Frontoparietal Network Integrity and Risk for Psychosis

描述(由申请人提供)：这是一份申请K23奖项的申请书，授予贾斯汀·贝克博士，他是麦克莱恩医院和哈佛医学院的精神病学家和神经学家。贝克博士在以病人为导向的临床研究中确立了自己作为年轻研究员的地位 精神分裂症和双相情感障碍。这一K23奖项将为贝克博士提供必要的支持，以实现以下目标：(1)成为以患者为导向的精神病临床研究方面的专家；(2)对精神病早期患者的神经生物学相关性进行调查；(3)在临床研究中实施先进的遗传方法；以及(4)发展独立的临床研究事业。为了实现这些目标，贝克博士组建了一个由两位主要导师组成的指导团队：马萨诸塞州总医院(MGH)精神病学遗传学主任Jordan Smoller博士(负责精神分裂症和双相情感障碍的遗传学研究)和Dost Ongur博士(McLean医院精神障碍科主任Dost Ongur博士，领导一个研究精神病生物学的神经成像实验室)。顾问包括麻省理工学院精神病学神经成像主任兰迪·巴克纳博士，他是一位提供先进神经成像专业知识的神经科学家，拉里·塞德曼博士，一位在精神分裂症和双相情感障碍早期阶段拥有专业知识的心理学家，以及本·尼尔博士，一位统计学和统计遗传学专家，特别是精神遗传学领域的专家。精神障碍，包括精神分裂症(SZ)和伴有精神病的双相情感障碍(BPP)是可遗传的疾病，但对遗传变异可能引起的大脑结构和功能变化并进而带来临床风险知之甚少。贝克博士的研究将集中在精神健康的年轻成人人群中伴随着SZ和BPP遗传风险增加的神经系统变化(目标1)，以及伴随SZ和BPP早期阶段的神经系统变化(目标2)。在目标1中，贝克博士将通过利用现有的来自精神健康个体的大量成像遗传学样本(&gt；1800)，建立从精神病学遗传学联合会获得的SZ和BPP的多基因风险因素对大脑结构和功能的影响。此外，他将根据健康志愿者脑功能的变化创建一种新的多基因风险评分，并在交叉诊断的患者样本中测试该评分是否会影响临床结果。在目标2中，贝克博士将分析精神病早期的两个脑部核磁共振数据集：一个是从北美前驱症状纵向研究的精神病前驱患者那里获得的现有结构和功能核磁共振扫描样本；另一个是贝克博士将利用麦克莱恩精神障碍部门的临床服务，进行一项横断面先导性研究，以产生关于新诊断的精神病对大脑结构和功能影响的初步数据。这项研究将为高危和新诊断的精神分裂症和双相情感障碍的风险预测建模研究奠定基础，该研究将在K奖结束前提出的R01拨款申请中提出。

DESCRIPTION (provided by applicant): This is an application for a K23 award for Dr. Justin Baker, a psychiatrist and neuroscientist at McLean Hospital and the Harvard Medical School. Dr. Baker is establishing himself as a young investigator in patient- oriented clinical research of schizophrenia and bipolar disorder. This K23 award will provide Dr. Baker with the support necessary to accomplish the following goals: (1) to become expert at patient-oriented clinical research in psychotic disorders; (2) to conduct investigations of neurobiological correlates in patients in early stages of psychotic illness; (3) to implement advanced genetic methods in clinical studies; and (4) to develop an independent clinical research career. To achieve these goals, Dr. Baker has assembled a mentoring team comprised of two primary mentors, Dr. Jordan Smoller, Director of Psychiatric Genetics at Massachusetts General Hospital (MGH), who conducts genetic investigations in schizophrenia and bipolar disorder, and Dr. Dost Ongur, Chief of the McLean Hospital Psychotic Disorders Division who leads a neuroimaging laboratory studying the biology of psychotic illness. Consultants include Dr. Randy Buckner, Director of Psychiatric Neuroimaging at MGH, a neuroscientist who contributes advanced neuroimaging expertise, Larry Seidman, a psychologist with expertise in the early phases of schizophrenia and bipolar disorder, and Dr. Ben Neale, an expert in statistics and statistical genetics, particularly in the field of psychiatric genetics. Psychotic disorders, including schizophrenia (SZ and bipolar disorder with psychosis (BPP) are heritable conditions, and yet little is known about changes to brain structure and function that may arise from genetic variation and in turn confer clinical risk. Dr. Baker's research will focus on the neural system changes that accompany elevated genetic risk for SZ and BPP in a psychiatrically healthy young adult population (Aim 1) and the neural system changes that accompany early stages of SZ and BPP (Aim 2). In Aim 1, Dr. Baker will establish the effects of polygenic risk factors for SZ and BPP, obtained from the Psychiatric Genetics Consortium, on brain structure and function, by leveraging a large existing imaging-genetics sample (>1800) from psychiatrically healthy individuals. In addition, he will create a novel polygenic risk score based on variation in brain function in healthy volunteers and test whether this score informs clinical outcomes in a cross-diagnostic patient sample. In Aim 2, Dr. Baker will analyze two data sets of brain MRI from early stages of psychosis: one from an existing sample of structural and functional MRI scans obtained from patients prodromal for psychosis from the North American Prodrome Longitudinal Study; for the second, Dr. Baker will conduct a cross-sectional pilot study to generate preliminary data on the effects of newly diagnosed psychosis on brain structure and function, leveraging the clinical services of the McLean Psychotic Disorders Division. This research will form the basis for a study of risk prediction modeling in high risk and newly diagnosed schizophrenia and bipolar disorder, to be proposed in an R01 grant application before the end of the K award.