EEG Biomarkers of Psychosis Risk and Adolescent Neurodevelopment

描述(由申请者提供)：随着越来越多的人认识到，一些以前被认为仅限于成年的精神疾病实际上在童年时显示出最初的迹象，并在青春期开始完全出现，NIMH在其战略计划中要求临床研究应“将健康发展的轨迹与精神障碍的轨迹进行比较，以便更好地理解当发展偏离轨道时的第一个或多个实例。”具体地说，这个目标涉及到需要“使用成像技术绘制精神障碍的轨迹图”，以及发现“早期发现精神障碍的风险因素”。与这些优先事项一致，目前的申请涉及一项计划，使申请者从一名成人精神病理学研究人员转变为一名发展认知神经科学家，具有研究青春期作为精神分裂症等精神障碍发展的敏感期的技能和专业知识。在咨询了一组临床和发展神经科学家，以及一名同时进行基础研究的发展心理学家和临床心理学家，以及一名在纵向工作方面具有专业知识的统计学家后，这份提案描述了一项为期一年的对三组青少年(12-17岁)的认知和神经连接的调查：被判断为精神分裂症临床高危人群(由于存在阈值以下症状)的求助患者，符合DSM-IV首发精神分裂症标准的患者，以及匹配的社区比较对象。在研究登记时，然后在12个月的随访中，所有参与者都将进行一系列实验性的认知测试，同时记录与事件相关的脑电数据。脑电能够为大规模神经回路中的同步活动提供时间敏感的测量。拟议的认知测试每个都招募了前额-后脑神经回路的不同子集。这些特殊的神经回路对于连接 前额叶皮质与更后方、更早成熟的皮质区域(如感觉和运动区)有关，是青春期大脑向稳定的成人功能过渡过程中一些最戏剧性发展和优化的场所。因此，这些神经回路在认知挑战下运作的效率应该提供基线功能障碍的证据，如果存在的话，在长达一年的研究中，这种效率的变化应该提供异常成熟的证据。事实上，精神分裂症的潜在风险被认为是这些功能连接的一个子集失调(例如，通过锥体神经元突触的选择性病理)；然而，这些疾病机制在什么时候出现明显的精神症状和典型青少年发育中的里程碑仍不清楚。总而言之，这些结果将为神经连接的完整性提供一个敏感的衡量标准，这些连接被认为是青少年神经发育和精神分裂症发病的底物。

DESCRIPTION (provided by applicant): With growing recognition that a number of psychiatric illnesses previously thought to be restricted to adulthood actually show their initial signs in childhood and begin to emerge fully during adolescence, NIMH mandated in its Strategic Plan that clinical research should, "compare trajectories of healthy development to those of mental disorders in order to better understand the first instance or instances, when development moves off course." Specifically, this objective involves the need to "map the trajectory of mental disorders using imaging technologies," and discovery of "early detection of risk factors for mental disorders." Consistent with these priorities, the current application involves a plan for th applicant to transform from an adult psychopathology researcher to a developmental cognitive neuroscientist with skills and expertise to study adolescence as a sensitive period in the development of psychotic disorders such as schizophrenia. Written in consultation with a team of clinical and developmental neuroscientists, as well as a developmental psychologist and clinical psychologist who both conduct basic research, and a statistician with expertise in longitudinal work, the proposal describes a one year-long investigation of cognition and neural connectivity in three groups of adolescents (ages 12-17 years) : help-seeking patients judged to be at clinical high-risk for developing schizophrenia (due to the presence of sub-threshold symptoms), patients who meet DSM-IV criteria for a first episode of schizophrenia, and matched community comparison subjects. At study enrollment and then again at 12 month follow-up, all participants will perform a set of experimental cognitive tests while event-related EEG data are recorded. EEG is capable of providing temporally-sensitive measures of synchronized activity in large-scale neural circuits. The proposed cognitive tests each recruit various subsets of prefrontal-posterior neural circuits. These particular neural circuits are critical for linking the prefrontal cortex to more posterior, earlier-maturing cortical regions (e.g., sensory and motor areas), and are the site of some of the most dramatic development and optimization that occurs in the brain during adolescence, as it transitions to stable, adult functioning. Therefore, the efficiency with which these neural circuits function under cognitive challenge should provide evidence of baseline dysfunction, and change in that efficiency over the year-long study should provide evidence of aberrant maturation if present. In fact, latent risk for developing schizophrenia is thought to dysregulate a subset of these functional connections (e.g., through selective pathology of pyramidal neurons synapses); however, exactly when these illness mechanisms arise with respect to the appearance of frank psychotic symptoms and with respect to landmarks in typical adolescent development remains unknown. Collectively, these results will provide a sensitive measure of the integrity of the neural connections that are thought to provide the substrate for both adolescent neurodevelopment and schizophrenia pathogenesis.