2016-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/648553摘要：研究背景： 注意力不足過動症(ADHD)是具臨床與遺傳異質性的常見兒童精神疾患，其對神經心理及社會功能之影響持續至成年。雖然在國外，成人 ADHD 已是熱門的研究主題，國內目前對成人 ADHD 所知極少。因此，此五年計畫的主要研究目的旨在：以患者與其未患病手足內表現型（第 1-3年執行）及個案長期追蹤（第 4、5 年執行）的研究設計，找尋可作為 ADHD 內表現型的神經心理功能、大腦結構與功能連結、及神經生理標記。 研究目的： (1) 以神經心理功能（如執行功能、持續注意力、反應時間變異性、視空間記憶）、額葉-紋狀體網絡、額頂葉網絡及其他神經迴路之結構性與功能性連結(Tract-based autonomic analysis, TBAA)、以及神經生理功能（停止信號作業事件關聯電位），藉由未患病手足的表現在成人 ADHD 患者及健康成人的中間位置，和 DAT1 基因、SLC6A2 基因的關聯性，以建立 ADHD 的內表現型。 (2) 了解自前青春期至後青春期及年輕成人期之多面向神經心理功能以及大腦網絡的發展軌跡。 (3) 在成人 ADHD 與健康成人者間、有無 DAT1/SLC6A2 基因、ADHD 患者與其非患病手足間、及不同發展階段，了解 ADHD 行為症狀與大腦網絡、神經心理、及神經生理功能的關聯性及其異同。 (4) 比較未曾用藥之成人 ADHD 和藥物治療過 ADHD(追蹤組)之神經影像、生理及心理功能已檢視藥物治療的影響。 研究方法： 第一至三年進行 ADHD 成人與其未患病手足收案：分四組至少共 180 至 240 位受試者(16-30歲，智商>80)，細分組包括（1）60 位未曾用藥之成人 ADHD 個案、（2）至少 30 位同性別之未患病手足、（3）60 位年齡、性別、智力與 ADHD 組匹配之健康對照者、（4）至少 30 位年齡、性別、智力與手足組匹配之健康對照者。第四至五年進行追蹤研究：收案 40 位青少年及成年的 ADHD 患者（13-25歲）及 40 位當時年齡、性別、智商匹配之健康對照者，這 80 位個案是在 8-17 歲時接受過第一階段的磁振造影掃描(MRI)，其同性別手足也將邀請參加本研究。所有受試者皆會接受精神科會談（ADHD+SADS, CAADID, ADI-R, ADOS），自填式問卷調查(ADHD 與行為症狀、精神病理、執行功能 (BRIEF) 、生活品質(AAQoL)、社會功能障礙(WFIRS))，神經心理測驗（魏氏兒童或成人智力測驗, 持續注意力測驗，CANTAB）、MRI（包括 T1 與 T2 影像、DSI、靜息態功能性 MRI 等）、停止信號作業事件關聯電位。 原創性與重要性： 本計畫旨在建立世界少有的完整研究並以新穎的磁振造影技術分析（Tract-based autonomic analysis, TBAA），找尋未曾用藥之成人 ADHD 患者其神經影像、生理及心理的內表現型；並利用長期追蹤設計以了解和 ADHD 相關之多面向大腦網絡及神經心理功能的發展軌跡。 預計進度： 我們計畫分別於第一年完成 54 至 72 位、第二年 72 至 96 位、第三年 54 至 72 位、第四年 70位、第五年 50 位受試者的臨床及神經影像、生理、心理評估；並於第二年開始，每年預計完成兩篇論文投稿。<br> Abstract: Background: Attention deficit/hyperactivity disorder (ADHD) is a common, clinically and genetically heterogeneous neuropsychiatric disorder with long-term neuropsychological and social impairments till adulthood. Despite much attention paid to adult ADHD in western research, little is known about adult ADHD in Taiwan. The ultimate goals of this 5-year project are to identify specific neuro-psychological, -imaging, and -physiological data that can be treated as effective endophenotypes (biomarkers) for ADHD using the endophenotype (1st-3rd years) and follow-up (4th-5th years) study designs. Specific Aims: (1) To validate the neuropsychological functions (e.g., executive functions, sustained attention, reaction time variability, and visuo-spatial memory), structural (assessed by tract-based automatic analysis, TBAA, based on diffusion spectrum imaging, DSI) and functional connectivity (assessed by resting-state fMRI) in frontostriatal, frontoparietal and other circuitries, neurophysiological functions (assessed by stop-signal event-related potential [ERP], N2, P3, ERN, Pe) as effective neurocognitive endophenotypes by demonstrating intermediate position of unaffected siblings between ADHD probands, and adult neurotypicals and associations with DAT1 or SLC6A2 (NET) genes; (2) To examine the developmental trajectory and stability of neuropsychological functions and structural and functional connectivity from childhood to late adolescence and young adulthood; (3) To correlate these data with ADHD core symptoms and school and social outcomes stratifying by the presence of ADHD and DAT1/SLC6A2 genes, proband-unaffected sibling dyads, and different developmental stages; and (4) To compare the neuro-psychological, -imaging, and –physiological data between drug-naïve adult ADHD and treated ADHD at follow-up to explore the treatment effect in adult ADHD. Methods: The 1st-3rd year (endophenotype) sample (n=180~240, 4 groups, ages 16-30, IQ > 80) consists of (1) 60 drug-naïve adult ADHD probands, (2) at least 30 same-sex unaffected siblings, (3) 60 age-, sex- and IQ-matched neurotypicals for ADHD probands, and (4) at least 30 age-, sex- and IQ-matched neurotypicals for unaffected siblings. The 4th -5th year (follow-up) sample consists of 40 adolescents and young adults, aged 13-25, with ADHD and 40 neurotypicals who received MRI assessments at the ages of 8-17 and their same-sex unaffected siblings (~20 for each group). The assessments include psychiatric interviews (ADHD+SADS & CAADID for ADHD and other diagnoses; ADI-R & ADOS for excluding autism), self-administered questionnaires forADHD /behavioral symptoms, psychopathology, executive function (BRIEF), life quality (AAQoL), and social impairment (WFIRS), and neuropsychological (WISC-III-R or WAIS-III for intelligence, Conner’s CPT, CANTAB), and MRI (T1- and T2-weighted images, DSI, and resting-state fMRI), and stop-signal ERP assessments. Originality and Significance This project is one of few imaging genetics studies in the world, using the novel diffusing image method (i.e., TBAA), to establish the neuroimaging and neurophysiological endophenotypes in drug-naïve adults with ADHD and to follow up ADHD children and adolescents with MRI assessments 4 to 8 years later to examine the stability and changes of structural and functional connectivity related to ADHD. Anticipated Timetable: We will complete the clinical, neuropsychological, imaging, and neurophysiological data of at least a final sample of 54~72, 72~96, 54~72, 60, 60 in the 1st, 2nd, 3rd, 4th, 5th year of the study and prepare 2 manuscripts per year since the 2nd year of the project.未曾用藥之成人注意力不足過動症內表現型擴散頻譜磁振造影(DSI)神經纖維束自動 化分析(TBAA)靜息態功能性磁振造影神經心理神經生理追蹤研究DAT1 基因SLC6A2 基因Drug-naïve Adult ADHDendophenotypetract-based automatic analysisdiffusion spectrum imagingresting-state fMRIneuropsychologyneurophysiologyfollow-upDAT1SLC6A2