Exploring Tobacco Effects on Attention in Schizophrenics and Controls Using fMRI

描述(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，尼古丁受体的药理调节已成为新的治疗干预措施的最近目标。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。持续的注意力会招募大脑区域的网络，最突出的是额顶网络，尤其是在右半球。一种用啮齿动物模型开发的任务--持续注意任务(SAT)，其中包括分心条件(DSAT)，已经开发并应用于精神分裂症患者。初步工作表明，患者总体表现不佳，特别是在DSAT情况下。在健康受试者中，DSAT状态会在右侧背外侧前额叶皮质招募大脑活动，这已被证明在精神分裂症患者中活动不足。我们建议使用功能磁共振成像(FMRI)通过动脉自旋标记(ASL)来测量大脑灌注，动脉自旋标记(ASL)是对神经元活动的间接测量，在两个单独的会话中(在受试者内)，使用尼古丁和不使用尼古丁。与血氧水平依赖(BOLD)测量不同，ASL提供了一种可量化的脑灌注测量方法，它可以捕捉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。ASL也更适合于研究持续注意力所需的长时间块的数据收集。具体地说，我们提出了以下建议：特定目标1-尼古丁在SAT操作中的神经效应：比较精神分裂症患者和健康烟草吸烟者在使用持续注意任务(SAT)激活额顶皮质的注意相关神经回路中，在有或没有预先给予尼古丁的情况下ASL的激活。假设1.与不使用尼古丁的实验相比，在尼古丁之后，精神分裂症患者和对照吸烟者在持续注意任务(SAT)中，与不使用尼古丁的任务激活相比，使用尼古丁会增加额叶-顶叶皮质的大脑激活。特定目的2-尼古丁在DSAT操作中的不同神经效应：比较健康吸烟者和精神分裂症受试者在持续注意任务(DSAT)中分心时的ASL激活，在基线(不含尼古丁)和吸烟后。假设2a。在没有尼古丁的情况下，精神分裂症受试者在DSAT期间注意力相关区域神经回路的激活程度将低于正常对照吸烟者。假设2b。有了尼古丁，精神分裂症受试者DSAT相关神经回路激活的增加将比正常对照吸烟者更大。 公共卫生相关性：这项研究项目很重要，因为它将使用大脑成像来获得有关精神分裂症患者和正常人群之间维持和集中注意力的大脑网络差异的基础的信息。这些注意力网络的功能障碍可能是精神分裂症患者常见的功能障碍的很大一部分原因。吸烟可能会改善注意力网络的功能，但目前用于治疗精神分裂症的药物并不能显著改善注意力。这项拟议的研究将有助于为烟草引起的先兆认知影响提供一个生物标记物，然后可以应用于动物模型，以预筛选精神分裂症患者可能的非烟草先兆药物候选。

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.