Antipsychotic Effects on Top Down Control of Sensory Processing in Schizophrenia

描述（由申请人提供）：与大量关于精神分裂症患者持续性认知缺陷的文献相比，对导致幻觉等阳性症状的病理生理学知之甚少。这些不正常的感觉体验常主导急性精神病状态。药物治疗可以缓解阳性症状，但治疗反应并不普遍，神经系统水平的疗效机制尚不清楚。本提案中的研究项目建立在这样一个模型之上：在幻觉体验中，感觉系统的活动被提升，而这种感觉过度驱动的一个重要原因是注意力过程自上而下调节的减少。该研究旨在确定在未治疗的首发精神分裂症患者中，感觉输入的注意调节障碍是否与幻觉的严重程度有关，以及广泛使用的抗精神病药物利培酮是否能减轻这种障碍。互补的功能磁共振成像和脑电图方法将用于敏感地评估大脑活动和表征支持这些过程的神经系统之间的连接。对所提出的研究的追求不仅将促进这一领域的知识，而且还将为实现职业发展计划的更广泛目标提供一个有价值的框架。候选人的直接目标是在神经认知精神分裂症研究领域发展独立研究者的职业生涯。候选人的导师和顾问团队（都积极与导师合作）是精神分裂症感觉处理，认知神经科学方法，行为药理学和临床试验方面的领先专家，并将指导候选人的学习和研究发展工作。候选人将专注于额外的特定培训活动，如课程作业、阅读、研讨会和访问顾问实验室，以获得以下方面的专业知识：1)自上而下控制感觉处理的神经科学；2)对精神分裂症患者进行临床试验以评估治疗的神经认知效果；3)适用于临床研究的活体神经系统测量的现代方法。研究和培训活动将在伊利诺伊大学认知医学中心进行，这是一个由候选人导师指导的多学科研究单位，其正在进行的首发精神病研究项目和其他精神分裂症研究利用现场fMRI和EEG为候选人提出的研究提供了一个结构。该职业发展奖将使候选人的长期目标有助于理解精神分裂症精神病症状的病理生理学，并为新的治疗开发和评估工作提供信息。

DESCRIPTION (provided by applicant): In contrast to the vast literature on persistent cognitive deficits in schizophrenia, much less is known about the pathophysiology leading to positive symptoms such as hallucinations. These abnormal sensory experiences often dominate the acute psychotic state. Pharmacologic treatments can alleviate positive symptoms, but treatment response is not universal and the mechanism of efficacy at the neural systems level is not well understood. The research program in this proposal builds on the model that activity in sensory systems is elevated during hallucinatory experiences, and that one important cause of this sensory overdrive is reduced top-down modulation by attentional processes. The proposed research aims to determine whether impairments in attentional modulation of sensory input are related to the severity of hallucinations in untreated first episode schizophrenia patients, and whether that disturbance is reduced by the widely used antipsychotic risperidone. Complementary fMRI and EEG approaches will be used to sensitively assess brain activity and characterize connections among neural systems supporting these processes. Pursuit of the proposed studies will not only advance knowledge in this area, but also provide a valuable framework for achieving the broader aims of the career development program. The candidate's immediate goal is to develop a career as an independent investigator in the field of neurocognitive schizophrenia research. The candidate's mentor and team of consultants (all actively collaborating with the mentor) are leading experts in sensory processing in schizophrenia, cognitive neuroscience methods, behavioral pharmacology, and clinical trials, and will guide the candidate's learning and study development efforts. The candidate will focus additional specific training activities such as coursework, readings, workshops, and visits to consultants' labs to achieve expertise in: 1) the neuroscience of top down control over sensory processing, 2) conducting clinical trials with schizophrenia patients to assess neurocognitive effects of treatments, and 3) modern methods of in vivo neural system measurement appropriate for clinical research. Research and training activities will be carried out within the University of Illinois' Center for Cognitive Medicine, a multi-disciplinary research unit directed by the candidate's mentor, whose ongoing first episode psychosis research program and other schizophrenia studies utilizing onsite fMRI and EEG provide a structure for the candidate's proposed studies. This career development award will enable the candidate's long term goals of contributing to the understanding of the pathophysiology of psychotic symptoms in schizophrenia and informing new treatment development and evaluation efforts.