Integrating brain imaging and genetic analysis of ADHD

描述(由申请人提供)：该提案旨在利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)中潜在的执行控制缺陷(以抑制控制、工作记忆和注意集转换为索引)的功能和结构性神经病理。由于多巴胺能功能异常，推测ADHD患者执行控制的前额叶-纹状体-小脑回路功能障碍。我们将检验这一假设的两个预测-(1)fMRI将揭示ADHD儿童在抑制控制(Exp 2)、工作记忆(Exp 3)和注意设置转换(Exp 4)过程中的前额-纹状体-小脑区域的功能激活将异常(相对于对照儿童)，并将通过在ADHD儿童中应用哌醋甲酯而恢复正常。实验2-4的样本将包括48名9-11岁的混合型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患者前额-纹状体抑制控制区域对哌甲酯的功能反应将受多巴胺转运体基因(DAT1)的影响(实验1)。实验一的样本将包括36名混合型ADHD儿童(12名携带者，分别为480BP-10/10、480BP-10/9、440BP-9/9)。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，在480bp的携带者中，哌甲酸甲酯的临床疗效优于440bp。在这些ADHD儿童中，我们有独特的机会来检测在抑制控制过程中对哌醋甲酯的脑功能反应。在所有实验中，将对ADHD儿童进行功能磁共振成像，同时给予哌甲酸甲酯和安慰剂；对照组儿童(在实验2-4中)将不使用哌醋甲酯进行成像。此外，高分辨率结构成像将被用来检查在功能磁共振期间激活的区域在ADHD亚组和对照组之间的灰质体积是否不同。我们建议的新特征包括：1)检查相同ADHD儿童和对照组儿童的大脑结构和功能差异，以及ii)检查ADHD儿童对哌醋甲酯的功能反应，在ADHD儿童中，哌醋甲酯的临床疗效因DAT1基因而异。这种基因-表型关系的检测将阐明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。

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.