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NeuroImage 24 (2005) 1032–1041

Involvement of right piriform cortex in olfactory

familiarity judgments

Jane Plailly,a,* Moustafa Bensafi,a Mathilde Pachot-Clouard,b Chantal Delon-Martin,b

David A. Kareken,c Catherine Rouby,a Christoph Segebarth,b and Jean-P. Royeta,d

aNeurosciences et Systemes Sensoriels, Universite Claude Bernard Lyon 1, UMR CNRS 5020, IFR 19, Institut Federatif des Neurosciences de Lyon,

50 Avenue Tony Garnier, 69366 Lyon Cedex 07, FrancebUnite mixte INSERM/Universite Joseph Fourier U594, LRC-CEA, Hopital Michallon, 38043 Grenoble, FrancecNeuropsychology Section, Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, USAdCERMEP, 69003 Lyon, France

Received 16 April 2004; revised 12 October 2004; accepted 26 October 2004

Available online 9 December 2004

Previous studies have shown activation of right orbitofrontal cortex

during judgments of odor familiarity. In the present study, we sought to

extend our knowledge about the neural circuits involved in such a task

by exploring the involvement of the right prefrontal areas and limbic/

primary olfactory structures. Fourteen right-handed male subjects

were tested using fMRI with a single functional run of two olfactory

conditions (odor detection and familiarity judgments). Each condition

included three epochs. During the familiarity condition, subjects rated

whether odors were familiar or unfamiliar. During the detection

condition, participants decided if odors were present. When contrasting

the familiarity with the detection conditions, activated areas were found

mainly in the right piriform cortex (PC) and hippocampus, the left

inferior frontal gyrus and amygdala, and bilaterally in the mid-fusiform

gyrus. Further analyses demonstrated that the right PC was more

strongly activated than the left PC. This result supports the notion that

the right PC is preferentially involved in judgments of odor familiarity.

D 2004 Elsevier Inc. All rights reserved.

Keywords: Olfaction; Familiarity judgment; Recognition memory; Piriform

cortex; fMRI

Introduction

Hemispheric asymmetry is well-established for high-level brain

functions such as language and spatial attention (e.g., Broca, 1863;

Weintraub and Mesulam, 1987). Hemispheric predominance also

exists in sensory functions such as hand somatosensory represen-

tation (Soros et al., 1999) and temporal and spectral auditory

resolution (Zatorre et al., 2002). Studies in olfaction lead to similar

conclusions. Early cerebral imaging studies showed functional

1053-8119/$ - see front matter D 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.neuroimage.2004.10.028

* Corresponding author. Fax: +33 4 37 28 76 01.

E-mail address: plailly@olfac.uni-lyon1.fr (J. Plailly).

Available online on ScienceDirect (www.sciencedirect.com).

lateralization of olfactory processes in the right hemisphere,

especially in orbitofrontal cortex (OFC) (Zatorre et al., 1992);

most subsequent studies confirm this result (Dade et al., 1998;

Sobel et al., 1998; Yousem et al., 1997). However, Zald and

colleagues reported stronger activation in the left OFC and

amygdala for very aversive odors, pointing to these areas as being

important in the emotional processing of olfactory information

(Zald and Pardo, 1997; Zald et al., 1998). Using positron emission

tomography (PET), Royet et al. (1999, 2001) found that judgments

of odor familiarity preferentially activated right OFC, whereas

hedonic judgments principally activated left OFC.

Beyond OFC, recent cerebral imaging data have extended these

observations to piriform cortex (PC). In a functional magnetic

resonance imaging (fMRI) study, we showed that left piriform–

amygdala region activation was associated with subjects’ ratings of

the odorants’ emotional intensities (Royet et al., 2003), a result

consistent with Gottfried et al.’s (2002) and Anderson et al.’s

(2003) findings. Convergent results from Dade et al.’s (2002)

lesion and PET studies further show that the piriform region

mediates olfactory long-term recognition memory, giving support

to the notion that this area may be more than primary sensory

cortex (e.g., Schoenbaum and Eichenbaum, 1995). Specifically,

Dade et al. (2002) found that the extent of piriform activity

corresponded with different cognitive demands, in which PC

activity followed a continuum between mnemonic encoding (no

significant activity), to short-term recognition (weak bilateral

activity), to long-term recognition (strong bilateral activity). These

authors further suggested that piriform activity could be related to

odor familiarity, which would require that subjects compare odors

with previously stored olfactory representations, and thus represent

a type of long-term olfactory reference memory.

In the present study, we explored that question by specifically

asking whether PC is involved in the processing of odor familiarity,

and if so, whether familiarity-evoked activations are lateralized, as

previously suggested (Royet et al., 1999, 2001). We studied

J. Plailly et al. / NeuroImage 24 (2005) 1032–1041 1033

familiarity judgments and their relation to PC activation with fMRI

using a classical block paradigm design. Familiar and unfamiliar

odors were presented in a same epoch allowing subjects to rate

familiarity in a binary fashion by pressing one of two buttons. A

control condition was employed in which subjects had to judge the

presence or absence of an odor. The contrast between both

conditions allowed us to identify the areas specifically involved

in the familiarity judgment of odors.

Materials and methods

Subjects

Fourteen healthy right-handed men (18–32 years old) partici-

pated in the study. Participation required a medical screening.

Exclusion criteria were rhinal disorders (colds, active allergies,

history of nasal-sinus surgery, or asthma), neurologic disease,

ferrous implants (e.g., pacemakers, cochlear implants), or claus-

trophobia. Participants scored at least 87% correct in a forced-

choice suprathreshold detection test, and had a breathing cycle

mean duration of 3.88 s (F0.72). All participants provided written

informed consent as approved by the local Institutional Review

Board, and according to French regulations on biomedical experi-

ments on healthy volunteers.

Odorous stimuli

One hundred and eight stimuli were used, 27 of which were

employed before imaging sessions and 81 of which were used

Table 1

List of odorants selected for the Da, Db, Dc, Fa, Fb, and Fc epochs

Da Db Dc

1 Plum Sage Acacia

2 Turpentine

3

4 Tarragon Orange

5 Parsley Acetophenone

6 Guaiacol

7 Jonquil Camphor

8 Neroli

9 Musk

10 Carrot Pine needle

11 EBA

12 1,4-Dichlorobutane Butanol

13 Eglantine

14

15 Cherry 2-Bromopheno

16 Acetol Liqueur wine Tangerine

17 2-Octanol

18 Liquorice Blackcurrant

Unfamiliar odors

Mean (SD) 4.00 (0.72) 4.11 (0.87) 4.29 (0.92)

Range 3.14–5.11 3.19–5.16 3.09–5.17

Familiar odors

Mean (SD)

Range

Note. EBA, ethyl benzoyl acetate; PPA, phenyl propionaldehyde; SD, standard d

scale, with 1 representing low familiarity, and 10 representing high familiarity (s

during scanning. For fMRI, 54 odorants were used for the

familiarity (F) condition and 27 odorants for the detection (D)

condition (Table 1). For F conditions, three sets (Fa, Fb, Fc)

contained nine familiar and nine unfamiliar odorants selected so as

to provide high- and low-familiarity scores from data as derived

from previous work (Royet et al., 1999). Analysis of variance

(ANOVA) indicated that familiarity scores were significantly

higher for familiar than for unfamiliar odorants [F(1,48) =

129.173, P b 0.0001]. For D conditions, three sets (Da, Db, Dc)

contained nine odorants with low familiarity and nine bottles with

odorless air. Odors with low familiarity were selected to avoid

implicit familiarity judgments. For training, three sets of nine low

familiarity odorants and nine bottles with odorless air were used. In

each set, the presentation order of stimuli was pseudorandomized,

but identical for all subjects. Odorants were diluted to a concen-

tration of 10% using mineral oil (Sigma Aldrich, France). For

presentation, 5 ml of this solution was absorbed into compressed

polypropylene filaments inside of a 100 ml white polyethylene

squeeze-bottles equipped with a dropper (Osi, France).

Stimulating and recording materials

Odors were presented using an airflow olfactometer, which

allowed synchronizing stimulation with breathing. The stimulation

equipment was essentially the one used in a previous PET study

(Royet et al., 1999), but adapted so as to avoid interference with

the static magnetic field of the scanner (Royet et al., 2003). Briefly,

the apparatus was split into two modules: the electronic part of the

olfactometer positioned outside the magnet room (shielded with a

Faraday cage), and the nonferrous (DuraluminR) air-dilution

Fa Fb Fc

Apricot Raspberry Citronella

Bergamot Orange Tetralin trans-2-Hexenal

Diethyl ether Mint Cypress

Pine Honey Geranium

Bornyl acetate Patchouli Vienna bread

Caramel Jasmine Anise

Grass Basil Iris

Strawberry Toluene Incense

Pepper Green lily Lavender

Oyster Banana Gingerbread

Gardenia Vanilla Apple

Celery Lily Garlic

Hazelnut Bitter almond PPA

Tar Caprylic aldehyde Rose

l Methyl acetate Passion fruit Thyme

Biscuit Eucalyptus Lime

Tobacco Coconut 1-Octen-3-ol

3-Methyl anisol Clove Camomile

4.56 (0.28) 4.38 (0.39) 4.37 (0.23)

4.03–4.91 3.41–4.69 3.89–4.61

6.53 (0.75) 6.28 (0.67) 6.24 (0.23)

5.13–7.27 4.89–7.24 4.96–6.91

eviation. Italic, familiar odorants. Odorants were rated on a 10-point rating

ee Royet et al., 1999).

J. Plailly et al. / NeuroImage 24 (2005) 1032–10411034

injection head placed within the stray-field of the magnet.

Compressed air (10 l/min) was pumped into the olfactometer,

and delivered continuously through a standard anesthesia mask. A

detailed description was recently given (Vigouroux et al., in press).

The ventral breathing rhythm of the subject was recordedwith the

aid of a foot bellows in polyvinyl chloride (Herga Electric Limited,

Suffolk, UK) held on the stomach with a weaved cotton belt.

Movements of the abdominal wall produced variations in the internal

volume of the foot bellows. The flow was transformed into an

electrical signal that was amplified, and then successively trans-

mitted to the acquisition system and to a headphone via a voltage-to-

frequency converter. The experimenter could therefore listen to the

progressive frequency variations that accompanied respiration (high

frequency during inspiration and low frequency during expiration).

This method made respiration easily detected for the experimenter

and allowed easy timing of the stimulus delivery. During scanning,

the subject was instructed to avoid sniffing or blocking his breathing,

but instead to breathe regularly, thus allowing the experimenter to

anticipate the beginning of an inspiration phase. One stimulus was

then injected into the olfactometer by squeezing one bottle into the

injection head, so that the odor (or odorless air) was carried to the

subject’s anesthesia mask.

Subjects rated familiarity or judged odor presence by pressing

one of two buttons. The response signal was then transmitted

outside the radiofrequency shielded room by fiber optics to analog-

to-digital converters powered by nickel–cadmium batteries.

Behavioral data were recorded on line (100 Hz sampling rate)

using a NEC PC computer equipped with a digital acquisition

board DAQCard-500 (National Instruments, USA). LabView 5.0

software (National Instruments) was used to acquire, store, and

read data. Data analysis was performed with the WinDaq Wave-

form Browser 1.91 software (DataQ Instruments, USA).

Experimental procedure

A single functional run was presented in blocks that consisted

of two olfactory conditions (F and D) alternating with odorless rest

(R) epochs (Fig. 1). Each epoch lasted 60 s. Both F and D

conditions were presented three times each, either three F followed

by three D conditions or vice versa. Within the same condition, the

presentation order of the three sets (a, b, c) was counterbalanced

across subjects according to a balanced experimental (Latin square)

design. For olfactory conditions, subjects were asked to judge

whether or not they smelled an odor (D condition) or whether the

odor was familiar or unfamiliar (F condition). Subjects were then

asked to make a dyesT or dnoT rating using the two buttons with

Fig. 1. Experimental procedure showing the functional run including 12

epochs of 60 s each. Two olfactory conditions were performed: one

detection condition with three epochs (Da, Db, Dc) and one familiarity

condition with three epochs (Fa, Fb, Fc). Example of an epoch (Da) for

which 15 stimuli (from S1 to S15) were delivered. R, rest.

their dominant hand. For half of the subjects, dyesT and dnoTresponses were obtained with the index and the middle fingers,

respectively. For the other half of the subjects, the meaning of the

two key-press buttons was reversed. For the R condition, no

stimulation was provided and the subjects were instructed not to

use the key-press buttons.

General instructions were provided to subjects before the

functional run. During the run, and 3 s before each experimental

condition (F, D or R), subjects were instructed orally by means of

specific keywords (dfamiliarity,T ddetection,T and drestT) which task

was to be performed next. Subjects wore earplugs to protect

hearing from excessive scanner noise and kept their eyes closed

during scanning. The day before the fMRI examination, subjects

were trained outside the MR facility to breathe regularly, to detect

odorants without sniffing during normal inspiration, and to give the

most rapid possible response (odor vs. no odor) using the buttons.

Imaging parameters

Functional MR imaging was performed on a 1.5-T MR imager

(Philips NT). Twenty-five adjacent 5-mm-thick axial slices were

imaged. The imaging volume covered the whole brain and was

oriented parallel to the bicommissural plane. The image planes

were positioned from scout images acquired in the sagittal plane. A

3D three-shot PRESTO MR imaging sequence (Liu et al., 1993)

was used with the following parameters: TR = 26 ms, TE = 38 ms,

flip angle = 148, field-of-view = 256 � 205 mm2, imaging matrix =

64 � 51 (voxel size of 4 � 4 � 5 mm3). This sequence is less

prone to magnetic susceptibility artifacts than the usual echo planar

imaging (EPI) sequence (Van Gelderen et al., 1995), particularly in

the OFC and mesial temporal region (Zald and Pardo, 2000).

During the functional run, the volume of interest was scanned 144

times successively. The signal was averaged three times, leading to

an acquisition time per volume of 5 s. A high-resolution anatomical

3D T1-weighted MR scan was acquired before the functional run.

Data processing and statistical analyses

Functional images were analyzed using SMP99 (Wellcome

Department of Cognitive Neurology, London, UK). Image process-

ing included interscan realignment, spatial normalization to stereo-

tactic space as defined by the Montreal Neurological Institute

(MNI) reference brain template, and image smoothing with a three-

dimensional Gaussian kernel (FWMH: 8 � 8 � 10 mm3) to

overcome residual anatomical variability during group analysis,

increase the signal-to-noise ratio and conform to Random Field

Theory assumptions underlying the statistical analysis (Friston et

al., 1995a). A boxcar reference function was convolved with

SPM99’s dcanonical hemodynamicT response function. A high-pass

filter (cutoff frequency of 1/720 Hz) was used to eliminate

instrumental and physiological very low frequency signal fluctua-

tions. Global differences in BOLD signal were covaried out from all

voxels, and comparisons across conditions were effected with t

tests. The statistical significance of signal differences was assessed

through Z scores in an omnibus sense, using an uncorrected height

threshold (P b 0.001). Only clusters of more than 10 adjacent

activated voxels were taken into account as a significant hemody-

namic response (Z N 3.20 at voxel level). Duvernoy’s (1991) and

Mai et al.’s (1997) anatomic atlases were used to localize and

describe activated anatomic regions as the often used Talairach’s

atlas (Talairach and Tournoux, 1988) describes subcortical and

Table 2

Behavioral data recorded for the three sets of odors (a, b, c) during the detection and familiarity judgment tasks

Parameter Task Response Set a Set b Set c

Mean number of stimulations Detection 13.33 F 1.87 14.11 F 3.02 13.89 F 1.96

Familiarity 12.89 F 2.20 13.33 F 2.24 13.44 F 2.65

Response accuracy Detection 0.962 F 0.050 0.857 F 0.104 0.930 F 0.078

Reaction time Detection Yes 1.597 F 0.462 1.698 F 0.624 1.625 F 0.487

No 2.125 F 0.602 2.092 F 0.758 2.033 F 0.620

Familiarity Yes 2.141 F 0.668 1.985 F 0.540 2.153 F 0.635

No 2.220 F 0.652 2.346 F 0.730 2.359 F 0.819

Proportion of familiar odors Familiarity 0.545 F 0.214 0.520 F 0.188 0.509 F 0.180

For reaction time, data are given according to whether the odors were detected or not (Yes or No), or whether they were recognized as being familiar or not (Yes

or No).

J. Plailly et al. / NeuroImage 24 (2005) 1032–1041 1035

limbic olfactory regions with much less detail. Activated areas were

indicated using the MNI coordinate system.

Specific effects for the familiarity judgment task were calculated

by comparing the signals during the F and D conditions using the

general linear model (Friston et al., 1995b). Intrasubject analyses

were first performed, followed by a random effects analysis which

extent statistical inferences into the healthy population. This two-

stage analysis accounted first for intrasubject variance (scan-to-

scan), and second for intersubject variance. In the first step, scan-to-

scan variance was separately modeled for each subject by creating a

summary contrast image from weighted parameter estimates that

represented each scan condition. In the second step, these contrast

images were then analyzed using a basic model one-sample t tests

to assess the F–D contrast against a null hypothesis.

A cluster analysis was further performed to compare activation

between the right and left PC. A region of interest (ROI)

corresponding to the right PC was defined by selecting an 8-

mm-diameter sphere centered on coordinates (30, 2, �16) of the

activation cluster obtained in the F–D contrast image from the

group analysis. An identical ROI was centered on the contralateral

coordinate in the left hemisphere (�30, 2, �16). Using the

MarsBar SPM toolbox (Brett et al., 2002), we then obtained a

mean activity level within both ROIs for each one of 12 subjects. A

statistical analysis was then performed to compare the activity

levels of left and right PC.

Fig. 2. Reaction times represented as a function of the olfactory task

(Detection vs. Familiarity) and of the type of response (Yes vs. No). Data

were normalized with respect to the number of stimulations per epoch. The

vertical bars show the standard errors of the means. *, significant difference

(P b 0.007).

Results

Behavioral data

Response accuracy was determined for the detection task only,

since the familiarity judgment depends on personal experience.

During the scanning day, two subjects scored very low response

accuracy (65% and 68%, respectively), due to a very small number

of odors detected (29% and 41%, respectively). The aberration of

both these values was rated with the Grubbs’ test (Dagnelie, 1975),

which indicated that they were indeed outliers (t = 5.414 and t =

5.052, respectively, for a theoretical value of t0.99815 = 3.663). One

of these subjects also did not provide behavioral responses during

the three epochs of the familiarity task. These two subjects were

therefore excluded from further analysis. For the 12 remaining

subjects, the mean numbers and response accuracies of odors

delivered per epoch for the three odor sets (Da, Db, Dc) of the

detection task are given in Table 2. A one-way ANOVA with

repeated measurements performed on response accuracy showed a

significant main effect of set factor [F(2,22) = 5.985, P = 0.0084],

indicating that odors of the Da and Dc sets were more easily

detected than those of the Db set.

For the F condition, the number of odorants judged as being

familiar or unfamiliar by the subjects was determined for the three

odor sets (Fa, Fb, and Fc). For each subject, data were normalized

with respect to the number of stimulations per epoch. The mean

number of stimulations and the mean ratios of familiar odorants

delivered per epoch are given in Table 2. A one-way ANOVAwith

repeated measurements performed on the ratios of familiar odor-

ants showed no significant effect of set factor [F(2,22) = 0.455, P =

0.640], indicating that the same proportion of familiar odorants was

found in the three odor sets.

Subjects’ reaction times for odor detection and familiarity

judgments were also calculated (Table 2). The number of

stimulations delivered per epoch depended on the subject’s

breathing rhythm. As this factor could affect reaction times by

creating a shorter interstimulus response period in those who

breathe more rapidly, the data were normalized with respect to the

number of stimulations, and analyzed as a function of task, odor

sets, and response (Yes or No) factors. A three-way ANOVA with

repeated measurements showed a significant effect of the judgment

task [F(1,11) = 33.380, P b 0.0001], of response [F(1,11) =

65.965, P b 0.0001], but no significant effect of odor set factor

[F(2,22) = 1.020, P = 0.3772]. Significant task � response

[F(2,22) = 10.153, P = 0.0087] (see Fig. 2) and task � set �

Table 3

Areas activated in the F–D contrast

Brain region L/R k Z value MNI coordinates

x y z

Amygdala L 54 4.29 �24 �6 �12

Cingulate gyrus L 67 4.21 �8 16 40

Mid-fusiform gyrus R 432 3.93 40 �40 �16

Amygdala R 3.85 20 �16 �10

Hippocampal

region (CA3)

R 3.84 22 �20 �8

Temporal

piriform cortex

R 3.75 30 2 �16

Parahippocampal

gyrus

R 3.61 42 �16 �10

Posterior Insula R 3.29 46 �10 �6

Superior occipital

gyrus

L 62 3.79 �16 �100 14

Inferior frontal gyrus,

pars orbitalis

L 13 3.27 �50 28 2

Note. F, familiarity; D, detection; L, left; R, right; k, size of the cluster in

number of connected voxels; x, y, z, MNI coordinates in mm of the

maximum in the Montreal Neurological Institute Brain template; CA,

Cornu Ammonis.

J. Plailly et al. / NeuroImage 24 (2005) 1032–10411036

response [F(2,22) = 3.833, P = 0.0373] interactions were noted.

Mean comparisons indicated that reaction times in the D condition

were longer when no odor was detected (P b 0.0001), longer in the

F condition when odors were perceived as more unfamiliar (P b

0.0070), and longer with unfamiliar odors during familiarity

judgments (as compared to detection judgments; P b 0.0001).

Breathing data

Breathing changes could be expected as a function of epoch, as

during F-epochs odors were delivered at each inspiration, and

during D epochs odors were delivered on 50% of inspirations.

Inspiratory airflow measures were therefore analyzed as a function

of task (Detection and Familiarity), three epochs (a, b, and c), and

subject responses (Yes and No) (Fig. 3). A three-way ANOVAwith

repeated measurements showed no significant effect of task

[F(1,22) = 2.169, P = 0.169], epochs [F(2,22) = 0.415, P =

0.665], and response [F(1,22) = 1.409, P = 0.260] factors.

fMRI data

F–D contrast

Familiarity-specific responses (F–D) were present in the right

temporal piriform area (30, 2, �16; Z = 3.75), spanning the

cortico-amygdaloid transition area, the preamygdalar claustrum,

the periamygdalar area, and the lateral amygdaloid nucleus (22,

�16, �10; Z = 3.85; Table 3 and Fig. 4A). PC activation was not

detected in the left hemisphere (using the same statistical

significance threshold), but strong activation was present in the

amygdala (�24, �6, �12; Z = 4.29) spanning approximate areas

for the basomedial, basolateral, central, lateral and medial

amygdaloid nuclei, and the anterior amygdaloid area. Familiarity-

related activation in the right PC extended into the right mid-

fusiform gyrus (40, �40, �16; Z = 3.93) and hippocampal region

(Fig. 4B; 22, �22, �8; Z = 3.84). The familiarity judgment task

also activated the left cingulate gyrus (�8, 16, 40; Z = 4.21) and

the left inferior frontal gyrus in its opercular part (�50, 28, 2; Z =

3.27), as depicted in Fig. 4C. Finally, we noted significant

activation in the left occipital gyrus (�16, �100, 14; Z = 3.79)

and the right middle frontal gyrus (44, 20, �18; Z = 3.40).

Fig. 3. Inspiratory airflow as a function of the olfactory task (Detection vs.

Familiarity) and of the type of response (Yes vs. No). Data were normalized

with respect to the number of stimulations per epoch. The vertical bars

show the standard errors of the means.

Comparison of activations between the right and left PC

Mean activity levels were measured in the right and left PC

using ROIs. A one-way ANOVA with repeated measurements on

these data showed significantly higher right than left PC activation

[F(1,11) = 4.846, P = 0.0499].

Discussion

The aim of this fMRI study was to determine the cerebral

regions that mediate judgments of odor familiarity. With such an

approach, we identified odor-evoked neural responses in several

olfactory and limbic regions, including piriform cortex, amygdala,

hippocampus, the pars orbitalis of the inferior frontal gyrus, and

the mid-fusiform gyrus.

Activation of the mesial temporal region

Olfactory-related activation of mesial temporal regions remains

inconsistent across studies. Whereas some authors have reported

activation in PC in PET studies (e.g., Kareken et al., 2001, 2003,

2004; Savic et al., 2000; Small et al., 1997; Zatorre et al., 1992),

we did not find any mesial temporal activation in our previous

studies (Royet et al., 1999, 2001). Piriform cortex activation has

also been inconsistently detected across fMRI studies (e.g., Sobel

et al., 1998; Yousem et al., 1999). A well-known problem with the

EPI pulse sequence usually applied in fMRI is magnetic

susceptibility artefact, which induces signal loss in these regions

(Zald and Pardo, 2000). The PRESTO sequence used in the current

study appears to reduce these artifacts and to provide stronger

signal in the regions affected by susceptibility differences.

Habituation may also contribute to signal loss in these ventral

regions, particularly with blocked designs and the use of only one

or two odorants (Poellinger et al., 2001; Sobel et al., 2000). Since

we used a different odorant on each breathing cycle (from 12 to 20

different odorants per 60-s epoch, depending on the duration of

breathing cycle of the subject), we minimized both self-adaptation

Fig. 4. Localization of task-specific activations in the F–D contrasts. (A) Piriform cortex; (B) hippocampus; (C) inferior frontal gyrus. Neural responses are

overlaid on coronal and axial sections from a subject’s normalized T1-weighted brain image. Clusters were thresholded at t = 3.10.

J. Plailly et al. / NeuroImage 24 (2005) 1032–1041 1037

(Engen, 1982) and sensory habituation (Demonet et al., 1993). As

in our previous fMRI study (Royet et al., 2003), the present data

suggest that the pulse sequence and stimulation paradigm provided

sufficient sensitivity to detect activation in primary olfactory areas.

A PC activation that is stronger in the F than D condition could

be explained by different factors. A possible confound lies first of

all in the higher proportion of odorous stimulations delivered in

the F than D condition. We decided for this particular design

because we considered it was important to keep the subjects’

attention focused during the detection task (in which they had to

respond dyesT and dnoT equivalently). At the same time, if we had

presented blanks during the familiarity task, this might have

confused the subjects and this would have introduced a third type

of event (no odor in addition to the familiar and the unfamiliar

odors). Further experiments are therefore needed to rule out this

specific confound. It would be of interest, in particular, to design

an event-related fMRI study in which familiar and unfamiliar

odors would be distinguished as discrete events in both conditions.

Unfamiliar odors of the F and D conditions could then be

contrasted and any PC activation could then be specifically

associated with the F task. It should nevertheless be noted that the

piriform cortex may become activated in retrieving odor associ-

ations alone, without any direct chemosensory stimulation

(Gottfried et al., 2004). This strongly suggests that the task

performed by subjects may be a decisive factor in activating the

piriform cortex.

A second source of potential confound may lie in the

different respiratory patterns across conditions, as it has

J. Plailly et al. / NeuroImage 24 (2005) 1032–10411038

previously been shown that sniffing alone can induce piriform

activation (Sobel et al., 1998; but also see Kareken et al., 2004

for contradictory results), and that odor imagery alone can lead

to breathing differences (Bensafi et al., 2003). In the present

study, however, inspiratory airflow was not higher in the F

condition than in the D condition. Finally, a third source of

potential confound is identified in the differences in odor

familiarity, since odors selected a priori as being familiar were

only delivered in the F condition. Nevertheless, the same number

of a priori unfamiliar odors were presented in both conditions.

We then noted that reaction times were much longer when the

unfamiliar odors were presented in the F condition, and even

longer than reaction times of familiar odors presented in this

same condition. This suggests that subjects performed different

judgments across conditions, and that activation differences in

PC could be better explained by the type of task than by

perceptual differences in odor familiarity. This could also explain

why Savic and Berglund (2004) did not find differential

activation in PC when subjects passively smelled familiar or

unfamiliar odorants. It nevertheless stands to reason, however,

that the task (when not explicitly required by the experiment)

should be facilitated by the intrinsic properties of the odors

themselves: That is, highly familiar odors would more easily

facilitate familiarity judgments, and highly pleasant or unpleasant

odors would more easily encourage emotional judgments.

Involvement of piriform cortex in recognition memory

Recognition memory is known to involve two different

processes: familiarity and recollection (Bogacz et al., 2001;

Mandler, 1980; Rajaram, 1998). According to the ddual processtheoryT, processes underlying familiarity are perceptual in nature,

and those subserving recollection include the retrieval of con-

textual information. Lehrner et al. (1999) demonstrated that these

two forms of recognition memory processes also exist in olfaction.

In other words, familiarity judgments are made on the basis of

feelings devoid of specific information about the encoding

episode, and thus relate to implicit memory. By contrast,

recollection is more directly tied to specific events, and thus

relates to explicit memory. To illustrate these concepts, Bogacz

et al. (2001) note that, b. . .it is not uncommon to be able to

recognize that a person is familiar to us even though we cannot

immediately recollect anything more about the person or our

previous encounters with themQ (Bogacz et al., 2001). Since

familiarity judgments are inherent in recognition memory, our

results relate to previous findings in humans indicating that PC is

involved in long-term odor recognition memory (Dade et al.,

2002). More recently, Gottfried et al. (2004) further reported that

PC responds to non-olfactory stimuli with which odors were

previously associated.

Further experiments are needed to compare activation

produced by different memory processes. Familiarity and

recollection could involve slightly different neural networks,

but the present experimental design cannot distinguish between

them. Our findings nevertheless cohere with a large body of

research using animal models, and lend support to the theory that

the piriform cortex is involved in learning- and memory-related

processes (e.g., Datiche et al., 2001; Schoenbaum and Eichen-

baum, 1995). For instance, synaptic potentiation has been shown

to occur in rat PC in vitro (e.g., Jung et al., 1990; Saar et al.,

2002) and in vivo at the conclusion of learning (Litaudon et al.,

1997; Roman et al., 1993). These findings are thus consistent

with models demonstrating that the primary olfactory cortex is a

parallel-distributed architecture characteristic of associative mem-

ory systems (e.g., Bower, 1991; Haberly, 2001; Haberly and

Bower, 1989).

Lateralization of familiarity judgment process

The current study shows that activation of the right PC was

stronger than that of the left PC. This is in line with the results of a

large body of other research. In a monorhinal odor recognition

task, Savic et al. (2000) noted significant right, but not left,

piriform activity. Although Dade et al. (2002) did not explicitly

report hemispheric asymmetry for long-term olfactory memory,

their results distinctly indicated strong activation in right OFC, and

more activation in right than left PC. Interestingly, Gottfried et al.’s

study of cross-modal visual–olfactory associations also showed

unilateral right PC activation, and in this case without direct

olfactory stimulation. Using behavioral measures, Broman et al.

(2001) finally observed that odors presented to the right nostril

were rated as more familiar than odors presented to the left nostril.

They also reported that episodic recognition via the right nostril

tended to nominally have more dknowT responses and fewer

drememberT responses than did odors recognized via the left nostril,which is in keeping with the right-nostril advantage for familiarity.

Taken together, these findings are consistent with the notion that

left temporal lobe structures mediate processing of distinctiveness

(i.e., what clearly distinguishes one percept from another), whereas

right temporal lobe structures subserve processes underlying

perceptual fluency (i.e., what involves perceptual analysis of the

surface features of an item; Blaxton and Theodore, 1997; Rajaram,

1998). Such a perceptual analysis of surface features is especially

observed for odors which are intrinsically difficult to name

(Lawless and Engen, 1977).

Findings in brain-damaged patients and results from neuro-

imaging studies converge with these data. For instance, epilepsy

patients with left temporal lobe lesions who were asked to

recognize previously seen abstract designs provided more dknowTthan drememberT responses, whereas right temporal lesioned

patients showed the opposite pattern (Blaxton and Theodore,

1997). Along the same line, Henson et al. (1999) explored word

recognition with fMRI and showed a dissociation whereby a

dknowT judgment induced right frontal activation, and a

drememberT judgment induced left frontal activation.

In conclusion, the present data, which are consistent with our

previous work in PET, indicate a preferential involvement of the

right hemisphere in familiarity judgments (Royet et al., 1999,

2001). An intriguing result in the present study is the lack of

activation in right OFC. When specifically examining activation

resulting from familiarity versus rest, and from detection versus

rest, we nevertheless saw activation in the right OFC for both

contrasts (44, 32, �16; Z = 3.62 and 46, 30, �12; Z = 2.79,

respectively). This could explain the lack of activation when we

compared images in the familiarity versus detection contrast.

Participation of the hippocampal region, inferior frontal and

mid-fusiform gyri in modality-independent mnemonic and semantic

processing

Since only a few authors have previously reported hippocampal

activations in olfaction studies (e.g., Kareken et al., 2003; Suzuki

J. Plailly et al. / NeuroImage 24 (2005) 1032–1041 1039

et al., 2001), the right hippocampal activation during the familiarity

judgment task was not anticipated in the present study. Inconsistent

activation of the hippocampal formation is not specific to olfaction,

and has been characteristic of other studies of memory (Andreasen

et al., 1995; Shallice et al., 1994; Tulving et al., 1996). Our data are

nevertheless consistent with a recent finding showing hippocampal

activation during the retrieval of olfactory episodic memories

(Gottfried et al., 2004).

Lesion studies recently examined whether the brain structures

that comprise the medial temporal lobe memory system (i.e., the

hippocampal and parahippocampal regions) differ in how they

support recollective and familiarity components (Manns et al.,

2003; Yonelinas et al., 2002). Our data do not permit distinguish-

ing these aspects of memory, as the subjects may well have had

consciously evoked memories from the odorants. They are,

however, consistent with the idea that both regions probably

contribute to olfactory recognition memory.

Activation of the left inferior frontal gyrus, in the pars

orbitalis, during familiarity judgments further supports the

hypothesis that this region is involved in the selection and

integration of semantic information in a modality-independent

manner (Homae et al., 2002; Kareken et al., 2003). In a recent

study, Savic and Berglund (2004) found that left frontal and right

parahippocampal region activation positively correlated with

familiarity ratings, showing the engagement of semantic circuits

during passive smelling of familiar odorants. Along the same line,

the mid-fusiform gyrus activation in the current study might lead

to similar interpretations, since it has further been associated with

visual, tactile and auditory recognition and categorization of

objects (Adams and Janata, 2002; Joseph and Gathers, 2003;

Stoeckel et al., 2003). Its involvement in olfactory object

recognition therefore reinforces the idea of the polymodal nature

of this area (Adams and Janata, 2002) and its role in semantic

processing (Price, 2000; Wagner et al., 1998).

Conclusion

Complementing previous PET studies that demonstrate right

OFC involvement in odor familiarity judgments, the present fMRI

study shows that right PC is also activated during this task, an

activation that may be related to olfactory recognition memory. In

previous fMRI and PET studies, we demonstrated that a neural

network in the left hemisphere, involving the OFC and primary

olfactory areas, mediated olfactory hedonic perception (Royet et al.,

2000, 2003). It thus appears that odor processing activates a large

neural network involving both hemispheres. Nevertheless, this

network possesses hemispheric predominance depending on the

type of olfactory task performed (see Royet and Plailly, 2004, for

review). The present data provide further evidence that the right

hippocampal region, left inferior frontal gyrus and mid-fusiform

gyrus take part in recognition memory, likely cross-modally to

assist in gathering relevant associations to enable identification of

olfactory percepts.

Acknowledgments

We thank the technical team (M. Vigouroux, B. Bertrand, and

V. Farget) for designing and building the stimulation and recording

materials and J.P. Lomberget and M.B. Sanglerat for medical

examinations of subjects participating in the study. We are grateful

to the companies Givaudan, International Flavors and Fragrances,

Lenoir, Davenne, and Perlarom for supplying the odorants used in

this study. This work was supported by research grants from the

dRegion Rhone-AlpesT and the dGIS Sciences de la Cognition,T thedCentre National de la Recherche Scientifique,T and the dUniversiteClaude-Bernard de Lyon.T

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