From receptors to the brain: Psychophysical clues to taste physiology.

To understand human taste requires not only physiological studies ranging from receptor mechanisms to brain circuitry, but also psychophysical studies that quantitatively describe the perceptual output of the system. As obvious as this requirement is, differences in research approaches, methodologies, and objectives complicate the ability to meet it. Discussed here is an example of how the discovery two decades ago of a perceptual taste illusion (thermal taste) has led to physiological and psychophysical research on both peripheral and central mechanisms of taste, including most recently a psychophysical study of the heat sensitivity of the human sweet taste receptor TAS1R2/T1R3, and an fMRI study of a possible central gain mechanism that may underlie, in part, differences in human taste sensitivity. In addition to the new data and hypotheses these studies have generated, they illustrate instances of research on taste motivated by evidence derived from different approaches and levels of analysis.

Development of MacroPics: A novel food picture set to dissociate the effects of carbohydrate and fat on eating behaviors.

Emerging evidence suggests that fat and carbohydrate interact to potentiate the reward value of food (DiFeliceantonio et al., 2018). The primary goal of the current study was to develop a novel picture set to facilitate research into the effects of macronutrient composition on food choice and eating behavior. Toward this aim, we developed "MacroPics." In Experiment 1, we photographed 120-kcal portions of 60 snack foods falling into one of the three macronutrient categories: (1) mostly carbohydrate, (2) mostly fat, or (3) a combination of fat and carbohydrate. Sixty-one participants rated the images for liking, familiarity, frequency of consumption, healthiness, estimated energy content (in kcal), and expected satiation. A subset of these images consisting of 36 items was then selected in an iterative process to minimize differences in ratings between the macronutrient categories while simultaneously ensuring similar within-category variability on a number of food characteristics (e.g., energy density, portion size, retail price) and visual properties (e.g., color, complexity, visual area). In Experiment 2, an independent sample of 67 participants rated the pictures of the final 36-item MacroPics. Both experiments reveal similar participant ratings across categories for item liking, familiarity, frequency, healthiness, and estimated energy content. Protein content was higher in the fat compared to the carbohydrate and combination categories, leading to higher ratings of estimated satiety and energy density for fatty foods. Item and macronutrient category characteristics of the final MacroPics set are reported.

NIH Workshop Report: sensory nutrition and disease.

In November 2019, the NIH held the "Sensory Nutrition and Disease" workshop to challenge multidisciplinary researchers working at the interface of sensory science, food science, psychology, neuroscience, nutrition, and health sciences to explore how chemosensation influences dietary choice and health. This report summarizes deliberations of the workshop, as well as follow-up discussion in the wake of the current pandemic. Three topics were addressed: A) the need to optimize human chemosensory testing and assessment, B) the plasticity of chemosensory systems, and C) the interplay of chemosensory signals, cognitive signals, dietary intake, and metabolism. Several ways to advance sensory nutrition research emerged from the workshop: 1) refining methods to measure chemosensation in large cohort studies and validating measures that reflect perception of complex chemosensations relevant to dietary choice; 2) characterizing interindividual differences in chemosensory function and how they affect ingestive behaviors, health, and disease risk; 3) defining circuit-level organization and function that link and interact with gustatory, olfactory, homeostatic, visceral, and cognitive systems; and 4) discovering new ligands for chemosensory receptors (e.g., those produced by the microbiome) and cataloging cell types expressing these receptors. Several of these priorities were made more urgent by the current pandemic because infection with sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing coronavirus disease of 2019 has direct short- and perhaps long-term effects on flavor perception. There is increasing evidence of functional interactions between the chemosensory and nutritional sciences. Better characterization of this interface is expected to yield insights to promote health, mitigate disease risk, and guide nutrition policy.

Surveying Chemosensory Dysfunction in COVID-19.

Soon after the outbreak of COVID-19, reports that smell and taste are disrupted by the illness drew the attention of chemosensory scientists and clinicians throughout the world. While other upper respiratory viruses are known to produce such disruptions, their occurrence with the deadly and highly infectious SARS-CoV-2 virus raised new questions about the nature of the deficits, their cause, and whether they might serve as indicators of the onset of the disease. Published in the July and August 2020 issues of Chemical Senses are 2 innovative, large-scale survey studies that were quickly devised and launched by separate multinational groups to address these questions in olfaction, taste, and chemesthesis. The surveys, which took different approaches and had somewhat different goals, add significant new data on the incidence and severity of smell loss in COVID-19, and the potential for olfactory dysfunction to serve as an indicator of the spread and severity of the disease. Less definitive evidence of the frequency, characteristics, and magnitude of disruptions in taste and chemesthesis point to the need for future survey studies that combine and refine the strengths of the present ones, as well as clinical studies designed to selectively measure deficits in all 3 chemosensory systems.

Identification of an Amygdala-Thalamic Circuit That Acts as a Central Gain Mechanism in Taste Perceptions.

Peripheral sources of individual variation in taste intensity perception have been well described. The existence of a central source has been proposed but remains unexplored. Here we used functional magnetic resonance imaging in healthy human participants (20 women, 8 men) to evaluate the hypothesis that the amygdala exerts an inhibitory influence that affects the "gain" of the gustatory system during tasting. Consistent with the existence of a central gain mechanism (CGM), we found that central amygdala response was correlated with mean intensity ratings across multiple tastants. In addition, psychophysiological and dynamic causal modeling analyses revealed that the connection strength between inhibitory outputs from amygdala to medial dorsal and ventral posterior medial thalamus predicted individual differences in responsiveness to taste stimulation. These results imply that inhibitory inputs from the amygdala to the thalamus act as a CGM that influences taste intensity perception.SIGNIFICANCE STATEMENT Whether central circuits contribute to individual variation in taste intensity perception is unknown. Here we used functional magnetic resonance imaging in healthy human participants to identify an amygdala-thalamic circuit where network dynamics and connectivity strengths during tasting predict individual variation in taste intensity ratings. This finding implies that individual differences in taste intensity perception do not arise solely from variation in peripheral gustatory factors.

Sweet Thermal Taste: Perceptual Characteristics in Water and Dependence on TAS1R2/TAS1R3.

The initial objective of this study was to determine if activation of the sweet taste receptor TAS1R2/TAS1R3 is necessary for perception of sweet thermal taste (swTT). Our approach was to inhibit the receptor with the inverse agonist lactisole using a temperature-controlled flow gustometer. Because all prior studies of thermal taste (TT) used metal thermodes to heat the tongue tip, we first investigated whether it could be generated in heated water. Experiment 1 showed that sweetness could be evoked when deionized water was heated from 20 to 35 °C, and testing with static temperatures between 20 and 35 °C demonstrated the importance of heating from a cool temperature. As in previous studies, thermal sweetness was reported by only a subset of participants, and replicate measurements found variability in reports of sweetness across trials and between sessions. Experiment 2 then showed that exposure to 8 mM lactisole blocked perception of swTT. Confirmation of the involvement of TAS1R2/TAS1R3 led to an investigation of possible sensory and cognitive interactions between thermal and chemical sweetness. Using sucrose as a sweet stimulus and quinine as a nonsweet control, we found that dynamic heating capable of producing thermal sweetness did not increase the sweetness of sucrose compared with static heating at 35 °C. However, swTT was disrupted if trials containing sucrose (but not quinine) were interspersed among heating-only trials. These findings provide new information relevant to understanding the perceptual processes and receptor mechanisms of swTT, as well as the heat sensitivity of sweet taste in general.

Selective Effects of Temperature on the Sensory Irritation but not Taste of NaCl and Citric Acid.

This study investigated the effect of temperature on taste and chemesthetic sensations produced by the prototypical salty and sour stimuli NaCl and citric acid. Experiment 1 measured the perceived intensity of irritation (burning, stinging) and taste (saltiness, sourness) produced on the tongue tip by brief (3 s) exposures to suprathreshold concentrations of NaCl and citric acid at 3 different temperatures (12, 34, and 42 °C). No significant effects of temperature were found on the taste or sensory irritation of either stimulus. Experiment 2 investigated the potential effects of temperature on sensory irritation at peri-threshold concentrations and its sensitization over time. Measurements were again made on the tongue tip at the same 3 temperatures. Heating was found to enhance the perception of irritation at peri-threshold concentrations for both stimuli, whereas cooling suppressed sensitization of irritation for NaCl but not for citric acid. These results (i) confirm prior evidence that perception of suprathreshold salty and sour tastes are independent of temperature; (ii) demonstrate that heat has only weak effects on sensory irritation produced by brief exposures to NaCl and citric acid; and (iii) suggest that sensitization of the irritation produced by NaCl and citric acid occur via different peripheral mechanisms that have different thermal sensitivities. Overall, the results are consistent with involvement of the heat-sensitive channel TRPV1 in the sensory irritation of both stimuli together with one or more additional channels (e.g., acid-sensing channel, epithelial sodium channel, TRPA1) that are insensitive to heat and may possibly be sensitive to cooling.

The effect of sucralose on flavor sweetness in electronic cigarettes varies between delivery devices.

The appeal of sweet electronic cigarette flavors makes it important to identify the chemical compounds that contribute to their sweetness. While volatile chemicals that produce sweet aromas have been identified in e-liquids, there are no published reports of sugars or artificial sweeteners in commercial e-liquids. However, the sweetener sucralose is marketed as an e-liquid additive to commercial flavors. The primary aims of the study were to determine if sucralose is delivered in sufficient concentration in the inhaled aerosol to enhance flavor sweetness, and whether the amount delivered depends on the e-liquid delivery system. Thirty-two adult smokers rated flavor intensity, sweetness, harshness and liking/disliking for 4 commercial flavors with and without sucralose (1%) using 2 e-cigarette delivery systems (cartridge and tank). Participants alternately vaped normally or with the nose pinched closed to block perception of volatile flavor components via olfaction. LC/MS was used to measure the concentration of sucralose in the e-liquid aerosols using a device that mimicked vaping. Sweetness and flavor intensity were perceived much more strongly when olfaction was permitted. The contribution of sucralose to sweetness was significant only for the cartridge system, and the chemical analysis showed that the concentration of sucralose in the aerosol was higher when the cartridge was used. Together these findings indicate that future regulation of sweet flavor additives should focus first on the volatile constituents of e-liquids with the recognition that artificial sweeteners may also contribute to flavor sweetness depending upon e-cigarette design.

Studying the interactive effects of menthol and nicotine among youth: An examination using e-cigarettes.

BACKGROUND: Tobacco products containing menthol are widely used by youth. We used e-cigarettes to conduct an experimental evaluation of the independent and interactive effects of menthol and nicotine among youth. PROCEDURES: Pilot chemosensory experiments with fourteen e-cigarette users identified low (barely perceptible, 0.5%) and high (similar to commercial e-liquid, 3.5%) menthol concentrations. Sixty e-cigarette users were randomized to a nicotine concentration (0mg/ml, 6mg/ml, 12mg/ml) and participated in 3 laboratory sessions. During each session, they received their assigned nicotine concentration, along with one of three menthol concentrations in random counterbalanced order across sessions (0, 0.5%, 3.5%), and participated in three fixed-dose, and an ad-lib, puffing period. Urinary menthol glucuronide and salivary nicotine levels validated menthol and nicotine exposure. We examined changes in e-cigarette liking/wanting and taste, coolness, stimulant effects, nicotine withdrawal and ad-lib use. RESULTS: Overall, the high concentration of menthol (3.5%) significantly increased e-cigarette liking/wanting relative to no menthol (p<0.001); there was marginal evidence of nicotine* menthol interactions (p=0.06), with an increase in liking/wanting when 3.5% menthol was combined with 12mg/ml nicotine, but not 6mg/ml nicotine. Importantly, both 0.5% and 3.5% menthol concentrations significantly improved taste and increased coolness. We did not observe nicotine or menthol-related changes in stimulant effects, nicotine withdrawal symptoms or ad-lib use. CONCLUSIONS: Menthol, even at very low doses, alters the appeal of e-cigarettes among youth. Further, menthol enhances positive rewarding effects of high nicotine-containing e-cigarettes among youth.

Differential modulation of the lactisole 'Sweet Water Taste' by sweeteners.

Pre-exposure to taste stimuli and certain chemicals can cause water to have a taste. Here we studied further the 'sweet water taste' (SWT) perceived after exposure to the sweet taste inhibitor lactisole. Experiment 1 investigated an incidental observation that presenting lactisole in mixture with sucrose reduced the intensity of the SWT. The results confirmed this observation and also showed that rinsing with sucrose after lactisole could completely eliminate the SWT. The generalizability of these findings was investigated in experiment 2 by presenting 5 additional sweeteners before, during, or after exposure to lactisole. The results found with sucrose were replicated with fructose and cyclamate, but the 3 other sweeteners were less effective suppressors of the SWT, and the 2 sweeteners having the highest potency initially enhanced it. A third experiment investigated these interactions on the tongue tip and found that the lactisole SWT was perceived only when water was actively flowed across the tongue. The same experiment yielded evidence against the possibility that suppression of the SWT following exposure to sweeteners is an aftereffect of receptor activation while providing additional support for a role of sweetener potency. Collectively these results provide new evidence that complex inhibitory and excitatory interactions occur between lactisole and agonists of the sweet taste receptor TAS1R2-TAS1R3. Receptor mechanisms that may be responsible for these interactions are discussed in the context of the current model of the SWT and the possible contribution of allosteric modulation.

Stimulus-Dependent Effects of Temperature on Bitter Taste in Humans.

This study investigated the effects of temperature on bitter taste in humans. The experiments were conducted within the context of current understanding of the neurobiology of bitter taste and recent evidence of stimulus-dependent effects of temperature on sweet taste. In the first experiment, the bitterness of caffeine and quinine sampled with the tongue tip was assessed at 4 different temperatures (10°, 21°, 30°, and 37 °C) following pre-exposure to the same solution or to water for 0, 3, or 10 s. The results showed that initial bitterness (0-s pre-exposure) followed an inverted U-shaped function of temperature for both stimuli, but the differences across temperature were statistically significant only for quinine. Conversely, temperature significantly affected adaptation to the bitterness of quinine but not caffeine. A second experiment used the same procedure to test 2 additional stimuli, naringin and denatonium benzoate. Temperature significantly affected the initial bitterness of both stimuli but had no effect on adaptation to either stimulus. These results confirm that like sweet taste, temperature affects bitter taste sensitivity and adaptation in stimulus-dependent ways. However, the thermal effect on quinine adaptation, which increased with warming, was opposite to what had been found previously for adaptation to sweetness. The implications of these results are discussed in relation to findings from prior studies of temperature and bitter taste in humans and the possible neurobiological mechanisms of gustatory thermal sensitivity.

The Effect of Temperature on Umami Taste.

The effect of temperature on umami taste has not been previously studied in humans. Reported here are 3 experiments in which umami taste was measured for monopotassium glutamate (MPG) and monosodium glutamate (MSG) at solution temperatures between 10 and 37 °C. Experiment 1 showed that for subjects sensitive to MPG on the tongue tip, 1) cooling reduced umami intensity whether sampled with the tongue tip or in the whole mouth, but 2) had no effect on the rate of umami adaptation on the tongue tip. Experiment 2 showed that temperature had similar effects on the umami taste of MSG and MPG on the tongue tip but not in the whole mouth, and that contrary to umami taste, cooling to 10 °C increased rather than decreased the salty taste of both stimuli. Experiment 3 was designed to investigate the contribution of the hT1R1-hT1R3 glutamate receptor to the cooling effect on umami taste by using the T1R3 inhibitor lactisole. However, lactisole failed to block the umami taste of MPG at any temperature, which supports prior evidence that lactisole does not block umami taste for all ligands of the hT1R1-hT1R3 receptor. We conclude that temperature can affect sensitivity to the umami and salty tastes of glutamates, but in opposite directions, and that the magnitude of these effects can vary across stimuli and modes of tasting (i.e., whole mouth vs. tongue tip exposures).

Sensory Effects of Menthol and Nicotine in an E-Cigarette.

INTRODUCTION: Despite the longstanding use and popularity of menthol as a flavorant in tobacco products, its sensory interactions with inhaled nicotine have never been measured independently of the other irritants in tobacco smoke. We therefore measured the perception of menthol in an E-cigarette with the primary goal of assessing its analgesic effect on the sensory irritation produced by inhaled nicotine. METHODS: Adult cigarette smokers sampled aerosolized E-liquids containing five different concentrations of nicotine with 0%, 0.5%, or 3.5% l-menthol, as well as two commercial menthol flavors with and without nicotine. For each of the E-liquids participants used a labeled magnitude scale to rate the Overall Sensation intensity, Coolness/Cold, and Irritation/Harshness they experienced, and a Labeled Hedonic Scale to indicate how much they liked/disliked the overall flavor. RESULTS: The main findings were that (1) perceived Irritation/Harshness was unaffected by a low (0.5%) menthol concentration, whereas a high menthol concentration (3.5%) led to higher perceived Irritation/Harshness at low nicotine concentrations but to lower Irritation/Harshness at the highest nicotine concentration (24mg/ml); (2) a commercial Menthol-Mint flavor produced similar results; (3) nicotine tended to enhance rather than suppress sensations of Coolness/Cold; and (4) menthol tended to slightly increase liking independently of nicotine concentration. CONCLUSION: In addition to adding a sensation of coolness, menthol can reduce perceived airway irritation and harshness produced by inhalation when nicotine concentration is high, and contributes to the sensory impact of E-liquids when nicotine concentration is low. IMPLICATIONS: The evidence presented here indicates that menthol can potentially improve the appeal of E-cigarettes not only via its coolness and minty flavor, but also by reducing the harshness from high concentrations of nicotine. As the first direct demonstration of an analgesic effect of menthol on inhaled nicotine in humans, these data also have implications for the role of menthol flavors in other inhaled tobacco products.

The Yale Craving Scale: Development and psychometric properties.

INTRODUCTION: The current study presents a psychometric evaluation of the Yale Craving Scale (YCS), a novel measure of craving for cigarettes and alcohol, respectively. The YCS is the first craving measure to use a generalized Labeled Magnitude Scale (gLMS) as the scoring format, which facilitates between-group comparisons of subjective craving and eliminates ceiling effects by assessing the full range of imaginable sensation intensities. METHODS: Psychometric evaluations of the YCS for use with cigarettes (YCS Smoking) and alcohol (YCS Drinking) included assessments of latent factor structure, internal consistency, ceiling effects, and test-criterion relationships. Study samples included 493 treatment-seeking smokers and 213 heavy drinkers. RESULTS: Factor analyses of the 5-item YCS Smoking and Drinking scores confirmed a 1-factor scale. The YCS Smoking and Drinking scores evidenced: (1) good internal consistency, (2) scalar measurement invariance within several subgroups (e.g., smoking/drinking status; nicotine/alcohol dependence), (3) convergent relationships with extant craving measures, and (4) concurrent relationships with smoking/drinking outcomes. CONCLUSIONS: These results suggest that the YCS represents a psychometrically sound scale for assessing smoking and drinking urges in dependent populations.

Temperature Affects Human Sweet Taste via At Least Two Mechanisms.

The reported effects of temperature on sweet taste in humans have generally been small and inconsistent. Here, we describe 3 experiments that follow up a recent finding that cooling from 37 to 21 °C does not reduce the initial sweetness of sucrose but increases sweet taste adaptation. In experiment 1, subjects rated the sweetness of sucrose, glucose, and fructose solutions at 5-41 °C by dipping the tongue tip into the solutions after 0-, 3-, or 10-s pre-exposures to the same solutions or to H2O; experiment 2 compared the effects of temperature on the sweetness of 3 artificial sweeteners (sucralose, aspartame, and saccharin); and experiment 3 employed a flow-controlled gustometer to rule out the possibility the effects of temperature in the preceding experiments were unique to dipping the tongue into a still taste solution. The results (i) confirmed that mild cooling does not attenuate sweetness but can increase sweet taste adaptation; (ii) demonstrated that cooling to 5-12 °C can directly reduce sweetness intensity; and (iii) showed that both effects vary across stimuli. These findings have implications for the TRPM5 hypothesis of thermal effects on sweet taste and raise the possibility that temperature also affects an earlier step in the T1R2-T1R3 transduction cascade.

In pursuit of taste phenotypes.

Notable progress has been made relating individual differences in bitter taste sensitivity to specific alleles and TAS2R receptors, but psychophysical evidence of reliable phenotypes for other tastes has been more elusive. In this issue, Wise and Breslin report a study of individual differences in threshold sensitivity to sour and salty taste, which, though failing to find clear phenotypes, exemplifies the type of approach and analysis necessary to disentangle sources of variance inherent in the psychophysical measures applied from those attributable to true differences in sensitivity. Methodological and theoretical lessons that can be taken from this work are discussed in the context of the early and dramatic evidence of chemosensory phenotypes that belied the complexity of taste receptor genetics and focused attention solely on peripheral determinants of sensitivity.

Somatosensory factors in taste perception: effects of active tasting and solution temperature.

Touch and temperature are recognized as important factors in food perception, but much remains to be learned about how they contribute to the perception of flavor. The present paper describes human psychophysical studies that investigated two recently discovered effects of temperature and mechanical stimulation on taste: (1) enhancement of the savory taste of MSG by active tongue and mouth movements, and (2) modulation of the rate of adaptation to sucrose sweetness by temperature. The first study provides evidence that for MSG but not other taste stimuli, movement of the tongue against the palate enhances taste intensity both by increasing spatial summation between opposing gustatory surfaces and by a hypothesized interaction with touch/kinesthesis. The second study shows that the rate of adaptation to sucrose sweetness (but not quinine bitterness) on the tongue tip is strongly influenced by temperature. It is hypothesized that warming slows adaptation to sucrose by increasing the sensitivity of an early stage of taste transduction. Together these results demonstrate that models of flavor perception must include somatosensory stimuli both as components of flavor perception and as modulators of taste.

Chemesthesis and the chemical senses as components of a "chemofensor complex".

An important function of the chemical senses is to warn against dangerous biological and chemical agents in the environment. The discovery in recent years of "taste" receptor cells outside the oral cavity that appear to have protective functions has raised new questions about the nature and scope of the chemical senses in general and of chemesthesis in particular. The present paper briefly reviews these findings within the context of what is currently known about the body's chemically sensitive protective mechanisms, including nonsensory processes that help to expel or neutralize threatening agents once they have been encountered. It is proposed that this array of defense mechanisms constitutes a "chemofensor complex" in which chemesthesis is the most ubiquitous, functionally diverse, and interactive chemosensory component.

Enhancement of retronasal odors by taste.

Psychophysical studies of interactions between retronasal olfaction and taste have focused most often on the enhancement of tastes by odors, which has been attributed primarily to a response bias (i.e., halo dumping). Based upon preliminary evidence that retronasal odors could also be enhanced by taste, the present study measured both forms of enhancement using appropriate response categories. In the first experiment, subjects rated taste ("sweet," "sour," "salty," and "bitter") and odor ("other") intensity for aqueous samples of 3 tastants (sucrose, NaCl, and citric acid) and 3 odorants (vanillin, citral, and furaneol), both alone and in taste-odor mixtures. The results showed that sucrose, but not the other taste stimuli, significantly increased the perceived intensity of all 3 odors. Enhancement of tastes by odors was inconsistent and generally weaker than enhancement of odors by sucrose. A second experiment used a flavored beverage and a custard dessert to test whether the findings from the first experiment would hold for the perception of actual foods. Adding sucrose significantly enhanced the intensity of "cherry" and "vanilla" flavors, whereas adding vanillin did not significantly enhance the intensity of sweetness. It is proposed that enhancement of retronasal odors by a sweet stimulus results from an adaptive sensory mechanism that serves to increase the salience of the flavor of nutritive foods.