique tool to investigate the molecular modulating mechanism of TBS in improving motor performance. Further study of TBS scheme of optogenetics could develop to be an efficient therapeutic protocol for targeting specific neural circuit of neurodegenerative disease with the evidence from optogenetic and cortical stimulation of animal model.

[1]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.
[2]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.
[3]Aravanis, A. M., Wang, L. P., Zhang, F., Meltzer, L. A., Mogri, M. Z., Schneider, M. B., & Deisseroth, K. (2007). An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology. J Neural Eng, 4(3), S143-156.
[4]Aroniadou, V. A., & Keller, A. (1995). Mechanisms of LTP induction in rat motor cortex in vitro. Cereb Cortex, 5(4), 353-362.
[5]Aydin-Abidin, S., Trippe, J., Funke, K., Eysel, U. T., & Benali, A. (2008). High- and low-frequency repetitive transcranial magnetic stimulation differentially activates c-Fos and zif268 protein expression in the rat brain. Exp Brain Res, 188(2), 249-261.
[6]Barker, A. T., Freeston, I. L., Jalinous, R., & Jarratt, J. A. (1985). Motor responses to non-invasive brain stimulation in clinical practice. Electroencephalography and Clinical Neurophysiology, 61(3), S70.
[7]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.
[8]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.
[9]Boyden, E. S., Zhang, F., Bamberg, E., Nagel, G., & Deisseroth, K. (2005). Millisecond-timescale, genetically targeted optical control of neural activity. Nat Neurosci, 8(9), 1263-1268.
[10]Braunewell, K. H., & Manahan-Vaughan, D. (2001). Long-term depression: a cellular basis for learning? Rev Neurosci, 12(2), 121-140.
[11]Butler, A. J., & Wolf, S. L. (2007). Putting the brain on the map: use of transcranial magnetic stimulation to assess and induce cortical plasticity of upper-extremity movement. Phys Ther, 87(6), 719-736.
[12]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.
[13]Cheng, M. Y., Wang, E. H., Woodson, W. J., Wang, S., Sun, G., Lee, A. G., . . . Steinberg, G. K. (2014). Optogenetic neuronal stimulation promotes functional recovery after stroke. Proc Natl Acad Sci U S A, 111(35), 12913-12918.
[14]De Rose, M., Guzzi, G., Bosco, D., Romano, M., Lavano, S. M., Plastino, M., . . . Lavano, A. (2012). Motor cortex stimulation in Parkinson's disease. Neurol Res Int, 2012, 502096.
[15]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.
[16]Di Lazzaro, V., Pilato, F., Dileone, M., Profice, P., Oliviero, A., Mazzone, P., . . . Rothwell, J. C. (2008). The physiological basis of the effects of intermittent theta burst stimulation of the human motor cortex. J Physiol, 586(16), 3871-3879.
[17]Duffau, H. (2006). Brain plasticity: from pathophysiological mechanisms to therapeutic applications. J Clin Neurosci, 13(9), 885-897.
[18]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.
[19]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.
[20]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.
[21]Fregni, F., Simon, D. K., Wu, A., & Pascual-Leone, A. (2005). Non-invasive brain stimulation for Parkinson's disease: a systematic review and meta-analysis of the literature. J Neurol Neurosurg Psychiatry, 76(12), 1614-1623.
[22]Gamboa, O. L., Antal, A., Laczo, B., Moliadze, V., Nitsche, M. A., & Paulus, W. (2011). Impact of repetitive theta burst stimulation on motor cortex excitability. Brain Stimul, 4(3), 145-151.
[23]Gradinaru, V., Mogri, M., Thompson, K. R., Henderson, J. M., & Deisseroth, K. (2009). Optical deconstruction of parkinsonian neural circuitry. Science, 324(5925), 354-359.
[24]Gradinaru, V., Zhang, F., Ramakrishnan, C., Mattis, J., Prakash, R., Diester, I., . . . Deisseroth, K. (2010). Molecular and cellular approaches for diversifying and extending optogenetics. Cell, 141(1), 154-165.
[25]Gutierrez, J. C., Seijo, F. J., Alvarez Vega, M. A., Fernandez Gonzalez, F., Lozano Aragoneses, B., & Blazquez, M. (2009). Therapeutic extradural cortical stimulation for Parkinson's Disease: report of six cases and review of the literature. Clin Neurol Neurosurg, 111(8), 703-707.
[26]Hoppenrath, K., & Funke, K. (2013). Time-course of changes in neuronal activity markers following iTBS-TMS of the rat neocortex. Neurosci Lett, 536, 19-23.
[27]Hsieh, T. H., Huang, Y.-Z., Chen, J.-J., Rotenberg, A., Chiang, Y.-H., Chien, W.-S., . . . Peng, C.-W. (2015). Novel Use of Theta Burst Cortical Electrical Stimulation for Modulating Motor Plasticity in Rats. Journal of Medical and Biological Engineering, 35(1), 62-68.
[28]Hsieh, T. H., Huang, Y. Z., Rotenberg, A., Pascual-Leone, A., Chiang, Y. H., Wang, J. Y., & Chen, J. J. (2014). Functional Dopaminergic Neurons in Substantia Nigra are Required for Transcranial Magnetic Stimulation-Induced Motor Plasticity. Cereb Cortex.
[29]Huang, Y. Z., Chen, R. S., Rothwell, J. C., & Wen, H. Y. (2007). The after-effect of human theta burst stimulation is NMDA receptor dependent. Clin Neurophysiol, 118(5), 1028-1032.
[30]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.
[31]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.
[32]Kimura, F., Nishigori, A., Shirokawa, T., & Tsumoto, T. (1989). Long-term potentiation and N-methyl-D-aspartate receptors in the visual cortex of young rats. J Physiol, 414, 125-144.
[33]Kobayashi, M., & Pascual-Leone, A. (2003). Transcranial magnetic stimulation in neurology. Lancet Neurol, 2(3), 145-156.
[34]Kravitz, A. V., Freeze, B. S., Parker, P. R., Kay, K., Thwin, M. T., Deisseroth, K., & Kreitzer, A. C. (2010). Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature, 466(7306), 622-626.
[35]Kreitzer, A. C., & Malenka, R. C. (2008). Striatal plasticity and basal ganglia circuit function. Neuron, 60(4), 543-554.
[36]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.
[37]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.
[38]Liebetanz, D., Nitsche, M. A., Tergau, F., & Paulus, W. (2002). Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor cortex excitability. Brain, 125(Pt 10), 2238-2247.
[39]Lisanby, S. H., & Belmaker, R. H. (2000). Animal models of the mechanisms of action of repetitive transcranial magnetic stimulation (RTMS): comparisons with electroconvulsive shock (ECS). Depress Anxiety, 12(3), 178-187.
[40]Mandat, T. S., Hurwitz, T., & Honey, C. R. (2006). Hypomania as an adverse effect of subthalamic nucleus stimulation: report of two cases. Acta Neurochir (Wien), 148(8), 895-897; discussion 898.
[41]Nagel, G., Szellas, T., Huhn, W., Kateriya, S., Adeishvili, N., Berthold, P., . . . Bamberg, E. (2003). Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proc Natl Acad Sci U S A, 100(24), 13940-13945.
[42]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.
[43]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.
[44]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.
[45]Roth, Y., Amir, A., Levkovitz, Y., & Zangen, A. (2007). Three-dimensional distribution of the electric field induced in the brain by transcranial magnetic stimulation using figure-8 and deep H-coils. J Clin Neurophysiol, 24(1), 31-38.
[46]Shirota, Y., Ohtsu, H., Hamada, M., Enomoto, H., & Ugawa, Y. (2013). Supplementary motor area stimulation for Parkinson disease: a randomized controlled study. Neurology, 80(15), 1400-1405.
[47]Siebner, H. R., & Rothwell, J. (2003). Transcranial magnetic stimulation: new insights into representational cortical plasticity. Exp Brain Res, 148(1), 1-16.
[48]Sukhotinsky, I., Chan, A. M., Ahmed, O. J., Rao, V. R., Gradinaru, V., Ramakrishnan, C., . . . Cash, S. S. (2013). Optogenetic Delay of Status Epilepticus Onset in an <italic>In Vivo</italic> Rodent Epilepsy Model. PLoS One, 8(4), e62013.
[49]Thickbroom, G. W. (2007). Transcranial magnetic stimulation and synaptic plasticity: experimental framework and human models. Exp Brain Res, 180(4), 583-593.
[50]Tonnesen, J. (2013). Optogenetic cell control in experimental models of neurological disorders. Behav Brain Res, 255, 35-43.
[51]Touge, T., Gerschlager, W., Brown, P., & Rothwell, J. C. (2001). Are the after-effects of low-frequency rTMS on motor cortex excitability due to changes in the efficacy of cortical synapses? Clin Neurophysiol, 112(11), 2138-2145.
[52]Vahabzadeh-Hagh, A. M., Muller, P. A., Pascual-Leone, A., Jensen, F. E., & Rotenberg, A. (2011). Measures of Cortical Inhibition by Paired-Pulse Transcranial Magnetic Stimulation in Anesthetized Rats. J Neurophysiol, 105(2), 615-624.
[53]Wang, H., Wang, X., & Scheich, H. (1996). LTD and LTP induced by transcranial magnetic stimulation in auditory cortex. Neuroreport, 7(2), 521-525.
[54]Xiong, W., & Jin, X. (2012). Optogenetic field potential recording in cortical slices. J Neurosci Methods, 210(2), 119-124.