Exploring Tobacco Effects on Attention in Schizophrenics and Controls Using fMRI

描述（由申请人提供）：精神分裂症认知缺陷的实验模型支持尼古丁胆碱能功能障碍的作用，并且尼古丁受体的药理学调节已成为新的治疗干预措施的最新目标。最近的工作为研究注意网络的胆碱能机制提供了重要的实验杠杆。持续的注意力调动了大脑区域的网络，最突出的是额-顶叶网络，特别是在右半球。持续注意力任务（SAT）是一项基于啮齿动物模型开发的任务，其中包括分心条件（dSAT），已被开发并应用于精神分裂症患者。初步研究表明，患者总体表现不佳，特别是在dSAT条件下。在健康受试者中，dSAT条件激发了右背外侧前额叶皮层的大脑活动，而在精神分裂症患者中，这一区域被证明是不活跃的。我们建议使用功能磁共振成像（fMRI）来测量脑灌注动脉自旋标记（ASL），这是一种间接测量神经元活动的方法，在两个单独的会话（受试者）中使用尼古丁和不使用尼古丁。与血氧水平依赖性（BOLD）测量不同，ASL提供了一种可量化的脑灌注测量方法，它可以捕获由对照组和研究组的差异或尼古丁等药物引起的基线灌注差异。美国手语也更适合于研究持续注意力所需的长块数据收集。具体而言，我们提出以下建议：1 -尼古丁在SAT表现中的神经效应：通过持续注意任务（SAT）激活额顶叶皮层，比较精神分裂症患者和健康吸烟者在事先给予或未给予尼古丁的情况下，在注意相关神经回路中的ASL激活。假设1。在持续注意力任务（SAT）中，与没有尼古丁的任务激活相比，在精神分裂症患者和对照组吸烟者中，尼古丁给药会增加持续注意力任务（SAT）中额顶叶皮层的大脑激活。特定目标2 -尼古丁在dSAT表现中的不同神经效应：比较健康吸烟者和精神分裂症受试者在基线（不含尼古丁）和吸烟后在持续注意任务（dSAT）中分心时的ASL激活。假设2。在dSAT测试中，不含尼古丁的精神分裂症受试者在注意力相关区域的神经回路中表现出比正常对照吸烟者更少的激活。假设2 b。使用尼古丁后，精神分裂症患者神经回路中与dsat相关的激活的增加将比正常对照吸烟者更大。

DESCRIPTION (provided by applicant): Experimental models of cognitive deficits in schizophrenia have supported a role for nicotinic cholinergic dysfunction, and the pharmacologic modulation of the nicotinic receptor has been a recent target of new treatment interventions. Recent work has provided important experimental leverage to investigate cholinergic mechanisms of attention networks. Sustained attention recruits a network of brain regions, most prominently frontal-parietal networks, particularly in the right hemisphere. A task developed with a rodent model, the sustained attention task (SAT), which includes a distractor condition (dSAT), has been developed and applied in schizophrenia patients. Preliminary work demonstrates that the patients show poor performance overall, particularly during the dSAT condition. In healthy subjects, the dSAT condition recruits brain activity in the right dorsolateral prefrontal cortex, which has been shown to be hypoactive in schizophrenia patients. We propose to use functional magnetic resonance imaging (fMRI) to measure cerebral perfusion with arterial spin labeling (ASL), an indirect measurement of neuronal activity, in two separate sessions (within subjects) with nicotine and without nicotine. ASL provides a quantifiable measure of cerebral perfusion, unlike the blood oxygenation-level dependent (BOLD) measure, and it can capture differences in baseline perfusion introduced by differences in control and study groups or a pharmacologic agent such as nicotine. ASL is also better- suited to data collection over long blocks necessary to study sustained attention. Specifically, we propose the following: Specific Aim 1 - Neural effects of nicotine during SAT performance: To compare ASL activation with or without prior administration of nicotine in the attention-related neurocircuits in schizophrenic and healthy tobacco smokers using a sustained attention task (SAT) to activate frontal-parietal cortex. Hypothesis 1. Relative to sessions without, nicotine administration will increase cerebral activation in frontal- parietal cortex during a sustained attention task (SAT) in both schizophrenic and control smokers, following nicotine, compared to task activation without preceding nicotine. Specific Aim 2 - Differential neural effects of nicotine during dSAT performance: To compare ASL activation during distraction in the sustained attention task (dSAT) in healthy tobacco smokers with our schizophrenic subjects, at baseline (without nicotine) and after smoking. Hypothesis 2a. Without nicotine, schizophrenic subjects will exhibit less activation than normal control smokers in attention-related region neurocircuits during the dSAT. Hypothesis 2b. With nicotine, the increase in dSAT-related activation of neurocircuits will be greater in schizophrenic subjects than in normal control smokers. PUBLIC HEALTH RELEVANCE: This research project is important because it will use brain imaging to yield information about the bases of differences in brain networks involved in maintaining and focusing attention between schizophrenics and the normal population. Dysfunction of these attention networks may be responsible for a significant proportion of the impairment of functioning commonly seen in those suffering from schizophrenia. Tobacco smoking may improve the functioning of attention networks, but the current medications used to treat schizophrenia do not significantly improve attention. The proposed research would help provide a biomarker for procognitive effects caused by tobacco that then can be applied to an animal model for prescreening of possible non-tobacco procognitive drug candidates in individuals suffering from schizophrenia.