帕金森氏症是一種常見於老年人之神經退化性疾病，常出現肌肉僵直、震顫和行動障礙等症狀。即使多巴胺取代性藥物對於大多數帕金森症患者提供良好的控制，但藥物治療對於症狀減輕並不完全，且長期的使用藥物往往會出現副作用。因此，對於此疾病新的治療方法將是目前發展的主要任務。間歇型陣發磁波刺激術為一種新穎的重複性經顱磁刺激模式，過去研究發現對於運動皮質的興奮性可維持較長的效果，這個效果或許可以減輕帕金森氏症所產生的運動障礙等症狀。然而，對於此模式的治療潛力目前仍尚未清楚研究。有鑑於此，在導入間歇型陣發磁波刺激對於帕金森氏症之臨床治療前，我們使用帕金森氏症動物模型並設計一系列之實驗方法來驗證陣發型磁波刺激對於帕金森氏症可能的治療潛力。
本實驗在大鼠之內側前腦束注射六-羥基多巴胺來建立半側損傷之帕金森大鼠模型，並進而評估間歇型陣發磁波刺激術之治療效果。從設計一個新式之重複性經顱磁刺激去治療帕金森氏症的觀點來看，需要就運動功能、動物行為與皮質塑性等之生物力學與電生理特性之交互作用來考量，本實驗的目的為使用新式的間歇性陣發磁波刺激(iTBS)模式為治療工具，在動物行為、皮質塑性、與免疫組織化學分析上探討磁波刺激對於帕金森氏大鼠之治療效果。
在使用磁刺激為治療模式之前，許多定量化平台被發展來評估帕金森大鼠在患病後所呈現之肌肉僵直、皮質塑性之長期增益能力、長時程皮質內抑制功能、運動不能與步行能力。肌肉僵直的改變可以在帕金森大鼠清醒時使用微小生物力學牽張系統去手動牽張下肢來測量，並在不同牽張頻率去測量反應的力矩和角度變化。神經塑性可以在重複性經顱磁刺激前後，使用電生理測量動作誘發電位來驗證；在行為評估上，除了在帕金森大鼠中使用傳統的阿朴嗎啡誘發的旋轉行為和單槓測試上肢運動不能外，常見的步態缺損可以在我們所設計之步道以及使用半自動影像分析去進行步態模式驗證。
為了在帕金森大鼠中調節皮質興奮性，本實驗使用高頻間歇型陣發磁波刺激模式來刺激大腦運動皮質，經由皮質脊髓徑路來誘發大腦皮質之長效增益模式，進而加強皮質塑性之產生。最後在治療組與控制組中藉由許多運動行為參數來進行每週療效性評估，並比較兩者在四週磁波治療後之成效差異。
關於間歇型陣發磁波刺激介入的立即性效果，正常大鼠經過磁波刺激後，動作誘發電位在刺激五分鐘後上升，並維持約30分鐘 (p < 0.05)，然而慢性帕金森氏大鼠則無明顯差別。此結果顯示間歇型陣發磁波刺激無法在帕金森氏症大鼠的運動皮質誘發出長期增益之神經塑性，其可能與多巴胺缺損的嚴重程度有關。另外，基於成對脈衝磁刺激之評估，慢性帕金森氏症大鼠在患側邊呈現缺少皮質抑制功能，此結果指出帕金森氏大鼠的運動皮質缺乏GABA抑制效應。最後，在長期進行重複性經顱磁刺激治療後，和未經過治療的帕金森大鼠相較下，即使磁波刺激對於皮質興奮性之提升效果只在早期損傷(損傷後一週)之帕金森氏大鼠中發現，但相對於控制組，連續四周之間歇型磁波刺激對於帕金森氏症大鼠之運動功能缺損有明顯的改善。
我們整合的神經工程平台可以在帕金森氏動物中施行連續性經顱磁刺激治療後，提供一個獨特的機會來觀察帕金森氏症大鼠之運動表現與神經塑性，此方法可以在未來對於帕金森氏症之人類臨床治療時提供一個客觀之評估工具。此外，我們的研究指出帕金森氏大鼠的運動功能缺損可以在早期且長期之連續性經顱磁刺激介入後獲得改善，也進而確認每天使用間歇型磁波刺激後可達到持續性治療之效果，我們希望此結果或許可以在未來轉譯至人類帕金森氏症之臨床治療。

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder of the elderly which is characterized by progressive muscular rigidity, tremor and gait problems. Although dopaminergic replacement therapy provides benefit to most PD patients, the symptom relief is often incomplete, and chronic drug therapy is often limited by side-effects. Thus, new nonpharmacologic treatments for PD remain an important unmet medical need. Inermittent theta-burst stimulation (iTBS), a novel form of repetitive transcranial magnetic stimulation (rTMS), induces long-lasting enhancement of motor cortex excitability and theoretically may relieve PD motor symptoms. However, its therapeutic potential in PD has not been investigated. Accordingly, we conducted the present series of experiments to test the therapeutic potential of iTBS in a PD rat model, as an early step toward possible eventual clinical use of iTBS in PD.
A hemiparkinsonian adult rat model, generated by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB), was used to evaluate the therapeutic potential of iTBS in PD. We deliberately used a rat PD model because the design of novel rTMS PD treatment necessitates consideration of the complex interactions of the biomechanical and electrophysiological aspects of motor function, behavior and cortical plasticity. The aim of these experiments was to investigate the efficacy of iTBS treatment in PD rats at three major levels: behavioral (as measured by targeted tasks), synaptic (as reflected in cortical plasticity) and molecular (as assayed by immunohistochemistry).
Prior to iTBS, several quantitative platforms were developed to assess the time course changes of muscular rigidity, long-term potentiation (LTP)-like cortical plasticity, long interval intracortical inhibition (LICI), akinesa and locomotor function of hemiparkinsonian rats following 6-hydroxydopamine lesion. Changes in muscle rigidity were evaluated by a novel miniature biomechanical stretching device which manually stretched the hindlimb of awake PD rats, from which the reactive torque and angular displacement at different stretching frequencies were measured. Neuroplasticity was verified by electrophysiological measurements of motor evoked potentials (MEPs) before and after rTMS. For behavioral tests, in addition to traditional apomorphine-induced rotation and bar tests for akinesia, the gait pattern in PD rats was quantified by walking track test using image analysis for semiautomatic measurement of gait parameters.
To modulate the cortical excitability in our preclinical studies, a human high frequency iTBS scheme was adapted to the rat PD model to induce lasting (LTP-like) changes in the excitability of the corticostriatal pathway in hemiparkinsonian rats. Several motor behavioral parameters were evaluated at weekly intervals for four consecutive weeks after daily administration of real or sham iTBS over the primary motor cortex.
Immediately after iTBS, MEP amplitudes in normal rats increased significantly 5 min after stimulation and remained enhanced for up to 30 min (p < 0.05). In contrast, in PD rats, the MEPs remained unchanged immediately after iTBS. These results indicate the absence of iTBS-induced LTP-like plasticity in the motor cortex of PD rats and may be related to the severity of dopamine depletion. Based on the paired-pulse transcranial magnetic stimulation (ppTMS) protocol, LICI in chronic PD rats was altered, showing less cortical inhibition, behavior which was most evident in the affected hindlimbs. The LICI observation suggested the impairment of GABAergic inhibition in the motor cortex of PD rats. Regarding the long-term effects of rTMS, although iTBS changed cortical excitability only at the early stage (post-lesion 1 week) of PD rats, iTBS did reduce motor deficits in PD rats over a 4-week time-course of observation when compared with a sham control group.
Our integrated neural engineering approach provides a unique opportunity to detect and measure the changes in motor performance and neuroplasticity in the PD rat model after rTMS interventions (such as iTBS), which might be useful for future objective assessment of novel treatments for human PD patients. In addition, our data suggest that the motor deficits in PD rats could be reduced by rTMS intervention early in the course of the disease. This confirms the existence of sustained benefits from consecutive daily iTBS, which we hope may be translated to human PD therapy.

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