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: 7931507
• 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/7931507
• 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. PUBLIC HEALTH RELEVANCE: The VA has consistently identified schizophrenia as an area of high priority research. Because the typical age of military service falls in the age range during which the incidence of schizophrenia peaks in males, it is likely that the disorder will continue to be prevalent among veterans. The total cost to VHA for patients with psychoses in fiscal year 2002 was 2.95 billion dollars and consumed 16% of the VHA's total VERA allocation. In recent years psychoses accounted for more discharges from VA medical centers than any other diagnosis- related group (VARRAC, 1997). Therefore understanding the causes of schizophrenia is of relevance to veterans' health. Identifying the role of susceptibility genes will benefit clinical care for veterans by a) improving diagnosis and risk prediction for genetic counseling in schizophrenia, b) understanding pathophysiological mechanisms so new medications and other therapeutic interventions can be developed, and c) in the distant future, implementing preventative interventions such as gene-replacement therapy.

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步提出了有关基因与脑异常之间确定的关联是否在诊断上是对精神分裂症的特异性的问题，以及该疾病的脑病理学是否在单个大脑区域的反应方面差异很差。要了解基因如何使大脑易于精神分裂症，有必要确定a）遗传易感性的哪些方面与异常大脑反应有关，b）候选基因和大脑反应之间的关联是否特定于精神分裂症，c）精神分裂症的神经基础是否有效地了解了功能相互作用的区域。 视觉刺激的异常处理是精神分裂症的遗传责任的几个有希望的标志之一。研究人员最近提出，视觉整合的赤字可能导致感知闭合不良，并且在该疾病中指出的对象识别问题。精神分裂症患者的生物学亲戚已经记录了类似的异常，尤其是在短暂呈现刺激或添加视觉噪声的情况下使对象感知变得困难时。几项研究表明，在物体感知期间，精神分裂症患者及其生物亲戚的脑电图（EEG）异常。同样，神经活动的动态度量似乎具有将精神分裂症与其他大脑条件分开并描述疾病中异常神经网络结构的实用性。然而，研究人员尚未清楚地确​​定脑功能的特定异常，这些异常是对象感知缺陷的基础，并反映了易感疾病的遗传变异。 以前的优秀审查资金部分用于收集脑电图数据，这是在感知来自400多个受到精神分裂症或双相情感障碍的家庭的视觉噪声中的物体中的脑电图数据，以及没有这些疾病家族史的人。对脑电图数据的时间域分析揭示了精神分裂症患者及其亲属的枕叶皮质的早期感觉水平异常。对额叶皮质上活性的时间和频率组成的分析表明，早期反应可能调节视觉感觉功能，而精神分裂症患者及其亲属的晚期低频异常，与候选基因相关的候选基因与额叶皮质中的多巴马疗法有关。 拟议的研究将检查精神分裂症和双极患者，这些患者群体的一级生物学亲戚，并控制受试者，以确定对象感知期间脑反应的时间频率和相位特征。基于家庭的设计包括两个诊断组和一级亲戚，用于测试诊断特异性的关键措施和作为遗传责任的标志。我们将：1。确定精神分裂症错误对物体感知期间明显的脑电图异常的时间，频率和相特征。 2。确定物体感知期间脑电图反应的异常时间频率和相位同步是否符合与精神分裂症患者及其亲戚的数据与对照组受试者，双相情感障碍患者的数据相比，符合内型型标准，以及双极疾病患者的亲戚。 3.确定对象感知期间脑电图反应的异常时间频率和相位同步是否与精神分裂症的特定候选基因有关。 我们的总体假设是，精神分裂症的特定基因在可检测到在视觉对象处理过程中记录的脑电图元素中可检测到的异常脑功能。我们认为，基于试验的脑电图信号的时频分析为标志着精神分裂症的遗传责任的功能性脑异常提供了敏感而动态的表征。 公共卫生相关性： VA一直将精神分裂症识别为高优先研究的领域。由于典型的兵役年龄属于男性精神分裂症峰值的年龄范围，因此这种疾病很可能会继续在退伍军人中普遍存在。 2002财政年度，精神病患者的VHA总成本为29.5亿美元，消耗了VHA总分配的16％。近年来，精神病占VA医疗中心的排放量要比任何其他诊断相关组都要多（Varrac，1997）。因此，了解精神分裂症的原因与退伍军人的健康有关。通过a）改善精神分裂症遗传咨询的诊断和风险预测，识别易感性基因的作用将使退伍军人受益，b）了解病理生理机制，因此可以开发新的药物和其他治疗性干预措施，并在遥远的未来中进行c），以实施预防性干预措施，例如进行基因干预措施。