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: 8035480
• 负责人: Britta Hahn
• 金额: $ 18.19万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035480
• 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(申请人提供)：神经成像研究表明，大脑结构的一套功能上相互关联的集合，即所谓的休息大脑功能的“默认网络”，在被动休息期间维持着思维过程，比如当大脑走神的时候。据报道，几种以认知功能障碍为特征的慢性病状态，如精神分裂症和阿尔茨海默病(AD)，在从事高注意力任务时，默认网络活动的下调存在缺陷。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疏忽。因此，从药理上操纵默认活动的可能性将为改善这些疾病人群的认知开辟一条新的途径。最近在最低限度剥夺吸烟者中进行的一项实验表明，大剂量尼古丁增强注意力可能是通过增强任务诱导的默认网络去激活来实现的。目前提出的这个项目旨在确定默认的网络活动是否受到尼古丁基调的调节。展示尼古丁配体的这种调节和相关的性能好处将打开一种新的机制来改善注意力，并将为研究这种机制的临床好处奠定基础。功能磁共振成像将被用来测量透皮尼古丁和尼古丁拮抗剂甲乙胺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，这些受试者将接受三次扫描，一次是在接受任何一种药物后，一次是在服用安慰剂后。所有参与者都将是非吸烟者；尼古丁依赖者中尼古丁对网络的默认调制将证明，这种影响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诱导的默认活动失活，特别是在引发任务独立思考和注意力疏忽的条件下。这一效果预计将与增强的性能相关。相比之下，甲戊胺预计会削弱任务诱导的默认去激活，这种影响预计与精神分裂症和阿尔茨海默病的表现减退和更大的表现变异性有关。因此，低尼古丁受体张力的状态将模拟这些患者群体中出现的默认调节失调和特定表现缺陷，并表明这可能是这些问题的原因。最后，将研究烟碱对缺省区域功能连通性的调制。这种连通性已被证明会影响认知表现，尼古丁的增强和甲氨基甲胺的减弱可能是另一种表现调节机制。展示尼古丁受体配体对默认网络活动的强大影响不仅将推动未来对这一机制的临床应用的广泛研究，而且将为寻找具有认知增强潜力的新型尼古丁激动剂提供一个重要的神经成像测试模型。 与公共健康相关：许多以注意力问题为标志的疾病，如阿尔茨海默病和精神分裂症，都表现出对所谓的静息大脑功能默认网络的异常调节，当大脑自由走动时，该网络维持内部指导的思维。这些区域可能过度活跃，或者在需要注意力的任务中不那么容易失活，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去激活默认网络来改善注意力，这种机制可能对上述疾病状态有治疗作用。目前的项目旨在通过证明尼古丁药物调节默认的网络功能来提供概念证明。

项目成果

Nicotinic receptor modulation of the default mode network.

默认模式网络的烟碱受体调节。

• DOI: 10.1007/s00213-020-05711-9
• 发表时间: 2021
• 期刊: Psychopharmacology
• 影响因子: 3.4
• 作者: Hahn,Britta;Harvey,AlexanderN;Concheiro-Guisan,Marta;Huestis,MarilynA;Ross,ThomasJ;Stein,ElliotA
• 通讯作者: Stein,ElliotA