Functional Neuroanatomy of Different Olfactory Judgments

NeuroImage 13, 506 –519 (2001) doi:10.1006/nimg.2000.0704, available online at http://www.idealibrary.com on

Functional Neuroanatomy of Different Olfactory Judgments Jean P. Royet,* Julie Hudry,* David H. Zald,† Damien Godinot,* Marie C. Gre´goire,‡ Franck Lavenne,‡ Nicolas Costes,‡ and Andre´ Holley* *Neurosciences and Sensory Systems, CNRS UMR 5020, Claude-Bernard University Lyon 1, 69622 Villeurbanne, France; †Department of Psychology, Vanderbilt University, Nashville, Tennessee 37240; and ‡Neurological Hospital, CERMEP, 69003 Lyon, France Received June 21, 2000; published online January 19, 2001

Humans routinely make judgments about olfactory stimuli. However, few studies have examined the functional neuroanatomy underlying the cognitive operations involved in such judgments. In order to delineate this functional anatomy, we asked 12 normal subjects to perform different judgments about olfactory stimuli while regional cerebral blood flow (rCBF) was measured with PET. In separate conditions, subjects made judgments about the presence (odor detection), intensity, hedonicity, familiarity, or edibility of different odorants. An auditory task served as a control condition. All five olfactory tasks induced rCBF increases in the right orbitofrontal cortex (OFC), but right OFC activity was highest during familiarity judgments and lowest during the detection task. Left OFC activity increased significantly during hedonic and familiarity judgments, but not during other odor judgments. Left OFC activity was significantly higher during hedonicity judgments than during familiarity or other olfactory judgments. These data demonstrate that aspects of odor processing in the OFC are lateralized depending on the type of olfactory task. They support a model of parallel processing in the left and right OFC in which the relative level of activation depends on whether the judgment involves odor recognition or emotion. Primary visual areas also demonstrated a differential involvement in olfactory processing depending on the type of olfactory task: significant rCBF increases were observed in hedonic and edibility judgments, whereas no significant rCBF increases were found in the other three judgments. These data indicate that judgments of hedonicity and edibility engage circuits involved in visual processing, but detection, intensity, and familiarity judgments do not. © 2001 Academic Press

Key Words: detection; intensity; hedonic; familiarity; edibility; orbitofrontal.

INTRODUCTION In a previous positron emission tomography (PET) study, we examined the organization of cognitive oper1053-8119/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.

ations involved in the perception of odors (Royet et al., 1999). We assessed regional cerebral blood flow (rCBF) while subjects performed judgments of familiarity, edibility, or attempted to detect odorants. We hypothesized that the familiarity and the edibility tasks, respectively, required either the activation of perceptual or the activation of both perceptual and semantic representations of odors, whereas the detection task required a superficial judgment that did not involve stored representations of odors. Our results showed that familiarity judgments selectively activated the right medial orbitofrontal cortex (OFC). Edibility judgments significantly activated visual regions suggesting that such judgments require (or engage) visual representations of food. Several other neuroimaging studies of olfaction using fMRI (Levy et al., 1997, 1998; Yang et al., 1997; Yousem et al., 1997; Fulbright et al., 1998; Sobel et al., 1997, 1998a,b, 2000) and PET (Zatorre et al., 1992; Small et al., 1997; Zald and Pardo, 1997, 2000; Dade et al., 1998; Zald et al., 1998a; Savic et al., 2000; Savic and Gulyas, 2000) have been reported. In most of these studies, significant activations localized to the OFC, especially in the right hemisphere. One of the few exceptions to this pattern is a series of studies by Zald and Pardo (1997, 2000) and ourselves (Royet et al., 2000) who observed greater left than right OFC (inferior frontal gyrus, pars orbitalis) activity during exposure to odorants with strong affective valences. In most of the above-mentioned studies, subjects were not asked to perform a specific task during the actual scanning period. However, as emphasized by De´monet et al. (1993b), “The presence of a ‘passive task’ in an activation paradigm ignores the nature of the cognitive components of such a task and therefore obscures the interpretation of any between-task differences in brain activity.” They suggested that subjects should perform tasks that require them to actively attend to sensory stimuli. They also proposed the use of active control conditions as opposed to so-called resting tasks in which subjects are not asked to engage in any particular activity. Such an uncontrolled resting state

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may variably involve heterogeneous processes including some form of imagery (Kosslyn et al., 1995; Zald et al., 1998a). Some neuroimaging studies have paid greater attention to the tasks performed in the control condition. However, in many cases, the effects of the control condition on rCBF are unclear. For instance, Zald and Pardo (1997) examined if the subjects could detect an odorant although none was presented (odor detection). Yet, it is possible that this condition induced activations that obscured the ability to see rCBF increases during odorant exposures. Similarly, in our previous study (Royet et al., 1999), there was no true baseline condition, leaving it possible that some areas (including primary olfactory cortex) were activated in all conditions, and thus was cancelled out in all subtraction analyses. An additional criticism of many studies arises because most neuroimaging studies use only a few odorants or even a single odorant during scanning. However, when subjects must perform a cognitive task for a scan, it is recommended that experimenters use different stimuli to avoid problems associated with sensory habituation or the performance of tasks in a routinized manner (De´monet et al., 1993a). The present study aimed to compare the cerebral areas involved in different olfactory tasks. The study improves upon our previous study in several regards. First, in addition to the three tasks used in our original study (Royet et al., 1999), we examined two new olfactory tasks: judgment of intensity and judgment of hedonic value. This allowed us to assess whether these olfactory judgments involve neural networks different from those activated by the familiarity and edibility judgments. Second, we performed control scans that did not involve olfactory stimulation. Instead, we utilized an auditory cognitive task to overcome difficulties related to a passive task. This allowed us to assess common activations across the different olfactory tasks. Third, we used a set of 185 odorants to avoid repetition of stimuli that can induce habituation. In addition, odorants were distributed into different tasks as a function of their olfactory properties to optimize odor judgments of the subjects. Fourth, we used a tomograph with a higher spatial resolution than in the previous study, so that structures of small size in the temporal lobe could be more clearly visualized. MATERIALS AND METHODS Subjects Twelve right-handed male subjects (20 –30 years of age) participated in the study. Prior to scanning subjects were screened with an odor detection task. Only subjects performing this task with at least 80% accuracy, and possessing a mean duration of breath cycle of 3– 6 s were kept for the final study. We applied this breath cycle criteria because a duration shorter than

507

3 s was not adequate to stimulate for each breath cycle and could result in mixing odorous stimuli to each other, while a duration longer than 6 s resulted in too few stimulations per scan and obliged subjects to concentrate on each stimulus for an extended period of time. Subjects with asthma or a pronounced tendency to have respiratory allergies were also excluded. Finally, subjects received a medical examination to rule out hereditary genetic diseases or other or contraindications to radiation exposure. All subjects provided informed written consent and the experiment was conducted as approved by the local Ethic Committee and according to French regulations on biomedical experiments on healthy volunteers. Odorous Stimuli The entire experiment required 247 odorant exposures. As it was not possible to acquire a sufficient number of different stimuli with definite characteristics (intensity, hedonicity, familiarity, and edibility), 91 odorants were used twice. Thus, 156 different odorants were used. They were diluted in mineral oil to produce 5 ml of odorous solution (10%) and presented in 100-ml polyethylene bottles (see Royet et al., 1999, for details). The concentration of the products with very high potency (e.g., mustard) was limited to 1‰. Odorants were distributed into eight sets containing 26 odorants each as a function of their intensity, hedonicity, familiarity, and edibility ratings (Royet et al., 1999). For each cognitive task, 13 odors were selected so as to provide the highest scores and 13 other odors were selected to provide the lowest scores within each respective dimension (i.e., the most intense and the least intense, the most pleasant and the least pleasant, the most familiar and the least familiar, and the most edible and the least edible) (see Table 1). For each detection task, 13 bottles with odorants that lacked characteristic features (i.e., medium rankings on all dimensions) and 13 bottles with no odor were used. For the training task, 13 bottles with odorants that lacked characteristic features and 13 bottles with no odor were also used. In each set, the order of presentation was pseudorandomized. Auditory Stimuli Fifty-two auditory stimuli were used for the control task. Half of these stimuli were composed of two successive sounds of different tonalities, and the other half was composed of one sound with a given tonality. Thus, for each scan, 13 stimuli with two sounds and 13 stimuli with one sound were presented. Each stimulus was presented for 1 s. When a stimulus with two contiguous sounds was used, each sound lasted 500 ms. The onesound stimuli differed by their frequency (high or bass tones). The two-sound stimuli were made with two tones of different frequencies. Half of these stimuli

No odor Celery

No odor Ethyl diglycol

No odor No odor Coffee No odor

19 20

21 22

23 24 25 26

No odor Hexyl cinnamaldehyde No odor No odor Eucalyptus No odor

No odor Tetrahydrofurane

No odor Camomile No odor 3-Methylanisol No odor No odor Gingerbread No odor Ethylpropionate Heptanal 2-Heptanol No odor Hexanal Nonyl acetate No odor Dimethyl sulfoxide Cucumber No odor

Detection

No odor No odor Diethylene glycol No odor

Wine No odor Pyrrole Acetic acid No odor No odor Eucalyptus Tetralin No odor Butanol Celery No odor 3-Methylanisol No odor No odor No odor 2-Heptanol Methyl isonicotinate No odor Propylidene phthalide Pizza No odor

Detection

Hazelnut Tomato Bergamote b-Piccoline

Liquorice Cyclohexane

White spirit Acetophenon Acetone b-Caryophyllene Mustard trans-2-Hexenal Tarragon Cypress Sandalwood Garlic Cinnamon Orange Peach Incense 4-Pentanoic acid Mushroom Wild rose Methyl isonicotinate Citronella Raspberry

Intensity

Ethyl diglycol Furfuryl mercaptan Bornyl acetate Tetrahydrothiophene

Anise Pizza

Camomile 4-Acetyl pyridine

Vanilla Onion Fir Ether Patchouli Cerise Heptanal Guaiacol Nerol Musk Apricot Butyric acid Lily Caramel Strawberry Petrol Muscat Banana

Intensity

Acacia Ethyl mercaptan Basil Coconut

4-Pentanoic acid Honeysuckle

Incense Lime

Lavender Tomato Methyl acetate Plum Garlic Rose Pepper Acetophenone Mint Hexanal Biscuit Gardenia Phenyl propionald. Ethyl propionate Chewing gum Hexane Isopropyl acetate Strawberry

Hedonicity

Bitter almond Geranium Passion fruit Isovaleric acid

Musk Toluene

Cumin Peach

Lemon Pine Jonquil Violet Clove Apple Ethyl pyrazine Butyric acid 2,5-Dimethyl pyrrole Lis Mustard Vervain Pear 1,4-Dichlorobutane Lilac ␤-Caryophyllene Green lemon Melon

Hedonicity

Cherry Hexane Carnation 2,5-Dimethyl pyrrole

Acetol Nutmeg

Diethylene glycol Gardenia

Anise Liquorice Caprylic aldehyde Wintergreen Lavender Black currant Green lemon Wheaten ⫹ bread Ether Amyl valerate Wild strawberry Neroli Carrot Mint Isopropyl acetate Persil Ethyl benzoyl acetate Thyme

Familiarity

Butyl bromide Fennel Caprylic aldehyde Acetone

Cinnamon Acetol

Muscat Citronella

Ethyl benzoylacetate Sage Valerolactone Diethyl maleate Lime 2-Octanol Apricot Rose Carrot Ethyl acetate Violet Ethyl phenylacetate Garrigue Chewing gum Jasmine Pyrrole 4-Acetyl pyridine Ginger

Familiarity

Jasmine Honeysuckle Patchouli Ethyl nitrite

Coconut Lemon

Biscuit Grass

Wild rose Hazelnut Wheaten bread Tobacco Petrol Strawberry Shellfish Cognac Banana Melissa Tangerine Lilac Pine needle Passion fruit Jonquil Vanilla Honey Mushroom

Edibility

Raspberry Isovaleric acid Bitter almond Lis

Hyacinth Tarragon

Cypress Thyme

Oak Caramel Fig Pear Cedar Smoked salmon Tar Apple Turpentine Pine Iris Vervain Sandalwood Camphor Fennel Grapefruit Fir Chocolate

Edibility

Note. Name in italic: odor selected as being either the most intense, or the most pleasant, or the most familiar, or the most edible. Underlined name: odorant of which the concentration was limited to 1‰.

Beer No odor No odor Melon No odor No odor Methyl acetate No odor Cyclohexane Gingerbread No odor No odor Wine Parsley Butanol No odor Cucumber Cumin

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Training

List of Odors Selected for Each Scan of Detection, Intensity, Hedonicity, Familiarity, and Edibility Judgments

TABLE 1

508 ROYET ET AL.

DIFFERENT KINDS OF ODOR PROCESSING

509

presented two tones with frequencies ranging from low to high, and the other half with frequencies ranging from high to low. The interval between tones differed for all stimuli (i.e., second, third, fourth, fifth, octave, . . .).

illumination was dimmed during all scans. Because pleasantness and edibility judgments for odors have been shown to be influenced by homeostatic factors (Cabanac and Duclaux, 1970; Cabanac, 1971), all subjects were tested in the morning.

Stimulation Materials

PET and MRI Scanning

Odors were presented with an air flow olfactometer that delivered stimulation synchronized with breathing (see Royet et al., 1999, for additional details). Subjects received odorant stimulation during each inspiration cycle for a total period of 80 s (60 s of brain activity recording and 20 s to prepare the subject before beginning data acquisition). Given an average respiratory cycle of 4 –5 s, this resulted in the presentation of approximately 20 of the possible 26 stimuli during each condition. Auditory stimuli were presented with stereo headphones. Only one auditory stimulus was presented in each breath cycle. The auditory stimulation was delivered when pure air was injected with an empty bottle in the air flow olfactometer.

High-resolution three-dimensional MRI images (171 slices, 1 mm thick) were obtained for each subject using a Siemens 1.5-T Magnetom camera. PET scanning was accomplished with a whole-body tomograph (Siemens Exact HR⫹) in 3-D mode, with a transaxial resolution of 4.5-mm full-width at half-maximum (FWHM). It provided 63 plans of 2.43 mm, presenting a field of axial view of 15.2 mm. The subject’s head was immobilized with a thermoplastic facemask (Tru-Scan Imaging Inc., Annapolis, MD) to reduce patient movement and to allow reproducible positioning. The effects of radiation self-attenuation were corrected by an initial transmission scan of each subject using an external positron-emitting isotope ( 68Ge). An iv bolus injection of 333 MBq H 215O was given for each run in the left forearm brachial vein through an indwelling catheter. Emission scans began when activity rose above the background noise level by 200%,and lasted 60 s. The images were attenuation-corrected and reconstructed with filtered back projection using a Hamming filter.

Procedure Prior to the day of scanning, subjects performed a training session in which they learned to breathe regularly, to detect stimulations, and to give a manual response with two key-press buttons (see Royet et al., 1999). On the scanning day, a total of 12 PET scans were taken of each subject, with two scans in each of the following six conditions: control, detection, intensity, hedonicity, familiarity, and edibility. For the control condition, the subjects were asked to determine whether they successively heard two sounds or they just heard one sound. For the olfactory conditions, they were asked to rate whether they smelled an odor or not or whether the odor was intense or not intense, pleasant or unpleasant, familiar or unfamiliar, and edible or not edible, respectively. The order of the six conditions differed among subjects, so as to obtain a balanced experimental design (Latin square). The scans were performed every 10 min. Instructions were provided to the subjects before every scan to limit the probability of interference between the different cognitive tasks. During each scan, and for each stimulus, subjects were asked to make a “yes” or “no” rating using the two key-press buttons (the right button with the middle finger of the right hand and the left button with the index finger of the same hand). For half of the subjects, the “yes” and “no” responses were obtained with the index finger and the middle finger, respectively. For the other half of the subjects, the meaning of the two key-press buttons was reversed. The yes/no judgments and the reaction times were recorded with a Macintosh LC 475 computer. Subjects wore a blindfold over their eyes, and room

Image Data Analysis PET scans were analyzed using statistical parametric mapping (SMP96, MRC Cyclotron Unit, London, UK) (Friston et al., 1995a,b). The steps involved included interscan realignment, normalization to stereotactic space as defined by the ICBM template provided by the Montreal National Institute (MNI), and smoothing of the images using a three-dimensional Gaussian filter (FWHM, 20 mm) to overcome residual anatomical variability. The localization of activated areas was also examined by reference to an MRI template, and the results are presented using the nomenclature of Duvernoy (1991) in labeling cortical regions. Global differences in CBF were covaried out for all voxels and comparisons across conditions were made using t tests. The significance of rCBF differences was assessed through z scores using the pixel and the spatial extent values, corrected in an omnibus sense (Friston et al., 1995b). Threshold for z maps was set at 3.09 and significance was set at P ⬍ 0.05. Main and simple effects. Simple effects were deduced from comparisons between olfactory (Olf) and control (Con) conditions (Olf ⫺ Con, Con ⫺ Olf) for each one of the olfactory tasks: detection (Det), intensity (Int), hedonicity (Hed), familiarity (Fam), and edibility (Edi). Odor detection may be treated as the simplest and least elaborated type of olfactory judgment task (Royet et al., 1999). As such it may serve as a useful

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by restricting the analysis to a small volume. We delineated a volume of interest (VOI) around the center of gravity of activated areas in both the right and the left OFC. Each VOI was defined by a sphere of 10-mm radius, and statistics were based on the ad hoc cluster level. Thus, the magnitude of the rCBF changes was the same as in the exploratory analysis, but the level of uncorrected statistical significance was reduced, due to the considerable decrease in the search space. Contrasts between Fam and other olfactory (Det, Int, Hed, and Edi) conditions and between Hed and other olfactory (Det, Int, Fam, and Edi) conditions were then performed. FIG. 1. Accuracy (%) of behavioral responses as a function of the type of cognitive task (Con, control; Det, detection; Int, intensity; Hed, hedonicity; Fam, familiarity; Edi, edibility) and run (scans 1 and 2).

control for more elaborate types of olfactory judgments: it cancels out some of the nonspecific activation associated with olfactory stimulation and basic judgment processes, without impairing the ability to detect activations related to specific higher level judgment conditions. We, therefore, also calculated simple effects for comparisons between the Det and the other four olfactory judgments. Main effects were determined to evidence brain areas significantly activated in the five olfactory tasks, by performing an analysis of conjunction according to the formula [(Det ⫺ Con) and (Int ⫺ Con) and (Hed ⫺ Con) and (Fam ⫺ Con) and (Edi ⫺ Con)]. We performed a conjunction analysis to determine common areas of activation across the olfactory conditions. As implemented in SPM96, this represents the main effect of the olfactory judgment tasks after elimination of the interactions between the simple effects (Price and Friston, 1997). Simple effects could be also deduced from contrasts between the higher-level olfactory tasks (Int, Hed, Fam, and Edi). We performed the seven following exploratory contrasts: Edi ⫺ Fam, Edi ⫺ Hed, Edi ⫺ Int, Fam ⫺ Hed, Fam ⫺ Int, Hed ⫺ Fam, and Hed ⫺ Int. Volumes of interest. Because the conjunction analysis revealed a common activation in the right OFC, and the exploratory SPM analyses failed to consistently demonstrate activations differences in this region between the olfactory conditions, these differences could be relatively small compared to the main effect of performing an olfactory judgment (see Price and Friston, 1997, for further elaboration of this issue). Nevertheless, more subtle differences between conditions could exist, and the existence of such differences was supported by our previous study, which observed increased right OFC activity in familiarity judgments relative to other judgments (Royet et al., 1999). To further explore the effect of different task conditions on rCBF within the right and left OFC, we performed a series of direct contrasts between olfactory conditions

RESULTS Behavioral Data Behavioral data are shown in Figs. 1 and 2. Accuracy of responses was determined as a function of results obtained in a previous study performed on 71 subjects (see Royet et al., 1999, first experiment). Thus, a binary response was considered as correct when it was congruent with mean scores found in the previous study. Although subject responses are subjective, odorous stimuli were selected so as to make judgments as homogeneous as possible. In this context, a response was considered “correct” if it was consistent with the judgments of a large sample of subjects. A two-way analysis of variance (ANOVA) with repeated measures (Winer, 1962) on the response accuracy (Fig. 1) showed a significant effect of the task [F(5,66) ⫽ 27.59; P ⬍ 0.0005], but no significant effect of run [F(1,66) ⫽ 0.00; n.s.], and no significant interaction [F(5,66) ⫽ 1.65; n.s.]. Multiple orthogonal comparisons revealed that the accuracy of responses was significantly higher for the auditory control condition than for the five olfactory conditions [F(1,66) ⱖ 20.06; P ⬎ 0.005] and higher for the detection than for the other olfactory tasks [F(1,66) ⱖ 5.19; P ⬎0.05 at least]. Two by two comparisons of the intensity, hedonicity, familiarity, and edi-

FIG. 2. Mean reaction times of subjects as a function of the correctness of responses, the type of cognitive task, and run.

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DIFFERENT KINDS OF ODOR PROCESSING

TABLE 2 Brain Regions with Significant rCBF Increases or Decreases When Subtracting the rCBF Images of the Control Task from Those of the Olfactory Tasks Cluster level Contrasts

Brain regions

BA

k

Voxel level

Pk

Z

Pz

x,y,z MNI (mm)

Det ⫺ Con

Middle frontal gyrus

10

661

0.095

4.15

0.028

30, 46, 10

Int ⫺ Con

Middle frontal gyrus

10

989

0.036

4.16

0.027

30, 46,

Hed ⫺ Con

Superior frontal gyrus Anterior cingulate/superior frontal gyrus Orbitofrontal/subcallosal Frontomarginal/middle frontal gyrus Anterior cingulate Inferior/middle temporal gyrus Cuneus/lingual gyrus

9 32/8 11/25/47 10/47 24/32 20/21 17/18

19,183

0.000

1,627 427 170 2,099

0.007 0.196 0.564 0.004

5.02 4.93 4.84 3.84 3.97 3.96 3.86

0.002 0.003 0.004 0.084 0.085 0.089 0.053

⫺6, 44, 34 0, 30, 38 ⫺26, 22,⫺10 36, 48, ⫺6 4, 28, 26 ⫺48, ⫺2,⫺34 ⫺6,⫺96, ⫺4

Anterior cingulate/sup frontal gyrus Superior frontal gyrus Superior frontal gyrus Middle frontal gyrus Orbitofrontal Orbitofrontal

32/8 6 9 10 11/47 11/47

15,042

0.001

1,893

0.004

1,610

0.007

5.41 4.77 4.60 4.43 3.66 4.28

0.000 0.006 0.012 0.010 0.156 0.017

0, ⫺8, ⫺4, 32, 28, ⫺26,

Orbitofrontal Cuneus/lingual gyrus

11/47 17/18

689 1,066

0.087 0.037

3.61 3.86

0.181 0.054

28, 26,⫺16 ⫺2,⫺84, 14

Anterior cingulate

32

1,050

0.019

Middle frontal gyrus Orbitofrontal

10 11

1,021

0.015

4.70 4.48 4.79 3.95

0.006 0.015 0.004 0.108

4, 4, 28, 26,

Fam ⫺ Con

Edi ⫺ Con Conjunction analysis

8

26, 38 22, 72 44, 36 46, 6 28,⫺10 24,⫺10

20, 38 22, 38 42, 6 30,⫺12

Note. Con, control; Det, detection; Int, intensity; Hed, hedonicity; Fam, familiarity; Edi, edibility; BA, Brodmann area; k, size of the cluster in number of connected voxels exceeding the threshold of 3.09. P k, corrected probability of finding the cluster in the Gaussian field. Z, score of the maximum of the cluster; P z, corrected probability of the maximum Z score; x,y,z MNI, coordinates of the maximum in the Montreal National Institute Brain template.

bility scores revealed that the number of correct responses always was higher in the intensity judgment task than in the hedonicity, the familiarity, and the edibility judgment tasks [F(1,66) ⱖ 4.84; P ⬍0.05 at least]. We also performed a three-way repeated measures ANOVA on the reaction times (Fig. 2), taking into account whether the response was correct, the type of condition, and the runs. The ANOVA demonstrated no significant effect of the correctness of responses [F(1,22) ⫽ 0.01], a significant effect of task [F(5,110) ⫽ 63.61; P ⬍ 0.0005], no significant effect of run [F(1,22) ⫽ 1.75], and a significant interaction between the last two factors [F(5,110) ⫽ 2.95; P ⬍ 0.05]. Multiple orthogonal comparisons showed that the subjects required less time to perform the auditory task than to perform any of the olfactory tasks (P ⬍ 0.0005). In addition, analyses revealed that reaction times in the detection task were faster in the first run than in the second run regardless of whether the responses were correct [F(1,110) ⫽ 4.836; P ⬍ 0.05] or incorrect [F(1,110) ⫽ 7.069; P ⬍ 0.01]. Taken together, these data indicate that subjects found the auditory task

easier than the olfactory tasks and that the olfactory detection task involved a more superficial processing than all of the other olfactory tasks. PET Results Olfactory tasks versus control task. When the rCBF images obtained in the auditory control task were subtracted from those obtained in the different olfactory tasks, significant differences in rCBF were detected in all comparisons, especially in the frontal lobe (Table 2). For the detection and intensity tasks, significant differences were observed in the right middle frontal gyrus (Brodmann’s area (BA) 10). A slight, but nonsignificant, increase was observed in the inferior frontal gyrus (BA 11/47). For the hedonicity task, activations were observed in the anterior cingulate gyrus (BA 24/ 32), the superior frontal gyrus (BA 9), the right inferior frontal gyrus (BA 10/47), the left OFC extending from the inferior frontal gyrus to the subcallosus gyrus, the left posterior OFC (BA 11, 25, 47), and the inferior/ middle temporal gyrus (BA 20/21). For the familiarity task, significant differences were found in the anterior

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TABLE 3 Brain Regions with Significant rCBF Increases or Decreases When Subtracting the rCBF Images of the Olfactory Tasks from Those of the Control Task Con ⫺ Det

Con ⫺ Int

Con ⫺ Hed

Con ⫺ Fam

Con ⫺ Edi

Superior temporal gyrus Middle temporal gyrus Superior temporal gyrus Superior parietal lobe/superior occipital gyrus

21/22/42 21 22 7/19

8,256 6,045

0.001 0.003

211

0.419

Superior temporal gyrus Middle temporal gyrus Middle temporal gyrus Superior temporal gyrus

21/22/42 21 21 22

5,816

0.000

10,231

0.001

Superior/middle temporal gyrus Superior temporal gyrus Superior temporal gyrus Superior temporal gyrus Middle occipital gyrus Superior parietal lobe/superior occipital gyrus

21/22/42 21 21/42 21 19 19

16,976

0.000

7,520

0.000

1,185

0.011

Superior/middle temporal gyrus Middle temporal gyrus Middle temporal gyrus Inferior temporal gyrus Fusiform gyrus Middle occipital gyrus Middle occipital/temporal gyrus Superior parietal lobe/superior occipital gyrus

21/22/42 21 21 19/37 37 19 19/39 19

31,680

0.000

671

0.066

920

0.027

484

0.135

Superior/middle temporal gyrus Middle temporal gyrus Middle temporal gyrus Cingulate gyrus/Precuneus Inferior temporal gyrus Precuneus

21/22/42 21 21 31/7 19/37 7

35,872

0.000

3,642

0.000

6.14 5.65 5.26 4.08

0.000 0.000 0.001 0.045

⫺58,⫺18, 2 66,⫺24, 4 56, 6, ⫺4 ⫺20,⫺74, 52

6.48 5.26 6.13 5.80

0.000 0.001 0.000 0.000

⫺54, ⫺4, ⫺2 ⫺54,⫺36, 14 64,⫺30, 6 56, 6, ⫺4

7.18 7.10 6.69 6.30 4.37 3.85

0.000 0.000 0.000 0.000 0.015 0.101

60, ⫺2, ⫺4 66,⫺20, 2 ⫺56,⫺22, 6 ⫺56, ⫺6, 0 ⫺38,⫺80, 28 ⫺24,⫺74, 44

7.14 6.37 6.33 4.36 3.94 4.33 4.11 3.89

0.000 0.000 0.000 0.015 0.075 0.018 0.041 0.089

⫺56,⫺14, 4 ⫺52,⫺34, 14 64,⫺26, 4 ⫺48,⫺62, 4 ⫺48,⫺60,⫺12 48,⫺76, 16 54,⫺66, 12 ⫺22,⫺74, 48

7.32 7.04 6.64 5.33 4.44 4.20

0.000 0.000 0.000 0.000 0.011 0.028

⫺56,⫺18, 4 ⫺52,⫺44, 12 62,⫺28, 2 6,⫺46, 40 ⫺48,⫺62, 4 6,⫺56, 44

Note. For abbreviations, see Table 2.

cingulate (BA 32), the middle frontal gyrus (BA 9/10), and the superior frontal gyrus (BA 6) and bilaterally in the OFC (BA 11/47). For the edibility task, a weak, not significant, difference was noted in the right OFC (BA 11/47). The edibility task also induced a rCBF increase in the cuneus/lingual gyrus region (BA 17/18). An analysis of conjunction performed between these different contrasts showed significant rCBF increases in the right anterior cingulate (BA 32) and an area extending from the right middle frontal gyrus (BA 10) to the right posterior OFC (BA 11). It is notable that no significant rCBF increases localized to the piriform cortex in any of the olfactory conditions. In order to ensure that this was not simply a result of spatial blurring, the data were reanalyzed using data smoothed to 12- and 16-mm FWHM. However, this reanalysis did not reveal activation in either the piriform region or in any other medial temporal areas. When the rCBF images obtained in the different olfactory tasks were subtracted from those obtained in the control task, significant differences in rCBF were observed in the right and left superior and middle temporal gyri (BA 21, 22) and included areas 41 and 42

(Table 3). These differences reflect the large rCBF increases associated with the auditory control task relative to the olfactory tasks. Significant differences were also found in several areas of the occipital and posterior temporal regions (BA 7, 19, 37, 39), again reflecting greater rCBF during the auditory task. Olfactory tasks versus olfactory detection task. When the rCBF images obtained in the olfactory detection task were subtracted from those obtained in the other olfactory tasks, significant differences in rCBF were detected in all comparisons, especially in the frontal lobe (Table 4). For the intensity task, a significant difference was observed in the left inferior frontal gyrus (BA 45/46). For the hedonicity task, activations were observed in the left superior frontal gyrus (BA 8), the left inferior frontal gyrus (BA 45/46), the left inferior temporal gyrus (BA 20), and the lingual gyrus (BA 17/18). For the familiarity task, significant differences were found in the left superior frontal gyrus (BA 6, 8/9) and the left inferior frontal gyrus (BA 45/46). For the edibility task, a significant difference was noted in the left superior frontal gyrus (BA 8/9). As might be expected given the olfactory perceptual and olfactory

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DIFFERENT KINDS OF ODOR PROCESSING

TABLE 4 Brain Regions with Significant rCBF Increases or Decreases When Comparing the rCBF Images of the Detection Task with Those of the Four Other Olfactory Tasks Contrasts

Brain regions

Int ⫺ Det

Inferior frontal gyrus

Hed ⫺ Det

Superior frontal gyrus Inferior frontal gyrus Orbitofrontal Inferior temporal gyrus Cuneus/lingual gyrus

BA

Size

P(n max⬎k)

Z

P(Z⬎u)

45

1129

0.025

4.02

0.045

⫺48, 30,

8 45 11/47 20 17/18

5506 5857

0.011 0.012

263 487

0.385 0.134

5.01 4.94 3.85 4.02 3.70

0.002 0.003 0.175 0.073 0.167

⫺12, 46, 42 ⫺44, 26, 8 ⫺28, 26, ⫺6 ⫺44, 0,⫺38 ⫺2,⫺90, 0

x,y,z MNI 4

Fam ⫺ Det

Inferior frontal gyrus Superior frontal gyrus Superior frontal gyrus

45 8/9 6

4173 5314

0.005 0.016

5.33 4.78 4.43

0.000 0.005 0.023

⫺50, 24, 6 ⫺10, 50, 42 ⫺6, 20, 72

Edi ⫺ Det

Superior frontal gyrus

8/9

190

0.237

3.95

0.059

⫺10, 54, 40

Det ⫺ Int

Precuneus

17/31

527

0.114

4.21

0.028

⫺10,⫺60, 16

Det ⫺ Hed

Middle temporal gyrus

21

4862

0.021

3.97

0.121

64, ⫺8, ⫺2

Det ⫺ Fam

Precuneus Superior frontal gyrus Middle temporal gyrus Fusiform gyrus/middle occipital gyrus

7 10 39 19

7826 194 822 421

0.005 0.454 0.038 0.174

4.35 3.80 4.10 3.98

0.032 0.099 0.041 0.065

8,⫺52, 52 16, 70, 0 54,⫺66, 12 ⫺48,⫺68, ⫺8

Det ⫺ Edi

Precuneus Middle occipital gyrus Superior temporal gyrus Posterior cingulate/precuneus

7/31 19 22 23/31

4302 5337

0.013 0.016

1230

0.010

4.94 4.23 4.13 3.90

0.003 0.050 0.071 0.087

6,⫺46, ⫺50,⫺64, ⫺52,⫺52, ⫺6,⫺58,

44 ⫺2 14 14

Note. Areas displayed in bold overlap with foci arising in contrasts between the same olfactory task (Int, Hed, Fam, or Edi) and the nonolfactory control condition. For abbreviations, see Table 2.

judgment aspects of the Det condition, a number of the activations that emerged in contrasts with the auditory control condition did not reach strict levels of significance in contrasts with the Det condition. This was consistently true for orbitofrontal foci, indicating that differences between orbitofrontal activations across different olfactory tasks were not dramatic. In contrast, as can be seen from Table 4, a number of the foci remained significant even in contrasts with the olfactory detection condition, suggesting that their involvement is relatively specific to the judgment in question. When the rCBF images obtained in the four olfactory tasks were subtracted from those obtained in the detection task, significant differences in rCBF were mainly observed in the right and left temporooccipital areas and the posterior cingulate gyrus (BA 7, 17, 22, 23/31, 39) and also in the right superior frontal gyrus (BA 10). Such differences were also observed when olfactory tasks were compared to the control task, but they could have been attributed to an auditory activation in the control condition. In contrast, differences obtained in the detection task minus the intensity, hedonicity, familiarity, and edibility tasks most likely reflect rCBF decreases occurring in higher-level olfactory tasks. As previously reported (Royet et al., 1999), it appears that frontal and temporooccipital areas in-

teract in an inverse manner, depending on the task requirements. Comparisons between higher-level olfactory tasks. When we performed simple exploratory contrasts between the different higher-level olfactory tasks, few areas that had emerged in previous contrasts with the control condition or detection task remained statistically significant. Strikingly, the cuneus/lingual gyrus remained significant when Hed was contrasted with Fam (⫺6, ⫺94, 4, Z score ⫽ 4.20; and 0, ⫺82, ⫺10, Z score ⫽ 4.08), indicating that the Hed task induced a task specific activation of posterior visual regions. Since activation was obtained in the OFC in the olfactory tasks when they were compared to the control and the detection tasks, but also tended to emerge in a few comparisons between the higher olfactory tasks, we further performed contrasts between olfactory conditions by restricting the analysis to a VOI. Results revealed significantly greater rCBF within the right OFC (x ⫽ 28, y ⫽ 22, z ⫽ ⫺10) during the performance of familiarity judgments relative to judgments of intensity and odor detection (both P ⬍ 0.017), but not relative to judgments of edibility (P ⬍ 0.429) or hedonicity (P ⬍ 0.167). In the left OFC (x ⫽ ⫺28, y ⫽ 16, z ⫽ ⫺10), a significantly greater rCBF was found for the hedonicity judgment than for the familiarity (P ⬍ 0.046),

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edibility (P ⬍ 0.012), intensity (P ⬍ 0.014), and detection (P ⬍ 0.011) judgments. DISCUSSION The present study provides an outline of the functional neuroanatomy of different types of olfactory processing. In other sensory modalities, multiple dissociable brain regions participate in sensory processing depending on the explicit judgments that need to be made about the stimuli. The present results indicate a similar pattern of organization in the olfactory modality. Specifically, several different cortical regions become active depending on whether subjects perform odor detection or judge the intensity, hedonicity, familiarity, or edibility of odorants. These data indicate that olfactory processing engages a complex and distributed network of brain regions whose pattern of activation varies depending on the specific requirements of the task. Odorants in the current study were selected to emphasize salient features along the dimension for which subjects were asked to make judgments. This selection process has the advantage of optimizing the homogeneity of judgments in each task across subjects. However, this means that the stimuli varied in their salient features across conditions. Thus, the study cannot address to what extent the differential activations reflect the automatic (sensation-driven) engagement of separate processing areas based on the odorants’ salient properties or the more top-down engagement of different areas based on the specific task demands. Nevertheless, the current study makes it evident that the central substrate of olfactory processing varies as a consequence of the stimulus features that are being attended to. The Right Orbitofrontal Cortex Conjunction analysis revealed a rCBF increase in the right OFC during all of the olfactory tasks. That is, all five olfactory tasks induced at least a modest rCBF increase in a posterior central portion of the right OFC. The OFC has been reported to play a role in odor processing in both animals and humans (Von Bonin and Green, 1949; Allison, 1954; Tanabe et al., 1975; Potter and Nauta, 1979; Potter and Butters, 1980; Eslinger et al., 1982; Jones-Gotman and Zatorre, 1993, 1998; Zatorre and Jones-Gotman, 1991). The consistent activation of this central OFC region in the right hemisphere converges with a number of other neuroimaging studies of olfaction, which similarly observed activation of this area of the right OFC (Zatorre et al., 1992; Levy et al., 1997; Yousem et al., 1997; Royet et al., 1999; Savic et al. 2000; Savic and Gulyas, 2000; Zald and Pardo, 2000; Zatorre and Jones-Gotman, 2000).

However, even in the right OFC, subtle differences in the degree of activation emerge depending upon the specific task demands. Among the olfactory tasks, familiarity judgments produced the highest magnitude activation, whereas odor detection produced the smallest increases (Fig. 3). The weak rCBF increase in the detection task might result from the fact that a rather low intensity was used in this task, and subjects received half as many odorants as in the other conditions. However, in the intensity task (for which intensity could be high and equivalent numbers of stimuli were used), the VOI analysis revealed a weaker activation than in the familiarity task. The higher level of activation for familiarity judgments in the right OFC is consistent with our previous finding (Royet et al., 1999). Familiarity judgments require subjects to compare odorants with previously stored representation of odorants and thus represent a type of olfactory memory task. The stronger activation of the right OFC during familiarity judgments thus appears highly consistent with the deficits in olfactory recognition and identification that arise as a consequence of right OFC lesions (Jones-Gotman and Zatorre, 1988, 1993). They also converge with the right OFC activation reported by Dade et al. (1998) and Savic et al. (2000) during an odor recognition memory task. Familiarity judgments produced only slightly greater, and nonsignificant, activation of the right OFC than judgments of hedonicity and showed no greater activation than judgments of edibility. This was unexpected given our previous observation of greater right OFC rCBF during odor familiarity than edibility judgments (Royet et al., 1999). The lack of greater differences in right OFC rCBF between the familiarity and edibility/hedonicity tasks may potentially reflect the utilization of familiarity information in making hedonic and edibility judgments of odors. Previous studies indicate that familiarity and hedonicity measures are correlated (Royet et al., 1999), with odors that are judged as more familiar receiving higher ratings of pleasantness and edibility. Thus, subjects may in some cases engage right OFC familiarity processing as an automatic extension of making hedonic or edibility judgments. Alternatively, the level of right OFC activity may reflect a more general depth-of-processing dimension, for which familiarity requires the greatest depth, odor detection and intensity the least, with hedonicity and edibility falling somewhere in between. The Left Orbitofrontal Cortex In the hedonic judgment task, a significant rCBF increase was found in the left posterior OFC (BA 11, 47, 25) in an area extending more posteriorly than that found in the right OFC for the familiarity judgment (Fig. 4). This activation is of particular interest in reference to previous studies by Zald and Pardo (1997,

DIFFERENT KINDS OF ODOR PROCESSING

515

FIG. 3. Sagittal and horizontal sections demonstrating a rCBF increase during the familiarity task relative to the control task. The increases are displayed as z maps overlaid on an anatomically normalized standard brain (x ⫽ 22, y ⫽ 18, z ⫽ ⫺10). Bottom right, plot showing rCBF levels in the six activation conditions for this coordinate. FIG. 4. Sagittal and horizontal sections demonstrating a rCBF increase during the hedonicity task relative to the control task. The increases are displayed as z maps overlaid on an anatomically normalized standard brain hedonic (x ⫽ ⫺22, y ⫽ 18, z ⫽ ⫺10). Bottom right, plot showing rCBF levels in the six activation conditions for this coordinate.

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2000) and ourselves (Royet et al., 2000) who have observed robust and consistent activations of the left OFC when subjects are exposed to stimuli with strong hedonic (pleasant/unpleasant characteristics). Taken together with the present study, these data suggest that the left OFC processes odorants when the hedonic meaning of the odorants is a dominant feature. It may be noted in this regard that activation of the left OFC does not appear limited to conditions in which subjects are explicitly performing hedonic judgments, since a significant rCBF increase was localized to the left posterior OFC during the familiarity and intensity judgments. However, the activation level for these familiarity and intensity judgments was significantly lower than that observed in hedonicity judgments as indicated by VOI measurements. It was also significantly lower for the detection task and the edibility judgments than for the hedonicity judgment. Thus, the left OFC appears to become most strikingly involved in situations in which the odorants are evaluated for their hedonic value. The reason that more robust differences did not occur in the left OFC in contrasts between Hed and other olfactory conditions may reflect a difficulty disregarding the emotional aspect of olfactory stimuli. Indeed, hedonicity emerges as the most dominant dimension in perceptual studies of olfaction (Richardson and Zucco, 1989). Interestingly, we recently demonstrated that the left OFC is also activated in response to emotional visual and auditory stimuli (Royet et al., 2000). Similarly, Zald et al. (1998b) reported left OFC activation during emotionally valenced gustatory stimulation. Thus, this area pertains to a neural network involved in emotion that is not modality specific, but rather appears to participate in similar functions across multiple sensory modalities. The Cingulate, the Middle Frontal Gyrus. and the Inferior Frontal Gyrus The conjunction analysis demonstrated a significant rCBF increase in the right cingulate gyrus (BA 32). This finding is of interest in that the cingulate gyrus has not typically been considered part of the olfactory system. The cingulate focus falls in the area that Vogt and colleagues (1995) label 32⬘. This area of the cingulate has been referred to as part of the cognitive cingulate and is frequently involved in tasks requiring attention to sensory features in the environment (Devinsky et al., 1995). It may thus be speculated that the cingulate becomes involved in olfactory tasks when they require attention to different features of the olfactory stimuli. Such a role may be supported by the connections between this region of the cingulate and orbital areas involved in olfaction (Vogt and Pandya, 1987; Barbas et al., 1999). Analysis of PET studies suggests that an area of the cingulate, which includes 32⬘, generally becomes more active as task difficulty

increases (Paus et al., 1998). Thus, cingulate activation in the present study may to some extent reflect the greater task difficulty associated with the olfactory tasks than the auditory control condition. The middle frontal gyrus (BA 10) also emerged in the conjunction analysis. Indeed this was the only area that showed significant activation in the detection and intensity conditions. The source of this activation remains unclear. The region has not previously been considered as part of the olfactory system. Given its lack of strong, direct, olfactory inputs, it more likely reflects a common cognitive demand of the olfactory judgment tasks. It is of note that activation of this region has also been seen during judgment tasks in the visual modality. For instance, Nakamura et al. (1998) reported a similarly located focus in subjects making judgments of facial attractiveness. Thus, this region is probably involved in high-level processing and may play a more multimodal role in certain types of sensory judgment tasks. The inferior frontal gyrus (BA 45) was found to be significantly activated in the familiarity, hedonicity, and intensity tasks when compared to the detection task. An activation was also present in the edibility minus detection contrast, but it was not significant. This area has previously been related to tasks involving semantic association (Petersen et al., 1988) or semantic encoding such as categorizing nouns as living or nonliving (Kapur et al., 1994). Thus, this area may participate in the semantic processing of odors. In many regards, such semantic processing may be regarded as the final step of odor identification, providing the basis for the verbalization and naming of odors. The Piriform Cortex Although we used a tomograph with better spatial resolution than in our previous study, we did not observe activation in the piriform cortex, even when we utilized smoothing filters of 12- and 16-mm FWHM. By contrast, Zatorre et al. (1992) observed increased activity in the piriform cortex when using a tomograph with a spatial resolution similar to that of our tomograph and using a filter of 20-mm FWHM to smooth images. Thus, it is highly unlikely that spatial resolution represents the limiting factor in obtaining piriform activation. A number of other studies have also reported difficulty observing activation in the piriform cortex (Zald and Pardo, 1997; Yousem et al., 1997; Sobel et al., 1998a), and several factors have been suggested to explain discrepancies between studies (Zald and Pardo, 2000). For example, Sobel et al. (2000) have reported that the piriform cortex rapidly habituates to odorants. Based on the neuroanatomical organization of the olfactory system (Carmichael et al., 1994), it may be assumed that the piriform cortex indeed processes odorants in all of the olfactory tasks in the present

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study. However, this processing probably is reflected in changes in the spatiotemporal patterns of cell firing within the piriform cortex, which in some circumstances may produce little observable change in rCBF. The Occipital Cortex When rCBF images obtained in the control condition were subtracted from those obtained in the hedonic and edibility conditions, significant rCBF increases were found in the cuneus and the lingual gyrus (BA 17, 18). Similar results were demonstrated for the edibility judgments in our previous work (Royet et al., 1999). We then explained that visual areas may participate in the semantic processing of odors in the sense that subjects attempt to visually imagine the object evoked by the odor to determine whether the odor evokes a food or not. Along the same line, we may suppose that subjects also recruit visual areas to determine whether the odor is pleasant or unpleasant. As in our previous study, no rCBF increase emerged in visual areas in the familiarity judgment compared with the control condition. First, we can conclude that activation of perceptual representations for odors in the familiarity judgment involves a neural network that does not necessitate visual areas. Second, activation of visual areas in the hedonic and edibility judgments is not an epiphenomenon olfactory stimulation, but represents a task-specific feature of certain types of odor judgments. A Sequential and a Parallel Distributed Processing of Odors Schab (1991) suggested that the process of olfactory identification includes different levels of analysis with performance ranging from nonverbal feelings of familiarity to specific object naming. We have previously argued that different modules become engaged in olfactory tasks depending upon the specific judgments performed (Royet et al., 1999). On the basis of different olfactory tasks, Savic et al. (2000) recently drew a similar, although more strongly articulated, conclusion that olfactory functions are organized in a parallel and hierarchical manner, depending of the character and complexity of the task. Our results seem to support three organizational features. On the one hand, although we did not observe activation in the piriform cortex, neuroimaging, neurophysiological, and neuroanatomical data reported in the literature suggest that this area is at least minimally engaged during all olfactory tasks. Similarly, it appears that some (albeit often modest) activity almost always emerges in the right OFC. Thus, core areas within the olfactory system may play a mandatory initial role. However, the extent of right OFC activation appears at least partially dependent on the type of processing demanded by the tasks. Performing a superficial processing of odor

detection induced only a weak rCBF increase in the right OFC, whereas performing a perceptual processing as in the familiarity task more robustly engaged this area. Furthermore, we observed that the pattern of activation varied depending on whether odor processing was related to emotional response (hedonic judgment) or recognition (familiarity judgment). These differences were primarily reflected in terms of subtle, but significant differences, in the relative activation of the left and right OFC. Although, our data cannot address the issue, Dade et al. (1998) have similarly suggested that the degree of pyriform activity may be modulated by the specific task demands. Finally, a third level of organization appears to involve a widely distributed network of structures that fall outside of the typically defined olfactory system, which become engaged during specific types of judgments. In sum, we suggest that odor processing comprises a serial processing of information from the primary to the secondary olfactory cortex, but also a parallel, distributed processing depending on the nature of the cognitive operations being performed. ACKNOWLEDGMENTS We thank all the members of CERMEP for their valuable assistance. We also thank L. Garcia-Larrea and N. Buonviso a for helpful comments on the manuscript. We are grateful to societies of perfume and/or aroma (Davenne, Givaudan-Roure, International Flavour and Fragrances, Lenoir, Perlarom) for supplying the odorants used in this study. The Rhoˆne-Alpes Region, the Centre National de la Recherche Scientifique (CNRS), l’Universite´ Claude-Bernard de Lyon, supported this research.

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