GENETICS, THE ADOLESCENT BRAIN, AND ADDICTION LIABILITY: A LONGITUDINAL TWIN STUDY

遗传学、青少年大脑和成瘾倾向：纵向双胞胎研究

• 批准号: 9030505
• 负责人: Andrey P. Anokhin
• 金额: $ 63.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-15 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9030505
• 关键词: Achievement; Address; Adolescence; Adolescent; Adolescent Development; Age; Alcohol or Other Drugs use; Behavior; Brain; Brain imaging; Brain region; Corpus striatum structure; Data; Development; Developmental Course; Electroencephalography; Electrophysiology (science); Environment; Etiology; Exposure to; Functional Magnetic Resonance Imaging; Functional disorder; Genetic; Genetic Research; Genetic Risk; Goals; Growth; Heritability; Image; Impulsive Behavior; Impulsivity; Individual; Individual Differences; Influentials; Knowledge; Laboratories; Longitudinal Studies; Mediating; Methods; Modeling; Neuroanatomy; Neurocognitive; Pathway interactions; Pattern; Population Growth; Preventive Intervention; Psychopathology; Recruitment Activity; Registries; Research; Research Design; Resolution; Resources; Rewards; Risk; Risk Marker; Risk-Taking; Role; Sampling; Substance abuse problem; Substance of Abuse; Symptoms; System; Testing; Twin Multiple Birth; Twin Studies; Validation; addiction; adolescent brain development; adolescent substance use; base; behavior test; brain behavior; brain pathway; cognitive control; cognitive function; design; developmental genetics; follow-up; imaging biomarker; imaging modality; insight; longitudinal design; neurodevelopment; notch protein; public health relevance; relating to nervous system; resilience; reward processing; substance misuse; success; theories

 DESCRIPTION (provided by applicant): The overall goal of the proposed study is to elucidate etiological mechanisms of adolescent substance use and abuse through the integration of developmental and genetic research designs. Previous studies have substantially advanced our understanding of adolescent brain development and the neural basis for impulsive and risk-taking behaviors. An influential neurodevelopmental model posits that accelerated development of reward-related brain regions combined with relative immaturity of the cognitive control regions predisposes adolescents to impulsive behavior and substance abuse. However, the majority of functional magnetic resonance imaging (fMRI) studies have relied on small samples and cross-sectional designs, precluding a direct test of the "maturational asynchrony" hypothesis. Furthermore, cross-sectional correlational studies are unable to delineate pre-existing determinants of substance misuse and its consequences for the brain. Another significant gap in knowledge is the lack of fMRI heritability studies of neural systems underlying reward-related behaviors and inhibitory control, precluding the identification and validation of endophenotypic markers of risk for addictions. A better understanding of the interplay between etiological factors and pathways to addiction and their dynamic changes across adolescent development requires an integration of genetic and developmental research, but so far this approach has been implemented only using electrophysiological markers of brain function (EEG, ERP) that provide limited insight into the underlying functional neuroanatomy of reward processing and cognitive control. These gaps in knowledge create critical barriers to further progress in understanding the etiology of addictive disorders. To address them, we propose a longitudinal (age 13 to 18) study of a large sample (n=320) of adolescent MZ and DZ twins involving multilevel, interdisciplinary, theory- driven assessments of the brain and behavior. The proposed integrative approach capitalizes on the availability of a unique recruitment resource (state-wide twin registry), top-notch imaging methods, and our prior success of recruiting a large sample of adolescent twins into a laboratory-based longitudinal study. The following Specific Aims will be pursued: 1) To examine developmental trajectories of two brain networks implicated in pathophysiology of addiction: the reward network (RN) and the cognitive control network (CCN) across adolescence, and to determine whether substance use interferes with normal brain development; 2) To estimate the heritability of fMRI markers of RN and CCN functioning throughout adolescence and overlap of genetic influences on RN and CCN across development; 3) To determine whether heritable individual differences in RN and CCN functioning and their relative maturation rates prospectively predict impulsivity, substance misuse, and a broader spectrum of externalizing problems. The achievement of these aims will substantially advance our understanding of the determinants and consequences of adolescent substance misuse and comorbid psychopathology.

 描述（由适用提供）：拟议的研究的总体目标是通过整合发展性和遗传研究设计来阐明青少年物质使用和滥用的病因机制。先前的研究大大提高了我们对青少年脑发育的理解以及冲动和冒险行为的神经元基础。一个有影响力的神经发育模型认为，与奖励相关的大脑区域的发展加速了认知控制区域的相对不成熟，使青少年倾向于冲动行为和药物滥用。然而，大多数功能磁共振成像（fMRI）研究依赖于小样本和横截面设计，从而排除了“成熟异步”假设的直接检验。此外，横截面相关研究无法描绘出滥用物质及其对大脑的后果的预先确定剂。知识的另一个重要差距是缺乏对奖励相关行为和抑制性控制的神经系统的fMRI遗传力研究，从而排除了成瘾风险的内生植物型标记的鉴定和验证。更好地理解病因学因素之间的相互作用 和成瘾的途径及其在青少年发展中的动态变化需要综合遗传和发展研究，但到目前为止，这种方法仅使用大脑功能的电生理标记（EEG，ERP）实施，该方法对奖励处理和认知控制的潜在功能性神经植物学提供了有限的见解。知识中的这些差距为进一步的进步造成了关键的障碍，以理解加性疾病的病因。为了解决这些问题，我们提出了一项纵向研究（13至18岁）的研究（n = 320）的青少年MZ和DZ双胞胎，涉及对大脑和行为的多层次，跨学科，理论驱动的评估。拟议的综合方法利用了独特的招聘资源（全州双胞胎注册表），一流的成像方法以及我们先前将大量青少年双胞胎样本招募到基于实验室的纵向研究中的成功。将追求以下具体目标：1）检查成瘾病理生理学中实施的两个大脑网络的发育轨迹：奖励网络（RN）和认知控制网络（CCN）跨青少年，并确定是否与正常脑发育的底物使用干扰底物的使用； 2）估计RN和CCN的fMRI标志物在整个青少年的整个过程中起作用以及对RN和CCN跨发育的遗传影响的重叠； 3）确定RN和CCN功能的遗传个体差异是否可以预测地预测冲动性，物质滥用和更广泛的外部化问题。这些目标的实现将大大提高我们对青少年物质滥用和合并心理病理学的决定者和后果的理解。