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（由申请人提供）：拟议研究的总体目标是通过发育和遗传研究设计的整合来阐明青少年药物使用和滥用的病因学机制，先前的研究极大地增进了我们对青少年大脑发育和神经基础的理解。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加速发展加上认知控制区域的相对不成熟使青少年容易出现冲动行为和药物滥用。功能磁共振成像（fMRI）研究依赖于小样本和横断面设计，排除了对“成熟异步”假设的直接检验。此外，横断面相关研究无法描述物质滥用和滥用的现有决定因素。其对大脑的影响的另一个重大缺陷是缺乏对奖励相关行为和抑制控制的神经系统的功能磁共振成像遗传性研究，从而妨碍了对成瘾风险的内表型标记的识别和验证。病因之间的相互作用 成瘾的途径及其在青少年发展过程中的动态变化需要整合遗传和发育研究，但到目前为止，这种方法仅使用脑功能的电生理学标记（EEG、ERP）来实施，这些标记对青少年潜在的神经功能解剖学提供的了解有限。为了解决这些问题，我们建议对青少年的大样本（n = 320）进行纵向（13 至 18 岁）研究。 MZ 和 DZ 双胞胎涉及对大脑和行为进行多层次、跨学科、理论驱动的评估，所提出的综合方法利用了独特的招募资源（全州双胞胎登记处）、一流的成像方法以及我们之前的成功。招募大量青少年双胞胎样本进行基于实验室的纵向研究，将追求以下具体目标：1）检查与成瘾病理生理学有关的两个大脑网络的发育轨迹：奖励网络。 (RN) 和整个青春期的认知控制网络 (CCN)，并确定物质使用是否会干扰正常的大脑发育；2) 估计整个青春期 RN 和 CCN 功能的 fMRI 标记的遗传力以及遗传影响对 RN 和 CCN 的重叠。 CCN 的发展；3) 确定 RN 和 CCN 功能的物质遗传个体差异及其相对成熟率是否能够前瞻性地预测冲动、滥用和更广泛的外在问题。大大增进我们对青少年药物滥用和共病精神病理学的决定因素和后果的理解。