2011-05-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/642967摘要：背景:我們在過去兩年中收集到80位精神分裂症患者，目前完成了部分的基因分型、功能性磁振造影(functional MRI, fMRI)和擴散頻譜造影(diffusion spectrum imaging, DSI)資料分析。初步結果顯示患者在進行語言工作記憶任務時活化呈現增強。另一方面，語言工作記憶網絡的結構性連結，尤其在右腦卻呈現顯著降低。這發現支持精神分裂症中認知功能異常的原因是由於結構性連結的缺損而不是神經功能的減弱之假說。另外，基因劑量和預設狀態網絡區域的活化呈正相關，而和認知功能有關區域的活化呈負相關。此發現指出進行認知任務時不當的活化增強或活化減弱可能是精神分裂症的內表現型。為了更進一步證實我們的發現，在此延伸計畫中我們將研究患者未罹病之親屬。特定目標:首先，我們欲證明基因劑量對腦結構和功能的影響。假說： DISC1和NRG1的SNP RPM的基因型在語言工作記憶網絡的功能性活化和結構性連結會受到基因劑量的影響。第二，我們欲證實以神經發育理論解釋精神分裂症的致病機制。在未罹病親屬中，我們預期看到其功能性活化接近正常，但結構性連結依然降低。其差異較病人來得小。第三，我們欲決定與認知功能外表現型和基因型相關的影像內表現型。假說：語言工作記憶fMRI和DSI存在和專注力及執行功能受損有關的影像內表現型。方法：我們將徵招60位第一等親的家屬。每一位受試者接受抽血以檢驗其基因型，磁振造影掃描以獲取其影像內表現型，以及神經認知測驗以確定其外表現型。受試者依據所攜帶的危險基因型NRG1-P3，DISC1-2和DISC1-27之基因劑量分類。我們將使用3T磁振造影掃描儀和32通道頭線圈進行影像實驗。我們使用斯騰伯格的工作記憶任務進行語言工作記憶fMRI，使用統計參數圖驥(Statistical Parametric Mapping, SPM)進行功能性活化分析。DSI實驗係使用102個擴散梯度向量，每一向量對應到q-space裡某一個卡氏三維網格點，最大的擴散敏感度為4000s/mm2，結構性連結之定量乃使用自家研發的以神經纖維束為基礎之分析程式。統計：我們將執行三項ANCOVA及五個層面的相關分析。根據我們所列之特定目標，三項ANCOVA可以顯示三個SNP的特定效應，而五個層面之相關分析可以確認基因型，內表現型和外表現型之間的關係。相關分析的結果可以證明基因劑量在腦結構和功能的影響，也可以證實精神分裂症以神經發育觀點之致病學說。結合以上兩項分析結果，我們可以決定與外表現型和基因型相關之影像內表現型。<br> Abstract: Background: In the last two years, we have recruited 80 patients with schizophrenia and partially completed the genotyping, and analysis of fMRI and diffusion spectrum imaging (DSI) data. Our preliminary results show that patients present increased activation areas during verbal working memory (VWM) task, whereas reduced structural connectivity of the network, especially in right hemispheres. The finding supports the hypothesis that impaired structural connectivity, rather than reduced neuronal function, might be the cause of cognitive dysfunction in schizophrenia. In addition, the gene dosage shows positive correlation with the areas involved in default mode network, whereas negative correlation with the areas involved in cognitive function. The finding suggests that the altered activation and deactivation during cognitive tasks might be potential endophenotypes of schizophrenia. To confirm our preliminary results, in this extended project we will recruit unaffected relatives of the patients with schizophrenia. Specific aims: Three specific aims will be achieved and three associated hypotheses will be tested. First, we will prove the gene dosage effect on brain structure and function identified as imaging endophenotypes. Hypothesis: The genotypes of SNP RPMs of DISC1 and NRG1 impose a gene dosage effect on the functional activation and structural connectivity of the VWM network. Second, we will verify the theory of neurodevelopment in pathology of schizophrenia. Hypothesis: There exist qualitatively similar but quantitatively different alteration in the functional activation and structural connectivity in patients with respect to their unaffected relatives. In the unaffected relatives, we expect to see that functional activation is close to normal but the structural connectivity remains reduced with less extent. Third, we will identify specific imaging endophenotypes bridging neurocognitive phenotypes and genotypes. Hypothesis: There exist specific imaging endophenotypes of VWM that are associated with the impairment of attention and executive function. Methods: A total of 60 first-degree relatives will be recruited. Each subject will receive blood samplings for genotypes, MRI scans for imaging endophenotypes, and neurocognitive tests for phenotypes. The subjects are categorized according to the number of risk genotypes of NRG1-P3, DISC1-2 and DISC1-27 carried. The MRI experiment will be carried out on a 3T scanner with a 32-channel head coil. Functional MRI of VWM will be performed using a Sternberg working memory task, and functional activation will be analyzed using a Statistical Parametric Mapping (SPM5) package. DSI experiment will be performed by applying 102 diffusion gradient vectors, each corresponding to one of the isotropic 3D grid points in the q-space and the maximum diffusion sensitivity=4000 s/mm2, and structural connectivity will be analyzed using tract-specific analysis developed in house. Statistics: Three ANCOVA and five correlation analysis layers will be conducted. As described in the Specific Aims, the three ANCOVA can exhibit the specific effects of the three SNPs, and the five correlation analysis can verify the relationships among genotypes, endophenotypes and phenotypes. The correlation results can prove the gene dosage effect on brain structure and function identified as imaging endophenotypes, also verify the neurodevelopmental hypothesis of pathology of schizophrenia. By combining the results of the two analyses, we can identify specific imaging endophenotypes bridging phenotypes and genotypes.精神分裂症擴散頻譜磁振造影功能性磁振造影基因型口語工作記憶