帕金森氏症目前為全球第二常見之神經退化疾病，因腦中黑質(substantia nigra) 的多巴胺神經元衰退而引發，病徵為非自主震顫、運動遲緩、認知障礙、行為異常等。對於左旋多巴(levodopa)治療有明顯副作用的患者，則大多會選擇進行深部腦刺激（DBS）的手術療法，透過對丘腦底核（STN）持續的高頻電刺激來治療晚期帕金森氏患者的運動障礙。
藉由6-OHDA手術誘導成的半帕金森氏症模式鼠的腦波中，有跟帕金森氏症患者一樣的強β振盪出現，且在β振盪完全表現之前大鼠還有出現高電壓主軸（HVS）發生頻率增加的現象，而此兩種特異訊號皆會被STN高頻電刺激所抑制，所以我們開始好奇HVS訊號與β振盪的形成是否有相關性。
本實驗所利用的HVS-Closed-loop系統在偵測到特定腦波HVS時可以立即給予STN腦區高頻電刺激，並發現了此即時的電刺激有抑制HVS的效果。在帕金森氏症模式鼠誘導手術後至β振盪尚未完全生成的這段期間，每日進行一次HVS-Closed-loop系統STN-DBS的大鼠，在手術後第2、3及4周從運動皮層檢測到的β 振盪增加能量比接受相同量但不是針對HVS隨機的STN-DBS大鼠與手術後完全沒有STN-DBS的組別明顯來的低。行為測試結果發現經HVS Closed-loop STN-DBS 導致β振盪上升較少之大鼠與手術後隨機刺激和手術後未經過任何刺激而β振盪能量高的兩組大鼠一樣，皆呈現運動遲緩的現象。
實驗結果似乎指向β振盪的生成可能和HVS訊號有某些的相連，而β振盪能量的多寡與運動能力沒有正相關。這讓我們開始懷疑β振盪是不是其實跟運動無關，而是和帕金森氏症其他病徵有相關性，所以在動物實驗上不易發現，而另一點是帕金森氏症病人腦波中並沒有HVS的訊號顯，所以我們好奇在帕金森氏症患者前期，是否也有類似於大鼠HVS訊號的特異腦波出現，如果發現了且針對此特異腦波做出相對的抑制，對帕金森氏症病患又會有哪些助益。

Parkinson's disease (PD) is currently the second most common neurological disease in the world. The major pathological hallmark of PD is the degeneration of dopaminergic neurons in the substantia nigra of the brain. The symptoms include tremor, bradykinesia, cognitive disturbance, and other psychological/behavioral abnormalities. For patients exhibiting significant side effects to medication, including levodopa, their movement symptoms could still be treated by deep-brain-stimulation (DBS) surgery. DBS involves the delivery of high-frequency electrical stimulations onto the subthalamic nucleus (STN) via long electrodes implanted in the brain of PD patients.

In the brain of the Parkinsonian rats as induced by unilateral injection 6-OHDA , exaggerated oscillation in the beta-regime is frequently detected. Exaggerated beta-oscillations are also detected in human PD patients. In hemi-Parkinsonian rats, the more High-Voltage-Spindle (HVS) episodes are detected before the full manifestation of exaggerated β-oscillation. And both specific waves are attenuated by applying high-frequency electrical stimulations on STN. These observations prompt us to wonder whether the HVS signal is related to the development of the β-oscillation.

The HVS-Closed-loop system used in this study can immediately give high-frequency electrical stimulations to the STN brain region shortly after the beginning of HVSs, enabling the suppression of the remaining part of HVS. Before the full development of the beta-oscillations in hemi-Parkinsonian rats, suppressing HVS by the abovementioned closed-loop device can effectively delay the development of β-oscillation. This conclusion is drawn by my observation that the β –oscillation detected from the motor cortex in hemi-Parkinsonian animals, appear to be smaller in power at 2 and 3 weeks post-injection than those detected from rats which received the same amounts of STN-DBS but not temporally related to HVSs signal’s and than those recorded from control rats which did not receive STN-DBS at all. However, there was no significant difference in the behavioral tests between the control rats and rats whose beta-oscillations were attenuated. Furthermore, all rats showed bradykinesia.

The experimental results suggest that the development of β-oscillation us somehow related to the HVSs and that the power of β-oscillation is not directly related to movement abnormality in hemi-Parkinsonian rats. This makes me wonder whetherβ-oscillations in PD are related to the psychological symptoms of Parkinson's disease. However, psychological symptoms are not easy to study in laboratory animals. Further more,that HVSs like those detected in the rat brain are not detected in the human brain. I speculate that there are brain waves corresponding to the HVSs in the rat brain. If such waves are identified in human brain, we may help suppress some symptoms related to beta-oscillations of human PD patients by suppressing the development of beta-oscillations by the closed-loop device as described in the thesis.

1. Beck, M. H., Haumesser, J. K., Kuhn, J., Altschuler, J., Kuhn, A. A., & van Riesen, C. (2016). Short- and long-term dopamine depletion causes enhanced beta oscillations in the cortico-basal ganglia loop of parkinsonian rats. Exp Neurol, 286, 124-136. doi: 10.1016/j.expneurol.2016.10.005
2. Berke, J. D., Okatan, M., Skurski, J., & Eichenbaum, H. B. (2004). Oscillatory entrainment of striatal neurons in freely moving rats. Neuron, 43(6), 883-896. doi: 10.1016/j.neuron.2004.08.035
3. Birkmayer, W., & Riederer, P. (1983a). How to care for peoplewith Parkinson’s disease. doi: 10.1007/978-3-7091-7635-1
4. Birkmayer, W., & Riederer, P. (1983b). Clinical Course of Parkinson’s Disease. 152-155. doi: 10.1007/978-3-7091-7635-1_5
5. Brown, P. (2007). Abnormal oscillatory synchronisation in the motor system leads to impaired movement. Curr Opin Neurobiol, 17(6), 656-664. doi: 10.1016/j.conb.2007.12.001
6. Buzsaki, G., Bickford, R. G., Ponomareff, G., Thal, L. J., Mandel, R., & Gage, F. H. (1988). Nucleus basalis and thalamic control of neocortical activity in the freely moving rat. The Journal of Neuroscience, 8(11), 4007-4026. doi: 10.1523/jneurosci.08-11-04007.1988
7. Chen, C. C., Hsu, Y. T., Chan, H. L., Chiou, S. M., Tu, P. H., Lee, S. T., . . . Brown, P. (2010). Complexity of subthalamic 13-35 Hz oscillatory activity directly correlates with clinical impairment in patients with Parkinson's disease. Exp Neurol, 224(1), 234-240. doi: 10.1016/j.expneurol.2010.03.015
8. de Lau, L. M. L., & Breteler, M. M. B. (2006). Epidemiology of Parkinson's disease. The Lancet Neurology, 5(6), 525-535. doi: 10.1016/s1474-4422(06)70471-9
9. Dejean C, Gross CE, Bioulac B, Boraud T (2007) Synchronous high-voltage spindles in the cortex-basal ganglia network of awake and unrestrained rats. Eur J Neurosci 25:772–784.
10. Deransart, C., Hellwig, B., Heupel-Reuter, M., Leger, J.-F., Heck, D., & Lucking, C. H. (2003). Single-unit Analysis of Substantia Nigra Pars Reticulata Neurons in Freely Behaving Rats with Genetic Absence Epilepsy. Epilepsia, 44(12), 1513-1520. doi: 10.1111/j.0013-9580.2003.26603.x
11. 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
12. Eusebio, A., & Brown, P. (2009). Synchronisation in the beta frequency-band--the bad boy of parkinsonism or an innocent bystander? Exp Neurol, 217(1), 1-3. doi: 10.1016/j.expneurol.2009.02.003
13. Fritsch, T., Smyth, K. A., Wallendal, M. S., Hyde, T., Leo, G., & Geldmacher, D. S. (2012). Parkinson disease: research update and clinical management. South Med J, 105(12), 650-656. doi: 10.1097/SMJ.0b013e318273a60d
14. Ge, S., Yang, C., Li, M., Li, J., Chang, X., Fu, J., . . . Gao, G. (2012). Dopamine depletion increases the power and coherence of high-voltage spindles in the globus pallidus and motor cortex of freely moving rats. Brain Res, 1465, 66-79. doi: 10.1016/j.brainres.2012.05.002
15. Hammond, C., Bergman, H., & Brown, P. (2007). Pathological synchronization in Parkinson's disease: networks, models and treatments. Trends Neurosci, 30(7), 357-364. doi: 10.1016/j.tins.2007.05.004
16. Hauser R: Parkinson Disease. Medscape. Retrieved 10/28/2013 from http://emedicine.medscape.com/article/1831191-overview. (2013)
17. Jain, S. (2011). Multi-organ autonomic dysfunction in Parkinson disease. Parkinsonism Relat Disord, 17(2), 77-83. doi: 10.1016/j.parkreldis.2010.08.022
18. Khoshbouei, H., Sen, N., Guptaroy, B., Johnson, L., Lund, D., Gnegy, M. E., . . . Javitch, J. A. (2004). N-terminal phosphorylation of the dopamine transporter is required for amphetamine-induced efflux. PLoS Biol, 2(3), E78. doi: 10.1371/journal.pbio.0020078
19. Kuhn, A. A., Kupsch, A., Schneider, G. H., & Brown, P. (2006). Reduction in subthalamic 8-35 Hz oscillatory activity correlates with clinical improvement in Parkinson's disease. Eur J Neurosci, 23(7), 1956-1960. doi: 10.1111/j.1460-9568.2006.04717.x
20. Leventhal, D. K., Gage, G. J., Schmidt, R., Pettibone, J. R., Case, A. C., & Berke, J. D. (2012). Basal ganglia beta oscillations accompany cue utilization. Neuron, 73(3), 523-536. doi: 10.1016/j.neuron.2011.11.032
21. Li, Q., Ke, Y., Chan, D. C., Qian, Z. M., Yung, K. K., Ko, H., . . . Yung, W. H. (2012). Therapeutic deep brain stimulation in Parkinsonian rats directly influences motor cortex. Neuron, 76(5), 1030-1041. doi: 10.1016/j.neuron.2012.09.032
22. Lim, S. Y., & Lang, A. E. (2010). The nonmotor symptoms of Parkinson's disease--an overview. Mov Disord, 25 Suppl 1, S123-130. doi: 10.1002/mds.22786
23. Loukas, C., & Brown, P. (2004). Online prediction of self-paced hand-movements from subthalamic activity using neural networks in Parkinson's disease. J Neurosci Methods, 137(2), 193-205. doi: 10.1016/j.jneumeth.2004.02.017
24. Magill, P. J., Sharott, A., Harnack, D., Kupsch, A., Meissner, W., & Brown, P. (2005). Coherent spike-wave oscillations in the cortex and subthalamic nucleus of the freely moving rat. Neuroscience, 132(3), 659-664. doi: 10.1016/j.neuroscience.2005.01.006
25. Oswal, A., Brown, P., & Litvak, V. (2013). Synchronized neural oscillations and the pathophysiology of Parkinson's disease. Curr Opin Neurol, 26(6), 662-670. doi: 10.1097/WCO.0000000000000034
26. Pan, M. K., Kuo, S. H., Tai, C. H., Liou, J. Y., Pei, J. C., Chang, C. Y., . . . Kuo, C. C. (2016). Neuronal firing patterns outweigh circuitry oscillations in parkinsonian motor control. J Clin Invest, 126(12), 4516-4526. doi: 10.1172/JCI88170
27. Pan, M. K., Tai, C. H., Liu, W. C., Pei, J. C., Lai, W. S., & Kuo, C. C. (2014). Deranged NMDAergic cortico-subthalamic transmission underlies parkinsonian motor deficits. J Clin Invest, 124(10), 4629-4641. doi: 10.1172/JCI75587
28. Paquette, M. A., Martinez, A. A., Macheda, T., Meshul, C. K., Johnson, S. W., Berger, S. P., & Giuffrida, A. (2012). Anti-dyskinetic mechanisms of amantadine and dextromethorphan in the 6-OHDA rat model of Parkinson's disease: role of NMDA vs. 5-HT1A receptors. Eur J Neurosci, 36(9), 3224-3234. doi: 10.1111/j.1460-9568.2012.08243.x
29. Paz, J. T., Deniau, J. M., & Charpier, S. (2005). Rhythmic bursting in the cortico-subthalamo-pallidal network during spontaneous genetically determined spike and wave discharges. J Neurosci, 25(8), 2092-2101. doi: 10.1523/JNEUROSCI.4689-04.2005
30. Pogosyan, A., Yoshida, F., Chen, C. C., Martinez-Torres, I., Foltynie, T., Limousin, P., . . . Brown, P. (2010). Parkinsonian impairment correlates with spatially extensive subthalamic oscillatory synchronization. Neuroscience, 171(1), 245-257. doi: 10.1016/j.neuroscience.2010.08.068
31. Sherer, T. B., Chowdhury, S., Peabody, K., & Brooks, D. W. (2012). Overcoming obstacles in Parkinson's disease. Mov Disord, 27(13), 1606-1611. doi: 10.1002/mds.25260
32. Slaght, S. J., Paz, T., Chavez, M., Deniau, J. M., Mahon, S., & Charpier, S. (2004). On the activity of the corticostriatal networks during spike-and-wave discharges in a genetic model of absence epilepsy. J Neurosci, 24(30), 6816-6825. doi: 10.1523/JNEUROSCI.1449-04.2004
33. Stein, E., & Bar-Gad, I. (2013). beta oscillations in the cortico-basal ganglia loop during parkinsonism. Exp Neurol, 245, 52-59. doi: 10.1016/j.expneurol.2012.07.023
34. Takeda, R., Ikeda, T., Tsuda, F., Abe, H., Hashiguchi, H., Ishida, Y., & Nishimori, T. (2005). Unilateral lesions of mesostriatal dopaminergic pathway alters the withdrawal response of the rat hindpaw to mechanical stimulation. Neurosci Res, 52(1), 31-36. doi: 10.1016/j.neures.2005.01.005
35. Timmermann, L., & Fink, G. R. (2011). Pathological network activity in Parkinson's disease: from neural activity and connectivity to causality? Brain, 134(Pt 2), 332-334. doi: 10.1093/brain/awq381
36. Wiest, M. C., & Nicolelis, M. A. (2003). Behavioral detection of tactile stimuli during 7-12 Hz cortical oscillations in awake rats. Nat Neurosci, 6(9), 913-914. doi: 10.1038/nn1107
37. Williams, D., Kuhn, A., Kupsch, A., Tijssen, M., van Bruggen, G., Speelman, H., . . . Brown, P. (2005). The relationship between oscillatory activity and motor reaction time in the parkinsonian subthalamic nucleus. Eur J Neurosci, 21(1), 249-258. doi: 10.1111/j.1460-9568.2004.03817.x
38. Yang, C., Zhang, J. R., Chen, L., Ge, S. N., Wang, J. L., Yan, Z. Q., . . . Gao, G. D. (2015). High frequency stimulation of the STN restored the abnormal high-voltage spindles in the cortex and the globus pallidus of 6-OHDA lesioned rats. Neurosci Lett, 595, 122-127. doi: 10.1016/j.neulet.2015.04.011
39. C. C. McIntyre, W. M. Grill, D. L. Sherman, and N. V. Thakor, (2004)“Cellular effects of deep brain stimulation: model-based analysis of activation and inhibition,” Journal of Neurophysiology, vol.91, no. 4, pp. 1457–1469, 2004.
40. A. A. Kuhn, F. Kempf, C. Brucke et al., (2008) “High-frequency ¨stimulation of the subthalamic nucleus suppresses oscillatory 𝛽 activity in patients with Parkinson’s disease in parallel with improvement in motor performance,” The Journal of Neuroscience, vol. 28, no. 24, pp. 6165–6173, 2008.
41. J. S. Perlmutter, J. W. Mink, A. J. Bastian et al., (2002) “Blood flow responses to deep brain stimulation of thalamus,” Neurology, vol. 58, no. 9, pp. 1388–1394, 2002. 8 Parkinson’s Disease
42. V. Vedam-Mai, E. Y. Van Battum, W. Kamphuis et al., (2012) “Deep brain stimulation and the role of astrocytes,” Molecular Psychiatry, vol. 17, no. 2, pp. 124–131, 2012.
43. V. Vedam-Mai, B. Gardner, M. S. Okun et al., (2004) “Increased precursor cell proliferation after deep brain stimulation for Parkinson’s disease: a human study,” PLoS ONE, vol. 9, no. 3, Article ID e88770, 2014.
44. Suarez-Cedeno G, Suescun J, Schiess MC. (2017) Earlier intervention with deep brain stimulation for Parkinson's disease. Parkinsons Dis 2017;2017:9358153.
45. Buzsáki, G. Rhythms of the Brain (Oxford Univ. Press, New York, 2006).