Odorant confusion matrix: the influence of patient history on patterns of odorant identification and misidentification in hyposmia.

The odorant confusion matrix (OCM) is an odorant identification test in which the number of correct odorant identifications quantifies the level of olfactory function. As with other confusion matrices, the OCM reflects distortions of sensory perception as errors in identification. Previous work with the OCM suggests that, within an individual, hyposmia is associated with a stable shift in odorant perception. The current study examined whether consistent shifts in odorant perception are also characteristic of the various pathologies that lead to an olfactory loss. In a retrospective study, OCM response patterns for 135 hyposmic patients were fit into a five-dimensional space in which the distances between subjects reflected the dissimilarities between their OCM response patterns. Multivariate regression was performed relating position in the five-dimensional space to each of 11 factors representing 33 demographic and medical history variables. One factor, named congestion (gathering the variables of past polyposis, current polyposis, and current nasal obstruction due to swelling), was significantly indicative of patterns of responses on the OCM, independent of the level of hyposmia. These data suggest that conductive olfactory loss may be associated with alterations in odorant perception, which are reflected in consistent odorant confusions. Such alterations in perception may eventually serve as a basis for a clinical test to provide differential diagnoses as to the sources of olfactory losses.

Odorant quality perception: a metric individual differences approach.

Perceptual spaces, in which similar stimuli are located close to each other and dissimilar stimuli are located far apart, have aided in the understanding of the physiological and psychological bases for sensory quality coding. Differences in perception between individuals should be reflected by differences in the spatial relationships between stimuli. If the dimensionality of the perceptual space is small (e.g., color space), individual differences that reflect specific pathologies are readily apparent from visual inspection. On the other hand, if the dimensionality of the perceptual space is large (as is proposed for odor space), visual inspection alone may not reveal individual differences in quality perception. The present work presents an information-theory-based method for quantifying individual differences in quality perception from perceptual confusion matrices. The ability of this method to quantify individual differences in quality perception is shown in a hypothetical example of specific anosmia. Finally, the method is applied to the examination of intrasubject consistency of odorant quality perception.

A comparative fMRI study of cortical representations for thermal painful, vibrotactile, and motor performance tasks.

Cortical activity due to a thermal painful stimulus applied to the right hand was studied in the middle third of the contralateral brain and compared to activations for vibrotactile and motor tasks using the same body part, in nine normal subjects. Cortical activity was demonstrated utilizing multislice echo-planar functional magnetic resonance imaging (fMRI) and a surface coil. The cortical activity was analyzed based upon individual subject activity maps and on group-averaged activity maps. The results show significant differences in activations across the three tasks and the cortical areas studied. The study indicates that fMRI enables examination of cortical networks subserving pain perception at an anatomical detail not available with other brain imaging techniques and shows that this cortical network underlying pain perception shares components with the networks underlying touch perception and motor execution. However, the thermal pain perception network also has components that are unique to this perception. The uniquely activated areas were in the secondary somatosensory region, insula, and posterior cingulate cortex. The posterior cingulate cortex activity was in a region that, in the monkey, receives nociceptive inputs from posterior thalamic medial and lateral nuclei that in turn are targets for spinothalamic terminations. Discrete subdivisions of the primary somatosensory and motor cortical areas were also activated in the thermal pain task, showing region-dependent differences in the extent of overlap with the other two tasks. Within the primary motor cortex, a hand region was preferentially active in the task in which the stimulus was painful heat. In the primary somatosensory cortex most activity in the painful heat task was localized to area 1, where the motor and vibratory task activities were also coincident. The study also indicates that the functional connectivity across multiple cortical regions reorganizes dynamically with each task.

Odorant threshold following methyl bromide-induced lesions of the olfactory epithelium.

The present study assessed the functional consequences of peripheral olfactory destruction on the minimum detectable levels of stimulation for the odorants 2-propanol, D-limonene, and ethyl acetoacetate. Using standard operant techniques, eight Long-Evans rats were trained to criterion on an air versus odor differential response task. Odorant threshold was then determined on 10 consecutive testing sessions, using a computer-automated olfactometer and psychophysical tracking procedure. Following the last testing session, the rats were lesioned by exposing them to 330 ppm methyl bromide gas for 6 h. For each lesioned animal the anatomical state of the olfactory epithelium was evaluated relative to behavioral performance on the odorant threshold task at 3 days postlesion. For the group of rats, a comparison of pre- and postlesion performance demonstrated that, on the average, odor sensitivity was not altered by lesions that destroy roughly 95-98% of the epithelium. However, analysis of individual cases illustrated that two of the eight rats showed an elevation in odor sensitivity, albeit minimally, that was considered different from the prelesion performance. For those animals affected, we could extract no apparent relationship between the behavioral findings and the extent of anatomical damage. The results of this study demonstrate the remarkable capacity of the olfactory system to maintain normal or near-normal detection sensitivity in the face of massive damage. This capacity presumably reflects both the normal exposure of the epithelium to continual injury and the importance of maintained olfactory function for the survival of the animal.

Odorant-specific spatial patterns in mucosal activity predict perceptual differences among odorants.

1. Using operant techniques, rats were trained to differentially report (i.e., identify) the odorants propanol, carvone, citral, propyl acetate, and ethylacetoacetate. After acquisition training, the animals were tested using a 5 x 5 confusion matrix design. The results of the behavioral tests were used to measure the degree of perceptual dissimilarity between any pair of odorants. These dissimilarity measures were then subjected to multidimensional scaling analysis to establish a two-dimensional perceptual odor space for each rat. 2. At the completion of behavioral testing, the fluorescence changes in the dye di-4-ANEPPS were monitored on the rat's nasal septum and medial surface of the turbinates in response to the same odorants. For each mucosal surface a 6.0 x 6.0 mm area was sampled at 100 contiguous sites with a 10 x 10 photodiode array. 3. Formal statistical analysis indicated a highly significant predictive relationship between the relative position of an odorant's mucosal loci of maximal activity or "hot spot" and the relative position of the same odorant in a psychophysically determined perceptual odor space (F = 15.6, P < 0.001). 4. The results of this study suggest for the first time that odorant-induced mucosal activity patterns serve as the substrate for the perception of odorant quality.

Olfactory performance during childhood. II. Developing a discrimination task for children.

OBJECTIVES: (1) To create a match-to-sample odorant discrimination task (MODT) for children and adolescents; (2) to assess whether nonolfactory factors affect olfactory performance more on an identification task than on the MODT; (3) to evaluate subjects with olfactory dysfunction; and (4) to create age-appropriate sets of odorants for use in the MODT format to test children of different ages. STUDY DESIGN: We tested 75 normal children, aged 2 to 18 years, and 17 other subjects, aged 7 to 53 years, with known or suspected olfactory dysfunction, with the MODT. We compared the age trends in variability of scores on the MODT with those on an odorant identification task, using a weighted linear regression analysis. RESULTS: The MODT was useful in children aged 5 years and older, but not generally in the 2- to 4-year-old children. There was an appreciable age trend in the variability of the scores on the identification task but not on the MODT. Mean MODT scores for subjects with suspected or known olfactory dysfunction were far below average. Finally, we created four sets of odorants that will likely be sensitive to age-specific changes in olfactory performance. CONCLUSIONS: The MODT appears to be a suitable test instrument to assess olfaction in children aged 5 and older and is less likely to be influenced by nonolfactory factors than an identification task. According to our preliminary results, it is likely that the MODT will allow us to detect olfactory deficits in children of many ages.

Assessment of an abbreviated odorant identification task for children: a rapid screening device for schools and clinics.

To validate the level of olfactory performance of children, we tested 825 volunteers, aged 4-17 years, with an abbreviated form of our pediatric odorant identification task. The test consisted of sniffing and identifying five odorants (baby powder, bubble gum, candy cane, licorice and peach). Mean olfactory scores increased as a function of age, reaching a plateau of about 94-95% correct at 8 years of age. In general, girls out-performed boys. Physicians require a test instrument such as the one we have devised to allow them to diagnose olfactory dysfunction in children. The present task is particularly applicable in screening large numbers of children in clinics or schools because it can be administered easily and rapidly. Adult subjects with olfactory dysfunction also performed poorly on this odorant identification task designed for children. Therefore, we expect that our odorant identification task will also detect children with severe olfactory dysfunction.

Mucosal inherent activity patterns in the rat: evidence from voltage-sensitive dyes.

1. Fluorescence changes in the dye di-4-ANEPPS were monitored on the rat's nasal septum and medial surface of the turbinates in response to odorant stimuli. For each mucosal surface a 6.0 x 6.0-mm area was sampled at 100 contiguous sites with a 10 x 10 photodiode array. The odorants were propyl acetate, 2-propanol, citral, L-carvone and ethylacetoacetate, each presented at a low and high concentration. 2. Like previous work using optical recording techniques and potential-sensitive dyes on the amphibian epithelium, the fluorescence signals elicited by odorant stimuli in the rat preparation were nearly identical in shape, time course, and response characteristics as the electroolfactogram (EOG). As with the EOG, a response could only be recorded in the presence of odorant stimuli (that is, no response was detected when nonodorized, humidified air was presented as the stimulus); the amplitude depended on odorant concentration, and the response was abolished both by ether and Triton X-100. 3. Although the entire expanse of each sampled tissue (i.e., septum and medial surface of the turbinates) responded to stimulation with each odorant, each stimulus induced a distinct spatial pattern of activity that was independent of odorant concentration and consistent from animal to animal. Furthermore, the spatial activity patterns recorded for the septum were mirror images of those recorded from the medial surface of the turbinates. 4. Formal statistical analysis of the loci of maximal activity or "hot spot" indicated highly significant effects of the odorants for both the septum and medial surface of the turbinates. 5. The results of these studies give further support to the hypothesis that odorant quality is encoded by differential spatial activity patterns in the olfactory epithelium that are characteristic of different odorants.

Levels in the follow-up of a long-term clinical process.

I developed a 5-stage, 7-compartment prognostic model for the long-term follow-up of 28 patients with sickle chronic lung disease. Estimated hazard functions for transition varied with Stage 1, 2, 3, or 4 sickle chronic lung disease as well as with stage at diagnosis and duration of observation with hematologic disease before the recognition of sickle chronic lung disease. Individualized hazard matrices produced 28 prognostic probability functions of time that had heterogeneous levels and shapes. The probability of death from the time of diagnosis to the end of each patient's period of follow-up determined that patient's prognostic integrated hazard. Such integrated hazard values, developed from a prognostic model, provide a superior context for carrying out standard formal tests and inferences regarding the effects of alternative treatments in randomized clinical trials.

Long-term risk of hysterectomy among 80,007 sterilized and comparison women at Kaiser Permanente, 1971-1987.

To study the long-term risk of hysterectomy after tubal sterilization, the authors analyzed historical hospital discharge data on 39,502 parous women sterilized during 1971-1984 and 40,505 comparison women matched on age, race, parity, and interval since last birth. Sterilized women were significantly more likely than were comparison women to undergo hysterectomy (relative risk (RR) = 1.35, 95% confidence interval (CI) 1.26-1.44), especially for diagnoses of menstrual dysfunction and pelvic pain (RR = 1.88, 95% CI 1.65-2.13). Higher relative risks were not associated with greater tissue-destructive methods of tubal occlusion. Relative risks were highest for women who were young on the reference date (RR = 2.45, 95% CI 1.79-3.36 for women aged 20-24 years), but declined steadily as age increased (RR = 0.96, 95% CI 0.72-1.28 for women aged 40-49 years). In all age groups, relative risks were significantly above 1.00 after 7 years of follow-up. Reasons for elevated risks may be related to a greater willingness of sterilized women to forgo their uteruses. The emergence of greater risk in all age groups, however, prevents the authors from ruling out a possible latent biologic effect of tubal sterilization.

PIP: To study the longterm risk of hysterectomy after tubal sterilization, the authors analyzed historical hospital discharge data on 39.502 parous women sterilized between 1971 and 1984, and 40,535 comparison women matched on age, race, parity, and interval since last birth. Sterilized women were significantly more likely than were comparison women to undergo hysterectomy (relative risk [RR] = 1.35, 95% confidence interval [CI] 1.26-1.44), especially for diagnoses of menstrual dysfunction and pelvic pain (RR = 1.88, 95% CI, 1.65-2.13). Higher relative risks were not associated with greater tissue-destructive methods of tubal occlusion. Relative risks were highest for women who were young on the reference data (RR = 2.45, 95% CI 1.79-3.36 for women aged 20-24 years), but declined steadily as age increased (RR = 0.96, 95% CI 0.72-1.28 for women aged 40-49 years).

Accidental gassing incidents and the pulmonary function of pulp mill workers.

A previous investigation of white male workers from a pulp and paper company in Berlin, New Hampshire identified decrements in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) associated with work in the pulping operations. A subset of those data were reanalyzed to consider another type of occupational exposure: gassing incidents in which workers were accidentally exposed to high levels of irritant gases, such as chlorine (Cl2) or sulfur dioxide (SO2). A total of 230 current and former workers (all white male) were included in the analysis. Gassing events were more common among pulp mill workers (34%) than workers from other parts of the company (9%). Average changes of -291.9 ml in FEV1 (p < 0.05) and -5.00% in FEV1/FVC (p < 0.05) were associated with gassing. Also, in each of the regression models for the three measures of pulmonary function (FEV1, FVC, and FEV1/FVC), there was a three-way interaction of cumulative smoking, cumulative pulp mill exposure, and gassing. The greatest decreases in FEV1 and FEV1/FVC associated with gassing were evident in the dual smoking/pulp mill exposure categories of none/high and high/none. The changes in pulmonary function appeared to be chronic effects that persisted beyond cessation of the exposure. Only limited information about the gassing episodes was requested from the subjects, and future research is discussed that will address some of the limitations.

Olfactory performance during childhood. I. Development of an odorant identification test for children.

Because there has been no suitable diagnostic instrument for evaluation of olfaction in children, we designed an odorant identification test for that purpose. We screened 40 microencapsulated odorants ("scratch 'n' sniff" cards) by randomly grouping them into 40 overlapping sets of five odorants each. Forty-one children, 4 and 5 years of age, tried to identify each test odorant, selecting their responses from among five photographs depicting the substances in the set of odorants. We used the results to select a subset of five odorants (baby powder, bubble gum, candy cane, fish, and orange). To determine how well these odorants could be identified by normal children, we tested another 134 subjects, 3 1/2 to 13 years of age. For children 3 1/2 years to 5 years 4 months of age, the mean (+/- SEM) percentage of correct responses increased from 66% +/- 8% to 92% +/- 2%. Thereafter the mean percentage of correct responses remained at a plateau of about 90%. The 10th percentile for the percentage of correct responses tended to be higher for girls than for boys throughout childhood. We concluded that this set of five odorants can be correctly identified by most normal children 5 years of age or older. The performances of three older subjects with Kallmann syndrome were all subnormal, but the overall efficacy of the test for evaluating children with olfactory deficits needs to be determined.

Prognostic modeling of clinical outcomes: an illustration with data from patients with membranous nephropathy.

Probabilities that a patient will occupy any of five clinically defined compartments at different future times are generated and graphed by a personal computer. The probabilities are functions of a patient's relevant baseline characteristics (treated or control group), clinical status, and follow-up time at which the prognosis is made. The illustrative prognostic model is based on a reanalysis of detailed individual records for 81 patients with idiopathic membranous nephropathy (42 treated with methylprednisolone and chlorambucil; 39 controls) in a randomized clinical trial. The compartments to and from which patients may pass are identified as (1) complete remission, (2) partial remission, (3) the nephrotic syndrome, (4) renal failure, and (5) death. Estimated risk functions for transitions between compartments involve baseline treatment, and intermediate and temporal variables, together with their relevant interactions. The model illustrates how, despite the overall advantage of treated over control patients, the comparative prognoses can change greatly and can even sometimes be reversed, depending on a variety of follow-up experiences.

Effect of ultrasound monitoring of follicular growth on the conception rate. A clinical study.

Periovulatory ultrasonography (POUS) was performed on 59 anovulatory women over 523 treatment cycles. Follicular development was stimulated with either clomiphene citrate (CC) or human menopausal gonadotropin (hMG). Thirty-one pregnancies were induced; 23 went to term. Three factors were considered in evaluating the incidence of conception: the patient's age, drug use and the presence or absence of POUS. There was no evidence that the pregnancy rate after POUS differed from that without it (estimated conception rate ratio = 1.2:1, P = .76). Similarly, conceptus viability was not demonstrably different whether POUS was used or not (P = 1.00). However, the data show a strong advantage of hMG over CC in achieving conception (estimated conception rate ratio = 5.85, P less than .0001) and no disadvantage in conceptus viability (P = 1.00). The data also suggest that in women less than 30 years of age with polycystic ovaries, ovulation induction is easier to achieve and the conception rate higher than in older women. There was no evidence that POUS decreased the conception rate or increased fetal wastage.

Olfactory deficits in boys with cleft palate.

An odor identification task was used to determine whether individuals with cleft palate (with or without cleft lip) also have an increased prevalence of olfactory deficits. Olfactory responses of 35 affected subjects (7 to 22 years of age) were compared with those of 68 subjects of comparable age without cleft palates. Subjects were requested to identify the smell of ten common household odors. They selected their responses from an alphabetized list of the test odorants. After a practice trial, the set of odorants was presented five times in randomized sequences. The percentage of correct responses increased with age for prepubertal and pubertal subjects without cleft palates. Although the olfactory scores of girls without cleft palates continued to increase after puberty, this trend was absent in boys. On the average, the girls with cleft palates, compared with only three of 34 boys without cleft palates, had olfactory scores less than 60% correct. There was no evidence of heterogeneity in the magnitude or direction of the relationship between any of the subtypes of cleft palate and olfactory dysfunction. In this study, cleft palate is more strongly associated with olfactory deficits in boys than in girls, suggesting the possibility that the deficit may be a sex-influenced trait.

Improvement of olfaction in laryngectomized patients with the larynx bypass.

Hyposmia following laryngectomy is an often recognized phenomenon. A larynx bypass device was used to determine whether this olfactory deficit could be reversed simply by restoring nasal airflow. Odorant detection thresholds and confusion matrix identification tests were administered to laryngectomy and normal comparison groups. Data on nasal airflow characteristics with and without the bypass were also analyzed. The results suggested that restoration of nasal airflow completely reversed the hyposmia for trigeminal nerve stimuli. However, the reversal of hyposmia was not complete for those odorants which primarily, if not exclusively, stimulate the olfactory nerve. This suggested that other factors may contribute to laryngectomy-induced hyposmia for olfatory nerve stimuli. Additionally, nasal airflow analysis revealed that confusion matrix identification scores were depedent upon inspiratory sniff flow rates with and without the larynx bypass. It is argued that rehabilitation for the laryngectomee should include efforts to restore and maintain preoperative olfactory acuity.

"Imposed" and "inherent" mucosal activity patterns. Their composite representation of olfactory stimuli.

Both regional differences in mucosal sensitivity and a gas chromatography-like process along the mucosal sheet have been separately proposed in two sets of earlier studies to produce different odorant-dependent activity patterns across the olfactory mucosa. This investigation evaluated, in one study, whether and to what degree these two mechanisms contribute to the generation of these activity patterns. Summated multiunit discharges were simultaneously recorded from lateral (LN) and medial (MN) sites on the bullfrog's olfactory nerve to sample the mucosal activity occurring near the internal and external nares, respectively. Precisely controlled sniffs of four odorants (benzaldehyde, butanol, geraniol, and octane) were drawn through the frog's olfactory sac in both the forward (H1) and reverse (H2) hale directions. By combining the four resulting measurements, LNH1, LNH2, MNH1, and MNH2, in different mathematical expressions, indexes reflecting the relative effects of the chromatographic process, regional sensitivity, and hale direction could be calculated. Most importantly, the chromatographic process and the regional sensitivity differences both contributed significantly to the mucosal activity patterns. However, their relative roles varied markedly among the four odorants, ranging from complete dominance by either one to substantial contributions from each. In general, the more strongly an odorant was sorbed by the mucosa, the greater was the relative effect of the chromatographic process; the weaker the sorption, the greater the relative effect of regional sensitivity. Similarly, the greater an odorant's sorption, the greater was the effect of hale direction. Other stimulus variables (sniff volume, sniff duration, and the number of molecules within the sniff) had marked effects upon the overall size of the response. For strongly sorbed odorants, the effect of increasing volume was positive; for a weakly sorbed odorant, it was negative. The reverse may be true for duration. In contrast, the effect of increasing the number of molecules was uniformly positive for all four odorants. However, there was little evidence that these other stimulus variables had a major influence upon the effects of the chromatographic process and regional sensitivity differences in their generation of mucosal activity patterns.

Airflow patterns in a human nasal model.

Nasal airflow patterns were studied by using xenon 133 gas to image the course taken by air as it flowed through a plastic model of the human nasal cavity. The model was produced from the head of a human cadaver, and was anatomically correct. A needle catheter was used to infuse the radioactive xenon into a continuous flow of room air maintained through the model by a variable vacuum source connected to the nasopharynx. The radioactive gas was infused at one of five release sites in the nostril, and the distribution of the radioactivity was imaged in the sagittal plane with a scintillation camera. The data were organized to show the activity in six contiguous regions of the midnose. For each catheter, release site activity patterns were determined for three flow rates. The results of this experiment showed that both catheter position and flow rate had significant and reproducible effects on the distribution of radioactivity within the model.