Integrating brain imaging and genetic analysis of ADHD

整合 ADHD 的脑成像和遗传分析

• 批准号: 6681726
• 负责人: Chandan J Vaidya
• 金额: $ 32.55万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-09 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6681726
• 关键词: attention; attention deficit disorder; behavior test; behavioral genetics; bioimaging /biomedical imaging; brain imaging /visualization /scanning; brain morphology; central nervous system stimulants; clinical research; dopamine; dopamine transporter; functional magnetic resonance imaging; genotype; human subject; impulsive behavior; methylphenidate; middle childhood (6-11); neuroanatomy; neuropathology; neuropharmacology; neurophysiology; patient oriented research; pharmacogenetics; phenotype; short term memory

DESCRIPTION (provided by applicant): The proposal aims to examine functional and structural neuropathology underlying deficits of executive control (indexed by inhibitory control, working memory, and attential set switching, in Attention Deficit Hyperactivity Disorder (ADHD) using whole-brain structural and functional magnetic resonance imaging (fMRI). It is hypothesized that prefontal-striatal-cerebellar circuitry underlying executive control is dysfunctional in ADHD due to abnormal dopaminergic function. We will test two predictions of this hypothesis - (1) fMRI will reveal that the functional activation in prefrontal-striatal-cerebellar regions during inhibitory control (Exp 2), working memory (Exp 3), and attentional set switching (Exp 4) will be abnormal in ADHD children (relative to control children) and will be normalized by the administration of methylphenidate in ADHD children. Sample for Experiments 2-4 will include 48 9-11 year old Combined type ADHD children (24 girls and 24 boys) and 48 age, gender, and IQ-matched healthy children. (2) Functional response to methylphenidate in prefrontal-striatal regions underlying inhibitory control in ADHD will be influenced by dopamine transporter genotype (DAT1) (Exp 1). Sample for Experiment 1 will include 36 Combined-type ADHD children (12 carriers of 480bp-10/10, 480bp-10/9, 440bp-9/9, each). These ADHD subjects were participants in an ongoing pharmacogenetic study at CNMC that found superior clinical efficacy of methylphenidate in carriers of 480bp than 440 bp. We have the unique opportunity to examine the functional brain response to methylphenidate during inhibitory control in those same ADHD children. In all experiments, fMRI will be performed on ADHD children with administration of methylphenidate and placebo; control children (in Experiments 2-4) will be imaged without methylphenidate. Further, high resolution structural imaging will be used to examine whether regions activated during fMRI differ in gray matter volume between ADHD subgroups and controls. Novel features of our proposal include: 1) examination of structural and functional brain differences in the same ADHD and control children and ii) examination of the functional brain response to methylphenidate in ADHD children in whom clinical efficacy of methylphenidate varied by DAT1 genotype. Examination of such genotype-phenotype relationships will elucidate potential etiological factors and neuropathophysiology of ADHD that will be useful in diagnosis, early intervention, and treatment planning.

描述（由申请人提供）：该提案旨在使用全脑结构和功能磁共振成像（fMRI）检查注意力缺陷多动障碍（ADHD）中执行控制缺陷的功能和结构神经病理学（以抑制控制、工作记忆和注意组转换为索引）。假设执行控制的前额叶-纹状体-小脑电路是 由于多巴胺能功能异常，ADHD 患者的功能障碍。我们将检验这一假设的两个预测 - (1) fMRI 将揭示 ADHD 儿童（相对于对照儿童）在抑制控制（实验 2）、工作记忆（实验 3）和注意力组转换（实验 4）期间前额叶-纹状体-小脑区域的功能激活将异常，并且将通过给药而正常化 哌醋甲酯治疗多动症儿童。实验2-4的样本将包括48名9-11岁混合型ADHD儿童（24名女孩和24名男孩）和48名年龄、性别和智商匹配的健康儿童。 (2) ADHD 抑制控制的前额叶-纹状体区域对哌醋甲酯的功能反应将受到多巴胺转运蛋白基因型 (DAT1) 的影响（实验 1）。 实验1的样本将包括36名组合型ADHD儿童（各12个480bp-10/10、480bp-10/9、440bp-9/9的携带者）。这些 ADHD 受试者是 CNMC 正在进行的一项药物遗传学研究的参与者，该研究发现哌醋甲酯在 480bp 携带者中的临床疗效优于 440bp 携带者。我们有独特的机会来检查 这些多动症儿童在抑制控制期间对哌醋甲酯的功能性大脑反应。在所有实验中，将对服用哌醋甲酯和安慰剂的 ADHD 儿童进行功能磁共振成像 (fMRI)；对照儿童（在实验 2-4 中）将在没有哌醋甲酯的情况下进行成像。此外，高分辨率结构成像将用于检查功能磁共振成像期间激活的区域在 ADHD 亚组和对照组之间的灰质体积是否存在差异。小说 我们提案的特点包括：1）检查同一 ADHD 儿童和对照儿童的大脑结构和功能差异；ii）检查 ADHD 儿童对哌甲酯的功能性大脑反应，其中哌甲酯的临床疗效因 DAT1 基因型而异。对这种基因型-表型关系的检查将阐明 ADHD 的潜在病因和神经病理生理学，这将有助于诊断、早期干预和治疗计划。