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

项目概要/摘要 这是一份K23奖的申请，申请者是精神病学家和系统神经科学家迈克尔·墨菲博士。 在姆克林医院和哈佛医学院。该奖项的培训目标是 候选人（1）发展磁共振光谱（MRS）专业知识，包括整合MRS 与脑电图数据，（2）发展的专业知识，在症状评估使用心理测量 规模和深表型，（3）准备候选人的独立研究生涯。博士 墨菲提出了一个严格的教学课程，以及一个熟练的指导团队，包括博士。 Dost Ongur，姆克林医院精神疾病科科长，作为主要导师。 精神障碍（PD）是一种严重的精神疾病， 病理生理学我们对这些疾病的理解受到一种有问题的综合症的限制- 基于疾病分类学和我们的神经成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， 这可能会在其自身的时间尺度上改变。因此，专注于特定症状的研究， 比综合征可能更好地能够改善当前技术的局限性。精神分裂 被认为是一种连接障碍综合症，鉴于这一假设， 精神分裂症可能是由特定的连接障碍模式引起的。思维障碍（TD）是一种 是精神障碍中常见的症状，与预后不良有关。我提议 为了验证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-皮质环内的连接障碍。拟议 连接障碍可能会部分地将保持有意识意识的网络与那些 调节注意力。将使用定向功能连接测试不适当的PMC连接 它可以区分PMC的异常输入和输出，这种区分将是 在没有方向的措施中被掩盖。丘脑和PMC内神经回路的功能将被 使用MRS评估谷氨酸和GABA的水平。拟议中的项目将测试一部小说 连接神经化学、定向功能连接和精神病学的假说。这 该项目将可能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.