Noam Sobel - US grants

DESCRIPTION (provided by applicant): The aim of this study is to use fMRI in order to characterize amygdaloid-complex function in human olfaction. This aim will be achieved through the following specific aims: 1. To discern which subunits of the human amygdaloid complex are involved in olfactory processing, and which are not. The amygdala is not one homogeneous nucleus, but rather a group of structures, referred to as the amygdaloid complex. State-of-the-art neuroimaging methods (event related design combined with high-field-strength high-resolution fMRI) will be used to determine which portion of the amygdaloid complex is involved in olfactory processing in humans. 2. To test the hypothesis that the amygdaloid complex is encoding the intensity of odorants. A major underlying theme on the role of the amygdala in the encoding of sensory input is that it is encoding stimulus intensity. This hypothesis will be directly addressed by measuring with fMRI the amygdala response to various concentrations (intensities) of odorants regardless of valance. 3. To test the hypothesis that the amygdaloid complex is encoding the valance of odorants. A competing to the above underlying theme on the role of the amygdala in the encoding of sensory input, is that it is encoding stimulus valance. This hypothesis will be directly addressed by measuring with fMRI the amygdala response to different odorants varying in valance but not intensity. Achievement of the above aims will pose a significant contribution to the systems-level characterization of the human olfactory system. This study will both pinpoint a component of primary olfactory cortex in humans, and elucidate its role in olfactory processing. In addition, this study will have used olfaction (as opposed to vision and audition) as a path by which to probe the role of the amygdala in sensory processing in general. In that, this study will further our understanding of human brain function, opening avenues to the understanding of the healthy brain and treatment of the diseased brain.

DESCRIPTION (provided by applicant): Cognitive Aspects of Human Olfaction: the "What" and "Where" subsystems Evidence from vision and audition suggests cortical processing of sensory information occurs along two anatomically dissociable streams. In the simplest form, these consist of a ventral stream that processes object identification, and a dorsal stream that processes object location. This concept relates to a major question on brain organization, namely, does the brain employ convergent or divergent mechanisms in processing information. Current evidence points to convergence in that spatial information from both vision and audition converges in dorsal regions, and stimulus identity information converges in ventral regions. Here this theoretical framework is tested using olfaction. This is accomplished through 3 specific aims: Aim 1 is a test of the hypothesis that humans can use information obtained through smell to create a spatial map. This is achieved by asking if humans can perform scent tracking, and by examining the effects of odor properties (e.g., identity) and sampling strategies (sniffing frequency) on this behavior. Aim 2 is a test of the hypothesis that humans can localize an odor source without moving their head. This is achieved by asking if humans can perform egocentric olfactory localization and by examining the effects of practice, odor properties (e.g., identity) and sampling strategies (sniffing frequency) on this behavior. Aim 3 consists of using fMRI to probe the neural mechanisms subserving spatial localization of odors. Pilot data from Aims 1 and 2 suggests humans do have some spatial abilities in olfaction. In Aim 3 functional imaging is used to test whether this spatial information is incorporated within previously identified cortical pathways (the dorsal "where" stream). These three aims, which include psychophysics in the field, psychophysics in the lab, and fMRI, combine to form the first comprehensive study of spatial abilities in human olfaction. Results promise to further our understanding of fundamental concepts in brain organization.

Neural substrates of human olfaction. Over the past 10 years there has been an explosion in knowledge on the molecular and cellular components of olfactory processing at the level of olfactory epithelium and bulb. However, the systems-level neural organization of olfactory processing in humans remains largely unknown. Here we aim to combine functional magnetic resonance imaging (fMRI) and olfactory psychophysics in order to characterize function in primary olfactory cortex. This long-term goal will be addressed through a series of specific aims that fall into two domains: Domain I: Primary olfactory cortex activity that reflects odorant content A. We will test the hypothesis that increased odorant intensity is encoded in increased levels of neural activity in primary olfactory cortex. B. We will test the hypothesis that odorant identity is spatially encoded in primary olfactory cortex. Domain II: Odor-independent activity in primary olfactory cortex A. We will test the hypothesis that activity in primary olfactory cortex is context dependant B. We will test the hypothesis that olfactory workin,q memory is reflected in activity patterns in primary olfactory cortex. Taken together, these specific aims promise to significantly contribute to our understanding of this poorly understood brain region, as well as offer a hypothesis-driven answer to the fundamental question of "what is "primary" about primary olfactory cortex?" The knowledge we aim to obtain here may significantly improve our understanding of olfaction in both health and disease.

This research addresses a fundamental aspect of sensory processing,
that is, the active nature of sensation. The term "sensation" itself
appears inherently passive, and conjures images of sensory stimuli
projected onto the sensory surface, as if it were a photodiode, microphone, or chemically sensitive polymer. The sensing mammal, however, actively seeks sensory input, and nowhere is this more evident than in olfaction, where the sensory search presents itself as a clearly noticeable sniff. This sniff is constantly and accurately modulated in accordance with the sensory input -- a strong odor is greeted with a weak sniff and a weak odor is greeted with a strong sniff. Recently, whole-brain imaging techniques have opened up a new look at the olfactory system. Although the cerebellum has never been considered as part of the olfactory system, nearly every olfaction imaging study to date has reported odorant-induced activity in the cerebellum in both humans and monkeys. The role of the cerebellum in olfaction, however, remains unknown. With NSF funding, Dr. Sobel is testing the hypothesis that the role of the cerebellum in olfaction is control of the olfactomotor response. Specifically, sniffs are modulated in accordance to odorant content: high intensity odorants are met with small sniffs, and low intensity odorants are met with large sniffs. This implies a neural feedback mechanism that measures odorant intensity and modulates sniff vigor accordingly. It is proposed that control of this mechanism is the cerebellar role in olfaction. To test this two different methods are being applied, 1) psychophysics in patients with cerebellar lesions, and 2) functional magnetic resonance imaging (fMRI). In cerebellar lesion patients, the question will be tested whether the well-documented inverse relation between odorant intensity and sniff volume breaks down. This would be predicted if the cerebellum indeed controls the olfactomotor response. With fMRI, the neural path from the nose to the cerebellum will be probed, specifically whether this link is ipsilateral or contralateral. This effort promises to elucidate both a fundamental component of olfactory processing, as well as shed light on cerebellar function in general.

The results of this project promise to further the understanding of basic mechanisms underlying sensory perception. Understanding of these
mechanisms may open doors towards both improved treatment of sensory
impairments, as well as incorporation of the elucidated mechanisms into
devices aimed at mimicking sensory perception. This is especially true in olfaction, considering the increased interest in technologies aimed at sensing air-borne markers in applications ranging from disease diagnostics to landmine and biological-agent detection.