背景：近年來研究指出Theta波穿顱磁刺激為憂鬱症有效替代治療方式。然而，Theta波穿顱磁刺激對於難治型重鬱症病患的神經調節機制至今仍不清楚。本研究目標為利用腦磁圖探討兩周的Theta波穿顱磁刺激治療其調控難治型重鬱症病患情緒網路之神經機轉。

材料與方法：本研究共招募14位難治型重鬱症病患及10位健康受試者。病患在兩周內接受十次施打於左背外側前額葉Theta波穿顱磁刺激之治療。病患在接受治療前、治療一周後及治療兩周後，分別進行臨床評估與腦磁圖實驗，並依據前後兩周漢式憂鬱量表分數改善程度評估治療效果。健康受試者僅進行一次腦磁圖實驗。我們採用306通道全頭型腦磁圖儀，紀錄受試者被動聆聽情緒音調的腦磁波訊號。腦磁波訊號進行前處理去除雜訊後，利用最大對比光束構成技術以估測腦神經活化之位置與大小。我們挑選與作業相關的兩個時間點，M50（30-80 毫秒）及M100（80-120 毫秒）為分析目標。我們將估測所得之神經活化反應轉換成大腦情緒反應指標：（情緒音調反應－中性音調反應）／中性音調反應，以觀察“情緒處理”之大腦反應。最後，以無母數統計分析比較病患大腦情緒反應指標在治療前後三週間之差異，並用相關及迴歸分析來估算大腦情緒反應指標與憂鬱程度的相關性。

結果：我們發現難治型重鬱症病患在接受兩周的Theta波穿顱磁刺激期間，大腦神經元的活化程度出現了動態性的改變。在左側的前側腦島、後側腦島、尾核、左側額下迴、前扣帶迴及中扣帶迴，我們都發現了病患對於情緒處理短期且可逆的大腦可塑性。抗憂鬱程度的改善與左側額上迴在治療前後的情緒反應指標改變量呈現正相關，而這個腦區與Theta波穿顱磁刺激所施打的位置鄰近。此外，我們發現難治型重鬱症病人在接受治療前，右側的前楔葉跟右側的上顳葉如果有較低的神經活性，可以預測該病人在接受兩週穿顱磁刺激治療後會有比較好的抗憂鬱療效。

結論：透過結果顯示難治型重鬱症病患在接受兩周的間歇性Theta波穿顱磁刺激治療期間，大腦神經元對於情緒感知處理有動態性的變化，以及可逆的大腦可塑性。這些結果都為間歇性Theta波穿顱磁刺激對於難治型重鬱症病患在短短幾周內的神經調節機制提供了神經影像學的證據。

Background: Theta-burst stimulation (TBS) appears to be a promising treatment alternative for depression. However, little is known about the underlying mechanism of its neuromodulation effect on emotion pathway for major depression. The aim of this study is to investigate the effect of neuromodulation on brain responses to emotional prosody in patients with treatment-resistant major depression by two-week TBS treatment using magnetoencephalography (MEG).

Materials and Methods: Fourteen patients with treatment-resistant major depressive disorder (trMDD) and ten healthy control subjects (HC) were recruited. Brain responses of each participant were recorded using a whole-head MEG system (Vectorview, Elekta Neuromag, Helsinki, Finland) while passively listening to emotional prosody (happy, sad, angry and neutral verbal tones). Each patient underwent clinical assessments and MEG experiments before (baseline) and after TBS treatment (week 1 and week 2). Each HC subject participated in the MEG experiment once. For each emotional prosody category, the beamforming method was applied to obtain spatiotemporal images of brain responses in a voxel-wise manner. Brain emotional response index (BERI) was then estimated at two time components (M50: 30-80 ms; M100: 80-120 ms). Nonparametric statistical analysis of BERI maps among three weeks as well as correlation analyses between baseline BERI and depressive severity were performed.

Results: We found changes of neuronal activity in trMDD patients by two-week TBS-treatment. Short-term and reversible plasticity of brain responses were found in the regions of the left anterior and posterior insular, caudate nucleus, left inferior frontal gyrus and anterior/middle cingulate cortex. There were positive correlation between the percent improvement of the HDRS-17 scores and the change of BERI in the left superior frontal gyrus nearby DLPFC which was the target of TBS. Furthermore, our results suggested lower activity in the right precuneus and STG before TBS treatment could predict better antidepressant treatment response in trMDD patients.

Conclusion: Our results demonstrated dynamic changes of neuronal processing in emotion perception and reversible plasticity of brain responses by two-week TBS-intervention in patients with trMDD, which provides a neuroimaging evidence of short-term neuromodulation on the time scale of weeks by TBS.

目錄
Contents
致謝 i
摘要 ii
Abstract iii
Contents iv
Lists of Figures vi
Lists of Tables vii
Chapter 1 Introduction 1
1.1 Major Depressive Disorder 2
1.1.1 Clinical Symptom and Diagnostic Criteria 2
1.1.2 Impaired Emotion Processing 3
1.2 Theta burst stimulation 4
1.2.1 An introduction to TMS and TBS 4
1.2.2 TBS Treatment for Patients with MDD 5
1.2.3 Comparison of TBS and ECT Treatment 6
1.3 An Introduction to Magnetoencephalography 6
1.4 Thesis Scope and Organization 9
Chapter 2 Materials and Methods 10
2.1 Participants 11
2.2 Study overview 12
2.3 TBS Procedures 12
2.4 Clinical Assessment 13
2.5 Stimuli and MEG Experimental Paradigm 14
2.7 Data Acquisition 15
2.8 MEG Data Analysis 16
2.8.1 Preprocessing 16
2.8.2 Source Reconstruction 16
2.8.3 Statistical Analysis 17
Chapter 3 Results 18
3.1 Demographic Data and Clinical Outcomes 19
3.2 Neuroimaging Results 22
3.2.1 Selection of Time Components 22
3.2.2 Source Imaging Results 25
3.2.3 Regional Brain Responses during Two-week TBS Treatment 25
3.2.4 Relationship between Brain Emotional Response and Depressive Symptom Improvement 32
Chapter 4 Discussion 40
4.1 Neuromodulation by Two-week iTBS Treatment 41
4.2 Emotion-Processing Mechanisms of Depressive Regulation 41
4.3 Prefrontal-Subcortical Circuitry and Depression 42
4.4 Prediction for iTBS Treatment 42
4.5 Limitation 43
Chapter 5 Conclusions 44
References 46


圖目錄
Lists of Figures
Figure 1 Model for the neural basis of the cognitive deficit in emotion perception and behavior in patients with MDD. 3
Figure 2 TMS stimulates in the brain. 4
Figure 3 Illustration for performing TMS with the mounted coil and TMS device. 5
Figure 4 Different protocols of TBS. 5
Figure 5 Magnetoencephalography (MEG) system. 7
Figure 6 Naming of MEG channels in Neuromag system. 8
Figure 7 Timeline of study design 12
Figure 8 Protocol of iTBS. 13
Figure 9 Target of stimulation site. 13
Figure 10 Emotional prosody paradigm in MEG recording. 14
Figure 11 Antidepressant effects of TBS within 2 weeks. 21
Figure 12 MEG responses of grand averaged evoked magnetic fields. 22
Figure 13 Topographies of grand averaged evoked magnetic fields at M50. 23
Figure 14 Topographies of grand averaged evoked magnetic fields at M100. 24
Figure 15 Source imaging using raw data in the MDD patients. 25
Figure 16 Differences in BERIs of sad condition during 2-week TBS treatment. 29
Figure 17 Differences in BERIs of angry condition among 2-week TBS treatment. 30
Figure 18 Differences in BERIs of happy condition among 2-week TBS treatment. 31
Figure 19 Changes in BERIs of sadness in the M50 in the left middle temporal gyrus after TBS treatment. 33
Figure 20 Changes in BERIs of sadness in the M50 in the left inferior parietal lobule after TBS treatment. 34
Figure 21 Changes in BERIs of sadness in the M100 in the left posterior insula after TBS treatment. 35
Figure 22 Changes in BERIs of sadness in the M100 in the left superior frontal gyrus after TBS treatment. 36
Figure 23 Changes in BERIs of happiness in the M50 in the right superior parietal lobule after TBS treatment. 37
Figure 24 Pretreatment BERI of sadness-M50 relating to depressive symptom improvement following a two-week TBS treatment. 38
Figure 25 Pretreatment BERI of sadness-M100 relating to depressive symptom improvement following a two-week TBS treatment. 38
Figure 26 Decreased activities in the right precuneus before TBS treatment predicts depression symptom improvement 39
Figure 27 Decreased activities in the right STG before TBS treatment predicts depression symptom improvement 39
表目錄
Table 1 DSM-IV Criteria for Major Depressive Disorder 2
Table 2 Stimuli 14
Table 3 Treatment outcome 20
Table 4 Comparison results of BERIs in each condition between pre- and post-TBS treatment. 27

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