藥理與電生理調控NMDA路徑對帕金森病患認知可塑功能與動作準備的影響

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Title:	藥理與電生理調控NMDA路徑對帕金森病患認知可塑功能與動作準備的影響
Authors:	蔡崇豪(Chon-Haw Tsai)*;陳右穎(You-Yin Chen);藍先元(Hsien-Yuan Lane);邱尚明(Shang-Ming CHIOU)
Contributors:	醫學院醫學系學士班神經學科;中國附醫神經部
Date:	2012-07-31
Issue Date:	2012-06-15 11:38:58 (UTC+8)
Abstract:	此三年計畫主要是研究帕金森病患其N-亞硝基二甲基胺(N-methyl-D-asparate)路徑的藥理和電性調節對認知可塑性和自主動作準備的影響。在藥理的部分，將以患有失智症的帕金森病患為對象探討病人在接受肌胺酸(sarcosine)（一種甘胺酸傳輸蛋白抑制劑，可活化N-亞硝基二甲基胺接受器的甘胺酸位置）前後對其臨床、神經影像與電生理的影響。在電性調節的部分，將探討下視丘核（N-亞硝基二甲基胺豐沛區域）深層腦部刺激對帕金森病患認知可塑性和動作準備的影響。本研究欲瞭解是否調節廣汎性的N-亞硝基二甲基胺接受器甘胺酸位置或微小的N-亞硝基二甲基胺豐沛區，下視丘核，均可能對帕金森病患大腦的認知可塑性和自主動作的準備有實質上的影響。本研究在瞭解N-亞硝基二甲基胺於帕金森病患治療與病態生理機轉之角色有很重要的意涵。第一年計畫-除了動作障礙的特徵外，約有15-20%的帕金森病患可能在疾病過程中會產生失智症。這類病患除了認知的衰退之外可能也會有間歇性的精神、幻覺症狀。在這些狀況之下，抗精神分裂藥物的投予雖可改善部分的症狀但往往也會造成帕金森病患動作障礙的惡化。對於失智的治療，中樞乙醯膽鹼酯?抑制劑的確有某種程度的療效。然而，高成本效益比率卻阻礙了帕金森併失智症病患使用這些藥物的普及性。近來的研究顯示經由阻斷紋狀體NR2A 或是經由N-亞硝基二甲基胺接受器甘胺酸位置的啟動可促進多巴胺之分泌。另外，之前的報告也發現N-亞硝基二甲基胺-甘胺酸接受器路徑與情緒、前額葉和受感知覺的功能有關聯。本研究將探討是否經由肌胺酸所導致之N-亞硝基二甲基胺 -甘胺酸接受器功能之提昇可改善帶有失智症的帕金森病患者的動作和認知功能且不會惡化病患的動作障礙。30 位帶有失智症的帕金森病患者將會隨機分配到試驗組或安慰劑組並進行 8 週的臨床試驗。在肌胺酸服用前、後，探討神經心理測試包括失智症評估、神經精神問卷測試和標準帕金森病量表的變化。電生理和神經影像也會一起施測來探討肌胺酸效應所引起的病理生理學機制。經由此新的策略，我們希望會尋找到帕金森併失智症病患新的附加治療方式。第二年計畫-下視丘核接受由大腦皮質來的神經傳入與由下視丘核輸出的神經訊息大部分倚賴穀胺酸鹽（一種興奮N-亞硝基二甲基胺受器的神經物質）。下視丘核是由三個功能部位組成：動作區、輔助聯合區、邊緣區。這些不同結構位置象徵下視丘核不只是在動作執行上扮演重要的角色而且在動作準備和認知彈性/概念轉移上亦具相當的份量。在第二年的第一部份，將於接受深層腦部刺激術後第四天帕金森病患探討自控性的手部動作對下視丘核局部域場電位(local field potential)的影響。訊號會以相位偶合分析(phase coupling analysis)來探討下視丘核的對神經資訊處理負載的程度。頭皮表面的動作關聯電位亦將同步的紀錄以暸解大腦皮質動作準備輔助區或下視丘核何者於動作準備時較先啟動。在研究的第二部分，我們將探討視丘下核的於執行事件-替換作業(task-switching test)的角色。事件-替換作業主要是量測認知過程的替換-成本(switch-cost)部分。替換-成本代表額葉基底核迴路於由一已選擇之測試規則轉換成另一種規則的觀念轉移功能。這種功能在帕金森病患通常會出現問題。此外大腦事件關聯電位(event related potential)亦會與下視丘核局部域場電位同步紀錄以暸解深部與表層神經訊號變化之相關性。此研究將有助於深入瞭解認知執行過程是如何來影響下視丘的訊號。本計畫預計邀集10 位病患來進行研究。第三年計畫-接續前兩年計畫，第三年計畫將研究不同的下視丘核刺激頻帶(含低頻、β波範圍和病患當前接受的高頻率的刺激)對已穩定的深層腦部刺激術的帕金森病患於執行事項-替換作業的影響。此研究主要是建立在之前的發現亦即以5 或20 赫茲刺激頻率刺激下視丘核相較於0 赫茲其手指敲擊速率會減慢。1 其結果說明低頻與β波的同步化刺激可提升帕金森病患基底核迴路的敏感度進而影響病患的動作執行。下視丘核是基底核-皮質電路很重要的一個中繼站。這微小的核承載以N-亞硝基二甲基胺為主的神經輸出及傳入。雖然它在動作執行上的角色已相對的較為清楚，但此核在認知和動作準備所扮演的研究則剛開始萌芽。在第三年計畫中，我們將在0，5，20 赫茲與高頻的深層腦部刺激頻率下測試受試者執行事件-替換作業的功能變化。此研究與前兩年之計劃將提供認知彈性操作/動作準備和下視丘核(N-亞硝基二甲基胺豐沛區)間可能存在的交互關係之重要線索。本計畫預計邀集10 位病患來進行研究。 The 3-year project will investigate the effect of pharmacological and electric modulation of N-methyl-D-aspartate (NMDA) pathway on the cognitive flexibility and volitional movement preparation in patients with Parkinson’s disease (PD). In the pharmacological session, the clinical impact of enhancement of NMDA-receptor glycine site will be investigated in PD with dementia (PD-D) patients receiving sarcosine, a glycine transporter-1 (GlyT-1) inhibitor. In the electric part, effect on cognitive flexibility and movement readiness by deep brain stimulation of the subthalamic nucleus (STN), a NMDA abundant region, will be probed in patients with PD. The proposal may help the understanding of the possible beneficial mechanism of modulation of the global NMDA receptor glycine site and the tiny NMDA warehouse, the STN, in cognitive flexibility and volitional motion preparation in PD patients. First year project- In addition to the salient motor characteristics, around 15-20% of the PD patients may also develop dementia in the later stage of the disease course. Apart from cognitive declining, PD-D patients may also develop intermittent neuropsychiatric symptoms. Under these situations, neuroleptic agents may be administrated to the patients and the symptoms can usually be suppressed by trading off patients’motor fluency. Concerning the treatment of dementia itself, central acetylcholine esterase inhibitors had ever been tried with certain success. Yet, the high cost-benefit ratio hinders the generalization of the popular use of these agents to PD-D patients. Recent animal studies have shown that dopamine secretion can be enhanced by activation of the NMDA-receptor glycine site. In addition, previous reports have illustrated that the glycine site is relevant to emotion, frontal lobe and perceptual functions. In this project, we will investigate whether enhancing NMDA-glycine receptor activity can improve cognitive and/or motor functions in patients with PD-D. Thirty patients with PD-D will be randomized into treatment and placebo groups for a study period of 8 weeks. A package of neuropsychological tests and Unified Parkinson’s Disease Rating Scale (UPDRS) will be conducted before and after sarcosine treatment. Task-switching event related potentials (ERP), movement-related cortical potentials (MRCP) and neuroimaging studies will also be delivered to investigate the pathophysiological mechanism of the sarcosine effect. Through the novel strategy, we try to charge a novel trail for the add-on management of PD-D patients. Second year project-The major cortical afferents to STN and efferents from the tiny structure rely mostly on glutamate. STN consists of 3 functional parts: motor, associative and limbic areas. These different anatomic landmarks suggest that the STN not only play a role in motor execution but also pivotal roles in movement preparation and cognitive flexibility. In the first part of the second year project, we will investigate the impact of self-paced volitional movement on the STN local field potentials in PD patients on the 4th day after deep brain stimulation operation. Concomitant MRCP recording will be conducted over the scalp. Phase coupling analysis of the STN signals will be conducted to allow the estimation of the load of information processing of the nucleus. The concomitant MRCP recording will also help identify the leading structure of movement preparation. In the second part of the project, we will probe the effect of task-switching performance on the STN. The task-switching paradigm measures mainly the switch-cost of the cognitive processing. Switch-cost presents the fronto-basal ganglia function in shifting from one self-chosen rule to another. Recording of scalp ERP will be conducted simultaneously with the subthalamic local field potential recording. The performance of the paradigm will shed us an insight of how the cognitive processing will affect the subthalamic signaling.We will recruit 10 patients for the study. Third year project-The third year proposal will investigate the impact of low, beta range and current high frequency stimulation to STN on the task-switching performances of PD patients. The rationale is based on the previous works that illustrated the finger tapping rate was decreased at 5 and 20 Hz stimulating frequencies as compared to the 0 Hz by direct stimulation to the STN.1 The result implied that the susceptibility of basal ganglia networks to the effects of excessive synchronization may be elevated across a broad low-frequency band in PD patients. Although the role of STN in motor execution is strongly evident, the function of the nucleus in cognitive processing and premovement preparation has just begun to be explored. In the third year project, we will probe the intriguing issue by conducting task-switching test before and during different deep brain stimulation frequencies. The study will provide crucial evidence of the role of STN in cognitive flexibility processing. The project along with the aforementioned projects will illustrate the possible reciprocal relationship between the cognitive flexibility performance/simple self-paced movement and the tiny NMDA rich nucleus.
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