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

说明(申请人提供)：物质使用障碍(肥胖症；酒精和药物滥用和依赖)与多个功能领域的严重负面后果和严重损害有关，包括身体健康和死亡率、精神健康、心理社会功能和神经认知缺陷。肥胖症还与结构性和功能性大脑偏差有关。然而，现有的绝大多数研究主要是横断性的，这意味着这些联系的因果基础仍然不清楚：滥用物质似乎对大脑有神经毒性影响，但也有可能是，在使用物质之前的病前大脑偏差影响肥皂泡和相关损害的发展。拟议的职业发展奖的目的有两个：(1)培训候选人在儿科神经成像技术方面，包括磁共振成像(MRI)、扩散张量成像(DTI)和静息状态连通性MRI，以评估关键发育时期的大脑结构和功能；(2)利用这种培训来检查高风险和低风险幼儿的大脑结构，使用单卵(MZ)共生双胞胎对照研究设计的创新和强大的后代，以分离对发育中的大脑的遗传和环境影响。候选人将在一支在物质使用、脑开发、儿科神经成像和行为遗传学方面拥有广泛专业知识的杰出导师团队的指导下，接受发展为独立研究科学家所必需的培训(William Iacono博士、凯瑟琳·托马斯博士、Matt McGue博士和Irving Gottesman博士)。这项培训建立在候选人已经很强的科学背景的基础上，并将确保她处于良好的地位，能够开始独立的研究生涯，并对物质使用文献做出实质性贡献。这项研究将在明尼苏达州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，在几个基于人群的大型双胞胎队列中检查遗传和环境对物质使用的影响，这些队列从青春期前到中年进行前瞻性评估。在这些双胞胎的120名7至11岁的后代样本中，将解决两个具体目标：(1)检查高风险和低风险的SODS子女的大脑结构，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出先前存在的物质滥用倾向，或者相反，反映了子女暴露在与受SUDS影响的父母相关的养育环境中。拟议项目的结果极有可能进一步了解肥胖症的病因和后果，进而指导所需的预防和干预努力，以减少药物滥用对公众健康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.