1Department of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575; 2Cyclotron and Radioisotope Center, Tohoku University, Sendai 980-8578; 3Aoba Brain Imaging Research Center, Telecommunications Advancement Organization, Sendai 980-8575, Japan; 4C. and O. Vogt-Institute of Brain Research, Heinerich-Heine University, D-40001 Dusseldorf; 5Institute of Medicine, Research Center, D-52425 Julich; and 6Institute for Neuroanatomy, Heinerich-Heine University, D-40001 Dusseldorf, Germany
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ABSTRACT |
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Qureshy, Ahmad, Ryuta Kawashima, Muhammad Babar Imran, Motoaki Sugiura, Ryoi Goto, Ken Okada, Kentaro Inoue, Masatoshi Itoh, Thorsten Schormann, Karl Zilles, and Hiroshi Fukuda. Functional Mapping of Human Brain in Olfactory Processing: A PET Study. J. Neurophysiol. 84: 1656-1666, 2000. This study describes the functional anatomy of olfactory and visual naming and matching in humans, using positron emission tomography (PET). One baseline control task without olfactory or visual stimulation, one control task with simple olfactory and visual stimulation without cognition, one set of olfactory and visual naming tasks, and one set of olfactory and visual matching tasks were administered to eight normal volunteers. In the olfactory naming task (ON), odors from familiar items, associated with some verbal label, were to be named. Hence, it required long-term olfactory memory retrieval for stimulus recognition. The olfactory matching task (OM) involved differentiating a recently encoded unfamiliar odor from a sequentially presented group of unfamiliar odors. This required short-term olfactory memory retrieval for stimulus differentiation. The simple olfactory and visual stimulation resulted in activation of the left orbitofrontal region, the right piriform cortex, and the bilateral occipital cortex. During olfactory naming, activation was detected in the left cuneus, the right anterior cingulate gyrus, the left insula, and the cerebellum bilaterally. It appears that the effort to identify the origin of an odor involved semantic analysis and some degree of mental imagery. During olfactory matching, activation was observed in the left cuneus and the cerebellum bilaterally. This identified the brain areas activated during differentiation of one unlabeled odor from the others. In cross-task analysis, the region found to be specific for olfactory naming was the left cuneus. Our results show definite recruitment of the visual cortex in ON and OM tasks, most likely related to imagery component of these tasks. The cerebellar role in cognitive tasks has been recognized, but this is the first PET study that suggests that the human cerebellum may have a role in cognitive olfactory processing as well.
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INTRODUCTION |
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From an evolutionary point of view, the sense of smell is among the most primitive of senses. This is an important modality by which animals interact with the environment. It helps in identification of food; enhances pleasure and warns against impending danger. Through different neural networks, the sense of smell ultimately exerts various effects on the rest of the body systems. The sense of smell is considered to be well developed in animals. Unfortunately, it is the least understood of the human senses. The lack of adequate knowledge about this sense is probably because its expression is very subjective; moreover, it is less developed in humans. Yet we know that a whiff of perfume or aroma of food elicits memories of certain objects, incidents, and emotions. To date, due to the lack of an appropriate animal model, the detailed analysis of olfactory processing was not possible.
The anatomical circuitry of the olfactory system has been well defined.
The peripheral-most part of the olfactory system, coming directly in
contact with the environment, consists of olfactory cells located in
the superior part of each nostril. From here, the signals are
transmitted to the olfactory bulb. The olfactory tract connects the
olfactory bulb with the central olfactory pathways, which can be
divided into three different systems (Martin 1989). The
medial olfactory system is associated with the most basic olfactory
reflexes. The lateral olfactory system consists of the prepiriform and
piriform cortices as well as the cortical portion of the amygdaloid
nuclei. From here the signals are relayed to almost all portions of the
limbic system that generate emotions (Nolte 1993
). A
phylogenetically new pathway, through the thalamus and into the
orbitofrontal cortex, is thought to be associated with the conscious
analysis of odor (Guyton and Hall 1996
).
Animal studies have revealed that the lateral posterior part of
orbitofrontal cortex is responsive, among others, to olfactory stimuli
(Rolls and Baylis 1994). It was regarded to be involved in olfactory discrimination tasks (Schoenbaum et al.
1998
). Hippocampal damage results in severe memory loss as was
noted in a case of temporal lobe surgery by Penfield and Milner
(Rawlins 1999
). Animal studies revealed that spatial and
nonspatial data, olfactory memory inclusive (Eichenbaum
1998
; Wood et al. 1999
), are stored in the hippocampal neurons. The role of amygdala in encoding olfactory cues
has been noted, and it is presumed that the orbitofrontal cortex uses
this information for further selection and decision making
(Schoenbaum et al. 1999
). Olfaction studies in animals show only a part of the whole scenario.
Our knowledge of the olfactory system in humans was mainly restricted
to that gleaned from clinical and pathological studies (Jones-Gotman and Zatorre 1993; Wu et al.
1993
). In the previous decade, attempts were carried out to
investigate olfactory disorders using X-ray computed tomography (x-CT)
and magnetic resonance imaging (MRI). These techniques have proved
useful in the assessment of the peripheral causes of olfactory deficits
only (Li et al. 1994
). Brain perfusion single photon
emission tomographic (SPECT) imaging has also been used to identify the
areas involved in odor identification (Malaspina et al.
1998
). However, this technique lacks the dynamicity required
for detailed assessment of olfaction. Recent advanced functional
neuroimaging techniques, i.e., positron emission tomography (PET) and
functional magnetic resonance imaging (fMRI) have added to our
understanding of olfactory processing in the human brain (Levy
et al. 1997
; Zatorre et al. 1992
). PET has been
found to be superior for evaluation of central neural circuits involved
in the olfactory processing (Jolles et al. 1989
). The
main thrust of olfactory fMRI studies until now has been on smell
perception only (Levy et al. 1998a
,b
; Sobel et
al. 1997
; Yousem et al. 1997
). Recently, there
is a trend of studying olfactory cognition by fMRI (Sobel et al.
1998a
,b
, 1999
). However, the fMRI techniques
suffer from certain setbacks such as the presence of air sinuses near
the base of the brain, where the relevant anatomical structures are
located. The studies so far reported have mainly concentrated only on
the brain regions classically attributed to the olfactory system
(Levy et al. 1998a
; Sobel et al. 1998a
).
There are very few human PET studies conducted that can elucidate
olfactory processing. Simple odor presentation to subjects resulted in
significant activation of the piriform cortices bilaterally, the right
orbitofrontal cortex, the left inferomedial frontal cortex, and the
insula/claustrum (Zatorre et al. 1992). In their study,
the cognitive aspects involved in olfactory processing were not
investigated, but it was concluded that the piriform cortex is the
functional primary olfactory cortex and the right orbitofrontal cortex
is the secondary olfactory cortex because it showed lateralization. In
another human olfactory study, the amygdala and left orbitofrontal
cortex showed increased regional cerebral blood flow (rCBF) in response
to aversive odorants (Zald and Pardo 1997
). Recently,
attempts have been made to map the brain regions involved in the
semantic analysis of olfactory stimuli. It was seen that the piriform
and orbitofrontal areas were involved in olfactory recognition tasks,
but a paucity of temporal lobe activation was noted (Dade et al.
1998
). Additionally, the prefrontal cortex was involved in the
short-delay olfactory recognition task. In another study on the
comestibility judgment based on odors, the visual areas and frontal
cortex were found to be selectively activated, while the olfactory
familiarity task involved, among others, the orbitofrontal cortex and
frontal gyri (Royet et al. 1999
).
Therefore this study was designed to map out the brain regions that are involved in short- and long-term olfactory memories. In olfactory naming task (ON), using familiar odors of common edible items, the source of the odor was to be identified. According to our hypothesis, this would involve long-term recognition memory of odors, which a person has encountered at some time during his life. Most probably, such odors are verbalized or labeled, i.e., associated with an item or a name. In olfactory matching task (OM), an unfamiliar odor introduced only recently was to be identified among certain number of unfamiliar odors. As such odors were not associated with any certain item, this task involves brain regions that control our ability to differentiate one odor from another. In our opinion, these naming and matching tasks will activate brain regions where higher semantic processing of odor information occurs. Two baseline tasks, one with no olfactory stimulation and one with olfactory stimulation without cognition, were used to provide appropriate comparison with the main olfactory tasks. Additionally corresponding visual tasks were also included to see the effect of pure olfactory-related cognition. Thus our study is an attempt to clarify the mechanisms underlying human olfaction left unexplored by previous studies.
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METHODS |
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Subjects
Eight subjects participated in the study. All subjects were right-handed, male native Japanese volunteers selected among local university students who responded to our advertisement. Their ages ranged from 18 to 26 yr (20.7 ± 2.4 yr). Written informed consent was obtained from each subject after full technical explanation regarding the experiment and the potential risks involved, in accordance with the principles of the Declaration of Helsinki. The study was approved by the Medical Ethics Committee of the Institute of Development, Aging and Cancer (IDAC), Tohoku University.
The subjects were selected after checking for strong right-handedness
and normal color vision. Right-handedness was assessed by the Edinburgh
Handedness Inventory (Oldfield 1971). None of the
subjects had a history of rhinal surgery, head injury, hypertension, diabetes mellitus, any recent upper respiratory tract infection or
related medication, alcoholism, or excessive smoking. On the day of the
PET study, each subject was screened for nasal congestion. The subjects
were instructed to abstain from any oral intake for about 4 h
prior to the study and not to use perfume, mouthwash, etc. before the
study. All the studies were performed in the morning hours to avoid the
high variability in the odor threshold (Lötsch et al.
1997
).
All the subjects underwent MRI scanning using a 0.5 Tesla Signa Contour GE/YMS Co. system within a week of the PET study. A T1-weighted spoiled gradient echo (SPGR) sequence was used with repetition time (TR) = 40 ms, echo time (TE) = 7 ms, a flip angle of 30°, voxel size of 1 × 1 × 1.5 mm, and matrix size of 256 × 256 × 128. All had normal brain MRI scans.
PET scanner description and study procedure
The rCBF was determined by PET during the performance of six
tasks (2 control and 4 activation tasks) by all of the eight subjects.
PET was performed using a Shimadzu SET2400SW Scanner in
three-dimensional (3-D) mode with a scatter shield in place and septa
retracted (Fujiwara et al. 1997). This PET imaging
system has axial and transverse fields of view (FOV) of 200 and 590 mm, respectively. Prior to the emission scans, a transmission scan with an
external source of 68Ge
68Ga was obtained.
For each task, 200 MBq H215O was administered via a cannula introduced into the right antecubital vein. Data were obtained from the time the peak count rate was observed in the head region, and data were collected for the next 60 s. For radioactive decay, an interval of 10 min was allowed between two consecutive studies. The subjects had no earplugs and were positioned supine on the PET scanner. Light and auditory disturbances in the room were kept to a minimum.
Task procedures
A pre-PET psychophysical test was carried out on a separate
group of 15 subjects to rate the ability to identify, the familiarity, the hedonicity, and the intensity of 50 odors available. Irritating odors were excluded from the PET study (Yousem et al.
1997). Among the remaining odors, one group was found familiar
to the general population as these odors were relatively easy to name.
This group included odors of fruits, flowers, and edible items. The
other group consisted of odors that were unfamiliar, difficult to
identify and did not elicit any memories (Table
1). The visual stimuli were chosen among
the commonly available edible items, and their identification was not
difficult for the subjects (Fig.
1A, Table 2).
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In each PET task, eight pairs of olfactory and visual stimuli were
presented. Each pair consisted of an odor and an image presented for
6 s. The presentation and withdrawal of these stimuli were
simultaneous. This was followed by a 4 s interstimulus interval to
allow response from the subject. Based on our experience with pre-PET
psychophysical study, the duration of odor presentation and withdrawal
was tailored to avoid desensitization of olfactory fibers and to allow
time for recovery (Hummel et al. 1996). The adequacy of
the duration of odor exposure conformed with other studies
(Hummel et al. 1997
; Royet et al. 1999
).
Only nose breathing at the normal respiratory rate was allowed;
sniffing was not allowed since it is known to induce different
activation pattern in the brain (Sobel et al. 1998a
).
The subject was instructed to fix his gaze on a red cross presented
against a white background during the interstimulus interval. Each task
was started 20 s prior to the PET scan.
Odor was presented birhinally using a "sniffing stick"
(Hummel et al. 1997), which was held 2-3 cm in front of
the anterior nares of the subject. Colored two-dimensional visual
stimuli were presented on a head-mounted display, (HMD; Eyetrek
FMD011F, Olympus, Tokyo), with the signals relayed from a Macintosh
PowerBook G3 computer. The visual stimulus was presented binocularly.
The size of the picture was set within a 5° visual angle, so that the
subject did not have to move his eyes excessively to see the picture in its entire detail. The subjects were also asked to fix their gaze on
the red cross presented at the center of the field of view to keep the
eye movements to a minimum.
The subjects were subjected to dummy runs with HMD and mock odor presentations prior to the PET study. This was carried out to familiarize them thoroughly with the task design and requirements. Randomization of the tasks across the eight subjects was carried out.
Certain instructions were common to all the tasks including the following: "Breathe through your nose normally. Please do not breathe through your mouth or sniff. Keep your eyes fixed on the red cross at the center of the screen."
Control task 1 (C1) consisted of fixing the eyes on the red cross, with no cognition involved. No olfactory or other visual stimuli were presented. The subjects were instructed as follows: "Do not concentrate on anything in particular."
Control task 2 (C2) consisted of gazing at a scrambled picture (without any specific shape or design) and smelling of an unfamiliar odor. No cognition was involved in this task either. For this task instructions were as follows: "Do not think of anything particular and do not concentrate on the stimuli."
In the ON task, a familiar olfactory stimulus was presented simultaneously with a scrambled picture. These odors were those of common easily recognizable items (Table 1). The subject was instructed to concentrate on the olfactory stimulus only and to name or categorize it within the next 4 s or say "Pass" if he could not. In this task additional instructions were as follows: "Each odor will be presented for the same duration as that of a simultaneously presented scrambled picture. Concentrate on the odor only and try to visualize and name it. Identify the odor after the picture is withdrawn. If unable to answer, please say `Pass'."
In the visual naming task (VN), a picture of an object was presented simultaneously with an unfamiliar olfactory stimulus. The pictures of common edible objects were shown in this task (Fig. 1A, Table 2). The subject was required to concentrate on the picture only and name it within the next 4 s or say "Pass" if he could not. For this task, additional instructions were as follows: "Each picture will be presented simultaneously with an odor. Please concentrate on the picture only and try to name it. Name the picture after it is withdrawn. If unable to answer, please say `Pass'." The answer in the naming tasks was required to be a single word in the Japanese language.
In the OM task, an unfamiliar target odor was presented around 2 min before the actual task. The subject was required to "memorize" it. During the task, the target odor was presented thrice among eight cycles of olfactory-visual pairs. Attention to the simultaneously presented scrambled visual stimulus was not required. For this task additional instructions were as follows: "Each odor will be presented for the same duration as that of a simultaneously presented scrambled picture. Please concentrate on the odor only and try to match it with the target odor sampled a while ago. If the presented and target odors appear the same, say `Yes,' if different say `No,' and if undecided, say `Pass.' Answer when the picture is withdrawn."
In the visual matching task (VM), two scrambled target pictures were presented around 2 min before the actual task (Fig. 1B). The subject was required to memorize their characteristics (colors and design). During the task, the target visual stimuli were presented thrice among eight cycles of olfactory-visual pairs. Attention to the simultaneously presented olfactory stimulus was not required. For this task additional instructions were as follows: "Each picture will be simultaneously presented with an odor. Please concentrate on the picture only and try to match it with target pictures shown a while ago. If the presented and target pictures appear the same, say `Yes,' if different say `No,' and if undecided say `Pass.' Answer when the picture is withdrawn."
In the OM and VM tasks, the expected answer was "yes," "no," or
"pass" when the presented stimulus matched the target stimulus, did
not match the target stimulus, or when the subject could not decide,
respectively. These tasks were the same as previously described delayed
matching to sample tasks, requiring short-term memory retrieval
(Hummel et al. 1997), and were different from n-back
memory tasks (Carlson et al. 1998
; Smith and
Jonides 1999
). In our tasks, the subject was thoroughly
familiarized with the target stimulus prior to the actual PET study. In
the OM task, only one unfamiliar odor was introduced for short-term
memory task. In the pre-PET psychophysical tests it was observed that introducing more than one odor for short-term memory task greatly reduced the percentage correct responses from the subjects. It is known
that unlabeled odors are difficult to recognize as compared with those
associated with some verbal labels (Jones-Gotman and Zatorre
1993
). As the group 2 odors (Table 1) were presumed
not to be associated with any specific names, encoding was based purely on the characteristics of the odor itself.
The group 1 odors (Table 1) were exclusively used during ON task and not in other tasks. Similarly, the target odor used in OM task was not included in any other tasks. Due to the limited number of odors available, repetition of certain odors was unavoidable; however, care had been taken to do so only in the VN and VM tasks with different order of presentation.
Image processing and statistical analysis
The raw PET images were corrected for attenuation by using the
68Ge 68Ga transmission
data. Each subject's MRI was normalized to the standard brain MRI of
the Human Brain Atlas (HBA) (Roland et al. 1994) using
affine transformation of Automated Image Registration (AIR)
(Woods et al. 1998
), followed by application of the 3-D deformation field of the Elastic transformation (Schormann et al. 1996
). These parameters were subsequently used to transform each subject's PET image and MRI into the standard brain anatomy. Statistical Parametric Mapping (SPM96, Wellcome Department of Cognitive
Neurology, London) (Friston et al. 1995
) software was used for smoothing and statistical analyses. A 3-D Gaussian filter of
16 mm was used for image smoothing.
For the same-task analysis, the cognitive contrasts of respective tasks with control conditions were computed by SPM96 (Tables 5 and 6). The masking (P < 0.01) was applied with appropriate contrasts to elimate the voxels that did not survive corrections for multiple comparison (P < 0.05). For the cross-task analysis, the cognitive contrasts of respective olfactory and visual tasks were computed without masking, with the uncorrected extent threshold value set at P < 0.05 (Tables 5 and 6).
For each comparison, voxels with Z values > 3.09 (P < 0.001) were considered to denote regions of
significantly increased rCBF. Anatomical localization of the activated
areas was performed in relation to the mean reformatted MRI of all the
eight subjects, and expressed in the stereotactic space defined by
Talairach and Tournoux (1988).
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RESULTS |
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The performance of the subjects during each task is shown in Table 3. The one-way ANOVA test was performed to check the individual performance of the subjects across the tasks, and it was found to be significantly different (F = 7.2, P < 0.001). The ON task was the most difficult, in contrast to the VN, which was the easiest task to perform. In post hoc analysis, the mean subject performance, in terms of the number of correct responses, between these two tasks was significantly different (P = 0.002: paired t-test). The mean subject performance, however, was not significantly different between the OM and VM tasks (P = 0.66: paired t-test).
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The significantly activated areas based on the computed cognitive contrasts are tabulated in Tables 4-6.
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The contrast C2-C1 shows the brain regions involved in olfactory and visual perception, without any cognitive effort required. The areas found to be activated were the left middle frontal lobe, the left orbitofrontal lobe, the right piriform cortex, the right lateral occipital lobe, and the left cuneus (Table 4).
The contrast ON-C1 masked by contrast ON-C2 showed significant activation of the left cuneus, the right anterior cingulate gyrus, the left insula, the left anterolateral cerebellum, and the right posteromedial cerebellum (Table 5, Fig. 2). This analysis reveals the areas involved in olfactory naming.
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In the contrast OM-C1 masked with OM-C2, significant activation was determined in the left cuneus, the left anterolateral cerebellum, and the right posteromedial cerebellum (Table 5, Fig. 3). This analysis reveals the areas activated during olfactory matching.
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In the cross-task contrast analysis of ON-VN, significant activation was determined in the left cuneus (Table 5, Fig. 4). This analysis shows the specific area for olfactory naming. The contrast analysis of OM-VM did not reveal significant activation of any brain area.
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The contrast VN-C1 masked with VN-C2 revealed significant activation in the left orbitofrontal cortex, the left fusiform gyrus, and the right anterior cingulate gyrus (Table 6). The VN task is primarily an object naming task combined with passive odor perception. The above analysis reveals the areas involved in visual naming.
In the contrast VM-C1 masked with VM-C2, significant activation was determined in the right inferior temporal gyrus, the left cuneus, the left anterolateral cerebellum, and the right anterior cingulate gyrus (Table 6). This analysis shows the areas involved in the visual matching.
In the cross-task contrast analysis of VN-ON, significant activation was determined in the right inferior parietal lobule, the left precuneus, the right superior temporal gyrus, the bilateral middle occipital gyri, the left fusiform gyrus, and the left anterior cingulate gyrus (Table 6). This analysis shows the areas activated specifically during visual naming. The contrast analysis of VM-OM did not reveal significant activation in any brain area.
In comparison of results of olfactory and visual matching, it was noted that the occipital activation foci were greater in number during the visual task and also included a part of the lingual gyrus. The cerebellum was bilaterally activated during the olfactory task, while only the right cerebellum was activated during the visual matching. There was a common site of activation in the cerebellum during the olfactory and visual tasks, i.e., the anterolateral part of the cerebellum (Tables 5 and 6).
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DISCUSSION |
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This study highlighted the neural substrates for human olfactory perception, long- and short-term memories. The tasks were designed to analyze simple detection as well as a more comprehensive semantic analysis of the olfactory stimuli. It was noted that semantic analysis of the odors involved brain regions that were not part of the classically defined olfactory regions. The most significant finding of this study was that performing semantic analysis resulted in, among others, the recruitment of the occipital cortex and the cerebellum. Although the activation of classically described olfactory areas during simple olfactory stimulation such as the piriform and orbitofrontal cortices was observed, their role in semantic analysis may not be as important as previously reported.
Task design
In this study, the odors were categorized and selected by a
pre-PET psychophysical test. Those odors found to be familiar and
relatively easy to recognize by the general population were used in the
ON task. The ON task involved recognition of olfactory stimuli, using
long-term olfactory memory, and naming. This places a greater semantic
load on the brain areas involved. The option of saying "pass" was
provided to prevent the factor of guessing. The odors were dispensed
with sniffing sticks instead of squeeze bottles. It is known that
headspace-air in the bottle produces tactile sensations in the nasal
epithelium (Hummel et al. 1997), which was expected to
change the true activation patterns.
As shown in Table 3, the mean percentage of correct answers in the ON task is 50.1%. This is in contrast to the 89.3% correct response in the VN task. The difference between the two reflects the degree of task load inherent in the ON and VN tasks. The VN task is easier to perform and involves the naming of common edible items, while the ON task involves some degree of mental imagination as well. In the OM and VM tasks, the percentages of correct responses were 73.9 and 79%, respectively, which show that the semantic load for these tasks is nearly the same.
Our study involved exposure of each subject to at least six olfactory
stimuli for each task. The duration of each task was optimal for a
standard PET study, i.e., 60 s. The number of olfactory stimuli in
each task could have been more, but it was not adopted due to the
logistical problems of increasing the scan time and the ever increasing
olfactory fatigue. The olfactory stimuli were presented to the subjects
manually. Recently the automated synchronized delivery of olfactory
stimuli has been used for fMRI imaging (Sobel et al.
1997). Probably the use of an olfactometer for delivery of the
olfactory stimuli would have yielded better results.
Brain activations
The C2-C1 contrast analysis revealed these brain
regions that are involved in the olfactory and visual perception only.
It is important to note that no cognitive effort was required in this
task design. The significantly activated regions included the left
middle frontal cortex, the left orbitofrontal region, and the right
piriform cortex. The piriform cortex is among the primary receiving
sites of information from the olfactory bulb. Hence, it is considered
to be part of the primary olfactory cortex (Nolte 1993).
In a pioneer PET study on olfaction, Zatorre et al.
(1992)
have shown that simple presentation of odors resulted in
bilateral activation of the piriform cortex. There was activation of
the right orbitofrontal cortex as well, which was designated as the
secondary olfactory cortex by the authors. Their theory was that the
unilateral activation of orbitofrontal cortex indicated its functional
specialization and that probably it was involved in higher order
processing of odor. However, their study design apparently did not
involve any cognitive analysis of odors. In our study, the left
orbitofrontal cortex was also activated, but again, there was no
cognitive effort required by our subjects. The bilateral activation of
the occipital cortex in C2-C1 contrast is most likely due to
visual perception.
Olfactory tasks
As stated earlier, the main purpose of our study was to analyze the cognitive component of the olfactory processing in the human brain. To our knowledge, there are few PET studies reported that elaborate the neural circuits involved in olfactory semantic processing and cognition by the human brain. Moreover, the main thrust of fMRI studies has been on olfactory perception.
The brain areas activated during olfactory naming were located in the
left cuneus, the right anterior cingulate gyrus, the left insula, the
left anterolateral cerebellum, and the right posteromedial cerebellum
(Table 5, Fig. 2). During olfactory naming, the piriform and
orbitofrontal cortices were not activated. The orbitofrontal cortex was
considered to be the area where olfactory discrimination and
identification occurs (Zatorre and Jones-Gotman 1991).
However, our data do not support this concept. Our findings are
partially supported by another olfactory study in which comestibility judgment about odors did not evoke activation of the orbitofrontal cortex (Royet et al. 1999
).
In our study, another interesting finding was the left insular
activation. Bilateral insular activation during olfactory stimulation was also reported by Zatorre et al. (1992). Sobel
et al. (1997)
also reported the activation of the peri-insular
areas during olfactory tasks. This activation was observed even when
there was no conscious perception of odor by the subject (Sobel
et al. 1999
). In our study, it is noteworthy that insular
activity has been localized in the left side only during olfactory
naming. This activation was not noted during olfactory matching,
indicating that the insula has some role in olfactory naming. The
insula is also involved in gustatory tasks (Cerf et al.
1998
). The authors showed that the lower part of the insula
showed strong lateralization related to handedness. In our institute, a
previous PET study revealed significant left insular activation during
a taste discrimination task. In that study, Kinomura et al.
(1994)
suggested that taste and smell modalities converge in a
specific area in the insular cortex. In our study, breathing through
the mouth was strictly prohibited so that the taste buds were not
activated during any of the various tasks. The insular activation
observed in our olfactory study seems to lend support to their
hypothesis. The lateralization of the insula to the left side of the
brain in our study is probably because all our subjects were strongly
right-handed with left hemisphere dominance.
The area found specific for olfactory naming was the left cuneus (Table
5, Fig. 4). This provides further credence to the role of the occipital
lobe in olfactory memory. The activation of the left cuneus during
olfactory naming indicates that this task may involve some imagination
to ascertain the origin of the odor. It has been observed in many
cognitive neuroimaging studies that the visual cortex is involved in
mental imagery tasks (Kosslyn 1988; Royet et al.
1999
).
The brain regions involved in olfactory matching were the left cuneus and bilateral cerebellar regions (Table 5, Fig. 3). In this task, the odors presented were unfamiliar to the general population. It was assumed that because these odors do not carry any labels, i.e., these are not associated with any particular object, so these can be used for study of olfactory short-term memory. No area was specifically activated during olfactory matching as determined by cross-task analysis.
It is interesting to note that the left cuneus and bilateral cerebellar activation was noted during the OM and ON tasks. One factor common to both tasks was the requirement of cognitive effort for olfactory assessment. Although the C2-C1 contrast also involved olfactory perception, no cognitive effort was required. As mentioned above, no cerebellar activation was seen in C2-C1 contrast analysis.
In our study, the most significant finding was the presence of
cerebellar activation during the olfactory tasks. As reported by
Yousem et al. (1997), cerebellar activation during the
olfactory tasks has been noted in PET studies, but we were not able to
find any detailed published reports. There was one preliminary study report by Savic et al. (1999)
in which right cerebellar
activation was noted during the olfactory tasks, but its importance was
not discussed. In the most recent PET studies, Dade et al.
(1998)
and Royet et al. (1999)
have not found
nor discussed the cerebellar role in olfaction.
Our data reveal bilateral cerebellar activation during the olfactory
tasks and unilateral activation during the visual matching (Tables 5
and 6). The number of activated sites is greater, as shown both in
terms of voxel numbers and the cluster size, during the olfactory tasks
as compared with visual task. Over the last two centuries, the role of
the cerebellum had been mainly thought to be as a controller of posture
and movement. In fact, previous historical studies by Babinski and
Holmes et al. in the early part of the century suggested that the
cerebellum is not involved in any sort of cognitive function
(Thach 1996). Isolated cerebellar lesions lead to motor
deficits, but the cognitive and sensory domains remain unaffected. On
the other hand, many diseases that affect the CNS including the
cerebellum, e.g., Parkinsonism, Alzheimer's disease, and Multiple
sclerosis, are characterized by olfactory dysfunction as well
(Doty 1997
). Recent research has indicated that the
cerebellum also has a role in nonmotor and learning behavior
(Allen et al. 1997
). Cerebellar activations have been
noted in sensory acquisition and discrimination tasks (Gao et
al. 1996
; Lejeune et al. 1997
). The
neocerebellum, which includes the entire posterior cerebellar lobe,
except for the uvula and pyramid, was thought to control fine motor
voluntary movements. A review of literature on the cerebellar
involvement in cognitive tasks has revealed that the neocerebellum is
also activated during movement imagination (Jueptner et al.
1997
). Kim et al. (1999)
reported that the
cerebellum may play a role in recognition processes as well.
Recent fMRI studies have also shown the cerebellar activation during
olfactory tasks (Sobel et al. 1998b; Yousem et
al. 1997
). Sobel et al. (1998b)
concluded that
cerebellar activation of the anterior medial region resulted from
active sniffing, regardless of presence of odor, while posterolateral
activation occurred in the mere presence of odor.
In our study, sniffing was not allowed, and the subjects did not
perform any motor movements. In the C2-C1 analysis where no
cognition was involved, no cerebellar involvement was observed (Table
4). However, widespread activation of different parts of the cerebellum
was noted during the olfactory naming and matching analyses, i.e.,
where cognitive or semantic analysis was involved. The cognitive
analysis for olfactory naming and matching revealed activation foci in
the right posteromedial and the left anterolateral portions of the
cerebellum (Table 5, Figs. 2 and 3), while the visual matching
activated the left anterolateral part of the cerebellum (Table 6).
Among the ON, VN, and VM tasks, the common cognitive features are
semantic analysis and speech. It has been reported that the
phonological retrieval of names of visually presented stimuli
activates, among others, the midline cerebellum (Price and
Friston 1997). This cerebellar area is different from the one
activated in our study. In our data, the right posteromedial cerebellum
was also activated during visual naming, but this activation did not
survive the correction for multiple comparisons. Whereas Sobel
et al. (1998b)
concluded that the cerebellum is involved in
olfaction in humans, our results indicate that this involvement is at
the level of cognition as well. It is known that the cerebellum is
connected to the frontal, parietal, temporal, and occipital lobes via
the efferent fibers (Snell 1992
). Our data demonstrates that the cortico-cerebellar connections are also part of the extensive neural network used for odor memory.
There is evidence that the cerebellum has a certain role in memory
retrieval without requiring any sensory or motor input or output
(Andreasen et al. 1999). The authors were able to find robust bilateral cerebellar activations, more on the right side, during
silent recall of a consciously retrieved episodic memory. Contents of
the retrieved memory have not been mentioned in the paper. It was
interesting to note that the sites of the cerebellar activations during
our olfactory tasks were almost the same as those noted by
Andreasen et al. (1999)
. In our tasks, the retrieval of
short- and long-term memories was required, and it may be possible that
the neural circuits involved in the conscious episodic memory retrieval, as described by the authors, were also involved in our
tasks. The next point to be explored is whether these circuits are
specific for olfactory tasks only or a part of the general conscious
memory recall. This question, probably, cannot be answered based on our
data and needs to be further studied.
In our olfactory tasks, we could not find any activation of the medial
temporal region. This included the long- as well as short-term memory
storage. The role of the medial temporal lobe in a variety of memory
encoding and retrieval tasks had been discussed in detail
(Schacter and Wagner 1999; Schacter et al.
1999
; Zola et al. 2000
). A closer investigation
showed no olfactory memory study among them. The medial temporal lobe
contains structures that receive fibers directly from the olfactory
bulb (Squire and Zola 1996
). The odor and taste memory
has been studied by fMRI (Levy et al. 1999a
,b
). In these
studies, the actual stimulus or its imagination resulted in activation
of the temporal regions. These included the inferior temporal region as
well as parahippocampal areas. However, in these studies scanning was
limited to the temporal areas only, not covering the entire brain.
Attention was specifically focused on the temporal lobe based on a
priori hypothesis of its importance in memory retrieval (Levy et
al. 1997
). In the limited number of PET studies available in
literature, concerning the olfactory memory and semantic analysis, a
lack of temporal lobe activation was noted (Dade et al.
1998
; Royet et al. 1999
). Royet et al.
(1999)
have attributed this absence of temporal lobe activation to the lack of a true nonstimulated baseline in their task design. In
our task design a true nonstimulated baseline condition (the C1 task) was included for better comparison among the
activation tasks. Still, we were not able to find any temporal lobe
activation during the odor naming and matching tasks. On the other
hand, in visual naming and matching, medial temporal/parahippocampal activations with high Z values were noted, although these
did not survive the correction for multiple comparisons (data not shown).
No prefrontal cortex activation was detected in any of our olfactory or
visual analyses. The review of literature shows that prefrontal
activity is associated with memory encoding, recognition, memory
retrieval effort and memory retrieval (Henson et al.
1999). Klinberg and Roland (1998)
have shown a
lack of right prefrontal activity during nonverbal memory retrieval
task. They attributed it to the near-perfect performance (<5% error
rate, low reaction time ~0.9 s) of their subjects during the
retrieval task. In their opinion, the fast and accurate long-term
memory retrieval may result in prefrontal cortex nonactivation. In our
study, the cognitive effort required during the naming and matching
tasks was expected. We did not take note of the reaction time of our
subjects precisely, and the correct responses were quite low, specially
during the olfactory naming task. Therefore in our case, the absence of
prefrontal activity cannot be attributed to such automatic responses.
One plausible explanation may be the low frequency of stimuli
presentation in our task. Our study consisted of six stimuli
presentations for each task. A greater number of stimuli presentations
in each task would probably reveal the rCBF changes in the prefrontal area.
Activation of the anterior cingulate gyrus has been noted in many
olfaction-related studies (Kiyosawa et al. 1996;
Levy et al. 1998a
; Royet et al. 1999
;
Sobel et al. 1997
, 1999
). In a PET study
by Posner et al. (1988)
, the rCBF of the anterior
cingulate gyrus was found to increase when the number of targets were
increased. Various tasks, evoking anterior cingulate activation have a
few common characteristics: either those were willful, nonautomatic, attention-seeking, or unique (Lenz et al. 1998
;
Pardo et al. 1990
; Posner 1990
).
Murtha et al. (1996)
have shown that simple anticipation during a PET study causes an increase in the rCBF to the anterior cingulate cortex. In our study, an increase in the rCBF to the right
anterior cingulate gyrus is observed in olfactory- as well as
visual-stimulus analyses. This may be attributable to simple anticipation. The presence of the right anterior cingulate gyrus activation in all these analyses was expected as the tasks required a
high degree of attention.
Visual tasks
The main emphasis of our study was to map the olfactory processing regions. The visual processing tasks were included in the study design to provide a comparison with the olfactory studies. The results of the visual processing are discussed here briefly.
The brain areas activated during visual naming were in the left
orbitofrontal cortex, the left fusiform gyrus, and the right anterior
cingulate gyrus. The cross-task analysis of contrast VN-ON reveal the
areas specific for visual naming (Table 6). These significantly
activated areas include, among others, the left fusiform gyrus and the
bilateral middle occipital gyri. A number of functional imaging studies
have investigated the brain regions associated with visual naming tasks
(Gorno Tempini et al. 1998; Kim et al.
1999
; Kiyosawa et al. 1996
; Petersen et
al. 1990
; Vandenberghe et al. 1996
). Our results
of visual naming are congruent with those of previously reported studies.
In human studies the role of the fusiform gyrus in visual recognition
has been well established. Within the fusiform cortex, the area
specific for face perception has been outlined (Gorno Tempini et
al. 1998; Haxby et al. 1994
; Malaspina et
al. 1998
). The object recognition area lies immediately medial
to this face recognition area (Kanwisher et al. 1997
).
The orbitofrontal cortex has been designated as the secondary olfactory
cortex (Zatorre et al. 1992), but it appears to be a
multimodal area as its activation was seen in our visual naming analysis. Animal studies have shown that the orbitofrontal cortex receives input from the visual, gustatory, and olfactory modalities. It
contains uni- as well as bimodal neurons that respond to one or more
than one modality (Rolls and Baylis 1994
).
In our study, visual matching involved activation of the right inferior temporal gyrus, the left cuneus, the left anterolateral cerebellum, and the right anterior cingulate gyrus. No area specific for visual matching was found in cross-task analysis.
In our study, the visual matching stimuli were software generated
abstract pictures (Fig. 1B). The bilateral primary visual cortices and the surrounding areas were found to be active during long-term memory retrieval of colored nonfigurative pictures
(Klinberg and Roland 1998). The left inferotemporal
cortex has been found to be involved in visual pattern discrimination
tasks as well (Kawashima et al. 1998
; Kikuchi and
Iwai 1980
; Roland and Guylás 1995
).
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ACKNOWLEDGMENTS |
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This research was supported by Grants-in-Aid for Scientific Research on priority from the Japanese Ministry of Education, Science, Sports and Culture (1145204, 09207102), from Research for the Future from the Japan Society for the Promotion of Science (JSPS-RFTF 97L00202), and from Comprehensive Research on Aging and Health from the Ministry of Health and Welfare, Japan. The supporting grant for the ELAST Transformation Software development (SFB 194/A6) was provided by BIOTECH Program, EC.
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FOOTNOTES |
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Address for reprint requests: A. Qureshy, Dept. of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryomachi, Aoba Ku, Sendai 980-8575, Japan (E-mail: ahmad{at}idac.tohoku.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 4 October 1999; accepted in final form 17 April 2000.
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REFERENCES |
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