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: 10542415
• 负责人: Amanda E Guyer
• 金额: $ 39.08万
• 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/10542415
• 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; Libido; 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; Shapes; Site; Source; Symptoms; System; Testing; Time; Treatment Protocols; Work; adolescent brain development; age related; 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; psychotic; response; reward processing; schizophrenia spectrum disorder; sex; sexual dimorphism; societal costs; timeline; 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.

尽管具有明确的科学性和与公共卫生的相关性，但精神分裂症的异质性机制 （SZ）人们知之甚少。迫切需要确定导致异质性的机制： 目前的治疗对大多数患者来说是无效的。异质性的来源之一是生物性别。我们的 中心假设是：（1）SZ 的性别差异症状源于特定神经系统的性别差异。 网络，以及（2）这些性别差异是由于青春期关键时期的影响而出现的。 青春期神经发育时期。青少年大脑和认知发展研究（ABCD）， 一项为期 10 年的纵向研究，跟踪 11,875 名 9-10 岁儿童进入成年早期，具有独特的测试能力 这个假设。为了响应此 FOA，我们建议使用 ABCD 基线和 1-6 年的后续数据来 检查性别和青春期对与性相关的两个神经网络青少年发育的影响 SZ 的差异。我们将评估额叶边缘情绪调节中基于任务的激活和连接 和使用情绪 N-Back 和货币激励延迟 fMRI 的额叶纹状体奖励处理网络 分别是任务数据。我们还将评估每个网络中的静息状态功能连接（rsFC）。我们将 测试性别和青春期对 ABCD 基线上每个网络的激活和连接的影响（目标 1），如 以及每个网络的性别、青春期和发育轨迹之间的关联（目标 2），以及 从基线 (9- 10 岁）到 6 年级（15-16 岁）。我们将追求以下具体目标： 1. 描绘性别特征 基线时青春期标记对额叶边缘和额叶纹状体网络的差异和影响 通过基于任务的 fMRI 和 rsFC 进行测量。我们假设青春期标志物（发育、 激素）与额叶边缘和额叶纹状体网络的变异性有关，并且性别调节这些 关系。 2. 测试性别和青春期标记对额叶边缘和年龄相关变化的影响 通过基于任务的 fMRI 和 rsFC 在基线、2 年、4 年和 6 年随访时测量的额叶纹状体网络 向上。我们假设青春期标记物中与年龄相关的变化介导了这些特征的发育轨迹 网络和性别调节这些关系。 3. 确定性别和/或青春期标志物是否适度 每个网络在基线、2 年、4 年和 6 年随访时的激活和连接情况 1-1 年内出现精神病以及与负价和正价系统相关的症状 6. 我们预测性别和青春期标记将随着时间的推移与额叶边缘和额叶纹状体网络共变 预测 SZ 性别差异症状的后续发展。这项工作将决定性别和青春期 神经发育轨迹的修饰因素有助于 SZ 的出现，这是 NIMH 的一个主要优先事项。 结果将回答有关深圳异质性潜在机制的关键问题，并将具有 通过推进新的基于性别的精准医学治疗，对公共卫生产生重大影响。