Brain Deviation Preceding Substance Use: An Offspring of Co-Twin Control Study

描述（由申请人提供）：物质使用障碍（SUDs；酒精和药物滥用和依赖）与多种功能领域的重大负面结果和重大损害相关，包括身体健康和死亡率、精神健康、社会心理功能和神经认知缺陷。sud还与大脑结构和功能偏差有关。然而，绝大多数现有研究的主要横截面性质意味着这些关联的因果基础仍然不清楚：药物滥用似乎对大脑有神经毒性作用，但在药物使用之前的发病前大脑偏差也可能影响sud和相关损害的发展。拟议的职业发展奖的目的有两个：(1)培训候选人在儿童神经影像学技术，包括磁共振成像（MRI），弥散张量成像（DTI）和静息状态连接MRI，以评估关键发育时期的大脑结构和功能；(2)使用创新且强大的单卵（MZ）同卵双生子对照研究设计，利用这一培训来检查高风险和低风险幼儿的大脑结构，以解决遗传和环境对发育中的大脑的影响。候选人将在一个在药物使用、大脑发育、儿童神经成像和行为遗传学方面具有广泛专业知识的优秀导师团队的指导下，接受必要的培训，使其成为一名独立的研究科学家。威廉·艾科诺，凯瑟琳·托马斯，马特·麦格，欧文·戈特斯曼)。该培训建立在候选人已经具备的强大的科学背景之上，并将确保她能够很好地开展独立的研究生涯，并为物质使用文献做出实质性贡献。这项研究将在明尼苏达双胞胎和家庭研究中心（MCTFR）进行，该中心提供了无与伦比的机会，可以应用遗传信息研究设计来检查遗传和环境对几个大型双胞胎群体中物质使用的影响，从青春期前到中年进行前瞻性评估。在这些双胞胎的120个7至11岁的后代样本中，将解决两个具体目标：(1)检查sud高风险和低风险后代的大脑结构，目的是确定与风险相关的发病前大脑偏差；(2)确定大脑偏差是否反映了先前存在的药物滥用责任，还是反映了后代所处的养育环境与父母是否患有sud有关。拟议项目的结果极有可能进一步了解sud的病因和后果，并反过来指导所需的预防和干预工作，以减少药物滥用对公共卫生和个人的巨大负面影响。

DESCRIPTION (provided by applicant): Substance use disorders (SUDs; alcohol and drug abuse and dependence) are associated with substantial negative outcomes and significant impairment in multiple domains of functioning, including physical health and mortality, psychiatric health, psychosocial functioning, and neurocognitive deficits. SUDs are also associated with structural and functional brain deviations. However, the primarily cross-sectional nature of the vast majority of existing research means that the causal basis of these associations remains unclear: substance misuse appears to have neurotoxic effects on the brain, but it is also plausible that premorbid brain deviations that precede substance use influence the development of both SUDs and related impairment. The aims of the proposed career development award are twofold: (1) to train the candidate in pediatric neuroimaging techniques, including magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and resting state connectivity MRI, for assessing brain structure and functioning during key developmental periods; and (2) to use this training to examine brain structure in young children at high and low risk for the development of problematic substance use using an innovative and powerful offspring of monozygotic (MZ) co- twin control study design that disentangles genetic and environmental effects on the developing brain. The candidate will receive training essential for her development as an independent research scientist under the guidance of an outstanding team of mentors with extensive expertise in substance use, brain development, pediatric neuroimaging, and behavioral genetics (Drs. William Iacono, Kathleen Thomas, Matt McGue, Irving Gottesman). This training builds upon the candidate's already strong scientific background and will ensure that she is well situated to launch an independent research career and make substantive contributions to the substance use literature. The research will be conducted at the Minnesota Center for Twin and Family Research (MCTFR), which offers unparalleled opportunities for applying genetically informative study designs to examine genetic and environmental influences on substance use in several large, population-based cohorts of twins, prospectively assessed from preadolescence into middle age. Two specific aims will be addressed in a sample of 120 7- to 11-year-old offspring of these twins: (1) examine brain structure in offspring at high and low risk for SUDs with the aim of identifying premorbid brain deviations associated with risk; and (2) determine whether brain deviations reflect preexisting liability for substance misuse or instead reflect offspring exposure to a rearing environment associated with having a SUDs-affected parent. Results of the proposed project have great potential to further understanding of the etiology and consequences of SUDs, and, in turn, guide needed prevention and intervention efforts to reduce the tremendous negative public health and personal implications of substance misuse.