2014-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658096摘要：背景：注意力不足過動症（attention-deficit/hyperactivity disorder，以下簡稱ADHD）的神經機轉逐漸由單一腦區的異常轉向神經聯結網絡的變化，其中以靜息態功能性磁振造影(resting state functional MRI, rs-fMRI)測量的功能性連結是理解此疾病神經網絡異常很重要的研究取向。另一方面，雖然臨床研究已經顯示藥物治療對於ADHD的成效，但仍然有許多病患無法持續接受治療，並且在藥物的耐受性與接受度方面存有許多差異，這些差異可能與基因和神經網路的變異有關。若了解ADHD治療效果的相關基因預測因子，將會有助於未來的臨床治療，並找出藥物治療效果的神經網路機轉。雖然目前國際上對於ADHD藥物基因學的研究正在增加，但主要都集中於臨床症狀的評估，而且個案大多已使用過藥物治療，目前並無研究探索從未使用過ADHD藥物病患之基因型對rs-fMRI的藥物反應之作用。目的：1. 使用重覆測量的方式找出ADHD藥物(methylphenidate和atomoxetine)治療對於rs-fMRI反應相關的基因調節因子；2. 找出rs-fMRI、神經心理學障礙以及行為症狀在藥物反應之間的關聯；3. 找出基因交互作用對於rs-fMRI、神經心理學障礙以及行為症狀在藥物反應上的影響；4. 探討ADHD從基因到神經影像學、神經心理學與行為症狀的病理生理機轉。個案與方法：本研究預計將在三年內收集60位7-18歲未曾使用過藥物治療的ADHD病患，這些病患將被隨機分配至兩個治療組，其中30人接受methylphenidate，另外30人接受atomoxetine，在12週的治療期間內將會規則地評估藥物療效，主要的行為症狀評估工具為ADHDRS-IV、SNAP-IV、CBCL、CGI-ADHD-S、CGI-ADHD-I、SAICA、以及FamilyAPGAR-C，另外也將施行神經心理學測驗，包含魏氏兒童智力測驗、持續注意力測驗、和劍橋神經心理學自動化測驗，我們在用藥前與用藥12週後將進行MRI掃描（包括T1與T2影像、靜息狀態的功能性MRI等），最後我們將收集受試者的DNA樣本，並針對可能會影響藥物效果的相關基因進行鑑定。預期結果：我們預期本研究將會發現ADHD基因型對於腦部神經聯結網絡之藥物反應的作用機轉，並找出腦部神經聯結網絡與神經心理學障礙和行為症狀之間的關聯性。藉著不同的測量方式所找出基因型對藥物反應的作用，將會幫助我們更加了解ADHD的病理生理學機轉，特別是發現從致病基因經由神經影像學異常、到神經心理學障礙和行為症狀的病理路徑。未來根據病患個別的基因型所發展的個人化治療，將會有效改善ADHD腦部神經聯結功能、提升藥物治療耐受性、以及增加藥物遵從度。<br> Abstract: Background: The neurobiological model of attention-deficit/hyperactivity disorder (ADHD)has shifted from assumed brain loci abnormalities to dysfunction in distributed networkorganization. Description of functional connectivity, inferring from resting state functionalMRI (rs-fMRI), among brain circuitry is central to better characterize disconnections inADHD. Although the efficacy of medications for ADHD is well demonstrated in clinicaltrials, substantial numbers of patients fail to remain on therapy, and there is tremendousvariability in tolerability and treatment acceptance. The variability may be related tovariations of genes and neural networks. An understanding of genetic predictors of ADHDmedication response is likely to influence future clinical treatments, and identify theunderlying neural networks of treatment effects for ADHD patients. Although interest inADHD pharmacogenetics is increasing, most of previous studies focus on the assessment ofclinical symptoms, with recruitment of subjects having used medications for ADHD. There isno study to investigate the effect of genotypes on the differential medication response inrs-fMRI among drug-naïve children with ADHD.Specific Aims:1. to identify the specific genetic moderators of methylphenidate and atomoxetine response inrs-fMRI using repeated outcome measurements;2. to identify the relationship between resting state rs-fMRI and drug response inneuropsychological and behavioral measures;3. to identify the gene-gene interactions in medication effects on the rs-fMRI,neuropsychological functions and behavioral phenotypes for ADHD; and4. to identify the pathophysiological mechanisms from genes, through neurobiologicalabnormalities, to neuropsychological functions and behavioral phenotypes in ADHD.Subjects and Methods: We will recruit 60 drug-naïve ADHD patients, aged 7-18 in this3-year project. The patients will be randomly assigned to two treatment groups, theOROS-methylphenidate group (n=30) and the atomoxetine group (n=30), respectively. Themedication response will be assessed regularly within 12-week treatment period. Thebehavioral efficacy measures include ADHDRS-IV, SNAP-IV, CBCL, CGI-ADHD-S,CGI-ADHD-I, SAICA, and Family APGAR-C. Neuropsychological testing, includingWISC-III, CPT, and CANTAB, will be performed. We will scan all the participants atbaseline and at week 12, by using MRI (T1 and T2 imaging, and rs-fMRI). The DNA will becollected, and the candidate genes hypothesized to influence medication effects for ADHDwill be genotyped.Anticipated Results: We anticipate that this study will determine the relationship betweenneural networks and genetic variants. In addition, we will identify the relationship betweenneural networks and drug response in neuropsychological and behavioral measures. Thesefindings of different approaches to identify the effects of genotypes on the drug response inthis study should help us to extend our understanding of the pathophysiological mechanismsof ADHD, especially the pathological pathway from risk genes, through neuroimagingabnormality, to neuropsychological dysfunction and behavioral phenotypes. In the future,development of individualized medication regimens based on genetic variability of patientswith ADHD might lead to normalization of neural network functions, improved treatmenttolerability, and concomitant improvements in patient adherence.注意力不足過動症藥物基因神經影像學神經心理學Attention-deficit/hyperactivity disordermedicationgeneticsneuroimagingneuropsychology