Excitation-inhibition imbalance, posteromedial cortical dysconnectivity, and thought disorder in first-episode psychosis

项目概要/摘要 这是精神科医生和系统神经科学家 Michael Murphy 博士的 K23 奖项申请 在麦克莱恩医院和哈佛医学院。该奖项的培训目标是 候选人 (1) 发展磁共振波谱 (MRS) 方面的专业知识，包括集成 MRS 利用脑电图数据，(2) 发展使用心理测量学进行症状评估的专业知识 量表和深度表型分析，(3) 为候选人的独立研究生涯做好准备。博士。 墨菲提出了严格的教学课程以及包括博士在内的熟练指导团队。 麦克莱恩医院精神病科主任多斯特·翁古尔 (Dost Ongur) 担任主要导师。 精神障碍（PD）是一种严重的精神疾病，人们对其知之甚少。 病理生理学。我们对这些疾病的理解受到有问题的综合症的限制—— 基于疾病分类学以及我们的神经影像和遗传技术固有的技术限制。这些 疾病由多种症状组成，每种症状都可能由不同的神经病理学驱动，并且 这可能会根据自己的时间尺度发生变化。因此，研究重点关注特定症状而不是 比综合症可能更能改善当前技术的局限性。精神分裂症 已被认为是一种脱节综合症，鉴于这一假设，症状 精神分裂症可能是由特定的联系失调模式引起的。思维障碍（TD）是一种 精神障碍中常见的症状，与不良预后相关。我建议 检验 TD 是由丘脑和后内侧皮质功能障碍引起的假设 (PMC) 以及涉及 PMC 的皮质-丘脑-皮质环内的连接失调。拟议的 连接失调可能会部分地使维持意识的网络与那些维持意识的网络脱钩。 调节注意力。不适当的 PMC 连接将通过定向功能连接进行测试 它可以区分 PMC 的异常输入和输出，这种区别是 被无方向的措施所掩盖。丘脑和 PMC 内神经回路的功能将 使用 MRS 来评估谷氨酸和 GABA 的水平。拟议的项目将测试一种新颖的 将神经化学、定向功能连接和精神病症状学联系起来的假设。这个 该项目可能会提供一种治疗生物标志物，可用于评估非人类模型 精神障碍和测试治疗方案。

PROJECT SUMMARY/ABSTRACT This is an application for a K23 award for Dr. Michael Murphy, a psychiatrist and systems neuroscientist at McLean Hospital and Harvard Medical School. The training objectives for this award are for the candidate to (1) develop expertise in magnetic resonance spectroscopy (MRS) including integrating MRS with electroencephalography data, (2) develop expertise in symptom assessment using psychometric scales and deep-phenotyping, and (3) prepare the candidate for an independent research career. Dr. Murphy has proposed a rigorous didactic curriculum as well as a skilled mentoring team including Dr. Dost Ongur, Chief of the McLean Hospital Psychotic Disorders Division, as primary mentor. Psychotic disorders (PDs) are severe psychiatric illnesses with poorly understood pathophysiologies. Our understanding of these illnesses is limited both by a problematic syndrome- based nosology and the technical limitations inherent in our neuroimaging and genetic techniques. These disorders consist of multiple symptoms each of which may be driven by a distinct neural pathology and which may change on its own timescale. Therefore, research that focuses on specific symptoms rather than syndromes may be better able to ameliorate the limitations of current technology. Schizophrenia has been proposed to be a dysconnection syndrome and given this hypothesis the symptoms of schizophrenia may be caused by particular patterns of dysconnectivity. Thought disorder (TD) is a commonly encountered symptom in psychotic disorders and is associated with poor prognosis. I propose to test the hypothesis that TD arises from dysfunction within the thalamus and posteromedial cortex (PMC) as well as dysconnectivity within cortico-thalamo-cortico loops involving the PMC. The proposed dysconnectivity may partially decouple networks that maintain conscious awareness from those that regulate attention. Inappropriate PMC connectivity will be tested with directional functional connectivity which can distinguish between aberrant inputs to and outputs from the PMC, a distinction that would be obscured in directionless measures. Functioning of neural circuits within the thalamus and PMC will be assessed using MRS to assess levels of glutamate and GABA. The proposed project will test a novel hypothesis linking neurochemistry, directed functional connectivity, and psychiatric symptomology. This project will potentially provide a treatment biomarker which could be used to assess non-human models of psychotic disorders and test treatment options.