Brain Structural Variations as Potential Endophenotypes for Psychopathic Traits

描述(申请人提供)：精神病是一种临床症状，影响大约2%的普通人口和约25%的罪犯，反映出正常社会交往和道德的失败。尽管越来越多的证据表明成年精神病患者的大脑结构异常，但青少年中缺乏精神病态特征的神经成像发现，阻碍了对这种复杂人格特征的病因学的进一步了解。应聘者的直接职业目标是发展结构脑成像和定量基因分析方面的专业知识，以确定哪些大脑形态特征是精神病态特征的候选内表型。了解与青少年精神病态特征有关的大脑形态变异的遗传贡献将为严格检查精神病态特征的遗传易感性奠定必要的基础，并使应聘者的长期职业目标成为可能，即利用神经成像表型和多元方法开发独立的大型项目，以调查从儿童到成年的精神变态和相关疾病的遗传贡献。为此，我们从一个更大的纵向双胞胎项目中收集了80对青少年双胞胎的现有神经成像、临床和行为数据，我们建议：1)使用几种复杂的神经成像分析方法，应用于结构磁共振成像(SMRI)和扩散张量成像(DTI)数据来表征结构脑表型，并检查它们与精神病态特征的关系(使用儿童精神病态量表和反社会过程筛查设备)；2)使用结构方程模型来估计遗传和非遗传因素对形态变异的相对贡献；以及3)从R00阶段更大的双胞胎项目中收集另外160对青少年双胞胎的新的成像和临床数据，以确定形态变异和精神病态特征之间的遗传重叠。候选人的正式培训将利用加州大学洛杉矶分校和南加州大学丰富的遗传专业知识和神经成像资源，将包括八个教学课程、两个强化研讨会和每周定期研讨会，旨在增强候选人在图像分析方法方面的先前经验，培养行为基因分析和儿童精神病方面的新知识，并促进开展独立纵向双胞胎项目的技能。此外，候选人将接受为学术进步做准备的培训，以促进顺利过渡到拟议的R00阶段研究的终身教职和全职助理教授职位。 公共卫生相关性：儿童和青少年的精神病态特征与几种成人精神障碍有关，但对青少年精神病态特征的神经基础知之甚少。通过确定心理病态特征的结构相关性，并利用青少年双胞胎样本检验形态特征的遗传力，我们可以确定心理病态特征的候选内表型。因此，这项拟议的研究具有确定精神病的病因学相关前兆的巨大潜力，这反过来将对开发新的假说、治疗和预防性干预至关重要。

DESCRIPTION (provided by applicant): Psychopathy is a clinical condition that affects approximately 2% of the general population, and ~25% of criminal offenders, and reflects a failure in normal social interaction and morality. Despite increasing evidence showing brain structural abnormalities in adult psychopaths, the lack of neuroimaging findings for psychopathic traits among adolescents has prevented further understanding in the etiology of such complex personality traits. The candidate's immediate career goal is to develop expertise in structural brain imaging and quantitative genetic analysis in order to identify which brain morphological characteristics pose as candidate endophenotypes for psychopathic traits. Understanding the genetic contributions of brain morphological variations in relation to psychopathic traits in adolescents will build the necessary foundation for a rigorous examination of the genetic predispositions to psychopathic traits and make possible the candidate's long-term career goal of developing independent large-scale projects using neuroimaging phenotypes and multivariate methods to investigate the genetic contributions of psychopathy and related disorders from childhood through adulthood. Towards this end, using the existing neuroimaging, clinical, and behavioral data of 80 adolescent twins collected from a larger longitudinal twin project, we propose to; 1) use several sophisticated neuroimaging analysis methods applied to structural magnetic resonance imaging (sMRI) and diffusion tensor imaging (DTI) data to characterize structural brain phenotypes and examine their association with psychopathic traits (identified using the Childhood Psychopathy Scale and the Antisocial Process Screening Device); 2) use structural equation modeling to estimate the relative contributions of genetic and non-genetic factors toward morphological variations; and to 3) collect new imaging and clinical data on an additional 160 adolescent twins from the larger twin project in the R00 phase to determine the genetic overlap between morphological variations and psychopathic traits. The candidate's formal training will take advantage of the rich genetic expertise and neuroimaging resources at UCLA and USC and will include eight didactic courses, two intensive workshops and regular weekly seminars designed to augment the candidate's prior experience in image analysis methods, foster new knowledge in behavioral genetic analysis and child psychopathy, and promote skills for conducting an independent longitudinal twin project. Additionally, the candidate will receive training for the preparation for academic advancement to enhance a smooth transitioning into a tenure-track, full-time assistant professorship for the proposed R00 phase research. PUBLIC HEALTH RELEVANCE: Psychopathic traits in children and adolescents have been linked to several adult psychiatric disorders, however extremely little is known regarding the neural basis of psychopathic traits in adolescents. By identifying structural correlates of psychopathic traits and examining the heritability for morphological characteristics using an adolescent twin sample, we can determine the candidate endophenotypes for psychopathic traits. This proposed study thus has great potential for identifying etiologically relevant precursors of psychopathy, which in turn would be crucial for developing new hypothesis, treatments, and preventative interventions.