What do brain oscillations tell about the human sense of smell?

Brain activity may manifest itself as oscillations which are repetitive rhythms of neuronal firing. These local field potentials can be measured via intracranial electroencephalography (iEEG). This review focuses on iEEG used to map human brain structures involved in olfaction. After presenting the methodology of the review, a summary of the brain structures involved in olfaction is given, followed by a review of the literature on human olfactory oscillations in different contexts. A single case is provided as an illustration of the olfactory oscillations. Overall, the timing and sequence of oscillations found in the different structures of the olfactory system seem to play an important role for olfactory perception.

The neural representations of valence transformation in indole processing.

Indole is often associated with a sweet and floral odor typical of jasmine flowers at low concentrations and an unpleasant, animal-like odor at high concentrations. However, the mechanism whereby the brain processes this opposite valence of indole is not fully understood yet. In this study, we aimed to investigate the neural mechanisms underlying indole valence encoding in conversion and nonconversion groups using the smelling task to arouse pleasantness. For this purpose, 12 conversion individuals and 15 nonconversion individuals participated in an event-related functional magnetic resonance imaging paradigm with low (low-indole) and high (high-indole) indole concentrations in which valence was manipulated independent of intensity. The results of this experiment showed that neural activity in the right amygdala, orbitofrontal cortex and insula was associated with valence independent of intensity. Furthermore, activation in the right orbitofrontal cortex in response to low-indole was positively associated with subjective pleasantness ratings. Conversely, activation in the right insula and amygdala in response to low-indole was positively correlated with anticipatory hedonic traits. Interestingly, while amygdala activation in response to high-indole also showed a positive correlation with these hedonic traits, such correlation was observed solely with right insula activation in response to high-indole. Additionally, activation in the right amygdala in response to low-indole was positively correlated with consummatory pleasure and hedonic traits. Regarding olfactory function, only activation in the right orbitofrontal cortex in response to high-indole was positively correlated with olfactory identification, whereas activation in the insula in response to low-indole was negatively correlated with the level of self-reported olfactory dysfunction. Based on these findings, valence transformation of indole processing in the right orbitofrontal cortex, insula, and amygdala may be associated with individual hedonic traits and perceptual differences.

Semantic context-dependent neural representations of odors in the human piriform cortex revealed by 7T MRI.

Olfactory perception depends not only on olfactory inputs but also on semantic context. Although multi-voxel activity patterns of the piriform cortex, a part of the primary olfactory cortex, have been shown to represent odor perception, it remains unclear whether semantic contexts modulate odor representation in this region. Here, we investigated whether multi-voxel activity patterns in the piriform cortex change when semantic context modulates odor perception and, if so, whether the modulated areas communicate with brain regions involved in semantic and memory processing beyond the piriform cortex. We also explored regional differences within the piriform cortex, which are influenced by olfactory input and semantic context. We used 2 × 2 combinations of word labels and odorants that were perceived as congruent and measured piriform activity with a 1-mm isotropic resolution using 7T MRI. We found that identical odorants labeled with different words were perceived differently. This labeling effect was observed in multi-voxel activity patterns in the piriform cortex, as the searchlight decoding analysis distinguished identical odors with different labels for half of the examined stimulus pairs. Significant functional connectivity was observed between parts of the piriform cortex that were modulated by labels and regions associated with semantic and memory processing. While the piriform multi-voxel patterns evoked by different olfactory inputs were also distinguishable, the decoding accuracy was significant for only one stimulus pair, preventing definitive conclusions regarding the locational differences between areas influenced by word labels and olfactory inputs. These results suggest that multi-voxel patterns of piriform activity can be modulated by semantic context, possibly due to communication between the piriform cortex and the semantic and memory regions.

Age-related differences in perception and coding of attractive odorants in mice.

Hedonic perception deeply changes with aging, significantly impacting health and quality of life in elderly. In young adult mice, an odor hedonic signature is represented along the antero-posterior axis of olfactory bulb, and transferred to the olfactory tubercle and ventral tegmental area, promoting approach behavior. Here, we show that while the perception of unattractive odorants was unchanged in older mice (22 months), the appreciation of some but not all attractive odorants declined. Neural activity in the olfactory bulb and tubercle of older mice was consistently altered when attraction to pleasant odorants was impaired while maintained when the odorants kept their attractivity. Finally, in a self-stimulation paradigm, optogenetic stimulation of the olfactory bulb remained rewarding in older mice even without ventral tegmental area's response to the stimulation. Aging degrades behavioral and neural responses to some pleasant odorants but rewarding properties of olfactory bulb stimulation persisted, providing new insights into developing novel olfactory training strategies to elicit motivation even when the dopaminergic system is altered as observed in normal and/or neurodegenerative aging.

Endogenous cannabinoids in the piriform cortex tune olfactory perception.

Sensory perception depends on interactions between external inputs transduced by peripheral sensory organs and internal network dynamics generated by central neuronal circuits. In the sensory cortex, desynchronized network states associate with high signal-to-noise ratio stimulus-evoked responses and heightened perception. Cannabinoid-type-1-receptors (CB1Rs) - which influence network coordination in the hippocampus - are present in anterior piriform cortex (aPC), a sensory paleocortex supporting olfactory perception. Yet, how CB1Rs shape aPC network activity and affect odor perception is unknown. Using pharmacological manipulations coupled with multi-electrode recordings or fiber photometry in the aPC of freely moving male mice, we show that systemic CB1R blockade as well as local drug infusion increases the amplitude of gamma oscillations in aPC, while simultaneously reducing the occurrence of synchronized population events involving aPC excitatory neurons. In animals exposed to odor sources, blockade of CB1Rs reduces correlation among aPC excitatory units and lowers behavioral olfactory detection thresholds. These results suggest that endogenous endocannabinoid signaling promotes synchronized population events and dampen gamma oscillations in the aPC which results in a reduced sensitivity to external sensory inputs.

Behavioural evidence for enhanced olfactory and trigeminal perception in congenital hearing loss.

Sensory deprivation, especially hearing loss (HL), offers a valuable model for studying neuroplasticity in the human brain and adaptive behaviours that support the daily lives of those with limited or absent sensory input. The study of olfactory function is particularly important as it is an understudied aspect of sensory deprivation. This study aimed to compare the effects of congenital HL on olfactory capacity by using psychophysical tasks. Methodological concerns from previous studies regarding the onset of HL and cognitive assessments were addressed. We recruited 11 individuals with severe-to-profound sensorineural HL (SNHL) since birth and 11 age- and sex-matched typical hearing non-signers. We used standardized neuropsychological tests to assess typical cognition among participants with SNHL. We evaluated olfactory functions by assessing olfactory detection threshold, odour discrimination and odour identification. Hearing-impaired participants outperformed their typical hearing counterparts in olfactory tasks. We further evaluated the accuracy and response time in identifying and localizing odours to disentangle olfactory sensitivity from trigeminal system sensitivity. Participants with SNHL demonstrated higher sensitivity to both the identification and localization tasks. These findings suggest that congenital SNHL is associated with enhanced higher-level olfactory processing and increased trigeminal sensitivity.

Molecular descriptors of icewine odorants: A first insight into their relationship with metabolism and olfactory perception.

To investigate the differences in physicochemical parameters of compounds that are metabolized from different precursors and contribute to the aroma perception of icewine, odor-active compounds in icewine were identified by gas chromatography-olfactometry (GC-O) analysis combined with comprehensive two-dimensional GC and time-of-flight mass spectrometry (GC  × â€¯GC-TOFMS) analysis, and the molecular descriptors of these odor-active compounds were calculated by computational chemistry software. The distribution pattern of these odorants classified by their precursors and their olfactory perception was visualized on the basis of their molecular descriptor differences. The results showed that the odorants sourced from different precursors could be clearly separated from each other based on their molecular descriptors, which belonged to blocks such as constitution indices and 2D matrix-based descriptors. The results also showed that honey and cooked potatoe descriptions or peach and smoke descriptions have quite different molecular descriptors. This study should contribute to future research that relates to computational chemistry-based aroma perception and prediction in fermented beverages. PRACTICAL APPLICATION: The results obtained from this study may be useful for the construction of a classification system of various odor-active compounds in a given product and may provide a molecular solution for the determination of different perceptual dimensions of an odor mixture.

An Antenna-Enriched Chemosensory Protein Plays Important Roles in the Perception of Host Plant Volatiles in Bactrocera dorsalis (Diptera: Tephritidae).

Olfaction plays indispensable roles in insect behavior such as host location, foraging, oviposition, and avoiding predators. Chemosensory proteins (CSPs) can discriminate the hydrophobic odorants and transfer them to the odorant receptors. Presently, CSPs have been identified in many insect species. However, their presence and functions remain unknown in Bactrocera dorsalis, a destructive and invasive insect pest in the fruit and vegetable industry. Here, we annotated eight CSP genes in the genome of B. dorsalis. The results of quantitative real-time polymerase chain reaction (RT-qPCR) showed that BdorCSP3 was highly expressed in the antennae. Molecular docking and in vitro binding assays showed that BdorCSP3 had a good binding ability to host volatiles methyl eugenol (ME, male-specific attractant) and ß-caryophyllene (potential female attractant). Subsequently, CRISPR/Cas9 was used to generate BdorCSP3-/- mutants. Electroantennograms (EAGs) and behavioral assays revealed that male mutants significantly reduced the preference for ME, while female mutants lost their oviposition preference to ß-caryophyllene. Our data indicated that BdorCSP3 played important roles in the perception of ME and ß-caryophyllene. The results not only expanded our knowledge of the olfaction perception mechanism of insect CSPs but also provided a potential molecular target for the control of B. dorsalis.

Investigation of olfactory perception by a putative adsorption process of sotolone and abhexone on human olfactory receptor OR8D1: Statistical physics modeling and molecular docking.

In the present paper, a double layer advanced model was used to investigate the adsorption process putatively involved in the olfactory perception of sotolone and abhexone molecules on the human olfactory receptor OR8D1. The number of adsorbed molecules or the fraction of adsorbed molecule per site, n, informed that the two odorants molecules are docked on OR8D1 binding sites with mixed parallel and nonparallel anchorages. Furthermore, the estimated molar adsorption energy (-ΔE1 and -ΔE2) were inferior to 40 kJ/mol for the two adsorption systems, which confirmed the physical nature and the exothermic character of the adsorption process. In addition, stereographic characterizations of the receptor sites surface were carried out through the determination of the receptor site size distribution (RSDs) via Kelvin equation, which spread out from 0.05 to 1.5 nm. The adsorption energy distributions (AEDs) via Polayni equation show an adsorption band spectrum localized between 17 kJ/mol and 22.5 kJ/mol for sotolone and abhexone molecules respectively. A molecular docking calculation was performed. The results indicate that the binding affinities are belonging to the spectrum of the energy band of the molecules sotolone and abhexone, with values 19.66 kJ/mol and 19.24 kJ/mol.

Olfactory cortex: Temporal segregation of inputs from the two nostrils.

Piriform cortex processes odor information coming from two nostrils to give rise to unified perception of odorant identity and intensity. A new study reveals that human piriform cortex harbours distinct representations of odor input from ipsilateral and contralateral nostrils through temporal segregation.

An olfactory perceptual fingerprint in people with olfactory dysfunction due to COVID-19.

The sense of smell is based on sensory detection of the molecule(s), which is then further perceptually interpreted. A possible measure of olfactory perception is an odor-independent olfactory perceptual fingerprint (OPF) defined by Snitz et al. We aimed to investigate whether OPF can distinguish patients with olfactory dysfunction (OD) due to coronavirus disease (COVID-19) from controls and which perceptual descriptors are important for that separation. Our study included 99 healthy controls and 41 patients. They rated 10 odors using 8 descriptors such as "pleasant," "intense," "familiar," "warm," "cold," "irritating," "edible," and "disgusting." An unsupervised machine learning method, hierarchical cluster analysis, showed that OPF can distinguish patients from controls with an accuracy of 83%, a sensitivity of 51%, and a specificity of 96%. Furthermore, a supervised machine learning method, random forest classifier, showed that OPF can distinguish patients and controls in the testing dataset with an accuracy of 86%, a sensitivity of 64%, and a specificity of 96%. Principal component analysis and random forest classifier showed that familiarity and intensity were the key qualities to explain the variance of the data. In conclusion, people with COVID-19-related OD have a fundamentally different olfactory perception.

Reduced neural responses to pleasant odor stimuli after acute psychological stress is associated with cortisol reactivity.

Acute stress alters olfactory perception. However, little is known about the neural processing of olfactory stimuli after acute stress exposure and the role of cortisol in such an effect. Here, we used an event-related olfactory fMRI paradigm to investigate brain responses to odors of different valence (unpleasant, pleasant, or neutral) in healthy young adults following an acute stress (Trier Social Stress Test, TSST) induction (N = 22) or a non-stressful resting condition (N = 22). We obtained the odor pleasantness, intensity, and familiarity ratings after the acute stress induction or resting condition. We also measured the participants' perceived stress and salivary cortisol at four time points during the procedure. We found a stress-related decrease in brain activation in response to the pleasant, but not to the neutral or unpleasant odor stimuli in the right piriform cortex extending to the right amygdala, the right orbitofrontal cortex, and the right insula. In addition, activation of clusters within the regions of interest were negatively associated with individual baseline-to-peak increase in salivary cortisol levels after stress. We also found increased functional connectivity between the right piriform cortex and the right insula after stress when the pleasant odor was presented. The strength of the connectivity was positively correlated with increased perceived stress levels immediately after stress exposure. These results provide novel evidence for the effects of acute stress in attenuating the neural processing of a pleasant olfactory stimulus. Together with previous findings, the effect of acute stress on human olfactory perception appears to depend on both the valence and the concentration (e.g., peri-threshold or suprathreshold levels) of odor stimuli.

Perceptual metrics for odorants: Learning from non-expert similarity feedback using machine learning.

Defining perceptual similarity metrics for odorant comparisons is crucial to understanding the mechanism of olfactory perception. Current methods in olfaction rely on molecular physicochemical features or discrete verbal descriptors (floral, burnt, etc.) to approximate perceptual (dis)similarity between odorants. However, structural or verbal descriptors alone are limited in modeling complex nuances of odor perception. While structural features inadequately characterize odor perception, language-based discrete descriptors lack the granularity needed to model a continuous perception space. We introduce data-driven approaches to perceptual metrics learning (PMeL) based on two key insights: a) by combining physicochemical features with the user's perceptual feedback, we can leverage both structural and perceptual attributes of odors to define dissimilarity, and b) instead of discrete labels, user's perceptual feedback can be gathered as relative similarity comparisons, such as "Does molecule-A smell more like molecule-B, or molecule-C?" These triplet comparisons are easier even for non-experts users and offer a more effective representation of the continuous perception space. Experimental results on several defined tasks show the effectiveness of our approach in evaluating perceptual dissimilarity between odorants. Finally, we investigate how closely our model, trained on non-expert feedback, aligns with the expert's similarity judgments. Our effort aims to reduce reliance on expert annotations.

Odor representations from the two nostrils are temporally segregated in human piriform cortex.

The human olfactory system has two discrete channels of sensory input, arising from olfactory epithelia housed in the left and right nostrils. Here, we asked whether the primary olfactory cortex (piriform cortex [PC]) encodes odor information arising from the two nostrils as integrated or distinct stimuli. We recorded intracranial electroencephalogram (iEEG) signals directly from PC while human subjects participated in an odor identification task where odors were delivered to the left, right, or both nostrils. We analyzed the time course of odor identity coding using machine-learning approaches and found that uni-nostril odor inputs to the ipsilateral nostril are encoded ∼480-ms faster than odor inputs to the contralateral nostril on average. During naturalistic bi-nostril odor sampling, odor information emerged in two temporally segregated epochs, with the first epoch corresponding to the ipsilateral and the second epoch corresponding to the contralateral odor representations. These findings reveal that PC maintains distinct representations of odor input from each nostril through temporal segregation, highlighting an olfactory coding scheme at the cortical level that can parse odor information across nostrils within the course of a single inhalation.

Effects of stochastic coding on olfactory discrimination in flies and mice.

Sparse coding can improve discrimination of sensory stimuli by reducing overlap between their representations. Two factors, however, can offset sparse coding's benefits: similar sensory stimuli have significant overlap and responses vary across trials. To elucidate the effects of these 2 factors, we analyzed odor responses in the fly and mouse olfactory regions implicated in learning and discrimination-the mushroom body (MB) and the piriform cortex (PCx). We found that neuronal responses fall along a continuum from extremely reliable across trials to extremely variable or stochastic. Computationally, we show that the observed variability arises from noise within central circuits rather than sensory noise. We propose this coding scheme to be advantageous for coarse- and fine-odor discrimination. More reliable cells enable quick discrimination between dissimilar odors. For similar odors, however, these cells overlap and do not provide distinguishing information. By contrast, more unreliable cells are decorrelated for similar odors, providing distinguishing information, though these benefits only accrue with extended training with more trials. Overall, we have uncovered a conserved, stochastic coding scheme in vertebrates and invertebrates, and we identify a candidate mechanism, based on variability in a winner-take-all (WTA) inhibitory circuit, that improves discrimination with training.

Odor modality is transmitted to cortical brain regions from the olfactory bulb.

Odor perception is the impetus for important animal behaviors with two predominate modes of processing: odors pass through the front of the nose (orthonasal) while inhaling and sniffing, or through the rear (retronasal) during exhalation and while eating. Despite the importance of olfaction for an animal's well-being and that ortho and retro naturally occur, it is unknown how the modality (ortho vs. retro) is even transmitted to cortical brain regions, which could significantly affect how odors are processed and perceived. Using multielectrode array recordings in tracheotomized anesthetized rats, which decouples ortho-retro modality from breathing, we show that mitral cells in rat olfactory bulb can reliably and directly transmit orthonasal versus retronasal modality with ethyl butyrate, a common food odor. Drug manipulations affecting synaptic inhibition via GABAA lead to worse decoding of ortho versus retro, independent of whether overall inhibition increases or decreases, suggesting that the olfactory bulb circuit may naturally favor encoding this important aspect of odors. Detailed data analysis paired with a firing rate model that captures population trends in spiking statistics shows how this circuit can encode odor modality. We have not only demonstrated that ortho/retro information is encoded to downstream brain regions but also used modeling to demonstrate a plausible mechanism for this encoding; due to synaptic adaptation, it is the slower time course of the retronasal stimulation that causes retronasal responses to be stronger and less sensitive to inhibitory drug manipulations than orthonasal responses.NEW & NOTEWORTHY Whether ortho (sniffing odors) versus retro (exhalation and eating) is encoded from the olfactory bulb to other brain areas is not completely known. Using multielectrode array recordings in anesthetized rats, we show that the olfactory bulb transmits this information downstream via spikes. Altering inhibition degrades ortho/retro information on average. We use theory and computation to explain our results, which should have implications on cortical processing considering that only food odors occur retronasally.

Appetite-regulating hormones modulate odor perception and odor-evoked activity in hypothalamus and olfactory cortices.

Odors guide food seeking, and food intake modulates olfactory function. This interaction is mediated by appetite-regulating hormones like ghrelin, insulin, and leptin, which alter activity in the rodent olfactory bulb, but their effects on downstream olfactory cortices have not yet been established in humans. The olfactory tract connects the olfactory bulb to the cortex through 3 main striae, terminating in the piriform cortex (PirC), amygdala (AMY), olfactory tubercule (OT), and anterior olfactory nucleus (AON). Here, we test the hypothesis that appetite-regulating hormones modulate olfactory processing in the endpoints of the olfactory tract and the hypothalamus. We collected odor-evoked functional magnetic resonance imaging (fMRI) responses and plasma levels of ghrelin, insulin, and leptin from human subjects (n = 25) after a standardized meal. We found that a hormonal composite measure, capturing variance relating positively to insulin and negatively to ghrelin, correlated inversely with odor intensity ratings and fMRI responses to odorized vs. clean air in the hypothalamus, OT, and AON. No significant correlations were found with activity in PirC or AMY, the endpoints of the lateral stria. Exploratory whole-brain analyses revealed significant correlations near the diagonal band of Broca and parahippocampal gyrus. These results demonstrate that high (low) blood plasma concentrations of insulin (ghrelin) decrease perceived odor intensity and odor-evoked activity in the cortical targets of the medial and intermediate striae of the olfactory tract, as well as the hypothalamus. These findings expand our understanding of the cortical mechanisms by which metabolic hormones in humans modulate olfactory processing after a meal.

Metaorganismal choline metabolism shapes olfactory perception.

Microbes living in the intestine can regulate key signaling processes in the central nervous system that directly impact brain health. This gut-brain signaling axis is partially mediated by microbe-host-dependent immune regulation, gut-innervating neuronal communication, and endocrine-like small molecule metabolites that originate from bacteria to ultimately cross the blood-brain barrier. Given the mounting evidence of gut-brain crosstalk, a new therapeutic approach of "psychobiotics" has emerged, whereby strategies designed to primarily modify the gut microbiome have been shown to improve mental health or slow neurodegenerative diseases. Diet is one of the most powerful determinants of gut microbiome community structure, and dietary habits are associated with brain health and disease. Recently, the metaorganismal (i.e., diet-microbe-host) trimethylamine N-oxide (TMAO) pathway has been linked to the development of several brain diseases including Alzheimer's, Parkinson's, and ischemic stroke. However, it is poorly understood how metaorganismal TMAO production influences brain function under normal physiological conditions. To address this, here we have reduced TMAO levels by inhibiting gut microbe-driven choline conversion to trimethylamine (TMA), and then performed comprehensive behavioral phenotyping in mice. Unexpectedly, we find that TMAO is particularly enriched in the murine olfactory bulb, and when TMAO production is blunted at the level of bacterial choline TMA lyase (CutC/D), olfactory perception is altered. Taken together, our studies demonstrate a previously underappreciated role for the TMAO pathway in olfactory-related behaviors.

A principal odor map unifies diverse tasks in olfactory perception.

Mapping molecular structure to odor perception is a key challenge in olfaction. We used graph neural networks to generate a principal odor map (POM) that preserves perceptual relationships and enables odor quality prediction for previously uncharacterized odorants. The model was as reliable as a human in describing odor quality: On a prospective validation set of 400 out-of-sample odorants, the model-generated odor profile more closely matched the trained panel mean than did the median panelist. By applying simple, interpretable, theoretically rooted transformations, the POM outperformed chemoinformatic models on several other odor prediction tasks, indicating that the POM successfully encoded a generalized map of structure-odor relationships. This approach broadly enables odor prediction and paves the way toward digitizing odors.