Hot topic: Mapping of the human intranasal mucosal thermal sensitivity: A clinical study on thermal threshold and trigeminal receptors.

INTRODUCTION: The olfactory and trigeminal system are closely interlinked. Existing literature has primarily focused on characterizing trigeminal stimulation through mechanical and chemical stimulation, neglecting thermal stimulation thus far. The present study aimed to characterize the intranasal sensitivity to heat and the expression of trigeminal receptors (transient receptor potential channels, TRP). METHODS: A total of 20 healthy participants (aged 21-27 years, 11 women) were screened for olfactory function and trigeminal sensitivity using several tests. Under endoscopic control, a thermal stimulator was placed in 7 intranasal locations: anterior septum, lateral vestibulum, interior nose tip, lower turbinate, middle septum, middle turbinate, and olfactory cleft to determine the thermal threshold. Nasal swabs were obtained in 3 different locations (anterior septum, middle turbinate, olfactory cleft) to analyze the expression of trigeminal receptors TRP: TRPV1, TRPV3, TRPA1, TRPM8. RESULTS: The thermal threshold differed between locations (p = 0.018), with a trend for a higher threshold at the anterior septum (p = 0.092). There were no differences in quantitative receptor expression (p = 0.46) at the different sites. The highest overall receptor RNA expression was detected for TRPV1 over all sites (p<0.001). The expression of TRPV3 was highest at the anterior septum compared to the middle turbinate or the olfactory cleft. The thermal sensitivity correlated with olfactory sensitivity and results from tests were related to trigeminal function like intensity ratings of ammonium, a questionnaire regarding trigeminal function, nasal patency, and CO2 thresholds. However, no correlation was found between receptor expression and psychophysical measures of trigeminal function. DISCUSSION: This study provided the first insights about intranasal thermal sensitivity and suggested the presence of topographical differences in thermal thresholds. There was no correlation between thermal sensitivity and trigeminal mRNA receptor expression. However, thermal sensitivity was found to be associated with psychophysical measures of trigeminal and olfactory function.

Olfactory perceptual fingerprints of people with olfactory dysfunction and healthy controls.

Objectives: An olfactory perceptual fingerprint (OPF) defines one's olfactory perception using perceptual descriptor ratings (such as odor pleasantness, intensity) for a set of odors. OPFs have been shown to distinguish patients with COVID-related olfactory dysfunction (OD) and healthy controls with 86% accuracy. However, all participants rated the same odorants. With the aim to evaluate whether the OPFs are indeed odorant independent, previously published dataset by Lötsch et al. was reanalyzed. Furthermore, this independent dataset was used to check whether the OPFs separate patients with OD due to various causes from controls. Methods: The study included 104 controls and 42 patients, who were randomized into four odor sets with 10 odorants each. Odorants were presented using a computer-controlled olfactometer and evaluated on scales from 1 (not at all) to 5 (very) using perceptual descriptors pleasant, intensive, familiar, edible, irritating, cold/warm, and painful. Results: Permutational multivariate analysis of variance showed that the odor set did not have a significant effect on the OPFs, confirming that the OPFs are indeed odorant independent. On the other hand, both diagnosis and age affected the OPFs (p < .001) and explained around 11% and 5% of the variance of the OPFs, respectively. Furthermore, a supervised machine learning method, random forest classifier, showed that OPF can distinguish patients and controls with 80% accuracy. Conclusion: OPFs are odorant independent. Patients perceived odors as less familiar, less intense, and less edible than controls. Other perceptual descriptors were much less important for the separation of patients and controls. Level of evidence: 3.

Identification of the needs of individuals affected by COVID-19.

BACKGROUND: The optimal management of COVID-19 symptoms and their sequelae remains an important area of clinical research. Policy makers have little scientific data regarding the effects on the daily life of affected individuals and the identification of their needs. Such data are needed to inform effective care policy. METHODS: We studied 639 people with COVID-19 resident in France via an online questionnaire. They reported their symptoms, effects on daily life, and resulting needs, with particular focus on olfaction. RESULTS: The results indicate that a majority of participants viewed their symptoms as disabling, with symptoms affecting their physical and mental health, social and professional lives. 60% of the individuals reported having unmet medical, psychological and socio-professional support needs. Finally, affected individuals were concerned about the risk and invasiveness of possible treatments as shown by a preference for non-invasive intervention over surgery to cure anosmia. CONCLUSIONS: It is important that policy makers take these needs into consideration in order to assist affected individuals to regain a normal quality of life.

The impact of COVID-19 has been substantial, both on individuals' health and on society. Information is needed to understand the biological mechanisms underlying the illness and to provide appropriate support for people affected. This study uses data from an online questionnaire of adults diagnosed with COVID-19 to characterize symptoms, understand their impact on peoples' everyday lives, and determine the support that people need. Our over-arching analysis of symptoms experienced reveals that heart- and skin-related symptoms are linked to chronic illness, and symptoms related to the sense of smell may have a different underlying disease mechanism. Most respondents had a mild initial illness, but their symptoms were long-lasting and had a severe impact. Our findings show that sufferers need different kinds of support in order to regain a normal quality of life.

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.

Influence of the human body odor compound HMHA on face perception.

Body odors convey information about the individuals, but the mechanisms are not fully understood yet. As far as human reproduction is concerned, molecules that are produced in sexually dimorphic amounts could be possible chemosignals. 3-hydroxy-3-methylhexanoic acid (HMHA) is one of them-more typical of men. Here, we investigated the possibility that the perception of gender and attractiveness in human faces could be implicitly influenced by this compound. Clearly feminine, ambiguous and clearly masculine faces were primed with an odor of HMHA, a control odor or air. Based on 100-ms face presentation, 40 raters had to identify the face's gender as quickly as possible and provide attractiveness evaluations. 3-hydroxy-3-methylhexanoic acid tended to be perceived as less pleasant and induced lower sniff duration in women compared with men. As to the effects of HMHA on face perception (vs. control conditions), we found that gender identification and the associated response time were unaffected by HMHA. Attractiveness of the faces, however, increased in presence of HMHA, but not in a sex-specific manner and only for unattractive faces with ambiguous gender. In sum, this study found no evidence in favor of a possible role of this sexually dimorphic compound in intrasexual competition nor in intersexual attraction.

The Human Affectome.

Over the last decades, theoretical perspectives in the interdisciplinary field of the affective sciences have proliferated rather than converged due to differing assumptions about what human affective phenomena are and how they work. These metaphysical and mechanistic assumptions, shaped by academic context and values, have dictated affective constructs and operationalizations. However, an assumption about the purpose of affective phenomena can guide us to a common set of metaphysical and mechanistic assumptions. In this capstone paper, we home in on a nested teleological principle for human affective phenomena in order to synthesize metaphysical and mechanistic assumptions. Under this framework, human affective phenomena can collectively be considered algorithms that either adjust based on the human comfort zone (affective concerns) or monitor those adaptive processes (affective features). This teleologically-grounded framework offers a principled agenda and launchpad for both organizing existing perspectives and generating new ones. Ultimately, we hope the Human Affectome brings us a step closer to not only an integrated understanding of human affective phenomena, but an integrated field for affective research.

Past, Present, and Future of Human Chemical Communication Research.

Although chemical signaling is an essential mode of communication in most vertebrates, it has long been viewed as having negligible effects in humans. However, a growing body of evidence shows that the sense of smell affects human behavior in social contexts ranging from affiliation and parenting to disease avoidance and social threat. This article aims to (a) introduce research on human chemical communication in the historical context of the behavioral sciences; (b) provide a balanced overview of recent advances that describe individual differences in the emission of semiochemicals and the neural mechanisms underpinning their perception, that together demonstrate communicative function; and (c) propose directions for future research toward unraveling the molecular principles involved and understanding the variability in the generation, transmission, and reception of chemical signals in increasingly ecologically valid conditions. Achieving these goals will enable us to address some important societal challenges but are within reach only with the aid of genuinely interdisciplinary approaches.

Investigating the human chemical communication of positive emotions using a virtual reality-based mood induction.

Humans can communicate their emotions to others via volatile emissions from their bodies. Although there is now solid evidence for human chemical communication of fear, stress and anxiety, investigations of positive emotions remain scarce. In a recent study, we found that women's heart rate and performance in creativity tasks were modulated by body odors of men sampled while they were in a positive vs. neutral mood. However, inducing positive emotions in laboratory settings remains challenging. Therefore, an important step to further investigate the human chemical communication of positive emotions is to develop new methods to induce positive moods. Here, we present a new mood induction procedure (MIP) based on virtual reality (VR), that we assumed to be more powerful than videos (used in our previous study) to induce positive emotions. We hypothesized that, consequently, given the more intense emotions created, this VR-based MIP would induce larger differences between the receivers' responses to the positive body odor versus a neutral control body odor, than the Video-based MIP. The results confirmed the higher efficacy of VR to induce positive emotions compared with videos. More specifically, VR had more repeatable effects between individuals. Although positive body odors had similar effects to those found in the previous video study, especially faster problem solving, these effects did not reach statistical significance. These outcomes are discussed as a function of the specificities of VR and of other methodological parameters, that may have prevented the observation of such subtle effects and that should be understood more in-depth for future studies on human chemical communication.

Phantom smells: a prevalent COVID-19 symptom that progressively sets in.

PURPOSE: One of the long-term symptoms of COVID-19 is phantosmia, a type of Olfactory Disorder (OD) that has deleterious impacts on patients' quality of life. The aim of this article was to study how this poorly understood qualitative OD manifests itself in the COVID-19. METHODS: 4691 patients with COVID-19 responded to our online questionnaire focusing on COVID-19-related OD. We first analyzed the prevalence of phantosmia in this population. Then, with the help of Natural Language Processing techniques, we investigated the qualitative descriptions of phantom smells by the 1723 respondents who reported phantosmia. RESULTS: The prevalence of phantosmia was of 37%. Women were more likely to report phantosmia than men, as well as respondents for whom OD was described as fluctuating rather than permanent, lasted longer, was partial rather than total and appeared progressively rather than suddenly. The relationship between OD duration and phantosmia followed a logarithmic function, with a prevalence of phantosmia increasing strongly during the first 2 months of the disease before reaching a plateau and no decrease over the 15 months considered in this study. Qualitative analyses of phantosmia descriptions with a sentiment analysis revealed that the descriptions were negatively valenced for 78% of the respondents. Reference to "tobacco" was more frequent in non-smokers. Source names and odor characteristics were used differently according to age and OD duration. CONCLUSION: The results of this descriptive study of phantosmia contribute to the current efforts of the medical community to better understand and treat this rapidly increasing COVID-19-related OD.

Systematic MRI in persistent post-Covid-19 olfactory dysfunction should be reassessed.

BACKGROUND: Magnetic resonance imaging (MRI) is the gold standard in the etiological assessment of a persistent olfactory dysfunction (OD). While the utility of imaging in COVID-19-related OD has yet to be established, MRI is recommended in all patients with persistent OD. The high prevalence of the latter after SARS-CoV-2 infection means evaluating this strategy is an important public health matter. METHODS: The main objective was to examine the impact of systematic MRI on the management of patients with OD. All adult patients consulting for persistent OD (>2 months) after primary SARS-COV-2 infection (PCR) between March 2020 and December 2021 were included (n = 67). The secondary objective was to evaluate the relationship between the severity of the OD as measured by psychophysical testing (ETOC) and the volume of the olfactory bulb (OB) measured by MRI. RESULTS: All patients underwent MRI, and none led to a change in diagnosis or treatment. Among them, 82% (55/67) were considered normal by the radiologist on initial interpretation. There were no significant differences (visual analysis or OB volume) between groups (mild, moderate, and severe hyposmia). CONCLUSION: Systematic MRI may be unnecessary in patients whose persistent OD began soon (a few days) after confirmed SARS-CoV-2 infection.

And I'm feeling good: effect of emotional sweat and perfume on others' physiology, verbal responses, and creativity.

Emotions can be communicated in social contexts through chemosignals contained in human body odors. The transmission of positive emotions via these signals has received little interest in past research focused mainly on negative emotional transmission. Furthermore, how the use of perfumed products might modulate this transmission remains poorly understood. To investigate human positive chemical communication, we explored the autonomic, verbal, and behavioral responses of receivers exposed to body odors of donors having undergone a within-subject positive or neutral mood induction procedure. These responses were compared with those obtained after exposure to the same body odors with added fragrance. Our findings suggest that positive emotions can be transmitted through body odor. They not only induced modifications at the physiological (heart rate) and verbal levels (perceived intensity and familiarity) but also at the behavioral level, with an improved performance on creativity tasks. Perfume did not modulate the physiological effects and had a synergistic effect on the positive body odor ratings (increased perceived differences between the neutral and positive body odor).

An olfactory self-test effectively screens for COVID-19.

Background: Key to curtailing the COVID-19 pandemic are wide-scale screening strategies. An ideal screen is one that would not rely on transporting, distributing, and collecting physical specimens. Given the olfactory impairment associated with COVID-19, we developed a perceptual measure of olfaction that relies on smelling household odorants and rating them online. Methods: Each participant was instructed to select 5 household items, and rate their perceived odor pleasantness and intensity using an online visual analogue scale. We used this data to assign an olfactory perceptual fingerprint, a value that reflects the perceived difference between odorants. We tested the performance of this real-time tool in a total of 13,484 participants (462 COVID-19 positive) from 134 countries who provided 178,820 perceptual ratings of 60 different household odorants. Results: We observe that olfactory ratings are indicative of COVID-19 status in a country, significantly correlating with national infection rates over time. More importantly, we observe indicative power at the individual level (79% sensitivity and 87% specificity). Critically, this olfactory screen remains effective in participants with COVID-19 but without symptoms, and in participants with symptoms but without COVID-19. Conclusions: The current odorant-based olfactory screen adds a component to online symptom-checkers, to potentially provide an added first line of defense that can help fight disease progression at the population level. The data derived from this tool may allow better understanding of the link between COVID-19 and olfaction.

Identification of new behavioral parameters to assess odorant hedonic value in humans: A naturalistic approach.

BACKGROUND: When you smell an odorant, your first reaction will certainly be either I like it or I dislike it. This primary reaction is a reflection of what is called the "hedonic value" of the odor. Very often, this hedonic value dominates the olfactory percept, more than olfactory identification or intensity. This component of olfactory perception is of primary importance for guiding behavior: avoiding danger (the smell of smoke, gas, etc.), consuming food, or seduction. Olfactory hedonics can be assessed using a large number of methods in humans, including psychophysical measures, autonomic responses, measurement of facial expressions or peripheral nervous activity. All of these techniques have their limitations: subjectivity, invasiveness, need for expertise, etc. A NEW METHOD: The olfactory system is closely linked to the reward system, the role of which is to mediate motivated behavior. In this context, we propose that the capacity odorants have of recruiting the reward system and thus inducing motivated behavior can be used to identify new behavioral parameters to assess odor hedonic value in humans. RESULTS: We recorded freely moving human participants exploring odors emanating from flasks, and showed that five parameters linked to motivated behavior were closely linked to odor hedonics: speed of approach to the nose and withdrawal of the flask containing the odorant, distance between flask and nose, number of samplings, and withdrawal distance (maximal distance between nose and flask after odor sampling). CONCLUSIONS: We highlighted new non-verbal and non-invasive parameters to evaluate olfactory hedonics in humans based on the assessment of odor-motivated behavior.

African Gene Flow Reduces Beta-Ionone Anosmia/Hyposmia Prevalence in Admixed Malagasy Populations.

While recent advances in genetics make it possible to follow the genetic exchanges between populations and their phenotypic consequences, the impact of the genetic exchanges on the sensory perception of populations has yet to be explored. From this perspective, the present study investigated the consequences of African gene flow on odor perception in a Malagasy population with a predominantly East Asian genetic background. To this end, we combined psychophysical tests with genotype data of 235 individuals who were asked to smell the odorant molecule beta-ionone (ßI). Results showed that in this population the ancestry of the OR5A1 gene significantly influences the ability to detect ßI. At the individual level, African ancestry significantly protects against specific anosmia/hyposmia due to the higher frequency of the functional gene (OR ratios = 14, CI: 1.8-110, p-value = 0.012). At the population level, African introgression decreased the prevalence of specific anosmia/hyposmia to this odorous compound. Taken together, these findings validate the conjecture that in addition to cultural exchanges, genetic transfer may also influence the sensory perception of the population in contact.

Recovery From COVID-19-Related Olfactory Disorders and Quality of Life: Insights From an Observational Online Study.

Although olfactory disorders (OD) are among the most significant symptoms of COVID-19, recovery time from COVID-19-related OD and their consequences on the quality of life remain poorly documented. We investigated the characteristics and behavioral consequences of COVID-19-related OD using a large-scale study involving 3111 French respondents (78% women) to an online questionnaire over a period of 9 months covering different epidemic waves (from 8 April 2020 to 13 January 2021). In the patients who subjectively recovered from COVID-19-related OD (N = 609), recovery occurred on average after 16 days and most of the time within 1 month ("normal" recovery range); 49 subjectively recovered in 1-2.5 months, and several cases took up to 6.5 months. Among the patients with ongoing OD (N = 2502), 974 were outside the "normal" recovery range (persistent OD) and reported OD for 1-10 months. Developing a persistent OD was more likely with increasing age and in women and was more often associated with parosmia and phantosmia. The deleterious impact of COVID-19-related OD on the quality of life was significantly aggravated by OD duration and was more pronounced in women. Because persistent OD is not infrequent after COVID-19, has deleterious consequences on the quality of life, and receives few solutions from the health practitioners, it would be beneficial to implement screening and treatment programs to minimize the long-term behavioral consequences of COVID-19-related OD.

Data-science based analysis of perceptual spaces of odors in olfactory loss.

Diminished sense of smell impairs the quality of life but olfactorily disabled people are hardly considered in measures of disability inclusion. We aimed to stratify perceptual characteristics and odors according to the extent to which they are perceived differently with reduced sense of smell, as a possible basis for creating olfactory experiences that are enjoyed in a similar way by subjects with normal or impaired olfactory function. In 146 subjects with normal or reduced olfactory function, perceptual characteristics (edibility, intensity, irritation, temperature, familiarity, hedonics, painfulness) were tested for four sets of 10 different odors each. Data were analyzed with (i) a projection based on principal component analysis and (ii) the training of a machine-learning algorithm in a 1000-fold cross-validated setting to distinguish between olfactory diagnosis based on odor property ratings. Both analytical approaches identified perceived intensity and familiarity with the odor as discriminating characteristics between olfactory diagnoses, while evoked pain sensation and perceived temperature were not discriminating, followed by edibility. Two disjoint sets of odors were identified, i.e., d = 4 "discriminating odors" with respect to olfactory diagnosis, including cis-3-hexenol, methyl salicylate, 1-butanol and cineole, and d = 7 "non-discriminating odors", including benzyl acetate, heptanal, 4-ethyl-octanoic acid, methional, isobutyric acid, 4-decanolide and p-cresol. Different weightings of the perceptual properties of odors with normal or reduced sense of smell indicate possibilities to create sensory experiences such as food, meals or scents that by emphasizing trigeminal perceptions can be enjoyed by both normosmic and hyposmic individuals.

Smells Influence Perceived Pleasantness but Not Memorization of a Visual Virtual Environment.

The present study aimed to investigate whether the perception of still scenes in a virtual environment in congruent versus incongruent condition can be influenced by odors. Ninety healthy participants were divided into three groups, including two experimental virtual reality (VR) environments: a rose garden, an orange basket, and a control condition. In each VR condition, participants were exposed to a rose odor, an orange odor, or no odor, resulting in congruent, incongruent, and control conditions. Participants were asked to describe (a) the content of the VR scene and rate its overall pleasantness and (b) the smell and to rate its intensity and pleasantness. For each condition, participants were tested twice. During the second test, participants provided ratings and descriptions of the content of the VR scenes without being exposed to odors or VR environments. Virtual scenarios tended to be remembered as more pleasant when presented with congruent odors. Furthermore, participants used more descriptors in congruent scenarios than in incongruent scenarios. Eventually, rose odor appeared to be remembered as more pleasant when presented within congruent scenarios. These findings show that olfactory stimuli in congruent versus incongruent conditions can possibly modulate the perception of the pleasantness of visual scenes but not the memorization.

Neural processing of the reward value of pleasant odorants.

Pleasant odorants are represented in the posterior olfactory bulb (pOB) in mice. How does this hedonic information generate odor-motivated behaviors? Using optogenetics, we report here that stimulating the representation of pleasant odorants in a sensory structure, the pOB, can be rewarding, self-motivating, and is accompanied by ventral tegmental area activation. To explore the underlying neural circuitry downstream of the olfactory bulb (OB), we use 3D high-resolution imaging and optogenetics and determine that the pOB preferentially projects to the olfactory tubercle, whose increased activity is related to odorant attraction. We further show that attractive odorants act as reinforcers in dopamine-dependent place preference learning. Finally, we extend those findings to humans, who exhibit place preference learning and an increase BOLD signal in the olfactory tubercle in response to attractive odorants. Thus, strong and persistent attraction induced by some odorants is due to a direct gateway from the pOB to the reward system.

Accounting for Subjectivity in Experimental Research on Human Olfaction.

Although olfaction is a modality with great interindividual perceptual disparities, its subjective dimension has been let aside in modern research, in line with the overall neglect of consciousness in experimental psychology. However, following the renewed interest for the neural bases of consciousness, some methodological leads have been proposed to include subjectivity in experimental protocols. Here, we argue that adapting such methods to the field of olfaction will allow to rigorously acquire subjective reports, and we present several ways to do so. This will improve the understanding of diversity in odor perception and its underlying neural mechanisms.