Nicotinic modulation of the default network of resting brain function

静息大脑功能默认网络的烟碱调节

• 批准号: 7772183
• 负责人: Britta Hahn
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7772183
• 关键词: Acute; Affect; Alzheimer' s Disease; Attention; Attentional deficit; Behavioral; Brain; Brain region; Chemosensitization; Chronic Disease; Clinical; Cognition; Cognitive; Custom; Development; Disease; Dose; Down-Regulation; Failure; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Heart; Human; Imaging Techniques; Impaired cognition; Impairment; Individual; Investigation; Lead; Ligands; Measures; Mecamylamine; Mediating; Mental Processes; Mind; Modeling; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Nicotinic Receptors; Participant; Performance; Pharmaceutical Preparations; Placebos; Population; Process; Publishing; Regulation; Reporting; Rest; Scanning; Schizophrenia; Selection Criteria; Signal Transduction; Smoker; Structure; Task Performances; Testing; Therapeutic; Time; Withdrawal; Work; clinical application; design; improved; neuroimaging; non-smoker; non-smoking; novel; novel strategies; patient population; public health relevance; research study

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.

描述（由申请人提供）：神经影像学研究表明，一组功能上相互关联的大脑结构，即所谓的静息大脑功能的“默认网络”，在被动休息期间（例如走神时）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，例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，默认网络活动的下调不足。众所周知，未能停用默认活动会导致严重的表现错误和注意力缺陷。因此，从药理学上操纵默认活性的潜力将为改善这些疾病人群的认知开辟一种新方法。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烟碱音的调节。证明烟碱配体的这种调节和相关的性能益处将开辟一种提高注意力的新机制，并为研究该机制的临床益处奠定基础。功能磁共振成像将用于测量透皮尼古丁和烟碱拮抗剂美加明对认知任务执行过程中默认网络活动的影响。这两种药物将在同一组受试者中进行测试，这些受试者将被扫描三次，一次在接受任何一种药物后，一次在服用安慰剂后。所有参与者均不吸烟；尼古丁对未接触尼古丁的个体的默认网络调节将证明该效果并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引起的默认活动失活，特别是在导致任务独立思维和注意力缺失的情况下。预计这种效果与性能的提高有关。相比之下，美加明预计会削弱任务引起的默认失活，并且这种效应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有关。因此，低烟碱受体张力状态将模拟这些患者群体中出现的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，将检查默认区域功能连接的烟碱调节。这种连通性已被证明会影响认知表现，尼古丁的增强和美加明的减弱可能是另一种表现调节机制。证明烟碱受体配体对默认网络活动的强大作用不仅会激发对该机制的临床应用进行广泛的未来研究，而且还为寻找具有认知增强潜力的新型烟碱激动剂提供重要的神经影像测试模型。 公共健康相关性：许多以注意力问题为标志的疾病，例如阿尔茨海默氏病和精神分裂症，显示出所谓的静息大脑功能默认网络的异常调节，该默认网络在思想自由走动时维持内部定向思维。这些区域可能会过度活跃，或者在执行需要注意力的任务时不太容易停用，而过度活动被认为会损害表现。有迹象表明，尼古丁可以通过帮助默认网络失活来提高注意力，这种机制可能对上述疾病状态有治疗作用。当前的项目旨在通过证明烟碱类药物调节默认网络功能来提供概念证明。