Neurophysiological Studies of Schizophrenia

描述（由申请人提供）：精神分裂症和双相情感障碍是严重的精神疾病，给受害者和他们的家人带来极大的痛苦，也是我们国家生产力损失和医疗费用的主要来源。然而，对它们的了解太少，特别是对疾病过程中最有效的治疗干预时间知之甚少。这个竞争性R01更新应用程序采用前瞻性纵向研究设计，主要目的是通过以下方式提高我们对精神分裂症（SZ）（和情感性精神病）神经生理学的认识：1)评估脑电图事件相关电位（ERPs）的功能异常，这些异常跨越处理的早期和后期阶段，特别关注早期听觉处理；2)将这些信息与MRI结构解剖相结合；3)将ERP和MRI测量与临床特征相结合。我们的研究以及其他人的研究结果表明，了解这种疾病的病程非常重要。我们对首次精神病发作受试者（FE，手术定义为首次住院）的前瞻性纵向研究的初步数据表明，MRI/ERP特征缺陷的发病后进展，包括脑灰质损失和伴随的ERP功能测量减少。在初次住院后的前1.5年，进展非常迅速，但慢性患者的进展要慢得多，甚至没有进展。本应用程序增加了第二个纵向研究人群，即临床精神病前驱（PRO）的受试者，我们建议跟踪其转化为精神病的进展和生物指标，特别是SZ精神病。统一我们的方法是基于NMDA神经传递异常的复发性抑制的基本细胞缺陷的神经生物学模型。具体来说，我们假设这种异常可能是在这种疾病中观察到的发育异常以及前驱和发病后进展的原因。这种基于细胞的模型和我们的初步数据导致了对早期大脑处理，特别是听觉处理的越来越多的关注，因为早期处理范式的结果似乎特别适合于与大脑解剖缺陷和疾病进展的文献相关。最后，我们将使用这些措施来评估FE精神分裂症精神病与FE情感性精神病（90%的生物极性）的特异性。就意义而言，无需强调的是，如果我们对前驱症状中ERP/MRI异常进展的预测得到证实，并构成转化的预测因子，这些发现可能会为社会心理和药物治疗干预提供合理的基础。此外，如果我们的初步发现得到证实——精神分裂症早期病程发病后进展迅速，后期变化较小——这将立即形成强调早期治疗的科学基础，也许还能预防疾病随着时间的推移而发展。

DESCRIPTION (provided by applicant): Schizophrenia and bipolar disorder are major mental illnesses that cause their victims and their families much anguish and are a major source of lost productivity and medical care expenses to our nation. Yet too little is known about them, especially about the most effective time of treatment intervention during the course of illness. The main goal of this competing R01 renewal application, which uses a prospective longitudinal study design, is to advance our knowledge of the neurophysiology of schizophrenia (SZ) (and affective psychosis) by: 1) evaluating functional abnormalities in EEG event-related potentials (ERPs) that span both early and late stages of processing, with a special focus on early auditory processing; 2) integrating this information with structural MRI anatomy; and 3) integrating both ERP and MRI measures with clinical features. Findings from our work, as well as others, suggest the importance of understanding the course of the disorder. Initial data from our prospective longitudinal study of first psychotic episode subjects (FE, operationally defined as first hospitalization)have shown which demonstrate post onset progression of MRI/ERP features deficits, including brain gray matter loss and concomitant reduction of ERP functional measures. Progression is very rapid in the first 1.5 years after initial hospitalization, but much slower or even absent in chronic patients. The present application adds a second longitudinally studied population, subjects who are clinically prodromal for psychosis (PRO) in whom we propose to track progression and biopredictors of conversion to psychosis, especially SZ psychosis. Unifying our approach is our neurobiological model of a fundamental cellular defect in recurrent inhibition, based on an NMDA neurotransmission abnormality. Specifically, we hypothesize that such an abnormality may be responsible for both the developmental abnormalities observed in this disorder as well as the prodromal and post-onset progression. This cellular- based model and our preliminary data have led to an increasing focus on early-stage brain processing, especially auditory processing, as results from early processing paradigms appear to be especially amenable to correlation with brain anatomical deficits and with documentation of progression of the disorder. Finally, we will use these measures to evaluate specificity to FE schizophrenic psychosis versus FE Affective Psychosis (90% biopolar). In terms of significance, it hardly needs emphasis that, should our prediction of progression of ERP/MRI abnormalities in prodromes be confirmed and constitute predictor(s) of conversion, such findings would likely form a rational basis for psychosocial and medication therapeutic interventions. Moreover, should our preliminary findings be confirmed -rapid post-onset progression in the early course of schizophrenia with lesser changes occurring later-this would immediately form a scientific foundation for emphasis on early treatment, and perhaps prevention of progression of illness over time.