探討大腦振盪在前額葉經顱磁刺激治療 難治型憂鬱症的關鍵角色

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姓名	蔡怡君(Yi-Chun Tsai) 查詢紙本館藏	畢業系所	認知與神經科學研究所
論文名稱	探討大腦振盪在前額葉經顱磁刺激治療難治型憂鬱症的關鍵角色 (The investigation of the critical role of brain oscillations in prefrontal repetitive transcranial magnetic stimulation for treatment-resistant depression)
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摘要(中)	重覆性經顱磁刺激（repetitive transcranial magnetic stimulation, rTMS）和間歇性叢集型陣發刺激（intermittent theta-burst stimulation, iTBS）是治療難治型憂鬱症患者（treatment-resistant depression, TRD）的有效治療方法。然而，不同參數的經顱磁刺激潛在的電生理機制仍不清楚。此外，研究經顱磁刺激在難治型憂鬱症中治療效果的有效電生理標誌物是臨床領域的關鍵問題之一。因此，本研究旨在探討難治型憂鬱症患者在靜息狀態下受不同型態之非侵入性磁刺激影響的大腦振盪，並進一步研究重覆性經顱磁刺激和間歇性叢集型陣發刺激在難治型憂鬱症中治療效果的潛在標誌物。本研究基於以下四個假設檢驗可能的神經生理標記：一、重覆性經顱磁刺激和間歇性叢集型陣發刺激在難治型憂鬱症中之夾帶（entrainment）刺激效果以驗證其神經機制。二、額葉α不對稱假說。三、γ振盪在憂鬱症者大腦中過度活躍，以及四、γ相關大腦聯結的調節。本研究共招募了61名符合難治型憂鬱症條件的參與者，並隨機分配到延長之間歇性叢集型陣發刺激（N=19）、十赫茲重覆性經顱磁刺激（N=20）或安慰劑組（N=22）。每位參與者在十個療程的治療階段前後都經過醫師臨床評估和靜息閉眼狀態腦電圖記錄。療效評估由治療前和完成治療階段之間漢密爾頓憂鬱量表（17-item Hamilton Depression Rating Scale, HDRS-17）分數的變化來定義。腦波數據資料分析應用了全息希爾伯特譜分析（Holo-Hilbert Spectral Analysis, HHSA）和全息-希爾伯特跨頻相位耦合（Holo-Hilbert cross-frequency phase clustering, HHCFPC）等非線性分析方法。結果顯示了在難治型憂鬱症患者中可由大腦振盪揭示重覆性經顱磁刺激和間歇性叢集型陣發刺激的不同作用機制。此外，亦探討了治療效果的幾種潛在生物標記，其中關鍵振盪是θ-α振幅調變（amplitude modulation, AM）、β振幅調變-γ頻率、γ相關之大腦聯結，它們在難治型憂鬱症中及經顱磁刺激治療中扮演著不同的重要角色，值得於未來臨床研究中應用及驗證。
摘要(英)	Repetitive transcranial magnetic stimulation (rTMS) and intermittent theta burst stimulation (iTBS) are effective treatments in treatment-resistant depressed (TRD) patients. However, the underlying mechanisms of variant TMS protocol revealed by the brain oscillations remained unclear. Besides, the investigation of effective electrophysiological biomarkers for TMS treatment efficacy in TRD is one of the critical issues in the clinical field. Therefore, the present study aimed to investigate the dynamic of the brain oscillations during resting state affected by different protocols of TMS in TRD patients and further investigate the potential markers for therapeutic efficacy of rTMS and iTBS. These indices were examined according to four hypotheses. (1) The neural entrainment aftereffects of rTMS and iTBS in TRD. (2) The frontal alpha asymmetry hypothesis. (3) The hyperactivity in gamma oscillations, and (4) the modulation of gamma related brain connectivity. A total of 61 TRD eligible participants were recruited and were randomly assigned to either prolong iTBS (piTBS) (N=19), 10-Hz rTMS (N=20), or sham group (N=22). Each participant completed clinical assessments and resting state EEG with eye-closed recording both before and after ten sessions’ treatment phase. The evaluation of efficacy was defined by the changes in scores on the Hamilton depression rating scales (HDRS-17) between the baseline and the stage after the treatment. Nonlinear analytical methods such as Holo-Hilbert Spectral Analysis (HHSA) and Holo-Hilbert cross-frequency phase clustering (HHCFPC) were applied. The results showed the distinct mechanisms of rTMS and piTBS revealed by the brain oscillations in TRD. Furthermore, several potential biomarkers for TMS treatment efficacy were investigated. The critical oscillations were theta-alpha AM, beta AM-gamma frequency, and gamma-related connectivity which play different roles in TRD and TMS treatment effects that are worthy of application and verification in future clinical research.
關鍵字(中)	★ 大腦振盪 ★ 全息-希爾伯特譜分析 ★ 全息希爾伯特跨頻相位耦合 ★ 間歇性叢集型陣發刺激 ★ 重覆性經顱磁刺激 ★ 難治型憂鬱症	關鍵字(英)	★ brain oscillations ★ Holo-Hilbert Spectral analysis (HHSA) ★ Holo-Hilbert cross-frequency phase clustering (HHCFPC) ★ intermittent theta burst stimulation (iTBS) ★ repetitive transcranial magnetic stimulation (rTMS) ★ treatment-resistant depression (TRD)
論文目次	中文摘要 i Abstract ii 致謝辭 iii Disclaimer iv Table of Contents………………………………………………………………………………v List of Figures vii Lists of Tables ix Chapter I General introduction 1 Chapter II Literature review 6 2-1 Major depressive disorder (MDD) 6 2-2 Treatment resistant depression (TRD) 7 2-3 TMS treatment and MDD 8 2-4 Electrophysiological (EEG) markers in MDD 10 2-4-1 Power based brain oscillations 10 1. Alpha oscillations 10 2. Theta oscillations 14 3. Gamma oscillations 16 2-4-2 EEG connectivity 18 2-5 Adaptive nonlinear analytical methods 46 2-5-1 Empirical mode decomposition (EMD) 46 2-5-2 Holo-Hilbert Spectral Analysis (HHSA) 48 2-5-3 Holo-Hilbert cross-frequency phase clustering (HHCFPC) 49 Chapter III Materials and Methods 51 3-1 Participants 51 3-2 Procedure 52 3-3 Non-invasive Brain stimulation (iTBS/rTMS) parameters and site localization 53 3-4 Electrophysiological recording parameters 55 3-5 Data analysis and statistical analysis 55 3-5-1 Behavioral data- Clinical outcomes 55 3-5-2 Resting EEG-Pre-processing 56 3-5-3 Resting EEG-Frontal alpha asymmetry analysis 57 3-5-4 Resting EEG-Holo-Hilbert spectral analysis 57 3-5-5 Resting EEG-Holo-Hilbert cross-frequency phase clustering analysis 58 Chapter IV Results 60 4-1 Demographic results 60 4-2 EEG results 64 4-2-1 Entrainment 64 4-2-2 Frontal alpha asymmetry 72 1. Prediction at the pretreatment stage 72 2. Changes after brain stimulation 74 3. Antidepressant efficacy 76 4-2-3 Gamma oscillations 77 1. Prediction at the pretreatment stage 77 2. Changes after brain stimulation 80 3. Antidepressant efficacy 81 4-2-4 EEG connectivity 83 1. Prediction at the pretreatment stage 83 2. Changes after brain stimulation 84 3. Antidepressant efficacy 85 Chapter V Discussions 87 5-1 Antidepressant efficacy in clinical outcomes 87 5-2 Neural correlates of piTBS and 10-Hz rTMS- Entrainment aftereffects 88 5-3 The possible roles of neurophysiological biomarkers 89 5-3-1 Frontal alpha asymmetry 90 5-3-2 Theta-alpha amplitude modulation 91 5-3-3 Hyperactivity of gamma oscillations 93 5-3-4 Gamma related EEG connectivity 94 5-4 The potential causes for heterogeneous results of previous studies 96 5-5 The approach for future works 98 Chapter VI Conclusions 101 References 106 Appendix A: The list of abbreviations 129 Appendix B: The related publications-1 130 Appendix C: The related publications-2 143
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指導教授	阮啟弘李正達(Chi-Hung Juan Cheng-Ta Li)	審核日期	2023-7-14
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