Appetite-regulating hormones modulate odor perception and odor-evoked activity in hypothalamus and olfactory cortices.

Odors guide food seeking, and food intake modulates olfactory function. This interaction is mediated by appetite-regulating hormones like ghrelin, insulin, and leptin, which alter activity in the rodent olfactory bulb, but their effects on downstream olfactory cortices have not yet been established in humans. The olfactory tract connects the olfactory bulb to the cortex through 3 main striae, terminating in the piriform cortex (PirC), amygdala (AMY), olfactory tubercule (OT), and anterior olfactory nucleus (AON). Here, we test the hypothesis that appetite-regulating hormones modulate olfactory processing in the endpoints of the olfactory tract and the hypothalamus. We collected odor-evoked functional magnetic resonance imaging (fMRI) responses and plasma levels of ghrelin, insulin, and leptin from human subjects (n = 25) after a standardized meal. We found that a hormonal composite measure, capturing variance relating positively to insulin and negatively to ghrelin, correlated inversely with odor intensity ratings and fMRI responses to odorized vs. clean air in the hypothalamus, OT, and AON. No significant correlations were found with activity in PirC or AMY, the endpoints of the lateral stria. Exploratory whole-brain analyses revealed significant correlations near the diagonal band of Broca and parahippocampal gyrus. These results demonstrate that high (low) blood plasma concentrations of insulin (ghrelin) decrease perceived odor intensity and odor-evoked activity in the cortical targets of the medial and intermediate striae of the olfactory tract, as well as the hypothalamus. These findings expand our understanding of the cortical mechanisms by which metabolic hormones in humans modulate olfactory processing after a meal.

Sensory Cueing of Autobiographical Memories in Normal Aging and Alzheimer's Disease: A Comparison Between Visual, Auditory, and Olfactory Information.

BACKGROUND: Alzheimer's disease (AD) is a chronic, neurodegenerative disease resulting in a progressive decline of autobiographical memories (AMs) which favors the development of psycho-behavioral disorders. One of the most popular psychosocial interventions in dementia care, Reminiscence Therapy, commonly uses sensory cueing to stimulate AMs retrieval. However, few empirical studies have investigated the impact of sensory stimulation on AMs retrieval in AD. OBJECTIVE: Our goal was to determine the most relevant cue for AMs retrieval in patients with early to mild AD when comparing odors, sounds and pictures. METHODS: Sixty AD patients, 60 healthy older adults (OA), and 60 healthy young adults (YA) participated in our study. Participants were presented with either 4 odors, 4 sounds, or 4 pictures. For each stimulus, they were asked to retrieve a personal memory, to rate it across 3 dimensions (emotionality, vividness, rarity) and then to date it. RESULTS: Overall, results showed no clear dominance of one sensory modality over the others in evoking higher-quality AMs. However, they show that using pictures is the better way to stimulate AD patients' AM, as it helps to retrieve a higher number of memories that are also less frequently retrieved, followed by odors. By contrast, auditory cueing with environmental sounds presented no true advantage. CONCLUSION: Our data should help dementia care professionals to increase the efficiency of Reminiscence Therapy using sensory elicitors. Other clinical implications and future directions are also discussed.

Subjective Effects of Inhaling Kuromoji Tea Aroma.

Teas and various herbal teas are well-known beverages and are commonly consumed around the world. In this study, we focused on kuromoji tea. Kuromoji is a deciduous shrub of the Lauraceae family, and the plucked leaves and branches have been drunk as a tea in production areas for a long time. However, no studies have investigated the subjective and physiological effects of kuromoji tea. In this study, the effects of kuromoji tea were examined on the basis of the measurements of heart rate variability and cerebral blood flow, core body temperature and subjective assessments. Moreover, the results of this study showed that a pleasant subjective feeling could be obtained by sniffing the aroma of kuromoji teas, especially tea leaves. It was also found that the aroma of kuromoji teas has the potential to stimulate saliva secretion and increase subjective and physiological excitements in the oral cavity. 1,8-Cineole, linalool, terpinen-4-ol, carvone and geraniol were determined in both kuromoji leaves and branches. In this study, the beneficial effects of kuromoji teas when drunk conventionally were investigated.

Secretagogin expression in the mouse olfactory bulb under sensory impairments.

The interneurons of the olfactory bulb (OB) are characterized by the expression of different calcium-binding proteins, whose specific functions are not fully understood. This is the case of one of the most recently discovered, the secretagogin (SCGN), which is expressed in interneurons of the glomerular and the granule cell layers, but whose function in the olfactory pathway is still unknown. To address this question, we examined the distribution, generation and activity of SCGN-positive interneurons in the OB of two complementary models of olfactory impairments: Purkinje Cell Degeneration (PCD) and olfactory-deprived mice. Our results showed a significant increase in the density of SCGN-positive cells in the inframitral layers of olfactory-deprived mice as compared to control animals. Moreover, BrdU analyses revealed that these additional SCGN-positive cells are not newly formed. Finally, the neuronal activity, estimated by c-Fos expression, increased in preexisting SCGN-positive interneurons of both deprived and PCD mice -being higher in the later- in comparison with control animals. Altogether, our results suggest that the OB possesses different compensatory mechanisms depending on the type of alteration. Particularly, the SCGN expression is dependent of olfactory stimuli and its function may be related to a compensation against a reduction in sensory inputs.

A measure of smell enables the creation of olfactory metamers.

Wavelength is a physical measure of light, and the intricate understanding of its link to perceived colour enables the creation of perceptual entities such as metamers-non-overlapping spectral compositions that generate identical colour percepts1. By contrast, scientists have been unable to develop a physical measure linked to perceived smell, even one that merely reflects the extent of perceptual similarity between odorants2. Here, to generate such a measure, we collected perceptual similarity estimates of 49,788 pairwise odorants from 199 participants who smelled 242 different multicomponent odorants and used these data to refine a predictive model that links odorant structure to odorant perception3. The resulting measure combines 21 physicochemical features of the odorants into a single number-expressed in radians-that accurately predicts the extent of perceptual similarity between multicomponent odorant pairs. To assess the usefulness of this measure, we investigated whether we could use it to create olfactory metamers. To this end, we first identified a cut-off in the measure: pairs of multicomponent odorants that were within 0.05 radians of each other or less were very difficult to discriminate. Using this cut-off, we were able to design olfactory metamers-pairs of non-overlapping molecular compositions that generated identical odour percepts. The accurate predictions of perceptual similarity, and the ensuing creation of olfactory metamers, suggest that we have obtained a valid olfactory measure, one that may enable the digitization of smell.

Evaluation of the effect of aroma oil as a bath salt on cognitive function.

BACKGROUND: Aromatherapy is a non-pharmacological therapy for the improvement of dementia symptoms. This study aimed to assess the effects of aroma oil as a bath salt on cognitive function, olfactory function and sleep quality. METHODS: This was a randomised controlled trial. Overall, 49 patients were able to provide consent, and 35 were finally analysed (Alzheimer's disease: 10, mild cognitive impairment: 25). The patients were randomly assigned to use 0.1%, 0.5% or 1% aroma bath salt. During daily bathing, bath salt was added to the bath water, and the subjects remained in the bathroom for ≥10 min. The intervention period was 24 weeks, and the observation periods were 4 weeks before and after using the aroma bath salt. We performed the Touch Panel-type Dementia Assessment Scale (TDAS), the Odour Stick Identification Test for Japanese (OSIT-J) and the Japanese version of the Pittsburgh Sleep Quality Index (PSQI-J) five times during the before and after observation periods and after the 12-week intervention. RESULTS: There were no significant changes in the TDAS, OSIT-J and PSQI-J scores before and after the intervention in all groups. Moreover, there were no significant differences in the TDAS, OSIT-J and PSQI-J scores between the groups before and after the intervention. In the correlation analysis of changes in the TDAS and other tests during the intervention period, significant associations between TDAS and sleep latency and sleep disturbances, which are sub-items of PSQI-J, were observed in the use of 0.1% aroma bath salt group. CONCLUSIONS: The use of aroma bath salt was not associated with improvement in cognitive function, olfactory function or sleep quality. However, sleep-related aspects were associated with changes in cognitive function before and after use of aroma bath salt, which suggested that there is a link between improvements in sleep and that in cognitive function.

Externalization Errors of Olfactory Source Monitoring in Healthy Controls-An fMRI Study.

Using a combined approach of functional magnetic resonance imaging (fMRI) and noninvasive brain stimulation (transcranial direct current stimulation [tDCS]), the present study investigated source memory and its link to mental imagery in the olfactory domain, as well as in the auditory domain. Source memory refers to the knowledge of the origin of mental experiences, differentiating events that have occurred and memories of imagined events. Because of a confusion between internally generated and externally perceived information, patients that are prone to hallucinations show decreased source memory accuracy; also, vivid mental imagery can lead to similar results in healthy controls. We tested source memory following cathodal tDCS stimulation using a mental imagery task, which required participants to perceive or imagine a set of the same olfactory and auditory stimuli during fMRI. The supplementary motor area (SMA) is involved in mental imagery across different modalities and potentially linked to source memory. Therefore, we attempted to modulate participants' SMA activation before entering the scanner using tDCS to influence source memory accuracy in healthy participants. Our results showed the same source memory accuracy between the olfactory and auditory modalities with no effects of stimulation. Finally, we found SMA's subregions differentially involved in olfactory and auditory imagery, with activation of dorsal SMA correlated with auditory source memory.

Iranian Herbalists, But Not Cooks, Are Better at Naming Odors Than Laypeople.

Odor naming is enhanced in communities where communication about odors is a central part of daily life (e.g., wine experts, flavorists, and some hunter-gatherer groups). In this study, we investigated how expert knowledge and daily experience affect the ability to name odors in a group of experts that has not previously been investigated in this context-Iranian herbalists; also called attars-as well as cooks and laypeople. We assessed naming accuracy and consistency for 16 herb and spice odors, collected judgments of odor perception, and evaluated participants' odor meta-awareness. Participants' responses were overall more consistent and accurate for more frequent and familiar odors. Moreover, attars were more accurate than both cooks and laypeople at naming odors, although cooks did not perform significantly better than laypeople. Attars' perceptual ratings of odors and their overall odor meta-awareness suggest they are also more attuned to odors than the other two groups. To conclude, Iranian attars-but not cooks-are better odor namers than laypeople. They also have greater meta-awareness and differential perceptual responses to odors. These findings further highlight the critical role that expertise and type of experience have on olfactory functions.

Human olfactory-auditory integration requires phase synchrony between sensory cortices.

Multisensory integration is particularly important in the human olfactory system, which is highly dependent on non-olfactory cues, yet its underlying neural mechanisms are not well understood. In this study, we use intracranial electroencephalography techniques to record neural activity in auditory and olfactory cortices during an auditory-olfactory matching task. Spoken cues evoke phase locking between low frequency oscillations in auditory and olfactory cortices prior to odor arrival. This phase synchrony occurs only when the participant's later response is correct. Furthermore, the phase of low frequency oscillations in both auditory and olfactory cortical areas couples to the amplitude of high-frequency oscillations in olfactory cortex during correct trials. These findings suggest that phase synchrony is a fundamental mechanism for integrating cross-modal odor processing and highlight an important role for primary olfactory cortical areas in multisensory integration with the olfactory system.

The Impact of Acoustic fMRI-Noise on Olfactory Sensitivity and Perception.

Sensory perception is neither static nor simple. The senses influence each other during multisensory stimulation and can be both suppressive and super-additive. As most knowledge of human olfactory perception is derived from functional neuroimaging studies, in particular fMRI, our current understanding of olfactory perception has systematically been investigated in an environment with concurrent loud sounds. To date, the confounding effects of acoustic fMRI-noise during scanning on olfactory perception have not yet been investigated. In this study we investigate how acoustic noise derived from the rapid switching of MR gradient coils, affects olfactory perception. For this, 50 subjects were tested in both a silent setting and an fMRI-noise setting, in a randomised order. We found that fMRI-related acoustic noise had a significant negative effect on the olfactory detection threshold score. No significant effects were identified on olfactory discrimination, identification, identification certainty, hedonic rating, or intensity rating.

A specific olfactory cortico-thalamic pathway contributing to sampling performance during odor reversal learning.

A growing body of evidence shows that olfactory information is processed within a thalamic nucleus in both rodents and humans. The mediodorsal thalamic nucleus (MDT) receives projections from olfactory cortical areas including the piriform cortex (PCX) and is interconnected with the orbitofrontal cortex (OFC). Using electrophysiology in freely moving rats, we recently demonstrated the representation of olfactory information in the MDT and the dynamics of functional connectivity between the PCX, MDT and OFC. Notably, PCX-MDT coupling is specifically increased during odor sampling of an odor discrimination task. However, whether this increase of coupling is functionally relevant is unknown. To decipher the importance of PCX-MDT coupling during the sampling period, we used optogenetics to specifically inactivate the PCX inputs to MDT during an odor discrimination task and its reversal in rats. We demonstrate that inactivating the PCX inputs to MDT does not affect the performance accuracy of an odor discrimination task and its reversal, however, it does impact the rats' sampling duration. Indeed, rats in which PCX inputs to MDT were inactivated during the sampling period display longer sampling duration during the odor reversal learning compared to controls-an effect not observed when inactivating OFC inputs to MDT. We demonstrate a causal link between the PCX inputs to MDT and the odor sampling performance, highlighting the importance of this specific cortico-thalamic pathway in olfaction.

Pepper with and without a sting: Brain processing of intranasal trigeminal and olfactory stimuli from the same source.

Humans have distinct and overlapping brain regions for the processing of intranasal olfactory or trigeminal stimuli. It may be assumed that trigeminal stimulants and "trigeminal-free" odorous stimuli from the same source are processed differently in the human brain. Using functional magnetic resonance imaging (fMRI), this study investigated the question whether the black pepper (Piper nigrum) derived trigeminal active compound piperine and the trigeminal-free pepper essential oil (pepperEO) are processed in relation to their degree of trigeminal stimulation. Twenty-one young healthy adults underwent a fMRI scan where piperine and pepperEO were delivered orthonasally using an olfactometer. Ratings for intensity, irritability, and pleasantness of each stimulus were obtained at the end of the scanning session. Results showed brain activation of the trigeminal network in response to piperine, and olfactory-related areas in response to pepperEO. PepperEO induced larger activations in the trigeminal network as compared to piperine. This was possibly due to the associative learning for the pungent sensations of pepperEO. In addition, conjunction analyses showed that the secondary somatosensory area, insula, and thalamus were involved in the processing of both piperine and pepperEO. In conclusion, the results strongly suggest that the cerebral representations of trigeminal irritants can be evoked by learned associations.

Wired for eating: how is an active feeding circuitry established in the postnatal brain?

From birth, mammals have to find food and maximize caloric intake to ensure growth and survival. Suckling must be initiated quickly after birth and then maintained and controlled until weaning. It is a complex process involving interactions between sensory and motor neuronal pathways. Meanwhile, the control of food intake and energy homeostasis is progressively established via the development of hypothalamic circuits. The development of these circuits is influenced by hormonal and nutritional signals and can be disturbed in a variety of developmental disorders leading to long-term metabolic, behavioral and cognitive dysfunctions. This review summarizes our current knowledge of the neuronal circuits involved in early postnatal feeding processes.

Centella asiatica increases hippocampal synaptic density and improves memory and executive function in aged mice.

INTRODUCTION: Centella asiatica is a plant used for centuries to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) attenuates age-related spatial memory deficits in mice and improves neuronal health. Yet the effect of CAW on other cognitive domains remains unexplored as does its mechanism of improving age-related cognitive impairment. This study investigates the effects of CAW on a variety of cognitive tasks as well as on synaptic density and mitochondrial and antioxidant pathways. METHODS: Twenty-month-old CB6F1 mice were treated with CAW (2 mg/ml) in their drinking water for 2 weeks prior to behavioral testing. Learning, memory, and executive function were assessed using the novel object recognition task (NORT), object location memory task (OLM), and odor discrimination reversal learning (ODRL) test. Tissue was collected for Golgi analysis of spine density as well as assessment of mitochondrial, antioxidant, and synaptic proteins. RESULTS: CAW improved performance in all behavioral tests suggesting effects on hippocampal and cortical dependent memory as well as on prefrontal cortex mediated executive function. There was also an increase in synaptic density in the treated animals, which was accompanied by increased expression of the antioxidant response gene NRF2 as well as the mitochondrial marker porin. CONCLUSIONS: These data show that CAW can increase synaptic density as well as antioxidant and mitochondrial proteins and improve multiple facets of age-related cognitive impairment. Because mitochondrial dysfunction and oxidative stress also accompany cognitive impairment in many pathological conditions this suggests a broad therapeutic utility of CAW.

Electrodermal reactivity to emotional stimuli in healthy subjects and patients with disorders of consciousness.

OBJECTIVES: After a coma, one major challenge is the detection of awareness in patients with disorders of consciousness. In some patients, the only manifestation indicative of awareness is an appropriate emotional response. Preferred music is a powerful medium to elicit emotions and autobiographical memory. Furthermore, music has been shown to improve cognitive functions both in healthy subjects and patients with neurological impairment. We hypothesized that signs of awareness could be enhanced in some patients with disorders of consciousness under appropriate emotional stimulation such as preferred music and also probably preferred odors. METHODS: To investigate an objective, easily recordable marker of emotions at the patients' bedside, electrodermal activity (skin conductance level, SCL) was assessed with stimulations in auditory and olfactory modalities, notably with preferred music, neutral sound, preferred odors, and neutral odors. The study was conducted in 11 patients with disorders of consciousness (DOC) and 7 healthy participants. RESULTS: In healthy subjects, the mean amplitude of the SCL was increased during exposure to preferred music as compared to neutral sounds (respectively: 0.00037±0.0004 vs. - 0.00004±0.00019µS). No significant difference between conditions was detected in patients. CONCLUSION: The results of this study suggest that electrodermal activity could be a useful marker of emotions induced by music in healthy controls. However, it failed to show any significant difference between conditions in patients with DOC.

A Functional Near-Infrared Spectroscopy Study of Trauma-Related Auditory and Olfactory Cues: Posttraumatic Stress Disorder or Combat Experience?

The prevalence of posttraumatic stress disorder (PTSD) among U.S. veterans deployed to Iraq or Afghanistan necessitates the need for comprehensive assessment and treatment strategies. This study investigated the utility of a combat-related PTSD symptom provocation paradigm to elicit unique neurological responses across three groups: combat veterans with PTSD, combat veterans without PTSD, and nonmilitary participants without PTSD. Using functional near-infrared spectroscopy (fNIRS) the results indicated that combat veterans with PTSD demonstrated significant activation to a trauma-related sound compared with nonmilitary personnel, channel 14: d = 1.03, 95% confidence interval (CI) [0.28, 1.76]; channel 15: d = 1.30, 95% CI [0.53, 2.06]; and combat veterans without PTSD, channel 14: d = 0.87, 95% CI [0.14, 1.59]. Specifically, this increased neural activation was approximately located in the right medial superior prefrontal cortex (Brodmann areas 9/10), an area associated with experiencing negative or threatening stimuli and emotional detachment. There were no differences across the groups for nontrauma-related sounds. Results were less clear with respect to a combat-related odor. These results suggest a specific neurophysiological response to trauma-related cues and, if replicated, may offer a biomarker for combat-related PTSD. Such a response could provide incremental validity over diagnostic assessments alone and assist in planning and monitoring of treatment outcome.

Interactions of Lemon, Sucrose and Citric Acid in Enhancing Citrus, Sweet and Sour Flavors.

Flavorants such as lemon extract that activate olfactory receptors may also evoke or enhance flavor qualities such as sour and sweet that are typically considered gustatory. Similarly, flavorants such as sucrose and citric acid that activate gustatory receptors may enhance flavors such as citrus that are typically considered olfactory. Here, we ask how lemon extract, sucrose, and citric acid, presented separately and together, affect sweet, sour, and citrus flavors. We accomplished this by testing, in the same 12 subjects, lemon extract and sucrose (Experiment 1), lemon extract and citric acid (Experiment 2), and lemon extract, sucrose, and citric acid (Experiment 3). Results showed that both lemon extract and citric acid increased the ratings of citrus and sour intensity. Lemon extract did not affect sweet, but citric acid did, mainly in Experiment 3. Sucrose systematically increased only sweet intensity and modulated the effect of lemon extract on sour. The most robust multiquality effect was the enhancement of sour by lemon extract. These outcomes suggest, first, a role played by experience with the statistical associations of gustatory and olfactory flavorants and, second, that lemon flavor is complex, having citrus and sour qualities that may not be fully separable in perception.

The Olfactory Mosaic: Bringing an Olfactory Network Together for Odor Perception.

Olfactory perception and its underlying neural mechanisms are not fixed, but rather vary over time, dependent on various parameters such as state, task, or learning experience. In olfaction, one of the primary sensory areas beyond the olfactory bulb is the piriform cortex. Due to an increasing number of functions attributed to the piriform cortex, it has been argued to be an associative cortex rather than a simple primary sensory cortex. In fact, the piriform cortex plays a key role in creating olfactory percepts, helping to form configural odor objects from the molecular features extracted in the nose. Moreover, its dynamic interactions with other olfactory and nonolfactory areas are also critical in shaping the olfactory percept and resulting behavioral responses. In this brief review, we will describe the key role of the piriform cortex in the larger olfactory perceptual network, some of the many actors of this network, and the importance of the dynamic interactions among the piriform-trans-thalamic and limbic pathways.

Olfactory stimulation induces delayed responses in epilepsy.

Precipitation and inhibition of seizures and epileptic discharges by sensory stimuli are receiving increasing attention because they provide insight into natural seizure generation in human epilepsies and can identify potential nonpharmacological therapies. We aimed to investigate modulation (provocation or inhibition) of epileptiform discharges (EDs) in mesial temporal lobe epilepsy (MTLE) versus idiopathic generalized epilepsy (IGE) by olfactory stimulation (OS) compared with standard provocation methods. The underlying hypothesis was that any response would be more likely to occur in MTLE, considering the anatomical connections of the temporal lobe to the olfactory system. This multicenter, international study recruited patients with either MTLE or IGE who were systematically compared for responses to OS using an EEG/video-EEG protocol including a 30-min baseline, twice 3-min olfactory stimulation with ylang-ylang, hyperventilation, and intermittent photic stimulation. The 95% confidence interval (CI) for the baseline EDs in each patient was calculated, and modulation was assumed when the number of EDs during any 3-min test period was outside this CI. A total of 134 subjects (55 with MTLE, 53 with IGE, and 26 healthy controls) were included. Epileptiform discharges were inhibited during OS in about half the patients with both MTLE and IGE, whereas following OS, provocation was seen in 29.1% of patients with MTLE and inhibition in 28.3% of patients with IGE. Olfactory stimulation was less provocative than standard activation methods. The frequent subclinical modulation of epileptic activity in both MTLE and IGE is in striking contrast with the rarity of reports of olfactory seizure precipitation and arrest. Inhibition during OS can be explained by nonspecific arousal. The delayed responses seem to be related to processing of olfactory stimuli in the temporal lobe, thalamus, and frontal cortex.

The neural circuits of mating and fighting in male mice.

Tinbergen proposed that instinctive behaviors can be divided into appetitive and consummatory phases. During mating and aggression, the appetitive phase contains various actions to bring an animal to a social target and the consummatory phase allows stereotyped actions to take place. Here, we summarize recent advances in elucidating the neural circuits underlying the appetitive and consummatory phases of sexual and aggressive behaviors with a focus on male mice. We outline the role of the main olfactory inputs in the initiation of social approach; the engagement of the accessory olfactory system during social investigation, and the role of the hypothalamus and its downstream pathways in orchestrating social behaviors through a suite of motor actions.