Functional Imaging of the Nicotinic Basis for Attention Deficits in Schizophrenia

描述（由申请人提供）：本研究的目的是更好地了解精神分裂症中选择性注意缺陷的神经相关性，并确定尼古丁如何对这些机制进行间接调节。患者通常报告被环境中的感官刺激所淹没，导致工作和社交困难，从而降低生活质量。神经生物学上，这种表型部分是由于 降低烟碱受体系统的调节抑制电路的功效，并且可以在功能磁共振成像研究中证明，显示皮质对噪音的反应过度。当噪声与任务无关时，对噪声的敏感性可能会对注意相关的神经元反应产生有害影响，尽管这一点尚未得到最终证明。拟议的研究将包括两个具体目标。在第一个目标中，分散注意力的环境噪声对听觉注意任务相关的神经元活动和行为的影响将在精神分裂症患者和健康对照组中使用fMRI进行研究。假设分心条件（噪音或噪音） 将观察到通过诊断（患者或对照）的相互作用，这是由噪声期间患者中与注意力网络相关的活动的相对减少（相对于沉默）驱动的，但对照中活动的相反效果（相对增加）。第二个目标将 确定在（a）被动听力和（B）噪声干扰的听觉注意力任务期间的反应异常是否可以通过烟碱激动剂（尼古丁）来改善。在第一个任务中，受试者将听到环境噪音或暗示的沉默。预计相对于安慰剂，尼古丁将使患者海马体中对噪声的反应正常化（即降低）。在第二个任务中，受试者将执行与第一个目标相同的听觉注意力任务;假设相对于安慰剂，噪声诱导的神经元反应和性能变化将通过尼古丁类似地正常化。目前的研究将是第一次检查胆碱能调节对精神分裂症选择性注意的神经元效应，并对治疗开发具有方法学和药理学意义。通过完成这项研究，结合额外的活动，包括课程作业，参与积极的临床研究小组，以及科罗拉多大学的研究社区，NRSA将使先生。1）获得精神分裂症神经生物学方面的专业知识2）扩大他在功能磁共振成像实验设计，数据采集，和统计分析，和3）成为熟练的介绍他的工作在期刊和会议。这些目标的实现是Smucny先生朝着成为精神健康领域富有成效的独立研究人员的长期目标迈出的重要一步，重点是使用神经影像学更好地了解精神分裂症的神经生物学和神经药理学。

DESCRIPTION (provided by applicant): The purpose of this study is to better understand the neural correlates of selective attention deficits in schizophrenia and determine how these mechanisms can be pharmacologically modulated by nicotine. Patients commonly report being overwhelmed by sensory stimuli in the environment, causing difficulties at work and social situations and thereby lowering quality of life. Neurobiologically, this phenotype is partially due to reduced efficacy of nicotinic receptor systems that modulate inhibitory circuitry, and may be demonstrated in fMRI studies showing cortical hyperactivity in response to noise. Sensitivity to noise may have deleterious effects on attention-related neuronal response when the noise is task-irrelevant, although this has not been conclusively demonstrated. The proposed study will include two specific aims. In the first aim, the effects of distracting environmental noise on auditory attention task-related neuronal activity and behavior will be studied in schizophrenia patients and healthy controls using fMRI. It is hypothesized that a distraction condition (noise or silence) by diagnosis (patient or control) interaction will be observed, driven by a relative decrease in activity associated with attention networks in patients during noise (relative to silence), but the reverse effect (a relative increase) in activity in controls. The second aim will determine if response abnormalities during (a) passive listening and (b) the auditory attention task with noise distraction can be improved by a nicotinic agonist (nicotine). In the first task, subjects will listen to environmental noise or cued silence. It is expected that relative to placeb, nicotine will normalize (i.e. reduce) response to noise in the hippocampus in patients. In the second task, subjects will perform the same auditory attention task as in the first aim; it is hypothesized that relative to placebo, noise-induced change in neuronal response and performance will be similarly normalized by nicotine. The current study will be the first to examine the neuronal effects of cholinergic modulation on selective attention in schizophrenia, and has methodological and pharmacologic implications for therapeutic development. Through completion of this research, in combination with additional activities including coursework, participation in an active clinical research group, and the University of Colorado research community, the NRSA will enable Mr. Smucny to achieve the following goals of his predoctoral training: 1) To acquire expertise in the neurobiology of schizophrenia 2) to expand his knowledge of fMRI experimental design, data acquisition, and statistical analyses, and 3) to become proficient in presenting his work in journals and at conferences. Achievement of these goals is an important step towards Mr. Smucny's long-term goal of becoming a productive independent researcher in the mental health field, with a focus on using neuroimaging to better understand the neurobiology and neuropharmacology of schizophrenia.