Spatiotemporal Mechanisms of Olfactory Processing in the Human Brain

摘要 我们实验室的研究重点是了解人脑如何编码和解释信息 关于气味刺激。通常被认为是微不足道的“第五感”，人类的嗅觉实际上是显著的。 很健壮。人类的鼻子可以辨别分子结构上有细微差异的气味，区分 成千上万种独特的气味，并将我们带回过去，重新激活遥远的记忆和情感状态。 此外，嗅觉系统(在人类和非人类动物中)是一种越来越有吸引力和强大的 研究正常和病理条件下脑功能的模型。 研究人类嗅觉系统传统上依赖于两种方法：功能性 磁共振成像(FMRI)和基于头皮的EEG。虽然这些非侵入性的方法已经产生了 关于气味处理的重要见解，可测试问题的范围因时间(MRI)和 空间(EEG)约束。特别是，在理解生理学知识方面存在关键的知识差距 人类嗅觉的基础。在过去的几年里，我们有机会获得颅内 癫痫患者的药物抵抗发作的脑电(IEEG)记录。作为标准外科手术的一部分 临床前评估，患者接受手术，在手术期间将侵入性深度电极植入眼底 脑部定位致痫灶。这种方法提供了一个难能可贵的机会来描述人类 具有高时空分辨率的嗅皮层处理。我们最近的研究证实了这种气味 刺激会在人梨状皮质(PC)引起3-7赫兹(“theta”频率)的节律性振荡，而且明显 气味在嗅觉开始后的100毫秒内立即唤起明显的theta活动。我们还展示了theta 在气味存在的情况下，PC和海马体之间的相位耦合增加，但空气不存在。 这些新颖的发现为这里概述的实验提供了一个平台。通过利用我们在嗅觉方面的专业知识 认知神经科学用最先进的iEEG信号分析工具，我们将建立一个生理学的 在种群动态和网络交互水平上为人类嗅觉加工奠定基础。我们的 根据动物模型的数据，拟议的研究旨在测试基于前瞻性的、假设驱动的 关于气味感知的机械基础的问题。目标1将解决如何在 气味刺激的基本特征改变PC神经动力学--通过theta振荡的变化来评估 功能。目的2将测试PC-海马区耦合在气味辨别中的作用。目标3将考察 PC theta在气味感知中起因果作用，并将识别theta可能通过的机制 形状气味处理。这里开发的概念性方法应该有助于指导未来的基础和临床 评估人脑嗅觉振荡生物学相关性的研究策略。

ABSTRACT Research in our laboratory focuses on understanding how the human brain encodes and interprets information about odor stimuli. Often regarded as the trivial “fifth” sense, the human sense of smell is in fact remarkably robust. The human nose can discriminate odors with subtle differences in molecular structure, distinguish thousands of unique smells, and transport us back in time to reactivate distant memories and emotional states. Additionally, the olfactory system (in human and non-human animals) is an increasingly attractive and powerful model for studying brain function under normal and pathological conditions. Studies investigating the human olfactory system have traditionally relied on two types of methods: functional magnetic resonance imaging (fMRI) and scalp-based EEG. While these non-invasive approaches have yielded important insights about odor processing, the scope of testable questions is limited due to temporal (MRI) and spatial (EEG) constraints. In particular, there is a critical knowledge gap in understanding the physiological basis of the human sense of smell. Over the last few years, we have had the opportunity to obtain intracranial EEG (iEEG) recordings from epilepsy patients with medically resistant seizures. As part of a standard surgical pre-clinical evaluation, patients undergo surgery during which invasive depth electrodes are implanted into the brain to localize epileptogenic foci. This approach provides an invaluable opportunity to characterize human olfactory cortical processing with high spatiotemporal resolution. Our recent studies have established that odor stimuli evoke rhythmic oscillations of 3-7 Hz (“theta” frequency) in human piriform cortex (PC), and that distinct odors evoke distinct theta activity as soon as 100 ms after the onset of a sniff. We have also shown that theta phase coupling between PC and hippocampus increases in the presence of odor but not air. These novel findings provide a platform for experiments outlined here. By leveraging our expertise in olfactory cognitive neuroscience with state-of-the-art iEEG signal analysis tools, we will establish a physiological foundation of human olfactory processing at the level of population dynamics and network interactions. Our proposed studies, informed by data from animal models, are designed to test forward-based, hypothesis-driven questions about the mechanistic underpinnings of odor perception. Aim 1 will address how changes in fundamental features of odor stimuli alter PC neural dynamics as assessed by changes in theta oscillatory features. Aim 2 will test the role of PC-hippocampal coupling in odor discrimination. Aim 3 will examine whether PC theta plays a causal role in odor perception, and will identify potential mechanisms by which theta can shape odor processing. The conceptual approaches developed here should help guide future basic and clinical research strategies for assessing the biological relevance of olfactory oscillations in the human brain.