Integrating brain imaging and genetic analysis of ADHD

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（通过抑制控制、工作记忆和注意力集中转换索引）。据推测，前额叶-纹状体-小脑回路的执行控制功能障碍的ADHD由于异常的多巴胺能功能。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（实验2）、工作记忆（实验3）和注意定势转换（实验4）过程中的前额叶-纹状体-小脑区域的功能激活将异常（相对于对照儿童），并将通过哌甲酯治疗而正常化。实验2-4的样品将包括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)多巴胺转运蛋白基因型（DAT 1）会影响ADHD患者前额叶-纹状体区对哌甲酯的功能反应（实验1）。实验1的样本包括36名混合型ADHD儿童（480 bp-10/10、480 bp-10/9、440 bp-9/9各12名携带者）。这些ADHD受试者是CNMC正在进行的药物遗传学研究的参与者，该研究发现哌甲酯在480 bp携带者中的临床疗效上级440 bp携带者。我们有独特的机会来检查这些ADHD儿童在抑制控制期间对哌甲酯的功能性大脑反应。在所有实验中，将对给予哌甲酯和安慰剂的ADHD儿童进行fMRI;对照儿童（实验2-4中）将在没有哌甲酯的情况下成像。此外，高分辨率的结构成像将被用来检查是否在ADHD亚组和对照组之间的灰质体积在功能磁共振成像过程中激活的区域不同。我们的建议的新功能包括：1）在相同的ADHD和对照儿童的结构和功能的大脑差异的检查和ii）在ADHD儿童的哌甲酯的临床疗效不同的DAT 1基因型哌甲酯的功能性大脑反应的检查。这种基因型-表型关系的检查将阐明ADHD的潜在病因学因素和神经病理生理学，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.