Induction of nitric oxide via humming does not improve short-term cognitive performance or influence emotional processing.

Nitric oxide (NO) is involved in a variety of biological functions including blood vessel dilation and neurotransmitter release. In animals, NO has been demonstrated to affect multiple behavioral outcomes, such as memory performance and arousal, whereas this link is less explored in humans. NO is created in the paranasal sinuses and studies show that humming releases paranasal NO to the nasal tract and that NO can then cross the blood brain barrier. Akin to animal models, we hypothesized that this NO may traverse into the brain and positively affect information processing. In contrast to our hypothesis, an articulatory suppression memory paradigm and a speeded detection task found deleterious effects of humming while performing the task. Likewise, we found no effect of humming on emotional processing of photos. In a fourth experiment, participants hummed before each trial in a speeded detection task, but we again found no effect on response time. In conclusion, either nasal NO does not travel to the brain, or NO in the brain does not have the expected impact on cognitive performance and emotional processing in humans. It remains possible that NO influences other cognitive processes not tested for here.

Metabolic state modulates neural processing of odors in the human olfactory bulb.

The olfactory and endocrine systems have recently been shown to reciprocally shape the homeostatic processes of energy intake. As demonstrated in animal models, the individual's metabolic state dynamically modulates how the olfactory bulb process odor stimuli using a range of endocrine signals. Here we aimed to determine whether the neural processing of odors in human olfactory bulb is modulated by metabolic state. Participants were exposed to food-associated odors, in separate sessions being hungry and sated, while neural responses from the olfactory bulb was obtained using electrobulbogram. We found significantly higher gamma power activity (51-100 Hz) in the OB's response to odors during the Hunger compared to Sated condition. Specifically, EBG gamma power were elevated while hungry already at 100 ms after odor onset, thereby suggesting intra-bulbar modulation according to metabolic state. These results demonstrate that, akin to other animal models, hunger state affects OB activity in humans. Moreover, we show that the EBG method has the potential to measure internal metabolic states and, as such, could be used to study specificities in olfactory processing of individuals suffering from pathologies such as obesity or anorexia.

Effects of dopamine and opioid receptor antagonism on the neural processing of social and nonsocial rewards.

Rewards are a broad category of stimuli inducing approach behavior to aid survival. Extensive evidence from animal research has shown that wanting (the motivation to pursue a reward) and liking (the pleasure associated with its consumption) are mostly regulated by dopaminergic and opioidergic activity in dedicated brain areas. However, less is known about the neuroanatomy of dopaminergic and opioidergic regulation of reward processing in humans, especially when considering different types of rewards (i.e., social and nonsocial). To fill this gap of knowledge, we combined dopaminergic and opioidergic antagonism (via amisulpride and naltrexone administration) with functional neuroimaging to investigate the neurochemical and neuroanatomical bases of wanting and liking of matched nonsocial (food) and social (interpersonal touch) rewards, using a randomized, between-subject, placebo-controlled, double-blind design. While no drug effect was observed at the behavioral level, brain activity was modulated by the administered compounds. In particular, opioid antagonism, compared to placebo, reduced activity in the medial orbitofrontal cortex during consumption of the most valued social and nonsocial rewards. Dopamine antagonism, however, had no clear effects on brain activity in response to reward anticipation. These findings provide insights into the neurobiology of human reward processing and suggest a similar opioidergic regulation of the neural responses to social and nonsocial reward consumption.

Connecting genomic results for psychiatric disorders to human brain cell types and regions reveals convergence with functional connectivity.

Understanding the temporal and spatial brain locations etiological for psychiatric disorders is essential for targeted neurobiological research. Integration of genomic insights from genome-wide association studies with single-cell transcriptomics is a powerful approach although past efforts have necessarily relied on mouse atlases. Leveraging a comprehensive atlas of the adult human brain, we prioritized cell types via the enrichment of SNP-heritabilities for brain diseases, disorders, and traits, progressing from individual cell types to brain regions. Our findings highlight specific neuronal clusters significantly enriched for the SNP-heritabilities for schizophrenia, bipolar disorder, and major depressive disorder along with intelligence, education, and neuroticism. Extrapolation of cell-type results to brain regions reveals important patterns for schizophrenia with distinct subregions in the hippocampus and amygdala exhibiting the highest significance. Cerebral cortical regions display similar enrichments despite the known prefrontal dysfunction in those with schizophrenia highlighting the importance of subcortical connectivity. Using functional MRI connectivity from cases with schizophrenia and neurotypical controls, we identified brain networks that distinguished cases from controls that also confirmed involvement of the central and lateral amygdala, hippocampal body, and prefrontal cortex. Our findings underscore the value of single-cell transcriptomics in decoding the polygenicity of psychiatric disorders and offer a promising convergence of genomic, transcriptomic, and brain imaging modalities toward common biological targets.

Phase-locked breathing does not affect episodic visual recognition memory but does shape its corresponding ERPs.

Recent studies have indicated that breathing shapes the underlying oscillatory brain activity critical for episodic memory, potentially impacting memory performance. However, the literature has presented conflicting results, with some studies suggesting that nasal inhalation enhances visual memory performance, while others have failed to observe any significant effects. Furthermore, the specific influence of breathing route (nasal vs. mouth) and the precise phase of the respiratory cycle during which stimuli are presented have remained elusive. To address this, we employed a visual recognition memory (VRM) and electroencephalography paradigm in which stimuli presentation was phase-locked to either inhalation or exhalation onset, using a within-subject design where participants performed the memory task while engaging in separate sessions of nose and mouth breathing. We show that neither breathing route nor breathing phase has a significant impact on VRM performance as measured by d-prime, with the data supporting the null hypothesis. However, we did find an effect of breathing phase on response bias, with participants adopting a more conservative decision criterion during exhalation. Moreover, we found that breathing phase during memory encoding shaped the late parietal effect (LPE) amplitude, while the Frontal Negative Component (FN400) and LPE during recognition were less impacted. While our study demonstrates that breathing does not shape VRM performance, it shows that it influences brain activity, reinforcing the importance of further research to elucidate the extent of respiratory influence on perception, cognition, and behavior.

Lifelong olfactory deprivation-dependent cortical reorganization restricted to orbitofrontal cortex.

Prolonged sensory deprivation has repeatedly been linked to cortical reorganization. We recently demonstrated that individuals with congenital anosmia (CA, complete olfactory deprivation since birth) have seemingly normal morphology in piriform (olfactory) cortex despite profound morphological deviations in the orbitofrontal cortex (OFC), a finding contradictory to both the known effects of blindness on visual cortex and to the sparse literature on brain morphology in anosmia. To establish whether these unexpected findings reflect the true brain morphology in CA, we first performed a direct replication of our previous study to determine if lack of results was due to a deviant control group, a confound in cross sectional studies. Individuals with CA (n = 30) were compared to age and sex matched controls (n = 30) using voxel- and surface-based morphometry. The replication results were near identical to the original study: bilateral clusters of group differences in the OFC, including CA atrophy around the olfactory sulci and volume increases in the medial orbital gyri. Importantly, no group differences in piriform cortex were detected. Subsequently, to assess any subtle patterns of group differences not detectable by our mass-univariate analysis, we explored the data from a multivariate perspective. Combining the newly collected data with data from the replicated study (CA = 49, control = 49), we performed support vector machine classification based on gray matter volume. In line with the mass-univariate analyses, the multivariate analysis could accurately differentiate between the groups in bilateral OFC, whereas the classification accuracy in piriform cortex was at chance level. Our results suggest that despite lifelong olfactory deprivation, piriform (olfactory) cortex is morphologically unaltered and the morphological deviations in CA are confined to the OFC.

Human scent as a first-line defense against disease.

Individuals may have a different body odor, when they are sick compared to healthy. In the non-human animal literature, olfactory cues have been shown to predict avoidance of sick individuals. We tested whether the mere experimental activation of the innate immune system in healthy human individuals can make an individuals' body odor be perceived as more aversive (intense, unpleasant, and disgusting). Following an endotoxin injection (lipopolysaccharide; 0.6 ng/kg) that creates a transient systemic inflammation, individuals smelled more unpleasant compared to a placebo group (saline injection). Behavioral and chemical analyses of the body odor samples suggest that the volatile components of samples from "sick" individuals changed qualitatively rather than quantitatively. Our findings support the hypothesis that odor cues of inflammation in axillary sweat are detectable just a few hours after experimental activation of the innate immune system. As such, they may trigger behavioral avoidance, hence constituting a first line of defense against pathogens of infected conspecifics.

Impairment of quality of life due to COVID-19-induced long-term olfactory dysfunction.

Introduction: Olfactory dysfunction is one of many long-lasting symptoms associated with COVID-19, estimated to affect approximately 60% of individuals and often lasting several months after infection. The associated daily life problems can cause a decreased quality of life. Methods: Here, we assessed the association between perceived quality of life and both qualitative and quantitative olfactory function (distorted and weakened sense of smell, respectively) in 58 individuals who had undergone confirmed SARS-CoV-2 infection and who complained about olfactory dysfunction. Results: Participants with large quantitative olfactory dysfunction experienced a greater reduction in their quality of life. Moreover, our participants had a high prevalence of qualitative olfactory dysfunction (81%) with a significant correlation between qualitative olfactory dysfunction and daily life impairment. Strong drivers of low quality of life assessments were lack of enjoyment of food as well as worries related to coping with long-term dysfunctions. Discussion: These results stress the clinical importance of assessing qualitative olfactory dysfunction and the need to develop relevant interventions. Given the poor self-rated quality of life observed, healthcare systems should consider developing support structures, dietary advice, and guidelines adapted to individuals experiencing qualitative olfactory dysfunction.

Disgusting odors trigger the oral immune system.

Recent research has characterized the behavioral defense against disease. In particular the detection of sickness cues, the adaptive reactions (e.g. avoidance) to these cues and the mediating role of disgust have been the focus. A presumably important but less investigated part of a behavioral defense is the immune system response of the observer of sickness cues. Odors are intimately connected to disease and disgust, and research has shown how olfaction conveys sickness cues in both animals and humans. This study aims to test whether odorous sickness cues (i.e. disgusting odors) can trigger a preparatory immune response in humans. We show that subjective and objective disgust measures, as well as TNFα levels in saliva increased immediately after exposure to disgusting odors in a sample of 36 individuals. Altogether, these results suggest a collaboration between behavioral mechanisms of pathogen avoidance in olfaction, mediated by the emotion of disgust, and mechanisms of pathogen elimination facilitated by inflammatory mediators. Disgusting stimuli are associated with an increased risk of infection. We here test whether disgusting odors, can trigger an immune response in the oral cavity. The results indicate an increase level of TNFα in the saliva. This supports that disease cues can trigger a preparatory response in the oral cavity.

Inconclusive evidence that breathing shapes pupil dynamics in humans: a systematic review.

More than 50 years ago, it was proposed that breathing shapes pupil dynamics. This widespread idea is also the general understanding currently. However, there has been no attempt at synthesizing the progress on this topic since. We therefore conducted a systematic review of the literature on how breathing affects pupil dynamics in humans. We assessed the effect of breathing phase, depth, rate, and route (nose/mouth). We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and conducted a systematic search of the scientific literature databases MEDLINE, Web of Science, and PsycInfo in November 2021. Thirty-one studies were included in the final analyses, and their quality was assessed with QualSyst. The study findings were summarized in a descriptive manner, and the strength of the evidence for each parameter was estimated following the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. The effect of breathing phase on pupil dynamics was rated as "low" (6 studies). The effect of breathing depth and breathing rate (6 and 20 studies respectively) were rated as "very low". Breathing route was not investigated by any of the included studies. Overall, we show that there is, at best, inconclusive evidence for an effect of breathing on pupil dynamics in humans. Finally, we suggest some possible confounders to be considered, and outstanding questions that need to be addressed, to answer this fundamental question. Trial registration: This systematic review has been registered in the international prospective register of systematic reviews (PROSPERO) under the registration number: CRD42022285044.

Losing the sense of smell does not disrupt processing of odor words.

Whether language is grounded in action and perception has been a key question in cognitive science, yet little attention has been given to the sense of smell. We directly test whether smell is necessary for comprehension of odor language, by comparing language processing in a group of participants with no sense of smell (anosmics) to a group of control participants. We found no evidence for a difference in online comprehension of odor and taste language between anosmics and controls using a lexical decision task and a semantic similarity judgment task, suggesting olfaction is not critical to the comprehension of odor language. Contrary to predictions, anosmics were better at remembering odor words, and rated odor and taste words as more positively valenced than control participants. This study finds no detriment to odor language after losing the sense of smell, supporting the proposal that odor language is not grounded in odor perception.

Loss of olfactory sensitivity is an early and reliable marker for COVID-19.

Detection of early and reliable symptoms is important in relation to limiting the spread of an infectious disease. For COVID-19, the most specific symptom is either losing or experiencing reduced olfactory functions. Anecdotal evidence suggests that olfactory dysfunction is also one of the earlier symptoms of COVID-19, but objective measures supporting this notion are currently missing. To determine whether olfactory loss is an early sign of COVID-19, we assessed available longitudinal data from a web-based interface enabling individuals to test their sense of smell by rating the intensity of selected household odors. Individuals continuously used the interface to assess their olfactory functions and at each login, in addition to odor ratings, recorded their symptoms and results from potential COVID-19 test. A total of 205 COVID-19-positive individuals and 156 pseudo-randomly matched control individuals lacking positive test provided longitudinal data which enabled us to assess olfactory functions in relation to their test result date. We found that odor intensity ratings started to decline in the COVID-19 group as early as 6 days prior to the test result date (±1.4 days). Symptoms, such as sore throat, aches, and runny nose appear around the same point in time; however, with a lower predictability of a COVID-19 diagnosis. Our results suggest that olfactory sensitivity loss is an early symptom but does not appear before other related COVID-19 symptoms. Olfactory loss is, however, more predictive of a COVID-19 diagnosis than other early symptoms.

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.

The perception of odor pleasantness is shared across cultures.

Humans share sensory systems with a common anatomical blueprint, but individual sensory experience nevertheless varies. In olfaction, it is not known to what degree sensory perception, particularly the perception of odor pleasantness, is founded on universal principles,1-5 dictated by culture,6-13 or merely a matter of personal taste.6,8-10,12,14 To address this, we asked 225 individuals from 9 diverse nonwestern cultures-hunter-gatherer to urban dwelling-to rank the monomolecular odorants from most to least pleasant. Contrary to expectations, culture explained only 6% of the variance in pleasantness rankings, whereas individual variability or personal taste explained 54%. Importantly, there was substantial global consistency, with molecular identity explaining 41% of the variance in odor pleasantness rankings. Critically, these universal rankings were predicted by the physicochemical properties of out-of-sample molecules and out-of-sample pleasantness ratings given by a tenth group of western urban participants. Taken together, this shows human olfactory perception is strongly constrained by universal principles.

The human olfactory bulb processes odor valence representation and cues motor avoidance behavior.

Determining the valence of an odor to guide rapid approach-avoidance behavior is thought to be one of the core tasks of the olfactory system, and yet little is known of the initial neural mechanisms supporting this process or of its subsequent behavioral manifestation in humans. In two experiments, we measured the functional processing of odor valence perception in the human olfactory bulb (OB)-the first processing stage of the olfactory system-using a noninvasive method as well as assessed the subsequent motor avoidance response. We demonstrate that odor valence perception is associated with both gamma and beta activity in the human OB. Moreover, we show that negative, but not positive, odors initiate an early beta response in the OB, a response that is linked to a preparatory neural motor response in the motor cortex. Finally, in a separate experiment, we show that negative odors trigger a full-body motor avoidance response, manifested as a rapid leaning away from the odor, within the time period predicted by the OB results. Taken together, these results demonstrate that the human OB processes odor valence in a sequential manner in both the gamma and beta frequency bands and suggest that rapid processing of unpleasant odors in the OB might underlie rapid approach-avoidance decisions.

A non-invasive olfactory bulb measure dissociates Parkinson's patients from healthy controls and discloses disease duration.

Olfactory dysfunction is a prevalent non-motor symptom of Parkinson's disease (PD). This dysfunction is a result of neurodegeneration within the olfactory bulb (OB), the first processing area of the central olfactory system, and commonly precedes the characteristic motor symptoms in PD by several years. Functional measurements of the OB could therefore potentially be used as an early biomarker for PD. Here, we used a non-invasive method, so-called electrobulbogram (EBG), to measure OB function in PD and age-matched healthy controls to assess whether EBG measures can dissociate PDs from controls. We estimated the spectrogram of the EBG signal during exposure to odor in PD (n = 20) and age-matched controls (n = 18) as well as identified differentiating patterns of odor-related synchronization in the gamma, beta, and theta frequency bands. Moreover, we assessed if these PD-EBG components could dissociate PD from control as well as their relationship with PD characteristics. We identified six EBG components during the initial and later stages of odor processing which dissociated PD from controls with 90% sensitivity and 100% specificity with links to PD characteristics. These PD-EBG components were related to medication, disease duration, and severity, as well as clinical odor identification performance. These findings support using EBG as a tool to experimentally assess PD interventions, potentially aid diagnosis, and the potential development of EBG into an early biomarker for PD.

Acquired olfactory loss alters functional connectivity and morphology.

Removing function from a developed and functional sensory system is known to alter both cerebral morphology and functional connections. To date, a majority of studies assessing sensory-dependent plasticity have focused on effects from either early onset or long-term sensory loss and little is known how the recent sensory loss affects the human brain. With the aim of determining how recent sensory loss affects cerebral morphology and functional connectivity, we assessed differences between individuals with acquired olfactory loss (duration 7-36 months) and matched healthy controls in their grey matter volume, using multivariate pattern analyses, and functional connectivity, using dynamic connectivity analyses, within and from the olfactory cortex. Our results demonstrate that acquired olfactory loss is associated with altered grey matter volume in, among others, posterior piriform cortex, a core olfactory processing area, as well as the inferior frontal gyrus and angular gyrus. In addition, compared to controls, individuals with acquired anosmia displayed significantly stronger dynamic functional connectivity from the posterior piriform cortex to, among others, the angular gyrus, a known multisensory integration area. When assessing differences in dynamic functional connectivity from the angular gyrus, individuals with acquired anosmia had stronger connectivity from the angular gyrus to areas primary responsible for basic visual processing. These results demonstrate that recently acquired sensory loss is associated with both changed cerebral morphology within core olfactory areas and increase dynamic functional connectivity from olfactory cortex to cerebral areas processing multisensory integration.

Seeing Beyond Your Nose? The Effects of Lifelong Olfactory Sensory Deprivation on Cerebral Audio-visual Integration.

Lifelong auditory and visual sensory deprivation have been demonstrated to alter both perceptual acuity and the neural processing of remaining senses. Recently, it was demonstrated that individuals with anosmia, i.e. complete olfactory sensory deprivation, displayed enhanced multisensory integration performance. Whether this ability is due to a reorganization of olfactory processing regions to focus on cross-modal multisensory information or whether it is due to enhanced processing within multisensory integration regions is not known. To dissociate these two outcomes, we investigated the neural processing of dynamic audio-visual stimuli in individuals with congenital anosmia and matched controls (both groups, n = 33) using functional magnetic resonance imaging. Specifically, we assessed whether the previously demonstrated multisensory enhancement is related to cross-modal processing of multisensory stimuli in olfactory associated regions, the piriform and olfactory orbitofrontal cortices, or enhanced multisensory processing in established multisensory integration regions, the superior temporal and intraparietal sulci. No significant group differences were found in the a priori hypothesized regions using region of interest analyses. However, exploratory whole-brain analysis suggested higher activation related to multisensory integration within the posterior superior temporal sulcus, in close proximity to the multisensory region of interest, in individuals with congenital anosmia. No group differences were demonstrated in olfactory associated regions. Although results were outside our hypothesized regions, combined, they tentatively suggest that enhanced processing of audio-visual stimuli in individuals with congenital anosmia may be mediated by multisensory, and not primary sensory, cerebral regions.