Chemical Senses

Background: Smell testing is increasingly recognized as essential in rhinology practice but remains underutilized because of time constraints and limited clinical resources. This study aimed to evaluate the performance (test-retest reliability, accuracy and test completion time) of a self-administered, digital version of SMELL-RS, a non-semantic test of olfactory resolution (SMELL-R) and sensitivity (SMELL-S). Methodology: We performed a test-retest reliability study in a tertiary care facility. We enrolled 100 subjects with and without smell dysfunction. The primary outcome measures were two replicates of olfactory test scores (SMELL-RS composite score, SMELL-R score, SMELL-S score). The secondary outcome measures were Sniffin Sticks score, test completion time, patient demographics, and other clinical characteristics (clinical symptoms, etiologies). Results: The SMELL-RS composite score was reliable (ICC=0.71; p<0.0001) and correlated with the Sniffin Sticks composite score (r=0.68; p<0.0001). Different etiologies have different magnitudes of smell loss as revealed by the SMELL-RS score. SMELL-S reduces misdiagnosis associated with Sniffin Sticks threshold tests. The average completion time of the olfactory resolution test (SMELL-R) was on average 5.9 minutes (SD=1.9), while the average completion time of the olfactory sensitivity test (SMELL-S) was 5.5 minutes (SD=2.7). This is two to three times faster than the corresponding Sniffin Sticks tests. Conclusions: SMELL-RS is a rapid, fully automated, reliable, and accurate olfactory test suitable for self-administration in a clinical setting.

The recovery period from post-COVID-19 smell and taste dysfunctions varies substantially, lasting from a few days to over a year. We aimed to assess the impact of COVID-19 on post-COVID-19 chemosensory sensitivity in a group of young convalescents of eastern/central European ancestry. We measured subjects smell and taste capabilities with a standard testing kit, Monell Flavor Quiz (MFQ), and collected surveys on COVID-19 history. During testing, subjects rated liking and intensity of six odor samples (galaxolide, guaiacol, beta-ionone, trimethylamine, phenylethyl alcohol, 2-ethyl fenchol) and six taste samples (sucralose, sodium chloride, citric acid, phenylthiocarbamide, menthol, capsaicin) on a scale from 1 (dislike extremely, or no intensity) to 9 (like extremely, or extremely intense). There was no statistical difference in intensity ratings or liking of any sample between subjects who reported a history of COVID-19 (n = 34) and those reporting no history (n = 40), independent of presence/absence or severity of smell/taste impairments (P > 0.05). Additionally, neither vaccination status (full vaccination or no vaccination) nor time from the COVID-19 onset (2-27 months) correlated with liking or intensity. These results suggest that most young adults who had COVID-19 recovered their sense of smell and taste.

Olfactory dysfunction following viral infection is a debilitating condition. Currently, the recommended treatment for olfactory dysfunction is olfactory training, a systematic and repeated exposure to odors over a prolonged period. A new tool has been proposed for olfactory training that present odors using nasal inserts rather than hand-held devices, to increase ease of training and thereby improving compliance and adherence to the training regimen. Here, we aimed to determine how olfactory training affects subjective experience of quality of life and olfactory function and potential differences training using regular versus the nasal insert setup. Using a randomized controlled design (N = 111), we investigated the effects of an 8-week olfactory training regimen using nasal inserts compared to standard care olfactory training in individuals with post-viral functional hyposmia. Subjective measures of quality of life as well as qualitative and quantitative olfactory function were assessed before and after the training regimen, and during a 1-year follow-up. Overall, participants showed significant and sustained improvements in both subjective olfactory function and quality of life following training. Critically, the nasal insert group demonstrated greater gains in social functioning and quantitative olfactory scores shortly after training, with enhanced olfactory benefits persisting at the 1-year follow-up. The magnitude of changes in quality of life was correlated with subjective olfactory improvement overall, with a stronger association for the nasal insert group. Thus, nasal insert training appears to enhance perceived olfactory function, which coincides with improved quality of life. Findings from this trial provide insight into the benefits of olfactory training on subjective functioning and quality of life, as well as the efficacy of nasal insert training in post-viral hyposmia.

People often confuse smell loss with taste loss, so it is unclear how much gustatory function is reduced in patients self-reporting taste loss. Our pre-registered cross-sectional study design included an online survey in 12 languages with instructions for self-administering chemosensory tests with ten household items. Between June 2020 and March 2021, 10,953 individuals participated. Of these, 3,356 self-reported a positive and 602 a negative COVID-19 diagnosis (COVID+ and COVID-, respectively); 1,267 were awaiting test results (COVID?). The rest reported no respiratory illness and were grouped by symptoms: sudden smell/taste changes (STC, N=4,445), other symptoms excluding smell or taste loss (OthS, N=832), and no symptoms (NoS, N=416). Taste, smell, and oral irritation intensities and self-assessed abilities were rated on visual analog scales. Compared to the NoS group, COVID+ was associated with a 21% reduction in taste (95% Confidence Interval (CI): 15-28%), 47% in smell (95%-CI: 37-56%), and 17% in oral irritation (95%-CI: 10-25%) intensity. In all groups, perceived intensity of smell (r=0.84), taste (r=0.68), and oral irritation (r=0.37) was correlated. Our findings suggest most reports of taste dysfunction with COVID-19 were genuine and not due to misinterpreting smell loss as taste loss (i.e., a classical taste-flavor confusion). Assessing smell and taste intensity of household items is a promising, cost-effective screening tool that complements self-reports and helps to disentangle taste loss from smell loss. However, it does not replace standardized validated psychophysical tests.

In vision and hearing, standardized units such as lumens (for brightness) and decibels (for loudness) allow consistent quantification of stimulus intensity, enabling precise control of sensory experiences. Olfaction, by contrast, currently lacks a robust quantitative framework linking physical stimulus properties directly to perceived odor intensity, complicating efforts to accurately characterize and manipulate aromas. To bridge this gap, we used a precisely controlled odor delivery system combined with deep learning models to predict the intensity of both single molecules and mixtures from physical properties. These models allowed us to develop an automated, quantitative method that accurately identifies which volatile components meaningfully contribute to aroma perception, overcoming the limitations of traditional heuristic approaches such as odor activity values and demonstrating practical utility in complex naturalistic odors.

INTRODUCTION: Despite their widespread prevalence and deleterious consequences, olfactory disorders remain little evaluated in clinical practice and neuroscientific studies, due to the lack of early, quick and reliable detection tools. To meet this demand, we developed a new connected olfactory test and evaluated its ability to discriminate dysosmia (i.e., altered sense of smell) from normosmia. METHODS: The Olfactory Screening with Connected And Rapid Detection test (OS-card, version 1.0) consisted of 8 RFID-equipped scratch-and-sniff cards interfaced with a dedicated mobile application. In this test, each micro-encapsulated odor is rated for perceived intensity on a 5-point scale and identified using a 4-alternative forced-choice procedure. The olfactory abilities of two matched samples of 25 normosmic and 25 dysosmic participants were evaluated using the OS-card 1.0 and two reference tests: the European Test for Olfactory Capabilities ETOC and the identification subtest of the Sniffin' Sticks. RESULTS: Intensity and identification OS-card scores were significantly lower in dysosmics than in normosmics. OS-card was easy to use and took less than 10 minutes to complete. OS-card scores were well correlated with ETOC scores and Sniffin' Sticks scores. According to a cross-validation approach using olfactory status categories provided by the ETOC, it was found that OS-card correctly classified 100% of the normosmic participants, 68% of the dysosmics (hyposmics and anosmics together), and 96% of the anosmics. CONCLUSION: OS-card is user friendly, rapid and reliable for detecting severe smell disorders (anosmia).

SCENTinel - a rapid, inexpensive smell test that measures odor detection, intensity, identification, and pleasantness - was developed for population-wide screening of smell function. SCENTinel was previously found to screen for multiple types of smell disorders. However, the effect of genetic variability on SCENTinel test performance is unknown, which could affect the tests validity. This study assessed performance of SCENTinel in a large group of individuals with a normal sense of smell to determine the test-retest reliability and the heritability of SCENTinel test performance. One thousand participants (36 [IQR 26-52] years old, 72% female, 80% white) completed a SCENTinel test at the 2021 and 2022 Twins Days Festivals in Twinsburg, OH, and 118 of those completed a SCENTinel test on each of the festivals two days. Participants comprised 55% percent monozygotic twins, 13% dizygotic twins, 0.4% triplets, and 36% singletons. We found that 97% of participants passed the SCENTinel test. Test-retest reliability ranged from 0.57 to 0.71 for SCENTinel subtests. Broad-sense heritability, based on 246 monozygotic and 62 dizygotic twin dyads, was low for odor intensity (r=0.03) and moderate for odor pleasantness (r=0.4). Together, this study suggests that SCENTinel is a reliable smell test with only moderate heritability effects, which further supports its utility for population-wide screening for smell function.

OBJECTIVESDiagnosis of smell/taste dysfunction is necessary for appropriate medical care. This study examines factors affecting testing and diagnosis of smell/taste disorders. METHODSThe online USA Smell and Taste Patient Survey was made available to US patients with smell/taste disorders between April 6-20, 2022. 4,728 respondents were included. RESULTS1,791 (38%) patients reported a documented diagnosis. Patients most often saw family practitioners (34%), otolaryngologists (20%), and Taste/Smell clinics (6%) for smell/taste dysfunction. 64% of patients who went to Taste/Smell clinics received smell testing, followed by 39% of patients who saw otolaryngologists, and 31% of patients who saw family practitioners. Factors associated with increased odds of diagnosis included age (25-39 years (OR 2.97, 95% CI [2.25, 3.95]), 40-60 (OR 3.3, 95% CI [2.56, 4.52]), and >60 (OR 4.25, 95% CI [3.21, 5.67]) vs. 18-24 years), male gender (OR 1.26, 95% CI [1.07, 1.48]), insurance status (private (OR 1.61, 95% CI [1.15, 2.30]) or public (OR 2.03, 95% CI [1.42, 2.95]) vs. uninsured), perception of their family practitioner to be knowledgeable (OR 2.12, 95% CI [1.16, 3.90]), otolaryngologic evaluation (OR 6.17, 95% CI [5.16, 7.38]), and psychophysical smell testing (OR 1.77, 95% CI [1.42, 2.22]). CONCLUSIONPsychophysical testing, otolaryngologic evaluation, patient assessment of family practitioner knowledge level, insurance, age, and gender are significant factors in obtaining smell/taste dysfunction diagnosis. This study identifies barriers to diagnosis including lack of insurance or access to specialist evaluation and highlights the importance of educating family practitioners in diagnosis and management of patients with smell/taste disorders.

BackgroundSigns of anosmia can help detect COVID-19 infection when testing for viral positivity is not available. Inexpensive mass-produced disposable olfactory sensitivity tests suitable for worldwide use might serve not only as a screening tool for potential infection but also to identify cases at elevated risk of severe disease as anosmic COVID-19 patients have a better prognosis. Methods and FindingsWe adopted paired crushable ampules with two concentrations of a standard test odorant (n-butanol) as standard of care in several clinics as community prevalence of COVID-19 infection waxed and waned. This was not a clinical trial; a chart review was undertaken to evaluate the operating characteristics and potential utility of the test device as RT-PCR testing became routine. The risk of anosmia was greater in COVID-19 patients. Olfactory sensitivity was concentration-dependent, decreased with aging, and was sex-dependent at the highest concentration. Hyposmia was detected across a wider age range than expected from the literature, and tests can be optimized to characterize different age groups. Conclusionsn-Butanol at 0.32 and 3.2% in crushable ampules can be used to characterize olfactory function quickly and inexpensively and thus has potential benefits in pandemic screening, epidemiology, and clinical decision-making.

Precise control of odorant concentration is essential for reliable olfactory research, yet existing odorant delivery methods often suffer from solvent interactions and dilution from ambient air, limiting stimulus consistency in olfactory research. We developed an odor sampling bag system using Nalophan plastic to create a closed headspace with air as the carrier medium, eliminating solvent-related variability and ambient air dilution. In two independent experiments, 15 trained panelists each rated the perceived intensity of seven concentrations of benzaldehyde and 2-heptanone using both gas-sampling bags and glass jars. Bags produced higher maximum perceptual intensities (p < 0.001) and greater test-retest reliability than jars (Experiment 1: r = 0.89 vs. 0.81, p < 0.001; Experiment 2: r = 0.86 vs. 0.72, p < 0.001). Notably, the two tested odorants showed different maximum intensities in bags (p < 0.001) but not jars (p = 0.85), suggesting bags better preserve odorant-specific concentration differences. Photoionization detector measurements confirmed stable headspace concentrations over time, comparable to industry-standard Tedlar bags. This cost-effective approach offers improved stimulus control for olfactory psychophysics research.

Configural odors are mixtures of odorant molecules that are perceived as an odor distinct from the components. They provide an attractive target for investigations of odor perception in the olfactory bulb. We investigated the perception of octanal and citronellal in mice using a Go/No-Go behavioral paradigm, and show that mice trained on the mixture of the two odorants respond selectively to the mixture, but not to the components delivered separately.

BackgroundChemosensory disorders (including smell, taste and chemesthesis) are among the established symptoms of COVID-19 infection; however, new data indicate that the changes in chemosensory sensation caused by COVID-19 may differ among populations and COVID-19 variants. To date, few studies have focused on the influence of the SARS-CoV-2 Omicron variant on qualitative changes and quantitative reductions in chemosensory function in China. MethodologyWe conducted a cross sectional study of patients with COVID-19 caused by the Omicron variant, to investigate the prevalence of chemosensory disorders and chemosensory function before and during infection, using an online questionnaire. ResultsA total of 1245 patients with COVID-19 completed the survey. The prevalence rates of smell, taste, and chemesthesis disorders were 69.2%, 67.7%, and 31.4%, respectively. Our data indicate that sex, age, smoking, and COVID-19-related symptoms, such as lack of appetite, dyspnea, and fatigue, may be associated with chemosensory disorders during COVID-19. ConclusionsSelf-rating of chemosensory function revealed that patients experienced a general decline in smell, taste, and chemesthesis function. Further longitudinal research studies are needed to generate additional data based on objective assessment and investigate the factors influencing chemosensory function in COVID-19.

Most smells, whether in food, perfume, or the environment, are complex mixtures of many odor molecules. A principled framework for modeling natural mixtures has been considered intractable because mixtures are widely assumed to generate nonlinear perceptual interactions that mirror nonlinear responses at the receptor and neural levels. We quantified perceptual interactions across 432 mixtures composed of 144 component odorants using a trained human panel, and nearly all mixtures were explained by a linear average of their component quality profiles. Within this linear modeling framework, averaging component profiles predicted mixture perception significantly better than the previous state-of-the-art and approached the ceiling set by measurement noise. Even mixtures previously reported to exhibit emergence were equally well predicted. These results suggest that the main challenge in modeling odor perception is characterizing individual components, rather than exhaustively mapping odor-odor interactions. Just as additive color mixing enabled colorimetry, linear mixing in olfaction opens the door to quantitative odorimetry, allowing mixtures to be predicted, reconstructed, and optimized computationally.

AO_SCPLOWBSTRACTC_SCPLOWFeaturizing odorants to enable robust prediction of their properties is difficult due to the complex activation patterns that odorants evoke in the olfactory system. Structurally similar odorants can elicit distinct activation patterns in both the sensory periphery (i.e., at the receptor level) and downstream brain circuits (i.e., at a perceptual level). Despite efforts to design or discover features for odorants to better predict how they activate the olfactory system, we lack a universally accepted way to featurize odorants. In this work, we demonstrate that feature-based approaches that rely on pre-trained foundation models do not significantly out-perform classical hand-designed features on odorant-receptor binding tasks, but that targeted foundation model fine-turning can increase model performance beyond these limits. To show this, we introduce a new model that creates olfaction-specific representations: LoRA-based Odorant-Receptor Affinity prediction with CROSS-attention (LORAX). We compare existing chemical foundation model representations to hand-designed physicochemical descriptors using feature-based methods and identify large information overlap between these representations, highlighting the necessity of fine-tuning to generate novel and superior odorant representations. We show that LORAX produces a feature space more closely aligned with olfactory neural representation, enabling it to outperform existing models on predictive tasks.

Since the onset of the COVID-19 infection, many patients reported sudden loss of smell (SLS). However, due to the lack of psychophysical testings, it remains difficult to know if these patients really have hyposmia or anosmia. Our group investigated the prevalence of anosmia and hyposmia in 28 COVID-19 patients and the potential association with nasal complaints.

AO_SCPLOWBSTRACTC_SCPLOWOlfaction is fundamental to perception, memory, and emotion, yet the neural basis of human odor processing remains poorly understood. Here, we demonstrate that odor-evoked brain activity is organized by respiratory phase-not absolute time-revealing that natural breathing structures olfactory cortical dynamics. Using simultaneous nasal respiration and electroencephalography (EEG) recordings in 17 participants, we delivered naturalistic odors (peppermint, oregano, and grapefruit) synchronized to individual breathing cycles. Odor presentation elicited distinct, respiratory phase-locked event-related spectral perturbations (RPL-ERSPs) in frontal and temporal regions, emerging during the first breath after stimulus onset. The most discriminative neural signatures were theta-band activity during inhalation and alpha-band activity during exhalation, patterns that were obscured in traditional time-locked analyses due to natural variability in breath duration. Leave-one-subject-out cross-validation of RPL-ERSPs achieved reliable odor discrimination (peppermint: AUC = 0.78; oregano: AUC = 0.68; grapefruit: AUC = 0.61), establishing that phase-locked features generalize across individuals. To connect neural responses to perceptual experience without relying on precise odor naming--which is notoriously difficult and can be disproportionately impaired in some populations--we quantified odor recognition using free-response descriptions scored with a semantic-similarity approach. Behavioral recognition strength paralleled the neural decoding hierarchy across odors, establishing the perceptual validity of RPL-ERSPs. RPL-ERSPs also revealed rapid habituation, with decoding performance declining over repeated presentations, due to selective degradation of the most informative phase-locked features. Together, these findings establish respiratory rhythm as a temporal scaffold for human olfactory cortical processing, positioning RPL-ERSPs as a sensitive, task-free approach for assessing olfactory function. We provide an open-source, respiration-synchronized olfactometer design (<$500) to enable replication and broader adoption of this approach. 1 TeaserAligning brain activity to natural breathing unlocks objective neural markers of human smell perception.

Many experimental studies have examined behavioral and electrophysiological responses of mosquitoes to odors. However, the differences across studies in data collection, processing, and reporting make it difficult to perform large-scale analyses combining data from multiple studies. Here we extract and standardize data for 12 mosquito species, along with Drosophila melanogaster for comparison, from over 170 studies and curate the Mosquito Olfactory Response Ensemble (MORE), publicly available at https://neuralsystems.github.io/MORE. We demonstrate the ability of MORE in generating biological insights by finding patterns across studies. Our analyses reveal that ORs are tuned to specific ranges of several physicochemical properties of odorants; the empty-neuron recording technique for measuring OR responses is more sensitive than the Xenopus oocyte technique; there are systematic differences in the behavioral preferences reported by different types of assays; and odorants tend to become less attractive or more aversive at higher concentrations.

From ancient incense to Chanel No. 5, perfumes are almost ubiquitous across the world and across history yet highly diverse. While they reflect the artistry of the creator and the personality of the wearer, the neurobiological processes driving fragrance preference are unknown. Recent research demonstrated that genetic variability in olfactory receptors modulates odor perception; however, regarding the preference for complex real-world stimuli, the relative importance of peripheral sensory encoding versus top-down cognitive evaluation--shaped by individual life history--remains a subject of debate. Here, we evaluate whether the perception of a commercially available fragrance depends on genetics, using the example of beta-ionone, a molecule routinely used in perfume composition, whose perception and appreciation have been linked to a single-nucleotide polymorphism in the OR5A1 gene (rs691536). A total of 168 participants rated their preference for three versions of a perfume designed by a professional perfumer, differing only in the concentration of {beta}-ionone used in the formula. Results showed that carriers of the G allele rated the 0% {beta}-ionone fragrance significantly higher than the 10% and 50% versions, while AA homozygotes showed no discrimination between the perfumes. By focusing on just one SNP (among hundreds of olfactory genes) and a single molecule, this study offers a proof of concept regarding the influence of genetics on aesthetic fragrance appreciation, advocating for the integration of genomic data to better understand the global diversity of perfume preferences.

Modern natural gas (NG) has little or no odor, so other compounds, usually mercaptans and thiols, are added as warning odorants. Federal regulations state that NG must be odorized so that it is readily detectable by people with normal senses of smell at one fifth the lower explosive limit, but regulations dont define "readily detectable" or "normal senses of smell." Methods to measure human odor detection have been available for decades. However, most previous work on NG odorants has underestimated human sensitivity, and measurements need to be repeated using the latest methods. More work is also needed to determine how odor sensitivity measured under optimal laboratory conditions is affected by real-world factors such as distraction and exposure to other odors in the environment. Regarding a "normal sense of smell," healthy people vary over orders of magnitude in the concentrations they can detect, so samples of subjects should be chosen to reflect the range of differences in the population.

When it comes to simultaneous versatility, speed, and specificity in detecting volatile chemicals, biological olfactory systems far outperform all artificial chemical detection devices. Consequently, the use of trained animals for chemical detection in security, defense, healthcare, agriculture, and other applications has grown astronomically. However, the use of animals in this capacity requires extensive training and behavior-based communication. Here we propose an alternative strategy, a bio-electronic nose, that capitalizes on the superior capability of the mammalian olfactory system, but bypasses behavioral output by reading olfactory information directly from the brain. We engineered a brain-machine interface that captures neuronal signals from an early stage of olfactory processing in awake mice, and used machine learning techniques to form a sensitive and selective chemical detector. We chronically implanted a grid electrode array on the surface of the mouse olfactory bulb and systematically recorded responses to a large battery of odorants and odorant mixtures across a wide range of concentrations. The bio-electronic nose has a comparable sensitivity to the trained animal and can detect odors on a variable background. We also introduce a novel genetic engineering approach designed to improve the sensitivity of our bio-electronic nose for specific chemical targets. Our bio-electronic nose outperforms current detection methods and unlocks a wide spectrum of civil, medical and environmental applications.