2012-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/650202摘要：計畫背景：巴金森症的病態生理與多巴胺缺乏的狀態下大腦基底核迴路異常功能緊密相關。視丘下核叢集式放電目前被視為在此一迴路異常功能中最具代表性的關鍵變化。我們最近的研究發現視丘下核神經元細胞膜的內部特性，尤其是T型鈣離子通道，在視丘下核的叢集式放電中扮演重要角色。抑制視丘下核神經元Ｔ型鈣離子通道能夠有效地改善巴金森症模型大鼠的運動障礙症狀。但是，視丘下核深腦刺激術是否也是借助此種機制發揮治療巴金森症的臨床效果，尚不得而知。目前我們進一步的研究結果，支持視丘下核電流刺激的效果其實與電流注射引起細胞膜去極化/再極化關係密切，而與目前所相信注射電流的頻率多或少無關。計畫方法：我們將藉由注射相反極性（負及正極）的持續電流，測試視丘下核深腦刺激治療臨床效果與電流注射引起細胞膜去極化/再極化關係密切的假說。並藉由此種電流注射後正常及巴金森症模型動物的運動行為及電氣生理反應來證明其效果變化。我們進一步研究持續電流在離體大腦切片及分離出來的視丘下核神經元電器生理上的作用。最後，我們將在五位巴金森症患者接受視丘下核深腦刺激手術中，針對不同的電流刺激方式，脈衝式130HZ或持續式電流刺激，進行臨床效果的頻估與比較。計畫預期結果：本計劃可以提供未來視丘下核深腦刺激治療巴金森症或其他運動障礙疾病患者（例如：舞蹈症）電流刺激方式的重要參考。藉由將目前常用的脈衝式電流刺激改為持續式電流刺激，我們將可為未來深腦刺激治療發展更寬廣的治療範疇，並對深腦刺激治療的治療機轉提供更深入的認識。<br> Abstract: Objective: The pathophysiology of Parkinson’s disease (PD) is closely related to aberrantcortico-basal ganglia loop functions in a dopamine-deficiency state. The subthalamic nucleus(STN) burst firing activity has been proposed to be a major electrophysiological feature in theabnormal functioning of the basal-ganglia circuitry in PD. In our recent study, intrinsicmembrane properties of subthalamic neurons, especially the T-type Ca2+ channel, play a keyrole in the genesis of STN burst firing, and inhibition of STN T-type Ca2+ channels effectivelyremedies parkinsonian locomotor symptoms in rats. However, whether subthalamic deepbrain stimulation (DBS) exerts its clinical effect on Parkinson’s disease (PD) through thismechanism remains elusive. Our perliminary results support the hypothesis that the effect ofSTN stimulation is closely associated with membrane depolarization/hyperpolarization bylocal current injection, in spite of stimulation frequency.Methods: We test the hypothesis that the clinical effect of subthalamic nucleus (STN) DBS isascribed to membrane depolarization/hyperpolarization by injection of constant currents ofopposite polarity, and documentation of the effects on both locomotor behavior and in vivoneural discharges in normal and parkinsonian rats. We further investigate the effect ofconstant current injection in vitro in both brain slice preparations of parkinsonian animalmodel and acute dissociated STN neurons. Finally, we recruit five PD patients receiving STNDBS implantation surgery and explore the differences between 130 Hz and constant currentstimulation paradigm of STN DBS according to the foregoing experimental results.Expected results: This project may well suggest a beneficial effect of DBS at STN (withinjection of constant rather than pulsatile currents) on parkinsonian patients or othermovement disorder patients (ie. chorea and ballism), and will further illustrate the potential ofthe much widened scope of DBS therapy with a better mechanistic understanding.