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研究生:倪信章
研究生(外文):Hsing-Chang Ni
論文名稱:年紀和自我調節對於自閉症男性大腦結構與功能的影響
論文名稱(外文):The impacts of age and self-regulation on the brain structure and function in boys with autism spectrum disorders
指導教授:高淑芬高淑芬引用關係
口試委員:楊偉勛吳文超葉啟斌李正達
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2019
畢業學年度:108
語文別:英文
論文頁數:234
中文關鍵詞:自閉症年紀自我調節大腦體積大腦皮質厚度大腦皮質皺褶白質連結完整性靜態內部連結
外文關鍵詞:autism spectrum disorderageregional brain volumecortical thicknesscortical gyrificationwhite matter microstructural integrityintrinsic connectivity at rest
DOI:10.6342/NTU201904359
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背景
自閉症是重要且常見的精神疾患。自閉症個案在兒童發展的初期就會出現人際和社會互動的困難同時伴隨著重複且固執的興趣和行為,這些困難大多持續終身,不僅影響個案的就學與就業,對於家庭教育以及整個社會帶來很大的衝擊。目前為止,自閉症並沒有任何有效的生物性治療方式可以改善患者的核心困難。
過去的大腦影像研究結果顯示,自閉症個案的大腦與一般人相比,在大腦灰質與白質體積,大腦皮質厚度,大腦皮質皺褶程度,白質結構連結的完整性以及大腦腦區之間的功能性連結等有非常明顯的差異。然而,過去的大腦影像研究結果常常並不一致,甚至可能出現相反的結果。造成這些結果不一致的可能原因包括年紀,性別或者智力程度。除了上述因素之外,是否有其他的原因會造成不同研究間結果的差異值得深入探討。
研究目的和方法
我們的研究主要是探討年紀以及自我調節程度對於自閉症和健康受試者男性大腦影像差異的影響。首先,在探討年紀對於大腦體積的影響時,我們採用三個步驟加以分析。第一步,我們會依照傳統的方法,在控制了年紀變項後,比較自閉症和健康受試者大腦體積的組間差異。第二步,我們在比較組間差異時,除了控制年紀,我們會在分析的模型中納入組別與年紀的交互作用。我們想知道,在控制了組別與年紀的交互作用後,組間差異是否有所不同。此外,我們也想知道,自閉症和健康受試者在哪些大腦區域出現組別與年紀的交互作用。第三步,我們會依照受試者的年齡將他們分成兒童組,青少年組,以及成人組,並進一步探討自閉症與健康受試者的組間差異是否在三個不同的年齡族群而有所不同。
探討自我調節程度對於自閉症和健康受試者男性大腦影像差異的影響時,我們會關注多種不同的大腦結構以及功能,包括體積,皮質厚度,皮質表面積,皮質皺褶,白質結構連結的完整性以及大腦靜態時腦區間的內在連結。我們會採用兩個步驟加以探討。第一步,我們將比較自閉症和健康受試者,在控制或者不控制自我調節程度時,兩者的組間差異是否有所不同。第二步,我們想了解自閉症和健康受試者男性,自我調節的程度與大腦結構的關聯性,在哪些腦區有相似或者相異的關係。
我們共招募102位自閉症男性個案以及90位正常對照組個男性,年紀介在7-29歲間。自我調節的程度使用Child behavior checklist中的三個分測驗加以評估,包括注意力(Attention),侵略(Aggression)及焦慮憂鬱(Anxiety/depression)。
局部大腦體積的分析是採用基於體素形態學分析(Voxel-based morphometry);大腦皮質厚度,皮質表面積以及皮質皺褶程度採用基於表面形態學分析(Surface-based morphometry);白質連結完整性是採用擴散頻譜造影分析(Diffusion spectrum imaging);靜態功能性的連結是使用靜態性功能造影分析(resting state functional MRI)。
研究結果
在考慮年紀和組別的交互作用後,自閉症和健康受試者的組間差異確實有所不同。特定局部腦區體積和年紀變化的方向性,自閉症和健康受試者有顯著不同,包括灰質中的cuneus, anterior prefrontal cluster, left cerebellum cluster, bilateral caudate clustery以及白質的forceps minor in anterior cingulate gyrus。此外,自閉症和健康受試者的組間差異在不同年紀的族群中有所變化。
與過去的研究結果相仿,未考慮自我調節程度時,自閉症和健康受試者在局部大腦體積,皮質皺褶程度,靜態腦區的內部連結有顯著的差異。然而,這些組間差異,在考慮了自我調節的程度後,大多消失不顯著。
自我調節程度和大腦結構/功能的關聯性,自閉症和健康受試者男性在特定的大腦區域有不同的形態,包括right middle frontal and right lateral orbitofrontal 的皮質皺褶; 牽涉到多個top-down以及bottom-up的白質連結完整性; 左右兩側inferior parietal sulcus-superior parietal lobe的靜態功能性內在連結。然而,我們發現自我調節程度和大腦結構/功能的關聯性,自閉症和健康受試者在特定的大腦區域有相同的型態,包括left orbitofrontal cluster的灰質體積,left inferior temporal and left lateral occipital cluster的皮質皺褶;dorsal anterior cingulate cortex to left lateral prefrontal cortex, thalamus to anterior cerebellum/right lingual, 以及thalamus to left postcentral gyrus的靜態功能性內在連結。
討論
我們的系列研究發現,年紀確實會明顯的影響自閉症和健康受試者的組間差異,是否控制年紀和組別的交互作用,對於自閉症和健康受試者的局部腦區體積差異將有所影響。此外,自閉症和健康受試者在大腦局部區域的體積變化,隨著年紀增加而有不同的趨勢變化。最後,自閉症與健康受試者的組間差異確實在三個不同的年齡族群而有所不同。整體來說,我們三個步驟的分析顯示,過去探討自閉症大腦影像研究結果不一致的現象,確實明顯的受到年紀的影響。
除了年紀之外,我們採用不同的大腦影像工具分析後發現,自我調節程度對於自閉症和健康受試者的大腦影像比較,也有非常重大的影響。整體來說,在考慮了自我調節程度後,自閉症和健康受試者的組間差異幾乎完全消失。這意味著,我們過去所發現的自閉症特定腦區,並非完全由自閉症解釋,部分可能是自我調節程度差異造成的結果。或者,這些特定的腦區同時在社交能力和情緒調節能力中都扮演著重要的角色。
呼應過去功能性影像分析的結果,我們的研究結果顯示,自閉症和健康受試者自我調節程度和特定腦區的變化存在著不同的趨勢。由於這些相關的腦區以及白質連結跟自我調節的歷程相關,這意味著自閉症和健康受試者在處理自我調節時,可能採用不同的機制。然而,跟過去的研究結果不同,我們發現自閉症和健康受試者自我調節程度和腦區的關係,在特定的腦區存在著相同的變化趨勢,而這些相同變化的腦區也牽涉到自我調節的歷程。綜合來說,我們的系列研究結果顯示,在處理自我調節時,自閉症和健康受試者在特定的腦區有著相同的變化,但其他腦區則有相異的變化。這個發現對於臨床的介入有非常重要的影響。如果說,自閉症和健康受試者在處理自我調節時使用一樣的腦區,那麼我們可以預期,對於健康受試者自我調節能力的介入方案同樣適用於自閉症個案。然而,如果自閉症和健康受試者在處理自我調節時在特定腦區的變化是截然不同的,那麼我們對於自閉症的自我調節介入,就應該採用與一般人有所不同甚至相反的策略。
結論
過去自閉症的大腦影像分析結果不一致的情況,除了年紀的影響之外,自我調節程度也明顯地影響了自閉症和健康受試者的大腦組間差異。此外,我們發現自閉症和健康受試者在處理自我調節的歷程中,部分腦區採用相同的機制,部分腦區採用不同的機制。這樣的結果對於未來發展自閉症自我調節的治療方式,將有重要且深遠的影響。
Background
Although previous MRI studies demonstrated that ASD and typically developing control (TDC) had different neural correlates, these results are inconsistent and even opposite across studies. The inconsistent MRI findings might come from several reasons, including age, gender, and intelligence. However, whether these are other important factors contributing the inconsistent MRI results deserve further investigation. Our study aimed to explore the impact of age and self-regulation on inconsistent MRI results in ASD.
Methods
The sample included 102 males with ASD and 90 male TDC, aged 7-29 years. The self-regulation is defined by the sum of T-scores of Attention, Aggression and Anxiety/Depression subscales in the Child Behavior Checklist. We used three steps analysis to explore the impact of age. First, we compared the regional brain volume difference between ASD and TDC by controlling age. Second, we added age-by-group interaction and compared the group difference in the first and second steps. Third, we used age-stratified analysis and compared the regional brain volume difference between ASD and TDC in children, adolescents, and adults.
We explored the impact of self-regulation on the neural mechanism of ASD using several MRI methods including the voxel-based morphometry (VBM), surface-based morphometry, diffusion spectrum imaging and resting-state fMRI. First, we explored whether there is significant group difference between ASD and TDC when the self-regulation is included in the model or not. Second, we explored whether there is similar or distinct relationship of self-regulation and neural mechanism in ASD and TDC.
Results
VBM analysis revealed altered regional brain volume in ASD as compared to TDC when age-by-group interaction was considered.The significant age-by-group interactions were found at the bilateral anterior prefrontal cortex, bilateral cuneus, bilateral caudate and left cerebellum Crus I for gray matter (GM) and left forceps minor for white matter (WM). Finally, age-stratified analyses showed different results across subsamples of children, adolescents, and adults. Furthermore, the results showed significant differences in regional brain volumes, cortical gyrification, and intrinsic connectivity at rest between ASD and TDC on several brain regions. However, most of the significances disappeared when the self-regulation level was controlled.
ASD and TDC had distinct associations of self-regulation and several neural mechanisms including the cortical gyrification of the right middle frontal and right lateral orbitofrontal regions, the intrinsic connectivity at rest of bilateral inferior parietal sulcus-superior parietal lobe, and the white matter microstructural integrity of several top-down and bottom-up white matter tracts. However, we also found that ASD and TDC had similar associations between self-regulation and several neural mechanisms including the regional GM volumes of the left orbitofrontal cluster, the cortical gyrification of the left inferior temporal and left lateral occipital cluster, the intrinsic connectivity between the dorsal anterior cingulate cortex and left lateral prefrontal cortex, and between thalamus and elements of somatomotor and visual networks.
Discussion
Different results with consideration of age-by-group and in age-stratified analyses suggest that the inconsistent findings on the atypical neuroanatomy of ASD may substantially originate from age variation in the study samples. In addition to age, we demonstrated the impact of self-regulation on the group difference between ASD and TDC in structural and functional brain connectivity. Overall speaking, the significance of the neuroanatomical difference between ASD and TDC disappeared after self-regulation is considered. It means that the identified ASD specific neural mechanism may partially be contributed from the self-regulation. Besides, these identified ASD specific brain regions may play essential roles for social and self-regulation at the same time.
Compatible to previous fMRI studies, we demonstrated several distinct relationships of self-regulation and neural mechanisms on several brain regions for ASD and TDC. Since these identified brain regions are involved in the process of self-regulation, our findings implied that ASD and TDC might use different neural processes in dealing with self-regulation. However, we also identified several similar relationships of self-regulation and neural mechanism on other brain regions, which are also involved in the process of self-regulation.
Conclusion
The inconsistent results of ASD MRI studies may be explained by the effects from the age and self-regulation. In addition, ASD and TDC had similar and distinct neural mechanisms underpinning self-regulation, which may facilitate the development of targeted intervention of self-regulation in the future.
目錄
口試委員會審定書 i
誌謝 ii
中文摘要 iii
英文摘要 iV
博士論文內容
1. Introduction 1
1.1. The neuroimaging findings in ASD 5
1.2. Inconsistent neuroimaging findings in ASD: Conceptual 7
1.3. Inconsistent neuroimaging findings in ASD 8
1.4. The rationale of this study: Unclear neural mechanism of 18
self-regulation in ASD
1.5. The specific aims and hypotheses of the doctoral thesis 20
2. Methods and materials 23
2.1. Participants and procedures 23
2.2. Assessment of self-regulation by Child Behavior Checklist 24
2.3. MRI methods 25
2.4. Structural image parameters 32
2.5. MRI processing 36
2.6. Statistical analysis 41
3. Results 55
3.1. Age effect 55
3.2. Self regulation: VBM approach 59
3.3. Self regulation: SBM approach 62
3.4 Self regulation: DSI approach 66
3.5 Self regulation: rsfMRI approach 71

4. Discussion 77
4.1. Age effect 77
4.2. Self regulation effect on group difference 85
4.3. Distinct patterns between neural correlates and self-regulation 93
in ASD and TDC
4.4. Similar patterns between neural correlates of self-regulation 103
in ASD and TDC
4.5. Impacts of intelligence 107
4.6. Limitations 109
4.7. Summary of our findings 111
5. Perspective 114
5.1. Age effect 114
5.2. Self regulation effect on group difference 117
5.3. Similar and distinct neural correlates underpinning self-regulation 119
in ASD and TDC
5.4. Different results across MRI methods 121
5.5. Summary 124
參考文獻 126
表1. Age effect 158
表2. Self regulation: VBM approach 171
表3. Self regulation: SBM approach 176
表4. Self regulation: DSI approach 181
表5. Self regulation: rsfMRI approach 198
表6. Summary Tables 203
圖1. Age effect 211
圖2. Self regulation: VBM approach 214
圖3. Self regulation: SBM approach 215
圖4. Self regulation: DSI approach 220
圖5. Self regulation: rsfMRI approach 222
圖 6. Summary Figures 228
附錄: 個人在碩博士班修業期間所發表之相關論文 234
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