Genetic and Time-Frequency Aspects of Neural Phenotypes in Schizophrenia

精神分裂症神经表型的遗传和时频方面

• 批准号: 8392950
• 负责人: Scott R Sponheim
• 金额: --
• 依托单位: MINNEAPOLIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392950
• 关键词: Accounting; Affect; Age; Alleles; Area; Binding Proteins; Biological; Biological Neural Networks; Bipolar Disorder; Brain; Brain Pathology; Brain region; COMT gene; Candidate Disease Gene; Characteristics; Clinical; Control Groups; Data; Detection; Diagnosis; Diagnosis-Related Groups; Diagnostic; Diagnostic Specificity; Disease; Distant; Dorsal; Elements; Exhibits; Family; Family history of; First Degree Relative; Frequencies; Functional disorder; Funding; Future; Gene Frequency; Genes; Genetic; Genetic Counseling; Genetic Determinism; Genetic Markers; Genetic Polymorphism; Genetic Predisposition to Disease; Glutamates; Haplotypes; Health; Incidence; Individual; Intervention; Lateral; Measures; Medical center; Military Personnel; Minor; NRG1 gene; Nature; Noise; Occipital lobe; Patients; Perceptual Closure; Pharmaceutical Preparations; Phase; Phenotype; Prefrontal Cortex; Process; Psychotic Disorders; Relative (related person); Research; Research Personnel; Research Priority; Risk; Role; Schizophrenia; Sensory; Services; Signal Transduction; Single Nucleotide Polymorphism; Specificity; Stimulus; Stream; Structure; Susceptibility Gene; Testing; Therapeutic Intervention; Time; Variant; Veterans; Visual; Work; base; clinical care; cost; design; dystrobrevin; endophenotype; falls; frontal lobe; gene replacement therapy; genetic variant; improved; indexing; male; neuromechanism; object perception; object recognition; performance tests; programs; relating to nervous system; response; visual object processing; visual process; visual processing; visual stimulus

DESCRIPTION (provided by applicant): Candidate genes for schizophrenia appear to be associated with the function and structure of specific brain regions. Promising advances regarding the genetic determinants of schizophrenia have raised questions about whether the identified associations between genes and brain abnormalities are diagnostically specific to schizophrenia, and whether the brain pathology of the disorder is poorly described in terms of responses of individual brain regions. To understand how genes predispose the brain to schizophrenia, it is necessary to determine a) what aspects of genetic susceptibility are associated with abnormal brain responses, b) whether associations between candidate genes and brain responses are specific to schizophrenia, and c) whether the neural basis for schizophrenia is effectively understood in terms of the functional interactions of brain regions. Anomalous processing of visual stimuli is one of several promising markers of genetic liability for schizophrenia. Researchers have recently suggested that a deficit in visual integration may result in poor perceptual closure and the problems with object recognition noted in the disorder. Similar abnormalities have been documented in biological relatives of schizophrenia patients, particularly when object perception is made difficult through brief presentation of stimuli or addition of visual noise. Several studies have revealed electroencephalographic (EEG) abnormalities in schizophrenia patients and their biological relatives during object perception. Also, dynamic measures of neural activity appear to have utility in separating schizophrenia from other brain conditions and describing aberrant neural network structures in the disorder. Nevertheless, investigators have yet to clearly identify specific abnormalities in brain function that underlie object perception deficits and reflect the genetic variants that predispose the disorder. The previous periods of Merit Review funding were in part used to gather EEG data during perception of objects in visual noise from over 400 individuals from families affected by schizophrenia or bipolar disorder, and individuals with no family history of these disorders. Time-domain analyses of the EEG data revealed early sensory-level abnormalities over occipital cortex in schizophrenia patients and their relatives. Analysis of the timing and frequency composition of activity over frontal cortex revealed early responses that may modulate visual sensory functions, and late low-frequency abnormalities in schizophrenia patients and their relatives that were associated with a candidate gene related to dopamanergic function in the prefrontal cortex. The proposed studies will examine schizophrenia and bipolar patients, first-degree biological relatives of these patient groups, and control subjects to determine the time-frequency and phase characteristics of brain responses during object perception. The family-based design includes two diagnostic groups and first- degree relatives to test key measures for diagnostic specificity and as markers of genetic liability. We will: 1. Determine time, frequency, and phase characteristics of EEG abnormalities evident during errant object perception in schizophrenia. 2. Determine whether abnormal time-frequency elements and phase synchrony of EEG responses during object perception conform to endophenotype criteria by contrasting data from schizophrenia patients and their relatives with data from control subjects, bipolar disorder patients, and relatives of bipolar disorder patients. 3. Determine whether the abnormal time-frequency elements and phase synchrony of EEG responses during object perception are associated with specific candidate genes for schizophrenia. Our overarching hypothesis is that specific genes for schizophrenia are expressed in abnormal brain function detectable in the time-frequency elements of EEG recorded during the processing of visual objects. We posit that trial-based time-frequency analysis of EEG signals provides a sensitive and dynamic characterization of functional brain abnormalities that mark genetic liability for schizophrenia.

描述（由申请人提供）： 精神分裂症的候选基因似乎与特定大脑区域的功能和结构有关。关于精神分裂症的遗传决定因素的有希望的进展提出了一些问题，即基因和大脑异常之间的关联是否在诊断上特异于精神分裂症，以及该疾病的大脑病理学是否在单个大脑区域的反应方面描述得很差。为了了解基因是如何使大脑易患精神分裂症的，有必要确定a）遗传易感性的哪些方面与异常的大脑反应有关，B）候选基因与大脑反应之间的关联是否是精神分裂症特有的，以及c）精神分裂症的神经基础是否可以从大脑区域的功能相互作用方面有效地理解。 视觉刺激的异常处理是精神分裂症遗传易感性的几个有希望的标志之一。研究人员最近提出，视觉整合的缺陷可能会导致感知闭合不良和障碍中注意到的物体识别问题。在精神分裂症患者的生物学亲属中也有类似的异常记录，特别是当物体感知因短暂的刺激或视觉噪音而变得困难时。一些研究揭示了精神分裂症患者及其生物亲属在物体感知过程中的脑电图（EEG）异常。此外，神经活动的动态测量似乎在将精神分裂症与其他大脑疾病区分开来以及描述这种疾病中异常的神经网络结构方面具有实用性。尽管如此，研究人员还没有清楚地确定大脑功能的特定异常，这些异常是物体感知缺陷的基础，并反映了易患这种疾病的遗传变异。 之前的Merit Review资助部分用于收集来自精神分裂症或双相情感障碍家庭的400多名个人在视觉噪声中感知物体时的EEG数据，以及没有这些疾病家族史的个人。脑电图数据的时域分析揭示了精神分裂症患者及其亲属枕叶皮层的早期感觉水平异常。对额叶皮层活动的时间和频率组成的分析显示，早期反应可能调节视觉感觉功能，精神分裂症患者及其亲属的晚期低频异常与前额叶皮层多巴胺能功能相关的候选基因有关。 拟议的研究将检查精神分裂症和双相情感障碍患者，这些患者群体的一级生物学亲属，并控制受试者，以确定对象感知过程中大脑反应的时频和相位特征。以家系为基础的设计包括两个诊断组和一级亲属，以测试诊断特异性的关键措施，并作为遗传易感性的标志物。我们将：1.确定精神分裂症患者错误物体感知过程中明显的EEG异常的时间、频率和相位特征。2.通过对比精神分裂症患者及其亲属与对照组、双相情感障碍患者及其亲属的数据，确定物体感知过程中EEG反应的异常时频成分和相位同步性是否符合内表型标准。3.确定物体感知过程中EEG反应的异常时频成分和相位同步性是否与精神分裂症的特定候选基因相关。 我们的总体假设是，精神分裂症的特定基因表达在异常的脑功能中，在视觉对象的处理过程中记录的EEG的时间-频率元素中可以检测到。我们认为，基于试验的EEG信号的时频分析提供了一个敏感的和动态的表征功能性脑异常，标志着精神分裂症的遗传易感性。