What Does the Human Olfactory System Do, and How Does It Do It?

Historically, the human sense of smell has been regarded as the odd stepchild of the senses, especially compared to the sensory bravado of seeing, touching, and hearing. The idea that the human olfaction has little to contribute to our experience of the world is commonplace, though with the emergence of COVID-19 there has rather been a sea change in this understanding. An ever increasing body of work has convincingly highlighted the keen capabilities of the human nose and the sophistication of the human olfactory system. Here, we provide a concise overview of the neuroscience of human olfaction spanning the last 10-15 years, with focus on the peripheral and central mechanisms that underlie how odor information is processed, packaged, parceled, predicted, and perturbed to serve odor-guided behaviors. We conclude by offering some guideposts for harnessing the next decade of olfactory research in all its shapes and forms.

Olfactory modulation of the medial prefrontal cortex circuitry: Implications for social cognition.

Olfactory dysfunction is manifested in a wide range of neurological and psychiatric diseases, and often emerges prior to the onset of more classical symptoms and signs. From a behavioral perspective, olfactory deficits typically arise in conjunction with impairments of cognition, motivation, memory, and emotion. However, a conceptual framework for explaining the impact of olfactory processing on higher brain functions in health and disease remains lacking. Here we aim to provide circuit-level insights into this question by synthesizing recent advances in olfactory network connectivity with other cortical brain regions such as the prefrontal cortex. We will focus on social cognition as a representative model for exploring and critically evaluating the relationship between olfactory cortices and higher-order cortical regions in rodent models. Although rodents do not recapitulate all dimensions of human social cognition, they have experimentally accessible neural circuits and well-established behavioral tests for social motivation, memory/recognition, and hierarchy, which can be extrapolated to other species including humans. In particular, the medial prefrontal cortex (mPFC) has been recognized as a key brain region in mediating social cognition in both rodents and humans. This review will highlight the underappreciated connectivity, both anatomical and functional, between the olfactory system and mPFC circuitry, which together provide a neural substrate for olfactory modulation of social cognition and social behaviors. We will provide future perspectives on the functional investigation of the olfactory-mPFC circuit in rodent models and discuss how to translate such animal research to human studies.

Anticipation-induced delta phase reset improves human olfactory perception.

Anticipating an odor improves detection and perception, yet the underlying neural mechanisms of olfactory anticipation are not well understood. In this study, we used human intracranial electroencephalography (iEEG) to show that anticipation resets the phase of delta oscillations in piriform cortex prior to odor arrival. Anticipatory phase reset correlates with ensuing odor-evoked theta power and improvements in perceptual accuracy. These effects were consistently present in each individual subject and were not driven by potential confounds of pre-inhale motor preparation or power changes. Together, these findings suggest that states of anticipation enhance olfactory perception through phase resetting of delta oscillations in piriform cortex.

Titrating the Smell of Fear: Initial Evidence for Dose-Invariant Behavioral, Physiological, and Neural Responses.

It is well accepted that emotional intensity scales with stimulus strength. Here, we used physiological and neuroimaging techniques to ask whether human body odor-which can convey salient social information-also induces dose-dependent effects on behavior, physiology, and neural responses. To test this, we first collected sweat from 36 males classified as low-, medium-, and high-fear responders. Next, in a double-blind within-subjects functional-MRI design, 31 women were exposed to three doses of fear-associated human chemosignals and neutral sweat while viewing face morphs varying between expressions of fear and disgust. Behaviorally, we found that all doses of fear-sweat volatiles biased participants toward perceiving fear in ambiguous morphs, a dose-invariant effect generally repeated across physiological and neural measures. Bayesian dose-response analysis indicated moderate evidence for the null hypothesis (except for the left amygdala), tentatively suggesting that the human olfactory system engages an all-or-none mechanism for tagging fear above a minimal threshold.

Identity-specific coding of future rewards in the human orbitofrontal cortex.

Nervous systems must encode information about the identity of expected outcomes to make adaptive decisions. However, the neural mechanisms underlying identity-specific value signaling remain poorly understood. By manipulating the value and identity of appetizing food odors in a pattern-based imaging paradigm of human classical conditioning, we were able to identify dissociable predictive representations of identity-specific reward in orbitofrontal cortex (OFC) and identity-general reward in ventromedial prefrontal cortex (vmPFC). Reward-related functional coupling between OFC and olfactory (piriform) cortex and between vmPFC and amygdala revealed parallel pathways that support identity-specific and -general predictive signaling. The demonstration of identity-specific value representations in OFC highlights a role for this region in model-based behavior and reveals mechanisms by which appetitive behavior can go awry.

De Novo Emergence of Odor Category Representations in the Human Brain.

Categorization allows organisms to efficiently extract relevant information from a diverse environment. Because of the multidimensional nature of odor space, this ability is particularly important for the olfactory system. However, categorization relies on experience, and the processes by which the human brain forms categorical representations about new odor percepts are currently unclear. Here we used olfactory psychophysics and multivariate fMRI techniques, in the context of a paired-associates learning task, to examine the emergence of novel odor category representations in the human brain. We found that learning between novel odors and visual category information induces a perceptual reorganization of those odors, in parallel with the emergence of odor category-specific ensemble patterns in perirhinal, orbitofrontal, piriform, and insular cortices. Critically, the learning-induced pattern effects in orbitofrontal and perirhinal cortex predicted the magnitude of categorical learning and perceptual plasticity. The formation of de novo category-specific representations in olfactory and limbic brain regions suggests that such ensemble patterns subserve the development of perceptual classes of information, and imply that these patterns are instrumental to the brain's capacity for odor categorization. SIGNIFICANCE STATEMENT: How the human brain assigns novel odors to perceptual classes and categories is poorly understood. We combined an olfactory-visual paired-associates task with multivariate pattern-based fMRI approaches to investigate the de novo formation of odor category representations within the human brain. The identification of emergent odor category codes within the perirhinal, piriform, orbitofrontal, and insular cortices suggests that these regions can integrate multimodal sensory input to shape category-specific olfactory representations for novel odors, and may ultimately play an important role in assembling each individual's semantic knowledge base of the olfactory world.

Nasal Respiration Entrains Human Limbic Oscillations and Modulates Cognitive Function.

The need to breathe links the mammalian olfactory system inextricably to the respiratory rhythms that draw air through the nose. In rodents and other small animals, slow oscillations of local field potential activity are driven at the rate of breathing (∼2-12 Hz) in olfactory bulb and cortex, and faster oscillatory bursts are coupled to specific phases of the respiratory cycle. These dynamic rhythms are thought to regulate cortical excitability and coordinate network interactions, helping to shape olfactory coding, memory, and behavior. However, while respiratory oscillations are a ubiquitous hallmark of olfactory system function in animals, direct evidence for such patterns is lacking in humans. In this study, we acquired intracranial EEG data from rare patients (Ps) with medically refractory epilepsy, enabling us to test the hypothesis that cortical oscillatory activity would be entrained to the human respiratory cycle, albeit at the much slower rhythm of ∼0.16-0.33 Hz. Our results reveal that natural breathing synchronizes electrical activity in human piriform (olfactory) cortex, as well as in limbic-related brain areas, including amygdala and hippocampus. Notably, oscillatory power peaked during inspiration and dissipated when breathing was diverted from nose to mouth. Parallel behavioral experiments showed that breathing phase enhances fear discrimination and memory retrieval. Our findings provide a unique framework for understanding the pivotal role of nasal breathing in coordinating neuronal oscillations to support stimulus processing and behavior. SIGNIFICANCE STATEMENT: Animal studies have long shown that olfactory oscillatory activity emerges in line with the natural rhythm of breathing, even in the absence of an odor stimulus. Whether the breathing cycle induces cortical oscillations in the human brain is poorly understood. In this study, we collected intracranial EEG data from rare patients with medically intractable epilepsy, and found evidence for respiratory entrainment of local field potential activity in human piriform cortex, amygdala, and hippocampus. These effects diminished when breathing was diverted to the mouth, highlighting the importance of nasal airflow for generating respiratory oscillations. Finally, behavioral data in healthy subjects suggest that breathing phase systematically influences cognitive tasks related to amygdala and hippocampal functions.

Human Amygdala Represents the Complete Spectrum of Subjective Valence.

Although the amygdala is a major locus for hedonic processing, how it encodes valence information is poorly understood. Given the hedonic potency of odor stimuli and the amygdala's anatomical proximity to the peripheral olfactory system, we combined high-resolution fMRI with pattern-based multivariate techniques to examine how valence information is encoded in the amygdala. Ten human subjects underwent fMRI scanning while smelling 9 odorants that systematically varied in perceived valence. Representational similarity analyses showed that amygdala codes the entire dimension of valence, ranging from pleasantness to unpleasantness. This unidimensional representation significantly correlated with self-reported valence ratings but not with intensity ratings. Furthermore, within-trial valence representations evolved over time, prioritizing earlier differentiation of unpleasant stimuli. Together, these findings underscore the idea that both spatial and temporal features uniquely encode pleasant and unpleasant odor valence in the amygdala. The availability of a unidimensional valence code in the amygdala, distributed in both space and time, would create greater flexibility in determining the pleasantness or unpleasantness of stimuli, providing a mechanism by which expectation, context, attention, and learning could influence affective boundaries for guiding behavior. SIGNIFICANCE STATEMENT: Our findings elucidate the mechanisms of affective processing in the amygdala by demonstrating that this brain region represents the entire valence dimension from pleasant to unpleasant. An important implication of this unidimensional valence code is that pleasant and unpleasant valence cannot coexist in the amygdale because overlap of fMRI ensemble patterns for these two valence extremes obscures their unique content. This functional architecture, whereby subjective valence maps onto a pattern continuum between pleasant and unpleasant poles, offers a robust mechanism by which context, expectation, and experience could alter the set-point for valence-based behavior. Finally, identification of spatial and temporal differentiation of valence in amygdala may shed new insights into individual differences in emotional responding, with potential relevance for affective disorders.

A designated odor-language integration system in the human brain.

Odors are surprisingly difficult to name, but the mechanism underlying this phenomenon is poorly understood. In experiments using event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI), we investigated the physiological basis of odor naming with a paradigm where olfactory and visual object cues were followed by target words that either matched or mismatched the cue. We hypothesized that word processing would not only be affected by its semantic congruency with the preceding cue, but would also depend on the cue modality (olfactory or visual). Performance was slower and less precise when linking a word to its corresponding odor than to its picture. The ERP index of semantic incongruity (N400), reflected in the comparison of nonmatching versus matching target words, was more constrained to posterior electrode sites and lasted longer on odor-cue (vs picture-cue) trials. In parallel, fMRI cross-adaptation in the right orbitofrontal cortex (OFC) and the left anterior temporal lobe (ATL) was observed in response to words when preceded by matching olfactory cues, but not by matching visual cues. Time-series plots demonstrated increased fMRI activity in OFC and ATL at the onset of the odor cue itself, followed by response habituation after processing of a matching (vs nonmatching) target word, suggesting that predictive perceptual representations in these regions are already established before delivery and deliberation of the target word. Together, our findings underscore the modality-specific anatomy and physiology of object identification in the human brain.

Central mechanisms of odour object perception.

The stimulus complexity of naturally occurring odours presents unique challenges for central nervous systems that are aiming to internalize the external olfactory landscape. One mechanism by which the brain encodes perceptual representations of behaviourally relevant smells is through the synthesis of different olfactory inputs into a unified perceptual experience--an odour object. Recent evidence indicates that the identification, categorization and discrimination of olfactory stimuli rely on the formation and modulation of odour objects in the piriform cortex. Convergent findings from human and rodent models suggest that distributed piriform ensemble patterns of olfactory qualities and categories are crucial for maintaining the perceptual constancy of ecologically inconstant stimuli.

A cortical pathway to olfactory naming: evidence from primary progressive aphasia.

It is notoriously difficult to name odours. Without the benefit of non-olfactory information, even common household smells elude our ability to name them. The neuroscientific basis for this olfactory language 'deficit' is poorly understood, and even basic models to explain how odour inputs gain access to transmodal representations required for naming have not been put forward. This study used patients with primary progressive aphasia, a clinical dementia syndrome characterized by primary deficits in language, to investigate the interactions between olfactory inputs and lexical access by assessing behavioural performance of olfactory knowledge and its relationship to brain atrophy. We specifically hypothesized that the temporal pole would play a key role in linking odour object representations to transmodal networks, given its anatomical proximity to olfactory and visual object processing areas. Behaviourally, patients with primary progressive aphasia with non-semantic subtypes were severely impaired on an odour naming task, in comparison with an age-matched control group. However, with the availability of picture cues or word cues, odour matching performance approached control levels, demonstrating an inability to retrieve but not to recognize the name and nature of the odorant. The magnitude of cortical thinning in the temporal pole was found to correlate with reductions in odour familiarity and odour matching to visual cues, whereas the inferior frontal gyrus correlated with both odour naming and matching. Volumetric changes in the mediodorsal thalamus correlated with the proportion of categorical mismatch errors, indicating a possible role of this region in error-signal monitoring to optimize recognition of associations linked to the odour. A complementary analysis of patients with the semantic subtype of primary progressive aphasia, which is associated with marked temporopolar atrophy, revealed much more pronounced impairments of odour naming and matching. In identifying the critical role of the temporal pole and inferior frontal gyrus in transmodal linking and verbalization of olfactory objects, our findings provide a new neurobiological foundation for understanding why even common odours are hard to name.

Leveraging Multi-echo EPI to Enhance BOLD Sensitivity in Task-based Olfactory fMRI.

Functional magnetic resonance imaging (fMRI) using blood-oxygenation-level-dependent (BOLD) contrast relies on gradient echo echo-planar imaging (GE-EPI) to quantify dynamic susceptibility changes associated with the hemodynamic response to neural activity. However, acquiring BOLD fMRI in human olfactory regions is particularly challenging due to their proximity to the sinuses where large susceptibility gradients induce magnetic field distortions. BOLD fMRI of the human olfactory system is further complicated by respiratory artifacts that are highly correlated with event onsets in olfactory tasks. Multi-Echo EPI (ME-EPI) acquires gradient echo data at multiple echo times (TEs) during a single acquisition and can leverage signal evolution over the multiple echo times to enhance BOLD sensitivity and reduce artifactual signal contributions. In the current study, we developed a ME-EPI acquisition protocol for olfactory task-based fMRI and demonstrated significant improvement in BOLD signal sensitivity over conventional single-echo EPI (1E-EPI). The observed improvement arose from both an increase in BOLD signal changes through a T 2 * -weighted echo combination and a reduction in non-BOLD artifacts through the application of the Multi-Echo Independent Components Analysis (ME-ICA) denoising method. This study represents one of the first direct comparisons between 1E-EPI and ME-EPI in high-susceptibility regions and provides compelling evidence in favor of using ME-EPI for future task-based fMRI studies.

Recruitment of grid-like responses in human entorhinal and piriform cortices by odor landmark-based navigation.

Olfactory navigation is universal across the animal kingdom. Humans, however, have rarely been considered in this context. Here, we combined olfactometry techniques, virtual reality (VR) software, and neuroimaging methods to investigate whether humans can navigate an olfactory landscape by learning the spatial relationships among discrete odor cues and integrating this knowledge into a spatial map. Our data show that over time, participants improved their performance on the odor navigation task by taking more direct paths toward targets and completing more trials within a given time period. This suggests that humans can successfully navigate a complex odorous environment, reinforcing the notion of human olfactory navigation. fMRI data collected during the olfactory navigation task revealed the emergence of grid-like responses in entorhinal and piriform cortices that were attuned to the same grid orientation. This result implies the existence of a specialized olfactory grid network tasked with guiding spatial navigation based on odor landmarks.

High-precision mapping reveals the structure of odor coding in the human brain.

Odor perception is inherently subjective. Previous work has shown that odorous molecules evoke distributed activity patterns in olfactory cortices, but how these patterns map on to subjective odor percepts remains unclear. In the present study, we collected neuroimaging responses to 160 odors from 3 individual subjects (18 h per subject) to probe the neural coding scheme underlying idiosyncratic odor perception. We found that activity in the orbitofrontal cortex (OFC) represents the fine-grained perceptual identity of odors over and above coarsely defined percepts, whereas this difference is less pronounced in the piriform cortex (PirC) and amygdala. Furthermore, the implementation of perceptual encoding models enabled us to predict olfactory functional magnetic resonance imaging responses to new odors, revealing that the dimensionality of the encoded perceptual spaces increases from the PirC to the OFC. Whereas encoding of lower-order dimensions generalizes across subjects, encoding of higher-order dimensions is idiosyncratic. These results provide new insights into cortical mechanisms of odor coding and suggest that subjective olfactory percepts reside in the OFC.

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

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

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

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

A time-based account of the perception of odor objects and valences.

Is human odor perception guided by memory or emotion? Object-centered accounts predict that recognition of unique odor qualities precedes valence decoding. Valence-centered accounts predict the opposite: that stimulus-driven valence responses precede and guide identification. In a speeded response time study, participants smelled paired odors, presented sequentially, and indicated whether the second odor in each pair belonged to the same category as the first (object evaluation task) or whether the second odor was more pleasant than the first (valence evaluation task). Object evaluation was faster and more accurate than valence evaluation. In a complementary experiment, participants performed an identification task, in which they indicated whether an odor matched the previously presented word label. Responses were quicker for odors preceded by semantically matching, rather than nonmatching, word labels, but results showed no evidence of interference from valence on nonmatching trials. These results are in accordance with object-centered accounts of odor perception.

State-dependent olfactory processing in freely behaving mice.

Decreased responsiveness to sensory stimuli during sleep is presumably mediated via thalamic gating. Without an obligatory thalamic relay in the olfactory system, the anterior piriform cortex (APC) is suggested to be a gate in anesthetized states. However, olfactory processing in natural sleep states remains undetermined. Here, we simultaneously record local field potentials (LFPs) in hierarchical olfactory regions (olfactory bulb [OB], APC, and orbitofrontal cortex) while optogenetically activating olfactory sensory neurons, ensuring consistent peripheral inputs across states in behaving mice. Surprisingly, evoked LFPs in sleep states (both non-rapid eye movement [NREM] and rapid eye movement [REM]) are larger and contain greater gamma-band power and cross-region coherence (compared to wakefulness) throughout the olfactory pathway, suggesting the lack of a central gate. Single-unit recordings from the OB and APC reveal a higher percentage of responsive neurons during sleep with a higher incidence of suppressed firing. Additionally, nasal breathing is slower and shallower during sleep, suggesting a partial peripheral gating mechanism.

Disruption of odour quality coding in piriform cortex mediates olfactory deficits in Alzheimer's disease.

Patients with early-stage Alzheimer's disease exhibit perceptual deficits in odour identification, often before the appearance of overt memory loss. This impairment coincides with the initial accumulation of pathological lesions in limbic olfactory brain regions. Although these data imply that odour stimuli may be effectively used as biological probes of limbic dysfunction, the precise neural mechanisms underlying the olfactory deficits in early Alzheimer's disease remain poorly understood. In the current study, we combined functional magnetic resonance imaging with an olfactory cross-adaptation paradigm to test the hypothesis that perceptual codes of odour quality in posterior piriform cortex are degraded in patients with Alzheimer's disease. In elderly control subjects, sequential presentation of qualitatively similar (versus qualitatively different) odourant pairs elicited cross-adapting responses in posterior piriform cortex, in accord with the pattern observed in healthy young adults. However, this profile was significantly blunted in patients with Alzheimer's disease, reflecting a functional disruption of odour quality coding in this olfactory brain area. These results highlight the potential of olfactory functional magnetic resonance imaging as a non-invasive bioassay of limbic functional integrity, and suggest that such an index could possibly aid in the early diagnosis of Alzheimer's disease. Furthermore, as a putative lesion model of odour quality processing in the human brain, our study suggests a causal role of posterior piriform cortex in differentiating olfactory objects.

Using your nose to find your way: Ethological comparisons between human and non-human species.

Olfaction is arguably the least valued among our sensory systems, and its significance for human behavior is often neglected. Spatial navigation represents no exception to the rule: humans are often characterized as purely visual navigators, a view that undermines the contribution of olfactory cues. Accordingly, research investigating whether and how humans use olfaction to navigate space is rare. In comparison, research on olfactory navigation in non-human species is abundant, and identifies behavioral strategies along with neural mechanisms characterizing the use of olfactory cues during spatial tasks. Using an ethological approach, our review draws from studies on olfactory navigation across species to describe the adaptation of strategies under the influence of selective pressure. Mammals interact with spatial environments by abstracting multisensory information into cognitive maps. We thus argue that olfactory cues, alongside inputs from other sensory modalities, play a crucial role in spatial navigation for mammalian species, including humans; that is, odors constitute one of the many building blocks in the formation of cognitive maps.