Normative data for the "Sniffin' Sticks" including tests of odor identification, odor discrimination, and olfactory thresholds: an upgrade based on a group of more than 3,000 subjects.

"Sniffin' Sticks" is a test of nasal chemosensory function that is based on pen-like odor dispensing devices, introduced some 10 years ago by Kobal and co-workers. It consists of tests for odor threshold, discrimination, and identification. Previous work established its test-retest reliability and validity. Results of the test are presented as "TDI score", the sum of results obtained for threshold, discrimination, and identification measures. While normative data have been established they are based on a relatively small number of subjects, especially with regard to subjects older than 55 years where data from only 30 healthy subjects have been used. The present study aimed to remedy this situation. Now data are available from 3,282 subjects as compared to data from 738 subjects published previously. Disregarding sex-related differences, the TDI score at the tenth percentile was 24.9 in subjects younger than 15 years, 30.3 for ages from 16 to 35 years, 27.3 for ages from 36 to 55 years, and 19.6 for subjects older than 55 years. Because the tenth percentile has been defined to separate hyposmia from normosmia, these data can be used as a guide to estimate individual olfactory ability in relation to subject's age. Absolute hyposmia was defined as the tenth percentile score of 16-35 year old subjects. Other than previous reports the present norms are also sex-differentiated with women outperforming men in the three olfactory tests. Further, the present data suggest specific changes of individual olfactory functions in relation to age, with odor thresholds declining most dramatically compared to odor discrimination and odor identification.

Eye closure in darkness animates olfactory and gustatory cortical areas.

In two previous fMRI studies, it was reported that eyes-open and eyes-closed conditions in darkness had differential effects on brain activity, and typical patterns of cortical activity were identified. Without external stimulation, ocular motor and attentional systems were activated when the eyes were open. On the contrary, the visual, somatosensory, vestibular, and auditory systems were activated when the eyes were closed. In this study, we investigated whether cortical areas related to the olfactory and gustatory system are also animated by eye closure without any other external stimulation. In a first fMRI experiment (n = 22), we identified cortical areas including the piriform cortex activated by olfactory stimulation. In a second experiment (n = 12) subjects lying in darkness in the MRI scanner alternately opened and closed their eyes. In accordance to previous studies, we found activation clusters bilaterally in visual, somatosensory, vestibular and auditory cortical areas for the contrast eyes-closed vs. eyes-open. In addition, we were able to show that cortical areas related to the olfactory and gustatory system were also animated by eye closure. These results support the hypothesis that there are two different states of mental activity: with the eyes closed, an "interoceptive" state characterized by imagination and multisensory activity and with the eyes open, an "exteroceptive" state characterized by attention and ocular motor activity. Our study also suggests that the chosen baseline condition may have a considerable impact on activation patterns and on the interpretation of brain activation studies. This needs to be considered for studies of the olfactory and gustatory system.

Intranasal trigeminal sensitivity in subjects with allergic rhinitis.

Trigeminal nerve endings of the human nasal mucosa are activated by chemical, physical or thermal stimuli. Activation of these A(delta) and C fibers can be quantified through the recording of chemo-somatosensory event-related potentials (ERP). The aim of this study was to investigate whether allergy-related activation of trigeminal nerve endings leads to changes in their responsiveness to intranasal trigeminal stimulation. Gaseous carbon dioxide (CO(2)) stimuli were applied in three sessions (baseline, after NaCl solution and after allergen application) to the nasal mucosa of 13 subjects with allergic rhinitis. Chemo-somatosensory ERP were recorded, and subjects rated the intensity of rhinitis symptoms. Administration of allergen produced a significant shortening of chemo-somatosensory ERP peak latencies P1 and N1. Observed changes of latencies were in line with rhinitis symptoms subjects indicated during the session. In addition, there was a negative relation between the general symptom score and ERP peak latencies, obtained both at baseline and after allergen exposure. In conclusion, it is hypothesized that in patients suffering from allergic rhinitis, nasal itching and sneezing after allergen exposure are, at least in part, clinical correlates of the activation of trigeminal nerve endings due to local inflammatory mechanisms. The correlations between ERP latencies and the patients' symptoms indicate that ERP latencies may possess a predictive value of the subjects' responsiveness to allergens.

Programming of a flexible computer simulation to visualize pharmacokinetic-pharmacodynamic models.

Teaching pharmacokinetic-pharmacodynamic (PK/PD) models can be made more effective using computer simulations. We propose the programming of educational PK or PK/PD computer simulations as an alternative to the use of pre-built simulation software. This approach has the advantage of adaptability to non-standard or complicated PK or PK/PD models. Simplicity of the programming procedure was achieved by selecting the LabVIEW programming environment. An intuitive user interface to visualize the time courses of drug concentrations or effects can be obtained with pre-built elements. The environment uses a wiring analogy that resembles electrical circuit diagrams rather than abstract programming code. The goal of high interactivity of the simulation was attained by allowing the program to run in continuously repeating loops. This makes the program behave flexibly to the user input. The programming is described with the aid of a 2-compartment PK simulation. Examples of more sophisticated simulation programs are also given where the PK/PD simulation shows drug input, concentrations in plasma, and at effect site and the effects themselves as a function of time. A multi-compartmental model of morphine, including metabolite kinetics and effects is also included. The programs are available for download from the World Wide Web at http:// www. klinik.uni-frankfurt.de/zpharm/klin/ PKPDsimulation/content.html. For pharmacokineticists who only program occasionally, there is the possibility of building the computer simulation, together with the flexible interactive simulation algorithm for clinical pharmacological teaching in the field of PK/PD models.

Quantitative assessment of gustatory function in a clinical context using impregnated "taste strips".

Assessment of gustatory sensitivity in a clinical setting is the prerequisite for correct diagnosis and adequate treatment of taste dysfunction. Despite of this, no taste test has been established for the routine clinical testing. The aim of the present study was to create a protocol which is easy to administer. The presently used technique is based on strips made from filter paper which were impregnated with different taste solutions (four concentrations each for sweet, sour, salty and bitter). These strips are placed on the tongue and subjects are asked to identify the taste quality. After establishing the concentration range of the taste solutions, the test was tried in 69 subjects. Each subject received eighteen taste strips (four concentrations of each taste quality plus two blanks) in a pseudo-randomized sequence. Results from this new procedure correlated significantly with the results of the well established extensive three-drop-technique (r69 = 0.67). Repeated measures indicated good reproducibility of the results for the taste strips (r69 = 0.68). These data suggest the usefulness of this new technique in routine clinical practice. Major advantages are long shelf-life, convenience of administration, short time needed for testing (approximately 8 min), and the possibility to test each side of the tongue separately.

Screening of olfactory function with a four-minute odor identification test: reliability, normative data, and investigations in patients with olfactory loss.

The study aimed to create a screening test on the basis of the odor identification test as used in the "Sniffin' Sticks" olfactory test kit. It should appeal to the practitioner in terms of 1) time required for testing, 2) reliability, 3) separation of "normal" from "abnormal," and 4) the fact that it allows lateralized screening. Experiments should provide a normative database (number of subjects > 1,000), establish test-retest reliability (n > 100), and compare results from patients with olfactory loss (n > 200). The correlation between results on 2 repetitive tests was .78. The test differentiated anosmics, hyposmics, and normosmics (p < .001). None of the 112 anosmics reached a score higher than 8; the 90th percentile was at a score of 6. When only 6 odors were used for calculating scores, for anosmics the 95th percentile was at a score of 4. These data provide a basis for the screening of patients by means of "Sniffin' Sticks."

Shared attentional resources for processing visual and chemosensory information.

For many years, researchers have argued that we have separate attentional resources for the processing of information impinging on each of our sensory receptor systems. However, a number of recent studies have demonstrated the existence of shared attentional resources for the processing of auditory, visual and tactile stimuli. In the present study, we examined whether there are also common attentional resources for the processing of chemosensory stimuli. Participants made speeded (left vs. right) footpedal discrimination responses to an unpredictable sequence of visual and chemosensory stimuli presented to either nostril. The participants' attention was directed to one or the other modality by means of a symbolic auditory cue (high or low tone) at the start of each trial, which predicted the likely modality for the upcoming target on the majority (80%) of trials. Participants responded more rapidly when the target occurred in the expected modality than when it occurred in the unexpected modality, implying the existence of shared attentional resources for the processing of chemosensory and visual stimuli.

Functional magnetic resonance imaging of human olfaction.

Olfaction is our basic sense phylogenetically and embryologically. Little is known, however, about how the human brain encodes the quality of odors, odor-associated memories, and emotions. Olfactory information is projected from the olfactory bulb to the primary olfactory cortex, which is composed of the anterior olfactory nucleus, the olfactory tubercle, the piriform cortex, the amygdala, the periamygdaloid region, and the entorhinal cortex. From there, the primary olfactory cortex projects to secondary olfactory regions including the hippocampus, ventral striatum and pallidum, hypothalamus, thalamus, orbitofrontal cortex, agranular insular cortex, and cingulate gyrus. Functional MR studies using olfactory stimuli as paradigms show activation of many of these areas and can advance our understanding of odor perception in humans.

Attention to olfaction. A psychophysical investigation.

Olfaction is unique among the senses in that signals from the peripheral sensory receptors bypass the thalamus on their way to the cortex. The fact that olfactory stimuli are not gated by the thalamus has led some researchers to suggest that people may be unable to selectively direct their attention toward the olfactory modality. We examined this issue in an experiment where participants made speeded intensity (strong vs weak)-discrimination responses to an unpredictable sequence of olfactory and visual stimuli. Attention was directed to either olfaction or to vision by means of an informative cue that predicted the likely modality for the upcoming target on the majority of trials. Participants responded more rapidly when the target was presented in the expected rather than the unexpected modality, showing that people can selectively attend to olfaction.

Patients with rheumatoid arthritis adapt differently to repetitive painful stimuli compared to healthy controls.

The aim of the study was to investigate whether there are changes of the nociceptive system in patients with chronic inflammatory joint pain. A pain model was used which is based on the recording of cortical chemo-somatosensory event-related potentials (CSSERP) after nociceptive stimulation of the nasal mucosa with gaseous carbon dioxide (CO(2)). Twenty-five patients with rheumatoid arthritis (RA) were compared to healthy controls matched for age and gender. Responses to both different intensities of painful stimuli and constant intensities of series of 4 stimuli were analysed. When testing increasing CO(2) concentrations ratings and CSSERP amplitudes increased for both patients and controls. However, when repetitive stimulation was performed with an interval of 2s CSSERP amplitudes N1 were significantly greater in RA patients. It is hypothesized that chronic inflammatory joint pain changes nociceptive processing in terms of generalized changes of the nociceptive system which may amplify chronic pain.

A threshold-like measure for the assessment of olfactory sensitivity: the "random" procedure.

Many tests of olfactory dysfunction are either too complex, too expensive, or too time-consuming to be of use in routine clinical testing. Thus, the present multicenter study was undertaken to investigate a new approach, the so-called "random" test. In this test different concentrations of citronellal and phenyl ethyl alcohol are applied according to a pre-established order; patients are asked to identify the odor if possible. The test score is the sum of correctly identified odors. Test administration takes about 10 min. Two studies were performed. Basic characteristics of the test were explored in experiment 1 in 176 healthy subjects (76 male, 100 female; age 12-85 years, mean age 30 years), namely test-retest reliability, correlation with other measures of olfactory sensitivity, and sensitivity of the test to differences in age and gender. In the second experiment the test was tried in 97 patients (45 male, 52 female; age 19-78 years, mean age 47 years) in a clinical environment to investigate its usefulness in diagnosing olfactory loss. The "random"-test was found (1) to exhibit a test-retest reliability similar to that reported for established measures of olfactory function (r = 0.71; P < 0.001), (2) to correlate with other measures of olfactory sensitivity (0.82 > r > 0.60; P < 0.001), (3) to differentiate between expected differences in olfactory sensitivity in relation to gender (t > 2.602, P < 0.011), and (4) to discriminate between different degrees of olfactory loss (F > 36.6, P < 0.001). Based on these data, and the fact that the new test requires little time and is easy to use, this approach can be expected to suit clinical needs.

Olfactory and trigeminal event-related potentials in migraine.

BACKGROUND: Trigeminal/neuronal hyperexcitability and spreading depression activating the trigemino-vascular system are discussed in migraine-pathophysiology. This study investigated trigeminal and olfactory event-related potentials in migraineurs. METHODS: Nasal chemosensitivity was assessed in 19 female migraineurs with or without aura > 72 h before or after an attack and in 19 healthy females employing event-related cortical potentials (ERPs) after specific trigeminal stimulation of nasal nociceptors with short pulses of CO2, and specific olfactory stimulation with H2S. Odour thresholds and odour identification performance were also tested. RESULTS: Migraineurs exhibited greater responses to trigeminal stimulation, indicated by significantly larger ERP amplitudes N1. In contrast, olfactory ERP amplitudes P1N1 were significantly smaller in migraineurs. A leave-one-out classification procedure on the basis of these two parameters assigned 76.3% cases correctly. The olfactory ERP amplitude discriminated better between groups than trigeminal ERPs (71.1 vs. 68.4% correct classification). CONCLUSIONS: Our data suggest trigeminal hyperexcitability in migraineurs. A general increase of nasal chemosensitivity is not supported because of smaller olfactory ERP amplitudes in migraineurs. Olfactory ERPs discriminate better than trigeminal ERPs between migraineurs and controls, emphasizing the significance of the olfactory system in migraine.

Selective attention to the chemosensory modality.

Previous studies have shown that behavioral responses to auditory, visual, and tactile stimuli are modulated by expectancies regarding the likely modality of an upcoming stimulus (see Spence & Driver, 1997). In the present study, we investigated whether people can also selectively attend to the chemosensory modality (involving responses to olfactory, chemical, and painful stimuli). Participants made speeded spatial discrimination responses (left vs. right) to an unpredictable sequence of odor and tactile targets. Odor stimuli were presented to either the left or the right nostril, embedded in a birhinally applied constant airstream. Tactile stimuli were presented to the left or the right hand. On each trial, a symbolic visual cue predicted the likely modality for the upcoming target (the cue was a valid predictor of the target modality on the majority of trials). Response latencies were faster when targets were presented in the expected modality than when they were presented in the unexpected modality, showing for the first time that behavioral responses to chemosensory stimuli can be modulated by selective attention.

[Olfactory testing with "sniffin' sticks" for clinical diagnosis of Parkinson disease]. / Riechprüfung mit "sniffin' sticks" zur klinischen Diagnostik des Morbus Parkinson.

Olfactory dysfunction seems to be one of the most frequent symptoms in idiopathic parkinsonian syndrome (IPS). In contrast to the increasing number of studies providing evidence of the usefulness of olfactory tests in the diagnosis of IPS, clinical assessment of olfactory function is rarely performed. This may be due to the lack of an easy-to-use, inexpensive, standardized, and reliable test. In this study, we administered the newly developed "sniffin' sticks" test to a group of 40 nondemented IPS patients and compared the results with 40 healthy controls matched for age, gender, and smoking habits. In all three subtests including odor identification, odor detection threshold, and odor discrimination, the control group scored significantly better than the IPS group, yielding a specificity and sensitivity of 90% each. Our results indicate that olfactory disturbances in IPS can be found at early stages of the disease, appear bilaterally, and do not correlate with the dominant side of parkinsonism. Therefore, we emphasize that olfactory testing may be a useful tool in the diagnosis of IPS.

Assessment of gustatory function by means of tasting tablets.

OBJECTIVE: To develop a simple test for the screening of gustatory function in clinical settings. STUDY DESIGN: We tested 101 healthy volunteers (44 male and 57 female volunteers; mean age, 47 y) with the following gustatory test: the substances sucrose (sweet), citric acid (sour), sodium chloride (salty), and caffeine (bitter) were presented as tablets (diameter 4 mm) similar to common sweetener tablets. For quantitative assessment of whole-mouth gustatory function we used six different dosages with dilutions of each tastant in 50% steps. The highest dosage could be easily detected (sucrose, 30 mg; citric acid, 3 mg; sodium chloride, 2 mg; caffeine, 2 mg), and the lowest concentration was within threshold range. METHODS: Twenty-eight tablets (six different dosages of the four basic tastes plus four tasteless tablets) were tried in a randomized order. The entire test required 15 to 20 minutes. To evaluate the within-subject test-retest reliability, sessions were repeated after 1 week. Results were compared with those obtained by means of a conventional three-drop, forced-choice procedure using the method of ascending limits. RESULTS: Results of the new gustatory test were significantly correlated with those obtained using the three-drop, forced-choice procedure (correlation coefficient [r] = 0.66, P<.001). In general, women performed better than men. Furthermore, younger subjects exhibited a significantly higher gustatory sensitivity in both tests compared with older subjects. CONCLUSIONS: This quantitative test of whole-mouth gustatory function is easy to use, can be self-administered, requires little time, and has a long shelf-life. It appears to be suited for routine clinical assessment of gustatory function.

Specific sensory detection, discrimination, and hedonic estimation of nicotine enantiomers in smokers and nonsmokers: are there limitations in replacing the sensory components of nicotine?

The aim of this study was to investigate in smokers and nonsmokers (1) the olfactory and trigeminal detection of R(+)- and S(-)-nicotine and (2) the discrimination ability and hedonic estimation of nicotine enantiomers in olfactory and trigeminal concentrations. Thirty healthy male subjects (15 smokers, 15 nonsmokers) participated in the experiments. A randomized sequence of R(+)- and S(-)-nicotine stimuli (seven R(+)- and seven S(-)-nicotine stimuli) were introduced into the right nostril of the subjects using a Kobal-olfactometer. The subjects were instructed to group the stimuli into two categories (A and B). To test the role of the olfactory and the trigeminal system in this discrimination task, the authors studied the olfactory detection threshold for the "odorous" sensation and the trigeminal detection thresholds for the "burning" and "stinging" sensations. Nicotine enantiomers were presented at the individual "olfactory" and "trigeminal" concentration levels. The subjects estimated the hedonic properties using a bipolar visual analog scale (from "very unpleasant" to "very pleasant"). A statistical evaluation (t-test) revealed that the subjects were able to identify R(+)- and S(-)-nicotine at olfactory and trigeminal concentrations (p < or = 0.01, p < or = 0.001, respectively). At concentrations near the detection thresholds, i.e., clearly below subjective pain thresholds, smokers rated both nicotine stereoisomers to be significantly more pleasant than did nonsmokers (t-test, R(+)-nicotine: p < or = 0.05; S(-)-nicotine: p < or = 0.01). Increasing the concentrations to above trigeminal thresholds resulted in a difference in hedonic estimates. Smokers perceived the S(-)-isomer as being less unpleasant than nonsmokers at trigeminal concentrations (t-test, p < or = 0.001). This difference in perception might be explained by the smokers' experience with S(-)-nicotine, which is the natural nicotine enantiomer in tobacco.

Multicenter investigation of 1,036 subjects using a standardized method for the assessment of olfactory function combining tests of odor identification, odor discrimination, and olfactory thresholds.

"Sniffin' Sticks" is a test of nasal chemosensory performance that is based on penlike odor-dispensing devices. It is comprised of three tests of olfactory function: tests for odor threshold, discrimination and identification. Previous work has already established its test-retest reliability and validity in comparison to established measures of olfactory sensitivity. The results of this test are presented as a composite TDI score--i.e., the sum of results obtained for threshold, discrimination and identification measures. The present multicenter investigation aimed at providing normative values in relation to different age groups. To this end, 966 patients were investigated in 11 centers. An additional study tried to establish values for the identification of anosmic patients, with 70 anosmics investigated in five specialized centers where the presence of anosmia was confirmed by means of olfactory evoked potentials. For healthy subjects, the TDI score at the 10th percentile was 24.5 in subjects younger than 15 years, 30.3 for ages from 16 to 35 years, 28.8 for ages from 36 to 55 years and 27.5 for subjects older than 55 years. While these data can be used to estimate individual olfactory abilities in relation to a subject's age, hyposmia was defined as the 10th percentile score of 16- to 35-year-old subjects. Our latter study revealed that none of 70 anosmics reached a TDI score higher than 15. This score of 15 is regarded as the cut-off value for functional anosmia. These results provide the basis for the routine clinical evaluation of patients with olfactory disorders using "Sniffin' Sticks."