Christina M. Zelano - US grants

DESCRIPTION (provided by applicant): In general, conscious perception of sensory stimuli depends on a pathway to neocortex, and in all modalities except for olfaction, this requires going through the thalamus. Careful anatomical studies have found that in olfaction, the pathway between olfactory cortex and prefrontal cortex is mostly direct, with only a small contingent of fibers going to mediodorsal thalamus. This fundamental difference in the structural organization of the olfactory system indicates a qualitatively different role for the thalamus in olfactory processing. The goal of this proposal is to elucidate that role. In Aim 1, I will use fMRI to characterize the nature of intentional modulation of activity in the thalamus. By systematically altering attention to different odors, I will test the hypothesis that distributed codes of odor quality are attention dependent in the mediodorsal nucleus of the thalamus, while they are attention independent in primary olfactory cortex. In Aim 2, I will use fMRI to Using hierarchical cluster analysis and a general linear model approach to data analysis, I will be able to distinguish between olfactory brain regions that are involved in basic sensory processing, accumulation of information and moment of recognition during odor valence decisions and quality recognition. In Aim 3, I will use fMRI to ask whether the mediodorsal thalamus integrates information from multiple modalities during olfactory decisions. During scanning, subjects will smell odors that are either presented alone or paired with stimuli from other modalities, enabling us to test for multimodal olfactory response profiles in the mediodorsal thalamus. PUBLIC HEALTH RELEVANCE: Understanding the functional organization of the olfactory system has numerous potential health benefits. For one, olfactory structures overlap with brain areas that are affected by many common diseases including Alzeimer's disease, epilepsy, Parkinson's disease and schizophrenia. The mediodorsal thalamus, which is the main focus of this proposal, has been implicated in all of the aforementioned diseases. Increased knowledge of the role of the mediodorsal thalamus in olfactory processing will increase our knowledge of the diseases that affect it.

DESCRIPTION (provided by applicant): A career development plan is proposed for Dr. Christina Zelano, who is committed to a research career studying the neural substrates of the human olfactory system. Dr. Jay Gottfried, a renowned scholar in the field of human olfaction at Northwestern University will function as the primary mentor. Furthermore, Dr. Stephan Schuele, Directory of the Comprehensive Epilepsy Center at Northwestern Memorial Hospital will contribute to the proposed research as a collaborator, and Dr. Robert Knight, Director of the Helen Wills Neuroscience Institute at University of California, Berkeley will contribute as a consultant on the proposed research projects. Training will involve electrocorticography (ECoG) and electrical stimulation techniques for the measurement of odor-evoked brain activity in patients who are undergoing brain surgery for epilepsy. The overall goal of the proposed research is to characterize the temporal evolution and frequency composition of olfactory attentional neural correlates in the human brain. Because olfactory brain structures are located deep within the limbic temporal and frontal portions of the brain, the electrical signals generated from these regions are severely attenuated at the scalp, limiting the value of surface EEG in measuring olfactory local field potentials. To overcome this problem, the proposed research will optimize an olfactory (ECoG) paradigm in which electrical signals are recorded directly from olfactory brain structures in patients who are undergoing brain surgery for intractable epilepsy. Using this technique, the precise timing and frequency of olfactory attentional oscillations will b investigated. Several aspects of olfactory attention will be explored, from basic (state-dependent gating of incoming odor information) to more complex (modality specific) mechanisms. Given the lack of a requisite pre-cortical thalamic relay in the olfactory system, the proposed research will test the hypothesis that sensory gating of olfactory information occurs at the level of the olfactory bulb, upstream from olfactory (piriform) cortex. Olfactory sensory gating will be explored through two separate experiments making use of ECoG and fMRI techniques. The proposed research will use ECoG approaches to test two specific hypotheses regarding complex forms of olfactory attention. First, experiments are proposed to determine the spatiotemporal composition of neural oscillatory responses in relation to modality-specific olfactory attentional mechanisms. Second, experiments are proposed to determine the neural origins and spectro-temporal patterns of olfactory predictive coding mechanisms. Further studies will make use of electrical stimulation techniques to establish the necessity of identified brain regions in the formation of predictive spectro-temporal odor templates. The proposed research has applications to a broad range of neurological disorders that present with olfactory deficits, including Alzheimer's disease, epilepsy, Parkinson's disease and schizophrenia.

Since it is not possible to encounter a smell in our external environment without first inhaling through the nose, stimulus sampling in the olfactory system is inextricably linked to breathing. Respiratory-driven local field potential (LFP) oscillations are important for odor coding mechanisms in the rodent olfactory bulb, but their role in higher olfactory structures such as piriform cortex is not well understood, with even less known about respiratory oscillations in the human brain. While breathing drives oscillations in the brain, the reverse must also be true; stimulus sampling in the olfactory system requires overriding of autonomic respiratory rhythms in order to achieve intentional sniffing and fast adaptive sniff modifications in response to chemical stimuli. The overarching goal of this proposal is to understand the function of respiratory oscillations in the human brain, including their role in the formation of odor-evoked responses in olfactory brain regions and fostering communication across limbic networks involved in odor sampling and fast adaptive sniffing modifications. We also aim to elucidate limbic networks involved in olfactory sampling behaviors. To measure LFPs from medial olfactory structures in the human brain, we will use intracranial electroencephalography (iEEG) with a high sampling rate (up to 10,000Hz), allowing analysis of limbic LFP oscillations across a range of frequencies. We will use a combination of iEEG, direct electrical stimulation, psychophysics and functional neuroimaging and tractography techniques to accomplish the goals of three Specific Aims. First, we will test the hypothesis that slow respiratory-linked LFP oscillations organize the spectral and temporal structure of odor-evoked responses in human piriform cortex. To isolate the impact of slow respiratory-driven oscillations on odor codes, we will deliver odors in the presence and absence of sniffs, accomplished by velopharyngeal closure paired with artificial air flow through the nose. Second, we will test the hypothesis that slow respiratory oscillations across a limbic network of regions important for respiratory control mediate odor sampling, or sniffing behaviors. Here we will use iEEG techniques, electrical stimulation and MRI techniques to study limbic networks involved in the control of nasal breathing with a particular emphasis on the amygdala. Third, we will use iEEG, electrical stimulation and psychophysics to test the hypothesis that adaptive fast sniffing reductions in response to potentially threatening odors are mediated by the amygdala, and can generalize to non-olfactory stimuli in anxious states. The proposed studies have several direct clinical applications. Research on Sudden Unexpected Death in Epilepsy (SUDEP), the most common cause of death in patients with Epilepsy, implicates respiratory dysfunction as a potential cause, with converging evidence for an amygdalar role in the disease (13,14). In so far as our proposal aims to deepen understanding of the neural mechanisms of the amygdala's role in respiratory control, these studies will be important in gaining a better understanding of SUDEP. Our research will also elucidate dysfunctional olfactory-limbic networks underlying clinical anxiety.

Several subregions of the human amygdala receive direct projections from the olfactory bulb, yet the functional and anatomical properties of these olfactory projections are not well understood. Rodent studies have begun to shed light on the functions of some of these olfactory amygdala subregions in mediating olfactory-guided social and approach/avoid behaviors. However, there are significant differences in the projections from the olfactory bulb to the amygdala between species. For example, in rodents, the medial amygdala receives highly dense fibers from the accessory olfactory bulb. In stark contrast, humans lack an accessory olfactory system entirely. There are also other apparent differences in the specific amygdalar targets of main olfactory bulb projections between species, although these targets have not been well-characterized in humans, further highlighting the need for human studies in this area. The goal of this proposal is to characterize the anatomical and functional properties of the olfactory projections into the human amygdala. We will take a multifaceted approach, combining functional neuroimaging, electrophysiology and stimulation, which will strengthen the reproducibility and rigor of our findings. The goal of Aim 1 is to anatomically and functionally localize the primary olfactory cortical regions of the human amygdala. At the structural level, we will use a novel new multi- shot diffusion-weighted imaging sequence to localize olfactory projections into amygdala subregions. At the functional level, we will use resting fMRI combined with k-means clustering algorithms to parcellate amygdalar subregions based on distinct whole-brain functional connectivity profiles, and event-related fMRI to functionally localize odor-responsive subregions of the amygdala. The goal of Aim 2 is to shed light on the roles of distinct amygdala subregions in olfactory perception. We will use event-related fMRI to acquire high-resolution multivariate signals from the amygdala during olfactory perceptual tasks. The goal of Aim 3 is to assess the necessity of the amygdala subregions in olfactory perception. We will use intracranial EEG techniques to measure different olfactory perceptual decisions during clinician-delivered, clinically prescribed, disruptive electrical stimulation directly into the human amygdala. The proposed studies will provide a detailed characterization of the functional and anatomical properties of an under-studied group of amygdala subregions, including the medial nucleus of the amygdala, the cortical amygdala and the periamygdaloid cortex. Recent studies suggest these anterior and medial amygdala areas may play a role in sudden unexpected death in epilepsy (SUDEP), which is the leading cause of death in patients with temporal lobe epilepsy and has no known cause or treatment. Furthering our understanding of the functional and structural properties of these brain regions has strong clinical importance for these patients.