自閉症患者大腦灰質區變異：灰質下皮質區及灰質皮質區的結構共變性以及年齡的影響

Abstract

研究目的：自閉症（Autism spectrum disorder, ASD）為一種神經發育障礙得精神疾病好發於兒童時期，其中包括社交溝通障礙以及制約性行為模式，也包括非典型的大腦結構與功能。在過去自閉症的患者在大腦核磁共振(MRI) 的研究成果上對於大腦結構上的發育成熟的變異尚未取得一致的研究的成果。在此次的研究中，我們的目的是更好地綜合考慮各種腦形態學參數表徵上的男性ASD患者的神經解剖學發展的影響，我們致力於探討從兒童時期到成年期年齡以及疾病對於大腦結構的影響和灰質下皮質區以及灰質皮質區的關係。我們假設ASD患者的大腦結構與修剪和建立新的連接神經發育過程的改變軌跡有關。在此基礎上，我們預計，自閉症人士將不同於一般的個人發展（TD）在皮層和皮層下的形態與年齡相關的影響，包括灰質體積反映這些神經發育的不同模式。此外，如果假設成立的話，這些差異應該是在兒童期更加明顯，並且可能會影響至成年。 研究方法：結構性MRI（3T）117個男性自閉症的圖像（平均年齡±標準差，14.6±4.4歲）和108 TD男性（平均年齡±標準差，15.0±5.9歲），年齡為7至30歲。為了更詳盡的探討兒童時期的灰質下皮質區以及皮質區的關係我們採用個案為（ASD：N=48，平均年齡±SD，10.8±1.2歲; TD：N =51，平均年齡±SD，10.5±1.5歲），並評價大腦形態學差異在發育在這些不同年齡階段。在體積形態分析使用FreeSurfer 5.2.0，並劃分灰質成不同的腦區的體積，而統計分析則使用多元回歸(multiple regression)。 研究成果：自閉症兒童有顯著疾病以及年齡交互效應，在左外側眶額葉皮質比正常的個案有著相對較小的灰質體積，右側喙額中回，島葉，左顳上回，雙側下頂葉皮質，扣帶皮質和第一視覺區皮層，自閉症患者在成長過程中灰質體積下降速度更為緩慢，而兩組的曲交叉點一致顯示為青少年時期（從12-15歲）。正如預期的那樣，皮質皮層下組織，在兒童時期，丘腦，殼核和伏隔核體積呈正相關區域皮質體積共同變異性自閉症患比起正常個案更為廣泛地呈現在共變性在童年時而其中更以右半腦為主要顯著的結果。 研究結論：我們的研究結果支持自閉症患者在神經發育形態的系統性變化。年齡調節著大腦體積結構的變異，但與年齡相關的效應模式是從兒童到成人階段自閉症患者以及正常個案有著相反的模式。重要的是，我們的結果強烈的指出自閉症患者以及正常個案之間的皮質以及皮質下相關性的新發現。此外，青春期期間有著較為複雜的結果，進而神經系統發育更一致指出一些自閉症患者有開始“趕上”正常患者的大腦結構變異而另一些人則沒有。

Objective: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with variable phenotypes including atypical brain structure and function. Magnetic Resonance Imaging (MRI) studies on the atypical brain structure over developmental age in individuals with ASD have yielded inconsistent results. In this study, we aimed to better characterize the developmental effects on the neuroanatomy of males with ASD by comprehensively considering various brain morphological parameters as well as their age-diagnosis effect and cortical - subcortical associations over childhood to young adulthood (Alexander-Bloch, et al., 2013c). We postulated that ASD is associated with altered trajectories of neurodevelopmental processes involving pruning and establishing new connections. Based on this, we anticipate that individuals with ASD would differ from typically developing individuals (TD) in the patterns of cortical and subcortical morphology with age- related effect including gray matter volume that reflect these neurodevelopmental differences. Moreover, if present, these differences should be more apparent in childhood and even out with greater age. Methods: Structural MRI (3T) images of 117 males with ASD (mean age ± SD), 14.6±4.4 years) and 108 TD males (mean age ± SD, 15.0 ± 5.9 years), with age ranging from 7 to 30 years were acquired. We separated the participants for structural covariance approach into childhood (ASD: n = 48, mean age ± SD, 10.8 ± 1.2 years; TD: n = 51, mean age ± SD, 10.5 ± 1.5 years), and to evaluate the brain morphological differences over these different stages of the developmental lifespan. Volume based morphometry analysis was implemented using FreeSurfer ver. 5.2.0, which percolated gray matter into various brain regions with volume. The statistical analysis was using multiple regressions. Results: Participants with ASD in childhood had significantly diagnosis- by-age interaction effects that smaller relative regional volumes than TDC in the left lateral orbital frontal cortex, right rostral middle frontal gyrus, insular cortex, left superior temporal gyrus, bilateral inferior parietal cortex, isthmus–cingulate cortex and right pericalarine cortex which that ASD had more slowly decrease through the maturation, and the cross point consistently shown in adolescents (from 12-15 years old). As expected, for cortical subcortical associations, during childhood, the thalamus, putamen and nucleus accumbens volumes were positively correlated with regional cortical volumes more extensively in ASD than TD during childhood and only specifically in right hemisphere. Conclusions: Our findings support a systemic alteration in neurodevelopmental morphology in ASD. The age modulated the global volume difference in ASD and TDC, however the pattern of age- related effect was opposite from child to young adult in two groups. Importantly, we report a novel finding of distinct patterns of cortical-subcortical associations between ASD and TD. Moreover, these effects of ASD were somewhat masked during adolescence, consistent with a more heterogeneous phase of neurodevelopment as some ASD individuals begin to 'catch up' with TD while some others do not.