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。;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.
