Factors associated with relevant olfactory recovery after olfactory training: a retrospective study including 601 participants.

OBJECTIVE: Olfactory training (OT) represents a therapeutic option for multiple etiologies of olfactory dysfunction (OD) that also benefits normosmic subjects. In this retrospective study, we report the effectiveness of OT and factors associated with relevant changes in olfactory function (OF) in large groups of normosmic participants and patients with OD, including a control group that performed no training. METHODS: This was a retrospective pooled analysis including 2 treatment cohorts of 8 previously published studies. Adult participants that either presented with the major complaint of quantitative OD or normosmic volunteers were recruited at various ENT clinics and received OT or no training. The outcome was based on changes in objective olfactory test scores after OT. RESULTS: A total of 601 patients with OD or normosmic subjects were included. OT was more effective compared to no training. No interaction was found between OT and OF. In multivariate analysis, higher baseline OF (adjusted odds ratio, aOR, 0.93) and posttraumatic (aOR, 0.29) or idiopathic OD (aOR, 0.18) compared to postinfectious causes were significantly associated with lower odds of relevant improvements in patients with OD receiving OT. Subgroup analysis of normosmic participants receiving OT further revealed a significant association of lower age and baseline olfactory function with improvements of overall OF. CONCLUSIONS: This study demonstrated that OT was more effective than no training in patients with various causes of OD. Additionally, baseline olfactory performance and etiology of OD were identified as important factors associated with relevant improvements after OT.

Factors associated with relevant olfactory recovery after olfactory training: a retrospective study including 601 participants.

BACKGROUND: Olfactory training (OT) represents a therapeutic option for multiple etiologies of olfactory dysfunction (OD) that also benefits normosmic subjects. In this retrospective study, we report the effectiveness of OT and factors associated with relevant changes in olfactory function (OF) in large groups of normosmic participants and patients with OD, including a control group that performed no training. METHODS: This was a retrospective pooled analysis including 2 treatment cohorts of 8 previously published studies. Adult partici- pants that either presented with the major complaint of quantitative OD or normosmic volunteers were recruited at various ENT clinics and received OT or no training. The outcome was based on changes in objective olfactory test scores after OT. RESULTS: A total of 601 patients with OD or normosmic subjects were included. OT was more effective compared to no training. No interaction was found between OT and OF. In multivariate analysis, higher baseline OF (adjusted odds ratio, aOR, 0.93) and posttraumatic (aOR, 0.29) or idiopathic OD (aOR, 0.18) compared to postinfectious causes were significantly associated with lower odds of relevant improvements in patients with OD receiving OT. Subgroup analysis of normosmic participants receiving OT further revealed a significant association of age and baseline olfactory function with improvements of overall OF. CONCLUSIONS: This study demonstrated that OT was more effective than no training in patients with various causes of OD. Additi- onally, baseline olfactory performance and etiology of OD were identified as important factors associated with relevant improve- ments after OT.

Spatial transcriptomics identifies spatially dysregulated expression of GRM3 and USP47 in amyotrophic lateral sclerosis.

AIMS: The mechanisms underlying the selective degeneration of motor neurones in amyotrophic lateral sclerosis (ALS) are poorly understood. The aim of this study was to implement spatially resolved RNA sequencing in human post mortem cortical tissue from an ALS patient harbouring the C9orf72 hexanucleotide repeat expansion to identify dysregulated transcripts that may account for differential vulnerabilities of distinct (i) cell types and (ii) brain regions in the pathogenesis of ALS. METHODS: Using spatial transcriptomics (ST) we analysed the transcriptome of post mortem brain tissue, with spatial resolution down to 100 µm. Validation of these findings was then performed using BaseScope, an adapted, in situ hybridization technique with single-transcript single-cell-resolution, providing extensive regional and cell-type specific confirmation of these dysregulated transcripts. The validation cohort was then extended to include multiple post mortem brain regions and spinal cord tissue from an extended cohort of C9orf72, sporadic ALS (sALS) and SOD1 ALS cases. RESULTS: We identified sixteen dysregulated transcripts of proteins that have roles within six disease-related pathways. Furthermore, these complementary molecular pathology techniques converged to identify two spatially dysregulated transcripts, GRM3 and USP47, that are commonly dysregulated across sALS, SOD1 and C9orf72 cases alike. CONCLUSIONS: This study presents the first description of ST in human post mortem cortical tissue from an ALS patient harbouring the C9orf72 hexanucleotide repeat expansion. These data taken together highlight the importance of preserving spatial resolution, facilitating the identification of genes whose dysregulation may in part underlie regional susceptibilities to ALS, crucially highlighting potential therapeutic and diagnostic targets.

Updated Sniffin' Sticks normative data based on an extended sample of 9139 subjects.

PURPOSE: To provide up-to-date and detailed normative data based on a large-scale sample, increasing diagnostic validity by reference to narrow age groups as previous normative values were based upon smaller sample sizes-especially in the group of older subjects. METHOD: Data were obtained from 9139 healthy subjects (4928 females aged 5-96 years and 4211 males aged 5-91 years). The standard "Sniffin' Sticks" test was applied, comprising threshold (T), discrimination (D) and identification (I) subtests, and yielding a TDI sum score. RESULTS: Hyposmia was established at a TDI score of less than 30.75. Age-related changes were found in each domain, most pronounced for thresholds. Individuals aged 20-30 years performed best, whereas children below the age of 10 and adults above the age of 71 scored only half as well. Sex-related differences were in favor of women. CONCLUSIONS: Data provide guidance for assessing individual olfactory performance in relation to specific age groups. Significant gender and age effects were observed, with a most pronounced increase of olfactory test scores between age 5 through 20 years and a dramatic decrease at the age of 60 through 71 years.

Size matters - The olfactory bulb as a marker for depression.

BACKGROUND: Major Depression is mainly related to structural and functional alterations in brain networks involving limbic and prefrontal regions. Reduced olfactory sensitivity in depression is associated with reduced olfactory bulb (OB) volume. We determined if the OB volume reduction is a specific biomarker for depression and whether its diagnostic accuracy allows its use as a valid biomarker to support its diagnosis. METHODS: 84 in-patients with mixed mental disorders and 51 age-matched healthy controls underwent structural MR imaging with a spin-echo T2-wheighted sequence. Individual OB volume was calculated manually (interrater-reliability = .81, p < .001) and compared between groups. Multiple regression analysis with OB volume as dependent variable and Receiver Operator Characteristic analysis to obtain its diagnostic accuracy for depression were ruled out. RESULTS: Patients exhibited a 13.5% reduced OB volume. Multiple regression analysis showed that the OB volume variation was best explained by depression (ß = -.19), sex (ß = -.31) and age (ß = -.29), but not by any other mental disorder. OB volume attained a diagnostic accuracy of 68.1% for depression. LIMITATIONS: The patient group mainly contained highly comorbid patients with mostly internalizing disorders which limits the generalisability of the results of the regression analysis. CONCLUSION: The OB may serve as a marker for depression. We assume that reduced neural olfactory input to subsequent limbic and salience processing structures moderates this relation. However, the OB was in an inferior position compared to conventional questionnaires for diagnosis of depression. Combination with further structural or functional measurements is suggested.

Short inter-stimulus intervals can be used for olfactory electroencephalography in patients of varying olfactory function.

Use of chemosensory event-related potentials (ERPs) is limited by relatively poor signal-to-noise ratios (SNRs). We hypothesized that by reducing the standard inter-stimulus interval (ISI), the increased number of trial repetitions possible may increase SNR. In order to further investigate this, we performed the largest study to date assessing chemosensory ERP using short and long ISIs in 101 participants of varying olfactory function. Using rose odor (phenylethylalcohol, PEA) as a relatively selective olfactory stimulant, we found no significant difference in the proportion of individuals in whom ERPs were recorded using short or long ISIs. This was true in normosmic, hyposmic and functionally anosmic individuals. We also demonstrated significantly increased SNR using short PEA-ISIs, in the normosmic and functionally anosmic groups. Comparing between groups of different olfactory function, hyposmic patients achieved faster onsets and greater amplitudes than normosmics under the PEA-10s protocol. This could be due to increased stimulus attendance, but requires confirmation with further research.

Influence of HLA on human partnership and sexual satisfaction.

The major histocompatibility complex (MHC, called HLA in humans) is an important genetic component of the immune system. Fish, birds and mammals prefer mates with different genetic MHC code compared to their own, which they determine using olfactory cues. This preference increases the chances of high MHC variety in the offspring, leading to enhanced resilience against a variety of pathogens. Humans are also able to discriminate HLA related olfactory stimuli, however, it is debated whether this mechanism is of behavioural relevance. We show on a large sample (N = 508), with high-resolution typing of HLA class I/II, that HLA dissimilarity correlates with partnership, sexuality and enhances the desire to procreate. We conclude that HLA mediates mate behaviour in humans.

[Specific anosmia as a principle of olfactory perception]. / Spezifische Anosmie als Prinzip olfaktorischer Wahrnehmung.

Specific anosmia, the inability to perceive a specific odor, while olfactory perception is otherwise intact, is known as a rather seldom phenomenon. By testing the prevalence of specific anosmia to 20 different odors in a sample of 1600 people, we were able to estimate the general prevalence of anosmia. This revealed that specific anosmia is not rare at all. In contrast, the general likelihood for specific anosmia approaches 1. In addition, specific anosmia can be very well reversed by "smell training" during the course of 3 months. To summarize, specific anosmia seems to be a rule, not an exception, of olfactory sensation. The lack of perception of certain odors may constitute a flexible peripheral filter mechanism, which can be adapted by exposure to odors.

Interpersonal stroking touch is targeted to C tactile afferent activation.

C tactile fibers are a specialized group of fibers innervating the non-glabrous skin that are tuned to light gentle stroking applied with velocities between 1 and 10 cm/s. Those fibers add to the sensation of interpersonal caressing and pleasant touch. It is unclear whether people spontaneously apply touch that is tuned to optimally activate those fibers. This was investigated in three studies. In study one, 45 participants (21.8 ± 2.3 years, 24 women) were asked to stroke an artificial arm. In study two, 32 participants (28.3 ± 8.7 years, 16 women) were asked to stroke their partner. In study three, 11 parents (29.4 ± 5.7 years, 6 women) were asked to stroke their babies. Stroking velocity was tracked in all conditions. Stroking velocities were significantly slower in the partner touch and baby touch condition than in the artificial arm condition and all of the participants stroking their partner or baby used velocities that can activate C tactile fibers. We conclude that human social stroking is optimized for C tactile stimulation.

Olfactory speed - Temporal odor processing of paired stimuli.

OBJECTIVES: Compared to other senses, temporal perception of odors seems fairly slow. In addition it has been shown in previous studies that even not consciously perceived odors could influence our behavior. Aim of the current study therefore was to study the interstimulus interval (ISI) length, which is necessary between two repetitive stimuli to be able to perceive them separately. The additional aim focused on observing central odor processing of not perceived odorous stimuli. MATERIALS AND METHODS: The study was divided into three parts. In each part healthy, normosmic volunteers were included. In part I and II stimulus pairs (CO2, H2S, orange and phenyl ethyl alcohol (PEA)) were presented to the subjects via a computer-controlled olfactometer with short ISI of 0.6-9s. The decision whether one or two stimuli were perceived was recorded. In addition the influence of odor valence, trigeminallity and concentrations was observed. In part III olfactory event-related potentials (OERPs) to perceived and not-perceived odors were recorded. RESULTS: The two stimuli of a stimulus pair were perceived separately more often with increasing ISI length. This increase was significant until an ISI between the stimuli of 4s. Odor intensity, pleasantness, trigeminallity and sex had no major influence on this. In addition we were able to observe that OERPs are less often detected in response to not perceived olfactory stimuli. However, the presence of OERP in response to not perceived stimuli in more than half of the cases indicated that even not perceived stimuli are centrally processed.

The smelling of Hedione results in sex-differentiated human brain activity.

A large family of vomeronasal receptors recognizes pheromone cues in many animals including most amphibia, reptiles, rhodents, and other mammals. Humans possess five vomeronasal-type 1 receptor genes (VN1R1-VN1R5), which code for proteins that are functional in recombinant expression systems. We used two different recombinant expression systems and identified Hedione as a ligand for the putative human pheromone receptor VN1R1 expressed in the human olfactory mucosa. Following the ligand identification, we employed functional magnetic resonance imaging (fMRI) in healthy volunteers to characterize the in vivo action of the VN1R1 ligand Hedione. In comparison to a common floral odor (phenylethyl alcohol), Hedione exhibited significantly enhanced activation in limbic areas (amygdala, hippocampus) and elicited a sex-differentiated response in a hypothalamic region that is associated with hormonal release. Utilizing a novel combination of methods, our results indicate that the putative human pheromone receptor VN1R1 is involved in extra-olfactory neuronal activations induced by the odorous substance Hedione. The activation of VN1R1 might play a role in gender-specific modulation of hormonal secretion in humans.

[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.

Habituation effects of pleasant and unpleasant odors.

OBJECTIVE: The hedonic value of odors is reflected in chemosensory evoked potentials with more salient unpleasant odors being processed differently from pleasant odors. However, it is not known if this effect is stable over time. It was examined if chemosensory evoked potentials towards pleasant and unpleasant odors change with repeated presentation. METHODS: 42 participants received two pleasant (Peach and PEA) and one unpleasant (H2S) intensity matched odors in a block design. Intensity and pleasantness were rated after each presentation. Subjective ratings, as well as N1 and P2 of the first stimulus of each block were compared with the two following stimuli of each block. RESULTS: Early and late components of the chemosensory evoked potentials had shorter latencies in response to the unpleasant H2S compared to PEA and Peach. Pleasantness ratings for H2S increased with repeated presentation but were far below neutral even for the third stimulus in a row. In line with this, for H2S only, the P2 amplitude diminished with repeated presentation. CONCLUSION: We assume that unpleasant stimuli catch more attention first hand. However, repeated presentation leads to reduced emotional salience of unpleasant stimuli only, which is mirrored in a decrease of neuronal activation.

Lateralized differences in olfactory bulb volume relate to lateralized differences in olfactory function.

The present study aimed to investigate whether side differences in olfactory bulb (OB) volume correlate to respective differences in olfactory function. In a total of 164 healthy volunteers volumetric measures of the OBs were performed plus lateralized measurements of odor thresholds and odor discrimination. Side differences were defined as 10% difference between the left and right OB. In 39 cases volumes on the right side were larger than on the left side, whereas in 29 cases it was the other way around. Subjects with larger right-sided OB volumes were found to be more sensitive to odorous stimulation of the right as compared to the left nostril in terms of odor thresholds and odor detection; higher sensitivity of the left nostrils (decreased odor threshold) was observed in individuals with larger OB volumes on the left side. These data appear to suggest that OB volume may be partly dependent on lateralized influences on the olfactory system, reflecting its lateralized organization.

[Isolated congenital anosmia--clinical and daily life aspects of a life without a sense of smell]. / Isolierte congenitale Anosmie - Klinische und alltägliche Aspekte eines Lebens ohne Geruchssinn.

BACKGROUND: Isolated congenital anosmia is a disorder (ICA) characterized by not or only rudimentary developed central olfactory structures. This results in the lack of the sense of smell since birth. Although this phenomenon is known among clinicians almost no knowledge exists on how those people cope with the disorder. MATERIAL AND METHODS: 43 people with ICA were asked with a standardised questionnaire about when they fi rst noticed their disorder, how they experience the lack of smelling ability and about different aspects of daily life. RESULTS: ICA is detected by the patients self or by their parents at the age of 10 in average. However about 13 years pass, until the right diagnosis is confirmed. In contrast to people with acquired olfactory loos ICA patients have developed strategies to adapt to the deficit in daily life. Nevertheless they report increased social insecurity and more hazardous events. CONCLUSION: The results can be of advantage for clinicians and patients to get a better understanding of the disorder.

Reduced olfactory bulb volume and olfactory sensitivity in patients with acute major depression.

The purpose of this study was to assess olfactory function and olfactory bulb volume in patients with acute major depression in comparison to a normal population. Twenty-one patients diagnosed with acute major depressive disorder and 21 healthy controls matched by age, sex and smoking behavior participated in this study. Olfactory function was assessed in a lateralized fashion using measures of odor threshold, discrimination and identification. Olfactory bulb volumes were calculated by manual segmentation of acquired T2-weighted coronal slices according to a standardized protocol. Patients with acute major depressive disorder showed significantly lower olfactory sensitivity and smaller olfactory bulb volumes. Additionally, a significant negative correlation between olfactory bulb volume and depression scores was detected. Their results provide the first evidence, to our knowledge, of decreased olfactory bulb volume in patients with acute major depression. These results might be related to reduced neurogenesis in major depression that could be reflected also at the level of the olfactory bulb.