Johan N. Lundström

One of the primary functions of olfaction is to assess whether a smell is pleasant or unpleasant (i.e., odor valence). This enables us to make crucial decisions about approaching or avoiding the odor (e.g., avoiding rotten food). Due to limitations in non-invasive brain imaging techniques, next to nothing is known about how the core and initial olfactory system —from the peripheral to the primary olfactory cortex — simultaneously encode this fundamental odor precept in humans. In this project, we will use new techniques that enable us to investigate the core olfactory system simultaneously, from the olfactory epithelium (EPT) to the olfactory bulb (OB), and the olfactory cortex (piriform cortex, PC). Specifically, we will determine how each node codes odor valence and how this information is communicated between each node to create the final odor valence percept. Exploring the mechanisms of odor valence is necessary to understand the most fundamental principle of human olfaction. Today, we have far more knowledge about how perception works in vision and hearing. This project aims to establish a similar level of knowledge for olfaction.

Intensity coding is at the core of perception, allowing us to discriminate between the candle and the sun, the whisper and the shout. Odors also exist across a vast intensity spectrum, from the barely perceptible fragrance of a light rain to the overwhelming blast of rotten meat. Unlike the well-documented mechanisms in vision and audition, the encoding of odor intensity in the olfactory system remains largely unexplored due to technological limitations. Our project aims to elucidate the most basic principles underlying perceived odor intensity. We will achieve this by studying the bottom-up and top-down mechanisms that shape perceived odor intensity by investigating the encoding and communication of odor signals across the major nodes of the olfactory system: the olfactory epithelium, olfactory bulb, and piriform cortex. Utilizing novel techniques developed in our lab, which enables simultaneous recordings from these critical nodes, we will conduct a series of behavioral experiments. Our objectives are threefold: to determine how odor intensity is coded within each node, how these perceptions are communicated across the system, and how cognitive processes and contextual information influence perceived intensity. Our approach addresses the limitations of traditional human and animal studies and holds promise for advancing our fundamental understanding of olfaction. Critically, the findings can offer insights into the common principles shaping perception across all our senses.

This proposal is framed by a technological goal: We aim to digitize smell. Achieving this is currently prevented by gaps in basic science. We aim to fill these gaps, culminating in a proof of concept for our model. The primary gap we identify is lack of data on what humans typically smell. Phrased conceptually, in Aim 1 we ask what are the natural statistics of human olfactory perceptual space. We address this in a series of three experiments, highlighted by one where we equip participants with a wearable sampling apparatus we designed and built for this proposal. The apparatus measures sniffing behaviour to identify odor sampling, measures neural activity to verify olfactory perception, takes video of the visual scene, analyses total levels of volatile organic compounds in real time, and collects odor samples for detailed analysis off line. In other words, we generate an olfactory equivalent of Google Street View, with the addition of chemical, perceptual and neural data. Using this we will characterise the natural statistics of human olfactory perceptual space. Moreover, a major contribution of this proposal will be in posting this massive data as a publicly available recourse. Next, in Aim 2 we will use this data to digitize human olfactory perceptual space. We build on a model that allows us to recreate odors using a restricted set of odor primaries. We will test our model in two frameworks: One we call SmelloVision, where we develop the algorithmic framework to generate an odor to match any digital image, and one we call TelleSmell, where we develop a device to sense the environment, the algorithmic framework to transfer the data, and a device to generate the corresponding odor remotely. We provide pilot data for Aim 2 where we sensed an odor in Mainz (Germany), transmitted the data over IP to Rehovot (Israel), where we successfully recreated the smell. This was, as far as we know, the first transmission of odor over IP.

Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia, but it is considerably under-diagnosed. The main reasons for this are the lack of a reliable biomarker for Lewy pathology, and that many DLB patients also have Alzheimer and cerebrovascular pathologies in their brains. ´Find-DLB’ is a leading international platform to tackle these problems.The purpose of ‘Find-DLB’ is to intensify DLB research in Sweden, with a strong focus on novel biomarkers and translation to precision medicine. ‘Find-DLB’ spans from 2023 to 2027, including (1) testing of a novel biomarker of Lewy pathology for immediate clinical use in hospitals across Sweden

(2) development of new imaging biomarkers to disentangle mixed pathologies and (3) elucidate what causes brain degeneration in DLB

(4) development of precision medicine risk profiles and diagnostic tools, with a strong focus on sex differences. ‘Find-DLB’ will create a prospective Swedish cohort and use unique large international data, including around 6000 participants, the largest platform of this kind.‘Find-DLB’ strives to transform the way we diagnose DLB today. It will improve management and care of our DLB patients, and will increase social awareness about the disease. Project’s findings will set the ground for precision medicine-based therapies. ‘Find-DLB’ is an unprecedented multicohort platform including collaborations among multiple centers across the world.

How our perception works is well explored, and yet we do not understand how the human brain accomplishes the high degree of plasticity demonstrated by our perceptual systems. Here, we will determine the central mechanisms that regulate human perceptual plasticity. This basic question of sensory psychology has remained largely unanswered due to methodological hindrances, among which the unfeasibility of a within-person design stands out, when exploring plastic changes due to sensory loss or gain. Utilizing a unique patient population that undergoes cyclic periods of olfactory dysfunction due to nasal blockage, we will use a multimodal neuroimaging approach and determine what neural changes are linked to behavioral change in sensory functions. Specifically, we will combine a new electro-cortical measuring method, which allows us to assess functional connectivity with millisecond resolution, with that of classic magnetic resonance methods to assess mechanisms of perceptual plasticity at multiple levels of processing. The proposed studies will answer the basic questions of what central mechanisms govern perceptual plasticity as well as whether sensory gain and sensory loss are merely opposite sides of the same mechanistic coin.

More than half of all individuals with confirmed COVID-19 experience smell dysfunctions at some point during the disease. Critically, recent data show that for individuals who had mild to medium acute COVID symptoms, a reduced or distorted sense of smell is the most prevalent symptom (34%) eight months after serologically confirmed SARS-CoV-2 infection. However, few treatments exist for smell dysfunction, an affliction associated with a range of negative long-term health outcomes. A transdisciplinary research team including primary and secondary care clinics as well as basic scientists will in the proposed project address two overarching aims. First, we will determine the prevalence, symptomatology, and pathogenesis of post-COVID olfactory dysfunctions in a serologically highly controlled longitudinal cohort study. Second, we will assess the efficacy of three novel therapeutic treatments for two common post-COVID olfactory dysfunctions, hyposmia and parosmia. These online treatments are scalable and easily implemented in the primary care system at little cost for both patients and the health care system. If successful, the treatment for hyposmia will help many individuals regain their sense of smell. Likewise, the treatment for parosmia, which will be the first and only treatment available, will provide individuals with medium to severe parosmia some potential refuge from the often debilitating difficulty they experience when eating and interacting with odors in their life.