Abstract

The olfactory and the trigeminal systems have a close relationship. Most odorants also stimulate the trigeminal nerve. Further, subjects with no sense of smell exhibit a decreased trigeminal sensitivity with unclear underlying mechanisms. Previous studies indicated that single stages of trigeminal processing may differently be affected by olfactory loss. A better knowledge of adaptive and compensatory changes in the trigeminal system of subjects with acquired anosmia (AA) will improve the understanding of interactive processes between the 2 sensory systems. Thus, we aimed to assess trigeminal function on different levels of processing in subjects with AA. Subjects with AA showed larger electrophysiological responses to irritants obtained from the mucosa than healthy controls. On central levels, however, they exhibited smaller event-related potentials and psychophysical measures to irritants. Over 9 months, they exhibited an increase in trigeminal sensitivity. Subjects with recovering olfactory function showed an even more increased peripheral responsiveness to irritants. These data suggest dynamic mechanisms of mixed sensory adaptation/compensation in the interaction between the olfactory and trigeminal systems, where trigeminal activation is increased on mucosal levels in subjects with AA and amplified on central levels in subjects with a functioning olfactory system.

Introduction

Most odorants also stimulate the trigeminal nerve (Doty 1975; Doty et al. 1978; Wysocki et al. 2003). Therefore, even anosmic subjects are able to distinguish between odorants based on their trigeminally mediated sensitivity (Laska et al. 1997). Thus, anosmic subjects are frequently investigated to assess the trigeminal impact of stimulants without concomitant olfactory stimulation (Cometto-Muniz et al. 1998, 1999). However, anosmic subjects show reduced trigeminal sensitivity when compared with healthy controls (Hummel, Barz, et al. 1996; Gudziol et al. 2001; Kendal-Reed et al. 2001; Walker et al. 2001; Hummel et al. 2003). This suggests that, in addition to the known mutual interactions between the olfactory and the trigeminal chemosensory systems in healthy subjects (Stone et al. 1968; Cain and Murphy 1980; Bouvet et al. 1987; Livermore et al. 1992; Livermore and Hummel 2004), even the absence or presence of a functioning olfactory system influences trigeminal perception. Anatomical and functional characteristics of the underlying mechanisms are largely unknown.

Recently established electrophysiological methods enable us to investigate the trigeminal chemosensory system in humans with high sensitivity and temporal resolution. The negative mucosal potential (NMP) allows researchers to investigate how trigeminal stimuli activate the trigeminal system on the level of the respiratory epithelium (Kobal 1985; Thürauf et al. 1991, 1993; Hummel, Schiessl, et al. 1996; Lötsch et al. 1997; Hummel et al. 2000; Wendler et al. 2001). In addition, investigators can examine trigeminal activation on a central level by means of trigeminal event-related potentials (tERPs), which are electroencephalographic responses generated in the cortex (Kobal et al. 1990; Hummel et al. 1994; Lötsch et al. 1997). Previously, we have used a parallel application of both techniques—which permits the localization of processes within the trigeminal pathway (Frasnelli and Hummel 2003; Dalton et al. 2006)—to investigate subjects born without a sense of smell (idiopathic congenital anosmia—ICA). ICA subjects had larger peripheral responses to intranasal trigeminal stimuli than healthy controls (Frasnelli et al. 2006). This finding led us to the development of a model where compensatory adaptive processes occur in the periphery of the trigeminal system of ICA subjects. However, we do not know if subjects with congenital anosmia are comparable with subjects with acquired anosmia (AA subjects). First, representing a minor subpopulation of anosmic subjects (approximately 1%), ICA subjects, born without a sense of smell, have a fundamentally different history than subjects with anosmia acquired during lifetime. Second, ICA subjects exhibit similar central electrophysiological responses as healthy controls, contrasting markedly the findings in AA subjects (Hummel, Barz, et al. 1996). Thus, it is unclear whether results from ICA subjects can be generalized to all subjects with olfactory dysfunction.

Therefore, here we aimed to perform a combined investigation of peripheral and central responses to trigeminal stimulation in subjects with acquired olfactory dysfunction and to compare their results with those of healthy controls. We hypothesized that AA subjects would exhibit larger peripheral and smaller central responses to irritants than healthy controls. Furthermore, the longitudinal design enabled us to examine the long-term impact of olfactory dysfunction (Hummel, Barz, et al. 1996; Hummel et al. 2003) and the effect of recovery in the olfactory system (Reden et al. 2006) on trigeminally mediated responses.

Materials and Methods

The study was conducted according to the Declaration of Helsinki on Biomedical Research Involving Human Subjects and was approved by the local Ethics Committee. During enrollment, subjects were given detailed information about all testing procedures. Written consent was obtained from all subjects prior to the study.

A total of 123 subjects participated in the study, divided in groups of subjects with olfactory dysfunction and healthy controls. The group of subjects with olfactory dysfunction (AA subjects) consisted of 50 women and 23 men. Olfactory dysfunction was caused either by a closed head trauma (posttraumatic, 16 males, 20 females, mean age [MA]: 45.7 [standard error of mean (SEM) 2.1] years) or by an upper respiratory tract infection (postinfectious, 7 males, 30 females, MA: 59.3 [1.5] years). Subjects were identified based on their medical history. Only subjects who provided clear anamnestic evidence that their olfactory dysfunction was caused by a trauma or a viral infection were included in the study. This included the occurrence of olfactory dysfunction directly/shortly after a trauma/viral infection and the absence of other factors known to cause olfactory dysfunction (e.g., nasal polyposis). Other than the olfactory dysfunction, subjects were in a good-health state as revealed by the otorhinolaryngological examination and a detailed history.

The duration of olfactory dysfunction had a median of 19 months (1–300 months). Subjects with olfactory dysfunction were compared with 50 healthy controls (26 females, 24 males, MA: 48.6 [2.5] years). The participants' age was distributed bimodally with a minimum at 42 years. Thus, participants were divided into age groups (young: <42 years; older: ≥42 years).

Subjects were investigated in 2 sessions, separated by at least 9 months and at most 15 months. All participating subjects were invited for the second session; all controls returned for the second session, whereas 12 of the subjects with olfactory dysfunction opted not to continue the experiment.

In each session, tests of both olfactory and trigeminal sensitivity were performed. Olfactory function was assessed by means of the “Sniffin' Sticks” test kit; trigeminal function was assessed by the NMP, tERP, intensity ratings of CO2 stimuli, and a lateralization task.

Test of Olfactory Function

All subjects underwent extensive tests of olfactory function. Olfactory function was measured with the “Sniffin' Sticks” olfactory test kit (Hummel et al. 1997; Kobal et al. 2000), where odorants are presented in commercially available felt-tip pens (Burghart, Wedel, Germany). The kit consists of separate tests for phenyl ethyl alcohol odor thresholds, odor discrimination, and identification. Results of the 3 subtests are presented as a composite threshold discrimination identification (TDI) score. Based on a multicenter investigation, subjects with a TDI score below 16 are considered functionally anosmic, with a score between 16 and 31 subjects are considered hyposmic, and with a score equal to or above 31 subjects are identified as normosmic (Kobal et al. 2000).

NMP Measurements

NMPs were measured as previously described (Frasnelli et al. 2006). In short, NMPs were recorded from one nostril by means of tubular electrodes (Teflon™ tubing filled with 1% Ringer agar containing a silver-chlorided silver wire) (Ottoson 1956). Placement of the electrode was controlled by nasal endoscopy (Leopold et al. 2000). For reference, a silver-chlorided silver electrode was attached to the bridge of the nose. The recording sites were selected according to accessibility, low signal-to-noise ratio, and/or absence of stimulus-induced artifacts (Hummel, Schiessl, et al. 1996). To keep the electrode in place, it was attached to clips mounted on a frame similar to lensless glasses.

In order to test whether at a given position a NMP could be recorded or not, CO2 stimuli of 500-ms duration and 60% v/v were applied after placing the electrode on the mucosa. Criteria for a reliable NMP were as follows: 1) response of the typical shape within the time range of NMP (Kobal 1985); 2) reproducible responses through 3 consecutive stimuli. If no reliable NMP could be recorded at a given position, the electrode was placed at another position. This procedure was repeated up to 6 times. If still no reliable NMP could be recorded, the procedure was repeated on another day. If no NMP could be recorded on the second day, the measurements were considered as “no reliable NMP recordable.”

Subjects received CO2 stimuli of 500-ms duration and concentrations of 40, 50, and 60% v/v. The interstimulus interval (ISI) was 40 s. Stimuli were presented to a randomly selected nostril by means of a computer-controlled air dilution olfactometer (OM 6B; Burghart). This stimulator allows for application of chemical stimuli with a very rapid onset and offset. Mechanical stimulation is avoided by embedding these stimuli in a constant flow of odorless, humidified air of controlled temperature (80% relative humidity; total flow 8 L/min; 36 °C) (Kobal 1981). Recordings were made with a DC amplifier (low pass 30 Hz; Toennies, Germany). After analog-to-digital conversion (sampling rate 62.5 Hz), records of 8192 ms were obtained. The pretrigger period was 500 ms. Using a video system, subjects were monitored for movements during the recording periods. Records that might have been contaminated by movements were excluded from further analysis. After averaging, the amplitude and latency of the negativity (peak N1) was measured.

The tERP Measurements

The tERPs were recorded following CO2 stimuli of 40, 50, and 60% v/v. Stimulus duration was 200 ms. Each stimulus concentration was presented 15 times. The ISI was 30 s.

This resulted in a duration of the session of 25 min. Stimuli were presented to the same nostril as in the NMP measurement. Subjects were seated comfortably in an air-conditioned room. They received white noise through headphones to mask switching clicks of the stimulation device. To stabilize vigilance, subjects performed a simple tracking task on a computer screen. Using a joystick, they had to keep a small square inside a larger one, which moved unpredictably (Hummel and Kobal 2002).

The tERPs were recorded at position Cz of the international 10-20 System. Eye movements were monitored via the Fp2 lead. The tERPs were referenced against linked earlobes (A1–A2). The sampling frequency was 250 Hz, and the pretrigger period was 500 ms with a recording time of 2048 ms per record (bandpass, 0.02–30 Hz). Recordings were filtered additionally off-line (low pass, 15 Hz). After records contaminated through motor artifacts or blink artifacts had been discarded, tERPs were averaged and analyzed for amplitudes and latencies of the major peaks N1 and P2.

Intensity Ratings

After each stimulus presentation during the tERP session, subjects rated stimulus intensity on a visual analog scale displayed on the computer screen. Using a joystick, subjects moved a marker on the scale. The right end of the scale indicated an “extremely strong” intensity (100%); the left end indicated that no stimulus had been perceived (0%) (Hummel and Kobal 2002). Data for each stimulus condition were averaged separately to obtain a mean rating.

Lateralization Task

Trigeminal sensitivity was quantified by the subjects' ability to lateralize stimuli presented to either the left or the right nostril. Based on previous studies, neat (99%) eucalyptol (Aldrich-Chemie, Steinheim, Germany) was used for the odor localization paradigm (Doty et al. 1978; Berg et al. 1998; Hummel et al. 2003; Frasnelli et al. 2006). The odor was presented to either one nostril in a high-density polyethylene squeeze bottle (total volume 250 mL) filled with 30 mL of the odorant; at the same time, an identical bottle filled with 30 mL of odorless propylene glycol was presented to the other nostril. The bottles had a pop-up spout that was placed into either nostril. A puff of approximately 15 mL air was delivered by pressing the 2 bottles at the same time by means of a hand-held squeezing device. The subjects held onto the spouts to prevent their movement inside the nostril, which accompanied squeezing of the bottles; movement of the spouts might produce mechanical irritation that, in turn, might interfere with the subject's ability to localize the odor. A total of 40 stimuli were applied to the blindfolded subjects/patients at an ISI of approximately 40 s; stimulation of the left or right nostril followed a pseudorandomized counterbalanced sequence. After each stimulus, subjects/patients were asked to identify the nostril where the odorant had been presented. The sum of correct identifications was used for further statistical analyses (Berg et al. 1998; Hummel et al. 2003). Testing required approximately 30min.

First and Second Session

AA subjects without recovery of olfactory function were expected to exhibit an increase of trigeminal sensitivity. In order to investigate the influence of a significant increase of olfactory function on trigeminal sensitivity, the group of the subjects with olfactory dysfunction was divided into 2 groups in the second session. In line with previous reports (Gudziol et al. 2006), an increase in the olfactory test result (TDI score) of at least 6 points was considered as a significant improvement. Subjects showing such recovery were compared with those who did not exhibit improvement (no recovery). In order to investigate the development of trigeminal sensitivity, the difference (Δ) between second and first session was calculated and used for statistical analyses.

Statistical Analysis

Statistical analyses were performed using SPSS 14.0 (SPSS Inc., Chicago, IL). Repeated measures analyses of variance were computed with variables of interest (between subject factors “age group” [young, old], “status” [olfactory dysfunction, control], and “sex” [female, male]; within subject factors “session” [first, second] and “concentration” [low, medium, high; where applicable]). For post hoc analyses, t-tests were calculated. The alpha level was set at 0.05. Means are indicated together with SEMs in square brackets.

Results

The posttraumatic subjects with olfactory dysfunction were significantly younger than both postinfectious subjects with olfactory dysfunction and controls (P < 0.03). However, no significant difference was detected between subjects anosmic after trauma and subjects anosmic after an infection with regard to any trigeminal measure. Therefore, for further analysis, subjects with olfactory dysfunction were grouped together and compared with healthy controls. We will, however, report the descriptive statistics for both groups of olfactory dysfunction and healthy controls (Table 1).

Table 1

Mean values and SEM for the most important measures

Measure (dimension) Condition Session Olfactory dysfunction Controls 
   Postviral SEM Posttraumatic SEM Healthy SEM 
Lateralization (score)  31.9 0.9 33.3 0.9 34.8 0.7 
 33.1 0.9 33.2 34.7 0.7 
Intensity ratings (units) 40% v/v CO2 20 16 17 
19 18 18 
50% v/v CO2 33 32 32 
26 27 25 
60% v/v CO2 45 46 49 
42 43 46 
NMP amplitude (μV) 40% v/v CO2 161 30 103 18 120 19 
148 24 111 31 100 15 
50% v/v CO2 308 60 156 30 158 30 
276 56 176 47 139 18 
60% v/v CO2 529 130 278 61 240 44 
312 64 291 75 184 21 
Event-related potential amplitude N1P2 ([μV) 40% v/v CO2 10.2 0.6 11.1 1.0 13.6 1.9 
11.7 0.9 11.6 1.2 15.2 1.0 
50% v/v CO2 16.4 1.2 16.4 1.2 19.3 1.3 
14.7 0.9 15.1 1.3 18.4 1.0 
60% v/v CO2 20.0 1.6 20.0 1.4 23.6 1.4 
20.6 2.2 20.8 1.4 22.3 1.2 
Smell function (TDI score)  14.9 0.8 12.4 0.6 35.3 0.6 
 19.1 1.1 14.3 1.0 34.1 0.6 
Measure (dimension) Condition Session Olfactory dysfunction Controls 
   Postviral SEM Posttraumatic SEM Healthy SEM 
Lateralization (score)  31.9 0.9 33.3 0.9 34.8 0.7 
 33.1 0.9 33.2 34.7 0.7 
Intensity ratings (units) 40% v/v CO2 20 16 17 
19 18 18 
50% v/v CO2 33 32 32 
26 27 25 
60% v/v CO2 45 46 49 
42 43 46 
NMP amplitude (μV) 40% v/v CO2 161 30 103 18 120 19 
148 24 111 31 100 15 
50% v/v CO2 308 60 156 30 158 30 
276 56 176 47 139 18 
60% v/v CO2 529 130 278 61 240 44 
312 64 291 75 184 21 
Event-related potential amplitude N1P2 ([μV) 40% v/v CO2 10.2 0.6 11.1 1.0 13.6 1.9 
11.7 0.9 11.6 1.2 15.2 1.0 
50% v/v CO2 16.4 1.2 16.4 1.2 19.3 1.3 
14.7 0.9 15.1 1.3 18.4 1.0 
60% v/v CO2 20.0 1.6 20.0 1.4 23.6 1.4 
20.6 2.2 20.8 1.4 22.3 1.2 
Smell function (TDI score)  14.9 0.8 12.4 0.6 35.3 0.6 
 19.1 1.1 14.3 1.0 34.1 0.6 

Note: Subjects with olfactory dysfunction are grouped depending on the etiology (postviral or posttraumatic).

Comparisons across All Subjects

Electrophysiological Measurements

Negative Mucosal Potential.

In the first session, a NMP could be recorded in 37 of 50 (74%) controls and 45 of 73 (61%) subjects with olfactory disorder. In the second session, the numbers were 37 of 50 (74%) and 46 of 58 (79%) for controls and subjects with olfactory loss, respectively. AA subjects were found to show higher levels of peripheral activation than controls (F1,49 = 4.8; P = 0.034). Post hoc tests revealed group differences to be significant at higher concentrations. The NMP amplitude was found to be significantly different for the 60% v/v stimulus in both sessions and for the 50% v/v stimulus in the second session (P < 0.05; see Fig. 1). No significant group difference was observed in the other conditions.

Figure 1.

Upper part: Amplitudes (means and SEM) of NMPs following stimuli of 40%, 50%, and 60% v/v CO2 in the first (left) and second (right) session for AA subjects (black bars) and controls (white bars). Lower part: Grand means of NMPs following stimuli of 60% v/v CO2. Graphs are displayed separately for first (left) and second session (right). Results for healthy subjects are indicated by gray lines and results of AA subjects are indicated by black lines. The black horizontal bar indicates the onset and duration of the CO2 stimulus.

Figure 1.

Upper part: Amplitudes (means and SEM) of NMPs following stimuli of 40%, 50%, and 60% v/v CO2 in the first (left) and second (right) session for AA subjects (black bars) and controls (white bars). Lower part: Grand means of NMPs following stimuli of 60% v/v CO2. Graphs are displayed separately for first (left) and second session (right). Results for healthy subjects are indicated by gray lines and results of AA subjects are indicated by black lines. The black horizontal bar indicates the onset and duration of the CO2 stimulus.

Trigeminal Event-Related Potential.

With regard to tERP measurements, subjects with olfactory dysfunction exhibited smaller base-to-peak amplitudes P2 and peak-to-peak amplitudes N1P2 when compared with controls (both F1,98 > 9.9; P < 0.003). Post hoc tests revealed significant group differences for P2 for each concentration and session (all P < 0.025) with the exception of the 50% v/v concentration on the first session and the 60% v/v concentration on the second session (see Fig. 2). With regard to N1P2, post hoc tests detected significant differences for each comparison except for 60% v/v on the second session (all P < 0.043).

Figure 2.

Upper part: Amplitudes P2 (means and SEM) of event-related potential (ERP) following stimuli of 40%, 50%, and 60% v/v CO2 in the first (left) and second (right) session for AA subjects (black bars) and controls (white bars). Lower part: Grand means of ERP following stimuli of 60% v/v CO2. Graphs are displayed separately for first (left) and second session (right). Results for healthy subjects are indicated by gray lines and results of AA subjects are indicated by black lines. The black horizontal bar indicates the onset and duration of the CO2 stimulus.

Figure 2.

Upper part: Amplitudes P2 (means and SEM) of event-related potential (ERP) following stimuli of 40%, 50%, and 60% v/v CO2 in the first (left) and second (right) session for AA subjects (black bars) and controls (white bars). Lower part: Grand means of ERP following stimuli of 60% v/v CO2. Graphs are displayed separately for first (left) and second session (right). Results for healthy subjects are indicated by gray lines and results of AA subjects are indicated by black lines. The black horizontal bar indicates the onset and duration of the CO2 stimulus.

Younger subjects were found to have larger amplitudes P2 and N1P2 than older subjects (both F1,98 > 9.2; P < 0.004). In addition, women were found to have larger amplitudes N1P2 than men (F1,98 = 6.2; P = 0.014). Furthermore, there was a significant interaction between “age group” and “status” for N1P2 (F1,98 = 6.8; P = 0.01). This indicated that differences in N1P2 were detected between subjects with olfactory dysfunction within the young participants, but not in the older group. The same interaction was detected for amplitude N1 (F1,98 = 4.38; P = 0.039), indicating that large differences for N1 appeared between young subjects with olfactory dysfunction and young controls; in older subjects, no such group difference was detected.

Psychophysical Measurements

Intensity Ratings.

With regard to intensity ratings, no main effect of status, sex, or age group could be detected.

Lateralization.

In the lateralization task, younger subjects had higher results than older ones (F1,103 = 7.6; P = 0.007). There was a tendency toward higher scores in controls than in subjects with olfactory dysfunction; it failed, however, to reach significance (F1,103 = 3.4; P = 0.068). On the first session, the difference between AA subjects and controls was significant (P = 0.023); on the second session, there was no significant difference between the 2 groups (see Fig. 3).

Figure 3.

Upper part: Intensity ratings (means, SEM) for 40%, 50%, and 60% v/v CO2 in the first (left) and second (right) session for AA subjects (black bars) and controls (white bars). Lower part: Results of the lateralization score ratings (means, SEM) in the first and second session for AA subjects (black bars) and controls (white bars). Results are given as absolute numbers, a score of 40 corresponds to 100% correct responses; chance level (50%) is at a score of 20.

Figure 3.

Upper part: Intensity ratings (means, SEM) for 40%, 50%, and 60% v/v CO2 in the first (left) and second (right) session for AA subjects (black bars) and controls (white bars). Lower part: Results of the lateralization score ratings (means, SEM) in the first and second session for AA subjects (black bars) and controls (white bars). Results are given as absolute numbers, a score of 40 corresponds to 100% correct responses; chance level (50%) is at a score of 20.

Comparisons within the Group of Subjects with Olfactory Dysfunction

Comparisons between First and Second Session for Subjects with Olfactory Dysfunction without Recovery

No difference between first and second session in any test of trigeminal sensitivity could be observed for those subjects who showed no increase in their olfactory function.

Comparisons of Subjects with Recovery of Olfactory Function and Subjects without Recovery of Olfactory Function

An increase of at least 6 points of the TDI score (recovery of olfactory function) was found for 38% and 12% of the subjects in the postinfectious and the posttraumatic group, respectively.

The duration of the olfactory dysfunction was not related to the improvement (ΔTDI) of olfactory function (r58 = −0.028). We further divided the anosmic subjects into 2 groups by using the median of the duration of olfactory dysfunction (19 months). The group with a shorter duration of olfactory loss showed, on average, an improvement of 3.4 (1.0) points in the TDI score; this number was 2.5 (0.9) for the subjects with a longer duration of olfactory dysfunction. The groups were not significantly different from each other.

There was a significant effect of “recovery” on ΔNMP (F1,28 = 12.6; P = 0.001). ΔNMP was larger in the recovery group than in the no recovery group following stimulation of each concentration (all P < 0.035; see Fig. 4), reflecting that NMPs became larger in the recovery group and smaller in the no recovery group. No other measure of trigeminal sensitivity revealed an effect of recovery.

Figure 4.

Amplitudes (means and SEM) of NMPs following stimuli of 40%, 50%, and 60% v/v CO2 in the first (left) and second (right) session for AA subjects who showed recovery of olfactory function at second session (black bars) and AA subjects who did not show recovery of olfactory function at second session (white bars).

Figure 4.

Amplitudes (means and SEM) of NMPs following stimuli of 40%, 50%, and 60% v/v CO2 in the first (left) and second (right) session for AA subjects who showed recovery of olfactory function at second session (black bars) and AA subjects who did not show recovery of olfactory function at second session (white bars).

Discussion

Subjects with olfactory dysfunction showed larger peripheral, but smaller central electrophysiological, responses than controls. With regard to psychophysical tests, subjects with olfactory dysfunction tended toward lower lateralization scores.

Central Measures

Subjects with olfactory dysfunction exhibited smaller tERP amplitudes than healthy controls. This is in line with earlier studies, where subjects with AA showed smaller central electrophysiological responses compared with controls (Hummel, Barz, et al. 1996). Similarly, they have been reported to exhibit lower scores in the lateralization task (Hummel et al. 2003) in line with the results in the first session of the present study.

These data indicate that, for full functionality, the trigeminal system relies on a functioning olfactory system (Hummel, Barz, et al. 1996; Kendal-Reed et al. 1998; Gudziol et al. 2001; Walker et al. 2001; Hummel et al. 2003; Frasnelli et al. 2006). We know that the olfactory system and the trigeminal system interact on central levels (Cain and Murphy 1980; Livermore et al. 1992). Further, trigeminal chemosensory stimulation and olfactory stimulation lead to considerable overlap in their activation patterns in the brain, for example, in the ventral insula, the middle frontal gyrus, and supplemental motor areas (Hummel et al. 2005). In addition, trigeminal stimulation produces activation in the orbitofrontal cortex, superior temporal gyrus, and the caudate nucleus (Hummel et al. 2005); these areas are involved in the processing of olfactory sensations (e.g., Jones-Gotman and Zatorre 1988; Zatorre et al. 1992; Kettenmann et al. 1996; Savic et al. 2000; Gottfried et al. 2002; for review, see Zald and Pardo 2000). Thus, data from the present study suggest that olfactory loss produces central nervous changes leading to a reduced responsiveness following trigeminal stimulation. To investigate this further and to localize the centers of interaction between olfactory and trigeminal systems, fMRI studies in anosmic subjects are currently underway.

Temporal Effects

In earlier studies, the duration of the olfactory dysfunction and both tERP amplitudes (Hummel, Barz, et al. 1996) and scores in the lateralization task (Hummel et al. 2003) were positively correlated. Based on cross-sectional data, the authors concluded that trigeminal sensitivity caused by an olfactory loss would improve over time. Further, ICA patients, who can be seen as subjects with the longest imaginable absence of olfactory function, showed a similar ability to lateralize eucalyptol as healthy controls, though they had a tendency toward lower scores (Frasnelli et al. 2006). The authors therefore speculated that with time, trigeminal sensitivity in subjects with acquired olfactory dysfunction could reach the level of controls. In line with earlier work (Hummel et al. 2003), in the present study, subjects with olfactory dysfunction also scored lower in the lateralization task in the first session than healthy controls. In the second session, however, both groups had similar scores. Thus, subjects with olfactory dysfunction reached the levels of normal controls over time. Although their lateralization score did not significantly increase, these data suggest that the effect of olfactory dysfunction on the ability to lateralize trigeminal stimulants tends to get less pronounced over time.

Temporal factors also affected the results of the tERP measurements. Group differences were most pronounced in the younger subjects group. Thus, older subjects with olfactory dysfunction and older controls appear to exhibit similar levels of central trigeminal activation. This, however, seems not to be due to regeneration in the olfactory dysfunction group because there was no change from the first to the second session. Moreover, it seems to be caused by the age-related decline of trigeminal sensitivity in healthy subjects (Frasnelli and Hummel 2003). Thus, creating additional distortion (olfactory loss) in an already dysfunctional system (age-related decline of trigeminal sensitivity) does not produce much reduction of overall function (trigeminal sensitivity). In other words, young subjects have more trigeminal sensitivity to lose, compared with elderly. Over time, as subjects get older, the difference between subjects with olfactory dysfunction and controls becomes less pronounced.

Peripheral Measures

On a peripheral level, other than on a central level, subjects with olfactory dysfunction responded stronger than controls. This is in line with an earlier report, where subjects with congenital anosmia exhibited larger NMP amplitudes in response to strong CO2 stimuli than controls (Frasnelli et al. 2006). As in the present study, this was most pronounced for stronger stimuli. Therefore, increased peripheral trigeminal chemosensory susceptibility seems to be a general feature of subjects without a functioning sense of smell because the trigeminal system's periphery responds comparably in both subjects with congenital anosmia and subjects with acquired olfactory dysfunction. The finding of higher peripheral trigeminal susceptibility in subjects with a loss of olfactory function (Frasnelli et al. 2006, present study) may lead to the hypothesis that a working olfactory system would inhibit the trigeminal system on peripheral levels. A similar mechanism occurs on central levels in the gustatory system (release of inhibition: Halpern and Nelson 1965). Here, input from the chorda tympani inhibits that of the glossopharyngeal nerve. Anesthesia or damage of the chorda tympani abolishes this inhibition that increases the input from areas innervated by the glossopharyngeal nerve. As a possible site of interaction between the olfactory and trigeminal systems, collaterals of the trigeminal nerve have been described that reenter the central nervous system and reach the olfactory bulb and terminate in its glomerular layer (Finger and Bottger 1993; Schaefer et al. 2002). We do not know in which direction information is transferred within these collaterals, but it is possible that they receive information from neurons of the olfactory bulb (Schaefer et al. 2002). Furthermore, in a recent study, Christie and Westbrook (2006) found mitral cells in the same glomerulus to excite each other laterally. The authors hypothesized that electrical coupling and spillover creates a lateral excitatory network within the glomerulus. This mechanism may also activate the trigeminal collaterals within the olfactory bulb and thus continuously stimulate trigeminal neurons in subjects with a normal sense of smell. Ongoing stimulation—due to chronic exposure to trigeminal agents—in turn, has been shown to reduce the overall and especially the peripheral responsiveness of the trigeminal chemosensory system, perhaps via a transient downregulation of receptors (Dalton et al. 2006). It is, however, not clear, whether the density or the responsiveness of trigeminal nerve endings changes. One could hypothesize that in a damaged olfactory system, no such excitatory network exists. Thus, trigeminal collaterals in the bulb are not excited continuously, and no reactive reduction of responsiveness in the trigeminal system would occur. In other words, missing inhibition via the trigeminal collaterals in the olfactory bulb would lead to a compensatory functional up regulation in the periphery of the trigeminal nerve in the case of olfactory loss. This would be followed by increased peripheral responsiveness, as reflected in enlarged NMP amplitudes. On central levels, however, this increased input would not sufficiently compensate for the missing amplification of the trigeminal signal, which seems to occur in healthy subjects (Fig. 5). This could be tested in animal models where we predict that both bulbectomy and/or transection of intrabulbar trigeminal collaterals would lead to higher peripheral responses to irritants.

Figure 5.

Proposed model of interaction between olfactory (gray arrows) and trigeminal (black arrows) systems. (A) Normal conditions. Peripheral responsiveness is decreased due to constant activation of intrabulbar trigeminal collaterals and consequent functional downregulation in the periphery of the trigeminal system. Functional integration of olfactory and trigeminal processes leads to augmented cortical signal. (B) Olfactory loss. Increased NMP due to top–down regulation; decreased event-related potential due to missing olfactory augmentation.

Figure 5.

Proposed model of interaction between olfactory (gray arrows) and trigeminal (black arrows) systems. (A) Normal conditions. Peripheral responsiveness is decreased due to constant activation of intrabulbar trigeminal collaterals and consequent functional downregulation in the periphery of the trigeminal system. Functional integration of olfactory and trigeminal processes leads to augmented cortical signal. (B) Olfactory loss. Increased NMP due to top–down regulation; decreased event-related potential due to missing olfactory augmentation.

AA subjects had larger NMPs than healthy controls. This is in agreement with an earlier study where congenitally anosmic subjects had larger NMPs than healthy controls (Frasnelli et al. 2006). Congenital anosmia represents a developmental disorder that is in contrast to AA, where olfactory loss is linked to a noxious event as trauma/viral infection. The similarity of the changes in at least the periphery of the trigeminal system supports the hypothesis that trauma/viral infection do not have a direct effect on the trigeminal system, but rather an indirect impact via the alterations of the olfactory system. This is further supported by the fact that, in contrast to the very thin olfactory nerve bundles, the trigeminal nerve is the thickest cranial nerve, which makes it less susceptible to a trauma. In addition, the olfactory nerve and the trigeminal nerve have very distinct anatomical pathways.

We could measure a NMP signal in 61–79% of our subjects. In other studies, similar numbers were reached. Scheibe et al. (2006) successfully recorded a NMP in 62% healthy subjects. Similarly, Frasnelli et al. (2006) report to have obtained a NMP in 44–84% of subjects. In the present study, the percentages of successful NMP recordings were similar across the subject groups; the fact that a NMP was not recordable in every subject should therefore not have impacted on the outcome of this study.

Further, we optimized stimulus delivery parameters for NMP and event-related potential paradigms, respectively. In the tERP measurements, both stimulus duration (tERP: 200 ms; NMP: 500 ms) and the ISI were shorter (tERP: 30 s; NMP: 40 s). We chose these parameters because they have been shown to be optimal stimuli for the respective measurements (Hummel and Kobal 2002; Frasnelli and Hummel 2003; Frasnelli et al., 2003). However, as tERP mainly depends on stimulus onset and stimulus concentration (Frasnelli et al., 2003), we do not expect the differences in stimulus characteristics to cause a major bias in the results (Frasnelli et al. 2006).

The Effect of Recovery of Olfactory Function

Reden et al. (2006) found that the sense of smell of 32% of the subjects with olfactory dysfunction following an infection of the upper respiratory tract recovered over the range of 1 year. In the group of subjects with posttraumatic olfactory dysfunction, only 10% exhibited improvement of their olfactory function. We found similar percentages, with 38% of the postinfectious group and 12% of the posttraumatic group showing a significant increase in their olfactory test score over the range of 9–15 months. With regard to trigeminal sensitivity, subjects with regenerated olfactory function had relatively larger NMP amplitudes than those without recovery. If the model proposed above applies, regained activity in the olfactory bulb via lateral excitation (Christie and Westbrook 2006) would add to the overall input to the trigeminal nerve, leading to an even higher peripheral responsiveness. However, over time, we expect NMP responses of subjects recovering from olfactory loss to decrease to the levels of normal controls.

Thus, data from the present study support the model of mixed sensory adaptation/compensation in the interactions between the olfactory and the trigeminal system (Frasnelli et al. 2006). In this dynamic model, healthy subjects exhibit a reduced primary trigeminal activation. On a central level, the trigeminal signal is amplified in subjects with a functioning olfactory system.

In conclusion, subjects with olfactory dysfunction exhibited larger peripheral, but smaller central electrophysiological, responses when compared with healthy controls. These data indicate mixed mechanisms of sensory adaptation/compensation to occur in the interactions between olfactory and the trigeminal system.

Research described in this article was supported by Philip Morris USA Inc. and Philip Morris International. Conflict of Interest: None declared.

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