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

尽管有明确的科学依据和与公共健康的相关性，精神分裂症的异质性背后的机制 对(SZ)的了解很少。迫切需要确定导致异构性的机制，如 目前的治疗方法对大多数患者无效。异质性的一个来源是生物性别。我们的 中心假设是：(1)SZ的性别差异症状是由特定神经的性别差异引起的 网络，以及(2)这些性别差异是关键时期青春期影响的结果 青春期神经发育期。青少年大脑和认知发展研究(ABCD)， 一项跟踪11,875名9-10岁儿童进入成年早期的为期10年的纵向研究，是唯一能够检验 这个假说。为了回应这一FOA，我们建议使用ABCD基线和跟踪数据1-6年至 检验性和青春期对青少年发育的影响两种与性有关的神经网络 深圳的差异。我们将评估额叶-边缘情绪调节中基于任务的激活和连通性 用情绪N-Back和金钱激励延迟fMRI研究额叶-纹状体奖赏加工网络 任务数据。我们还将评估每个网络中的静态功能连接(RsFC)。我们会 在ABCD基线测试性别和青春期对每个网络的激活和连通性的影响(目标1)，AS 以及性别、青春期和每个网络的发展轨迹之间的联系(目标2)，以及 精神病、负价和正价系统症状的发展(目标3)从基线(9- 10岁)至6岁(15-16岁)。我们将追求以下具体目标：1.定性 青春期标志物在基线AS前额-边缘和额-纹状体网络上的差异和影响 由基于任务的功能磁共振成像和rsFC测量。我们假设青春期标志的可变性(发育， 激素)与额叶-边缘和额叶-纹状体网络的变异性有关，性别对此有调节作用 两性关系。2.性别和青春期标志物对额叶-边缘和青春期年龄相关性变化的影响 在基线、2年、4年和6年随访时，用基于任务的功能磁共振成像和rsFC测量额叶-纹状体网络 向上。我们假设青春期标志物中与年龄相关的变化中介了这些人的发育轨迹 网络和性行为缓和了这些关系。3.确定性别和/或青春期标志是否适中 每个网络在基线、2年、4年和6年内的激活和连接情况 精神病的发展和与负价系统和正价系统有关的症状1- 6.我们预测，随着时间的推移，性别和青春期标志将与额叶-边缘和额叶-纹状体网络共同变化 预测深圳地区随后的性别差异症状的发展。这项工作将决定性别和青春期 神经发育轨迹的修饰物，有助于SZ的出现，这是NIMH的一个主要优先事项。 结果将回答关于深圳异质性基础机制的关键问题，并将有 通过推进新的以性为基础的精准医学治疗，对公共健康产生重大影响。

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.