Abstract

Single odors are processed differently from odor mixtures in the cortex of rodents. We investigated whether single and binary odor mixtures activate different regions also in the human brain. We analyzed data from positron emission tomography scans using pyridine, citral, and 5 mixtures of pyridine and citral in proportions varying from 10/90 to 90/10, with 50/50 being the most impure. Comparing mixtures with single odorants gave activation in the left cingulate and right parietal and superior frontal cortices and bilateral activation in the anterior and lateral orbitofrontal cortices. We also found that brain activity in the lateral orbitofrontal cortex (OFC) increased with odorant impurity, whereas the anterior OFC was activated for binary odor mixtures and deactivated for single components. We conclude that binary odor mixtures and their individual components are processed differently by the human brain. The lateral portion of the OFC responds to mixture impurity in a graded fashion, whereas the anterior portion acts like an on–off detector of odor mixtures.

When moving around in the world, humans rarely encounter single odorants but rather encounter complex mixtures of odorants that sum up to a single odor percept. Though the last decade has brought considerable understanding about how single odors are processed by the brain, little research has explored olfactory mixtures. The aim of this study was to investigate whether there is a functional dissociation in the brain between perception of single odorants and odor mixtures, using H2O15 positron emission tomography (PET).

Most of our knowledge about odor mixture processing in the brain comes from research done in rodents. In rodents, the synthesis of odorants into a unified whole percept occurs in primary olfactory cortex, although some processing of binary odor mixtures occurs in olfactory sensory neurons (Duchamp-Viret et al. 2003). Conversely, nonprimary cortical areas are involved in the processing of complex auditory and visual stimuli in nonhuman primates (Hubel and Wiesel 1965; Gross et al. 1972; Brugge and Merzenich 1973). In a series of studies, neurons of nonprimary visual cortex responded poorly to simple visual stimuli (Hubel and Wiesel 1965; Gross et al. 1972), whereas extrastriate neurons responded preferentially to complex visual stimuli (Hegde and Van Essen 2000). Moreover, neurons in relevant nonprimary auditory cortex respond poorly to conventional pure tone stimuli and are predominantly activated by complex stimuli (Rauschecker 1998, 2005).

We used binary mixtures of isointense odorants in varying physical proportions to identify regions that could dissociate pure odorants from mixtures and different proportions of odorants within mixtures. Based on prior studies investigating mixtures in the olfactory bulb and in other sensory modalities, we predicted that there would be a difference in how the brain processes single and binary odor mixtures. In accordance with the recent findings by Zou and Buck (2006), we also predicted that binary odor mixtures would recruit a greater number of cortical regions than would their respective isointense components. Lastly, based on observations from other sensory modalities in humans, we predicted that some of the higher order olfactory regions, such as the orbitofrontal cortex (OFC), would respond preferentially to odor mixtures.

Materials and Methods

Subjects

Twelve right-handed subjects (6 women; mean age of 22.5 years) who all reported a normal sense of smell and absence of respiratory infections, active allergies, history of neurological or psychiatric conditions, or other conditions associated with an abnormal sense of smell participated. A brief olfactory test was used to confirm normal olfactory functioning prior to scanning. It consisted of 7 trials using suprathreshold concentrations of phenyl ethyl alcohol or distilled water in a 3-alternative, forced-choice paradigm. All subjects made at least 6 correct choices, constituting a binomial probability of less than 0.007. All subjects provided written informed consent, and the study was approved by the Research Ethics Board of the Montreal Neurological Institute (MNI).

Stimuli

The 2 single odorants used were citral (CIT; 13.7% v/v) and pyridine (PYR; 1.8% v/v), both diluted in propylene glycol (diluent and odors obtained from Sigma, Oakville, ON, Canada). In addition, we used the substitution–reciprocity method introduced by Olsson and Cain (Olsson and Cain 2000) to create 5 isointense binary mixtures of CIT and PYR with physical proportions varying from 10/90 to 90/10 of original concentrations, with a 50/50 mixture being the midpoint as shown in Fig 1. Based on piloting done in an independent sample (n = 20), both odorants and their mixtures were deemed to be isointense. In addition, the stimuli were linearly organized with respect to odor pleasantness ratings; CIT was perceived as pleasant, PYR as unpleasant, and the 50% v/v mixture fell in between with a neutral pleasantness rating. Double-distilled water was used as an odorless baseline condition (“baseline”) during scanning. All stimuli were presented birhinally in 60-mL amber bottles containing either 10 mL of a single odorant, binary odor mixture, or distilled water. During each scan, 2 bottles containing identical stimuli were used in alternation to maximize the accumulation of odor headspace.

Figure 1.

A) Illustration of single olfactory stimuli, their 5 isointense mixtures, and the baseline condition. CIT and PYR were mixed in varying physical proportion from 90% CIT and 10% PYR (90C/10P) to 10% CIT and 90% PYR (10C/90P). B) Schematic representation of protocol used during individual scanning conditions. Timing of events was identical in each of the 8 scanning conditions, with the only difference between them being that subjects smelled different odors (or water in the baseline). Each scan lasted 60 s, whereas the stimulation lasted 90 s, starting before and ending after the scan.

Figure 1.

A) Illustration of single olfactory stimuli, their 5 isointense mixtures, and the baseline condition. CIT and PYR were mixed in varying physical proportion from 90% CIT and 10% PYR (90C/10P) to 10% CIT and 90% PYR (10C/90P). B) Schematic representation of protocol used during individual scanning conditions. Timing of events was identical in each of the 8 scanning conditions, with the only difference between them being that subjects smelled different odors (or water in the baseline). Each scan lasted 60 s, whereas the stimulation lasted 90 s, starting before and ending after the scan.

Procedure

The 8 stimulus conditions were CIT, Mix 1 (10% PYR and 90% CIT), Mix 2 (30% PYR, 70% CIT), Mix 3 (50% PYR, 50% CIT), Mix 4 (70% PYR, 30% CIT), Mix 5 (90% PYR, 10% CIT), PYR, and baseline (Fig. 1A). These stimuli were presented independently in 1 scan each, rendering a total of 8 scans.

Each 60-s PET scan consisted of passive smelling of one of the 8 stimuli, which were presented in a randomized order. During each scan, subjects focused their gaze on a designated mark directly above their heads. They were asked to breathe normally and consistently throughout all scans, regardless of the presented stimulus, and to inhale when they saw the bottle approaching in their peripheral vision. The 90-s stimulus sequence (20 s prior to the start of the scan to 10 s after its termination) consisted of 9 trials; odor was presented for 2 s, followed by an ISI of 8 s (Fig 1B). Immediately prior to the baseline scan, subjects were informed that in the next scan they would be given an odorless “blank stimulus.” This was done to prevent active search behaviors known to recruit olfactory regions (Porter et al. 2005). Following each scan, subjects rated the stimulus for perceived pleasantness and intensity using an 11-point visual analog scale ranging from 0 to 10. The verbal anchors on the scales were “unperceivable” and “extremely intense” for the intensity scale and “extremely unpleasant” and “extremely pleasant” for the pleasantness scale.

PET Scanning

The distribution of regional cerebral blood flow (rCBF) was measured with a Siemens Exact HR+ tomograph operating in 3-dimensional (3-D) acquisition mode. T1-weighted structural magnetic resonance imaging (MRI) scans (160 of 1-mm slices) were obtained for each subject with 1.5-T Siemens Sonata MRI Scanner (Siemens, Erlangen, Germany) to provide anatomical detail. rCBF images were reconstructed using a 14-mm Hanning filter, normalized for differences in global CBF, coregistered with the individual MRI data and transformed into the MNI-standardized proportional stereotaxic space (ICBM305), which is based on the Talairach and Tournoux atlas (Talairach and Tournoux 1988).

Data Analyses

PET images were averaged across subjects for each condition, and a mean change image volume was obtained for each comparison; this volume was then converted to a t statistic map, and the significance of focal CBF changes was assessed by a method based on a 3-D Gaussian random-field theory as described in detail elsewhere (Worsley et al. 1992; Worsley et al. 1996). We used 3-D Gaussian random-field theory to calculate the P value for the global maximum; the P value is proportional to the volume searched divided by the product of the full widths at half maximum of the image reconstruction process or number of resolution elements (Worsley et al. 1992). Significant changes were established using 2 threshold values: for the exploratory search of the gray matter volume of approximately 500 cc (182 resolution elements or roughly the volume of the cortex scanned), the threshold was set at t = 3.52, corresponding to an uncorrected probability of P < 0.0002 (Worsley et al. 1992). For the directed search within a priori selected regions, volumes of interest (VOIs) previously activated by odor perception (piriform cortex and OFC), the threshold was set at t = 3.00, representing an uncorrected P value of < 0.004.

Differences in subjects’ perception of the 7 olfactory stimuli were assessed using repeated-measures analyses of variance (ANOVA) performed separately for intensity and for pleasantness, with odor stimulus as a within-subject factor.

Results

Behavioral Data

There were no significant differences in subjects’ perceived intensity of the odor stimuli, F1,11 = 1.17, P > 0.05. In contrast, subjects did rate the pleasantness of the 7 olfactory stimuli differently, F1,11 = 15.60, P < 0.05. CIT was rated as most pleasant, PYR as most unpleasant, and the 50/50 mixture as neutral on an 11-point scale (Fig. 2).

Figure 2.

Results from ratings obtained immediately after each scan. A) Perceived intensity and B) perceived pleasantness ratings obtained using 11-point visual analog scale. Error bars denote standard error of the mean.

Figure 2.

Results from ratings obtained immediately after each scan. A) Perceived intensity and B) perceived pleasantness ratings obtained using 11-point visual analog scale. Error bars denote standard error of the mean.

PET Data

rCBF Increases Specific to Binary Odor Mixtures

To determine whether adding 2 single components (i.e., creating a mixture) would result in activation of anatomical regions not responsive to the single components, we performed a direct subtraction of mixtures minus single odorants. We found increased activation in bilateral anterior and lateral OFC, left middle cingulate, right parietal cortex, and right superior frontal gyrus (Table 1; Fig. 3). The contrast single odorants minus mixtures did not yield any significant activation.

Table 1

Significant peaks of increased rCBF specific to perception of odor mixtures

Mixtures versus single odorants
 
Areas Left
 
Right
 
 x y z t value x y z t value 
Secondary olfactory cortical region         
Anterior orbitfrontal cortex −20 63 −14 3.84 30 57 −15 3.62 
Lateral OFC −39 39 −15 3.43 41 37 −16 2.96a 
Frontal cortex         
Middle cingulate −16 −9 44 4.17     
Superior frontal gyrus     23 37 41 3.91 
Parietal cortex         
Angular gyrus     34 −54 47 4.23 
Mixtures versus single odorants
 
Areas Left
 
Right
 
 x y z t value x y z t value 
Secondary olfactory cortical region         
Anterior orbitfrontal cortex −20 63 −14 3.84 30 57 −15 3.62 
Lateral OFC −39 39 −15 3.43 41 37 −16 2.96a 
Frontal cortex         
Middle cingulate −16 −9 44 4.17     
Superior frontal gyrus     23 37 41 3.91 
Parietal cortex         
Angular gyrus     34 −54 47 4.23 
a

Denotes below significance in a predicted region.

Figure 3.

Areas of rCBF increase demonstrated by the mixtures minus single odorants subtraction. Increased activations in the bilateral anterior OFC (aOFC) and lateral OFC (lOFC) are shown on the horizontal section at z = −16, and the lOFC is shown in the coronal section at y = 39; left superior frontal gyrus (SFG) and angular gyrus (ANG) in the parietal cortex and right middle cingulate cortex (mCING) are shown on the horizontal section at z = 42.

Figure 3.

Areas of rCBF increase demonstrated by the mixtures minus single odorants subtraction. Increased activations in the bilateral anterior OFC (aOFC) and lateral OFC (lOFC) are shown on the horizontal section at z = −16, and the lOFC is shown in the coronal section at y = 39; left superior frontal gyrus (SFG) and angular gyrus (ANG) in the parietal cortex and right middle cingulate cortex (mCING) are shown on the horizontal section at z = 42.

Using VOI, we extracted rCBF in 3 regions bilaterally to determine whether any of these regions would respond preferentially to varying proportions of the mixture: the regions were anterior OFC, lateral OFC, and the piriform cortex. VOIs were centered on the Talairach coordinates indicating peak activations. Mean rCBF values were extracted using a 6-mm sphere search volume in the 2 OFC regions and a 4-mm search volume in the piriform, given that it is a smaller anatomical region. VOI analyses done in the left and right lateral OFC indicated maximal rCBF for the 50/50 mixture and the least amount of activation in response to the pure odorants (Fig. 4A). Curvilinear regression analyses on the rCBF in both the left, r = 0.85, P < 0.05, and the right, r = 0.76, P < 0.05, lateral OFC were significant. In contrast, the rCBF response in the anterior OFC did not respond in a curvilinear fashion (Fig. 4B). Increased rCBF in that region was associated with smelling binary mixtures regardless of proportion of components in each mixture, whereas stimulation with either CIT or PYR resulted in a decrease in rCBF compared with baseline, as indicated by one-way ANOVAs for the right (F2,22 = 4.27, P < 0.05) and left (F2,22 = 5.03, P < 0.05) anterior OFC. Lastly, one-way ANOVAs of the VOI values in the left (F2,22 = 0.84, P> 0.05) and right (F2,22 = 1.41, P > 0.05) piriform cortex showed that there was no significant difference among activations elicited by the olfactory stimuli but that piriform cortex responded more to odors than to water (Fig. 4C).

Figure 4.

A) rCBF values extracted from the left and right lateral OFC show increased activation as odor impurity increases. B) rCBF values extracted from the left and right anterior OFC show increased activation in response to odor mixtures but not to single odorants. C) rCBF values extracted from the left and right piriform cortex show an equal increase in activation in response to all odor stimuli. All rCBF changes were calculated as a mean percent change from baseline.

Figure 4.

A) rCBF values extracted from the left and right lateral OFC show increased activation as odor impurity increases. B) rCBF values extracted from the left and right anterior OFC show increased activation in response to odor mixtures but not to single odorants. C) rCBF values extracted from the left and right piriform cortex show an equal increase in activation in response to all odor stimuli. All rCBF changes were calculated as a mean percent change from baseline.

To address the possibility that the 2 odors used in this study might produce opposing rCBF effects at specific brain sites, we compared mixtures minus CIT and mixtures minus PYR. The comparison mixtures minus CIT revealed increases in rCBF bilaterally in the anterior and lateral OFC and in the right angular gyrus (Table 2). The comparison mixtures minus PYR revealed identical significant activations (Table 2).

Table 2

Significant peaks of increased rCBF in the subtraction involving perception of binary mixtures and their single components CIT and PYR

Mixtures versus CIT
 
Areas Left
 
Right
 
 x y z t value x y z t value 
Secondary olfactory cortical region         
Anterior orbitfrontal cortex −21 65 −14 3.63 33 67 −12 3.34 
Lateral OFC 47 41 −15 3.54 39 41 −17 3.16 
Parietal cortex         
Angular gyrus     41 −45 55 3.53 
Mixtures versus PYR         
Secondary olfactory cortical region         
Anterior orbitfrontal cortex −20 63 −15 3.69 18 63 −16 3.21 
Lateral OFC −46 43 −13 3.56 40 42 −19 3.03 
Parietal cortex         
Angular gyrus     43 −45 56 3.77 
Mixtures versus CIT
 
Areas Left
 
Right
 
 x y z t value x y z t value 
Secondary olfactory cortical region         
Anterior orbitfrontal cortex −21 65 −14 3.63 33 67 −12 3.34 
Lateral OFC 47 41 −15 3.54 39 41 −17 3.16 
Parietal cortex         
Angular gyrus     41 −45 55 3.53 
Mixtures versus PYR         
Secondary olfactory cortical region         
Anterior orbitfrontal cortex −20 63 −15 3.69 18 63 −16 3.21 
Lateral OFC −46 43 −13 3.56 40 42 −19 3.03 
Parietal cortex         
Angular gyrus     43 −45 56 3.77 

A contrast between mixtures and (odorless) baseline was done in order to elucidate the neural correlates of binary odor mixtures. The comparison revealed activations in the left piriform cortex, left medial OFC, and bilateral posterior OFC (Table 3). In addition, activation in the left anterior cingulate cortex was observed.

Table 3

Significant peaks of increased rCBF in the subtraction involving perception of binary odor mixtures and baseline

Mixtures minus baseline
 
Areas Left
 
Right
 
 x y z t value x y z t value 
Primary olfactory cortical region         
Piriform cortex −13 −2 −12 3.16     
Secondary olfactory cortical regions         
Medial OFC     29 −10 3.32 
Posterior OFC −10 19 −11 3.07     
Posterior OFC     18 −16 3.01 
Frontal cortex         
Anterior cingulate     11 36 3.59 
Mixtures minus baseline
 
Areas Left
 
Right
 
 x y z t value x y z t value 
Primary olfactory cortical region         
Piriform cortex −13 −2 −12 3.16     
Secondary olfactory cortical regions         
Medial OFC     29 −10 3.32 
Posterior OFC −10 19 −11 3.07     
Posterior OFC     18 −16 3.01 
Frontal cortex         
Anterior cingulate     11 36 3.59 

rCBF Increases Associated with Single Odorants

The contrast between single odorants and the (odorless) baseline also revealed activations in traditional olfactory regions (Zatorre et al. 1992; Zatorre and Jones-Gotman 2000): the left piriform cortex and bilateral medial OFC (Table 4). We also found a peak of activation in the left anterior cingulate cortex.

Table 4

Significant peaks of increased rCBF in the subtraction involving perception of single odorants

Single odorants minus baseline
 
Areas Left
 
Right
 
 x y z t value x y z t value 
Primary olfactory cortical region         
Piriform cortex −12 −9 3.3     
Secondary olfactory cortical region         
Medial OFC     30 −18 3.52 
Frontal cortex         
Inferior frontal gyrus −22 32 −6 3.72     
Anterior cingulate     34 −2 3.58 
Parietal cortex         
Superior parietal lobule     16 −84 48 3.68 
Single odorants minus baseline
 
Areas Left
 
Right
 
 x y z t value x y z t value 
Primary olfactory cortical region         
Piriform cortex −12 −9 3.3     
Secondary olfactory cortical region         
Medial OFC     30 −18 3.52 
Frontal cortex         
Inferior frontal gyrus −22 32 −6 3.72     
Anterior cingulate     34 −2 3.58 
Parietal cortex         
Superior parietal lobule     16 −84 48 3.68 

Discussion

We have shown that single odorants and binary odor mixtures are processed differently by the human brain (Fig. 3). Although we found that both types of odors activate primary and secondary olfactory regions, the direct contrast of interest between mixtures and single odorants revealed activation in the middle cingulate cortex, superior frontal gyrus, angular gyrus, and most interestingly lateral and anterior regions of the OFC. We also showed that the latter 2 regions respond in a preferential manner to the binary odor mixtures. By extracting rCBF from the lateral and anterior OFC, we found that these 2 regions responded to mixtures in different ways. Specifically, activation in the lateral OFC increased with increasing odorant impurity, as indicated by an inversed U-shaped function peaking at the most impure mixture (50/50). On the other hand, the anterior region of the OFC was equally activated by all binary odor mixtures and deactivated by the single odors. Neither of these patterns was found in the piriform cortex, which was equally responsive to all odor stimuli.

Activations in the lateral OFC have been most commonly reported in studies that used unpleasant single odorants (Royet et al. 2000; Gottfried et al. 2002; Anderson et al. 2003; Rolls et al. 2003) or unpleasant mixtures (Zald and Pardo 1997), and recently, this region was reported to be activated by the pleasant aspects of a mixture composed of pleasant and unpleasant odors (Grabenhorst et al. 2007). However, our findings in the lateral OFC are clearly independent of hedonicity. Both the activation pattern (maximum rCBF change for the neutral odor) and its nonspecific character (the neutral, pleasant and unpleasant mixtures yielded a similar cluster location) demonstrate this independence. Notably, the neural correlates of odor impurity have never been studied before, and here, we show that the lateral OFC responds selectively to this property of odor mixtures. Strikingly, this region responds differentially to relatively small differences in odor impurity.

Like the lateral portion of the OFC, the anterior OFC is also preferentially activated by binary odor mixtures compared with their single components. To date, only 2 studies investigating the neural correlates of olfaction (Sobel et al. 2000; Kareken et al. 2003) have reported activation in the anterior OFC in response to single olfactory stimuli. The paucity of reported activations in the OFC may be at least partially explained by the widespread use of functional MRI, which limits one's ability to find activation in the OFC and particularly in the anterior OFC due to a low signal-to-noise ratio (LaBar et al. 2001). An additional explanation may be the limited use of odor mixtures in neuroimaging studies to date. We demonstrate that the anterior OFC, like the lateral OFC, has an important role in processing odor mixtures. We found that the anterior OFC acts as a sort of on–off switch: this region is similarly activated in response to all odor mixtures and deactivated in response to single odorants. Further, by comparing the mixtures with CIT and PYR independently, we showed that our main findings, namely the anterior and lateral OFC activations, were not being driven specifically by either of the 2 individual components.

Interestingly, our current findings are consistent with research on other sensory modalities in nonhuman primates where higher order cortex, unlike primary cortex, responds preferentially to complex compared with simpler stimuli (Kobatake and Tanaka 1994; Rauschecker et al. 1995). Further, neurophysiological data acquired in monkeys (Takagi 1986; Tanabe, Iino, et al. 1975; Tanabe, Yarita, et al. 1975) showed that many, if not the majority of odor-responsive cells in the OFC had far greater stimulus selectivity than cells in the piriform cortex and the olfactory bulb. The lack of preferential activation to mixtures in the human piriform cortex is consistent with recent findings suggesting that the central processing by rodents and humans may differ based on different cellular and synaptic organization of the bulb (Maresh and Greer 2007).

Conclusions

We conclude that binary odor mixtures and their individual components are processed differently by the human brain. First, more brain regions are recruited in response to mixtures than to their single components. Second, 2 regions of the OFC play a distinct role in mixture processing: the lateral portion of the OFC responds to mixture impurity in a graded fashion whereas the anterior portion acts like an on–off detector of odor mixtures. The finding that mixtures are treated differently by the brain than are single components, independent of hedonicity or intensity, demonstrates that the study of odor mixtures has a great potential for furthering the understanding of human olfactory processing.

Funding

Canadian Institutes of Health Research (MOP-57846 to M.J.-G.); Swedish Research Council (VR 421-2005-1779 to M.J.O.); Swedish Research Council (postdoctoral research grant VR 2005-960 to J.N.L.).

We would like to thank the staff of the PET and cyclotron unit at the MNI for their technical assistance. J.N.L. is now at the Monell Chemical Senses Center, Philadelphia. Conflict of Interest: None declared.

References

Anderson
AK
Christoff
K
Stappen
I
Panitz
D
Ghahremani
DG
Glover
G
Gabrieli
JD
Sobel
N
Dissociated neural representations of intensity and valence in human olfaction
Nature neuroscience
 , 
2003
, vol. 
6
 (pg. 
196
-
202
)
Brugge
JF
Merzenich
MM
Responses of neurons in auditory cortex of the macaque monkey to monaural and binaural stimulation
J Neurophysiol
 , 
1973
, vol. 
36
 (pg. 
1138
-
1158
)
Duchamp-Viret
P
Duchamp
A
Chaput
MA
Single olfactory sensory neurons simultaneously integrate the components of an odour mixture
Eur J Neurosci
 , 
2003
, vol. 
18
 (pg. 
2690
-
2696
)
Gottfried
JA
O'Doherty
J
Dolan
RJ
Appetitive and aversive olfactory learning in humans studied using event-related functional magnetic resonance imaging
J Neurosci
 , 
2002
, vol. 
22
 (pg. 
10829
-
10837
)
Grabenhorst
F
Rolls
ET
Margot
C
da Silva
MA
Velazco
MI
How pleasant and unpleasant stimuli combine in different brain regions: odor mixtures
J Neurosci
 , 
2007
, vol. 
27
 (pg. 
13532
-
13540
)
Gross
CG
Rocha-Miranda
CE
Bender
DB
Visual properties of neurons in inferotemporal cortex of the Macaque
J Neurophysiol
 , 
1972
, vol. 
35
 (pg. 
96
-
111
)
Hegde
J
Van Essen
DC
Selectivity for complex shapes in primate visual area V2
J Neurosci
 , 
2000
, vol. 
20
 pg. 
RC61
 
Hubel
DH
Wiesel
TN
Receptive fields and functional architecture in two nonstriate visual areas (18 and 19) of the cat
J Neurophysiol
 , 
1965
, vol. 
28
 (pg. 
229
-
289
)
Kareken
DA
Mosnik
DM
Doty
RL
Dzemidzic
M
Hutchins
GD
Functional anatomy of human odor sensation, discrimination, and identification in health and aging
Neuropsychology
 , 
2003
, vol. 
17
 (pg. 
482
-
495
)
Kobatake
E
Tanaka
K
Neuronal selectivities to complex object features in the ventral visual pathway of the macaque cerebral cortex
J Neurophysiol
 , 
1994
, vol. 
71
 (pg. 
856
-
867
)
LaBar
KS
Gitelman
DR
Mesulam
MM
Parrish
TB
Impact of signal-to-noise on functional MRI of the human amygdala
Neuroreport
 , 
2001
, vol. 
12
 (pg. 
3461
-
3464
)
Maresh
A
Greer
CA
Cellular and synaptic organization of the human olfactory bulb
2007
 
Sarasota (FL): The Association for Chemoreception Sciences
Olsson
MJ
Cain
WS
Psychometrics of odor quality discrimination: method for threshold determination
Chem Senses
 , 
2000
, vol. 
25
 (pg. 
493
-
499
)
Porter
J
Anand
T
Johnson
B
Khan
RM
Sobel
N
Brain mechanisms for extracting spatial information from smell
Neuron
 , 
2005
, vol. 
47
 (pg. 
581
-
592
)
Rauschecker
JP
Cortical processing of complex sounds
Curr Opin Neurobiol.
 , 
1998
, vol. 
8
 (pg. 
516
-
521
)
Rauschecker
JP
Neural encoding and retrieval of sound sequences
Ann N Y Acad Sci
 , 
2005
, vol. 
1060
 (pg. 
125
-
135
)
Rauschecker
JP
Tian
B
Hauser
M
Processing of complex sounds in the macaque nonprimary auditory cortex
Science
 , 
1995
, vol. 
268
 (pg. 
111
-
114
)
Rolls
ET
Kringelbach
ML
de Araujo
IE
Different representations of pleasant and unpleasant odours in the human brain
Eur J Neurosci
 , 
2003
, vol. 
18
 (pg. 
695
-
703
)
Royet
JP
Zald
D
Versace
R
Costes
N
Lavenne
F
Koenig
O
Gervais
R
Emotional responses to pleasant and unpleasant olfactory, visual, and auditory stimuli: a positron emission tomography study
J Neurosci
 , 
2000
, vol. 
20
 (pg. 
7752
-
7759
)
Sobel
N
Khan
RM
Hartley
CA
Sullivan
EV
Gabrieli
JDE
Sniffing longer rather than stronger to maintain olfactory detection threshold
Chem Senses
 , 
2000
, vol. 
25
 (pg. 
1
-
8
)
Takagi
SF
Studies on the olfactory nervous system of the Old World monkey
Prog Neurobiol
 , 
1986
, vol. 
27
 (pg. 
195
-
250
)
Talairach
J
Tournoux
P
Co-planar stereotaxic atlas of the human
 , 
1988
New York
Thieme
Tanabe
T
Iino
M
Takagi
SF
Discrimination of odors in olfactory bulb, pyriform-amygdaloid areas, and orbitofrontal cortex of the monkey
J Neurophysiol
 , 
1975
, vol. 
38
 (pg. 
1284
-
1296
)
Tanabe
T
Yarita
H
Iino
M
Ooshima
Y
Takagi
SF
An olfactory projection area in orbitofrontal cortex of the monkey
J Neurophysiol
 , 
1975
, vol. 
38
 (pg. 
1269
-
1283
)
Worsley
KJ
Evans
AC
Marrett
S
Neelin
P
A three-dimensional statistical analysis for CBF activation studies in human brain
J Cereb Blood Flow Metab
 , 
1992
, vol. 
12
 (pg. 
900
-
918
)
Worsley
KJ
Marrett
S
Neelin
P
Vandal
AC
Friston
KJ
Evans
AC
A unified statistical approach for determining significant signals in images of cerebral activation
Hum Brain Mapp
 , 
1996
, vol. 
4
 (pg. 
58
-
83
)
Zald
DH
Pardo
JV
Emotion, olfaction, and the human amygdala: amygdala activation during aversive olfactory stimulation
Proc Natl Acad Sci U S A
 , 
1997
, vol. 
94
 (pg. 
4119
-
4124
)
Zatorre
RJ
Jones-Gotman
M
Toga
AW
Mazziotta
JC
Functional imaging of the chemical senses
Brain mapping: the applications
 , 
2000
San Diego (CA)
Academic Press
(pg. 
403
-
424
)
Zatorre
RJ
Jones-Gotman
M
Evans
AC
Meyer
E
Functional localization and lateralization of human olfactory cortex
Nature
 , 
1992
, vol. 
360
 (pg. 
339
-
340
)
Zou
Z
Buck
LB
Combinatorial effects of odorant mixes in olfactory cortex
Science
 , 
2006
, vol. 
311
 (pg. 
1477
-
1481
)