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The Journal of Neuroscience, December 15, 2002, 22(24):10819-10828
Functional Heterogeneity in Human Olfactory Cortex: An
Event-Related Functional Magnetic Resonance Imaging Study
Jay A.
Gottfried,
Ralf
Deichmann,
Joel S.
Winston, and
Raymond J.
Dolan
Wellcome Department of Imaging Neuroscience, Institute of
Neurology, London, WC1N 3BG, United Kingdom
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ABSTRACT |
Studies of patients with focal brain injury indicate that smell
perception involves caudal orbitofrontal and medial temporal cortices,
but a more precise functional organization has not been characterized.
In addition, although it is believed that odors are potent triggers of
emotion, support for an anatomical association is scant. We sought to
define the neural substrates of human olfactory information processing
and determine how these are modulated by affective properties of odors.
We used event-related functional magnetic resonance imaging (fMRI) in
an olfactory version of a classical conditioning paradigm, whereby
neutral faces were paired with pleasant, neutral, or unpleasant odors,
under 50% reinforcement. By comparing paired (odor/face) and unpaired
(face only) conditions, odor-evoked neural activations could be
isolated specifically. In primary olfactory (piriform) cortex,
spatially and temporally dissociable responses were identified
along a rostrocaudal axis. A nonhabituating response in posterior
piriform cortex was tuned to all odors, whereas activity in anterior
piriform cortex reflected sensitivity to odor affect. Bilateral
amygdala activation was elicited by all odors, regardless of valence.
In posterior orbitofrontal cortex, neural responses evoked by pleasant
and unpleasant odors were segregated within medial and lateral
segments, respectively. The results indicate functional heterogeneity
in areas critical to human olfaction. They also show that brain regions
mediating emotional processing are differentially activated by odor
valence, providing evidence for a close anatomical coupling between
olfactory and emotional processes.
Key words:
olfaction; odor; emotion; neuroimaging; fMRI; piriform
cortex; olfactory cortex; amygdala; orbitofrontal cortex
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INTRODUCTION |
How odors access central brain
structures has been well characterized in animal models (Carmichael et
al., 1994 ; Haberly, 1998). Odor-evoked responses are conducted from
olfactory receptor neurons at the nasal mucosa toward the olfactory
bulb. Second-order projections transmit via the lateral olfactory tract
and terminate in adjacent structures collectively labeled "primary
olfactory cortex." Piriform cortex is the major recipient of bulbar
afferents, but additional targets comprise olfactory tubercle, anterior
olfactory nucleus, periamygdaloid cortex, and entorhinal area.
Higher-order projections converge on orbitofrontal cortex (OFC),
agranular insula, mediodorsal thalamus, and hypothalamus (Haberly,
1998). Although each of these anatomical zones participates
differentially in olfactory processing, it is apparent that the
piriform cortex may be functionally heterogeneous, particularly along
its rostral-caudal extent (Litaudon et al., 1997; Haberly, 1998).
The neurobiology of human olfaction has received less attention
compared with other sensory modalities. It is generally agreed that the
human sense of smell involves posterior orbitofrontal and anteromedial
temporal lobes (Eslinger et al., 1982). Studies of patients with brain
damage to these regions reveal defects in odor identification,
discrimination, and memory (Potter and Butters, 1980; Eskenazi et al.,
1983; Zatorre and Jones-Gotman, 1991). However, the large size and
spatial extent of such lesions preclude careful structural delineation,
especially given the close proximity of so many critical regions. Thus,
despite the abundance of clinical data, a more precise functional
organization of human olfaction has not been elucidated.
Neuroimaging studies have begun to identify important olfactory
structures, but one notable feature is the inconsistent activation of
piriform cortex (Zald and Pardo, 2000). This may reflect two factors.
First, conventional functional magnetic resonance imaging (fMRI)
sequences are associated with signal loss (susceptibility artifact) at
air-tissue interfaces, reducing image quality in ventral temporal
areas, specifically in piriform cortex (Ojemann et al., 1997). Second,
olfactory habituation occurs with prolonged odor exposure in rodent
piriform cortex (Wilson, 1998), and analogous phenomena have been
confirmed with fMRI in humans (Sobel et al., 2000; Poellinger et al.,
2001). Because many previous olfactory neuroimaging studies used
blocked designs, with constant odor presentation over 30-60 sec,
habituation has been an unavoidable confound.
To overcome these difficulties, we combined event-related techniques
with a novel fMRI acquisition sequence that reduced signal dropout. Our
principal objective was to define regions responsive to olfactory
stimulation and odor valence. Olfactory perception is thought to be
dominated by hedonic (pleasurable) properties (Schiffman, 1974), and it
is commonly held that odors are potent emotional cues. Thus, we
hypothesized that if the olfactory system is sensitive to hedonics,
then manipulations of odor valence should highlight differences within
olfactory regions and elicit activations in structures implicated in
emotional processing, such as amygdala and OFC. Here we describe the
functional neuroanatomy of human olfaction, with specific reference to
dissociations between unpleasant and pleasant odors. A companion paper
in this issue (Gottfried et al., 2002) focuses on the neural components
of olfactory learning.
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MATERIALS AND METHODS |
Subjects. Informed consent was obtained from 17 healthy, right-handed subjects (10 women; age range, 18-31 years; mean
age, 23 years), who were recruited by advertisement. No subject had a
history of neurological or psychiatric illness, respiratory or
ear-nose-throat problems, or known defects of smelling. The study was
devised in accordance with the rules and regulations of the joint
National Hospital for Neurology and Neurosurgery and Institute of
Neurology Ethics Committee. The data from two subjects (one woman) were
rejected because of technical failures during the scanning procedure.
Experimental paradigm and stimuli. Subjects participated in
an olfactory version of classical conditioning in which a neutral item
[the conditioned stimulus (CS+)] acquires behavioral significance by
predicting the occurrence of an emotionally salient item [the unconditioned stimulus (UCS)] after repeated pairings. In this instance, a series of neutral faces represented the CS+, and three different odors varying in pleasantness were used as the UCS. Although
the paradigm enabled us to investigate olfactory-visual associative
learning (Gottfried et al., 2002), it also permitted an independent
analysis of olfactory sensory processing, to provide an account of the
functional anatomy of human olfaction unhindered by previous
methodological limitations.
Four neutral, grayscale faces (two male, two female) taken from the
Ekman series of facial affect (Ekman and Friesen, 1976) comprised the
one nonconditioned (CS ) and 3 conditioned (CS+) stimuli. All facial
hair was removed from the pictures to increase task difficulty (see
below). Images were 150 pixels wide × 205 pixels high and
subtended visual angles of ~8 × 10° when back-projected onto
the display screen of a head box. Subjects viewed the faces in the
center of a gray background.
The odor stimuli were selected as follows. In a pilot study involving
20 different odors (Sigma-Aldrich Company Ltd., Dorset, UK), visual
analog ratings of odor valence were collected from an independent group
of 12 subjects outside the scanner. Three odors were identified that
varied widely in perceived pleasantness, could be easily distinguished
from each other, and showed good intersubject agreement. These were as
follows: vanillin (VAN; 8% w/v in propylene glycol), the pleasant
odor; phenethyl alcohol (PEA; 0.1% v/v in propylene glycol), the
neutrally valenced odor; and 4-methyl-pentanoic acid (4MP; 5% v/v in
mineral oil), the unpleasant (aversive) odor. At the concentrations
used, these compounds have been shown to be relatively specific to
olfactory nerve (cranial nerve I) stimulation, with minimal activation
of trigeminal (cranial nerve V) pathways (Doty et al., 1978).
Odor delivery. Odors were delivered via a four-channel,
computer-controlled olfactometer that was constructed after a design by
Lorig et al. (1999), with the exception that air dilution channels were
not included. The apparatus is suitable for the MRI environment because
all metal components are outside the scanner room, and it generates
discrete pulses of odor with a rapid on-off time on the order of
250-500 msec. In addition, the system is free of tactile, thermal, or
auditory shifts that might otherwise interfere with task demands or
mental set. Under baseline conditions, room air is normally conveyed to
the subject through a nasal cannula nosepiece. At odor onset, a
computer signal simultaneously toggles a control (air) valve off and an
odor valve on, resulting in the administration of odorized air to the
subject. At odor offset, the signal sequence is reversed, which
reintroduces room air and guarantees rapid washout of residual odor
within the system. Airflow was kept constant at 2.5 l/min. Both the
presentation of the visual stimuli and the triggering of the odor
valves were accomplished using Cogent 2000 software (Wellcome
Department of Imaging Neuroscience, London, UK), as implemented in
Matlab 6.0 (The Mathworks Inc., Natick, MA).
Respiratory monitoring. Subjects were pretrained to make an
appropriate sniff with instruction to maintain the same volume and rate
for each trial. Because the act of sniffing induces activations within
primary olfactory cortex (Sobel et al., 1998), the breathing patterns
of each subject were monitored on-line during the experiment to ensure
that sniffing was kept constant across all event types. A pair of
breathing belts made of corrugated rubber tubing (Siemens, Erlangen,
Germany) was affixed around the chest and abdomen. As the subject
breathed, pressure changes within the rubber tubing (caused by chest
and abdominal movements) could be detected by means of a
piezo-resistive differential pressure sensor (0-1 psi; Honeywell,
Morristown, NJ) positioned outside the scanner room. This signal was
subsequently sampled at 100 Hz and recorded digitally on a PC computer
using Spike2 software (version 3.16, Cambridge Electronic Design Ltd.,
Cambridge, UK). Subject-specific sniff waveforms were pooled across
each condition and adjusted by subtracting the mean activity in the 400 msec preceding sniff onset to account for baseline fluctuations. These
were then normalized to the peak amplitude of the CS condition to
permit analysis at the group level. In addition, temporal trends in the
data were investigated by performing linear regression (least squares)
on subject-specific peak amplitudes independently for each condition.
The estimated regression slopes were used to quantify the degree of
change in sniff amplitude over time, which then could be averaged
across subjects for statistical analysis.
Task. Subjects were not informed about face-odor
contingencies but were simply asked to make a forced-choice pushbutton
response regarding facial gender. At the start of the experiment, and
between successive trials, a dull-red cross-hair appeared on a gray
background. The onset of a given trial was heralded by the appearance
of a face just above the cross-hair (t = 0). After 500 msec (t = 500), the cross-hair turned bright red as a
prompt to sniff, and the olfactometer was triggered to deliver an odor
or control air, depending on trial type (Fig.
1A). The sniff cue
remained bright for 750 msec (t = 1250), after which
time it returned to its dull red color (sniff stop). It has been shown
that single sniffs of this duration are optimal for odor detection
(Laing, 1986). Note that the face and odor overlap for 250 msec and
that the offset of the face (t = 750) always occurs
before the offset of the sniff cue (t = 1250). Also
note that subjects complete a sniff on each and every trial, regardless
of odor presence. An intertrial interval of 7.5 sec allowed the subject
to take one to two regular breaths in between sniffs and was sufficient
to clear residual odor from the olfactometer and the nasal
passages.
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Figure 1.
Task and imaging protocol. A, A
series of neutral faces (top row) was paired with odors
(middle row) that varied in pleasantness. Under 50%
reinforcement, only one-half of all faces were paired with odor. A
brightening of a cross-hair (bottom row, +) was used to
prompt the subject to sniff. The four faces and three odors comprised
seven different event types and are depicted schematically. See
Materials and Methods for abbreviations and further details.
B, Functional images were acquired in an oblique
orientation tilted at 30°. On the left, the plane of acquisition and
the effective brain coverage are shown overlaid on a subject's
sagittal T1-weighted scan. The resulting echoplanar image
(z = 22) averaged from 15 subjects is shown
beside an image obtained using a standard (untilted) acquisition
sequence (average of 11 subjects). Preservation of signal is apparent
in the basal frontal and medial temporal lobes. Signal dropout is also
diminished in lateral posterior temporal areas.
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During the experiment, 50% of all face (CS+) presentations were paired
with their corresponding odor (UCS) under a partial-reinforcement strategy. This allowed us to model event-related responses specific to
the compound response (paired face/odor) separately from the unpaired
CS+ (face only) and resulted in seven unique event-types: (1)
"appetitive" face, paired with pleasant odor
(appCS+P); (2) appetitive face, unpaired
(appCS+U); (3) "neutral" face, paired with
neutral odor (ntCS+P) ; (4) neutral face,
unpaired (ntCS+U); (5) "aversive" face,
paired with unpleasant odor (avCS+P) ; (6) aversive face, unpaired (avCS+U) ; and (7) CS
(face never paired with odor) (Fig. 1A). For a given
subject, the same face was always paired with the same odor, but
face-odor combinations were counterbalanced across subjects. There were
25 replications of each event type, except for the CS, which was
repeated 50 times, and the order of stimulus presentations was
randomized. On the basis of an experimental length of 25 min, a given
odor was repeated on average every 50-60 sec, an interval found to
mitigate olfactory habituation (Kobal and Hummel, 1991).
Image acquisition. Gradient echo T2*-weighted echoplanar
images (EPI) were acquired with blood-oxygen level-dependent (BOLD) contrast on a 2-Tesla Siemens Vision MRI scanner (Siemens, Erlangen, Germany), using a novel combination of image tilting and
z-shimming to improve functional sensitivity in
orbitofrontal and medial temporal regions (Deichmann and Turner, 2002).
Briefly, multislice EPI datasets were acquired in an oblique
orientation 30° to the anterior commissure-posterior
commissure line (rostral > caudal), with the following
parameters: echo time, 35 msec; field-of-view, 192 mm; in-plane
resolution, 3.0 mm. Because of the oblique slice orientation, signal
losses caused by susceptibility gradients in phase-encoding direction
could be avoided. Additionally, spin dephasing attributable to through
plane susceptibility gradients was reduced by including a preparation
pulse with a duration of 1 msec and an amplitude of 2 mT/m in slice
selection direction directly before data acquisition, similar to
z-shimming (Constable and Spencer, 1999). In contrast to
standard z-shimming, however, the new technique does not
require the combination of several images. Thus, the temporal
resolution is not compromised.
Volumes consisted of 33 slices (1.8 mm thickness, 1.2 mm gap) that
covered ~80% of the whole brain, apart from superior aspects of the
parietal lobes (Fig. 1B), and they were collected
continuously every 2.31 sec. The entire data set was then reconstructed
into conventional three-dimensional (untilted) space using
trajectory-based reconstruction (Josephs et al., 2000) after a
trajectory scan was calibrated at 30° during a gel-phantom
experiment. High-resolution T1-weighted anatomical images with 1 mm
in-plane resolution were also acquired for each subject.
Subject debriefing. Post hoc ratings of odor
valence were collected from each subject outside the scanner, using a
visual analog scale (16 mm line) delimited with anchors signifying
"extremely pleasant" and "extremely unpleasant." Ratings of
odor intensity were acquired similarly, with endpoints representing
"undetectable" and "extremely strong."
Image preprocessing. A total of 650 image volumes were
collected from each subject. After discarding the first six volumes ("dummy scans") to allow for T1-equilibration effects, functional images were realigned to the first volume to correct for subject motion
(Friston et al., 1995a) and then slice-time corrected to the middle
slice of each volume. This generated a set of volume-specific movement
parameters included as regressors of no interest in subsequent models
of the data. The realigned images were then spatially normalized into a
standard anatomical space, which permitted data analysis at the group
level, and smoothed with an 8 mm (full-width half-maximum) Gaussian
kernel, to account for residual intersubject differences. Each of the
subject's structural T1 scans was transformed into EPI space by
coregistration to the mean functional image and then spatially
normalized using the parameters derived from EPI normalization.
Analysis of olfactory-evoked responses. Event-related fMRI
data were analyzed using Statistical Parametric Mapping (SPM99, Wellcome Department of Imaging Neuroscience) in the context of a
random-effects model. First, events were modeled by a set of delta
(stick) functions that corresponded to the onset times of each face for
each of the seven event types (i.e., appCS+P,
appCS+U, ntCS+P,
ntCS+U, avCS+P,
avCS+U, and CS). Regressors of interest were
then created by convolving the  functions with a canonical hemodynamic response function (HRF) along with its temporal and spatial
derivatives to accommodate shifts in response latency and dispersion
(Friston et al., 1998). The influence of olfactory habituation was also
incorporated into the model as condition × time interactions by
multiplying each regressor of interest by a mean-corrected exponential
function, using a time-constant (one-eighth session length, or
186 sec) similar to that demonstrated in previous olfactory
neuroimaging studies (Sobel et al., 2000; Poellinger et al., 2001).
Movement parameters were entered into the model as effects of no
interest, as were low-frequency drifts in signal (cutoff 120 sec).
Condition-specific parameter estimates (pertaining to the height of the
HRF) were calculated independently for each brain voxel using the
general linear model (Friston et al., 1995b). Contrasts of parameter
estimates from the 15 subjects were subsequently entered into one-way
t tests (random-effects analysis), each of which constituted
an SPM{T}. Odor-evoked neural responses were specifically
isolated by conducting comparisons between paired and unpaired CS+
conditions. For example, the contrast of (appCS+P appCS+U) was performed to highlight
activations specific to the pleasant odor. In other words, the unpaired
CS+ events served as a useful olfactory baseline or control by
canceling out nonspecific effects of visual stimulation (face and
cross-hair), sniffing, and motor (button press) activity.
Regions of activation were localized using the human brain atlas
of Duvernoy (1999) and Mai et al. (1997). In areas where odor-evoked
responses were predicted a priori (namely, primary and
secondary olfactory projection zones, including amygdala, OFC, insula,
hypothalamus, and mediodorsal thalamus), we report activations
surviving a threshold of p < 0.001 uncorrected,
although in piriform and entorhinal cortex, a more liberal threshold of p < 0.005 uncorrected was used (Ojemann et al., 1997).
A correction for multiple comparisons was also performed across small
volumes of interest (Worsley et al., 1996) by constructing bilateral
anatomical masks of each region using MRIcro software (Rorden and
Brett, 2000), with reference to a normalized T1-weighted structural
scan, to limit the effective search space. In mediodorsal thalamus, a
sphere of 10 mm radius was positioned at its center (0, 20, +6). The
statistical threshold used to report these activations was set at
p < 0.05 corrected. All reported voxels of interest conform to the Montreal Neurological Institute (MNI) template coordinate system.
A conjunction analysis examined brain regions commonly activated
by all odors (Price and Friston, 1997). First, subject-specific parameter estimates were calculated for each of six effects of interest: the three paired CS+ conditions (appetitive, neutral, aversive) and their three respective unpaired CS+ baselines. Second, these estimates from all 15 subjects were entered into a
repeated-measures ANOVA using a correction for nonsphericity (Glaser et
al., 2002). This procedure is based on the assumptions that
within-subject variance is not identical across conditions (e.g., a
given subject might adopt different cognitive strategies between paired
and unpaired events) and that between-subject covariance is not
independent over conditions (e.g., one subject might be a better
"smeller" than another). By testing linear contrasts of each paired
CS+ relative to its corresponding unpaired CS+, we were able to isolate odor-evoked neural responses independent of hedonic context. This process was also applied to the set of six regressors parametrically modulated by time.
Finally, an illustrative model of the data were constructed to depict
the time course of activation within (piriform) voxels identified
as significant in the primary model. By subdividing the 25 events of a
given condition into six blocks of four (or five) temporally contiguous
events, six regressors of interest were defined for each condition
type. Subsequent analysis was performed identically to the primary
model, except that condition × time interactions were not
included. By testing linear contrasts of parameter estimates between
paired and unpaired conditions for each of the six blocks, the response
profile of a given voxel across time could be assessed. Because of the
inherently low signal-to-noise ratio of individual event-related
responses, data were displayed as means of parameter estimates for
every two successive blocks (that is, mean of first and second block,
mean of third and fourth block, mean of fifth and sixth block).
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RESULTS |
Behavioral
None of the subjects reported change in odor valence or intensity
over the course of the experiment. One subject thought that VAN became
slightly less pleasant over time, so her score represented the average
of two ratings based on the start and end of scanning. Mean
pleasantness ratings (8 to +8) for the three odors were as follows:
VAN, 3.29 ± 0.75 (±SEM); PEA, 0.82 ± 0.86; and 4MP, 5.01 ± 0.62 (Fig.
2A). There was a
significant difference among these ratings, as determined by a Friedman
Test for related samples ( 2 = 20.133;
df = 2; p < 0.001). Pairwise post hoc
comparisons showed that VAN was perceived as significantly more
pleasant than both PEA and 4MP and that 4MP was judged to be
significantly less pleasant than PEA (p < 0.05;
one-tailed Wilcoxon signed ranks test). Mean ratings of odor intensity
(0 to +16) revealed the following: VAN, 8.95 + 0.79; PEA, 7.45 + 0.77;
and 4MP, 11.72 + 1.10 (Fig. 2B). There was a
significant trend toward differences between intensity ratings
(2 = 8.169; df = 2;
p = 0.017; Friedman Test), and in pairwise tests, 4MP
was judged as significantly more intense than VAN and PEA (p < 0.05; one-tailed Wilcoxon Test), but the
intensity of VAN did not differ significantly from that of PEA
(p = 0.3).
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Figure 2.
Behavioral results. A, Subjective
ratings of odor valence for pleasant (VAN),
neutral (PEA), and unpleasant (4MP) odors
(mean ± SEM; n = 15 subjects).
B, Mean subjective ratings of odor intensity (±SEM;
n = 15). C, Single-subject sniff
waveforms, time-locked to trial onset, averaged over each of the seven
condition types, and normalized to the CS peak. An intervening
respiration can be seen between two cued sniffs (marked by
asterisk). D, Group mean sniff amplitudes
(normalized to CS) for each condition type and collapsed across all
subjects (±SEM). Note that there are no error bars for the CS
condition because this was normalized to 1.0 for all subjects.
P, Paired; U, unpaired. E,
Group mean sniff latency (time-to-peak) for each condition
(±SEM).
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Analysis of sniff waveforms was pooled across all subjects for
each condition type. The condition-specific responses of a single
subject are shown (Fig. 2C), and the group mean amplitudes and latencies are charted (Figs.
2D,E). Although there was a slight amplitude decrement (17%) in sniffing the unpleasant odor
(avCS+P) relative to the CS as well as a mild
increment (8%) in sniffing the pleasant odor
(appCS+P), there was no significant difference in
the peak sniff amplitude between any of these conditions
(F = 2.149; df = 1.54; p = 0.149;
one-way repeated-measures ANOVA; df adjusted by the Greenhouse-Geisser
procedure). There was also no significant difference in sniff latency
(measured from sniff-cue onset to time-to-peak) among the various
conditions (F = 0.956; df = 1.91;
p = 0.394). Finally, no significant temporal trends in
peak sniff amplitude were observed for any of the seven conditions, as
determined by regression analysis. Specifically, there was no
significant difference between the mean regression slopes among the
different conditions (F = 1.102; df = 1.95;
p = 0.345; one-way repeated-measures ANOVA; df
adjusted), nor did the mean regression slopes for any single condition
differ significantly from zero in a series of one-sample t
tests (all p > 0.1; two-tailed).
Neuroimaging
Valence-independent odor activations
Conjunction analysis permitted an evaluation of brain regions
activated by all odors, independent of hedonic context. The combination
of (appCS+P appCS+U) and
(ntCS+P ntCS+U) and
(avCS+P avCS+U) showed
significant activations in piriform cortex bilaterally along its
posterior aspect (Fig.
3A,D,i).
On the left side, this response spanned both frontal and temporal
piriform areas (x, y, z coordinates:
32, 4, 20; p < 0.05 corrected for small volumes (SVC); and 26, 2, 26; Z = 3.10; p < 0.001 uncorrected) and was bounded by the amygdala medially and by
peri-insular cortex/claustrum laterally. On the right, activity was
confined to temporal piriform cortex (24, 0, 24; Z = 2.75; p < 0.005 uncorrected). Significant responses
were also seen in bilateral amygdala (left, 14, 10, 18;
Z = 4.41; p < 0.05 SVC; right, 24, 8, 18; Z = 3.80; p < 0.05 SVC),
with extensive activation along the mediodorsal edge from
y = 10 to 4 extending superiorly into ventral
pallidum (Fig. 3B,D,ii).
Within posterior regions of bilateral OFC, significant activations were
also detected (20, 30, 20; Z = 3.76;
p = 0.053 SVC; and 24, 34, 16; Z = 3.31;
p < 0.001 uncorrected) (Fig. 3C,D,iii). Finally, in
contrast to the above regions, which showed sustained responses over
the course of the experiment, a conjunction of the three condition × time interactions revealed a single area of habituating response in
right agranular insular cortex (36, 8, 22; Z = 4.33;
p < 0.001 uncorrected) (Table
1).
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Figure 3.
Valence-independent neural activations.
A, Piriform cortex. i, The SPM
(threshold, p < 0.005) is superimposed on a
subject's normalized T1-weighted scan and depicts bilateral
activations in posterior piriform cortex. Note in this and all
subsequent figures that the left side of the brain corresponds to the
left side of the figure (neurological convention).
ii, iii, The region bounded by the
rectangle in i is shown magnified in
ii for comparison with a high-resolution anatomical
image of posterior piriform cortex (iii) [modified from
Mai et al. (1997) and used with permission of Academic Press and the
author]. Fp, Frontal piriform cortex;
Tp, temporal piriform cortex; A,
amygdala; C, caudate; P, putamen,
I, insula. B, Amygdala. Neural responses
in bilateral dorsomedial amygdala are shown (threshold,
p < 0.001). C, Orbitofrontal
cortex. Caudal central regions of orbitofrontal cortex were bilaterally
activated by all odors (threshold, p < 0.001).
D, Contrasts of parameter estimates ( , arbitrary
units) were derived from each subject for each of the main effects in
posterior piriform cortex (i) (at 26, 2, 26),
posterior amygdala (ii) (at 14, 10, 18), and
centroposterior OFC (iii) (at 20, 30, 20) and
collapsed across all subjects (means ± SEM). Each of the odors,
regardless of valence, elicits significant activation.
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Activations induced by unpleasant odor
The contrast of (avCS+P avCS+U) identified olfactory-evoked responses
specific to the unpleasant odor context. This revealed significant
activity in the left lateral-posterior OFC (26, 36, 16;
Z = 3.15; p < 0.001 uncorrected) (Fig.
4A) and in the right dorsal amygdala (22, 10, 16; Z = 3.20; and 18, 6,
16; Z = 3.14; p < 0.001 uncorrected). Significant activations were also observed in the left
lateral hypothalamus and right insula/frontal operculum. Although
piriform regions were not identified in this main effect, the contrast
of condition × time interactions [namely, (avCS+P) × time (avCS+U) × time] demonstrated significant
habituating responses within an anterior sector of the left frontal
piriform cortex (30, 10, 28; Z = 3.70;
p < 0.05 SVC) (Fig. 4B). This activation was 8-10 mm more anterior than the foci detected in the
odor conjunction. Note that piriform habituation was also observed on
the right side (30, 10, 28), but this did not reach statistical
significance (Z = 2.42; p = 0.008). In
a direct comparison of time-modulated unpleasant
[(avCS+P) × time (avCS+U) × time] and pleasant
[(appCS+P) × time (appCS+U) × time] olfactory conditions, significant habituation was seen in left anterior piriform cortex and
mediodorsal thalamus (Table 2), which
reflected greater differential responses to unpleasant than to pleasant
odor.
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Figure 4.
Neural activations evoked by unpleasant odor.
A, Orbitofrontal cortex. i, The main
effect of unpleasant odor (avCS+P avCS+U) showed significant BOLD increases within
left lateral posterior orbitofrontal cortex, which is superimposed on a
T1-weighted scan (threshold, p < 0.001).
ii, The contrasts of parameter estimates for each main
effect are plotted for this region and highlight significantly greater
responses to negative odor valence. B, Piriform cortex.
i, Habituating neural activations in left anterior
piriform cortex were revealed by contrasting the condition × time
interactions (avCS+P avCS+U)
(threshold, p < 0.005). ii,
Contrasts of parameter estimates in anterior piriform cortex are
plotted for each odor. iii, iv, The brain
region outlined in i is magnified in iii
and can be compared with a high-resolution atlas image of anterior
piriform cortex in iv [modified from Mai et al. (1997),
and used with permission of Academic Press and the author].
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Activations induced by pleasant odor
Neural responses related to pleasant odor valence were evaluated
by testing the main effect (appCS+P appCS+U). Significant activations were identified
in medial anterior (frontal) piriform cortex (24, 12, 30;
Z = 3.70; p < 0.05 SVC) bordering the
olfactory tubercle and extending posteriorly toward the junction of
frontal and temporal cortices (Fig.
5A). A second focus of
activation was found in the medial OFC (18, 16, 16; Z = 3.54; p < 0.001 uncorrected) (Fig. 5B).
The direct comparison of [(appCS+P) (appCS+U)] to
[(avCS+P) (avCS+U)] revealed significant activity within
anterior piriform cortex (Table 3) driven
primarily by an enhanced activation to pleasant odor. Conversely,
neither of the condition × time interactions [that is,
(appCS+P) × time (appCS+U) × time; or
(appCS+P) × time (appCS+U) × time) [(avCS+P) × time (avCS+U) × time)] showed significant
effects. To discount the possibility that piriform cortex was simply
habituating with a slower time course, the data were remodeled using a
slower exponential decay-function (one-quarter session length, as
opposed to one-eighth), but again no effect could be
demonstrated. Thus, in contrast to the habituating profile elicited by
unpleasant odor, a sustained, nonhabituating pattern of activity was
observed in the presence of pleasant odor. These temporal
dissociations are illustrated at the single-subject and group levels in
Figure 6.
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Figure 5.
Neural activations evoked by pleasant odor.
A, Piriform cortex. i, The main effect of
pleasant odor (appCS+P appCS+U)
showed nonhabituating responses in right anterior piriform cortex that
are overlaid on a normalized T1-weighted scan (threshold,
p < 0.005). ii, Contrasts of
parameter estimates in this anterior piriform region (at 24, 12,
30) are depicted for each of the main effects. B,
Orbitofrontal cortex. i, Significant neural activations
were also observed in right caudomedial orbitofrontal cortex (at 18, 16, 16) (threshold, p < 0.001).
ii, The corresponding plots of parameter estimates are
charted.
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[in this window]
[in a new window]
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Figure 6.
Temporal dynamics of olfactory processing are
modulated by odor valence within anterior piriform cortex.
A, C, Habituating neural response to
unpleasant odor. A, The response profile in anterior
piriform cortex (at 30, 10, 28) from a representative subject is
depicted three-dimensionally. With successive stimulus repetitions, the
percentage change in (fitted) signal activity (avCS+P avCS+U) declined progressively. C,
The contrasts of parameter estimates for unpleasant odor were computed
over three successive experimental blocks and averaged over all
subjects. The BOLD activity was significantly increased during the
first third of the experiment but declined markedly in the remaining
two-thirds. B, D, Sustained neural
response to pleasant odor. B, The response profile in
anterior piriform cortex (at 24, 12, 30) is shown three-dimensionally
from the same subject as in A and reveals no decline in
signal with repetitions of pleasant odor (appCS+P appCS+U). D, Contrasts of parameter
estimates show persistence of neural activity over the
experiment.
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Activations induced by neutral odor
Activations specific to the neutral-valenced odor were tested by
contrasting ntCS+P relative to
ntCS+U. Significant olfactory-evoked responses
were limited to a region of left posterior piriform cortex that
bordered the amygdala medially (20, 0, 24; Z = 3.12; p < 0.001 uncorrected). An adjacent piriform
area (26, 2, 24; Z = 3.24; p < 0.001 uncorrected) exhibited a significant habituating response in the
condition × time interaction (Table
4). Both of these activations overlapped
the same regions of piriform cortex identified in the conjunction
analysis described above.
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DISCUSSION |
The successful application of event-related techniques to
olfactory fMRI, as described here, allows the implementation of more
flexible experimental paradigms that are protected against changes in
cognitive set, a standard confound of blocked designs (Josephs et al.,
1997). In the context of olfaction, an important benefit is to reduce
total stimulus exposure and limit olfactory habituation, which may have
hindered detection of piriform cortex in previous neuroimaging studies.
Using such approaches, we identified odor-evoked neural responses in
several putative olfactory regions, including piriform cortex,
amygdala, and caudal OFC. By manipulating odor valence, we observed
both regional and temporal dissociations of function.
Odor-evoked responses in piriform cortex
Posterior piriform cortex was activated bilaterally by all odors,
independent of valence (Fig. 3A). The significance of these effects at the group level indicates that central olfactory projections converge on an area of piriform cortex conserved across subjects. These
activations persisted over a 25 min experiment, which helps validate
the efficacy of event-related designs in mitigating olfactory habituation. On the basis of cognitive assumptions underlying conjunction analyses (Price and Friston, 1997), it is likely that posterior piriform cortex mediates basic odor perception and detection. Such a role complements theories derived from animal models suggesting that piriform cortex is broadly tuned to odors (Tanabe et al., 1975;
Schoenbaum and Eichenbaum, 1995) and conforms to recent neuroimaging
studies demonstrating similar activation patterns in response to
low-level olfactory processes. In this regard, the posterior piriform
activations described here are situated close (albeit slightly more
lateral) to those identified in previous imaging experiments of
"passive" smelling [for example, at 21, 6, 21 (Zatorre et al.,
1992); at 20, 2, 10 (Savic et al., 2000); at 24, 1, 11 (Sobel
et al., 2000); and at 21, 0, 9 (Poellinger et al., 2001); note that
some discrepancy inevitably results in comparing MNI and non-MNI
coordinate systems]. This anatomical consistency among studies
supports the argument that posterior piriform cortex is critical to
elementary olfactory processing.
We also observed activations within an anterior segment of piriform
cortex in response to unpleasant and pleasant odors (Figs. 4B, 5A). This area corresponds to human
frontal (pre)-piriform cortex (Eslinger et al., 1982; Mai et al., 1997)
and lies caudal to the posterior-most extent of OFC. Significant
responses were seen in the main contrasts for each valence type and in
direct comparisons between valence types, implying a robust effect at the group level. Thus, it appears that anterior piriform cortex is
receptive to hedonic quality, especially at extremes of odor valence.
The fact that piriform activations evoked by the neutral (nonvalenced)
odor were comparatively restricted to posterior areas lends support to
this argument. The strong reciprocal connections between anterior
piriform cortex and orbitofrontal structures (Ekstrand et al., 2001)
would allow ready dissemination of affective olfactory information to
areas responsible for modulating behavior. Interestingly, in a recent
PET study by Dade and colleagues (2002), the activation of an
anatomically contiguous piriform region (at 28, 10, 21) during
short-term odor recognition is in keeping with the idea of increasing
specialization within more anterior segments of human olfactory cortex.
Although pleasant and unpleasant odors elicited common spatial patterns
in anterior piriform cortex, their temporal patterns deviated. Anterior
piriform activity was sustained in response to VAN but decreased
steadily over time to 4MP (Fig. 6). This temporal dissociation may
reflect physiological differences in the encoding of biologically
salient olfactory information. Such an idea accords with animal
evidence that underscores the importance of temporal dynamics to the
olfactory code (Eeckman and Freeman, 1990; Laurent, 1996) and its
sensitivity to odor salience (Freeman and Schneider, 1982; Chabaud et
al., 2000). Alternately, it is possible that odor valence directly
influences anterior piriform habituation. In our study, whether neural
habituation was exaggerated by unpleasant odor or attenuated by
pleasant odor could not be determined. Nevertheless, it is worth noting
that the habituating responses routinely observed in rodent olfactory
bulb are blocked by reward-associated odors (Wilson and Sullivan,
1992).
These results suggest functional heterogeneity in subregions of
piriform cortex. Different areas (anterior, posterior) exhibited divergent responses to the same odor (4MP), and the same area (anterior) variably responded to different odors (4MP, VAN). It is
difficult to corroborate our findings with the human literature, because previous imaging studies of odor valence did not detect significant piriform activation (Zald and Pardo, 1997; Fulbright et
al., 1998; Royet et al., 2001). On the other hand, anatomical and
functional distinctions have been described in animal models along the
rostral-caudal axis of piriform cortex (Litaudon et al., 1997;
Haberly, 1998; Chabaud et al., 2000). Moreover, activity in olfactory
bulb and cortex can be modulated by biologically meaningful odors
(Chabaud et al., 2000) and behaviorally conditioned odors (Pager, 1974;
Freeman and Schneider, 1982; Wilson and Sullivan, 1992). Our findings
extend the validity of these concepts to human olfactory processing.
Odor-evoked responses in amygdala
The odor conjunction revealed extensive, and sustained, activation
in the amygdala along its dorsomedial sector (Fig. 3B). This
spatial pattern accords with the known distribution of olfactory efferents in animal models of amygdala. Projections from olfactory bulb
and piriform cortex terminate in periamygdaloid cortex, anterior and
posterior cortical nuclei, and medial nucleus (Carmichael et al.,
1994), which overlap the activations described here. It is interesting
to note that, in contrast to other sensory modalities, olfaction has no
direct inputs into the lateral nuclei. Although it can be argued that
the observed activations spare lateral amygdala, we would caution
against too strong an inference, given the limits of spatial resolution
imposed by our technique.
Neurophysiological recordings in animals (Cain and Bindra, 1972; Tanabe
et al., 1975) and humans (Hughes and Andy, 1979; Hudry et al., 2001)
suggest that the amygdala is broadly tuned to various odors. From an
evolutionary perspective, the physical expansion of primate amygdala
paralleled increases in paleocortex, mostly comprising piriform cortex,
and consequently much of the amygdala was committed to olfactory
processing (Barton and Aggleton, 2000). Despite a relative decline in
human odor sensibility, our findings suggest that much of this
circuitry is still functional. Note that although amygdala responded to
all odors, independent of hedonic content, neural activity was more
pronounced in the presence of unpleasant odor. This was evident in the
conjunction analysis, where markers of neural activity ( values)
showed an increasing trend with increasing odor aversiveness (Fig.
3D,ii) and in the main effect of
unpleasant odor. Thus, odor-evoked activity in the amygdala is not
restricted to aversive-odor processing but exhibits a tendency in that
direction, which complements notions that the amygdala may show
preferential involvement in negative emotional processing of both
olfactory (Hughes and Andy, 1979; Zald and Pardo, 1997) and
non-olfactory (Morris et al., 1996; Zald et al., 1998) stimuli.
Odor-evoked responses in orbitofrontal cortex
Significant responses were revealed by the odor conjunction in
caudal OFC (Fig. 3C). These activations correspond to the
so-called "central-posterior orbitofrontal cortex" (CPOF)
identified by Yarita et al. (1980), who considered it a broadly tuned
area of primate olfactory association cortex. According to Carmichael et al. (1994), the CPOF is roughly homologous to orbital areas 13m,
13a, and Iam and represents the primary prefrontal locus of olfactory
input. By hosting a convergence of primary sensory, visceral, and
limbic information, olfactory OFC may enable stimulus-reward associations and the organization of odor-guided behavior (Carmichael et al., 1994). Single-unit recordings in animals show that OFC responds
to complex aspects of olfactory processing (Schoenbaum and Eichenbaum,
1995; Critchley and Rolls, 1996). In humans, olfactory discrimination
is impaired in patients with OFC lesions (Potter and Butters, 1980;
Zatorre and Jones-Gotman, 1991), and the OFC, particularly caudal
regions, is detected consistently in olfactory neuroimaging studies
(Zald and Pardo, 2000). The data presented here offer further evidence
that posterior OFC is a critical component of human olfaction.
The regional patterns of activation within caudal OFC diverged
according to valence. Unpleasant odor evoked activity in (left) lateral-central OFC (Fig. 4A); pleasant odor evoked
activity in (right) medial OFC (Fig. 5B). Similar to
piriform cortex, this suggests a segregation of odor valence processing
within caudal OFC. There is limited evidence in primates that medial
and lateral portions of OFC are functionally distinct (Carmichael and
Price, 1996), and human imaging data illustrate such dissociations.
Medial OFC activity correlates with numerous measures of pleasantness such as monetary reinforcers (O'Doherty et al., 2001), tastes (Small
et al., 2001), and facial attractiveness (, whereas lateral OFC responses are more aligned with negative or
punishing aspects of these stimuli. Our findings indicate that this
concept is applicable to the olfactory domain.
Although formal side × condition interactions were beyond the
scope of this report, it is worth reemphasizing that unpleasant odor
was associated with left-sided OFC activation. Similarly, in their PET
study of aversive olfactory stimulation, O'Doherty et al., Zald and Pardo (1997) observed
a comparable pattern of activity in this region, whereas Royet et al.
(2001) reported left OFC activation during odor judgments of hedonic
quality. Given these findings, it is plausible that left OFC is
preferentially activated when hedonic features dominate olfactory perception.
Nevertheless, it is important to note that nonhedonic differences
between the three odorants, such as edibility, familiarity, or
nameability, may also contribute to the differential activation patterns described not only in OFC but also in piriform cortex and
amygdala. For example, the VAN-evoked neural activity could have been
equally a product of odor "vanilla-ness" as odor pleasantness, thereby activating OFC regions independent of hedonic valence. As such,
our conclusions regarding functional dissociations along the hedonic
dimension are tentative.
Olfactory references to Proust's (1913) tea-soaked madeleines are
often summoned as prima facie proof for an emotional primacy of odors. It is also claimed that the structural overlap of olfactory and limbic structures necessarily dictates an intimate functional relationship. However, although odor perception appears to be dominated
by hedonic qualities (Schiffman, 1974), there is little anatomical
evidence connecting human olfaction to emotional states. Our study
lends biological credence to the link between olfaction and
emotion-based processes in so far as neural representations of pleasant
and unpleasant odor are spatially and temporally separable within key
olfactory structures and within areas implicated in emotional
processing. The fact that affective properties of odors are encoded
within primary olfactory cortex affirms the idea that hedonic value is
an important determinant of odor identity.
| |
FOOTNOTES |
Received July 16, 2002; revised Sept. 23, 2002; accepted Sept. 27, 2002.
This research was supported by a Physician Postdoctoral Fellowship from
the Howard Hughes Medical Institute (J.A.G.) and by a Wellcome Trust
Programme Grant (R.J.D.). We are grateful to P. Aston, E. Featherstone,
and O. Josephs for design and construction of the olfactometer, and to
D. Corfield and J. O'Doherty for helpful discussions. We also thank
the radiology staff of the Wellcome Department of Imaging Neuroscience.
Correspondence should be addressed to Dr. Jay A. Gottfried, Wellcome
Department of Imaging Neuroscience, Functional Imaging Laboratory, 12 Queen Square, London WC1N 3BG, UK. E-mail:
j.gottfried{at}fil.ion.ucl.ac.uk.
| |
REFERENCES |
-
Barton RA,
Aggleton JP
(2000)
Primate evolution and the amygdala.
In: The amygdala: a functional analysis (Aggleton JP,
ed), pp 479-508. New York: Oxford UP.
-
Cain DP,
Bindra D
(1972)
Responses of amygdala single units to odors in the rat.
Exp Neurol
35:98-110[ISI][Medline].
-
Carmichael ST,
Price JL
(1996)
Connectional networks within the orbital and medial prefrontal cortex of macaque monkeys.
J Comp Neurol
371:179-207[ISI][Medline].
-
Carmichael ST,
Clugnet MC,
Price JL
(1994)
Central olfactory connections in the macaque monkey.
J Comp Neurol
346:403-434[ISI][Medline].
-
Chabaud P,
Ravel N,
Wilson DA,
Mouly AM,
Vigouroux M,
Farget V,
Gervais R
(2000)
Exposure to behaviourally relevant odour reveals differential characteristics in rat central olfactory pathways as studied through oscillatory activities.
Chem Senses
25:561-573[Abstract/Free Full Text].
-
Constable RT,
Spencer DD
(1999)
Composite image formation in z-shimmed functional MR imaging.
Magn Reson Med
42:110-117[Medline].
-
Critchley HD,
Rolls ET
(1996)
Olfactory neuronal responses in the primate orbitofrontal cortex: analysis in an olfactory discrimination task.
J Neurophysiol
75:1659-1672[Abstract/Free Full Text].
-
Dade LA,
Zatorre RJ,
Jones-Gotman M
(2002)
Olfactory learning: convergent findings from lesion and brain imaging studies in humans.
Brain
125:86-101[Abstract/Free Full Text].
-
Deichmann R,
Turner R
(2002)
Improvement of local BOLD sensitivities in the presence of susceptibility gradients by using tilted slices.
Proc Int Soc Magn Reson Med
10:1414.
-
Doty RL,
Brugger WE,
Jurs PC,
Orndorff MA,
Snyder PJ,
Lowry LD
(1978)
Intranasal trigeminal stimulation from odorous volatiles: psychometric responses from anosmic and normal humans.
Physiol Behav
20:175-185[Medline].
-
Duvernoy HM
(1999)
In: The human brain: surface, blood supply, and three-dimensional sectional anatomy. Vienna: Springer.
-
Eeckman FH,
Freeman WJ
(1990)
Correlations between unit firing and EEG in the rat olfactory system.
Brain Res
528:238-244[ISI][Medline].
-
Ekman P,
Friesen WV
(1976)
In: Pictures of facial affect. Palo Alto, CA: Consulting Psychologists Press.
-
Ekstrand JJ,
Domroese ME,
Johnson DM,
Feig SL,
Knodel SM,
Behan M,
Haberly LB
(2001)
A new subdivision of anterior piriform cortex and associated deep nucleus with novel features of interest for olfaction and epilepsy.
J Comp Neurol
434:289-307[ISI][Medline].
-
Eskenazi B,
Cain WS,
Novelly RA,
Friend KB
(1983)
Olfactory functioning in temporal lobectomy patients.
Neuropsychologia
21:365-374[ISI][Medline].
-
Eslinger PJ,
Damasio AR,
Van Hoesen GW
(1982)
Olfactory dysfunction in man: anatomical and behavioral aspects.
Brain Cogn
1:259-285[Medline].
-
Freeman WJ,
Schneider W
(1982)
Changes in spatial patterns of rabbit olfactory EEG with conditioning to odors.
Psychophysiology
19:44-56[ISI][Medline].
-
Friston KJ,
Ashburner J,
Frith CD,
Poline J-B,
Heather JD,
Frackowiak RSJ
(1995a)
Spatial registration and normalization of images.
Hum Brain Mapp
2:165-189.
-
Friston KJ,
Holmes AP,
Worsley KJ,
Poline J-P,
Frith CD,
Frackowiak RSJ
(1995b)
Statistical parametric maps in functional imaging: a general linear approach.
Hum Brain Mapp
2:189-210[Medline].
-
Friston KJ,
Fletcher P,
Josephs O,
Holmes A,
Rugg MD,
Turner R
(1998)
Event-related fMRI: characterizing differential responses.
NeuroImage
7:30-40[ISI][Medline].
-
Fulbright RK,
Skudlarski P,
Lacadie CM,
Warrenburg S,
Bowers AA,
Gore JC,
Wexler BE
(1998)
Functional MR imaging of regional brain responses to pleasant and unpleasant odors.
AJNR Am J Neuroradiol
19:1721-1726[Abstract].
-
Glaser D,
Penny W,
Henson R,
Friston KJ
(2002)
Coping with the variance structure of neuroimaging data.
Abstr Cogit Neurosci Soc
9:141.
-
Gottfried JA,
O'Doherty J,
Dolan RJ
(2002)
Appetitive and aversive olfactory learning in humans studied using event-related functional magnetic resonance imaging.
J Neurosci
22:10829-10837[Abstract/Free Full Text].
-
Haberly LB
(1998)
Olfactory cortex.
In: The synaptic organization of the brain (Shepherd GM,
ed), pp 377-416. New York: Oxford UP.
-
Hudry J,
Ryvlin P,
Royet JP,
Mauguiere F
(2001)
Odorants elicit evoked potentials in the human amygdala.
Cereb Cortex
11:619-627[Abstract/Free Full Text].
-
Hughes JR,
Andy OJ
(1979)
The human amygdala. I. Electrophysiological responses to odorants.
Electroencephalogr Clin Neurophysiol
46:428-443[ISI][Medline].
-
Josephs O,
Turner R,
Friston K
(1997)
Event-related fMRI.
Hum Brain Mapp
5:243-248.
-
Josephs O,
Deichmann R,
Turner R
(2000)
Trajectory measurement and generalized reconstruction in rectilinear EPI.
Proc Int Soc Magn Reson Med
8:1517.
-
Kobal G,
Hummel C
(1991)
Olfactory evoked potentials in humans.
In: Smell and taste in health and disease (Getchell TV,
Doty RL,
Bartoshuk LM,
Snow JB,
eds), pp 255-275. New York: Raven.
-
Laing DG
(1986)
Identification of single dissimilar odors is achieved by humans with a single sniff.
Physiol Behav
37:163-170[Medline].
-
Laurent G
(1996)
Dynamical representation of odors by oscillating and evolving neural assemblies.
Trends Neurosci
19:489-496[ISI][Medline].
-
Litaudon P,
Datiche F,
Cattarelli M
(1997)
Optical recording of the rat piriform cortex activity.
Prog Neurobiol
52:485-510[ISI][Medline].
-
Lorig TS,
Elmes DG,
Zald DH,
Pardo JV
(1999)
A computer-controlled olfactometer for fMRI and electrophysiological studies of olfaction.
Behav Res Methods Instrum Comput
31:370-375[ISI][Medline].
-
Mai JK,
Assheuer J,
Paxinos G
(1997)
In: Atlas of the human brain. San Diego: Academic.
-
Morris JS,
Frith CD,
Perrett DI,
Rowland D,
Young AW,
Calder AJ,
Dolan RJ
(1996)
A differential neural response in the human amygdala to fearful and happy facial expressions.
Nature
383:812-815[Medline].
-
O'Doherty J,
Kringelbach ML,
Rolls ET,
Hornak J,
Andrews C
(2001)
Abstract reward and punishment representations in the human orbitofrontal cortex.
Nat Neurosci
4:95-102[ISI][Medline].
-
O'Doherty J,
Winston JS,
Critchley H,
Perrett D,
Burt DM,
Dolan RJ
(2003)
Beauty in a smile: the role of medial orbitofrontal cortex in facial attractiveness.
Neuropsychologia
41:147-155[ISI][Medline].
-
Ojemann JG,
Akbudak E,
Snyder AZ,
McKinstry RC,
Raichle ME,
Conturo TE
(1997)
Anatomic localization and quantitative analysis of gradient refocused echo-planar fMRI susceptibility artifacts.
NeuroImage
6:156-167[ISI][Medline].
-
Pager J
(1974)
A selective modulation of the olfactory bulb electrical activity in relation to the learning of palatability in hungry and satiated rats.
Physiol Behav
12:189-195[Medline].
-
Poellinger A,
Thomas R,
Lio P,
Lee A,
Makris N,
Rosen BR,
Kwong KK
(2001)
Activation and habituation in olfaction
 an fMRI study.
Neuro-Image
13:547-560[ISI][Medline]. -
Potter H,
Butters N
(1980)
An assessment of olfactory deficits in patients with damage to prefrontal cortex.
Neuropsychologia
18:621-628[ISI][Medline].
-
Price CJ,
Friston KJ
(1997)
Cognitive conjunction: a new approach to brain activation experiments.
NeuroImage
5:261-270[ISI][Medline].
-
Proust M
(1913)
In: Swann's way (Moncrieff CKS, translator). New York: Modern Library, 1956.
-
Rorden C,
Brett M
(2000)
Stereotaxic display of brain lesions.
Behav Neurol
12:191-200[ISI][Medline].
-
Royet JP,
Hudry J,
Zald DH,
Godinot D,
Gregoire MC,
Lavenne F,
Costes N,
Holley A
(2001)
Functional neuroanatomy of different olfactory judgments.
NeuroImage
13:506-519[ISI][Medline]
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TOP
ABSTRACT
INTRODUCTION
