Respiration-triggered olfactory stimulation reduces obstructive sleep apnea severity: A prospective pilot study.

Obstructive sleep apnea is a prevalent sleep-disordered breathing condition characterized by repetitive reduction in breathing during sleep. The current care standard for obstructive sleep apnea is continuous positive air pressure devices, often suffering from low tolerance due to limited adherence. Capitalizing on the unique neurocircuitry of olfactory perception and its retained function during sleep, we conducted a pilot study to test transient, respiration-based olfactory stimulation as a treatment for obstructive sleep apnea markers. Thirty-two patients with obstructive sleep apnea (apnea-hypopnea index ≥ 15 events per hr) underwent two polysomnography sessions, "Odour" and "Control", in random order. In "Odour" nights, patients were presented with transient respiratory-based olfactory stimulation delivered via a computer-controlled commercial olfactometer (Scentific). The olfactometer, equipped with a wireless monitoring, analysed respiratory patterns and presented odour upon detection of respiratory events. No odours were presented in "Control" nights. Following exclusions, 17 patients entered the analysis (four women, 47.4 (10.5) years, body mass index: 29.4 (6.3) kg m-2). We observed that olfactory stimulation during sleep reduced the apnea-hypopnea index ("Odour": 17.2 (20.9), "Control": 28.2 (18.6), z = -3.337, p = 0.000846, BF10 [Bayesian Factor 10]= 57.9), reflecting an average decrease of 31.3% in the number of events. Relatedly, stimulation reduced the oxygen desaturation index by 26.9% ("Odour": 12.5 (15.8), "Control": 25.7 (25.9), z = -3.337, p = 0.000846, BF10 = 9.522). This effect was not linked to the severity of baseline obstructive sleep apnea markers (ρ = -0.042, p = 0.87). Olfactory stimulation did not arouse from sleep or affect sleep structure, measured as time per sleep stage (F1,16 = 0.088, p = 0.77). In conclusion, olfactory stimulation during sleep was effective in reducing the severity of obstructive sleep apnea markers without inducing arousals, and may provide a novel treatment for obstructive sleep apnea, prompting continued research.

Dopamine and serotonin in human substantia nigra track social context and value signals during economic exchange.

Dopamine and serotonin are hypothesized to guide social behaviours. In humans, however, we have not yet been able to study neuromodulator dynamics as social interaction unfolds. Here, we obtained subsecond estimates of dopamine and serotonin from human substantia nigra pars reticulata during the ultimatum game. Participants, who were patients with Parkinson's disease undergoing awake brain surgery, had to accept or reject monetary offers of varying fairness from human and computer players. They rejected more offers in the human than the computer condition, an effect of social context associated with higher overall levels of dopamine but not serotonin. Regardless of the social context, relative changes in dopamine tracked trial-by-trial changes in offer value-akin to reward prediction errors-whereas serotonin tracked the current offer value. These results show that dopamine and serotonin fluctuations in one of the basal ganglia's main output structures reflect distinct social context and value signals.

Neural patterns differentiate traumatic from sad autobiographical memories in PTSD.

For people with post-traumatic stress disorder (PTSD), recall of traumatic memories often displays as intrusions that differ profoundly from processing of 'regular' negative memories. These mnemonic features fueled theories speculating a unique cognitive state linked with traumatic memories. Yet, to date, little empirical evidence supports this view. Here we examined neural activity of patients with PTSD who were listening to narratives depicting their own memories. An intersubject representational similarity analysis of cross-subject semantic content and neural patterns revealed a differentiation in hippocampal representation by narrative type: semantically similar, sad autobiographical memories elicited similar neural representations across participants. By contrast, within the same individuals, semantically similar trauma memories were not represented similarly. Furthermore, we were able to decode memory type from hippocampal multivoxel patterns. Finally, individual symptom severity modulated semantic representation of the traumatic narratives in the posterior cingulate cortex. Taken together, these findings suggest that traumatic memories are an alternative cognitive entity that deviates from memory per se.

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.

Humans use forward thinking to exploit social controllability.

The controllability of our social environment has a profound impact on our behavior and mental health. Nevertheless, neurocomputational mechanisms underlying social controllability remain elusive. Here, 48 participants performed a task where their current choices either did (Controllable), or did not (Uncontrollable), influence partners' future proposals. Computational modeling revealed that people engaged a mental model of forward thinking (FT; i.e., calculating the downstream effects of current actions) to estimate social controllability in both Controllable and Uncontrollable conditions. A large-scale online replication study (n=1342) supported this finding. Using functional magnetic resonance imaging (n=48), we further demonstrated that the ventromedial prefrontal cortex (vmPFC) computed the projected total values of current actions during forward planning, supporting the neural realization of the forward-thinking model. These findings demonstrate that humans use vmPFC-dependent FT to estimate and exploit social controllability, expanding the role of this neurocomputational mechanism beyond spatial and cognitive contexts.

Emotional adaptation during a crisis: decline in anxiety and depression after the initial weeks of COVID-19 in the United States.

Crises such as the COVID-19 pandemic are known to exacerbate depression and anxiety, though their temporal trajectories remain under-investigated. The present study aims to investigate fluctuations in depression and anxiety using the COVID-19 pandemic as a model crisis. A total of 1512 adults living in the United States enrolled in this online study beginning April 2, 2020 and were assessed weekly for 10 weeks (until June 4, 2020). We measured depression and anxiety using the Zung Self-Rating Depression scale and State-Trait Anxiety Inventory (state subscale), respectively, along with demographic and COVID-related surveys. Linear mixed-effects models were used to examine factors contributing to longitudinal changes in depression and anxiety. We found that depression and anxiety levels were high in early April, but declined over time. Being female, younger age, lower-income, and previous psychiatric diagnosis correlated with higher overall levels of anxiety and depression; being married additionally correlated with lower overall levels of depression, but not anxiety. Importantly, worsening of COVID-related economic impact and increase in projected pandemic duration exacerbated both depression and anxiety over time. Finally, increasing levels of informedness correlated with decreasing levels of depression, while increased COVID-19 severity (i.e., 7-day change in cases) and social media use were positively associated with anxiety over time. These findings not only provide evidence for overall emotional adaptation during the initial weeks of the pandemic, but also provide insight into overlapping, yet distinct, factors contributing to depression and anxiety throughout the first wave of the pandemic.

Containment of COVID-19: Simulating the impact of different policies and testing capacities for contact tracing, testing, and isolation.

Efficient contact tracing and testing are fundamental tools to contain the transmission of SARS-CoV-2. We used multi-agent simulations to estimate the daily testing capacity required to find and isolate a number of infected agents sufficient to break the chain of transmission of SARS-CoV-2, so decreasing the risk of new waves of infections. Depending on the non-pharmaceutical mitigation policies in place, the size of secondary infection clusters allowed or the percentage of asymptomatic and paucisymptomatic (i.e., subclinical) infections, we estimated that the daily testing capacity required to contain the disease varies between 0.7 and 9.1 tests per thousand agents in the population. However, we also found that if contact tracing and testing efficacy dropped below 60% (e.g. due to false negatives or reduced tracing capability), the number of new daily infections did not always decrease and could even increase exponentially, irrespective of the testing capacity. Under these conditions, we show that population-level information about geographical distribution and travel behaviour could inform sampling policies to aid a successful containment, while avoiding concerns about government-controlled mass surveillance.

A measure of smell enables the creation of olfactory metamers.

Wavelength is a physical measure of light, and the intricate understanding of its link to perceived colour enables the creation of perceptual entities such as metamers-non-overlapping spectral compositions that generate identical colour percepts1. By contrast, scientists have been unable to develop a physical measure linked to perceived smell, even one that merely reflects the extent of perceptual similarity between odorants2. Here, to generate such a measure, we collected perceptual similarity estimates of 49,788 pairwise odorants from 199 participants who smelled 242 different multicomponent odorants and used these data to refine a predictive model that links odorant structure to odorant perception3. The resulting measure combines 21 physicochemical features of the odorants into a single number-expressed in radians-that accurately predicts the extent of perceptual similarity between multicomponent odorant pairs. To assess the usefulness of this measure, we investigated whether we could use it to create olfactory metamers. To this end, we first identified a cut-off in the measure: pairs of multicomponent odorants that were within 0.05 radians of each other or less were very difficult to discriminate. Using this cut-off, we were able to design olfactory metamers-pairs of non-overlapping molecular compositions that generated identical odour percepts. The accurate predictions of perceptual similarity, and the ensuing creation of olfactory metamers, suggest that we have obtained a valid olfactory measure, one that may enable the digitization of smell.

Unexplained repeated pregnancy loss is associated with altered perceptual and brain responses to men's body-odor.

Mammalian olfaction and reproduction are tightly linked, a link less explored in humans. Here, we asked whether human unexplained repeated pregnancy loss (uRPL) is associated with altered olfaction, and particularly altered olfactory responses to body-odor. We found that whereas most women with uRPL could identify the body-odor of their spouse, most control women could not. Moreover, women with uRPL rated the perceptual attributes of men's body-odor differently from controls. These pronounced differences were accompanied by an only modest albeit significant advantage in ordinary, non-body-odor-related olfaction in uRPL. Next, using structural and functional brain imaging, we found that in comparison to controls, most women with uRPL had smaller olfactory bulbs, yet increased hypothalamic response in association with men's body-odor. These findings combine to suggest altered olfactory perceptual and brain responses in women experiencing uRPL, particularly in relation to men's body-odor. Whether this link has any causal aspects to it remains to be explored.

Women Have Reduced Ability to Discriminate Body Odors During the Withdrawal Period of Oral Contraception.

INTRODUCTION: Women's olfactory perception varies across the menstrual cycle. The influence of oral contraceptives on this variability remains unclear. METHODS: To further estimate this, we assessed discrimination performance for both body odors and ordinary odorants in 36 women, 18 naturally ovulating, and 18 using oral contraceptives. Each participant was tested once a week over the course of a month, and data was then parsed into menstrual phases. RESULTS: In naturally ovulating women, at the transition from follicular to luteal phases, there was a decline of 19% (p = 0.003) in olfactory discrimination of body odors but not ordinary odorants. In turn, in women using oral contraceptives, only at a later time of the month, at a point corresponding to the late luteal phase and shift from post-ovulation to pre-menstruation, was there a decline of 20% (p = 0.002) in olfactory discrimination performance. Moreover, when we reorganized the data from women using oral contraceptives in order to separately assess the contraceptive withdrawal period (the few days off pills), we observed a 23% reduction (p = 0.01) in discrimination accuracy of body odors but not ordinary odorants during this time alone. CONCLUSIONS: Women have reduced ability to discriminate body odors during the withdrawal period of oral contraception. IMPLICATIONS: If women indeed consider men's body odor in their mate selections, then the oral contraception withdrawal period may not be the best time to make such decisions.

Containment of future waves of COVID-19: simulating the impact of different policies and testing capacities for contact tracing, testing, and isolation.

We used multi-agent simulations to estimate the testing capacity required to find and isolate a number of infections sufficient to break the chain of transmission of SARS-CoV-2. Depending on the mitigation policies in place, a daily capacity between 0.7 to 3.6 tests per thousand was required to contain the disease. However, if contact tracing and testing efficacy dropped below 60% (e.g. due to false negatives or reduced tracing capability), the number of infections kept growing exponentially, irrespective of any testing capacity. Under these conditions, the population's geographical distribution and travel behaviour could inform sampling policies to aid a successful containment.

Relationship between odor intensity estimates and COVID-19 prevalence prediction in a Swedish population.

In response to the COVID-19 pandemic, countries have implemented various strategies to reduce and slow the spread of the disease in the general population. For countries that have implemented restrictions on its population in a step-wise manner, monitoring of COVID-19 prevalence is of importance to guide decision on when to impose new, or when to abolish old, restrictions. We are here determining whether measures of odor intensity in a large sample can serve as one such measure. Online measures of how intense common household odors are perceived and symptoms of COVID-19 were collected from 2440 Swedes. Average odor intensity ratings were then compared to predicted COVID-19 population prevalence over time in the Swedish population and were found to closely track each other (r=-0.83). Moreover, we found that there was a large difference in rated intensity between individuals with and without COVID-19 symptoms and number of symptoms was related to odor intensity ratings. Finally, we found that individuals progressing from reporting no symptoms to subsequently reporting COVID-19 symptoms demonstrated a large drop in olfactory performance. These data suggest that measures of odor intensity, if obtained in a large and representative sample, can be used as an indicator of COVID-19 disease in the general population. Importantly, this simple measure could easily be implemented in countries without widespread access to COVID-19 testing or implemented as a fast early response before wide-spread testing can be facilitated.

Are humans constantly but subconsciously smelling themselves?

All primates, including humans, engage in self-face-touching at very high frequency. The functional purpose or antecedents of this behaviour remain unclear. In this hybrid review, we put forth the hypothesis that self-face-touching subserves self-smelling. We first review data implying that humans touch their faces at very high frequency. We then detail evidence from the one study that implicated an olfactory origin for this behaviour: This evidence consists of significantly increased nasal inhalation concurrent with self-face-touching, and predictable increases or decreases in self-face-touching as a function of subliminal odourant tainting. Although we speculate that self-smelling through self-face-touching is largely an unconscious act, we note that in addition, humans also consciously smell themselves at high frequency. To verify this added statement, we administered an online self-report questionnaire. Upon being asked, approximately 94% of approximately 400 respondents acknowledged engaging in smelling themselves. Paradoxically, we observe that although this very prevalent behaviour of self-smelling is of concern to individuals, especially to parents of children overtly exhibiting self-smelling, the behaviour has nearly no traction in the medical or psychological literature. We suggest psychological and cultural explanations for this paradox, and end in suggesting that human self-smelling become a formal topic of investigation in the study of human social olfaction. This article is part of the Theo Murphy meeting issue 'Olfactory communication in humans'.

Local Targeted Memory Reactivation in Human Sleep.

Memory consolidation can be promoted via targeted memory reactivation (TMR) that re-presents training cues or context during sleep. Whether TMR acts locally or globally on cortical sleep oscillations remains unknown. Here, we exploit the unique functional neuroanatomy of olfaction with its ipsilateral stimulus processing to perform local TMR in one brain hemisphere. Participants learned associations between words and locations in left or right visual fields with contextual odor throughout. We found lateralized event-related potentials during task training that indicate unihemispheric memory processes. During post-learning naps, odors were presented to one nostril in non-rapid eye movement (NREM) sleep. Memory for specific words processed in the cued hemisphere (ipsilateral to stimulated nostril) was improved after local TMR during sleep. Unilateral odor cues locally modulated slow-wave (SW) power such that regional SW power increase was lower in the cued hemisphere relative to the uncued hemisphere and negatively correlated with select memories for cued words. Moreover, local TMR improved phase-amplitude coupling (PAC) between slow oscillations and sleep spindles specifically in the cued hemisphere. The effects on memory performance and cortical sleep oscillations were not observed when unilateral olfactory stimulation during sleep followed learning without contextual odor. Thus, TMR in human sleep transcends global action by selectively promoting specific memories associated with local sleep oscillations.

The contribution of temporal coding to odor coding and odor perception in humans.

Whether neurons encode information through their spike rates, their activity times or both is an ongoing debate in systems neuroscience. Here, we tested whether humans can discriminate between a pair of temporal odor mixtures (TOMs) composed of the same two components delivered in rapid succession in either one temporal order or its reverse. These TOMs presumably activate the same olfactory neurons but at different times and thus differ mainly in the time of neuron activation. We found that most participants could hardly discriminate between TOMs, although they easily discriminated between a TOM and one of its components. By contrast, participants succeeded in discriminating between the TOMs when they were notified of their successive nature in advance. We thus suggest that the time of glomerulus activation can be exploited to extract odor-related information, although it does not change the odor perception substantially, as should be expected from an odor code per se.

Human non-olfactory cognition phase-locked with inhalation.

Olfactory stimulus acquisition is perfectly synchronized with inhalation, which tunes neuronal ensembles for incoming information. Because olfaction is an ancient sensory system that provided a template for brain evolution, we hypothesized that this link persisted, and therefore nasal inhalations may also tune the brain for acquisition of non-olfactory information. To test this, we measured nasal airflow and electroencephalography during various non-olfactory cognitive tasks. We observed that participants spontaneously inhale at non-olfactory cognitive task onset and that such inhalations shift brain functional network architecture. Concentrating on visuospatial perception, we observed that nasal inhalation drove increased task-related brain activity in specific task-related brain regions and resulted in improved performance accuracy in the visuospatial task. Thus, mental processes with no link to olfaction are nevertheless phase-locked with nasal inhalation, consistent with the notion of an olfaction-based template in the evolution of human brain function.

SmellSpace: An Odor-Based Social Network as a Platform for Collecting Olfactory Perceptual Data.

A common goal in olfaction research is modeling the link between odorant structure and odor perception. Such modeling efforts require large data sets on olfactory perception, yet only a few of these are publicly and freely available. Given that individual odor perception may be informative on personal makeup and interpersonal relationships, we hypothesized that people would gladly provide olfactory perceptual estimates in the context of an odor-based social network. We developed a web-based infrastructure for such a network we called SmellSpace and distributed 10 000 scratch-and-sniff registration booklets each containing a subset of 12 out of 35 microencapsulated odorants. Within ~100 days, we obtained data from ~1000 participants who rated the odorants along 13 verbal descriptors. To verify that these estimates are comparable to lab-collected estimates we tested 26 participants in a controlled lab setting using the same odorants and descriptors. We observed remarkably high overall group correlations between lab and SmellSpace data, implying that this method provides for credible group-representations of odorants. We further estimated the usability of the data by applying to it two previously published models that used odorant structure alone to predict either odorant pleasantness or pairwise odorant perceptual similarity. We observed statistically significant predictions in both cases, thus further implying that the current data may be helpful toward future efforts of modeling olfactory perception from structure. We conclude that an odor-based social network is a potentially useful instrument for collecting extensive data on olfactory perception and here post the complete raw data set from the first ~1000 participants.

Altered responses to social chemosignals in autism spectrum disorder.

Autism spectrum disorder (ASD) is characterized by impaired social communication, often attributed to misreading of emotional cues. Why individuals with ASD misread emotions remains unclear. Given that terrestrial mammals rely on their sense of smell to read conspecific emotions, we hypothesized that misreading of emotional cues in ASD partially reflects altered social chemosignaling. We found no difference between typically developed (TD) and cognitively able adults with ASD at explicit detection and perception of social chemosignals. Nevertheless, TD and ASD participants dissociated in their responses to subliminal presentation of these same compounds: the undetected 'smell of fear' (skydiver sweat) increased physiological arousal and reduced explicit and implicit measures of trust in TD but acted opposite in ASD participants. Moreover, two different undetected synthetic putative social chemosignals increased or decreased arousal in TD but acted opposite in ASD participants. These results implicate social chemosignaling as a sensory substrate of social impairment in ASD.

Odors enhance slow-wave activity in non-rapid eye movement sleep.

Most forms of suprathreshold sensory stimulation perturb sleep. In contrast, presentation of pure olfactory or mild trigeminal odorants does not lead to behavioral or physiological arousal. In fact, some odors promote objective and subjective measures of sleep quality in humans and rodents. The brain mechanisms underlying these sleep-protective properties of olfaction remain unclear. Slow oscillations in the electroencephalogram (EEG) are a marker of deep sleep, and K complexes (KCs) are an EEG marker of cortical response to sensory interference. We therefore hypothesized that odorants presented during sleep will increase power in slow EEG oscillations. Moreover, given that odorants do not drive sleep interruption, we hypothesized that unlike other sensory stimuli odorants would not drive KCs. To test these hypotheses we used polysomnography to measure sleep in 34 healthy subjects (19 women, 15 men; mean age 26.5 ± 2.5 yr) who were repeatedly presented with odor stimuli via a computer-controlled air-dilution olfactometer over the course of a single night. Each participant was exposed to one of four odorants, lavender oil (n = 13), vetiver oil (n = 5), vanillin (n = 12), or ammonium sulfide (n = 4), for durations of 5, 10, and 20 s every 9-15 min. Consistent with our hypotheses, we found that odor presentation during sleep enhanced the power of delta (0.5-4 Hz) and slow spindle (9-12 Hz) frequencies during non-rapid eye movement sleep. The increase was proportionate to odor duration. In addition, odor presentation did not modulate the occurrence of KCs. These findings imply a sleep-promoting olfactory mechanism that may deepen sleep through driving increased slow-frequency oscillations.

A social chemosignaling function for human handshaking.

Social chemosignaling is a part of human behavior, but how chemosignals transfer from one individual to another is unknown. In turn, humans greet each other with handshakes, but the functional antecedents of this behavior remain unclear. To ask whether handshakes are used to sample conspecific social chemosignals, we covertly filmed 271 subjects within a structured greeting event either with or without a handshake. We found that humans often sniff their own hands, and selectively increase this behavior after handshake. After handshakes within gender, subjects increased sniffing of their own right shaking hand by more than 100%. In contrast, after handshakes across gender, subjects increased sniffing of their own left non-shaking hand by more than 100%. Tainting participants with unnoticed odors significantly altered the effects, thus verifying their olfactory nature. Thus, handshaking may functionally serve active yet subliminal social chemosignaling, which likely plays a large role in ongoing human behavior.