Trigeminal cold receptors and airflow perception are altered in chronic rhinosinusitis.

BACKGROUND: In chronic rhinosinusitis (CRS), nasal obstruction can often be explained by anatomical deformities, polyps, or congested nasal mucosa. However, in cases with little deformity or inflammation, perceived nasal obstruction may result from reduced airflow perception caused by an alteration of the intranasal trigeminal system. The aim of this study was to assess this association. METHODOLOGY: We performed a prospective case-control study of 15 CRS patients, 18 patients with a deviated nasal septum (DNS) and 16 healthy controls. We assessed olfactory function using the Sniffin' Sticks test and Visual Analog Scales (VAS). We used the Trigeminal Lateralization Task (TLT) with eucalyptol and cinnamaldehyde to examine intranasal trigeminal function. Further, we assessed nasal patency with Peak Nasal Inspiratory Flow and VAS. Finally, we measured protein levels of trigeminal receptors (TRPM8, TRPA1 and TRPV1) and inflammatory markers (IL-13, INF-y and eosinophils) in CRS and DNS patients' mucosal biopsies using Western Blots. RESULTS: CRS patients had significantly lower olfactory function than DNS and healthy controls. They also had significantly lower TLT scores for eucalyptol than both other groups. CRS patients had significantly lower nasal patency than controls; for DNS patients this was limited to subjective measures of nasal patency. In line with this, CRS patients exhibited significantly higher levels of sTRPM8-18 than DNS patients. CONCLUSIONS: Intranasal trigeminal function is decreased in CRS patients, possibly due to the overexpression of short isoforms of TRPM8 receptors.

Position paper on olfactory dysfunction: 2023

BACKGROUND: Since publication of the original Position Paper on Olfactory Dysfunction in 2017 (PPOD-17), the personal and societal burden of olfactory disorders has come sharply into focus through the lens of the COVID-19 pandemic. Clinicians, scientists and the public are now more aware of the importance of olfaction, and the impact of its dysfunction on quality of life, nutrition, social relationships and mental health. Accordingly, new basic, translational and clinical research has resulted in significant progress since the PPOD-17. In this updated document, we present and discuss currently available evidence for the diagnosis and management of olfactory dysfunction. Major updates to the current version include, amongst others: new recommendations on olfactory related terminology; new imaging recommendations; new sections on qualitative OD and COVID-19 OD; updated management section. Recommendations were agreed by all co-authors using a modified Delphi process. CONCLUSIONS: We have provided an overview of current evidence and expert-agreed recommendations for the definition, investigation, and management of OD. As for our original Position Paper, we hope that this updated document will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency, and generalisability of work in this field.

Developing a core outcome set for clinical trials in olfactory disorders: a COMET initiative.

STATEMENT OF PROBLEM: Evaluating the effectiveness of the management of Olfactory Dysfunction (OD) has been limited by a paucity of high-quality randomised and/or controlled trials. A major barrier is heterogeneity of outcomes in such studies. Core outcome sets (COS) - standardized sets of outcomes that should be measured/reported as determined by consensus-would help overcome this problem and facilitate future meta-analyses and/or systematic reviews (SRs). We set out to develop a COS for interventions for patients with OD. METHODS: A long-list of potential outcomes was identified by a steering group utilising a literature review, thematic analysis of a wide range of stakeholders' views and systematic analysis of currently available Patient Reported Outcome Measures (PROMs). A subsequent e-Delphi process allowed patients and healthcare practitioners to individually rate the outcomes in terms of importance on a 9-point Likert scale. RESULTS: After 2 rounds of the iterative eDelphi process, the initial outcomes were distilled down to a final COS including subjective questions (visual analogue scores, quantitative and qualitative), quality of life measures, psychophysical testing of smell, baseline psychophysical testing of taste, and presence of side effects along with the investigational medicine/device and patient's symptom log. CONCLUSIONS: Inclusion of these core outcomes in future trials will increase the value of research on clinical interventions for OD. We include recommendations regarding the outcomes that should be measured, although future work will be required to further develop and revalidate existing outcome measures.

Trigeminal impairment in treatment-refractory chronic nasal obstruction.

BACKGROUND: Patients with anatomically unexplained, chronic nasal obstruction (CNO) that is refractory to medical treatment pose a challenge for clinicians. A surgical solution, addressing mechanical obstacles, is unsuited for these patients. CNO may result from disrupted airflow perception due to activation of the intranasal trigeminal system; therefore, aim of this study is to evaluate if intranasal trigeminal function of these CNO patients is decreased. METHODS: In this retrospective cross-sectional study, we compared 143 CNO patients and 58 healthy volunteers, between 18 to 80 years old. We assessed nasal patency by means of rhinomanometry (RM) and measured susceptibility of intranasal trigeminal system by the trigeminal lateralization task (TLT). RESULTS: TLT scores were significantly lower in CNO patients compared to controls (p less than 0.001), but RM scores were not different between groups. Accordingly, TLT allowed to identify CNO patients with an accuracy of the area under the curve (AUC) of 0.78, while the value for RM was at chance (AUC=0.47). CNO patients showed normal reaction to vasoconstrictive agents with significantly lower RM values after Xylomethazoline application. CONCLUSION: Results suggest that reported nasal obstruction in CNO patients without any obvious anatomical obstacle and resistant to medical treatment may be linked to decreased perception of nasal airflow rather than physical obstruction. In this sub-set of CNO patients, trigeminal testing more adequately reflects the reported obstruction than nasal resistance assessment does. In future studies, the relation of the trigeminal status and the subjective sensation of nasal obstruction needs to be addressed with validated patient rated outcome measures (PROMs).

Position paper on olfactory dysfunction.

Background: Olfactory dysfunction is an increasingly recognised condition, associated with reduced quality of life and major health outcomes such as neurodegeneration and death. However, translational research in this field is limited by heterogeneity in methodological approach, including definitions of impairment, improvement and appropriate assessment techniques. Accordingly, effective treatments for smell loss are limited. In an effort to encourage high quality and comparable work in this field, among others, we propose the following ideas and recommendations. Whilst the full set of recommendations are outlined in the main document, points include the following: • Patients with suspected olfactory loss should undergo a full examination of the head and neck, including rigid nasal endoscopy with small diameter endoscopes. • Subjective olfactory assessment should not be undertaken in isolation, given its poor reliability. • Psychophysical assessment tools used in clinical and research settings should include reliable and validated tests of odour threshold, and/or one of odour identification or discrimination. • Comprehensive chemosensory assessment should include gustatory screening. • Smell training can be helpful in patients with olfactory loss of several aetiologies. Conclusions: We hope the current manuscript will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency and generalisability of work in this field.

Position paper on olfactory dysfunction.

BACKGROUND: Olfactory dysfunction is an increasingly recognised condition, associated with reduced quality of life and major health outcomes such as neurodegeneration and death. However, translational research in this field is limited by heterogeneity in methodological approach, including definitions of impairment, improvement and appropriate assessment techniques. Accordingly, effective treatments for smell loss are limited. In an effort to encourage high quality and comparable work in this field, among others, we propose the following ideas and recommendations. Whilst the full set of recommendations are outlined in the main document, points include the following: - Patients with suspected olfactory loss should undergo a full examination of the head and neck, including rigid nasal endoscopy with small diameter endoscopes. - Subjective olfactory assessment should not be undertaken in isolation, given its poor reliability. - Psychophysical assessment tools used in clinical and research settings should include reliable and validated tests of odour threshold, and/or one of odour identification or discrimination. - Comprehensive chemosensory assessment should include gustatory screening. - Smell training can be helpful in patients with olfactory loss of several aetiologies. CONCLUSIONS: We hope the current manuscript will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency and generalisability of work in this field.

Olfactory function in acute traumatic brain injury.

OBJECTIVE: Traumatic brain injury (TBI) represents a significant public health problem and is associated with a high rate of mortality and morbidity. Although TBI is amongst the most common causes of olfactory dysfunction the relationship between injury severity and olfactory problems has not yet been investigated with validated and standardized methods in the first days following the TBI. METHODS: We measured olfactory function in 63 patients admitted with TBI within the first 12 days following the trauma by means of the Sniffin' Sticks identification test (quantitative assessment) and a parosmia questionnaire (qualitative assessment). TBI severity was determined by means of the Glasgow Coma Scale (GCS) and by duration of post-traumatic amnesia (PTA) as measured by the Galveston Orientation and Amnesia Test. RESULTS: Poor olfactory scores correlated with a longer amnesia period, but not with GCS scores. Further, we observed higher parosmia scores in assault victims than in victims of falls or motor vehicle collisions. CONCLUSIONS: We show that PTA is intimately related to olfactory problems following a TBI. Thus, a thorough evaluation of olfaction is essential in order to detect posttraumatic olfactory dysfunction and to take appropriate actions early on to help the individual deal with this impairment.

Olfactory and executive dysfunctions following orbito-basal lesions in traumatic brain injury.

OBJECTIVE: To study the acute relationship between olfactory function and traumatic brain injury (TBI), cognitive functions and outcome. METHODS: Sixty-two patients with TBI were evaluated within the first 2 weeks following TBI. The Sniffin'Sticks identification test was used to assess olfaction. A neuropsychological evaluation was carried out to assess attention, verbal fluency, naming, memory, problem-solving and mental flexibility. The extended Glasgow Outcome Scale (GOSE) and the Disability Rating Scale (DRS) were rated at discharge from acute care. RESULTS: Traumatic lesions located in the basal frontal area resulted in odour identification scores that were significantly lower than when lesions were elsewhere (p < 0.001). A significant positive correlation was shown between odour identification scores and mental flexibility scores (p = 0.004) and patients with hyposmia had worse performances on executive tests measuring problem-solving, verbal fluency and mental flexibility (p < 0.01). Moreover, the odour identification score and the DRS total score were related (p = 0.019). CONCLUSIONS: These findings add information regarding acute olfactory status following TBI and provide evidence on the importance of assessing olfaction very early post-TBI in order to plan intervention and determine what accident prevention advice will be required for home or work re-integration.

[How we smell and what it means to us: basic principles of the sense of smell]. / Wie wir riechen und was es für uns bedeutet : Grundlagen des Geruchssinns.

The origins of the sense of smell lie in the perception of environmental molecules and go back to unicellular organisms such as bacteria. Odors transmit a multitude of information about the chemical composition of our environment. The sense of smell helps people and animals with orientation in space, warns of potential threats, influences the choice of sexual partners, regulates food intake and influences feelings and social behavior in general. The perception of odors begins in sensory neurons residing in the olfactory epithelium that express G protein-coupled receptors, the so-called olfactory receptors. The binding of odor molecules to olfactory receptors initiates a signal transduction cascade that converts olfactory stimuli into electrical signals. These signals are then transmitted to the olfactory bulb, the first relay center in the olfactory pathway, via the axons of the sensory neurons. The olfactory information is processed in the bulb and then transferred to higher olfactory centers via axons of mitral cells, the bulbar projection neurons. This review describes the mechanisms involved in peripheral detection of odorants, outlines the further processing of olfactory information in higher olfactory centers and finally gives an overview of the overall significance of the ability to smell.

Response times and response accuracy for odor localization and identification.

Although significant progress has been made over the last decades, the chemical senses remain less well explored than vision or audition. One method to assess participants' ability to identify or localize odors consists in the application of dichotomous stimuli (e.g., left- and right-sided stimulation). In this study we aimed to explore localization and identification mechanisms by investigating whether response times and response accuracy were correlated, with the aim of establishing the pertinence of response times as an additional measure for assessment of the olfactory function (1). We further examined an advantage of the right nostril which has been reported in several publications (2). We delivered two mixed olfactory/trigeminal odors (benzaldehyde and eucalyptol) to one nostril at a time in a pseudorandomized order to 23 normosmic participants; the other nostril received an odor-free air puff. In half of the trials we asked the participants to detect the stimulated nostril; in the other half, they indicated which odor they had received. We recorded response accuracy and response times. Participants reached higher accuracy in odor identification than in localization, driven by benzaldehyde. For the stimulus eucalyptol exclusively, we observed that participants were faster to respond after stimulation of the right nostril than to the left nostril, in the localization task. Finally, response times were correlated with response accuracy in the identification task, but not in localization. Our findings suggest that odor identification is easier than odor localization. In addition, we find further support for an advantage of the right nostril over the left nostril. Moreover, the measurement of reaction times may supplement other techniques of the assessment of odor identification.

Perception of specific trigeminal chemosensory agonists.

The intranasal trigeminal system is a third chemical sense in addition to olfaction and gustation. As opposed to smell and taste, we still lack knowledge on the relationship between receptor binding and perception for the trigeminal system. We therefore investigated the sensitivity of the intranasal trigeminal system towards agonists of the trigeminal receptors TRPM8 and TRPA1 by assessing subjects' ability to identify which nostril has been stimulated in a monorhinal stimulation design. We summed the number of correct identifications resulting in a lateralization score. Stimuli were menthol (activating TRPM8 receptors), eucalyptol (TRPM8), mustard oil (TRPA1) and two mixtures thereof (menthol/eucalyptol and menthol/mustard oil). In addition, we examined the relationship between intensity and lateralization scores and investigated whether intensity evaluation and lateralization scores of the mixtures show additive effects. All stimuli were correctly lateralized significantly above chance. Across subjects the lateralization scores for single compounds activating the same receptor showed a stronger correlation than stimuli activating different receptors. Although single compounds were isointense, the mixture of menthol and eucalyptol (activating only TRPM8) was perceived as weaker and was lateralized less accurately than the mixture of menthol and mustard oil (activating both TRPM8 and TRPA1) suggesting suppression effects in the former mixture. In conclusion, sensitivity of different subpopulations of trigeminal sensory neurons seems to be related, but only to a certain degree. The large coherence in sensitivity between various intranasal trigeminal stimuli suggests that measuring sensitivity to one single trigeminal chemical stimulus may be sufficient to generally assess the trigeminal system's chemosensitivity. Further, for stimuli activating the same receptor a mixture suppression effect appears to occur similar to that observed in the other chemosensory systems.

Intranasal localizability of odorants: influence of stimulus volume.

When an odorant is presented to one side of the nose and air to the other, the ability to localize which side received the odorant depends upon trigeminal nerve stimulation. It has been shown that performance on this lateralization task increases as stimulus concentration increases. In this study, we determined the influences of stimulus volume and sex on the ability to localize each of 8 odorants presented at neat concentrations: anethole, geraniol, limonene, linalool, menthol, methyl salicylate, phenyl ethanol, and vanillin. At a low stimulus volume (11 mL), only menthol was localized at an above-chance level. At a high stimulus volume (21 mL), above-chance localization occurred for all odorants except vanillin. Women were significantly better than men in localizing menthol. Stimuli rated as most intense were those that were most readily localized. The detection performance measures, as well as rated intensity values, significantly correlated with earlier findings of the trigeminal detectability of odorants presented to anosmic and normosmic subjects. This study suggests that differences in stimulus volume may explain some discrepant findings within the trigeminal chemosensory literature and supports the concept that vanillin may be a "relatively pure" olfactory stimulus.

The fish is bad: Negative food odors elicit faster and more accurate reactions than other odors.

Dissociating between 'good' or 'bad' odors is arguable of crucial value for human survival, since unpleasant odors often signal danger. Therefore, negative odors demand a faster response in order to quickly avoid or move away from negative situations. We know from other sensory systems that this effect is most evident for stimuli from ecologically-relevant categories. In the olfactory system the classification of odors into the food or non-food category is of eminent importance. We therefore aimed to explore the link between odor processing speed and accuracy and odor edibility and valence by assessing response time and detection accuracy. We observed that reaction time and detection accuracy are influenced by both pleasantness and edibility. Specifically, we showed that an unpleasant food odor is detected faster and more accurately than odors of other categories. These results suggest that the olfactory system reacts faster and more accurately to ecologically-relevant stimuli that signal a potential danger.

Olfactory dysfunction affects thresholds to trigeminal chemosensory sensations.

Next to olfaction and gustation, the trigeminal system represents a third chemosensory system. These senses are interconnected; a loss of olfactory function also leads to a reduced sensitivity in the trigeminal chemosensory system. However, most studies so far focused on comparing trigeminal sensitivity to suprathreshold stimuli; much less data is available with regard to trigeminal sensitivity in the perithreshold range. Therefore we assessed detection thresholds for CO(2), a relatively pure trigeminal stimulus in controls and in patients with olfactory dysfunction (OD). We could show that OD patients exhibit higher detection thresholds than controls. In addition, we were able to explore the effects of different etiologies of smell loss on trigeminal detection thresholds. We could show that in younger subjects, patients suffering from olfactory loss due to head trauma are more severely impaired with regard to their trigeminal sensitivity than patients with isolated congenital anosmia. In older patients, we could not observe any differences between different etiologies, probably due to the well known age-related decrease of trigeminal sensitivity. Furthermore we could show that a betterment of the OD was accompanied by decreased thresholds. This was most evident in patients with postviral OD. In conclusion, factors such as age, olfactory status and etiology of olfactory disorder can affect responsiveness to perithreshold trigeminal chemosensory stimuli.

Central processing of trigeminal activation in humans.

Although numerous fMRI studies have been performed on the processing of olfactory information, the intranasal trigeminal system so far has not received much attention. In a pilot study stimulants were presented within a constantly flowing airstream birhinally to activate the olfactory (phenylethyl alcohol, H(2)S) or the trigeminal (CO(2)) nerves. Both olfactory and trigeminal stimulation activated the ventral insular cortex. Intranasal trigeminal stimulation additionally led to an activation of the midbrain, superior temporal gyrus, anterior caudate nucleus, and the dorsolateral orbitofrontal cortex. Cerebellar activation was reduced relative to odorous stimuli. For all stimuli, right-sided activity was more pronounced. These results suggested that processing of intranasal activation follows a pattern which is, at least to some degree, similar for both trigeminal and olfactory stimulation. This and results from several other studies emphasize the fact that there is a high degree of interaction between the different aspects of the chemical senses, also in the sense that chemosensory-induced activation in the nasal cavity is processed in similar cortical networks. Interactions between the olfactory and trigeminal system can also be seen in patients with acquired olfactory loss, who exhibit reduced trigeminal sensitivity, possibly due to the lack of a central-nervous interaction. Both the orbitofrontal cortex and the rostral insula appear to be of significance in the amplification of trigeminal input, which is missing in patients with olfactory loss.

Cross-modal integration of intranasal stimuli: a functional magnetic resonance imaging study.

Most odorants, in addition to the olfactory system, also activate the intranasal trigeminal system. Recent studies have shown that pure trigeminal stimulation activates somatosensory regions as well as regions traditionally thought of as primary olfactory areas. As a main aim of this study we wished to a) ascertain which brain regions are responsive to an "artificially" bimodal odor composed of a trigeminal (CO(2)) and an olfactory stimulant (phenyl ethyl alcohol, PEA) and b) determine if presenting CO(2) and PEA simultaneously activates different brain regions than when presenting them individually. Fifteen men were scanned using functional magnetic resonance imaging while smelling PEA, CO(2), and a mixture of both stimuli (CO(2)PEA) presented simultaneously. Odors were presented monorhinally to the right nostril in a block design. The contrast between CO(2)PEA and baseline revealed areas implicated in the processing of both olfactory and trigeminal stimuli. When the mixture was contrasted with the sum of its single components (CO(2)PEA-{CO(2)+PEA}), activations in integration centers (left superior temporal and right intraparietal sulcus) and in orbitofrontal areas (left medial and lateral orbitofrontal cortex) were detected. The opposite contrast ({CO(2)+PEA}-CO(2)PEA) did not reveal any significant activation. In contrast to studies which have used natural mixed olfactory/trigeminal stimuli, we have shown that the perception of an artificial mixed olfactory/trigeminal stimulus activates, as opposed to inhibiting the olfactory cortex. Further, we also conclude that a mixed olfactory/trigeminal stimulus appears to lead to higher cortical activations than the sum of its parts.

Cerebral processing of gustatory stimuli in patients with taste loss.

Aim was to investigate differences in the central-nervous processing of gustatory stimuli between normogeusic subjects and patients with taste disorders. Twelve subjects with normal gustatory function and eight patients suffering from hypo- to ageusia underwent one fMRI run each in a 1.5 T scanner where they received liquid gustatory stimuli. fMRI analyses were performed by means of SPM2. Across all participants clusters of activated voxels were mainly found in orbitofrontal and insular regions of interest. Even those patients who did not perceive any stimuli showed some activation of gustatory centers. Group comparisons revealed higher activation of the insular and orbitofrontal cortices in patients compared to the group of healthy subjects. While further studies are needed, this finding may be interpreted in terms of enhanced neuronal recruitment due to functional impairment in patients with gustatory loss. It may ultimately prove useful in terms of the prognostic evaluation of individual patients.

Interactions between the chemical senses: trigeminal function in patients with olfactory loss.

The intranasal trigeminal and the olfactory system are intimately connected. There is evidence showing that acquired olfactory loss leads to reduced trigeminal sensitivity due to the lack of a central-nervous interaction. Both, the orbitofrontal cortex and the rostral insula appear to be of significance in the amplification of trigeminal input which is missing in patients with olfactory loss. On peripheral levels, however, adaptive mechanisms seem to produce an increase in the trigeminal responsiveness of patients with hyposmia or anosmia.

Intranasal trigeminal function in subjects with and without an intact sense of smell.

The intranasal trigeminal system is involved in the perception of odors. To investigate the cerebral processing of sensory information from the trigeminal nerve in detail we studied subjects with and without olfactory function using functional magnetic resonance imaging. A normosmic group (n=12) was compared with a group of anosmic subjects (n=11). For trigeminal stimulation gaseous CO(2) was used. Following right-sided stimulation with CO(2) controls exhibited a stronger right-sided cerebral activation than anosmic subjects. Stronger activation was found in controls compared to anosmic subjects for the right prefrontal cortex, the right somatosensory cortex (SI), and the left parietal insula. In contrast, relatively higher activation was found in anosmic subjects for the left supplementary motor area in the frontal lobe, the right superior and middle temporal lobe, the left parahippocampal gyrus in the limbic lobe, and the sub-lobar region of the left putamen and right insula which was mostly due to a decreased BOLD signal of controls in these areas. Additional conjunction analysis revealed that activated areas common to the two groups were the cerebellum and the right premotor frontal cortex. These data suggest that the processing of the trigeminally mediated information is different in the presence or absence of an intact sense of smell, pointing towards the intimate connection between the two chemosensory systems.

The neural representation of odor is modulated by the presence of a trigeminal stimulus during odor encoding.

OBJECTIVES: Odor perception does not simply consist in hierarchical processing from transduction to a single "true" cerebral representation. Odor sensation may be modulated by available sensory information during encoding. The present study set out to examine whether the presence of a pure trigeminal stimulus during odor encoding may modulate odor perception at both behavioral and cortical levels. METHODS: Participants were tested in a 2-session within-subject design: first, an odor encoding session included a delay conditioning procedure in which relatively selective olfactory stimulants (phenyl ethyl alcohol or vanillin, Conditioned Stimulus+, CS+) were presented either with a pulse of CO(2) (Unconditioned Stimulus, US), or alone (Conditioned Stimulus-, CS-); then, in the second session, both pure odorants (CS+ and CS-) were presented alone. During this second session, olfactory event-related potentials were simultaneously recorded and analyzed at different electrode sites including Cz and Pz (sites known to have maximal amplitudes for trigeminal and olfactory stimuli, respectively). After each trial, subjects were asked to rate odor intensity and hedonics. RESULTS: The results showed that CS+ intensity ratings increased in 8 subjects and decreased in 6. Cortically, a group effect was observed for P2 amplitude, which increased in the "CS+ intensity increase" group vs. the "CS+ intensity decrease" group at Cz (p<0.05) but not at Pz (p>0.05). CONCLUSIONS: This result suggests that the presence of a pure trigeminal stimulus (CO(2)) during odor encoding alters the neural representation of a pure odor. SIGNIFICANCE: The neural representation of odors comprises not only the odor itself but also contextual information (trigeminal in the present case) presented during encoding.