Hemispheric asymmetry and visuo-olfactory integration in perceiving subthreshold (micro) fearful expressions

Multisensory integration is ubiquitous, facilitating perception beyond the limit of individual senses. This mechanism is especially salient when individual sensory input is weak (i.e., the principle of inverse effectiveness), fusing subthreshold cues into tangible percepts. Nevertheless, it is unclear how this rule applies to threat perception, synthesizing elusive, discrete traces of a threat into a discernible danger signal. In light of hemispheric asymmetry in threat processing, we combined parafoveal stimulus presentation and the contralateral P1 visual event-related potential to investigate how aversive olfactory inputs enhance visual perception of highly degraded, subthreshold fearful expressions. The dominant right hemisphere exhibited early visual discrimination between subtle fear and neutral expressions, independently of accompanying odors. In the left hemisphere, differential visual processing occurred only at the convergence of negative odors and minute facial fear, highlighting the success and necessity of visuo-olfactory threat integration in this disadvantaged hemisphere. Reaction time data from a subsequent dot-detection task complemented these neural findings, revealing odor-dependent and hemisphere-specific modulation of spatial attention to facial expressions. Our evidence thus indicates cross-modal threat integration in basic visual perception in humans that captures minimal threat information, especially in the blind right hemifield. Critically, this interaction between multisensory synergy and hemispheric asymmetry in threat perception may underlie the multifaceted fear experiences of everyday life.     

Experience induces functional reorganization in brain regions involved in odor imagery in perfumers

Areas of expertise that cultivate specific sensory domains reveal the brain's ability to adapt to environmental change. Perfumers are a small population who claim to have a unique ability to generate olfactory mental images. To evaluate the impact of this expertise on the brain regions involved in odor processing, we measured brain activity in novice and experienced (student and professional) perfumers while they smelled or imagined odors. We demonstrate that olfactory imagery activates the primary olfactory (piriform) cortex (PC) in all perfumers, demonstrating that similar neural substrates were activated in odor perception and imagination. In professional perfumers, extensive olfactory practice influences the posterior PC, the orbitofrontal cortex, and the hippocampus; during the creation of mental images of odors, the activity in these areas was negatively correlated with experience. Thus, the perfumers' expertise is associated with a functional reorganization of key olfactory and memory brain regions, explaining their extraordinary ability to imagine odors and create fragrances.     

Role of dorsomedial thalamic nucleus and piriform cortex in processing olfactory information

Four experiments were conducted to characterize the role of primary and secondary olfactory projection areas (piriform cortex and dorsomedial thalamic nucleus (DMN] in olfactory information processing. Rats had to learn to discriminate between odors that were simultaneously released from different arms of an automated olfactory maze. When standard training conditions were used, damage of the DMN severely impaired both preoperatively trained and naive animals in acquiring an odor discrimination set (i.e. in most problems no learning was demonstrated). An additional group of DMN animals that received 4 times the standard amount of daily trials was unable to acquire the first two problems but successfully solved the third and all subsequent discriminations. Analysis of performance patterns suggested that destruction of the DMN initially leads to a strong procedural impairment that can be overcome by extensive training. After solving the third problem the animals with DMN damage required much less training to reach the learning criterion but generally made more errors than controls. Transfer of savings rarely occurred when a problem was repeated. Whether this secondary learning deficit observed in later discriminations is due to a specific effect of the lesion on the encoding of olfactory cues and thus on memory formation, or due to a disturbance in the regulation of emotional factors such as motivation, arousal, and attention is discussed. Lesions of the thalamus that spared the DMN had no effect on learning or retention of olfactory discriminations. Animals with ablations of the piriform cortex only acquired odor discriminations if they had been trained in the olfactory maze before the lesion. Moreover, their performance depended on the odor quality: they had great difficulty learning complex cues consisting of several odorants and learned simple odors virtually identical to control rats. The results indicate that an intact piriform cortex is needed to acquire the procedures involved to perform an olfactory discrimination task as well as to build neural representations of olfactory cues.     

The fundamental role of memory in olfactory perception

Current emphasis on odorant physiochemical features as the basis for perception largely ignores the synthetic and experience-dependent nature of olfaction. Olfaction is synthetic, as mammals have only limited ability to identify elements within even simple odor mixtures. Furthermore, olfaction is experience-bound, as exposure alone can significantly affect the extent to which stimuli can be discriminated. We propose that early analytical processing of odors is inaccessible at the behavioral level and that all odors are initially encoded as 'objects' in the piriform cortex. Moreover, we suggest that odor perception is wholly dependent on the integrity of this memory system and that its loss severely impairs normal perception.     

Plasticity in the olfactory system: lessons for the neurobiology of memory.

We are rapidly advancing toward an understanding of the molecular events underlying odor transduction, mechanisms of spatiotemporal central odor processing, and neural correlates of olfactory perception and cognition. A thread running through each of these broad components that define olfaction appears to be their dynamic nature. How odors are processed, at both the behavioral and neural level, is heavily dependent on past experience, current environmental context, and internal state. The neural plasticity that allows this dynamic processing is expressed nearly ubiquitously in the olfactory pathway, from olfactory receptor neurons to the higher-order cortex, and includes mechanisms ranging from changes in membrane excitability to changes in synaptic efficacy to neurogenesis and apoptosis. This review will describe recent findings regarding plasticity in the mammalian olfactory system that are believed to have general relevance for understanding the neurobiology of memory.     

Neural substrates of olfactory processing in schizophrenia patients and their healthy relatives

Odorants represent powerful stimuli capable of eliciting various emotional responses. In schizophrenia patients and their non-affected relatives, olfactory and emotional functions are impaired, revealing a familial influence on these deficits. We aimed at determining the neural basis of emotional olfactory dysfunctions using odors of different emotional valence for mood induction and functional magnetic resonance imaging (fMRI) by comparing 13 schizophrenia patients, their non-affected brothers and 26 matched healthy controls. Blood-oxygen-level-dependent (BOLD) effects and subjective mood changes were assessed during negative (rotten yeast), positive (vanilla) and neutral (ambient air) olfactory stimulation. Group comparisons of brain activation were performed in regions of interest. Subjective ratings were comparable between groups and indicated successful mood induction. However, during stimulation with the negative odor, hypofunctional activity emerged in regions of the right frontal and temporal cortex in the patients. A familial influence in the neural substrates of negative olfactory dysfunction was indicated by a similar reduced frontal brain activity in relatives. Dysfunctions therefore appeared to be located in regions involved in higher cognitive processes associated with olfaction. No familial influences were indicated for cerebral dysfunctions during positive olfactory stimulation. Results point to a differentiation between trait and state components in cerebral dysfunctions during emotional olfactory processing in schizophrenia.     

Brain activation during odor perception in males and females.

Several studies indicate that women outperform men in olfactory identification tasks. The psychophysical data are more divergent when it comes to gender differences at levels of odor processing which are cognitively less demanding. We therefore compared cerebral activation with H2(15)O PET in 12 females and 11 males during birhinal passive smelling of odors and odorless air. The odorous compounds (odorants) were pure olfactory, or mixed olfactory and weakly trigeminal. Using odorless air as the baseline condition, activations were found bilaterally in the amygdala, piriform and insular cortices in both sexes, irrespective of the odor. No gender difference was detected in the pattern of cerebral activation (random effect analysis SPM99, corrected p < 0.05) or in the subjective perception of odors. Males and females seem to use similar cerebral circuits during the passive perception of odors. The reported female superiority in assessing olfactory information including odor identification is probably an effect of a difference at a cognitive, rather than perceptive level of olfactory processing.     

Sniffing out the contributions of the olfactory tubercle to the sense of smell: Hedonics, sensory integration, and more?

Since its designation in 1896 as a putative olfactory structure, the olfactory tubercle has received little attention in terms of elucidating its role in the processing and perception of odors. Instead, research on the olfactory tubercle has mostly focused on its relationship with the reward system. Here we provide a comprehensive review of research on the olfactory tubercle—with an emphasis on the likely role of this region in olfactory processing and its contributions to perception. Further, we propose several testable hypotheses regarding the likely involvement of the olfactory tubercle in both basic (odor detection, discrimination, parallel processing of olfactory information) and higher-order (social odor processing, hedonics, multi-modal integration) functions. Together, the information within this review highlights an understudied yet potentially critical component in central odor processing.     

Olfactory learning-related NCAM expression is state, time, and location specific and is correlated with individual learning capabilities

The notion that long-term synaptic plasticity is generated by activity-induced molecular modifications is widely accepted. It is well established that neural cell adhesion molecule (NCAM) is one of the prominent modulators of synaptic plasticity. NCAM can be polysialylated (PSA-NCAM), a reaction that provides it with anti-adhesion properties. In this study we have focused on NCAM and on its polysialylated state, and their relation to learning of an olfactory discrimination task, which depends on both the piriform (olfactory) cortex and hippocampus. We trained rats to distinguish between pairs of odors until rule learning was achieved, a process that normally lasts 6-8 days. At four time points, during training and after training completion, synaptic NCAM and PSA-NCAM expression were assessed in the piriform cortex and hippocampus. We report that NCAM modulation is specific to PSA-NCAM, which is upregulated in the hippocampus one day after training completion. We also report a correlation between the performance of individual rats in an early training stage and their NCAM expression, both in the piriform cortex and hippocampus. Since individual early performance in our odor discrimination task is correlated with the performance throughout the training period, we conclude that early NCAM expression is associated with odor learning capability. We therefore suggest that early synaptic NCAM expression may be one of the factors determining the capability of rats to learn.     

Passive perception of odors and semantic circuits

The sense of smell has been traditionally assumed to be different from other sensory modalities in that odors are encoded perceptually, without a semantic component. Recent findings of improved odor memory upon encoding with verbal cues question this view. Furthermore, familiar odors are easier to remember and discriminate than are unfamiliar ones, and odor familiarity is reported to predict odor naming. To investigate whether familiar odors are processed by different cerebral structures than those that process unfamiliar odors, (15)O H(2)O-positron emission tomography (PET) measurements of cerebral blood flow were carried out in 14 healthy men. The task was passive, birhinal, smelling of familiar odors (FAM), unfamiliar odors (uFAM), and odorless air (AIR). Significant activations (P < 0.05) were calculated using the contrasts FAM-AIR, uFAM-AIR, and FAM-uFAM, and deactivations running these contrasts in the opposite direction. In relation to AIR, both FAM and uFAM activated amygdala, piriform cortex, and parts of anterior cingulate cortex. FAM activated, in addition, left frontal cortex (Brodmann's areas 44,45,47), left parietal cortex incorporating precuneus, and right parahippocampus. Clusters covering parahippocampus and precuneus were observed also in FAM-uFAM. The activation of left frontal cortex and right parahippocampus was positively correlated with familiarity ratings. Smelling of familiar but not unfamiliar odorants seems to engage cerebral circuits mediating memory and language functions, in addition to the engagement of olfactory cortex. Already the most elemental form of odor processing, passive perception thus seems to engage semantic circuits. This is achieved by the ability of odorants to immediately elicit associations and judgments of odor characteristics.     

Neural mechanisms of individual and sexual recognition in Syrian hamsters (Mesocricetus auratus)

Recognizing the individual and sexual identities of conspecifics is critical for adaptive social behavior and, in most mammals this information is communicated primarily by chemosensory cues. Due to its heavy reliance on odor cues, we have used the Syrian hamster as our model species for investigating the neural regulation of social recognition. Using lesion, electrophysiological and immunocytochemical techniques, separate neural pathways underlying recognition of individual odors and guidance of sex-typical responses to opposite-sex odors have been identified in both male and female hamsters. Specifically, we have found that recognition of individual odor identity requires olfactory bulb connections to entorhinal cortex (ENT) rather than other chemoreceptive brain regions. This kind of social memory does not appear to require the hippocampus and may, instead, depend on ENT connections with piriform cortex. In contrast, sexual recognition, through either differential investigation or scent marking toward opposite-sex odors, depends on both olfactory and vomeronasal system input to the corticomedial amygdala. Preference for investigating opposite-sex odors requires primarily olfactory input to the medial amygdala (ME) whereas appropriately targeted scent marking responses require vomeronasal input to ME as well as to other structures. Within the ME, the anterior section (MEa) appears important for evaluating or classifying social odors whereas the posterodorsal region (MEpd) may be more involved in generating approach to social odors. Evidence is presented that analysis of social odors may initially be done in MEa and then communicated to MEpd, perhaps through micro-circuits that separately process male and female odors.     

Functional magnetic resonance imaging of human olfaction

Olfaction is our basic sense phylogenetically and embryologically. Little is known, however, about how the human brain encodes the quality of odors, odor-associated memories, and emotions. Olfactory information is projected from the olfactory bulb to the primary olfactory cortex, which is composed of the anterior olfactory nucleus, the olfactory tubercle, the piriform cortex, the amygdala, the periamygdaloid region, and the entorhinal cortex. From there, the primary olfactory cortex projects to secondary olfactory regions including the hippocampus, ventral striatum and pallidum, hypothalamus, thalamus, orbitofrontal cortex, agranular insular cortex, and cingulate gyrus. Functional MR studies using olfactory stimuli as paradigms show activation of many of these areas and can advance our understanding of odor perception in humans.     

Regional autonomy in the peripheral processing of odor signals in newborn rabbits

In newborn rabbits, small and apparently arbitrary regions of the olfactory bulb and associated epithelium appear capable of a high degree of odor processing. After medial or lateral removal of up to 80% of the olfactory bulbs, including the accessory bulb, newborn pups were still able to respond appropriately to the pheromone-governing suckling behavior (Expt. I), could rapidly learn to associate a novel, artificial odor with suckling (Expt. II), and continued to respond appropriately to artificial odors learned prior to lesioning (Expt. III). These findings suggest that the perception and recognition of such suckling signals does not depend on the integration of information from the entire bulb or epithelium, and question the extent to which patterns of 2-deoxyglucose uptake in the bulb reflect the neural coding for specific odors. However, as the tasks set here only required detection of odor signals and not true odor discrimination, it may still be that the full bulbar pattern of activation is necessary for higher-order processing, such as distinguishing between odors and attributing different meanings to them.     

Distributed auditory sensory input within the mouse olfactory cortex

The mammalian olfactory cortex is commonly considered critical for odor information processing and perception. It is becoming increasingly apparent, however, that the olfactory cortex receives input from multiple sensory channels. Previous work from our group demonstrated the presence of auditory sensory convergence within one olfactory cortical structure, the olfactory tubercle (OT). Interestingly, anatomical evidence for auditory input into the neighboring olfactory piriform cortex (PCX) posits the possibility that auditory sensory input is a distributed property of the olfactory cortex. To address this question, we performed in vivo extracellular recordings from the OT and PCX of anesthetized mice and measured modulations in unit firing in the presence of tones. In support for auditory sensory input being a distributed feature of the olfactory cortex, we found that 29% of units sampled within the PCX display tone‐evoked responses. This population compares with that found within the OT using the same stimuli (37%). While overall tone‐evoked response magnitudes were comparable between the two structures, tone signal : noise was significantly greater within the OT than in the PCX. No effect of tone frequency (1–55 kHz) was found within either structure, with most units being narrowly tuned to a single frequency. These results suggest that a major portion of odor‐evoked output from the olfactory bulb (i.e. that entering the OT and PCX) is subject to auditory sensory input in a manner that may modulate odor information processing, odor‐guided behaviors and perception.     

Severity of olfactory deficits is reflected in functional brain networks—An fMRI study

Even though deficits in olfactory function affect a considerable part of the population, the neuronal basis of olfactory deficits remains scarcely investigated. To achieve a better understanding of how smell loss affects neural activation patterns and functional networks, we set out to investigate patients with olfactory dysfunction using functional magnetic resonance imaging (fMRI) and olfactory stimulation. We used patients’ scores on a standardized olfactory test as continuous measure of olfactory function. 48 patients (mean olfactory threshold discrimination identification (TDI) score = 16.33, SD = 6.4, range 6 ‐ 28.5) were investigated. Overall, patients showed piriform cortex activation during odor stimulation compared to pure sniffing. Group independent component analysis indicated that the recruitment of three networks during odor stimulation was correlated with olfactory function: a sensory processing network (including regions such as insula, thalamus and piriform cortex), a cerebellar network and an occipital network. Interestingly, recruitment of these networks during pure sniffing was related to olfactory function as well. Our results support previous findings that sniffing alone can activate olfactory regions. Extending this, we found that the severity of olfactory deficits is related to the extent to which neural networks are recruited both during olfactory stimulation and pure sniffing. This indicates that olfactory deficits are not only reflected in changes in specific olfactory areas but also in the recruitment of occipital and cerebellar networks. These findings pave the way for future investigations on whether characteristics of these networks might be of use for the prediction of disease prognosis or of treatment success.     

Perceptual and Neural Plasticity of Odor Quality Coding in the Human Brain

Current neurobiological models of odor perception tend to emphasize the “bottom-up” contributions of odorant chemistry in determining the perceptual features of an odor. However, increasing research suggests that “top-down” effects related to learning and experience play equally important roles in human olfactory perception, implying that a given set of olfactory receptors activated by an odorant does not neatly map onto a given odor percept. Rather, odor perception may rely on more synthetic mechanisms subserved by higher order brain regions. This review article focuses on the modulatory effects of learning, context, and experience on human odor perception. Recent psychophysical and neuroimaging work from our laboratory indicates that sensory-specific information about odor quality is not static within human piriform and orbitofrontal cortices but can be rapidly updated by mere sensory exposure. This experience-dependent neural plasticity parallels behavioral improvements in odor perception, providing direct evidence for the role of learning in shaping neural representations of odor quality in the human brain.     

Pyriform cortex beta-waves: odor-specific sensitization following repeated olfactory stimulation

The first exposure to the odors of carbon tetrachloride, isopentenyl methyl sulfide, methyl ethyl ketone, 2-propylthietane, salicylaldehyde, toluene, 2,4,5-trimethyl thiazoline, or xylene elicits a weakly developed 20 Hz wave response (beta-waves) in central olfactory structures in the rat. Repeated presentations of these odors produces a gradual enhancement or sensitization of olfactory beta-waves over 5-10 trials given in 1-3 min. The odors of 2-aminoacetophenone and 2-hydroxyacetophenone produce sensitization after an average of 15-17 presentations. The sensitized beta-wave response to the odors of 2-propylthietane and xylene persists for at least 5 days and probably much longer. Sensitization to one odor transfers partially or not at all to other novel odors even though repeated presentation of the new odor also produces sensitization. Since the initial negative response of the olfactory mucosa (presumably due to receptor depolarization) is not enhanced by repeated olfactory stimulation, it is presumed that the altered responsivity is due to synaptic changes in central olfactory structures such as the olfactory bulb or pyriform cortex. Finally, data are presented to show that behavioral antifeedant activity by an odorant does not invariably mean that the odorant has the ability to elicit an olfactory beta-wave response.     

Modulation of olfactory perception by visual cortex stimulation

When attempting to identify an object based on smell alone, people often visualize the perceived source of the odorant. This close association between olfactory and visual functions is supported by neuroimaging studies demonstrating activation of visual cortex during performance of purely olfactory tasks. Such activation might simply reflect the correlation between olfactory percepts and the corresponding visual images, or it might reflect a causal contribution of visual processing to olfactory perception. Here we provide evidence in support of the latter possibility. Using repetitive transcranial magnetic stimulation, we show that stimulating human visual cortex improves performance on a task requiring discrimination among different odor qualities. No significant improvement is found for tasks involving discrimination between intensities of the same odor, from stimulation of auditory cortex, or from "sham" stimulation. These results are thus consistent with a specific visual cortical influence on high-level olfactory perception. They also demonstrate that unimodal perceptual tasks are influenced by processing within cortical areas of other, seemingly unrelated, sensory systems.     

Projections from orbitofrontal cortex to anterior piriform cortex in the rat suggest a role in olfactory information processing

The orbitofrontal cortex (OFC) has been characterized as a higher-order, multimodal sensory cortex. Evidence from electrophysiological and behavioral studies in the rat has suggested that OFC plays a role in modulating olfactory guided behavior, and a significant projection to OFC arises from piriform cortex, the traditional primary olfactory cortex. To discern how OFC interacts with primary olfactory structures, the anterograde tracer Phaseolus vulgaris leucoagglutinin was injected into orbitofrontal cortical areas in adult male rats. Labeled fibers were found in the piriform cortex and olfactory bulb on the side ipsilateral to the injection. Notably, the projection to piriform cortex was predominantly from ventrolateral orbital cortex, and was not uniform; rostrally, the projection to the ventral portion of the anterior piriform cortex (APC) was substantial, while the dorsal APC was virtually free of labeled fibers. Labeled fibers were found in both the dorsal and ventral portions in more caudal regions of APC. Most labeled fibers were found in layer III, although a substantial number of fibers were observed in layers Ib and II. Labeled fibers in posterior piriform cortex also were seen after injection into orbitofrontal areas. Taken together with previous reports, these findings suggest that piriform cortex includes multiple subdivisions, which may perform separate, parallel functions in olfactory information processing. Further, these results suggest that the OFC, in addition to its putative role in encoding information about the significance of olfactory stimuli, may play a role in modulating odor response properties of neurons in piriform cortex.     

Impairment of odor hedonics in men with schizophrenia

OBJECTIVE: Olfactory deficits in patients with schizophrenia, including those of odor identification, detection threshold sensitivity, discrimination, and memory, have been well described. Deficits in emotional perception, processing, and experience have also been reported, with anhedonia being one of the core features. While anatomical connections testify to the relationship between olfaction and emotion, there has been little investigation of the hedonic properties of odors in schizophrenia. This study examined intensity and hedonic judgments in patients with schizophrenia to determine whether these functions were differentially impaired. METHOD: Suprathreshold scaling of odor intensity and pleasantness was acquired by using the Suprathreshold Amyl Acetate Odor Intensity and Odor Pleasantness Rating Test given to 30 patients (15 men and 15 women) with a DSM-IV diagnosis of schizophrenia and 30 age- and sex-matched healthy comparison subjects. RESULTS: Despite virtually identical ratings of odor intensity, male patients were impaired in the assignment of odor pleasantness to amyl acetate. This gender-specific diagnostic group difference was not explained by variability in symptom severity or negative/positive symptoms. The impact of smoking status and general cognitive impairment on this deficit was also insignificant. CONCLUSIONS: Findings reveal a gender-specific disruption in the ability to attribute appropriate hedonic valence to odors in male patients with schizophrenia. This difficulty in identifying the hedonic valence of odors, despite intact intensity ratings, is consistent with clinical observations of anhedonia and points to a neural substrate that might contribute to the emotional disturbances seen in patients with schizophrenia.