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（如走神）期间维持心理过程。据报道，一些以认知功能障碍为特征的慢性疾病状态，如精神分裂症和阿尔茨海默病（AD），在参与注意力要求任务时显示出默认网络活动的下调不足。不停用默认活动会导致严重的性能错误和注意力缺失。因此，药理学上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的途径。最近一项针对轻度剥夺吸烟者的实验表明，大剂量尼古丁增强的注意力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受到尼古丁音调的调节。证明尼古丁配体的这种调节和相关的性能益处将开辟一种新的机制来提高人们的注意力，并为研究这种机制的临床益处奠定基础。功能磁共振成像将被用于测量透皮尼古丁和尼古丁拮抗剂甲美胺对认知任务执行过程中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，一次是在服用任何一种药物后，一次是在服用安慰剂后。所有参与者均为非吸烟者；尼古丁对尼古丁无源个体的默认网络调节将证明尼古丁的作用并不反映戒断状态的逆转，并为临床应用提供必要的概念证明。尼古丁有望帮助任务诱导的默认活动的失活，特别是在引起任务独立思考和注意力缺失的情况下。预计这种效果将与增强的性能相关联。相比之下，甲胺有望减弱任务诱导的默认失活，这种效果有望与精神分裂症和阿尔茨海默氏症的表现障碍和更大的表现变异性有关。因此，在这些患者群体中，低尼古丁受体张力状态将模拟默认失调和特定表现缺陷，并表明它可能是这些问题的原因。最后，尼古丁对默认区域功能连接的调节将被检查。这种连通性已被证明会影响认知表现，尼古丁的增强和甲胺的减弱可能是另一种表现调节机制。证明尼古丁受体配体对默认网络活性的强大作用不仅将激发对该机制的临床应用的广泛研究，而且还将为寻找具有认知增强潜力的新型尼古丁激动剂提供重要的神经影像学测试模型。

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.