簡介
從過去的研究及文獻搜尋中得知，腦創傷之後可能會產生憂鬱症，原因和損傷後神經發炎作用有關。在我們過去的研究中顯示，使用高壓氧治療在腦創傷急性期所誘發的神經發炎作用有療效。另外我們也發現，高血脂是腦創傷後產生憂鬱症的危險因子之一。本論文中，在基礎研究上，我們將在大白鼠腦創傷急性期給予高壓氧（HBO）及降血脂藥物辛伐他汀（Simvastatin）治療，探討對腦創傷所產生的憂鬱樣行為是否有療效。同樣是中樞神經創傷的脊髓損傷，是否也會產生損傷後憂鬱行為。因此，在臨床研上，我們將透過大型資料庫研究，回溯性研究，來比較脊髓損傷後及健康族群新生憂鬱焦慮相關性。我們也假設前置因子高血脂是脊髓損傷後新生憂鬱焦慮的危險因子。
方法與結果
本論文分為基礎研究及臨床研究兩個部份：
一、基礎研究：我們利用液柱撞擊器造成麻醉大白鼠創傷性損傷，實驗一中動物分成三組，分別為假手術組、撞擊組及撞擊HBO治療組。HBO治療組在撞擊後，立即給予每天60分鐘HBO治療（100%氧氣，2ATA大氣壓力），連續3天。
實驗二中，動物分成五組，分別為假手術組、撞擊組、撞擊Simvastatin 4mg/kg治療組，撞擊Simvastatin 10mg/kg治療組，及撞擊Simvastatin 20mg/kg治療組。Simvastatin於撞擊後第0小時、第24小時及第48小時經腹膜注射給予。
所有組別在撞擊後第4、第8及第15天透過傾斜板上量測腳能抓取的最大角度來紀錄其運動功能變化，並使用強迫游泳試驗中的不動性來評估大白鼠的憂鬱情形。並在大白鼠犧牲後取組織以免疫螢光染色法測量神經元細胞數及神經元細胞凋亡的情況，並測量海馬迴CA3區中微小膠細胞和星狀細胞的活化及具腫瘤壞死因子-α表達的數目。
結果發現撞擊後接受高壓氧治療或Simvastatin 20mg/kg的大白鼠，在第15天強迫游泳試驗中顯著減少了不動性的時間（憂鬱樣行為）。大白鼠在創傷性損傷後會導致神經元細胞減少、神經元細胞凋亡數目增加、海馬迴CA3區中的微小膠細胞和星狀細胞數目增加、微小膠細胞及星狀細胞的腫瘤壞死因子-α增加表現量。而這些參數會因為給予早期連續三天的高壓氧治療或Simvastatin治療（三天20mg/kg的劑量）而得到顯著改善。
二、臨床研究：在創傷性脊髓損傷的流行病學研究方面，我們運用全民健康保險資料庫（National health insurance research database, NHIRD），進行回溯性世代研究。利用國際疾病分類代碼（ICD-9），尋找出脊髓損傷病患實驗組，和健康對照組進行Cox迴歸模式分析。
統計結果顯示，創傷性脊髓損傷的患者，有較高的風險產生憂鬱症，尤其是年輕患者。另一方面，在所有脊髓損傷患者中，原已有高血脂的患者，較沒有高血脂者容易患有憂鬱症。
結論
我們推論創傷性神經損傷後急性期給予老鼠高壓氧治療或Simvastatin腹腔注射可以減少神經細胞凋亡、減少微小膠細胞和腫瘤壞死因子-α的表現，進而改善憂鬱行為。本研究結果建議高壓氧治療及Simvastatin可用於治療創傷性損傷所引起的憂鬱行為。另一方面，大型資料庫的世代研究顯示，脊髓損傷和腦創傷有類似的結果，在創傷後及原已有高血脂的患者，有較高的風險產生憂鬱症。

Introduction
Previous researches showed that depression is the most frequently diagnosed psychiatric disorder after traumatic brain injury (TBI). Neuroinflammation plays an important role in this issue. Our previous study demonstrated that hyperbaric oxygen (HBO) therapy in after TBI can attenuate neuroinflammation, resulting in a neuroprotective effect. We also found preexisting hyperlipidemia to be an independent predictor of new-onset depression and anxiety in patients with TBI. In this thesis, in the basic research, we will elucidate the therapeutic effect of HBO and Simvastatin in acute stage of TBI-induced anti-depression-like behavior by rat model. In addition to TBI, psychological disorders may also occur after traumatic spinal cord injury (tSCI). Therefore, in the clinical research, we conducted a large nationwide Taiwanese population-based study to retrospectively examine the relationship between tSCI and the risk of new-onset anxiety or depression in comparison with other health condition groups. We also hypothesized that preexisting hyperlipidemia may also a risk factor for new-onset of anxiety and depression in patient with tSCI.

Methods and results
There are basic research and clinical research two parts in this study:
Fluid percussion device was used in anesthetized rats to produce a moderate severity brain trauma. In the basic research I study, animals were divided into 3 groups: sham operation plus normobaric air (NBA), TBI plus NBA, and TBI plus HBO. HBO was applied immediately for 60min/d after TBI for 3 days.
In the basic research II study, animals were divided into 5 groups: sham-operated controls, TBI controls, and TBI treatment with Simvastatin 4, 10, or 20mg/kg. Simvastatin was intraperitoneally injected 0, 24, and 48 hours after TBI. The motor function was measured using an inclined plane, and depression-like behavior was evaluated using forced swimming tests on the 4th, 8th, and 15th day after TBI in all groups. Neuronal apoptosis, microglia and astrocyte activation, and TNF-α expression in the microglia and astrocytes of the hippocampal CA3 area were investigated using immunofluorescence assay.
TBI-induced depression-like behavior, which increased duration of immobility, was significant attenuated by HBO or 20mg Simvastatin therapy on day 15 after TBI. TBI-induced neuronal apoptosis, microglia and astrocyte activation, and TNF-α expression in the microglia and astrocytes of the CA3 area of the hippocampus were significant reduced by HBO or Simvastatin treatment, particularly when 20mg/kg was administered for 3 days.
In the clinical research for tSCI, the Longitudinal Health Insurance Database (LHID) from Taiwan’s National Heath Insurance Research Database (NHIRD) was used for retrospective cohort study. Individuals with tSCI were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes. The relative risk of anxiety or depression was estimated using a Cox regression analysis between patients with tSCI and health control group.
Our findings indicated that tSCI patients have a high risk of anxiety or depression, especially among the younger tSCI patients. In addition, preexisting hyperlipidemia is and independent predictor of new-onset anxiety or depression in patients with tSCI.

Conclusion
We concluded that HBO or Simvastatin intraperitoneal therapy during the acute stage of neurotrauma in rats attenuates neuronal apoptosis, microglia, and TNF-α expression, resulting in a reduction of depressive-like behavior. Our results suggest that HBO or Simvastatin may be a promising treatment for neurotrauma-induced drepression-like behavior. In large nationwide population-based, patients with tSCI have high risk of anxiety or depression. tSCI patients with hyperlipidemia were more likely to develop the new-onset anxiety or depression that those without hyperlipidemia.

國立中山大學論文審定書 i
論文公開授權書 ii
誌謝 iii
中文摘要 iv
Abstract vi
Table of Contents ix
1. Table list xi
2. Figure List xii
2.1 Basic research xii
2.2 Clinical research xiv
3. Abbreviations xv
4. Background 1
5. Materials and methods 7
5.1 Basic research 7
5.2 Clinical research 18
6. Results 29
6.1 Basic research 29
6.2 Clinical research 36
7. Discussion 40
7.1 Basic research 40
7.2 Clinical research 54
8. Conclusions 71
9. References 72
10. Tables 98
11. Figures 103
12. Appendix 120
12.1 Basic concept of study 120
12.2 Mechanism in neurotrauma-related depression 121
12.3 Conceptual Framework 122
12.4 Overview of our basic study 123
12.5 Overview of our clinical study 124
12.6 Traumatic brain injury model 125
12.7 Treatment intervention – HBO 126
12.8 Treatment intervention – Simvastatin 127
12.9 Forced swimming test (FST) 128
12.10 Motor function test – inclined plane 129
12.11 Summary of basic study 130
13. Publications during 2013-2018 131
14. Curriculum vitae 135

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