帕金森氏症(Parkinson’s disease, PD)是一種常見的退化性神經疾病，對視丘下核（subthalamic nucleus, STN)施以腦深層電刺激(deep brain stimulation, DBS)是對PD晚期患者常用的療法。而beta oscillation是PD患者在主要運動皮質(primary motor cortex, M1)常見的病徵，在接受DBS期間可被抑制。雖然DBS被認定是安全的療法，但因需使用高頻率、24小時不間斷的刺激，因此研究如何降低刺激的強度以減少治療的副作用便成為重要的課題。
　　近來研究顯示beta oscillation與STN的異常放電有關，而抑制M1腦區的神經活性可以抑制STN的異常放電進而降低beta oscillation的能量。意味著M1到STN的直接連結，也就是超直接路徑(hyperdirect pathway)可能在STN DBS對PD症狀的改善中扮演重要角色。由於M1到STN的直接連結與beta oscillation的抑制有關，因此觀察M1腦區的活性便可用來調整STN DBS的抑制效果。
　　本研究的主要目的是利用電生理方法研究刺激STN對M1腦區活性所造成的變化。實驗結果發現對STN的刺激會透過STNM1神經元直接投射到M1並抑制M1的中間神經元產生約100 ms先正(促進作用)後負(抑制作用)的evoked potentials (EPs)。在連續刺激的情況下，貢獻正向EPs的神經元會快速的習慣化(habituation)，而產生負向EPs的神經元習慣化則較慢程度也較輕。因此我們懷疑STN DBS得以抑制beta oscillation是由於抑制了M1的活性所致。
觀察結果顯示，在STN DBS啟動後1秒內對M1活性的抑制效果最高。我們利用這個時段對STN進行間斷式的刺激可在降低50%以上刺激次數的同時保有與持續刺激相近的抑制效果。此外，增加STN DBS刺激脈波的波寬，也可以加強對M1活性的抑制，在同時降低刺激電壓與降低刺激頻率的條件下，提高刺激波寬的DBS甚至可以較傳統DBS對beta oscillation有更高的抑制效果。

Parkinson’s disease (PD) is a common neuron degeneration disease. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a preferred treatment for advanced PD patients. Beta oscillation is abnormal signals of PD patients in the primary motor cortex (M1) and can be suppressed during DBS. Although DBS is recognized as a safe treatment, high-frequency, 24-hour uninterrupted stimulation is required. Therefore, investigating the method to reduce the intensity of stimulation in order to decline the side effects had become an important issue.
　　Recent studies indicated that the inhibition of M1 neuron activity may contribute to decreasing of excessive STN bursts and the power of beta oscillation. It implies that the hyperdirect pathway may play an important role in the therapeutic effect of STN DBS. Since the direct connection between M1 and STN is related to the inhibition of beta oscillation, observing the activity of M1 can be used to adjust the inhibitory effect of STN DBS.
　　The main purpose of our study was to investigate the changes in M1 neuron activity caused by STN stimulation. The results suggested that STN stimulation would directly project to M1 and inhibit interneuron activity through STNM1 pathway. Once the activities of interneurons were inhibited, the potentials changes in M1 area of about 100 ms would be evoked. In the case of high frequency continuous stimulation, the positive evoked potentials (EPs) would habituate rapidly, and the habituation of the interneurons with the inhibitory effect would be slower and lighter. Therefore, we suspected that the inhibitory effect to beta oscillation by STN DBS is owing to the inhibition of M1 activity.
Results showed that the inhibitory effect on M1 activity is the highest within 1 second after STN DBS is started. We took advantage of the time window to alter the pattern of DBS. The intermittent pattern could reduce the number of stimulations by more than fifty percent while maintaining the inhibitory effect. In addition, increasing the pulse width of STN DBS could also enhance the inhibition of M1 neuron activity. Under the conditions of both lowering the voltage and frequency, DBS with increased pulse width could have a higher inhibitory effect on beta oscillation than traditional DBS.

第一章 緒論 1
第二章 實驗材料與方法 4
1. 實驗材料 4
1.1 實驗動物 4
1.2 實驗藥品 4
1.3 實驗儀器 4
2. 實驗方法 5
2.1 電極植入及Reserpine誘導帕金森氏症模式鼠 5
2.2 記錄、刺激電極材料 6
2.3 腦波記錄 6
2.4 電刺激 6
2.5 快速傅立葉轉換(Fast Fourier Transform, FFT)與譜密度(Power Spectral Density, PSD)分析 7
2.6 時頻分析 8
2.7 單次刺激STN引發M1誘發電位變化量測 8
2.8 Beta power計算 8
第三章 實驗結果 9
1. 帕金森氏症模式動物誘導 9
2. STNM1神經元 10
3. 誘發電位與M1中間神經元 10
4. 中間神經元習慣化 11
5. M1神經活性與beta oscillation 12
6. 間斷刺激 13
7. 刺激波寬與抑制效果 13
第四章 結果討論 15
1. 刺激STN對M1造成的反應探討 15
2. 比較透過提高電壓或波寬增加刺激效果 16
第五章 圖表 17
第六章 參考文獻 32

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