Functional Imaging of the Nicotinic Basis for Attention Deficits in Schizophrenia

描述(申请人提供)：这项研究的目的是更好地了解精神分裂症患者选择性注意缺陷的神经关联，并确定尼古丁如何在药理上调节这些机制。患者通常报告被环境中的感官刺激淹没，造成工作和社交场合的困难，从而降低生活质量。从神经生物学角度讲，这种表型部分是由于 与调节抑制电路的尼古丁受体系统的有效性降低有关，并可能在显示皮质对噪声的反应过度的功能磁共振研究中得到证实。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确凿的证明。拟议的研究将包括两个具体目标。在第一个目标中，将使用功能磁共振成像技术研究分心环境噪声对精神分裂症患者和健康对照组听觉注意任务相关神经元活动和行为的影响。假设一种分心状态(噪音或 通过诊断(患者或对照)的互动将被观察到，其驱动因素是患者在噪音期间与注意力网络相关的活动相对减少(相对于静默)，但对照组的活动相反(相对增加)。第二个目标是 确定在(A)被动倾听和(B)有噪音干扰的听觉注意任务中的反应异常是否可以通过尼古丁激动剂(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。预计与安慰剂相比，尼古丁将使患者海马区对噪音的反应正常化(即减少)。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任务；假设相对于安慰剂，噪声诱导的神经元反应和表现的变化将类似地被尼古丁正常化。这项研究将首次考察胆碱能调节对精神分裂症患者选择性注意的神经元效应，并对治疗发展具有方法学和药理学意义。通过完成这项研究，再加上其他活动，包括课程作业、参加一个活跃的临床研究小组和科罗拉多大学的研究社区，NRSA将使斯莫尼先生能够实现他博士前培训的以下目标：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实验设计、数据获取和统计分析方面的知识；3)熟练地在期刊和会议上展示他的工作。这些目标的实现是朝着斯莫尼先生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，重点是利用神经成像来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.