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

 描述(由申请人提供)：拟议研究的总体目标是通过整合发育和基因研究设计来阐明青少年药物使用和滥用的病因机制。以前的研究大大提高了我们对青少年大脑发育和冲动和冒险行为的神经基础的理解。一个有影响力的神经发育模型假设，与奖励相关的大脑区域的加速发展，加上认知控制区的相对不成熟，使青少年容易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断面设计，排除了对“成熟不同步”假说的直接测试。此外，横断面相关研究无法描述物质滥用及其对大脑的影响的先前存在的决定因素。知识上的另一个重大差距是缺乏对奖励相关行为和抑制控制背后的神经系统的fMRI遗传性研究，排除了对成瘾风险的内表型标记的识别和验证。更好地理解致病因素之间的相互作用 成瘾的途径及其在青少年发展过程中的动态变化需要遗传和发育研究的整合，但到目前为止，这种方法只使用大脑功能的电生理标记物(EEG、ERP)来实现，这些标记物对奖励处理和认知控制的潜在功能神经解剖学提供了有限的见解。这些知识上的差距为进一步了解成瘾障碍的病因造成了关键障碍。为了解决这些问题，我们建议对MZ和DZ双胞胎的大样本(n=320)进行纵向(13至18岁)研究，包括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募资源(全州范围的双胞胎登记)、一流的成像方法，以及我们之前成功地招募了大量青春期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)检测与成瘾的病理生理学有关的两个大脑网络：青春期的奖赏网络(RN)和认知控制网络(CCN)的发育轨迹，并确定物质使用是否干扰正常的大脑发育；2)估计RN和CCN功能的功能磁共振标志物在整个青春期的遗传度，以及在整个发育过程中对RN和CCN的遗传影响的重叠；3)确定RN和CCN功能的可遗传个体差异及其相对成熟率是否可预测冲动、物质滥用和更广泛的外化问题。这些目标的实现将极大地促进我们对青少年滥用药物和共病精神病理学的决定因素和后果的理解。

 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.