Genetic and Time-Frequency Aspects of Neural Phenotypes in 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。在精神分裂症的遗传决定因素方面取得了可喜的进展，这引发了人们的疑问：已发现的基因和大脑异常之间的关联是否在诊断上是精神分裂症特有的，以及从单个大脑区域的反应来看，这种疾病的大脑病理描述是否很糟糕。为了了解基因如何使大脑易患精神分裂症，有必要确定a)遗传易感性的哪些方面与大脑异常反应有关，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，以及c)根据大脑区域的功能相互作用是否有效地理解了精神分裂症的神经基础。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记之一。研究人员最近提出，视觉整合的缺陷可能会导致知觉闭合不良，以及在这种障碍中注意到的物体识别问题。在精神分裂症患者的亲生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呈现或视觉噪音增加而变得困难时。一些研究表明，精神分裂症患者及其生物亲属在物体感知过程中会出现脑电(EEG)异常。此外，神经活动的动态测量似乎有助于将精神分裂症与其他大脑疾病区分开来，并描述精神分裂症中的异常神经网络结构。然而，研究人员还没有清楚地确定大脑功能的具体异常，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。之前的功绩审查资金部分用于收集视觉噪音中物体感知过程中的脑电数据，这些数据来自受精神分裂症或双相情感障碍影响的家庭的400多名个人，以及没有这些疾病家族史的个人。脑电数据的时间域分析揭示了精神分裂症患者及其亲属枕叶皮质早期感觉水平的异常。对额叶皮质活动的时间和频率成分的分析揭示了可能调节视觉感觉功能的早期反应，以及精神分裂症患者及其亲属的晚期低频异常，这些异常与前额叶皮质中与多巴胺能功能相关的候选基因有关。这项拟议的研究将检查精神分裂症和躁郁症患者，这些患者组的一级生物亲属，并控制受试者，以确定在物体感知过程中大脑反应的时频和相位特征。这项以家庭为基础的设计包括两个诊断小组和一级亲属，以测试诊断特异性和遗传易感性的关键指标。我们将：1.确定精神分裂症患者错误物体知觉过程中脑电异常的时间、频率和相位特征。2.通过将精神分裂症患者及其亲属的数据与对照组、双相情感障碍患者及双相情感障碍患者亲属的数据进行对比，确定物体知觉过程中脑电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.确定物体知觉时脑电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。我们的主要假设是，精神分裂症的特定基因在异常的大脑功能中表达，在视觉对象处理过程中记录的脑电的时频元素中可以检测到。我们假设，基于试验的脑电信号的时频分析提供了标志精神分裂症遗传易感性的功能性大脑异常的敏感和动态特征。 公共卫生相关性： 退伍军人管理局一直将精神分裂症列为高度优先研究的领域。由于服兵役的典型年龄处于男性精神分裂症发病率最高的年龄段，这种疾病很可能会继续在退伍军人中流行。2002财政年度用于精神病患者的VHA总成本为29.5亿美元，占VHA VERA拨款总额的16%。近年来，退伍军人医疗中心出院的精神病患者比任何其他与诊断相关的群体都要多(VARRAC，1997)。因此，了解精神分裂症的病因对退伍军人的健康具有重要意义。识别易感基因的作用将有助于退伍军人的临床护理，方法是a)改善精神分裂症遗传咨询的诊断和风险预测，b)了解病理生理机制，以便开发新的药物和其他治疗干预措施，以及c)在遥远的未来，实施预防性干预措施，如基因替代疗法。

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.