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遗传研究设计来阐明青少年物质使用和滥用的病因学机制。以前的研究大大提高了我们对青少年大脑发育以及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认为，与奖励相关的大脑区域的加速发育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。然而，大多数功能性磁共振成像（fMRI）研究都依赖于小样本和横断面设计，排除了直接测试的“成熟性痴呆”的假设。此外，横断面相关性研究无法描绘预先存在的物质滥用的决定因素及其对大脑的影响。另一个重要的知识缺口是缺乏奖励相关行为和抑制控制的神经系统的fMRI遗传性研究，排除了成瘾风险的内表型标记的识别和验证。更好地理解病因因素之间的相互作用 成瘾的途径及其在青少年发展中的动态变化需要整合遗传和发展研究，但到目前为止，这种方法仅使用脑功能的电生理标志物（EEG，ERP）来实现，这些标志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。这些知识上的差距对进一步了解成瘾性疾病的病因造成了严重的障碍。为了解决这些问题，我们提出了一个纵向（年龄13至18岁）的大样本（n=320）的青少年MZ和DZ双胞胎的研究，涉及多层次，跨学科，理论驱动的大脑和行为的评估。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，以及我们之前成功招募了大量青少年双胞胎样本进入实验室纵向研究的可用性。具体目标如下：1）研究成瘾病理生理学中涉及的两个脑网络：奖赏网络（RN）和认知控制网络（CCN）在青春期的发展轨迹，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fMRI标记物在整个青春期的遗传力以及RN和CCN在整个发育过程中的遗传影响的重叠; 3）确定RN和CCN功能的遗传个体差异及其相对成熟率是否前瞻性地预测冲动，物质滥用和更广泛的外化问题。这些目标的实现将大大推进我们对青少年物质滥用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.