2012-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/642965摘要：注意力不足過動症(Attention-Deficit/Hyperactivity Disorder, ADHD)是一常見、具長期執行功能障礙、高臨床及基因異質性神經精神疾患。此三年期個案對照、影像基因研究計畫的目標為建立ADHD 腦造影之內表現型，經由收集ADHD 族群、其非患病手足與典型發展對照組之擴散頻譜磁振造影(DSI)以檢測和認知/執行功能相關之腦部結構性連結，以靜態功能性磁振造影(rsfMRI)檢測腦部和認知/執行功能相關之功能性連結，以瞭解腦部連結是否和有無ADHD 以及多巴胺轉運基因(DAT1)變異有關。研究目的：1. 檢測執行功能、視覺空間記憶、額葉-紋狀體迴路與額葉-頂葉迴路的結構與功能性連結，是否可作為有用的ADHD 神經認知內表現型。2. 以ADHD 及未患病手足以及是否有DAT1 基因變異探討腦部結構與功能性連結、神經心理學及與ADHD 核心症狀之關連。3. 除了DAT1 基因之外，亦將針對其他與多巴胺及腎上腺素神經傳導系統相關的候選基因 (如DRD4, MAO-A, ADRA2A, ADRA2C, NET, COMT)，進行與神經認知內表現型的相關分析。研究方法：研究對象:將收集240 位10 至20 歲、IQ 大於80 的ADHD 患者、其未患病手足及典型發展對照組，包括(1)30 位ADHD具有DAT1 致病基因變異患者，(2)其30 位同性別之未患病手足，(3)30 位ADHD未具有DAT1 致病基因變異患者，(4) 其30 位同性別之未患病手足，(5)120 位與前四組以性別及IQ 配對的典型發展個案。評估工具: 包括診斷會談、自填量表(CBCL 和SNAP-IV 評估行為及ADHD 症狀；SAICA 評估學校及社會功能)、神經心理學測驗(WISC-III 和WAIS-III 評估智能；CPT 評估持續注意力、抑制及警醒度；CANTAB 評估執行功能及視覺空間記憶)，以及腦部核磁共振造影。腦造影: (1) 我們將運用3T 磁振造影儀與32 頻道頭部線圈執行結構性磁振造影(T1-與T2 權重影像)、擴散頻譜磁振造影與靜態功能性磁振造影，擴散頻譜磁振造影時將應用脈衝梯度自旋迴訊與面迴訊成像技術配合102 個擴散梯度向量和4000 秒/毫米2 最大擴散靈敏度進行掃描，而靜態功能性磁振造影則應用面迴訊成像技術掃描180 次腦容積，掃描時間為六分鐘。(2) 結構性連結分析:擴散頻譜磁振造影神經連結圖譜將運用DSI studio (http://dsi-studio.labsolver.org/Home)軟體進行資料重組與分析，除了定位額葉-紋狀體迴路與額葉-頂葉迴路內的目標白質纖維束外，並沿著每條目標白質神經束進行微結構完整性的分析。(3) 功能性連結分析:靜態功能性磁振造影資料將使用SPM8 與實驗室內部所建構的MATLAB 程式進行分析，有興趣的腦部區域 (ROIs)將根據目標白質神經束迴路的解剖位置(WFU_PickAtlas 3.03)放置。ROIs 可輔助白質神經束起始點與終點的判定，同時也可視為分析血氧濃度相依對比訊號時所放置的種子區域，並進行種子區域之間迴歸分析。預期目標：我們將於三年期間分別於第一、二、三年分別完成80 位、96 位及64 位個案之臨床症狀、神經心理學、影像學、基因學資料庫的收集。<br> Abstract: Background: Attention deficit/hyperactivity disorder (ADHD) is a common, impairing, clinically andgenetically heterogeneous neuropsychiatric disorder with lifelong executive dysfunctions. The ultimategoal of this 3-year case-control imaging genomic study with unaffected siblings and typicallydeveloping (TD) children as controls is to identify useful imaging endophenotype for ADHD byinvestigating the structural connectivity, as assessed by diffusion spectrum imaging (DSI), andfunctional connectivity, as assessed by resting-state fMRI (rsfMRI) of brain regions related tocognitive/executive controls with regards to the ADHD status and the presence of dopamine transportergene variants (DAT1).Specific Aims:(1) to validate the executive functions, visuospatial memory, and structural and functional connectivityin frontostriatal, and frontoparietal circuitries as effective neurocognitive endophenotypes;(2) to correlate the data from structural and functional connectivity, neuropsychology, and ADHD coresymptoms stratifying by the presence of ADHD, proband-unaffected sibling dyads, and the presenceof DAT1 variant; and(3) To investigate reported candidate genes, in addition to DAT1 variant, related to dopamine andnoradrenergic neurotransmitter systems in the association with neurocognitive endophenotypessuch as DAT1, DRD4, MAO-A, ADRA2A, ADRA2C, NET, and COMT.Methods: The sample (n=240, 8 groups, ages 10-20, IQ > 80) consists of (1) 30 ADHD probands withDAT1 variants, (2) 30 same-sex unaffected siblings, (3) 30 ADHD probands without DAT1 genevariants, who were age-, sex-, and IQ-matched to Group 1, (4) 30 same-sex unaffected siblings ofGroup 3, (5) 30 age-, sex- and IQ-matched TD controls for each of 4 groups (Groups 1, 2, 3 & 4).The assessments include psychiatric interviews, self-administered questionnaires (CBCL andSNAP-IV for ADHD and behavioral problems; the SAICA for school and social function),neurocognitive assessments (WISC-III-R or WAIS-III for intelligence, Conner’s CPT for sustainedattention, inhibition, and vigilance, CANTAB for executive functions and visuo-spatial memory), andMRI assessments (Structural MRI, DSI and rsfMRI).Brain Imaging: (1) Structural MRI (T1- and T2-weighted images), DSI and rsfMRI data will beacquired on a 3T MRI system with a 32-channel head coil. DSI employs a pulsed-gradient spin-echoecho planar imaging (EPI) sequence by applying 102 diffusion gradient vectors and the maximumdiffusion sensitivity = 4000 s/mm2, and rsfMRI is a 6-minute scan using a gradient-echo EPI sequencewith 180 volumes. (2) Structural connectivity analysis: DSI tractography will be performed usingin-house software (DSI studio, http://dsi-studio.labsolver.org/Home). Tracts-of-interest in thefrontostriatal circuit and the frontoparietal circuit will be identified, and tract-specific analysis will beused to analyze the microstructural integrity along individual tract bundles. (3) Functional connectivityanalysis: SPM8 program and in-house MATLAB codes will be used for analyses of rsfMRI data.Region-of-interests (ROIs) will be placed in the nodes of the corresponding circuits according to ananatomical template (WFU_PickAtlas 3.03). These ROIs will serve for tract determination in thetractography procedure and for seed regions in which BOLD signals are extracted for regressionanalysis among nodes.Anticipated Timetable: We will complete the clinical, neuropsychological, imaging, and genetic datacollection of 80, 96, 64 subjects in the 1st, 2nd, and 3rd year of the study.注意力不足過動症內表現型執行功能擴散頻譜磁振造影靜態功能性磁振造影額葉-紋狀體與額葉-頂葉迴路多巴胺轉運基因(DAT1)ADHDendophenotypeexecutive functiondiffusion spectrum imagingresting-state fMRIfrontostriatal and frontoparietal circuitriesDAT1