Elucidating dynamic reorganization of whole-brain networks during anesthetic-induced unconsciousness

阐明麻醉引起的无意识期间全脑网络的动态重组

• 批准号: 10181929
• 负责人: Nanyin Zhang
• 金额: $ 33.22万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-02 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10181929
• 关键词: Altered Level of Consciousness; Anesthesia procedures; Anesthetics; Animal Behavior; Animal Model; Animals; Biological Markers; Brain; Characteristics; Claustral structure; Conscious; Data; Development; Dexmedetomidine; Dose; Electrophysiology (science); Functional Magnetic Resonance Imaging; Goals; Grant; Graph; Immobilization; Individual; Isoflurane; Ketamine; Light; Link; Measures; Molecular; Parietal; Pattern; Property; Propofol; Rattus; Recovery; Reflex action; Research; Rest; Signal Transduction; Site; System; Testing; Thalamic structure; Unconscious State; Wakefulness; awake; behavior test; experimental study; flexibility; imaging approach; neural circuit; neural network; neuromechanism; relating to nervous system; segregation; study characteristics; tool

Project Summary Despite fairly clear understanding on the molecular basis of various anesthetic agents, the systems-level neural mechanism by which anesthetics induce unconsciousness remains elusive. Substantial evidence suggests that anesthetic-induced unconsciousness (AIU) is a brain network phenomenon. Anesthetics appear to suppress consciousness by disrupting information exchange across large-scale brain networks. Therefore, to understand the systems-level mechanism underlying AIU, a critical step is to comprehensively characterize how whole-brain networks dynamically reorganize to support different patterns of information exchange during AIU. This issue can be studied using resting-state functional magnetic resonance imaging (rsfMRI), as it measures between-region functional connectivity (FC) with a whole-brain field of view. In particular, applying rsfMRI to animal models offers several advantages for studying AIU: 1) Intracranial electrophysiology can be concurrently measured with rsfMRI in animals to reveal characteristic neural activity/connectivity patterns and the corresponding global brain network dynamics during AIU; 2) distinct anesthetic agents can be applied to the same group of animals so that common brain network changes during AIU shared by different anesthetics, if any, can be identified; and 3) anesthetic depths can be easily manipulated. However, a major obstacle to fully realize these potentials is that animal fMRI experiments typically use anesthesia to immobilize animals first. Consequently, it is very difficult to reveal how brain networks change from the awake state into an unconscious state. To bridge this gap, our group has established the approach of conducting rsfMRI experiments in fully awake animals. In addition, we have integrated our awake rat rsfMRI approach with multi-laminar electrophysiology recording and animal behavior, which allows us to directly link brain network reorganization to concurrent neural activity patterns and animal’s consciousness states. By using rsfMRI, electrophysiology and behavioral tests, the primary objective of this grant is to comprehensively elucidate the dynamic reorganization of the whole-brain functional network to support different patterns of information exchange from the awake state into an unconscious state. Four anesthetics, including isoflurane, propofol, ketamine and dexmedetomidine will be tested. In Aim 1, we will identify characteristic neural activity and brain connectivity patterns at different steady consciousness levels. In Aim 2, we will systematically characterize topological changes of brain networks during AIU. In Aim 3, we will elucidate layer-specific cortical activity and connectivity patterns, as well as brain network dynamics during the loss and recovery of consciousness. Successful completion of the proposed research will provide a comprehensive framework of how whole-brain networks dynamically reconfigure during AIU. Given the tight link between FC and conscious states, it will broadly shed light onto the neural basis of consciousness, and help reveal biomarkers to indicate levels of consciousness.

项目摘要 尽管对各种麻醉剂的分子基础有相当清楚的了解，但系统层面的 麻醉剂导致昏迷的神经机制仍然难以捉摸。确凿的证据 提示麻醉剂诱导的无意识(AIU)是一种脑网络现象。麻醉药出现了 通过扰乱大规模大脑网络的信息交换来抑制意识。因此，要 理解AIU背后的系统级机制，关键的一步是全面描述 全脑网络如何动态重组以支持不同的信息交换模式 在AIU期间。这个问题可以使用静息状态功能磁共振成像(RsfMRI)来研究，因为 它以全脑视野测量区域间的功能连接(FC)。特别是， 将rsfMRI应用于动物模型为研究AIU提供了几个优点：1)颅内电生理学 可与动物的rsfMRI同时测量，以揭示特有的神经活动/连接 AIU期间的模式和相应的全局脑网络动力学；2)不同的麻醉剂可以 应用于同一组动物，使不同动物在AIU期间共同的大脑网络发生变化 如果有麻醉剂，可以识别；3)麻醉深度可以很容易地操纵。然而，一个主要的 充分实现这些潜力的障碍是动物fMRI实验通常使用麻醉来 先让动物动弹不得。因此，很难揭示大脑网络是如何从清醒状态变化的 进入无意识状态。为了弥合这一差距，我们小组确立了进行 在完全清醒的动物身上进行rsfmri实验。此外，我们还整合了清醒大鼠rsfmri方法。 用多层电生理记录和动物行为，这让我们可以直接联系大脑 并行神经活动模式和动物意识状态的网络重组。通过使用 RsfMRI，电生理学和行为测试，这项拨款的主要目标是全面 阐明全脑功能网络的动态重组以支持不同的模式 从清醒状态到无意识状态的信息交换。包括异氟醚在内的四种麻醉剂， 将对异丙酚、氯胺酮和右美托咪定进行测试。在目标1中，我们将识别特征神经 不同稳定意识水平下的活动和大脑连接模式。在目标2中，我们将 系统地刻画AIU期间脑网络的拓扑变化。在目标3中，我们将阐明 层特定的皮质活动和连接模式，以及在丢失和 意识的恢复。成功完成拟议的研究将提供全面的 全脑网络如何在AIU期间动态重构的框架。鉴于FC之间的紧密联系 和意识状态，它将广泛地阐明意识的神经基础，并有助于揭示 指示意识水平的生物标记物。