Parsing the schizophrenia-bipolar spectrum: an MEG based schizoaffective endophen

描述（由申请人提供）：本申请涉及广泛的挑战领域03：生物标志物发现和验证以及特定的挑战主题03-MH-101“精神疾病中的生物标志物。“该提案旨在为情感障碍（SAD）开发生物标志物和生理内表型。分裂情感性障碍，很像自闭症，已经从一种罕见的-卡萨宁在他1933年的原始报告中描述了9例-变成了一种比精神分裂症（SZ）更常见的精神病性障碍-丹佛精神健康公司，丹佛-博尔德大都市地区精神健康服务的主要提供者-有813名患者诊断为SAD，但到目前为止只有748人被诊断为SZ。在研究中，SAD通常与精神分裂症（SZ）分组，但如果它实际上是一个独立的实体，正如我们的初步数据所表明的那样，这可能是一个错误。我们相信，我们可能能够使用MEG记录来建立SAD的客观可靠的生物标志物或内表型，并将其与SZ区分开来。如果SAD有一个独立的内表型分组，我们怀疑可能是这种情况下，合并SAD和SZ患者在同一队列中只能混淆和引入错误的病理生理学，治疗和这些严重的精神疾病的结果的研究。受试者听40 Hz调幅的1 Kz音调的爆发的全头部MEG记录显示了被称为稳态响应（SSR）的新皮层伽马带响应，其幅度和相位控制被认为估计GABA能中间神经元活动的功能状态，所述GABA能中间神经元活动调节Heschl's gyrus的听觉皮层中的第3层锥体细胞的放电模式。精神分裂症（SZ）患者表现出显着的功能障碍，在这伽玛波段SSR反应在左侧和右侧的听觉皮层，被解释为受损的神经元间抑制机制。然而，我们最近记录了一小群诊断为SAD的患者，他们在左半球表现出与SZ相似的功能障碍，但在右半球保留了MEG γ波段SSR反应，振幅和相位控制与正常对照（NC）没有差异。我们假设，这种保留右半球听觉皮层功能活动可能与SAD受试者中描述的表型特征有关，SAD受试者通常具有更好的病前功能，更多的情感反应（听觉情感韵律），以及与SZ受试者相比更有利的结果。最终，有效的生物标志物应该能够区分个体病例，而不仅仅是群体差异。我们相信，248导全脑脑磁图结合源空间投影和基于小波的复解调的相位和振幅分析方法，可能能够提供必要的功能和结构准确性，以允许建立群体正常值，这将证明对个体患者的诊断有用。本研究旨在使用全头部MEG记录来严格检验3个假设：1）SAD受试者将表现出右半球伽马带SSR的相位控制的相对保留，与NC中的相位控制没有显著差异，而SZ受试者将表现出与NC和SAD相比显著降低的右半球SSR相位控制，2）R半球γ波段SSR反应将在听觉情感韵律的正式测试上指示表现，其将与NC中的表现相似并且显著优于SZ受试者，3）SSR γ波振幅和相位控制与磁共振波谱（MRS）估计的听皮层内GABA浓度显著相关。拟议研究的结果将有助于将SAD作为SZ-双极谱内的独立实体放置，并产生基于行为和MEG的生理内表型，以将SAD与SZ分开。客观的生物标志物识别和个性化的主要精神疾病将大大有助于优化设计未来的研究有关的病理生理学，诊断，治疗反应和结果。 公共卫生叙述：包括精神分裂症在内的主要精神疾病是美国医疗保健费用的主要组成部分之一。我们无法根据客观可靠的生理生物标志物准确诊断这些疾病，这是寻找根本原因和开发合理治疗方法的主要限制。这项提议旨在鉴定和分离情感障碍的生理生物标志物，情感障碍是一种与精神分裂症混淆的疾病，但可能代表一种单独的独立疾病。将情感障碍与精神分裂症分开将极大地促进有针对性的病理生理学研究和对每种疾病治疗的更合理的研究。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area 03: Biomarker Discovery and Validation and specific Challenge Topic, 03-MH-101 "Biomarkers in mental disorders." The proposal is designed to develop a biomarker and physiological endophenotype for schizoaffective disorder (SAD). Schizoaffective disorder, much like autism, has gone from a rarity - Kasanin described but 9 cases in his original 1933 report - to a psychotic disorder more common than schizophrenia (SZ) - the Mental Health Corp of Denver, the primary provider of mental health services to the Denver- Boulder metropolitan region - has 813 patients with a SAD diagnosis, but only 748 with a SZ diagnosis as of this date. SAD is usually grouped with schizophrenia (SZ) in research studies, but if it is in fact an independent entity as our preliminary data suggests, this may be an error. We believe we may be able to use MEG recordings to establish an objective and reliable biomarker, or endophenotype, for SAD, and to differentiate it from SZ. If SAD has an independent endophenotypic grouping, as we suspect may be the case, combining SAD and SZ patients in the same cohort can only confuse and introduce error into studies of pathophysiology, treatment, and outcome of these serious psychotic disorders. Whole head MEG recordings of subjects listening to bursts of 1Kz tones amplitude modulated at 40Hz, demonstrate a neocortical gamma band response termed the Steady State Response (SSR), whose amplitude and phase control is thought to estimate functional status of GABAergic interneuronal activity regulating firing patterns of layer 3 pyramidal cells in auditory cortex of Heschl's gyrus. Schizophrenic (SZ) patients demonstrate a significant functional impairment in this gamma band SSR response in both left and right auditory cortex, interpreted as impaired interneuronal inhibitory mechanisms. We have recently however recorded a small cohort of patients with a diagnosis of SAD who exhibit functional impairments in the left hemisphere similar to that found in SZ, but demonstrate preservation of the MEG gamma band SSR response in the right hemisphere, with amplitude and phase control no different from normal controls (NC). We hypothesize that this preservation of right hemisphere auditory cortex functional activity may relate to phenotypic characteristics that have been described in SAD subjects, who often have better premorbid function, more emotional responsivity (auditory emotional prosody), and more favorable outcome compared to SZ subjects. Ultimately an effective biomarker should be capable of distinguishing individual cases, not just group differences. e believe that 248 channel whole head MEG in combination with the methods of source space projection and phase and amplitude analysis using wavelet based complex demodulation may be able to provide the functional and structural accuracy necessary to permit establishment of group normal values that will prove useful in the diagnosis of individual patients. This study is designed to use whole head MEG recordings to rigorously test 3 hypotheses: 1) SAD subjects will demonstrate relative preservation of phase control of right hemisphere gamma band SSR, not significantly different from that in NC, whereas SZ subjects will demonstrate significantly reduced right hemisphere SSR phase control compared to NC and SAD, 2) R hemisphere gamma band SSR response will index performance on a formal test of auditory emotional prosody which will be similar to that in NC and significantly better than in subjects with SZ, 3) SSR gamma band amplitude and phase control will be significantly correlated with intra- cortical GABA concentration in auditory cortex as estimated by magnetic resonance spectroscopy (MRS). The outcome of the proposed research will facilitate placement of SAD as an independent entity within the SZ- bipolar spectrum, and result in a behavioral and MEG based physiological endophenotype to separate SAD from SZ. Objective biomarkers identifying and individuating the major mental illness will greatly facilitate optimal design of future studies relating to pathophysiology, diagnosis, treatment response, and outcome. PUBLIC HEALTH NARRATIVE: The major mental disorders including schizophrenia represent one of the major components of health care costs in the United States. Our inabilities to accurately diagnose these disorders based on objective and reliable physiological biomarkers that separate one from another is a major limitation to finding underlying causes and develop rational treatments. This proposal is designed to identify and isolate a physiological biomarker for schizoaffective disorder, a disorder confused with schizophrenia, but which may represent a separate independent disorder. Separation of schizoaffective disorder from schizophrenia will greatly facilitate targeted research in pathophysiology and more rational studies of treatment of each.