2012-01-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/642966摘要：[目標]本計劃使用擴散頻譜造影(diffusion spectrum imaging, DSI)及功能性磁振造影(functional MRI, fMRI)在精神分裂症患者之手足身上研究精神分裂症的風險基因對腦結構及功能的影響，並以此為依據找到大腦在結構性與功能性連結的內表現型(endophenotype)。DSI 藉由量測水分子擴散以檢測腦白質神經束的微結構狀態，而fMRI 藉由量測血氧濃度依存訊號(blood oxygenated level dependent, BOLD)以檢測腦灰質的活性。本計劃將以大腦預設迴路(default mode network, DMN)為研究重點。DMN 主要包含有中前額葉，後扣帶回，楔前葉以及側頂葉。此迴路與內省及自我指認等功能相關。近年來，DMN 已被報導在精神分裂症患者身上有顯著變化。此外我們以患者之未患病手足為研究對象將可排除因藥物治療或疾病進展所造成的變因。[假說] 根據目前以神經發育理論來解釋精神分裂症之致病機轉之觀點，我們假設在NRG1 及DISC1 上的三個基因型變異(即NRG1-P3, DISC1-2 and DISC1-27)將影響DMN 的結構性連結及功能性連結。我們假設 (一)風險基因的存在會造成DMN 結構性連結的下降，因而導致功能性連結代償性之增強。(二)隨著基因劑量的增加，患者手足跟正常組相比，在結構性和功能性連結上會有更明顯的變化。(三)基因劑量隨著以下各項檢測應有由強而弱漸進性的相關性：DMN 的結構性連結，DMN 的功能性連結，言語工作記憶的正作業活性(task-positive activation)及反作業活性(task-negative activation)，以及神經生理測驗的認知表現。[方法] 本計劃分別使用 DSI 及fMRI 來研究DMN 的結構性連結及功能性連結。從DSI 資料我們可重建DMN 之神經纖維束，並計算神經纖維束之廣泛不等向性(generalized fractional anisotropy, GFA)，作為結構性連結之參數。在fMRI 方面，我們同時掃瞄靜態fMRI(resting state fMRI)以及言語工作記憶fMRI。從靜態fMRI 資料我們可計算DMN 不同區域間訊號的同步性，作為功能性連結之參數。從言語工作記憶fMRI 資料我們可計算受試者在執行言語工作記憶時，大腦的正作業及反作業之活性狀態。在每個受試者身上我們將取得以下資料：NRG1-P3, DISC1-2 和DISC1-27 的基因型，由DSI 計算出的DMN 結構性連結，由靜態fMRI 計算出的DMN 功能性連結，此兩者將視為內表現型，而神經生理檢測的結果將視為外表現型。而言語工作記憶的反作業活性將視為內表現型與外表現型之間的橋樑。[重要性]本計劃以DMN 的結構性連結及功能性連結為核心，探討DMN 在精神分裂症所產生的異常。並試圖找出此異常與三個與神經發育有關之基因型以及注意力導向有關之外表現型之間的關係。此研究將有助於瞭解精神分裂症之部分致病機轉，也有可能找到有效的影像標誌(imaging biomarker)，用來偵測出未患病手足或具前驅症狀的患者將來會發病的高危險群。<br> Abstract: [Aim] This research project investigates the dosage effects of three promising vulnerability genes of schizophrenia (NRG1-P3, DISC1-2 and DISC1-27) on the brain structure and function. Diffusion spectrum imaging (DSI) and functional magnetic resonance imaging (fMRI) will be performed on unaffected siblings of the patients and normal controls. DSI examines neural tracts of the white matter by the water molecular diffusion, whereas fMRI measures cortical activity of the gray matter by the blood oxygenation level dependent (BOLD) signal. In this study, we focus on the default mode network (DMN). The DMN typically involves the medial prefrontal cortex, posterior cingulate cortices / precuneus, and lateral parietal lobule, and is considered to be related to introspective and self-referential thought. Alterations of the DMN have been robustly reported in schizophrenia patients. The unaffected siblings are recruited to minimize confounds by the medication and disease process of the illness.[Hypothesis] Based on the neurodevelopmental perspective on psychopathology of schizophrenia, our hypotheses are as follow. 1) The existence of risk gene alleles is associated with the decrease in structural connectivity, as well as, the compensatory increase in functional connectivity of the DMN. 2) The alterations in the structural and functional connectivity would be observed in the sibling group as compared with the control group, and the alterations are associated with the gene dosage. 3) The gene dosage would exhibit cascading effects on the brain structure, function and cognitive behavior. The gene dosage poses the strongest effect on the structural connectivity of the DMN, followed by the functional connectivity of the DMN, the task-negative activation of the verbal working memory affecting the task-positive activation, and the weakest on the cognitive performance in the neuropsychological assessments. [Methods] We use DSI and fMRI to examine, respectively, the structural connectivity and functional connectivity of the DMN. From DSI data, we reconstruct neural fiber tracts of the DMN and along each tract compute the generalized fractional anisotropy (GFA) to serve as an index of structural connectivity. For the fMRI, we acquire both resting state fMRI and task-employed fMRI of verbal working memory (VWM). From resting state fMRI, we determine the functional connectivity of the DMN by computing the temporal correlation of the signal fluctuation between different brain regions. From task-employed fMRI, we compute condition contrasts including task-positive and task-negative networks regarding the VWM. From each subject, we will obtain NRG1-P3, DISC1-2 and DISC1-27 as genotype data, structural connectivity and functional connectivity of the DMN as endophenotype, and neuropsychological tests as phenotype data. To serve as a bridge between endophenotype and phenotype, task-negative activation in VWM fMRI will be acquired. [Significance] Using structural connectivity and functional connectivity of the DMN as a core, we may characterize the alterations of the DMN in schizophrenia, and may also discover the relations of the alterations with the genotype and phenotype. From this research, we may find evidence supporting neurodevelopmental theory of schizophrenia, and might discover effective imaging biomarker that could help identify people who are at risk of developing full-blown schizophrenia.擴散頻譜造影功能性磁振造影