摘要:機器輔助復健與鏡像療法是中風轉譯科學時代裡新崛起的輔助療法。機器輔助復健源自機械與生醫工程的科技性治療輔具,是目前極具潛力且以活動為基礎的療法,此療法融入中風動作學習要素於治療中,如:密集訓練、重複練習、任務專一、回饋提供、及雙側練習等。另一崛興中的神經復健療法是鏡像治療,該療法是鏡像神經元研究所轉譯形成的動作學習療法,病患在健側肢與患側肢間放一面鏡子,以阻斷對患側肢的視線,藉由健側肢動作倒影在鏡中的視幻,在腦中建立兩側肢體功能正常的假象,並透過視幻覺來促進患肢動作能力。鏡像治療所提供的動作視覺刺激,可能徵召前動作皮質區、主動作皮質區及體感覺皮質區,來達到改善病患感覺、知覺和動作的進步。此外,功能性電刺激治療也是日漸普及的創新科技,常應用於協助低功能患者動作執行或增加主動關節活動時肌肉的收縮。將功能性電刺激治療合併至神經復健療法(如機器輔助療法),可望將治療適用對象的範圍,擴大到中、重度損傷病患。機器輔助療法與鏡像療法雖各有療效證據廣見於科研文獻,然而兩者的直接對比尚闕如。此外,功能性電刺激治療是否能搭配強調肌力強化與動作誘發的機器輔助療法,形成更具成效的混合療法,也有待探研。近年來在中風動作復健領域裡,重視創新療法間的療效對比,以建立個別化介入方案,並提升臨床醫學與轉譯科學的交叉整合。然而,現有的機器輔助療法與鏡像治療成效多限於動作功能,欠缺對感覺功能、生活功能(特別是工具性日常生活功能)、及生活品質的評量。此外,密集性動作復健治療對施力後疲勞與細胞氧化反應等可能的不利影響,極度欠缺以人體為對象的轉譯研究,亟需嚴謹的對比試驗與轉譯研究,來對照機器輔助復健、鏡像治療、與控制療法對中風各層面功能恢復之影響,並探究治療成效的預測因子及評估工具的臨床計量特性,以釐清這些療法適用的對象、臨床適用的評量工具,及成效的預測因素。本研究旨在對照機器輔助復健與鏡像治療,相較於控制療法對各層面功能的立即與長期成效,並進一步分析合併功能性電刺激治療是否能增強機器輔助復健的成效。累積療效分析資料庫後,另可尋求調節療效大小的相關因子,並分析常用評量工具之臨床計量特性,推算臨床上有意義的改變之閾值。具體而言,本計畫目的:(一) 對比劑量配對的機器輔助復健與鏡像療法,相較於控制療法對中度損傷的中風病患之介入成效與動作控制機制;(二) 對比機器輔助復健合併功能性電刺激,相較於機器輔助復健,對中重度損傷的中風病患之療效與動作控制機轉; (三)分析機器輔助復健、鏡像療法、和機器輔助復健合併功能性電刺激等各種治療的成效決定因子,並界定適用對象。依據先導研究與理論模型,預計分析的潛在預測因子包含年齡、性別、患側邊、發病時間、上肢動作能力,及日常生活功能等。在上述對比試驗完成後,將驗證各種成效評量工具之臨床計量特性 (如:信度、效度、反應性、最小可偵測改變值、最小臨床重要差異值),以建立成效判定的閾值,並提供日後工具選擇之依據。為深化多元成效評量的轉譯發展,本研究將評量的功能範疇,將涵蓋世界衛生組織國際健康功能與身心障礙分類中的身體功能、身體構造、及活動與參與,除了神經與動作控制、動作表現、肌肉功能、感覺功能、基本與工具性日常生活活動功能、及中風相關生活品質外,也將分析密集動作復健後的疲勞與細胞氧化傷害標記,以發展神經復健領域的轉譯研究。本研究擬以三年為期,分三階段進行頭兩年的臨床試驗及最後一年的計量分析,依據統計檢定力的推估,預計延攬100 位第一次中風病患。第一階段(第一年)將進行隨機控制試驗,對比機器輔助復健、鏡像療法,與劑量配對的控制療法。在此對比試驗中,60 位中度或中輕度損傷的中風病患將隨機分配到三組之一(機器輔助復健、鏡像療法、控制療法)。治療計畫為期四週,治療頻率為每天一個半小時,每星期五天。在治療前、治療結束時、治療結束後一個月與三個月,分別接受單側及雙側上肢的運動學分析,以及臨床評估(動作損傷、動作表現、肌肉功能、感覺功能、基本與工具性日常生活功能、中風相關生活品質、及疲勞與細胞氧化指標)。第二個階段(第二年)將評估機器輔助復健合併功能性電刺激,相較於機器輔助復健加上假功能性電刺激(仍貼有電極片但無電刺激的安慰性介入),對中風病患之療效與動作控制機轉。40 位中重度損傷的中風病患將隨機分配到兩組之一。療效評估項目類如第一年計畫。第三個階段(第三年)將分析治療成效的決定因子及成效評量工具之臨床計量特性。此計畫完成後,可望提供機器輔助復健、鏡像治療、及機器輔助復健合併功能性電刺激治療於中風患者之具體成效證據,並闡明密集動作復健對疲勞與細胞氧化的可能影響。此研究計畫之結果將有助於了解上述治療在提升中風患者功能之可能機制,帶動後續神經復健的發展,並將動作科學與代謝生理學轉譯應用至神經復健的實務與研究。
Abstract: Emerging stroke rehabilitation therapies have shown promise for improving motorrecovery after stroke and involve elements of high-intensity and repetitive task-specificpractice, which might be the essential elements of treatment success. Two prominentexamples of advances in innovative rehabilitation therapies after stroke include roboticrehabilitation (RR) and mirror therapy (MT). Based on the development of mechanical andbiomedical engineering, RR has emerged that incorporates therapeutic elements for success inmotor rehabilitation: high-intensity, repetitiveness, task-specificity, feedback, and bilateraltraining into its design. MT has been proposed in the light of translational research of mirrorneurons. In MT, patients place a mirror beside the unaffected limb to block their view of theaffected limb, creating the illusion that both limbs are intact. The motor visual input from MTfacilitates the activations in the premotor, primary motor and somatosensory areas, whichenhance sensory, perception and motor abilities. The MT may be used to restore sensoryfunctions, improve grip/grasp strength and motor function. In addition, an innovativetechnology, functional electrical stimulation (FES), is proposed as an adjunct to assist inmovement execution and increase the electric activity of muscles for movement and the activerange of motion in patients with low functioning. Robotic rehabilitation that emphasizesmuscle strengthening and motor restoration may be implemented in combination with the FESto improve treatment outcomes in stroke patients with moderate-to-severe motor impairmentsin movement performance and functional outcomes. Despite these promises, research studiesthat investigate comparative efficacy of the rival therapies and the effects of combinedtherapy relative to mono-therapy are lacking. An additional gap in contemporaryneurorehabilitation is the lack of sufficient information on the threshold values of clinicallysignificant change in a variety of functional domains relevant for individualized medicine. Inaddition, research on the potential vales of biomarkers (eg, level of oxidative stress) for use inoutcomes study in intense rehabilitation falls far behind disciplines of basic sciences. Thisproposed research project will be devoted to comparative efficacy trials and clinimetric studyto promote evidence-based neurorehabilitation and translational research in stroke.It has been called for comparative effectiveness research of the innovative treatments topromote evidence-based practice and translational science in stroke motor rehabilitation.Scientific evidence for comparative effectiveness research of RR versus MT on functionaloutcomes (e.g., motor, muscle, sensory, and daily functions) and adverse physiologicalresponses (e.g., fatigue and oxidative responses) in stroke patients is limited. More rigorousstudies are needed to compare the efficacy of RR and MT with control intervention (CI), toidentify the predictors of treatment success, and to study change in functions (motor, muscle,sensory, and daily) and level of fatigue and oxidative stress after intense training in order topromote translational science in movement therapy. Therefore, this comparative efficacyresearch aims at performing a randomized controlled trial (RCT) to (1) verify the efficacy andmotor control mechanisms of dose-matched RR, MT, and CI; (2) examine whether RRcombined with FES will enhance the effect of RR; (3) study the predictors of treatmentoutcomes and clinimetric properties of the outcome measures. We hypothesize the RR andMT groups would produce better performance in motor control, muscle function, sensoryfunction, daily functions, and quality of life than the CI group. We further hypothesize thatthere will be a differential improvements in movement performance and sensory functionsbetween the RR and MT. Combined therapy of the RR and FES (RR-FES) will enhance theeffect of RR as compared with the RR plus placebo intervention (RR-PI).Specific objectives of this proposed research are as follows. First, we will comparethe efficacy of the RR, MT, and CI on UL motor control and performance, muscleperformance, sensory functions, daily functions, stroke-related quality of life, fatigue, anda biomarker of oxidative stress (i.e., 8-hydroxydeoxyguanosine). Secondly, we willcompare the efficacy of the RR-FES versus the RR-PI on outcome measures. Thirdly, we will identify the clinical predictors that will potentially influence the functional outcomesafter interventions. The potential predictors will include side of lesion, time since stroke,motor impairment, and activities of daily living function. Additionally, we will examineand compare the clinimetric properties (e.g., reliability, validity, responsiveness, minimaldetectable change, and minimal clinically important difference) of the clinical measures ofrehabilitation outcome to inform selection of instruments that may detect real change andclinically meaningful change after therapy.This 3-year project will be implemented in three stages and will recruit 100 patientswith chronic stroke (post-stroke onset of at least 6 months). At the first stage (the firstyear), 60 patients with moderate or moderate-to-mild motor impairment (Brunnstromstage III or above; Fugl-Meyer Assessment [FMA] score 26-56) will be randomized todose-matched RR or MT or CI. In the second year, the investigators will investigate therelative effects of RR-FES versus RR-PI for 40 patients with moderate ormoderate-to-severe motor impairment (Brunnstrom stage III or below; FMA score 18-50).Treatment regimens will be designed to ensure that patients in the 3 groups in Study 1 and2 groups in Study 2 will receive an equivalent amount of treatment (1.5 hours/day, 5days/week for 4 consecutive weeks). In the third year, the investigators will determine thepotential predictors for different functional outcomes of the interventions and examineclinimetric properties of outcome measures.The outcome measures will be in accordance with the International Classification ofFunctioning, Disability and Health framework, including outcomes associated with bodyfunctions or structure (impairment), activity (disability), and participation (handicap).Furthermore, possible adverse effects (eg, physiological fatigue) will be monitored inaddition to the study of treatment benefits. Motor control strategies and muscle functionwill be evaluated using kinematic analyses, Modified Ashworth Scale, myometer, and theMedical Research Council scale. Movement performance will be assessed using clinicalmeasures, such as the FMA and the Action Research Arm Test. Sensory functions will beassessed using the sensory scale of the FMA, revised Nottingham Sensory Assessment,and Touch-Test sensory evaluator. Daily functions will be evaluated using the MotorActivity Log, ABILHAND Questionnaire, and the Nottingham Extended Activities ofDaily Living Scale. Quality of life will be assessed using the Stroke Impact Scale. Thegeneral subscale of the Multidimensional Fatigue symptom Inventory will be used tomeasure general fatigue of the patients after interventions. Urinary8-hydroxydeoxyguanosine will be analyzed as a biomarker of oxidative stress afterinterventions. The kinematic protocol and clinical measures will be administered beforeand after intervention for the effects of interventions, 1-month follow-up, and 3-monthfollow-up assessments for the retention of treatment effects. The potential predictors oftreatment outcomes after each treatment approach and the clinimetric properties ofoutcome measures will be studied to improve clinical decision making and to validate theutility of outcome measures in clinical practice.The investigators anticipate that this research project will shed light on the evidenceof immediate and long-term effects of RR, MT, and RR-FES for stroke patients, possibleeffects of intense training on fatigue and oxidative stress, factors that may influencetreatment outcomes, and clinimetric properties of the outcome measures. The findingswill contribute to our understandings of possible mechanisms underlying the therapeuticbenefits conferred by specific interventions as well as possible physiological fatigue andoxidative responses in intense training and guide the development of more effectiverehabilitation programs.