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研究生: 王誠鴻
Wang, Cheng-Hong
論文名稱: 整合電與光刺激於光基因轉殖小鼠癲癇抑制之研究
Research on Integrating Electrical and Photic Stimulations for Suppressing Epileptiform Discharge in Optogenetic Mice
指導教授: 朱銘祥
Ju, Ming-Shaung
學位類別: 碩士
Master
系所名稱: 工學院 - 機械工程學系
Department of Mechanical Engineering
論文出版年: 2018
畢業學年度: 106
語文別: 中文
論文頁數: 92
中文關鍵詞: 癲癇電刺激光基因刺激Thy1-mhChR2-YEP毛果芸香鹼樣本熵閉迴路控制
外文關鍵詞: seizures, electrical stimulation, optogenetic stimulation, lithium-pilocarpine, Thy1-mhChR2-YEP, sample entropy, closed-loop control
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  • 顳葉癲癇為一種常見的慢性腦部神經疾病,病患中有將近三成無法由藥物有效控制,其中適用切除手術的病患又占少數,因此有必要發展新的治療方法以抑制癲癇之發作,本研究的目的為整合電刺激與光基因刺激發展新的治療方法,利用電刺激來抑制癲癇並輔以光基因刺激來延長下次癲癇發作的時間。首先,在Thy1-mhChR2-YEP轉殖小鼠施打鋰鹽與毛果芸香鹼於以誘發急性癲癇。接著,以擷取的深腦電刺激訊號計算出樣本熵值來辨識癲癇狀態並以之設計出電刺激開關控制法則與光基因刺激分段比例控制法則,建構出閉迴路控制系統。由12隻小鼠實驗結果顯示本研究發展的控制系統在急性癲癇發作期間辨識率高達92%以上,而由6隻小鼠實驗結果顯示在急性癲癇的抑制成效上,不管整合電與光刺激還是電刺激皆能有效的抑制癲癇發作,兩者抑制成功率皆在83.3%以上。而整合電與光刺激之抑制成功率大致皆比電刺激高。而在平均抑制時間上,整合電與光刺激可以提升達1.47秒。總之,整合電與光刺激的系統可能對未來的顳葉癲癇治療提供新的發展方向。

    Temporal lobe epilepsy is the most common form of partial epilepsy. Although drug therapy have been found, there are one-third of patients who cannot benefit from these treatments. So it is necessary to develop new treatments to suppress epilepsy. The purpose of this study is to develop a control system to suppress acute seizures by integrating electrical and photic stimulations. In this study the electrical stimulation was proposed for seizure suppression and the photic stimulation was proposed for seizure prevention. Thy1-mhChR2-YEP transgenic mice were injected with lithium and pilocarpine to induce acute seizure. Depth-EEG from hippocampus was acquired and the sample entropy was calculated and served as the input to a closed-loop control system. An on-off control law for electrical stimulation and a piecewise proportional control law for photic stimulation were integrated in the control system. The results from 12 subjects show seizure recognition rate rises up to 92% in the acute stage. Both the electrical stimulation alone and the integrated electrical and photic stimulations can effectively inhibit seizure, with suppression rate greater than 83.3%. The suppression rate of integrated electrical and photic stimulation is generally higher than that of electrical stimulation. The average suppression time was prolonged by 1.47 seconds when the electrical was integrated with the photic stimulation. In conclusion, integrated electrical and photic stimulations may provide a new direction of development on treating seizure in the future.

    摘要i 誌謝xiii 目錄xiv 圖目錄xvi 表目錄xix 符號表xx 第一章 緒論1 1.1癲癇介紹1 1.2癲癇治療4 1.2.1深腦電刺激(Deep Brain Stimulation)5 1.2.2光基因技術(Optogenetic stimulation)8 1.3動物癲癇模型11 1.4研究動機與目的12 第二章 方法及實驗14 2.1光基因轉殖鼠15 2.2實驗設備16 2.2.1立體定位儀和手術設備16 2.2.2訊號擷取與控制系統17 2.2.3光刺激系統17 2.2.4電刺激系統18 2.3實驗步驟20 2.3.1立體定位手術20 2.3.2癲癇誘導26 2.4癲癇辨識器27 2.5開迴路實驗設計30 2.5.1電刺激實驗30 2.5.2光刺激實驗31 2.6閉迴路控制器設計32 2.7性能指標36 第三章 結果38 3.1鋰鹽-毛果芸香鹼癲癇模型38 3.2開迴路控制實驗結果48 3.2.1電刺激開迴路結果48 3.2.2光刺激開迴路實驗58 3.3閉迴路實驗60 3.3.1電刺激結果60 3.3.2整合電與光刺激結果64 3.4性能指標70 3.4.1辨識率70 3.4.2抑制成功率72 3.4.3平均抑制時間73 第四章 討論78 4.1低劑量鋰鹽-毛果芸香鹼模型78 4.2電刺激參數選擇80 4.3光基因抑制82 4.4癲癇辨識演算法比較83 4.5控制法則與抑制指標比較85 4.6臨床應用86 第五章 結論87 5.1結論 87 5.2建議 88 參考文獻 89

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