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 th...