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研究生：	許煜承 Hsu, Yu-Cheng
論文名稱：	透過急性經皮耳迷走神經刺激對皮質－邊緣系統局部場電位的電生理調節：與壓力感受反射自動調節的機制區別 Electrophysiological Modulations of Cortico-Limbic Local Field Potentials via Acute Transcutaneous Auricular Vagus Nerve Stimulation: A Mechanistic Differentiation from Baroreflex Autoregulation
指導教授：	林宙晴 Lin, Chou-Ching K.
學位類別：	碩士 Master
系所名稱：	工學院 - 生物醫學工程學系 Department of BioMedical Engineering
論文出版年：	2026
畢業學年度：	114
語文別：	英文
論文頁數：	90
中文關鍵詞：	經皮耳迷走神經刺激、局部場電位、血反射、孤束核、後島葉皮質、中央杏仁核、gamma振盪
外文關鍵詞：	Transcutaneous Auricular Vagus Nerve Stimulation (taVNS), Local Field Potentials (LFP), baroreflex, Nucleus Tractus Solitarius (NTS), Posterior Insular Cortex (PIC), Central Amygdala (CeM), gamma Oscillations
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【背景】
　　經皮耳迷走神經刺激（transcutaneous auricular vagus nerve stimulation, taVNS）已被視為治療抗藥性癲癇與情緒障礙的一種具潛力的非侵入式神經調控方法。儘管其臨床療效已有相當研究支持，但 taVNS 對中央自主神經網路（central autonomic network, CAN）內即時頻帶特異性神經動態之影響，尤其是在後島葉皮質（posterior insular cortex, PIC）與杏仁核中央內側核（central medial amygdala, CeM）中的調控機制，仍未完全釐清。此外，迷走神經研究中的重要挑戰之一，在於區分所觀察到的中樞電生理變化是經由孤束核上行迷走神經傳入活化的直接結果，或僅為周邊壓力反射與血流動力學所驅動的次級效應。
【方法】
　　本研究以麻醉大鼠為動物模型，利用三通道（其一位於CeM，另外兩通道為雙螺旋通道位於PIC）局部場電位（local field potential, LFP）記錄，分析急性 taVNS 刺激前、後不同時間區段的神經活動變化。為進一步區分直接神經調控效應與被動自主神經回饋，本研究另建立藥理性壓力反射（baroreflex）對照組，透過去氧腎上腺素與硝普鈉誘發全身性血壓波動。壓力反射效應分別以兩種分析框架評估：注射前後 30 秒之急性窗口分析（Method A），以及縱向趨勢分析（Method B）。
【結果】
　　結果顯示，taVNS 與 baroreflex 組之間呈現明顯不同的神經電生理特徵。於 taVNS 停止後，功率譜密度（PSD）整體呈上升趨勢，在中央杏仁核（CeM）與後島葉皮質（PIC）區域皆觀察到 alpha 頻段（8-12 Hz）的功率調升趨勢。此外，taVNS 成功突破深度麻醉下的代謝抑制狀態，於 PIC 通道誘發出高度一致的響應性 gamma 頻段（55-70 Hz）活化。相較之下，baroreflex 對照組在周邊血壓劇烈波動下，並未引發高頻 gamma 的同步活化，僅於低血壓恢復階段呈現局部性的 delta 頻段衰減，且完全未觀察到跨區域 alpha 或皮質 gamma 頻段的顯著響應。
【討論】
　　相較之下，baroreflex 對照組在急性升壓衝擊下雖然引發了短暫的 theta 抑制（*p=0.031），並於藥效消退的恢復階段（Rest vs. Vaso）呈現次級的 alpha 功率衰減（*p=0.047），但完全未出現類似於 taVNS 的高頻 gamma 活化或跨區域 alpha 功率提升。顯示 taVNS 所誘發的中樞電生理變化並非單純來自周邊血流動力學效應，而較可能與上行迷走神經傳入活化直接相關。機制上，PIC區域之gamma增強可能反映皮質去同步化（desynchronization）狀態，有助於抑制癲癇相關病理同步活動；而CeM中的alpha增強則可能涉及杏仁核中央外側核（central lateral amygdala, CeL）至中央內側核CeM去抑制迴路之神經調控，並與抗焦慮效應相關。整體而言，本研究支持taVNS具有直接調控皮質－邊緣系統網路活動之能力，並提供其神經生物學機制的重要實驗證據。

[Background]
Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a promising non-invasive neuromodulatory approach for treatment-resistant epilepsy and affective disorders. Although its clinical efficacy is well supported, the immediate impact of acute taVNS on real-time, band-specific neural dynamics within the central autonomic network (CAN)—particularly its regulatory mechanisms in the posterior insular cortex (PIC) and the central amygdala (CeM)—remains incompletely understood. Furthermore, a major challenge in vagal nerve research is distinguishing whether these observed central electrophysiological changes are direct consequences of ascending vagal afferent activation via the nucleus tractus solitarius (NTS), or merely secondary effects driven by peripheral baroreflex and hemodynamic regulation.
[Methods]
To address these gaps, this study utilized multi-channel local field potential (LFP) recordings in anesthetized rat models to track the real-time chronological adjustments across pre-, peri-, and post-stimulation temporal windows under an acute taVNS protocol. Crucially, to isolate direct neuromodulatory effects from passive autonomic feedback, a standalone pharmacological baroreflex control cohort was established. Systemic blood pressure fluctuations were dynamically induced using Phenylephrine and Sodium Nitropruss, and evaluated across two distinct scales: an acute 30-second pre-to-post injection window (Approach A) and a longitudinal trend analysis (Approach B).
[Results]
The empirical data unveiled a distinct neurobiological divergence between the two cohorts. Following the cessation of acute taVNS, a generalized upward shift in power spectral density was captured across individual subject profiles, presenting as consistent low-frequency alpha (8-12 Hz) power elevations within both the subcortical CeM and cortical PIC nodes. Most notably, active taVNS successfully broke through the metabolic depression of deep anesthesia, triggering a robust and highly reproducible enhancement localized within the high-frequency responsive gamma band (55-70 Hz) in the posterior insular channels. Conversely, the standalone baroreflex control group exhibited localized, minor shifts restricted primarily to the delta band during severe hypotensive transitions, while maintaining stationary gamma and alpha dynamics during hemodynamic surges.
[Discussion]
In contrast, the baroreflex control group exhibited acute theta suppression (*p=0.031) alongside a secondary post-pressor alpha decay during the 10-minute recovery phase (*p=0.047, Rest relative to Vaso), while completely failing to engage high-frequency gamma networks or mimic the spectral elevations observed post-taVNS. Instead, they are validated as direct central effects mediated specifically by ascending transcutaneous vagal recruitment. Mechanistically, the localized post-stimulation insular gamma enhancement reflects a state of cortical desynchronization capable of destabilizing the pathological synchrony underlying ictal progression, providing an empirical baseline for anticonvulsant actions. Simultaneously, the alpha modulation within the CeM implies an electrophysiological gating mechanism within the central lateral amygdala (CeL)–CeM inhibitory loop, offering a neural substrate for clinical anxiolytic regulation. Together, these findings solidify the neurobiological validity of taVNS and provide crucial insights into real-time cortico-limbic network interventions.

摘要  i
Abstract  ii
誌謝  iv
Declaration on the Use of Artificial Intelligence and AI-Assisted Technologies  vi
List of Contents  vii
List of Tables  x
List of Figures  xi
CHAPTER 1 INTRODUCTION  1
1 The VNS-NTS-Limbic Circuit: The Neuroanatomical Foundation of Vagus Nerve Stimulation  1
2 Modalities of VNS  2
2.1 Overview of Invasive and Non-Invasive Vagus Nerve Stimulation  2
2.2 Clinical Advantages and Mechanisms of taVNS  5
3 Mechanisms of Central Network Regulation via Vagal Modulation of the Posterior Insula and Central Amygdala  6
4 TaVNS Effects on Typical Frequency Bands  8
5 Experimental Exploration of NTS-Mediated Baroreflex Modulations: Impact on Autonomic Stability  10
6 Safety Considerations and Stimulation Parameter Configurations for taVNS  13
7 Current Research Lacunae and the Critical Imperative of Local Field Potential (LFP) Recording  14
8 Research Hypotheses and Thesis Objectives  15
CHAPTER 2 MATERIALS AND METHODS  16
1 Experimental Animals  16
1.1 Animal Preparation and Ethic Statement  16
1.2 Grouping: taVNS and baroreflex Subjects  16
2 Surgical Procedures and Data Acquisition  18
2.1 Selection and Specification of Recording Electrodes  18
2.2 Signal Acquisition System and Instrumentation  18
3 Experimental Protocols  21
3.1 Transcutaneous Auricular Vagus Nerve Stimulation (taVNS)  21
3.2 Baroreflex: Pharmacological Induction of Blood Pressure Fluctuations  25
4 Histological Verification  28
5 Signal Processing and Feature Extraction  29
5.1 Group-Specific Digital Filtering and Power Line Hum Noise Removal  29
5.2 Artifact Rejection via Median Absolute Deviation (MAD) and Voltage Threshold  30
5.3 Timeline Segmentation and Analytics for the taVNS Group  32
5.4 Data array Segmentation and Analytics for the baroreflex Group  32
6 Statistical Analysis  34
6.1 Baroreflex Group Analytics  34
6.2 TaVNS Group Analytics  34
CHAPTER 3 RESULTS  36
1 Acute Pre- vs. Post-Injection Comparison Intra-phase of both Vaso and Depre phases (Approach A)  36
2 baroreflex Group Results: Time-Anchored Longitudinal Trend Analysis of NTS LFP (Approach B)  39
2.1 Continuous Rolling Variation Rate of NTS LFP Bands Across Sustained Blocks  39
2.2 Phase-Rolling Alterations and Multi-Phase Trends  39
3 Results of taVNS Group  47
3.1 Representative LFP Responses to taVNS  47
2.2 Methodological Challenges: Environmental and Physiological Artifacts  51
3.3 Statistical Profiling of Normalized Power Spectral Density (PSD)  56
4 Histological Verification of Surgical Implantation and Targeting Accuracy  61
CHAPTER 4 DISCUSSION  64
1 Methodological Contrast of Central Spectral Profiles  64
2 Functional Implications of Channel and Band Specificity  66
3 Neuroanatomical Circuits and the Confounding Effects of Deep Anesthesia on Theta Oscillations  67
4 Translational Implications for Clinical Neuromodulation  69
4.1 Cortical Gamma Oscillations in the Posterior Insula and Anticonvulsant Mechanisms  69
4.2 Amygdaloid Alpha Shifts and Anxiolytic Regulation via the CeL-CeM Inhibitory Loop  69
CHAPTER 5 CONCLUSION AND FUTURE WORK  71
1 Conclusion  71
2 Future Work  72
Reference  73
                                    

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