臺灣博碩士論文加值系統

背景：重度憂鬱症病患有情緒調節不良及認知功能缺失的問題。過去文獻指出施打高頻重複性穿顱磁刺激能改善憂鬱症病患的憂鬱症狀以及認知功能。然而，目前重複性穿顱磁刺激對情緒調節及認知功能間的交互機制仍尚未釐清。本研究欲探討重複性穿顱磁刺激對重度憂鬱症病患在認知以及情緒間交互作用的大腦可塑性；並評估受試者在執行認知作業－「情緒性反應激發/抑制作業」時的大腦活化是否可預測接下治療的效果。我們假設施打重複性穿顱磁刺激可降低病患在參與負向情緒抑制控制時大腦背側前側扣帶迴的活化。
資料與方法：本研究採用二十九位藥物難治的重度憂鬱症病患（二十二位女性，年齡介於27至63歲之間），於兩周內讓病患接受十次施打在左背側前額葉的高頻重複性穿顱磁刺激治療。在接受治療前、治療一週後及治療兩週後，我們紀錄病患執行「情緒性反應激發/抑制作業」的腦波訊號。另外收錄二十五位性別年齡與病患相符的健康受試者的資料作為對照組。腦波訊號的量測是使用具有306個通道涵蓋全頭部的腦磁圖儀。憂鬱症的治療效果評估是採用漢氏憂鬱量表分數下降超過百分之五十以上。為了估測全腦皮質活化的動態過程，我們將經過前處理後的腦磁訊號，使用光束構成法去估算大腦訊號源的位置。接著，我們挑選了與作業有關的時間點，包括80毫秒、120毫秒、180毫秒以及280毫秒。再將這些影像資料作統計比較，使用的方法是混合設計變異數分析。最後，使用相關性分析檢測大腦皮質活化、行為以及憂鬱量表分數之間的相關性。
結果：在兩週重複性穿顱磁刺激療程結束後，二十九位中有十七位病患（百分之五十九）是治療有效組。在行為結果，於治療前整體憂鬱症病患尤其是治療無效組在行為表現上顯著多於正常控制組的錯誤率，因此我們發現在治療無效組有一個接近顯著的治療效果。在腦部影像上我們發現一個重要結果，於治療前在280毫秒時參與抑制控制時的左背側前額葉活化愈低落者，錯誤率愈低，憂鬱症狀改善程度愈多。除此之外，在治療有效組，我們發現重複性穿顱磁刺激的確降低了在280毫秒時參與抑制控制時的右背側前扣帶迴的活化，表示調節病患重複性穿顱磁刺激的確調節了在參與負向情緒抑制控制的大腦資源。
討論：我們證實了重複性穿顱磁刺激治療調節對於負向情緒抑制控制的大腦資源，這項結果我們推測，對於治療有效組來說重複性穿顱磁刺激治療改善了他們對負向情緒的注意力偏誤。重複性穿顱磁刺激不僅影響了刺激位置而且也調節了其他與刺激位置有關連的腦區，這個結果與以往研究一致。對憂鬱症病患來說，重複性穿顱磁刺激治療影響了前額葉皮質的活化，可能是透過額葉與前扣帶迴皮質之間的迴路。除此之外，我們認為對於藥物難治的重度憂鬱症病患，參與抑制控制的左背側前額葉活化可能可以作為重複性穿顱磁刺激治療的預測因子之一。
結論：本研究提供了一個高頻重複性穿顱磁刺激對重度憂鬱症病患的情緒調節神經機轉的可塑性之神經影像證據。

Background: Major depressive disorder (MDD) is characterized by emotion dysregulation and cognitive impairments. High-frequency repetitive transcranial magnetic stimulation (rTMS) that has been proposed could improve depressive symptoms as well as cognitive function in depression. However, the neural mechanism of rTMS on cognitive-emotional interactions is still unclear. The current study aimed to investigate effects of rTMS on the interaction between emotion regulation and cognitive functions in MDD patients. We also aimed to evaluate predictive value of neuroimaging data under a flanker-emotional go/nogo task so as to guide subsequent rTMS sessions. We hypothesized that rTMS decreased the neural activity in the dorsal anterior cingulate cortex (dACC) during inhibitory control to negative stimuli in depression.
Materials and methods: Twenty-nine medication-resistant patients with MDD (22 females, aged 27-63 years) were applied 10-session high-frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC) for consecutive 2 weeks. Event-related magnetic field (ERMF) were measured as patients performed a flanker-emotional go/nogo task that required the inhibitory controls to emotional stimuli pre-treatment, after 5th, and 10th rTMS treatment sessions. Twenty-five gender- and age-matched healthy subjects were recruited as controls. The magnetoencephalographic (MEG) recordings were using a 306-channel whole head neuromagnetometer. Clinical response to rTMS was defined as a decrease of 50% or more in the 17-item Hamilton Rating Scale for depression (HDRS) score from baseline to the end of treatment. To estimate the dynamic changes of neuronal activity, noise-free MEG data were underwent a source reconstruction using the beamformer-based source imaging technique. The time components related to the task were selected (80 ms, 120 ms, 180 ms, and 280 ms). Image data were analyzed using mixed design ANOVAs (i.e., flexible factorial model in SPM8). Pearson correlation analysis was performed to assess the relation between treatment outcome, behavior changes, and cortical activity.
Results: Seventeen out of 29 MDD patients (59%) were treatment responders after 2-week rTMS therapy. The behavioral results showed that MDD patients, particularly the non-responders, produced more false alarm than controls. A trend rTMS treatment effect was found in the non-responder. The key findings of this study indicate that, lower baseline left dPFC activity involving inhibitory control in nogo trials at 280 ms was positively correlated with false alarm and negatively correlated with depression improvement. Beside, decreased activity in the right dACC to negative stimuli in nogo trials at 280 ms from baseline to the end of treatment was found in the responder, which reflected emotional bias toward negative stimuli modulated by rTMS.
Discussion: We demonstrated that rTMS modulated the mood-congruent bias that decreased the inhibitory resources to sad stimuli in the responder. The results suggested that rTMS ameliorated the emotional bias to negative stimuli in the responders. Repetitive TMS produced effects at the stimulated cortical regions but also at distant connected sites, which in line with previous studies. Repetitive TMS treatment may modulate the neuronal activity in the prefrontal cortex, which through frontal-cingulate trans-synaptic connections in depression. Moreover, the left dPFC in inhibitory control may predict response for rTMS treatment in medication-resistant depression.
Conclusions: These findings provided neuroimaging evidence of brain plasticity increasing our understanding of HF-rTMS treatment effects on emotion regulation in patients of major depressive disorder.

Contents
Signature Page i
Thesis Approval Form ii
Acknowledgments iii
Chinese Abstract iv
English Abstract vi
Contents viii
Lists of Figures xii
Lists of Tables xiii
Chapter 1 Introduction 1
1.1 Major Depressive Disorder 2
1.1.1 Diagnostic Criteria and Clinical Symptom 2
1.1.2 Affective and Cognitive Dysfunction 3
1.2 Repetitive Transcranial magnetic stimulation (rTMS) 4
1.2.1 An Introduction to TMS and rTMS 4
1.2.2 Repetitive TMS treatment in MDD Patients 6
1.2.3 rTMS comparison with ECT 7
1.3 Flanker-emotional Go/Nogo Task 8
1.4 An Introduction to Magnetoencephalography 9
1.5 Thesis Scope and Organization 14
Chapter 2 Methods and Material 15
2.1 Participants 16
2.2 Study Design 18
2.3 rTMS Procedures 18
2.4 Clinical and Neuropsychological Assessments 19
2.5 MEG Paradigm Design 20
2.6 Data Acquisition 21
2.7 Behavior Data Analysis 22
2.8 MEG Data Analysis 22
2.8.1 Preprocessing 22
2.8.2 Time-Frequency Analysis 22
2.8.3 Source Reconstruction 22
2.9 Statistical Analysis 23
Chapter 3 Results 25
3.1 Demographic Data and Clinical Outcomes 26
3.2 Neuropsychological Outcomes 29
3.3 Behavioral Results 31
3.4 ERD/ERS Results 35
3.5 Neuroimaging Results 38
3.5.1 Evoked Responses and Induced Responses 38
3.5.2 Selection of Time Components 38
3.5.3 Group Difference among Responders, Non-responders and Controls 40
3.5.4 Attentional Bias for Emotional Stimuli Modulated by rTMS in Nogo Condition 43
3.5.5 Attentional Bias for Emotional Stimuli Modulated by rTMS in Go Condition 43
Chapter 4 Discussion 47
4.1 Cortical Plasticity Induced by rTMS 48
4.2 Group Difference among Responders, Non-responders and Controls 48
4.3 Attentional Bias for Emotional Stimuli Modulated by rTMS during Inhibitory Control 49
4.4 Attentional Bias for Emotional Stimuli Modulated by rTMS during Early Perception 50
4.5 Limitation 51
Chapter 5 Conclusions 52
References 54

Lists of Figures
Figure 1.1 Model for the neural basis of the emotion and cognitive deficits in MDD patients 4
Figure 1.2 Transcranial magnetic stimulation (TMS) in the brain 5
Figure 1.3 Treatment of repetitive transcranial magnetic stimulation (rTMS) 7
Figure 1.4 Magnetoencephalography (MEG) system 10
Figure 1.5 306-channel sensor arrangement of Neuromag system 11
Figure 1.6 Evoked responses and rhymic activity 13
Figure 2.1 The timeline of study design 18
Figure 2.2 Localization of stimulation site over the left DLPFC 19
Figure 2.3 The experimental design of a flanker-emotional go/nogo task 21
Figure 3.1 Clinical rating over time. 28
Figure 3.2 Behavioral results in patients and healthy controls 32
Figure 3.3 Correlation between the improvement of task performance and the depressive symptom improvement. 33
Figure 3.4 Topographies of α-band ERD/ERS in go condition in the responders 36
Figure 3.5 Topographies of α-band ERD/ERS in nogo condition in the responders 37
Figure 3.6 Brain construction using average data and raw data 38
Figure 3.7 MEG responses of grand averaged evoked magnetic fields 39
Figure 3.8 Decreased activity in the left dPFC before rTMS treatment predicts depression symptom improvement 41
Figure 3.9 Emotional bias modulated by rTMS in nogo condition 44
Figure 3.10 Emotional bias modulated by rTMS in go condition 45

Lists of Tables
Table 1.1 Criteria for Major depressive episode from DSM-IV 2
Table 2.1 Demographic data and clinical characteristics 17
Table 3.1 Clinical ratings over study course 27
Table 3.2 Cognitive outcomes at baseline and 3 months 30
Table 3.3 Performance of subjects on the flanker-emotional go/nogo task 34
Table 3.4 Group differences among responder, non-responder, and controls 42
Table 3.5 Brain regions showing emotion × rTMS treatment interaction 46

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