目前市面上已發展各式各樣應用於神經調變的腦電刺激方案，其中，高精度經顱直流電刺激 (HD-tDCS) 提供聚焦和非侵入式的刺激方式。陣列式脈衝刺激 (TBS) 是一種特定的刺激模組，已被應用於重複性經顱刺激 (rTMS) 並在臨床上證能達到更佳的神經塑性效果。此篇研究旨在高精度經顱直流電刺激的原則下，開發一款能同時輸出直流以及陣列式脈衝刺激波形的多功能電刺激系統，目的在於腦神經的調變。在電路設計上，我們著重在一對四通道的電刺激和阻抗之調整，在刺激開始之前，系統會以直流電的方式量測各通道的阻抗並進行補償，接下來，直流以及陣列式脈衝刺激波形會經由電流波形產生電路輸出。系統驗證上會在電阻補償後量測電流是否從陽極均分到四個陰極通道。系統驗收方面，我們使用此系統刺激大鼠之第一運動皮質 (M1) 並同時量測其阻抗以及運動誘發電位 (MEP)。動物實驗之目的在於探討經顱直流電刺激 (tDCS) 結合間歇性陣列式脈衝刺激 (iTBS) 與單獨間歇性陣列式脈衝刺激 (iTBS) 對於腦神經塑性調變之比較。我們從量測之運動誘發電位的結果顯示30分鐘內，兩者對於動作活性皆有增益的情形。此外，前者具有更顯著的增益並於30分鐘後依然有向上增益的趨勢，而後者對動作活性之增益則有趨緩的態勢。我們認為經顱直流電刺激結合間歇性陣列式脈衝刺激於腦神經之調變比間歇性陣列式脈衝刺激還要強大且長期。

Varied forms of brain stimulation schemes have been developed for neuromodulation purposes. Among them, high-definition transcranial direct current stimulation (HD-tDCS) provides a focal and non-invasive brain stimulation modality. A specific stimulation protocol, theta burst stimulation (TBS), has been demonstrated in repetitive transcranial magnetic stimulation (rTMS) to elicit the neuroplasticity more effectively for the clinical rehabilitation purposes. This study aimed to design a versatile brain stimulation system which can output the dc plus TBS waveform for neuroplasticity modulation purpose under HD-tDCS. In circuit design, we focused on the one to four channels stimulation and impedance adjustment. Before the stimulation, the system was able to measure the impedance of each channels and compensate them to identical level under dc condition. Next, the dc or TBS current output was generated via the current waveform generator. For the system verification, the current output was able to distribute evenly through an anode to four cathode electrodes after impedance compensation. For validation purpose, we used this brain stimulation system to stimulate the primary motor cortex (M1) of rats where the brain impedance and motor evoked potentials (MEPs) were measured. The animal experiment was designed to explore the neuroplastic effects underlying tDCS combined with iTBS protocol (DC+ iTBS) compared to iTBS protocol only. Our results showed that both iTBS and DC+iTBS groups can facilitate the motor excitability which was measured using motor evoked potentials (MEPs) which can observe 30 min post stimulation. In addition, DC+iTBS group showed more robust in facilitation effects observed from the uprising trend of MEPs change whereas iTBS group had downward trend at post 30 min. Our study suggests that DC+iTBS protocol exhibits more powerful and can provide long-lasting scheme for neuromodulation than iTBS.

Barron, D., & Starkman, S. (1995). Emergency evaluation and management of stroke, part II: ischemic stroke. Hosp Physician, 21-49.
Barry, M. D., Boddington, L. J., Igelstrom, K. M., Gray, J. P., Shemmell, J., Tseng, K. Y., . . . Reynolds, J. N. J. (2014). Utility of intracerebral theta burst electrical stimulation to attenuate interhemispheric inhibition and to promote motor recovery after cortical injury in an animal model. Experimental Neurology, 261, 258-266. doi:10.1016/j.expneurol.2014.05.023
Bestmann, S., Baudewig, J., Siebner, H. R., Rothwell, J. C., & Frahm, J. (2004). Functional MRI of the immediate impact of transcranial magnetic stimulation on cortical and subcortical motor circuits. European Journal of Neuroscience, 19(7), 1950-1962. doi:10.1111/j.1460-9568.2004.03277.x
Cai, T. T., Xia, X. Y., Zhang, H., Guo, Y. K., & Bai, Y. (2019). High-definition transcranial direct current stimulation modulates neural activities in patients with prolonged disorders of consciousness. Brain Stimulation, 12(6), 1619-1621. doi:10.1016/j.brs.2019.08.017
Caparelli-Daquer, E. M., Zimmermann, T. J., Mooshagian, E., Parra, L. C., Rice, J. K., Datta, A., . . . Wassermann, E. M. (2012, 28 Aug.-1 Sept. 2012). A pilot study on effects of 4×1 High-Definition tDCS on motor cortex excitability. Paper presented at the 2012 Annual International Conference of the IEEE Engineering in Medicine and Biology Society.
Cunningham, D. A., Varnerin, N., Machado, A., Bonnett, C., Janini, D., Roelle, S., . . . Plow, E. B. (2015). Stimulation targeting higher motor areas in stroke rehabilitation: A proof-of-concept, randomized, double-blinded placebo-controlled study of effectiveness and underlying mechanisms. Restorative Neurology and Neuroscience, 33(6), 911-926. doi:10.3233/rnn-150574
Dimyan, M. A., & Cohen, L. G. (2010). Contribution of Transcranial Magnetic Stimulation to the Understanding of Functional Recovery Mechanisms After Stroke. Neurorehabilitation and Neural Repair, 24(2), 125-135. doi:10.1177/1545968309345270
Duffau, H. (2016). Chapter 18 - Brain Plasticity and Reorganization Before, During, and After Glioma Resection Glioblastoma (pp. 225-236): Elsevier.
Duque, J., Hummel, F., Celnik, P., Murase, N., Mazzocchio, R., & Cohen, L. G. (2005). Transcallosal inhibition in chronic subcortical stroke. Neuroimage, 28(4), 940-946. doi:10.1016/j.neuroimage.2005.06.033
Fregni, F., & Pascual-Leone, A. (2007). Technology Insight: noninvasive brain stimulation in neurology - perspectives on the therapeutic potential of rTMS and tDCS. Nature Clinical Practice Neurology, 3(7), 383-393. doi:10.1038/ncpneuro0530
Hademenos, G. J., & Massoud, T. F. (1997). Biophysical mechanisms of stroke. Stroke, 28(10), 2067-2077. doi:10.1161/01.str.28.10.2067
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., Chen, R. S., Lu, C. S., & Chuang, W. L. (2011). The theoretical model of theta burst form of repetitive transcranial magnetic stimulation. Clinical Neurophysiology, 122(5), 1011-1018. doi:10.1016/j.clinph.2010.08.016
Irlbacher, K., Brocke, J., Mechow, J. V., & Brandt, S. A. (2007). Effects of GABA(A) and GABA(B) agonists on interhemispheric inhibition in man. Clinical Neurophysiology, 118(2), 308-316. doi:10.1016/j.clinph.2006.09.023
Klomjai, W., Katz, R., & Lackmy-Vallee, A. (2015). Basic principles of transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS). Annals of Physical and Rehabilitation Medicine, 58(4), 208-213. doi:10.1016/j.rehab.2015.05.005
Klomjai, W., Lackmy-Vallee, A., Roche, N., Pradat-Diehl, P., Marchand-Pauvert, V., & Katz, R. (2015). Repetitive transcranial magnetic stimulation and transcranial direct current stimulation in motor rehabilitation after stroke: An update. Annals of Physical and Rehabilitation Medicine, 58(4), 220-224. doi:10.1016/j.rehab.2015.05.006
Lemon, R. N. (1997). Mechanisms of cortical control of hand function. Neuroscientist, 3(6), 389-398. doi:10.1177/107385849700300612
Li, Y. T., Chen, S. C., Yang, L. Y., Hsieh, T. H., & Peng, C. W. (2019). Designing and Implementing a Novel Transcranial Electrostimulation System for Neuroplastic Applications: A Preliminary Study. Ieee Transactions on Neural Systems and Rehabilitation Engineering, 27(5), 805-813. doi:10.1109/tnsre.2019.2908674
Liebetanz, D., Koch, R., Mayenfels, S., Konig, F., Paulus, W., & Nitsche, M. A. (2009). Safety limits of cathodal transcranial direct current stimulation in rats. Clinical Neurophysiology, 120(6), 1161-1167. doi:10.1016/j.clinph.2009.01.022
Lindenberg, R., Renga, V., Zhu, L. L., Betzler, F., Alsop, D., & Schlaug, G. (2010). Structural integrity of corticospinal motor fibers predicts motor impairment in chronic stroke. Neurology, 74(4), 280-287. doi:10.1212/WNL.0b013e3181ccc6d9
Murray, C. J. L., & Lopez, A. D. (1997). Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet, 349(9061), 1269-1276. doi:10.1016/s0140-6736(96)07493-4
Nitsche, M. A., Cohen, L. G., Wassermann, E. M., Priori, A., Lang, N., Antal, A., . . . Pascual-Leone, A. (2008). Transcranial direct current stimulation: State of the art 2008. Brain Stimulation, 1(3), 206-223. doi:10.1016/j.brs.2008.06.004
Nitsche, M. A., & Paulus, W. (2000). Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. Journal of Physiology-London, 527(3), 633-639. doi:10.1111/j.1469-7793.2000.t01-1-00633.x
Palmer, L. M., Schulz, J. M., Murphy, S. C., Ledergerber, D., Murayama, M., & Larkum, M. E. (2012). The Cellular Basis of GABA(B)-Mediated Interhemispheric Inhibition. Science, 335(6071), 989-993. doi:10.1126/science.1217276
Plow, E. B., Cunningham, D. A., Varnerin, N., & Machado, A. (2015). Rethinking Stimulation of the Brain in Stroke Rehabilitation: Why Higher Motor Areas Might Be Better Alternatives for Patients with Greater Impairments. Neuroscientist, 21(3), 225-240. doi:10.1177/1073858414537381
Pouliquen, P., Vogelstein, J., & Etienne-Cummings, R. (2008, 20-22 Nov. 2008). Practical considerations for the use of a Howland current source for neuro-stimulation. Paper presented at the 2008 IEEE Biomedical Circuits and Systems Conference.
Stinear, C. M., Barber, P. A., Smale, P. R., Coxon, J. P., Fleming, M. K., & Byblow, W. D. (2007). Functional potential in chronic stroke patients depends on corticospinal tract integrity. Brain, 130, 170-180. doi:10.1093/brain/awl333
Swartz, R. H., Bayley, M., Lanctot, K. L., Murray, B. J., Cayley, M. L., Lien, K., . . . Herrmann, N. (2016). Post-stroke depression, obstructive sleep apnea, and cognitive impairment: Rationale for, and barriers to, routine screening. Int J Stroke, 11(5), 509-518. doi:10.1177/1747493016641968
Takeuchi, N., & Izumi, S. I. (2012). Maladaptive Plasticity for Motor Recovery after Stroke: Mechanisms and Approaches. Neural Plasticity. doi:10.1155/2012/359728
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. Journal of Neurophysiology, 105(2), 615-624. doi:10.1152/jn.00660.2010