Development of Thalamocortical Circuits and Cognitive Function in Healthy Individuals and Youth At-Risk for Psychosis

项目概述：连接皮层和丘脑的大脑网络对认知、感觉和运动至关重要 功能丘脑皮质网络的破裂与脑缺血的病理生理学有关。 神经发育障碍，包括精神病，和临床表型的机制，特别是 认知障碍这一观点得到了神经影像学的支持，包括Co-PI的一系列研究， 这些研究一致发现丘脑与前额叶皮层（PFC）的连接减少， 精神分裂症和双相情感障碍中的感觉运动-丘脑超连通性虽然取得了重大进展， 尽管已经取得了进展，但在正常的发展轨道方面仍然存在严重的知识差距， 丘脑皮质网络与精神病连接障碍的发生;认知功能与神经功能的关系 由丘脑皮层回路和丘脑皮层连接生物标志物支持的功能;和临床效用 丘脑皮层网络的成像。几个大规模的横截面数据集的可用性， 多模态神经成像数据和广泛的健康和高危个体的表型数据， 这是一个前所未有的机会，可以弥补这些关键的知识差距。其中包括剑桥中心 老龄化和神经科学（Cam-CAN：n=656，年龄18-88）; Nathan Kline研究所-罗克兰样本（NKI- RS：n=932，年龄6-85）;儿科成像、神经认知和遗传学数据集（PING：N=1239，年龄3-20）; 费城神经发育队列（PNC：n=1601，年龄8-21），包括精神病谱（PS） 北美前驱期纵向研究（NAPLS：n=397）。基于我们之前在 临床人群和利用这些数据集的大量资源，我们建议绘制 健康受试者（目标1）和PS症状青年（目标2）的丘脑皮质网络发育， 描述丘脑皮质生物标志物与认知之间的关联（目标3），并研究 丘脑皮质连接性生物标志物在识别个体非典型脑发育中的临床应用 跨精神病连续体的受试者和预测临床高危个体转化为精神病的受试者 (Aim 4）。拟议的目标将：1）建立关键的规范性寿命开发数据， 不仅测试精神病的病因模型，还测试其他神经发育障碍以及衰老的病因模型， 相关疾病; 2）告知精神病性障碍的病理生理学，并有助于 精神病; 3）帮助定义执行认知能力的神经基础，从而提供必要的 精神病中正常认知功能和认知障碍的机制模型的基础;以及4） 潜在地为处于发展精神障碍风险中的青年提供风险生物标志物和干预目标。

Project Summary: Brain networks linking the cortex to thalamus are critical for cognitive, sensory, and motor functioning. Dysruption of thalamocortical networks has been implicated in the pathophysiology of neurodevelopmental disorders, including psychosis, and mechanisms of clinical phenotypes, especially cognitive impairment. This view is supported by neuroimaging, including a series of studies by the Co-PIs, which consistently find a combination of reduced thalamic connectivity with the prefrontal cortex (PFC) and sensorimotor-thalamic hyper-connectivity in schizophrenia and bipolar disorder. While significant progress has been made, critical knowledge gaps remain with respect to the normal developmental trajectory of thalamocortical networks and onset of connectivity disturbances in psychosis; relationship between cognitive functions supported by thalamocortical circuits and thalamocortical connectivity biomarkers; and clinical utility of imaging thalamocortical networks. The availability of several large-scale cross-sectional datasets containing multi-modal neuroimaging data and extensive phenotypic data on healthy and at-risk individuals has created an unprecedented opportunity to address these critical knowledge gaps. They include the Cambridge Center for Ageing and Neuroscience (Cam-CAN: n=656, ages 18-88); Nathan Kline Institute-Rockland Sample (NKI- RS: n=932, ages 6-85); Pediatric Imaging, Neurocognition, and Genetics dataset (PING: N=1239, ages 3-20); Philadelphia Neurodevelopmental Cohort (PNC: n=1601, ages 8-21), which includes psychosis spectrum (PS) youth; and the North American Prodromal Longitudinal Study (NAPLS: n=397). Building on our prior work in clinical populations and leveraging the considerable resources of these datasets, we propose to chart the development of thalamocortical networks in healthy subjects (Aim 1) and youth with PS symptoms (Aim 2), characterize the associations between thalamocortical biomarkers and cognition (Aim 3), and investigate the clinical utility of thalamocortical connectivity biomarkers at identifying atypical brain development in individual subjects across the psychosis continuum and predicting conversion to psychosis in clinical high risk individuals (Aim 4). The proposed Aims will: 1) establish critical normative lifespan development data for refining and testing etiological models of not just psychosis, but other neurodevelopmental disorders, as well as aging- related disorders; 2) inform the pathophysiology of psychotic disorders and contribute to dimensional models of psychosis; 3) help define the neural basis of executive cognitive abilities thereby providing the necessary foundation for mechanistic models of normal cognitive function and cognitive impairment in psychosis; and 4) potentially provide risk biomarkers and intervention targets for youth at risk for developing a psychotic disorder.