「經顱直流電刺激結合感覺輸入調節治療模式」於慢性中風患者上肢動作復原之療效與機制驗證

Abstract

背景與目的 有效復原患側手部動作與功能，是中風復健領域之重大挑戰，然而目前針對嚴重至中度上肢動作損傷之中風患者，臨床療效仍不彰。Nick Ward與Leonardo Cohen二位學者提出中風後動作復原潛在機制之參考架構，並建議5種治療策略：包含（1）降低健側肢體遠端之感覺輸入；（2）增加患側肢體遠端之感覺輸入；（3）降低患側肢體近端之感覺輸入；（4）強化患側腦動作皮質的活化；（5）調降健側腦動作皮質的活化。近期研究發現各別策略於上肢中、輕度損傷之患者具備療效潛能。由於研究證據支持結合多種治療較單一治療更有助於中風患者的動作復原，故發展同時結合上述5種策略之「經顱直流電刺激結合感覺輸入調節治療模式（Transcranial direct current stimulation with sensory modulation intervention，tDCS-SM）」，應具備最大潛能促進長期嚴重上肢動作損傷患者之動作復原，然tDCS-SM之立即及長期追蹤療效尚待驗證。 此外，本研究採用2種影像技術來驗證 tDCS-SM療效的可能機制，包含水分子擴散頻譜影像（diffusion spectrum image，DSI）及功能性磁振造影（functional meganetic resonance image，fMRI）。此2種影像分別驗證個案之大腦白質結構與皮質活化之變化。 本論文之研究目的為：（1） 驗證tDCS-SM於嚴重至中度上肢動作損傷患者之療效；（2）應用醫學影像技術驗證tDCS-SM之療效機制。 研究方法 本研究以雙盲隨機分配試驗，驗證tDCS-SM之療效。共募集25位慢性期嚴重至中度上肢動作損傷之中風患者，並以電腦亂數表將個案隨機分配至2組。其中14位分配至實驗組接受tDCS-SM治療，包含患側手被動重複動作訓練、雙側經顱直流電刺激（transcranial direct current stimulation, tDCS）及患側手近端與健側手遠端表皮麻醉。11位分配至控制組治療，包含患側手被動重複動作訓練、假性（sham）雙側tDCS刺激及假性患側手近端與健側手遠端表皮麻醉。每組所接受的治療量均相同，並接受4次（治療前、治療後、治療後3個月及治療後6個月）臨床行為療效評估。臨床行為療效評估內容包含：上肢自主動作、上肢肌肉張力、上肢功能評量與基本日常生活功能。本研究採用意向處理分析（intention-to-treat）的原則驗證療效。tDCS-SM與控制組之療效差異，以ANCOVA分析，並控制個案治療前初始分數的差異。療效效應值（effect size）為依據共變數分析所得之partial eta-square（ηp2）大小進行判斷。 另外，符合收案條件之缺血性中風患者（n = 13），在治療前後1週內除前述臨床行為療效評估外，亦進行DSI與fMRI之影像掃描。以DSI技術重建上肢皮質脊髓徑（corticospianl tract to upper extremity，CST-UE）與胼胝體運動纖維（callosal motor fiber，CMF）。CST-UE又區分為2個分段，以瞭解不同位置之CST結構情形：（1）CST-UEABOVE：CST-UE由內囊後肢以上至主要運動皮質區灰白質交界處的分段；（2）CST-UEPLIC：單純內囊後肢的分段。每個神經束分段，分別計算其患側、健側之平均綜合非等向性指標值（mean generalized fractional anisotropy, mGFA）與側化指標（laterality index，LI），以驗證神經束之結構變化，並以曼-惠特尼U檢定（Mann-Whitney U test）驗證兩組間是否有差異。 fMRI掃描採區集設計（block design），掃描時所有個案進行被動手指伸展的活動。由具備核磁相容性之氣動儀帶動個案手指進行快速之被動掌指關節伸直（metacarpophalangeal joint extension）動作，手指活動頻率為2Hz。分析以SPM8軟體進行，先完成個別個案之む治療後 – 治療前め對比影像分析，再比較tDCS組與控制組組間之む治療後 – 治療前め對比影像之訊號強度有顯著差異之區域。顯著之統計檢定值為 p < 0.001 （未校正法）。 結果 上肢自主動作結果發現tDCS-SM相較控制組有中度立即療效（ηp2 = 0.14），且tDCS-SM之療效可持續至治療後6個月（ηp2 = 0.12）。在降低上肢肌肉痙攣上，tDCS-SM相對控制組有低度立即療效（ηp2 = 0.04）。3個月與6個月追蹤評估時，則為控制組優於tDCS-SM組，具低度療效差異（ηp2 = 0.03 - 0.09）或無差異。上肢功能方面，tDCS-SM相對控制組有低度立即療效（ηp2 = 0.02），3個月與6個月追蹤評估結果為，tDCS-SM相對控制組有低度療效（ηp2 = 0.04 - 0.09）。基本日常功能方面，tDCS-SM相對控制組有低度立即療效（ηp2 = 0.02），3個月時，兩組療效無差異，至6個月追蹤評估時，tDCS-SM相對控制組有低度療（ηp2 = 0.09）。 比較治療前後神經束結構指標改變量，CST-UEABOVE LI、患側CST-UEABOVE mGFA與健側CST-UEABOVE mGFA，tDCS-SM組與控制組皆無顯著差異（p = 1.000）。但CST-UEPLIC LI、健側CST-UEPLIC mGFA，在兩組間有顯著差異（p = 0.038）。患側CST-UEPLIC mGFA結果，兩組間無顯著差異（p = 0.461）。CMF因多數個案無法成功重建，使得控制組只有1個有效數值，樣本數過低，不進行統計推論。 fMRI結果，未發現兩組間之治療前後皮質活化變化，有任何顯著不同之腦區。各組別來看，tDCS-SM組治療後，在患側腦中央後回（postcentral gyrus）與雙側腦的旁中央小葉（paracentral lobule）活化降低。控制組在治療後發現，患側腦中央後回與健側腦中央前回（precentral gyrus）活化降低。 結論 結合5策略之tDCS-SM相較於僅給予患側手被動動作訓練，更可以促進慢性期嚴重至中度上肢動作損傷中風患者的上肢自主動作復原，且其療效可持續至治療後6個月。在降低上肢肌痙攣方面，tDCS-SM顯示具備立即療效，但無長期療效。而tDCS-SM對上肢動作復原之療效，尚不足以有效轉化為促進嚴重至中度上肢動作損傷患者之手功能及基本日常生活功能。最後，本研究發現tDCS-SM可能可阻止或延緩患者之腦部運動相關神經纖維結構持續被破壞，同時降低患側腦感覺皮質之活性。整體而言，tDCS-SM有潛力應用於嚴重至中度損傷之中風患者，以改善其上肢動作，但療效相關之神經復原機制仍須後續驗證。

Backgroud and purposes Up to 60% of people with stroke suffered from severe to moderate long-term upper extremity（UE）motor impairment. The deficits of UE can greatly impact patients‘ daily living independence and quality of life. However, treatment effect of current interventions is still limited. Nick Ward and Leonardo Cohen suggested 5 intervention strategies for stroke motor recovery:（1）reduction of somatosensory input from the intact;（2）increase in somatosensory input from the paretic;（3）anesthesia of a body part proximal to the paretic hand;（4）activity within the affected motor cortex may be up-regulated;（5）activity within the intact motor cortex may be down-regulated. Recent studies have shown each strategy to be effective in stroke patients with mild or moderate UE impairment. However, evidence for people with severe UE impairment after stroke remains unclear. Since research has found a greater effect for combined strategies than a single strategy, this proposal develops a combined intervention with the above 5 strategies, named Transcranial direct current stimulation with sensory modulation intervention (tDCS-SM). tDCS-SM is expected to be most effective for people with severe UE impairment after stroke. In addition, neuroimaging can provide in vivo information about the brain plasticity which underpinning the motor recovery after stroke. However, image indexes that can be used in stroke patients with severe UE impairment remained examined. Therefore, this study aimed to examined whether a multi-strategy intervention (i.e., tDCS-SM) enhanced motor outcome immediately and longitudinally in patients with chronic severe to moderate upper extremity paresis. In addition, the underline mechanism of the tDCS-SM’s efficacy was examined using neuroimaging technology. Methods A total of 25 stroke participants were randomly assigned to either a transcranial direct current stimulation with sensory modulation (tDCS-SM) group or a control group for an 8-week intervention. The tDCS-SM group (n = 14) received bilateral tDCS stimulation, bilateral cutaneous anesthesia, and high repetitions of passive movements on the paretic hand. The control group (n = 11) received the same repetitive passive motor training but with sham tDCS and sham anesthesia. Outcomes were assessed at baseline, at post-intervention, and at 3- and 6-month follow-ups. All enrolled participants who were diagnosed as ischemic stroke received diffusion spectrum and functional magnetic resonance imaging at 3T. Corticospinal tract (CST) and callosal motor fiber (CMF) integrity was assessed by measuring the mean generalized fractional anisotropy (mGFA) of the reconstructed tracts. The CST tractogram was segmented from the internal capsule to the motor cortex (CSTABOVE) and the internal capsule parts only (CSTPLIC). The CMF tractogram was segmented from the mid-sagittal plane to the motor cortex. For the functional magnetic resonance imaging, all participants received passive finger extension movemnt during scanning. Data were analyzed with SPM99. Results The Fugl-Meyer motor score improved more in the tDCS-SM group than in the control group, with a moderate between-group effect size (partial η2, ηp2 = 0.14), and long-term effects of tDCS-SM were found (ηp2 =0.17 and 0.12). The tDCS-SM group exhibited a slightly better immediate effect (ηp2 = 0.02 – 0.04) on reducing spasticity than the control group, but no long-term effect. Small immediate and long-term treatment effects of tDCS-SM were found on hand function and daily function recovery (ηp2 = 0.02 - 0.09). No difference between groups was found for the lateraliry index and the mGFA of CSTABOVE. Significant differences between groups were found for the mGFA and the laterality index of the unaffected CSTPLIC. The control group showed a large decrease of mGFA at the unaffected CSTPLIC. The CMF integrity was not compared due to limited no sufficient case number in the control group. Conclusion tDCS-SM showed better immediate and long-term effects on voluntary UE movement recovery than intensive passive movement intervention. The effects of tDCS-SM on spasticity control and functional changes were found in the short term but not in the long term in patients with severe to moderate UE paresis. For ischemic stroke, the tDCS-SM maintained the unaffected CST structural integrity from being degenerated. The results of this study suggested that the tDCS-SM has potential to improve UE motor recovery in patients with severe to moderate UE paresis, however, the treatment effects of tDCS-SM to improve patients‘ functional recovery were still limited.