Spatiotemporal Mechanisms of Olfactory Processing in the Human Brain

This is a request to the NIH/NIDCD for renewal of an Investigator-Initiated Research Project Grant (R01)Award for Jay A. Gottfried, MD, PhD, Professor of Neurology and Psychology at the University of Pennsylvania in Philadelphia, PA.Research in my laboratory focuses on understanding how the human brain encodes and interprets information about smell. Although often considered to be an unheralded sense, the human sense of smell is remarkably robust and highly malleable. Our noses can discriminate odors with subtle differences in molecular structure, distinguish thousands of unique smells, transport us back in time to reactivate distant memories and emotional states, and detect certain odors with greater sensitivity than observed in other animals. Additionally, the olfactory system (in humans and other vertebrates) is an increasingly attractive and powerful model for studying brain function under normal and pathological conditions, especially in Parkinson’s Disease and Alzheimer’s Disease, where deficits in the sense of smell often arise in a “pre-clinical” stage prior to the onset of more traditional symptoms and signs.Our neuroscientific understanding of the human olfactory system has principally come from two types of methods: functional magnetic resonance imaging (fMRI) and surface-based EEG. While these approaches have brought important insights to the functional substrates of odor processing in the human brain, there are key limitations of both temporal resolution (in the case of fMRI) and spatial resolution (in the case of EEG). During the current funding period of this R01 grant, we have had the opportunity to obtain intracranial EEG (iEEG) recordings from epilepsy patients with medically refractory seizures. Such techniques provide an invaluable window for characterizing the basic electrophysiology of human olfactory brain areas with unrivaled temporal and spatial resolution. Our recent iEEG work has found that odor stimuli induce rhythmic oscillations of 3-7 Hz (“theta” frequency) in piriform (olfactory) cortex, and that odor-specific information can be read out from these oscillatory cycles as fast as 110 milliseconds after stimulus onset. These initial exciting findings have established first principles of olfactory oscillations in the human brain and will serve as a springboard for new experiments proposed here. By leveraging our expertise in olfactory cognitive neuroscience with sophisticated iEEG signal analysis tools, we will be able to gain an in-depth mechanistic understanding of the role that theta oscillatory signals play in odor coding and perception. Studies will address fundamental questions about what perceptual features are specifically represented in piriform oscillations, when those features are represented on a millisecond time scale, and how olfactory feature coding evolves across time and frequency space. Complementary studies will examine some of the external parameters that drive the emergence of theta oscillations, and will also attempt to establish causal links between piriform oscillatory activity and odor perception. Together these experiments will advance knowledge of the electrophysiological determinants of olfactory processing in the human brain, and the principles and mechanisms identified here should have a far-reaching impact on basic models of human olfactory system function and more generally on the role of theta oscillations in information processing. Finally, this work should also hold relevance for clinical translational models of neurological disorders, including Parkinson’s, Alzheimer’s, a