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: 7829212
• 负责人: Martin Reite
• 金额: $ 47.74万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7829212
• 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：生物标志物发现和验证以及具体挑战主题 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障碍（SAD）的生物标志物和生理内表型。精神分裂情感性障碍，很像自闭症，已经从一种罕见的现象——卡萨宁在其 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) 更常见的精神障碍。丹佛心理健康公司是丹佛-博尔德都会区心理健康服务的主要提供者，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 通常与精神分裂症 (SZ) 归为一类，但如果它实际上是一个独立的实体，如我们的初步数据所示，这可能是一个错误。我们相信，我们或许能够使用 MEG 记录来建立客观可靠的 SAD 生物标志物或内表型，并将其与 SZ 区分开来。如果 SAD 具有独立的内表型分组（我们怀疑可能是这种情况），那么将 SAD 和 SZ 患者合并在同一队列中只会造成混淆，并给这些严重精神障碍的病理生理学、治疗和结果的研究带来错误。受试者聆听 40Hz 幅度调制的 1Kz 音调突发的整个头部 MEG 记录，展示了称为稳态响应 (SSR) 的新皮质伽马带响应，其幅度和相位控制被认为可以估计调节赫施尔回听觉皮层第 3 层锥体细胞放电模式的 GABA 能中间神经元活动的功能状态。精神分裂症 (SZ) 患者的左右听觉皮层的伽玛带 SSR 反应均表现出显着的功能障碍，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，他们的左半球表现出与 SZ 相似的功能障碍，但在右半球表现出 MEG 伽玛带 SSR 反应的保留，其幅度和相位控制与正常对照 (NC) 没有什么不同。我们假设这种右半球听觉皮层功能活动的保留可能与 SAD 受试者中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、更多的情绪反应性（听觉情绪韵律）和更有利的结果。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 通道全头 MEG 与源空间投影方法以及使用基于小波的复数解调的相位和幅度分析方法相结合，可能能够提供必要的功能和结构精度，以允许建立组正常值，这将在个体患者的诊断中证明是有用的。本研究旨在使用全头 MEG 记录严格测试 3 个假设：1) SAD 受试者将表现出右半球伽马带 SSR 相位控制的相对保留，与 NC 没有显着差异，而 SZ 受试者将表现出与 NC 和 SAD 相比，右半球伽马带 SSR 相位控制显着减少，2) R 半球伽马带 SSR 反应将在正式听觉测试中表现出表现 情绪韵律将与 NC 中的类似，并且明显优于 SZ 受试者，3）SSR 伽马带幅度和相位控制将与磁共振波谱（MRS）估计的听觉皮层中的皮质内 GABA 浓度显着相关。拟议研究的结果将有助于将 SAD 作为一个独立实体置于 SZ 双相谱中，并产生基于行为和 MEG 的生理内表型，以将 SAD 与 SZ 分开。识别和个体化主要精神疾病的客观生物标志物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。 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来准确诊断这些疾病，这是寻找根本原因和开发合理治疗的主要限制。该提案旨在识别和分离分裂情感障碍的生理生物标志物，这种疾病与精神分裂症相混淆，但可能代表一种单独的独立疾病。将分裂情感性障碍与精神分裂症分开将极大地促进病理生理学的针对性研究以及对每种疾病治疗的更合理的研究。