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In our study, we explored the influence of blast method introduction of odorant on evoked response. Several reports about olfactory evoked potentials have pointed out that, although stable, constant responses were not easily elicited owing to problems associated with control of stimulus [1-3]. The study population consisted of seven male, anosmic Japanese nonsmokers, 37-48 years old. Next, we explored the response to the highest concentration of skatole E5 in anosmic patients.
Olfaction must be stimulated precisely at a certain time so as to calculate accurately the origin of olfactory evoked responses, which may not yet be confirmed.
Some discussion has centered around whether a response was evoked by the excitation of the trigeminal nerve or by the olfactory nerve [1,2].
If the responses are elicited by nasal trigeminal afferent stimulation or sound of the stimulation, positive response should be recognized even if the odorant is not introduced synchronously with the subject's inspiration, such as by the introduction of odorant at the end of inspiration or during t expiration or in anosmic patients. Our findings suggest that the evoked potential technique and olfactory electroencephalographic response as measured by our method could be beneficial in a clinical setting for assessing abnormal olfaction. Department of Otorhinolaryngology, National Center of Neurology and Psychiatry, Chiba, Japan. In Alzheimer's disease, a rapid adaptation was recognized by suprathreshold odorant stimulation.
Several reports have discussed olfactory evoked potentials [1-3], and our technique for olfactory stimulation synchronized with a subject's inspiration has been introduced [4-7]. An Electroencephalograph was recorded as upper negative from the central midline by an active Electrode using a monopolar recording.
Each subject was tested using skatole by an ascending method from an undetectable level to a clearly detectable level, with eight presentations in each concentration.
The study involved six cases of Alzheimer's disease in Japanese male nonsmokers (64-72 years old).
The positive waves were distinguishable as an evoked response by using the superimposition technique before averaging, and the positive response became obvious after averaging [4-7]. A reproducible and stable response as recorded by our technique is obtained by a slow respiration with a constant rhythm. Kobal and Hummel [2] reported that a change of peak latency depends on the odorant concentration presented. In healthy aged subjects tested, saturation was recorded after four to five averagings, as it was in young normal subjects [4,6,7]. Age-related changes occur in one's ability to perceive odors at both threshold and suprathreshold levels. Recently, the alterations in smeil function associated with age-related disease, such as Alzheimer's disease, became a current medical topic [9]. In the future, the assessment of olfactory function with chemosensory event-related potentials to olfactory stimulations should be applied to the discussion of aging in olfaction and for the early diagnosis of Alzheimer's disease. In normal patients, no detectable response was observed in the absence of an odor, and introduction of an odorant at the end of inspiration or during expiration did not result in any detectable positive response.
We introduced our technique of synchronizing olfactory stimulation with a patient's inspiration for the study of eventrelated potentials [4-7].
An electroencephalogram was recorded as upper negative from the central midline by an active electrode using a monopolar recording. Their olfactory abilities were determined to be anosmic by testing them with an olfactometer that was adopted by the Japanese Society of Otorhinolaryngology as a standard olfactory acuity test [8]. Response to skatole E5 in anosmic patients, in whom the highest concentration of skatole E5 did not result in any detectable positive response. Nonetheless, according to our data, in many cases at least, the peripheral system of the olfactory nerve path appears to be important, and adaptation may be influenced by peripheral and central factors.
However, we did not consider it necessary to distinguish one from the other, because both the trigeminal and olfactory nerves are usually affected by an odorant.
Furthermore, trigeminal stimulation or auditory stimulation must not show the saturation only by the averaging of four to five responses. This adaptation in Alzheimer's disease may be caused by dysfunction of the mechanism in adaptation of a quickly recovering central process. The highest concentration of skatole (E5) was reported as being detected clearly by all subjects. When the odorous stimulation was introduced at the end of inspiration or during the expiration, the evoked response was undetectable. Evoked response to E5 (9.75% skatole, the highest concentration of skatole) in a normal young subject.
The evoked response to the highest concentration of skatole (ES) in same subject as in Figure 6.


Introduction of an odorant stimulation at the end of inspiration or during expiration did not result in any detectable positive response. In their study, the shortening of peak latency was recorded by the much higher concentrated odorant stimulation. According to our results in healthy aged subjects, after eight averagings, the clear positive response was detectable.
Such changes are robust and include deficits in an absolute olfactory sensitivity, odor identification or recognition, suprathreshold odor discrimination, the perception of odor pleasantness, and odor memory [9]. Now, a relatively large body of literature addresses changes within the higher sectors of the olfactory system of persons with Alzheimer's disease. In anosmic patients, glacial acetic acid, which is thought to be a strong trigeminal stimulating agent, evoked a negative response without detection of odor. Here, we discuss the influence of extraneous stimuli associated with its introduction, such as nasal trigeminal afferent stimulations, auditory stimulations, or both.
Each patient was tested using odorant E5 (the highest concentration [9.75%] of skatole) and glacial acetic acid, which is thought to be a trigeminal stimulating agent.
The responses showed good reproducibility before averaging, and the positive responses were detectable at a certain peak latency by using a superimposition technique. For this reason, we opted to deliver the aerosol odorant to the olfactory fissure via pressurized air synchronized with a patient's inspiration [4,5].
To exclude specific influences, we tested the effect of inserting a nozzle and sudden blast of odorant (glacial acetic acid), thought to be a trigeminal stimulating agent, in anosmic patients. Thus, we are certain that positive responses are evoked by the odorant and not by some extraneous stimuli associated with its introduction, such as a reaction to the insertion of the stimulator, presentation of pressurized air, respiration, or the sound of the stimulation. Precise measurements of human olfactory evoked potentials for odorant stimuli synchronized with respirations.
Clinical olfactory test by evoked potentials to odorous stimuli, (in Japanese) Jpn J Taste Smell Res 2:100-108,1995.
Change of chemosensory event-related potentials to olfactory stimulations as a function of odorant concentrations. In this article, we discuss a change of olfactory evoked response in Alzheimer's disease that is considered to show olfactory disorder at its early stage. Skatole is one of the standard odorants supplied with the T & T olfactometer that has been adopted by the Japanese Society of Otorhinolaryngology (Fig. Odorant E is skatole, which is one of the standard odorants adopted by the Japanese Society of Otorhinolaryngology. Positive responses were rendered distinguishable by using superimposition technique before averaging. As shown here, a rapid adaptation was recognized more clearly on stimulation by the much higher concentrations of odorant.
Also, stimulating olfaction at a precise time is essential for discussing olfactory evoked response.
If slow and regular respiration is achieved, respiration will be repeated at a constant speed; consequently, the odorant air will be delivered to the olfactory fissure at a certain time in the same subject. The olfactory threshold measured by chemosensory event-related potentials to olfactory stimulations were E-1, E0, or E1 (in young healthy subjects [7], E-1 or E-2).
Furthermore, aging is associated with a greater susceptibility to olfactory adaptation and a slower rate of recovery from such adaptation [9]. The saturation phenomenon was related to the amplitude of the evoked potentials for repeated pulse stimuli and was found to be related to olfactory fatigue. Accordingly, the positively evoked response to odorant was thought to be elicited mainly by the odorant, not by the trigeminal stimulations or the auditory stimulations (or both). When the odorous stimulant was introduced at the end of inspiration or during expiration, no positive evoked response was detectable.
Furthermore, glacial acetic acid evoked a negative deflection without detection of odor (Fig.
That a reproducible and stable response is recorded by our technique can be explained as follows: Respiration is constant in the same patient.
Glacial acetic acid evoked a negative response without detection of odor, whereas a blast of skatole E5 produced no effect. Wave 8 represents eight times the total; thus, wave 4 to S showed the largest amplitude and wave 7 or 8 represented the clearest wave. Figure 7 shows the evoked response to the highest concentration of skatole (E5) in the same subject.
Therefore, we decided to deliver the aerosolized odorant by pressurized air synchronized with a subject's inspiration. No detectable response in the absence of the odor was noted, and glacial acetic acid, which is thought to be a trigeminal nerve-sensitive substance, evoked a negative response without detection of odor in anosmic patients [4-7].


Most studies report an accelerating decline in the ability to smell after the age of 60 [8] but, in our results, the age-related change in the olfactory threshold by the evoked response technique was small. At least two mechanisms are involved in adaptation: a quickly recovering central process and a slowly recovering peripheral process. A typical pattern of an evoked response to skatole E5 in a healthy young patient before averaging is shown in Figure 3. If slow and regular respiration is achieved, respiration will be repeated at a constant speed and, consequently, odorous air will be delivered to the olfactory fissure at a certain time in the same patient. Also, introduction of an odorant at the end of inspiration or during expiration did not result in any detectable positive response; in other words, the pressurized odorous air itself did not result in any positive response when an odorant was introduced but not synchronized with patient's inspiration. Just prior to the onset of the subject's inspiration, the tip of the stimulator was inserted atraumatically 1 cm into the nostril. The highest concentration of skatole is defined as E5 (9.75% skatole) and is diluted to a 10% solution in turn. Positive responses were detectable at a certain peak latency by using the superimposition technique and, after the averaging, a positive response became obvious (Fig. The highest concentration of skatole (ES) evoked a positive response, with a peak latency of between 68 and 84 msec in eight normal young subjects.
Also shown, a rapid adaptation was recognized more clearly on stimulation by the much higher concentrations of odorant.
Accordingly, the evoked response to skatole reported in this study was thought to be elicited mainly by odorant stimulation to the olfactory nerve. Age-related changes in the olfactory threshold are considered to be affected by the alteration in respiration, with a decrease of lung capacity caused by aging. The extent of adaptation appears to depend on both the strength and the duration of the preceding stimulation, and adaptation has a degree of specificity so as not to block the influx of new information.
Just prior to the onset of a patient's inspiration, the tip of the stimulator was atraumatically inserted 1 cm into the nostril. Positive responses were distinguishable as the evoked response at a certain peak latency by using the technique of superimposition before averaging (see Fig. E5 evoked a positive response with a peak latency of between 68 and 84 msec in eight normal young patients.
Hence, the age-related change in olfactory threshold was not very remarkable using our method of pressurized air delivering aerosolized odorant synchronized with a subject's inspiration. Adaptation is believed to be an important functional mechanism preventing overflow in the central parts of the system by neural activity resulting from stimuli that are either too strong or of long duration [10]. After the odorant was introduced, the tip of the stimulator was removed gently from the nostril. In this graph, the number 8 wave represents eight times the total; thus, wave 4 or 5 shows the largest amplitude, and wave 7 or 8 represents the clearest wave.
Rapid adaptation recognized in Alzheimer's disease may be caused by the dysfunction of the mechanism in adaptation of a quickly recovering central process.
Trigger pulses were generated by a hand switch attached at the stimulator just after the start of inspiration and were determined by visual inspection of the subject's abdominal movement at a rate of once in four slow, regular respirations.
E5 evoked a positive response, with a peak latency of between 68 and 84 msec in eight normal young subjects. An electric valve was used to introduce the odorant stimulations and was activated for 300 msec by a trigger pulse generated by a hand-operated switch attached at the stimulator. In this graph, wave 8 represents eight times the total, forming the basis for the following remarks.
After eight responses to a given concentration of odorant had been recorded, the results were averaged by a Neuropack Four Computer (Nihon Kohden Co., Tokyo, Japan).
Trigger pulses were generated just after the start of inspiration and were determined by visual inspection of the patient's abdominal movement at a rate of once in four slow, regular respirations. The largest amplitude of "main positive response" is recognized by averaging four or five responses, and clearest wave may tend to be shown by averaging of seven to eight responses. An Electrical valve was thus used to introduce odorant stimulations and was activated for 300 msec by a trigger pulse generated by the hand switch. That is, the saturation of evoked responses is considered to have been recognized by averaging four or five responses. After eight responses to a given concentration of odorant had been recorded, the results were averaged by a Neuropack 4 computer (NIHON KOHDRN Co., Japan) [4-7].
Skatole E5 evoked a positive response with a peak latency of between 68 and 84 msec in eight normal young patients [4,5].



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