Nicotinic modulation of the default network of resting brain function

描述（由申请人提供）：神经影像学研究表明，一组功能上相互连接的大脑结构，即所谓的静息大脑功能的“默认网络”，在被动休息期间（例如当思维漫游时）维持心理过程。据报道，以认知功能障碍为特征的几种慢性疾病状态，如精神分裂症和阿尔茨海默病（AD），在从事需要注意力的任务时，显示出默认网络活动的下调不足。众所周知，不去激活默认活动会导致严重的表现错误和注意力缺失。因此，操纵默认活动的潜力将为改善这些疾病人群的认知开辟一条新途径。最近一项针对轻度剥夺吸烟者的实验表明，大剂量尼古丁引起的注意力增强可能是通过增强任务诱导的默认网络失活来介导的。目前提出的项目旨在确定默认网络活动是否由烟碱张力调节。通过烟碱配体证明这种调节和相关的性能益处将开辟一种改善注意力的新机制，并为研究这种机制的临床益处奠定基础。将采用功能性磁共振成像来测量经皮尼古丁和尼古丁拮抗剂美加明对认知任务表现期间默认网络活动的影响。两种药物将在同一组受试者中进行测试，受试者将接受三次扫描，一次是在接受任何一种药物后，一次是在接受安慰剂后。所有受试者均为非吸烟者;尼古丁-戒断个体中尼古丁的默认网络调节将证明该效应不反映戒断状态的逆转，并提供临床应用所需的概念证明。尼古丁有望帮助任务诱导的默认活动失活，特别是在邀请任务独立思考和注意力缺失的条件下。这种效应预计与性能增强有关。相比之下，美加明预计会削弱任务诱导的默认失活，并且这种效果预计与精神分裂症和AD中所见的表现受损和更大的表现变异性相关。因此，低烟碱受体张力的状态将模拟这些患者人群中观察到的默认失调和特定性能缺陷，并表明它可能是这些问题的原因。最后，烟碱调制的默认区域的功能连接将进行检查。这种连接性已被证明会影响认知能力，尼古丁的增强和美加明的减弱可能是另一种能力调节机制。烟碱受体配体对默认网络活性的强大作用的证明不仅将激发对该机制的临床应用的广泛的未来研究，而且还在寻找具有认知增强潜力的新型烟碱受体激动剂中提供了重要的神经成像测试模型。 公共卫生相关性：许多以注意力问题为标志的疾病，如阿尔茨海默氏病和精神分裂症，都表现出所谓的静息脑功能默认网络的异常调节，该网络在思想自由漫游时维持内部导向思想。这些区域可能过度活跃，或者在需要注意力的任务中不太容易被关闭，过度的活动被认为会损害表现。有迹象表明，尼古丁可以通过帮助失活默认网络来改善注意力，并且这种机制可能对上述疾病状态具有治疗益处。目前的项目旨在通过证明尼古丁药物调节默认网络功能来提供概念验证。

DESCRIPTION (provided by applicant): Neuroimaging studies indicate that a functionally interconnected set of brain structures, the so-called "default network" of resting brain function, maintains mental processes during passive rest such as when the mind wanders. Several chronic disease states characterized by cognitive dysfunction, such as schizophrenia and Alzheimer's disease (AD), are reported to display deficient down-regulation of default network activity when engaging in attention-demanding tasks. Failure to deactivate default activity is known to lead to acute performance errors and attentional lapses. The potential of manipulating default activity pharmacologically would thus open up a novel approach to improving cognition in these disease populations. A recent experiment in minimally deprived smokers suggests that enhanced attention by large- dose nicotine may be mediated by enhanced task-induced deactivation of the default network. The currently proposed project is designed to determine whether default network activity is modulated by nicotinic tone. Demonstrating such modulation and associated performance benefits by nicotinic ligands would open up a novel mechanism to improving attention, and would lay the groundwork for investigations on clinical benefits of this mechanism. Functional Magnetic Resonance Imaging will be employed to measure effects of transdermal nicotine and the nicotinic antagonist mecamylamine on default network activity during cognitive task performance. Both drugs will be tested in the same group of subjects, who will be scanned three times, once after receiving either drug and once after placebo. All participants will be non-smokers; default network modulation by nicotine in nicotine-naove individuals would demonstrate that the effect does not reflect reversal of a withdrawal state and provide the proof of concept needed for a clinical application. Nicotine is expected to aid task-induced deactivation of default activity, particularly under conditions that invited task- independent thought and attentional lapses. This effect is expected to be associated with enhanced performance. Mecamylamine, in contrast, is expected to weaken task-induced default deactivation, and this effect is expected to be associated with performance impairment and greater performance variability as seen in schizophrenia and AD. A state of low nicotinic receptor tone would thus model default dysregulation and specific performance deficits seen in these patient populations and suggest that it may be causal to these problems. Finally, nicotinic modulation of functional connectivity of default regions will be examined. Such connectivity has been shown to influence cognitive performance, and a strengthening by nicotine and weakening by mecamylamine may be another mechanism of performance modulation. Demonstration of robust effects of nicotinic receptor ligands on default network activity would not only motivate a broad range of future investigations on clinical applications of this mechanism but also provide an important neuroimaging test model in the search for novel nicotinic agonists with cognitive-enhancing potential. PUBLIC HEALTH RELEVANCE: Many disorders where attentional problems are a hallmark, such as Alzheimer's disease and schizophrenia, display abnormal regulation of the so-called default network of resting brain function that maintains internally directed thought when the mind is free to wander. These regions can be overactive or less readily deactivated with attention-demanding tasks, and excess activity is thought to impair performance. There is indication that nicotine may improve attention by aiding the deactivation of the default network, and this mechanism may be of therapeutic benefit for the above disease states. The current project aims at providing a proof of concept by demonstrating that nicotinic drugs modulate default network function.