Sex and pubertal influences on developmental trajectories of brain networks involved in schizophrenia

性别和青春期对精神分裂症大脑网络发育轨迹的影响

• 批准号: 10181545
• 负责人: Laura Magdalen Tully
• 金额: $ 40.37万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10181545
• 关键词: 10 year old; 16 year old; Address; Adolescence; Adolescent; Adolescent Development; Affect; Age; Anhedonia; Anxiety; Back; Brain; Child; Child Behavior; Clinical; Corpus striatum structure; Data; Delusions; Development; Diagnostic; Dimensions; Emotional; Exhibits; Female; Functional Magnetic Resonance Imaging; Gonadal Steroid Hormones; Grant; Hallucinations; Heterogeneity; Hormones; Interview; Literature; Longitudinal Studies; Measures; Mediating; Mental Depression; Mission; Moods; National Institute of Mental Health; Negative Valence; Outcome; Patients; Population; Positive Valence; Psychopathology; Psychoses; Puberty; Public Health; Questionnaires; Research; Research Domain Criteria; Rest; Schizophrenia; Sex Differences; Source; Symptoms; System; Testing; Time; TimeLine; Treatment Protocols; Work; adolescent brain development; age related; anxiety symptoms; base; biological sex; cognitive development; disability; effective therapy; emerging adult; emotion regulation; financial incentive; follow-up; ineffective therapies; innovation; lens; male; negative mood; network dysfunction; neural network; neurobehavioral; neurodevelopment; precision medicine; response; reward processing; schizophrenia-spectrum disorder; sex; sexual dimorphism; societal costs; treatment response

Despite clear scientific and relevance to public health, the mechanisms underlying heterogeneity in schizophrenia (SZ) are poorly understood. There is a critical need to identify mechanisms that contribute to heterogeneity as current treatments are ineffective for the majority of patients. One source of heterogeneity is biological sex. Our central hypothesis is that: (1) sex-differential symptoms in SZ arise from sex differences in specific neural networks, and (2) these sex differences emerge as a consequence of pubertal influences during the critical neurodevelopmental period of adolescence. The Adolescent Brain and Cognitive Development study (ABCD), a 10-year longitudinal study following 11,875 9-10-year-olds into early adulthood, is uniquely capable of testing this hypothesis. In response to this FOA, we propose to use ABCD baseline and follow up data years 1-6 to examine sex and pubertal influences on adolescent development of two neural networks associated with sex differences in SZ. We will assess task-based activation and connectivity in the frontal-limbic emotion regulation and frontal-striatal reward processing networks using Emotional N-Back and Monetary Incentive Delay fMRI task data respectively. We will also assess resting state functional connectivity (rsFC) in each network. We will test sex and pubertal influences on activation and connectivity in each network at ABCD baseline (Aim 1), as well as associations between sex, puberty, and developmental trajectories of each network (Aim 2), and the development of psychosis, negative valence, and positive valence system symptoms (Aim 3) from baseline (9- 10 years old) to Year 6 (15-16 years old). We will pursue the following Specific Aims: 1. Characterize sex differences and effects of puberty markers on frontal-limbic and frontal-striatal networks at baseline as measured by task-based fMRI and rsFC. We hypothesize variability in puberty markers (development, hormones) relates to variability in frontal-limbic and frontal-striatal networks and that sex moderates these relationships. 2. Test effects of sex and puberty markers on age-related changes in frontal-limbic and frontal-striatal networks as measured by task-based fMRI and rsFC at baseline, 2-, 4-, and 6-year follow up. We hypothesize age-related changes in puberty markers mediate developmental trajectories of these networks and that sex moderates these relationships. 3. Determine if sex and/or puberty markers moderate activation and connectivity of each network at baseline, 2-, 4-, and 6-year follow up in relation to development of psychosis and symptoms related to negative and positive valence systems in years 1- 6. We predict sex and puberty markers will covary with frontal-limbic and frontal-striatal networks over time to predict subsequent development of sex-differential symptoms in SZ. This work will determine sex and pubertal modifiers of neurodevelopmental trajectories that contribute to the emergence of SZ, a major NIMH priority. Results will answer critical questions about mechanisms underlying heterogeneity in SZ and will have a substantial public health impact by advancing new sex-based precision medicine treatments.

尽管科学明确并且与公共卫生相关，但精神分裂症的异质性的基本机制 （SZ）知之甚少。迫切需要确定有助于异质性的机制 目前的治疗对大多数患者无效。异质性的一种来源是生物学性别。我们的 中心假设是：（1）SZ中的性别差异症状是由特定神经的性别差异引起的 网络，（2）由于临界期间青春期影响而出现了这些性别差异 青春期神经发育期。青少年的大脑和认知发展研究（ABCD）， 11,875个9-10岁的成年早期，一项为期10年的纵向研究，具有独特的测试 这个假设。为了响应此FOA，我们建议使用ABCD基线，然后跟踪数据年1-6 检查性别和青春期影响与性别相关的两个神经网络的青少年发展 SZ的差异。我们将评估基于任务的激活和额叶情绪调节中的连通性 使用情绪N-BACK和货币激励延迟fIMRI和额叶纹状体奖励处理网络 任务数据分别。我们还将评估每个网络中的静止状态功能连接（RSFC）。我们将 测试性别和青春期对ABCD基线每个网络激活和连通性的影响（AIM 1），AS 以及每个网络的性别，青春期和发展轨迹之间的关联（AIM 2）和 基线的精神病，负价和正价系统症状的发展（目标3）（9-- 10岁）至6年（15-16岁）。我们将追求以下具体目标：1。描述性 青春期标记对基线时额叶和额叶网络的差异和影响 通过基于任务的fMRI和RSFC衡量。我们假设青春期标记的变异性（开发， 激素）与额叶和额叶网络的变异性有关，性别适度 关系。 2。性别和青春期标记对额叶和年龄相关的变化的测试影响和 基线，2年，4和6年的额叶网络通过基于任务的fMRI和RSFC衡量 向上。我们假设青春期标记中与年龄相关的变化介导了这些的发展轨迹 网络和性别缓和了这些关系。 3。确定性别和/或青春期标记是否适中 每个网络在基线，2年，4和6年的随访中的激活和连通性 在1-年内的精神病和症状的发展以及与负和正价系统有关的症状 6。我们预测，随着时间的推移，性别和青春期标记将与额叶和额叶网络相关 预测SZ中性别差异症状的随后发展。这项工作将决定性和青春期 神经发育轨迹的修饰符有助于SZ的出现，这是一个主要的NIMH优先级。 结果将回答有关SZ中异质性基本机制的关键问题，并将具有 通过推进新的基于性别的精密医学治疗，实质性的公共卫生影响。