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研究生： 黃聖閔
Huang, Sheng-Min
論文名稱： 注意力不足過動症之動物模式的大腦網路
The Brain Networks of an ADHD Animal Model
指導教授： 王福年
Wang, Fu-Nien
口試委員: 葉子成
鍾孝文
林發暄
黃騰毅
彭旭霞
彭馨蕾
學位類別： 博士
Doctor
系所名稱： 原子科學院 - 生醫工程與環境科學系
Department of Biomedical Engineering and Environmental Sciences
論文出版年： 2016
畢業學年度： 104
語文別： 英文
論文頁數： 85
中文關鍵詞： 靜息態功能性磁振造影 、大腦網路 、注意力不足過動症過動症 、自發性高血壓大鼠 、疾病發展
外文關鍵詞： resting state fMRI, brain network, ADHD, Spontaneously hypertensive rat, disease development
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    • 靜息態功能性磁振造影在近幾年來受到受到相當大的注目。藉由偵測大腦於休息狀態下的低頻訊號擾動，可以得到於休息狀態下的大腦連結，稱之為靜息態網路。靜息態功能性磁振造影目前已被運用於許多神經精神疾病的臨床研究，如注意力不足過動症。然而在注意力不足過動症的動物模式上，仍幾乎未有相關的靜息態網路研究。由於動物模式能協助我們了解人類疾病的病理，本篇論文將利用靜息態功能性磁振造影與擴散磁振造影來探討注意力不足過動症的大鼠模式：自發性高血壓大鼠(SHR) 的大腦網路。
    首先，我們比較SHR與其對照組WKY大鼠於6週齡時的靜息態網路差異。結果顯示SHR大鼠的預設模式網路中，大腦紋狀體與與海馬迴部分區域有異常的活化現象。我們亦發現，這兩種大鼠在這些腦區的擴散磁振造影結果也有所不同。由於前額葉-紋狀體迴路的異常一直以來被認為與注意力不足過動症有所相關，我們的發現應能支持SHR大鼠的紋狀體功能異常與其症狀有關。
    於論文第二部分，我們針對不同週齡的大鼠進行研究，包含6週至10週大的SHR與WKY。相對於穩定的WKY，我們發現SHR大鼠的預設模式網路強度會隨著週齡增長而減小，主要在於紋狀體區域與前額葉皮質內側。而在擴散磁振造影方面，擴散參數亦能反映出SHR與WKY的差異，包含紋狀體與前額葉皮質內側。這些研究結果顯示，紋狀體與前額葉皮質內側這兩個區域在SHR大鼠的疾病發展上有著重要的地位。
    總結而言，紋狀體區域在SHR大鼠這個注意力不足過動症的動物模式上扮演著一個重要的角色。除了一般常見的動物行為分析以外，本篇論文的研究結果提供了腦功能層面上的資訊。因此，未來將能利用靜息態功能性磁振造影與SHR大鼠這個動物模式，來拓展注意力不足過動症的研究。

    Resting state functional magnetic resonance imaging (rs-fMRI) has received enormous attention since its discovery more than a decade ago. Rs-fMRI detects the intrinsic low-frequency fluctuations of brain and uncovers the brain connectivity termed resting state networks (RSNs). This technique has been employed on investigating several neuropsychological disorders including attention deficit and hyperactivity disorder (ADHD). However, the rs-fMRI study on ADHD animal model remains unexplored. Since animal model provides a beneficial pathway to discover the pathologies of diseases, we aim to investigate brain networks of an ADHD rodent model: spontaneously hypertensive rat (SHR). In this dissertation, rs-fMRI and diffusion MRI were utilized for exploring the brain networks of SHR rat.
    In the first part, SHR and Wistar Kyoto rat (WKY) at 6 weeks old were compared. The default mode network (DMN), which is the most prominent RSN, was derived by using retrosplenial cortex as seed. Our results showed that the major DMN differences are the activities in caudate putamen and hippocampus region. Diffusion scalars also reported abnormality in these regions. Since the dysfunction of prefrontal striatal circuits has long been considered a correlate of ADHD, our findings could support that the striatal dysfunction in SHR rats is related to ADHD symptom.
    In the second part, the developmental changes in brain networks were investigated. Animals from 6 to 10 weeks old underwent rs-fMRI and diffusion MRI experiments. The age-related reduction of DMN activity was identified in the caudate putamen and the medial prefrontal cortex of SHR rats. Furthermore, diffusion scalars reflect the microstructural differences between SHR and WKY rats at the same time. Our results suggest the importance of caudate putamen and medial prefrontal cortex in the development of ADHD research using SHR model.
    In summary, the striatal area plays an important role in this ADHD rat model. In addition to the conventional behavior evidence on SHR rat, the network details in this dissertation offer an insight into brain function, suggesting the possibility of further ADHD research on rodent models through rs-fMRI techniques.

    CONTENTS ABSTRACT………………………………………………..……………………I CONTENTS…………………………………………………………….…..IV LIST OF FIGURES……………………………………………….………VI LIST OF TABLES………………………………………….….....………VII Chapter 1: Introduction 1 1.1 Background 1 1.2 Attention deficit and hyperactivity disorder and its animal model 4 1.3 Resting state functional MRI and ADHD 8 1.4 Diffusion MRI and ADHD 13 1.5 Objectives 15 Chapter 2: The brain networks of ADHD rat model 16 2.1 Introduction 16 2.2 Materials and Methods 18 2.2.1 Identification of the resting state functional networks 19 2.2.1.1 Resting state MRI acquisition 19 2.2.1.2 Data analysis 20 2.2.2 The effect of isoflurane anesthesia on stimulus-provoked BOLD signal changes 23 2.2.2.1 Forepaw stimulation paradigm 23 2.2.2.2 fMRI acquisition 23 2.2.2.3 Data analysis 24 2.2.3 Diffusion MRI on ADHD rat model 25 2.2.3.1 Diffusion MRI acquisition 25 2.2.3.2 Data analysis 25 2.3 Results 28 2.3.1 Identification of the resting state functional networks 28 2.3.2 The effect of isoflurane anesthesia on stimulus-provoked BOLD signal changes 36 2.3.3 Diffusion MRI on ADHD rat model 38 2.4 Discussions 40 2.5 Conclusion 52 Chapter 3: Age effect on brain networks of ADHD rodent model: A preliminary study 53 3.1 Introduction 53 3.2 Materials and Methods 55 3.3 Results 56 3.3.1 Age effect on resting state networks 56 3.3.2 Age effect on diffusion scalars 58 3.4 Discussions 60 3.5 Conclusion 64 Chapter 4: Summary and Future Works 65 4.1 Summary 65 4.2 Future works 67 Bibliography 68 Appendices 80 Appendix A 80 Appendix B 82 Appendix C 84

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