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

解析精神分裂症-双相情感谱：基于 MEG 的分裂情感内啡肽

• 批准号: 7937802
• 负责人: Martin Reite
• 金额: $ 47.85万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937802
• 关键词: Address; Affective; Area; Auditory; Auditory area; Autistic Disorder; Behavioral; Biological Markers; Biological Preservation; Bipolar Disorder; Characteristics; Complex; Data; Diagnosis; Diagnostic; Disease; Emotional; Exhibits; Functional disorder; Future; Goals; Grouping; Head; Health Care Costs; Individual; Left; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mental Health; Mental Health Services; Mental disorders; Methods; Metric; Neocortex; Normal Range; Outcome; Patients; Pattern; Performance; Phase; Physiologic pulse; Physiological; Provider; Psychotic Disorders; Public Health; Pyramidal Cells; Relative (related person); Reporting; Research; Schizoaffective Disorders; Schizophrenia; Source; Stimulus; System; Targeted Research; Testing; Treatment outcome; United States; Validation; base; cohort; design; endophenotype; functional disability; functional status; gamma-Aminobutyric Acid; improved; indexing; metropolitan; neocortical; research study; response; treatment response

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.

描述（由申请人提供）：本申请涉及广泛的挑战领域03：生物标志物的发现和验证，以及特定的挑战主题03- mh -101“精神障碍中的生物标志物”。该提案旨在开发分裂情感性障碍（SAD）的生物标志物和生理内表型。精神分裂情感障碍，就像自闭症一样，已经从罕见——卡萨宁在他1933年的原始报告中只描述了9例——变成了一种比精神分裂症更常见的精神障碍（SZ）——丹佛精神健康公司，丹佛-博尔德大都市区精神健康服务的主要提供者，有813名患者被诊断为SAD，但到目前为止只有748名患者被诊断为SZ。在研究中，SAD通常与精神分裂症（SZ）归为一类，但如果它实际上像我们的初步数据所显示的那样是一个独立的实体，这可能是一个错误。我们相信我们可以使用MEG记录建立一个客观可靠的生物标志物，或内表型，用于SAD，并将其与SZ区分开来。如果SAD有一个独立的内表型分组，正如我们所怀疑的那样，将SAD和SZ患者合并在同一队列中只会使这些严重精神障碍的病理生理、治疗和结果的研究混淆和引入错误。实验对象在聆听40Hz振幅调制的1Kz音调爆发时的全头部脑磁图记录显示了一种被称为稳态响应（SSR）的新皮质伽马带反应，其振幅和相位控制被认为可以估计调节Heschl’s回听觉皮层第3层锥体细胞放电模式的gaba能神经元间活动的功能状态。精神分裂症（SZ）患者在左右听觉皮层的伽马波段SSR反应中表现出明显的功能障碍，这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群被诊断为SAD的患者，他们在左半球表现出与SZ相似的功能障碍，但在右半球表现出MEG γ波段SSR反应的保存，其振幅和相位控制与正常对照（NC）没有区别。我们假设这种右半球听觉皮层功能活动的保存可能与SAD受试者所描述的表型特征有关，与SZ受试者相比，SAD受试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。最终，一种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通道全头部脑磁图结合源空间投影和基于小波复杂解调的相位和幅度分析方法，可能能够提供必要的功能和结构准确性，以允许建立组正常值，这将证明对个体患者的诊断有用。本研究旨在使用全头部脑磁图记录来严格检验3个假设：(1) SAD被试表现出右半球γ带SSR相位控制的相对保存，与NC无显著差异，而SZ被试表现出右半球SSR相位控制较NC和SAD显著降低。(2)R半球γ带SSR反应在听觉情绪韵律正式测试中的表现与NC相似，显著优于SZ被试。3)磁共振波谱分析结果表明，SSR γ带振幅和相位控制与听觉皮层内GABA浓度显著相关。拟议的研究结果将有助于将SAD作为一个独立的实体置于SZ-双相谱系中，并导致基于行为和MEG的生理内表型将SAD与SZ分开。客观的生物标志物识别和个性化主要精神疾病将极大地促进与病理生理学、诊断、治疗反应和结果相关的未来研究的优化设计。