Sniff magnitude test: relationship to odor identification, detection, and memory tests in a clinic population

Recently a novel measure of olfactory function, the Sniff Magnitude Test (SMT), was developed that relies on changes in inhalation in response to an odor. The relationship of this unique test to that of other olfactory tests has received little investigation. In this study, we assessed, in 132 patients presenting to a chemosensory disorders clinic, the relationship of SMT scores to those from 3 standardized psychophysical tests: the University of Pennsylvania Smell Identification Test (UPSIT), a phenyl ethyl alcohol odor detection threshold test, and a short-term odor memory/discrimination test. SMT scores were roughly related to olfactory dysfunction categories defined for the UPSIT and correlated moderately with the other tests. Malodors (1% and 3% methylthiobutyrate [MTB], 1% ethyl 3-mercaptoproprionate) exhibited stronger correlations than nonmalodors (3% phenyl ethyl alcohol [PEA], 3% amyl acetate, 3% n-butanol) and elicited greater sniff suppression. In a principal component analysis, the SMT measures loaded on components different from those of the other tests, which loaded on a separate component. Anticipatory responses (i.e., smaller sniffs) occurred across trials for the first malodor (1% MTB), but not for the first nonmalodor (3% PEA), that was encountered. These results, along with those of an earlier factor analysis, suggest that sniff magnitude is influenced by odorant quality and intensity, as well as by cognitive factors.     

Odorant-specific patterns of sniffing during imagery distinguish 'bad' and 'good' olfactory imagers

There are large individual differences in the self-reported ability to form vivid olfactory mental imagery. Based on such self-reports, subjects have been classified as 'bad' or 'good' imagers. The present study examined whether a differential strategy in re-enacting the olfactomotor response during imagery may explain the dissociation between 'bad' and 'good' olfactory imagers. As previously reported, odor imagery was accompanied by sniffing. Although 'bad' and 'good' olfactory imagers did not differ in their overall sniffing volume, they used different strategies when re-enacting the motor component of olfaction during imagery. Particularly, as in real perception, 'good' but not 'bad' imagers generated bigger sniffs when imagining a pleasant smell compared with an unpleasant smell (P<0.02). Furthermore, preventing sniffing significantly hampered mental imagery of pleasant odors in 'good' but not 'bad' imagers (P<0.03). Taken together, these results suggest (i) the validity of the dissociation between 'bad' and 'good' olfactory imagers as revealed by self-report; (ii) that sniffing may be a causal factor in the creation of olfactory imagery; and (iii) that sniff measurements may serve as a reliable non-verbal tool in exploring individual differences in odor imagery.     

Intranasal Odorant Concentrations in Relation to Sniff Behavior

Knowledge on how odorants are transported through the nasal cavity to the olfactory epithelium is limited. One facet of this is how the sniffing behavior affects the abundance of odorants transferred to the olfactory cleft and in turn influences odor perception. A novel system that couples an online mass spectrometer with an odorant pulse delivery olfactometer was employed to characterize intranasal odorant concentrations of butane‐2,3‐dione (or butanedione, commonly known as diacetyl) at the interior naris and the olfactory cleft. Volunteers (n=12) were asked to perform different modes of sniffing in relation to the sniff intensity that were categorized as ‘normal’, ‘rapid’ and ‘forced’. The highest concentrations of butanedione at both positions in the nose were observed during normal sniffing, with the lowest concentrations correlating with periods of forced sniffs. This corresponded to the panelists' ratings that normal sniffing elicited the highest odor intensities. These feasibility assessments pave the way for more in‐depth analyses with a variety of odorants of different chemical classes at various intranasal positions, to investigate the passage and uptake of odorants within the nasal cavity.     

The initial phase of auditory and visual scene analysis

Auditory streaming and visual plaids have been used extensively to study perceptual organization in each modality. Both stimuli can produce bistable alternations between grouped (one object) and split (two objects) interpretations. They also share two peculiar features: (i) at the onset of stimulus presentation, organization starts with a systematic bias towards the grouped interpretation; (ii) this first percept has 'inertia'; it lasts longer than the subsequent ones. As a result, the probability of forming different objects builds up over time, a landmark of both behavioural and neurophysiological data on auditory streaming. Here we show that first percept bias and inertia are independent. In plaid perception, inertia is due to a depth ordering ambiguity in the transparent (split) interpretation that makes plaid perception tristable rather than bistable: experimental manipulations removing the depth ambiguity suppressed inertia. However, the first percept bias persisted. We attempted a similar manipulation for auditory streaming by introducing level differences between streams, to bias which stream would appear in the perceptual foreground. Here both inertia and first percept bias persisted. We thus argue that the critical common feature of the onset of perceptual organization is the grouping bias, which may be related to the transition from temporally/spatially local to temporally/spatially global computation.     

Odor similarity does not influence the time needed for odor processing

The brain's link between perception and action involves several steps, which include stimulus transduction, neuronal coding of the stimulus, comparison to a memory template and choice of an appropriate behavioral response. All of these need time, and many studies report that the time needed to compare two stimuli correlates inversely with the perceived distance between them. We developed a behavioral assay in which we tested the time that a honeybee needs to discriminate between odors consisting of mixtures of two components, and included both very similar and very different stimuli spanning four log-concentration ranges. Bees learned to discriminate all odors, including very similar odors and the same odor at different concentrations. Even though discriminating two very similar odors appears to be a more difficult task than discriminating two very distinct substances, we found that the time needed to make a choice for or against an odor was independent of odor similarity. Our data suggest that, irrespective of the nature of the olfactory code, the bee olfactory system evaluates odor quality after a constant interval. This may ensure that odors are only assessed after the olfactory network has optimized its representation.     

Dose-dependent nonassociative olfactory learning in a fly

Olfactory sensory stimulation induces a fast-phase arrest response (FPA-R) of the blowfly heart activity that has been described as a sensitive tool for testing insect reactivity to odor perception. We analyzed FPA-R occurrence to repeated olfactory stimulation with low and high 1-hexanol concentrations that are behaviorally attractant and repellent, respectively, in the blowfly. FPA-R occurrence diminished and ceased with repeated presentations of low and medium odor concentrations, according to dynamics inversely related to odor doses. On the other hand, repeated stimulation with higher odor concentrations induced persistent FPA-Rs. Sensory input amplitude to repeated presentations of singly tested odor concentrations did not change throughout stimulation sessions. A spontaneous restoration of FPA-R to olfactory stimulation was recorded 30 min after cessation of FPA-R to a previous olfactory stimulation session. However, a prompt restoration of FPA-R to olfactory stimulation after cessation of FPA-R was obtained following mechano-taste stimulation of labellar sensilla. Our findings show that the FPA-R habituates to olfactory sensory stimulation with low and medium odor concentrations according to dynamics inversely related to odor intensities. On the other hand, the FPA-R does not habituate to higher odor concentrations. Therefore, flies learn to disregard nonaversive odor information, but they cannot ignore iterative detection of a repellent volatile.     

Configurational and Elemental Odor Mixture Perception Can Arise from Local Inhibition

Contrast enhancement via lateral inhibitory circuits is a common mechanism in sensory systems. We here employ a computational model to show that, in addition to shaping experimentally observed molecular receptive fields in the olfactory bulb, functionally lateral inhibitory circuits can also mediate the elemental and configurational properties of odor mixture perception. To the extent that odor perception can be predicted by slow-timescale neural activation patterns in the olfactory bulb, and to the extent that interglomerular inhibitory projections map onto a space of odorant similarity, the model shows that these inhibitory processes in the olfactory bulb suffice to generate the behaviorally observed inverse relationship between two odorants' perceptual similarities and the perceptual similarities between either of these same odorants and their binary mixture.     

Dynamical vs. judgmental comparison: hysteresis effects in motion perception

Perceptual comparison was investigated by gradually varying the relative length of two apparent motion paths, and independently determining when an initial percept was lost during the course of attribute change and when an alternative percept emerged. Dynamical comparison was indicated by a range of attribute values for which perception was bistable. Within this range, a percept that lost stability was immediately replaced by an alternative percept. Judgmental comparison was indicated by a range of attribute values for which perception was uncertain. When an initial percept was lost, an alternative percept did not immediately emerge because the alternatives being compared could not be distinguished. Differences in the effects of random noise on dynamical vs. judgmental comparison were demonstrated with computational simulations, and implications are discussed for motion energy models and solutions to the motion correspondence problem.     

From musk to body odor: Decoding olfaction through genetic variation

The olfactory system combines input from multiple receptor types to represent odor information, but there are few explicit examples relating olfactory receptor (OR) activity patterns to odor perception. To uncover these relationships, we performed genome-wide scans on odor-perception phenotypes for ten odors in 1000 Han Chinese and validated results for six of these odors in an ethnically diverse population (n = 364). In both populations, consistent with previous studies, we replicated three previously reported associations (β-ionone/OR5A1, androstenone/OR7D4, cis-3-hexen-1-ol/OR2J3 LD-band), but not for odors containing aldehydes, suggesting that olfactory phenotype/genotype studies are robust across populations. Two novel associations between an OR and odor perception contribute to our understanding of olfactory coding. First, we found a SNP in OR51B2 that associated with trans-3-methyl-2-hexenoic acid, a key component of human underarm odor. Second, we found two linked SNPs associated with the musk Galaxolide in a novel musk receptor, OR4D6, which is also the first human OR shown to drive specific anosmia to a musk compound. We noticed that SNPs detected for odor intensity were enriched with amino acid substitutions, implying functional changes of odor receptors. Furthermore, we also found that the derived alleles of the SNPs tend to be associated with reduced odor intensity, supporting the hypothesis that the primate olfactory gene repertoire has degenerated over time. This study provides information about coding for human body odor, and gives us insight into broader mechanisms of olfactory coding, such as how differential OR activation can converge on a similar percept.     

Combined behavioral and c-Fos studies elucidate the vital role of sodium for odor detection

Salt, known as taste quality, is generally neglected in olfaction, although the olfactory sensory neurons stretch into the salty nasal mucus covering the olfactory epithelium (OE). Using a psychophysical approach, we directly and functionally demonstrate in the awake rat for a variety of structurally diverse odorants that sodium is a critical factor for olfactory perception and sensitivity, both very important components of mammalian communication and sexual behavior. Bathing the olfactory mucus with an iso-osmotic sodium-free buffer solution results in severe deficits in odorant detection. However, sensitivity returns fully within a few hours, indicating continuous mucus production. In the presence of sodium in the mucus covering the OE, all odorants induce odorant-specific c-Fos expression in the olfactory bulb. Yet, if sodium is absent in the mucus, no c-Fos expression is induced as demonstrated for n-octanal. Our noninvasive approach to induce anosmia in mammals here presented--which is fully reversible within hours--opens new possibilities to study the functions of olfactory communication in awake animals.     

Multi-timescale perceptual history resolves visual ambiguity

When visual input is inconclusive, does previous experience aid the visual system in attaining an accurate perceptual interpretation? Prolonged viewing of a visually ambiguous stimulus causes perception to alternate between conflicting interpretations. When viewed intermittently, however, ambiguous stimuli tend to evoke the same percept on many consecutive presentations. This perceptual stabilization has been suggested to reflect persistence of the most recent percept throughout the blank that separates two presentations. Here we show that the memory trace that causes stabilization reflects not just the latest percept, but perception during a much longer period. That is, the choice between competing percepts at stimulus reappearance is determined by an elaborate history of prior perception. Specifically, we demonstrate a seconds-long influence of the latest percept, as well as a more persistent influence based on the relative proportion of dominance during a preceding period of at least one minute. In case short-term perceptual history and long-term perceptual history are opposed (because perception has recently switched after prolonged stabilization), the long-term influence recovers after the effect of the latest percept has worn off, indicating independence between time scales. We accommodate these results by adding two positive adaptation terms, one with a short time constant and one with a long time constant, to a standard model of perceptual switching.     

Loss of the V-ATPase B1 Subunit Isoform Expressed in Non-Neuronal Cells of the Mouse Olfactory Epithelium Impairs Olfactory Function

The vacuolar proton-pumping ATPase (V-ATPase) is the main mediator of intracellular organelle acidification and also regulates transmembrane proton (H⁺) secretion, which is necessary for an array of physiological functions fulfilled by organs such as the kidney, male reproductive tract, lung, bone, and ear. In this study we characterize expression of the V-ATPase in the main olfactory epithelium of the mouse, as well as a functional role for the V-ATPase in odor detection. We report that the V-ATPase localizes to the apical membrane microvilli of olfactory sustentacular cells and to the basolateral membrane of microvillar cells. Plasma membrane V-ATPases containing the B1 subunit isoform are not detected in olfactory sensory neurons or in the olfactory bulb. This precise localization of expression affords the opportunity to ascertain the functional relevance of V-ATPase expression upon innate, odor-evoked behaviors in B1-deficient mice. This animal model exhibits diminished innate avoidance behavior (revealed as a decrease in freezing time and an increase in the number of sniffs in the presence of trimethyl-thiazoline) and diminished innate appetitive behavior (a decrease in time spent investigating the urine of the opposite sex). We conclude that V-ATPase-mediated H⁺ secretion in the olfactory epithelium is required for optimal olfactory function.     

Duality in Binocular Rivalry: Distinct Sensitivity of Percept Sequence and Percept Duration to Imbalance between Monocular Stimuli

Background

Visual perception is usually stable and accurate. However, when the two eyes are simultaneously presented with conflicting stimuli, perception falls into a sequence of spontaneous alternations, switching between one stimulus and the other every few seconds. Known as binocular rivalry, this visual illusion decouples subjective experience from physical stimulation and provides a unique opportunity to study the neural correlates of consciousness. The temporal properties of this alternating perception have been intensively investigated for decades, yet the relationship between two fundamental properties - the sequence of percepts and the duration of each percept - remains largely unexplored.

Methodology/Principal Findings

Here we examine the relationship between the percept sequence and the percept duration by quantifying their sensitivity to the strength imbalance between two monocular stimuli. We found that the percept sequence is far more susceptible to the stimulus imbalance than does the percept duration. The percept sequence always begins with the stronger stimulus, even when the stimulus imbalance is too weak to cause a significant bias in the percept duration. Therefore, introducing a small stimulus imbalance affects the percept sequence, whereas increasing the imbalance affects the percept duration, but not vice versa. To investigate why the percept sequence is so vulnerable to the stimulus imbalance, we further measured the interval between the stimulus onset and the first percept, during which subjects experienced the fusion of two monocular stimuli. We found that this interval is dramatically shortened with increased stimulus imbalance.

Conclusions/Significance

Our study shows that in binocular rivalry, the strength imblanace between monocular stimuli has a much greater impact on the percept sequence than on the percept duration, and increasing this imbalance can accelerate the process responsible for the percept sequence.     

Olfactory deficits in patients affected by minimal hepatic encephalopathy: a pilot study

Minimal hepatic encephalopathy (MHE) is the earliest stage of hepatic encephalopathy and is associated with changes in cognitive functions, in electrophysiological parameters, and in cerebral neurochemical/neurotransmitter homeostasis. MHE can be observed in patients with cirrhosis who have no clinical evidence of hepatic encephalopathy (HE). At present, no data are available on a possible olfactory dysfunction in such a syndrome, although the pathophysiology of HE may alter olfactory functions since some of the neurotransmitters impaired in the syndrome are involved in the transmission of olfactory information. In the present paper, we performed a preliminary study aimed at detecting whether identification and recognition odor memory is altered in patients with MHE. Twelve patients diagnosed as MHE on the basis of their scores at the portosystemic encephalopathy (PSE)-syndrome test battery, and 12 age-matched controls were studied. Consistent with the hypothesis, patients performed significantly worse than controls for both odor identification and recognition tasks. In addition, a significant correlation between the two olfactory tests and the PSE-syndrome test score was found. This pattern supports the notion that olfactory alterations related to cognitive dysfunction in patients with MHE may be linked to the pathophysiology of HE.     

A comparison of methods for sniff measurement concurrent with olfactory tasks in humans

There is a growing appreciation for the role of sniffing inthe formation of the olfactory percept. With this in mind, monitoringand measurement of sniffing is an important aspect of olfactoryexperiments. There are several methods for measuring human sniffsconcurrent with odor delivery in olfactory experiments. Here,we set out to compare the temporal sensitivity and power ofthese different methods by applying them all simultaneouslywith an olfactory task. We discuss the advantages and disadvantagesof each method and conclude in recommending the use of a nasalcannula linked to a pressure sensor whenever possible.     

Strong single-fiber sensory inputs to olfactory cortex: implications for olfactory coding

Olfactory information is first encoded in a combinatorial fashion by olfactory bulb glomeruli, which individually represent distinct chemical features of odors. This information is then transmitted to piriform (olfactory) cortex, via axons of olfactory bulb mitral and tufted (M/T) cells, where it is presumed to form the odor percept. However, mechanisms governing the integration of sensory information in mammalian olfactory cortex are unclear. Here we show that single M/T cells can make powerful connections with cortical pyramidal cells, and coincident input from few M/T cells is sufficient to elicit spike output. These findings suggest that odor coding is broad and distributed in olfactory cortex.     

Odorant-receptor interactions and odor percept: a chemical perspective

Receptor-ligand interaction models are generally based on a 'lock and key' concept. How far this holds true for olfactory receptors and odor molecules is currently uncertain. Here, we have investigated the response of a human olfactory receptor, OR1D2, to a broad array of odorants and found that there is no simple, direct correlation between a molecule's ability to activate this receptor and the odor impression elicited in the brain. In a parallel study on specific anosmia, we have found no evidence for odor-specific anosmia to either musk or amber, but rather to specific molecules within these categories. Cluster analysis confirmed that there is no simple correlation between molecular structure and impaired perception in either odor type. There are some differences in patterns of impairment between the two odor types and some evidence to suggest that subjects with specific anosmia to a given substance can identify its presence in a mixture. Taken together, our results show that simplistic 'lock and key' models of olfaction based on a concept of odor-quality-tuned receptors are inadequate, irrespective of the nature of the lock-key interaction. Receptor activation is only one step in a long chain of events leading from inhalation of odorants to perception of odor in the higher brain, and, therefore, although structure-odor correlations are useful tools for the design of novel odorants, caution should be exercised when extrapolating them to models of olfactory perception. Those seeking to understand the odorant-receptor interaction should use receptor activation rather than odor as input data.     

SURE,why not? The SUbstitution-REciprocity method for measurement of odor quality discrimination thresholds: replication and extension to nonhuman primates

Recently, Olsson and Cain (2000, Chem. Senses, 25: 493) introduced a psychometric method which, for the first time, allows the standardized determination of odor quality discrimination (OQD) thresholds. The method defines a threshold value that is an average fraction by which one odorant has to be substituted with another to reach a criterion level of discrimination. This measure of discrimination is reciprocal in the sense that it is a result of two separate psychometric functions involving two different standards but the same comparison stimuli. Using the same odor stimuli as Olsson and Cain, with six human subjects but adopting a slightly different experimental design, we were able to replicate their finding that the proportion of correct discriminations changes monotonically with the proportion of adulterant in mixtures of eugenol and citral. As the SURE (SUbstitution-REciprocity) method is based on discriminative responses, it should also be applicable with nonhuman species which can be trained to give unequivocal discriminative responses at the behavioral level. Using an olfactory conditioning paradigm, we therefore trained four squirrel monkeys to discriminate between exactly the same pairs of odor stimuli as our human subjects. We found the psychometric functions of the monkeys to be similar to those of the human subjects. Our results show that the SURE method can successfully be employed with nonhuman primates and thus offers a new approach to study the odor spaces of nonhuman species. Future studies should elucidate whether the SURE method allows for direct comparisons of OQD thresholds and of similarities and differences between odor quality perception of different species.     

G protein-coupled receptors in human fat taste perception

In contrast to carbohydrates and proteins, which are detected by specialized taste receptors in the forms of their respective building blocks, sugars, and L-amino acids, the third macronutrient, lipids, has until now not been associated with gustatory receptors. Instead, the recognition of fat stimuli was believed to rely mostly on textural, olfactory, and postingestive cues. During the recent years, however, research done mainly in rodent models revealed an additional gustatory component for the detection of long-chain fatty acids (LCFAs), the main taste-activating component of lipids. Concomitantly, a number of candidate fat taste receptors were proposed to be involved in rodent's gustatory fatty acid perception. Compared with rodent models, much less is known about human fat taste. In order to investigate the ability of the human gustatory system to respond to fat components, we performed sensory experiments with fatty acids of different chain lengths and derivatives thereof. We found that our panelists discriminated a "fatty" and an irritant "scratchy" taste component, with the "fatty" percept restricted to LCFAs. Using functional calcium-imaging experiments with the human orthologs of mouse candidate fat receptors belonging to the G protein-coupled receptor family, we correlated human sensory data with receptor properties characterized in vitro. We demonstrated that the pharmacological activation profile of human GPR40 and GPR120, 2 LCFA-specific receptors associated with gustatory fat perception in rodents, is inconsistent with the "scratchy" sensation of human subjects and more consistent with the percept described as "fatty." Expression analysis of GPR40 and GPR120 in human gustatory tissues revealed that, while the GPR40 gene is not expressed, GPR120 is detected in gustatory and nongustatory epithelia. On a cellular level, we found GPR120 mRNA and protein in taste buds as well as in the surrounding epithelial cells. We conclude that GPR120 may indeed participate in human gustatory fatty acid perception.     

Behavioral responses to odorants in drosophila require nervous system expression of the beta integrin gene myospheroid

Integrins are cell adhesion molecules that mediate numerous developmental processes in addition to a variety of acute physiological events. Two reports implicate a Drosophila beta integrin, betaPS, in olfactory behavior. To further investigate the role of integrins in Drosophila olfaction, we used Gal4-driven expression of RNA interference (RNAi) transgenes to knock down expression of myospheroid (mys), the gene that encodes betaPS. Expression of mys-RNAi transgenes in the wing reduced betaPS immunostaining and produced morphological defects associated with loss-of-function mutations in mys, demonstrating that this strategy knocked down mys function. Expression of mys-RNAi transgenes in the antennae, antennal lobes, and mushroom bodies via two Gal4 lines, H24 and MT14, disrupted olfactory behavior but did not alter locomotor abilities or central nervous system structure. Olfactory behavior was normal in flies that expressed mys-RNAi transgenes via other Gal4 lines that specifically targeted the antennae, the projection neurons, the mushroom bodies, bitter and sweet gustatory neurons, or Pox neuro neurons. Our studies confirm that mys is important for the development or function of the Drosophila olfactory system. Additionally, our studies demonstrate that mys is required for normal behavioral responses to both aversive and attractive odorants. Our results are consistent with a model in which betaPS mediates events within the antennal lobes that influence odorant sensitivity.