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

基本信息

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
项目类别：
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&apos 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

项目摘要

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，在功能上相互联系的大脑结构集，所谓的静止大脑功能的“默认网络”，在被动休息期间保持心理过程，例如何时徘徊。据报道，以认知功能障碍为特征的几种慢性疾病状态，例如精神分裂症和阿尔茨海默氏病（AD），在从事注意力的任务时表现出缺乏默认网络活动的下调。已知未能停用默认活动会导致急性绩效错误和注意力失误。因此，在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方法开辟一种新的方法。最近对最低剥夺吸烟者的实验表明，大剂量尼古丁的关注可能通过增强的任务诱导的默认网络失活而介导。当前建议的项目旨在确定默认网络活动是否由烟碱音调调节。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新的机制来提高注意力，并为调查该机制的临床益处奠定基础。功能磁共振成像将用于衡量透皮尼古丁和烟碱拮抗剂美甲基胺对认知任务性能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，后者将在接受任何一种药物后一次进行三次扫描。所有参与者将是非吸烟者； Nicotine在Nicotine-Naove个体中对Nicotine进行的默认网络调节将证明，这种影响并不能反映撤回状态的逆转，并提供了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停用，特别是在邀请任务独立思想和注意力失误的条件下。预计这种效果将与增强的性能相关。相比之下，美甲基胺有望削弱任务引起的默认失活，预计这种效果与性能障碍和更大的性能变异性有关，如精神分裂症和AD所示。因此，低烟碱受体音调的状态将模拟这些患者人群中看到的默认失调和特定性能缺陷，并表明这可能是这些问题的因果关系。最后，将检查默认区域功能连接性的烟碱调制。已经证明这种连通性会影响认知性能，尼古丁的增强和通过甲基胺削弱的增强可能是性能调节的另一种机制。烟碱受体配体对默认网络活性的强大影响的证明不仅会激励对该机制的临床应用进行广泛的研究，而且还为寻找具有认知增强潜力的新型烟碱激动剂时提供了重要的神经影像学测试模型。公共卫生相关性：注意问题是标志的许多疾病，例如阿尔茨海默氏病和精神分裂症，都表现出异常调节所谓的默认脑功能默认默认网络，当思想自由徘徊时，它可以保持内在定向的思想。这些区域可能会过度活跃，也可以通过关注任务轻易停用，而过多的活动被认为会损害性能。有迹象表明，尼古丁可以通过帮助默认网络的失活来提高注意力，并且该机制可能对上述疾病状态具有治疗益处。当前的项目旨在通过证明烟碱药物调节默认网络功能来提供概念证明。