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：生物标记物的发现和验证，以及具体的挑战主题，03-MH-101“精神障碍中的生物标记物”。该提案旨在开发一种分裂情感障碍(SAD)的生物标志物和生理内表型。分裂情感障碍，就像自闭症一样，已经从一个罕见的-卡萨宁在他1933年的原始报告中描述了9个病例-变成了一种比精神分裂症(SZ)更常见的精神障碍-丹佛心理健康公司，丹佛-博尔德大都市地区的主要心理健康服务提供商-有813名患者被诊断为SAD，但截至目前只有748名患者被诊断为SZ。在研究中，SAD通常被归类为精神分裂症(SZ)，但如果像我们初步数据显示的那样，它实际上是一个独立的实体，这可能是一个错误。我们相信，我们可以利用脑磁图建立一个客观可靠的SAD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，正如我们怀疑的那样，将SAD和SZ患者合并在同一队列中只会混淆这些严重精神障碍的病理生理学、治疗和预后的研究，并引入错误。受试者听到以40赫兹调幅的1Kz音调时的全头脑磁图记录显示了一种被称为稳态反应(SSR)的新皮质伽马频段反应，其幅度和相位控制被认为是评估GABA能神经元间活动调节Heschl回听觉皮质中第三层锥体细胞的放电模式的功能状态。精神分裂症(SZ)患者在左侧和右侧听觉皮质的这一伽马频段SSR反应中表现出明显的功能障碍，被解释为神经元间抑制机制受损。然而，我们最近记录了一小部分被诊断为SAD的患者，他们在左半球表现出与SZ相似的功能损害，但在右半球表现出保留的MEG伽马频段SSR反应，幅度和相位控制与正常对照组(NC)没有区别。我们推测，这种右半球听觉皮质功能活动的保留可能与SAD患者所描述的表型特征有关，与SZ患者相比，SAD患者通常具有更好的病前功能、更多的情绪反应(听觉情绪韵律)和更有利的结果。归根结底，一个有效的生物标记物应该能够区分个别病例，而不仅仅是群体差异。相信248道全头脑磁图结合源空间投影和基于小波的复数解调的相位和幅度分析方法，可能能够提供所需的功能和结构精度，以允许建立在个体患者的诊断中被证明有用的组正常值。本研究旨在使用全头部脑磁图记录严格检验3个假设：1)SAD受试者将表现出右侧大脑半球伽马频段SSR的相对控制，与正常对照组没有显著差异，而SZ受试者将表现出显著低于正常对照组和SAD受试者的右半球SSR相位控制；2)R半球伽玛频段SSR反应将指标在听觉情绪韵律正式测试中的表现，这将与NC相似，但显著好于SZ受试者；3)根据磁共振波谱(MRS)估计，SSR伽玛频段的幅度和相位控制与听觉皮质内GABA浓度显著相关。建议的研究结果将有助于将SAD作为一个独立的实体放置在SZ-双极谱中，并导致基于行为和MEG的生理内表型来区分SAD和SZ。目的识别和个体化主要精神疾病的生物标志物将极大地促进未来有关病理生理学、诊断、治疗反应和结果的研究的优化设计。 公共卫生叙述：包括精神分裂症在内的主要精神障碍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记物准确诊断这些疾病，这是寻找潜在原因和开发合理治疗方法的主要限制。这项提议旨在识别和分离分裂情感障碍的生理生物标记物，分裂情感障碍是一种与精神分裂症混淆的疾病，但可能代表一种独立的疾病。分裂情感障碍和精神分裂症的分离将极大地促进病理生理学的靶向研究和更合理的治疗研究。

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.