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Neural correlates of olfactory processing in congenital blindness
Neuropsychologia 49 (2011) 2037–2044
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Neural correlates of olfactory processing in congenital blindness R. Kupers a,∗,1 , M. Beaulieu-Lefebvre b,c,1 , F.C. Schneider d,e,f , T. Kassuba g , O.B. Paulson g,h , H.R. Siebner g , M. Ptito b,g a
Institute of Neuroscience and Pharmacology, Panum Institute, University of Copenhagen, Blegdamsvej 3B, 2300 Copenhagen, Denmark Chaire de Recherche Harland Sanders, School of Optometry, University of Montreal, Montreal, Canada Psychology Department, University of Montreal, Montreal, Canada d Université de Saint Etienne, Jean Monnet, F-42023 Saint Etienne, France e Radiology Department, University Hospital of Saint-Etienne, France f CNRS UMR 5229, Centre de Neurosciences Cognitives, Bron, France g Danish Research Center for Magnetic Resonance, Copenhagen University Hospital, Hvidovre, Denmark h Neurobiology Research Unit, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark b c
a r t i c l e
i n f o
Article history: Received 7 October 2010 Received in revised form 15 March 2011 Accepted 22 March 2011 Available online 30 March 2011 Keywords: Blindness Olfaction Cross-modal plasticity Behavior fMRI
a b s t r a c t Adaptive neuroplastic changes have been well documented in congenitally blind individuals for the processing of tactile and auditory information. By contrast, very few studies have investigated olfactory processing in the absence of vision. There is ample evidence that the olfactory system is highly plastic and that blind individuals rely more on their sense of smell than the sighted do. The olfactory system in the blind is therefore likely to be susceptible to cross-modal changes similar to those observed for the tactile and auditory modalities. To test this hypothesis, we used functional magnetic resonance imaging to measure changes in the blood-oxygenation level-dependent signal in congenitally blind and blindfolded sighted control subjects during a simple odor detection task. We found several group differences in taskrelated activations. Compared to sighted controls, congenitally blind subjects more strongly activated primary (right amygdala) and secondary (right orbitofrontal cortex and bilateral hippocampus) olfactory areas. In addition, widespread task-related activations were found throughout the whole extent of the occipital cortex in blind but not in sighted participants. The stronger recruitment of the occipital cortex during odor detection demonstrates a preferential access of olfactory stimuli to this area when vision is lacking from birth. This finding expands current knowledge about the supramodal function of the visually deprived occipital cortex in congenital blindness, linking it also to olfactory processing in addition to tactile and auditory processing. © 2011 Elsevier Ltd. All rights reserved.
1. Introduction The sense of smell is critical for almost all species since it contributes to basic vital needs such as finding the right food, choosing a mate or avoiding predators. Smells may evoke strong emotions and vivid memories, and influence social interactions (Gottfried, 2006). Although it is believed that humans have a less refined sense of smell than animals, they are nonetheless able to distinguish thousands of different odors. Notwithstanding, the human sense of smell is not always reliable, especially not when it comes to odor identification. Psychophysical studies have shown that humans are only able to name about one third of the odors when they are presented without other sensory cues (Cain, 1979; Engen & Ross, 1973), suggesting that other modalities provide associative cues
∗ Corresponding author. Tel.: +45 35456890; fax: +45 3545 3989. E-mail address: [email protected] (R. Kupers). 1 These authors contributed equally to this work. 0028-3932/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2011.03.033
that contribute to odor identification. For instance, there is evidence that vision may aid in odor identification. Thus, Gottfried and Dolan (2003) showed that odor recognition is faster and better when odors are paired with semantically congruent visual cues. The cross-modal facilitation of olfactory processing by visual information is mediated by pathways linking olfactory and visual brain areas (Cooper, Parvopassu, Herbin, & Magnin, 1994; Rolls & Bayliss, 1994; Rolls, Critchley, Mason, & Wakeman, 1996). Another example is that identification of odors improves when they are presented with a semantically congruent color combination (Zellner, Bartoli, & Eckard, 1991). Previous psychophysical studies revealed differences in olfactory performance between sighted and congenitally blind individuals. Cuevas, Plaza, Rombaux, De Volder, and Renier (2009) reported that blind individuals are better than sighted controls in the free identification of odors. In addition, a recent study by BeaulieuLefebvre, Schneider, Kupers, and Ptito (2011) demonstrated that blind subjects have a lower odor detection threshold and are more aware of their olfactory environment. This raises the question of
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how the olfactory system is influenced by the absence of vision from birth. Adaptive neuroplastic changes in congenitally blind individuals have been well documented for the processing of tactile and auditory information. Congenitally blind individuals outperform their sighted counterparts in a variety of sensory and cognitive tasks, and thereby recruit their visual cortex (reviewed by Kupers, Pietrini, Ricciardi, & Ptito, 2011; Merabeth & Pascual-Leone, 2010). These cross-modal responses have been attributed to brain reorganization, in particular to an increase in cortico-cortical projections (Ptito, Schneider, Paulson, & Kupers, 2008). Behavioral, imaging and anatomical studies therefore suggest that the so-called “visual” cortex of the blind has acquired multimodal functions (Pietrini, Ptito, & Kupers, 2009). To the best of our knowledge, no published reports exist on how olfactory information is processed following visual deprivation. Since the olfactory system is very plastic (Li, Luxenberg, Parrish, & Gottfried, 2006; Plailly, Delon-Martin, & Royet, in press; Wilson, Best, & Sullivan, 2004), it is highly susceptible to crossmodal changes similar to those observed for the tactile and auditory modalities. Here we used functional magnetic resonance imaging (fMRI) to study the purported role of olfactory brain areas and the occipital cortex in olfactory processing in subjects lacking vision from birth. In light of previous findings on cross-modal plasticity in early blindness (Pietrini et al., 2009), we hypothesized that besides the primary and higher order olfactory brain areas, blind subjects will also recruit their visual cortex during odor detection. 2. Materials and methods 2.1. Participants Eleven congenitally blind subjects without light perception (4 females; mean age: 32 ± 14 years; mean education: 13 ± 2 years) and fourteen sighted controls (8 females; mean age: 30 ± 9 years; mean education: 16y ± 2 years) participated in this study. Origin of blindness was peripheral in all cases: retinopathy of prematurity (N = 8), glaucoma (N = 1), congenital cataract (N = 1) and one whose cause of blindness was unknown. Ten subjects were blind from birth and the remaining became blind before the age of 6 months. None of the participants had a documented history of psychiatric disorders, nor did they suffer from any allergies or from nasal deformities, fractures or obstruction. The local ethics committee of the county of Copenhagen approved the study and all subjects gave informed consent.
2.2. Stimuli and stimulation equipment To prevent odorant-specific habituation during the fMRI data acquisition period, we used two different odors: phenylethyl alcohol 5% (v/v) in propenediol and butanol 5% (v/v) in propenediol (Sigma–Aldrich). These odors are widely used in olfactory testing and their detection thresholds are known to be the same (Croy et al., 2009). At the used concentration, they mainly activate the olfactory nerve with minimal co-activation of the trigeminal nerve (Doty et al., 1978). We used a custom-made, fMRI-compatible, computer-controlled olfactometer to present the odors. The device allows rapid delivery of odors without accompanying thermal, tactile or auditory stimulation. The olfactometer consisted of a control and a stimulation module. The control module was placed in the scanner control room, while the stimulation module was positioned close to the subject. The stimulation module comprised three 125-ml large glass jars, two of them contained 60 ml of odorant liquids and one 60 ml of odorless propenediol. The jars were tightly sealed with a rubber cap. Two 2-m long TeflonTM tubes with an inner diameter of 4 mm, one for the inlet and another for the outlet, entered the jars through a small hole in the rubber seals. A constant airflow of 4 l/min was injected into the jar where it was mixed with the liquid before leaving the bottle. This permits a rapid delivery of odor in the absence of tactile or auditory confounds (Li et al., 2006). The three outlet tubes, coming from each jar, merged into a single tube that ended 2 cm in front of the subject’s nose. Subjects were asked whether they felt any tactile sensation from the tube or odor presentation and none did so. The low-pressure flow was generated by a pump, located in the control module. The output of the pump was sent through an 8 m long tube to the stimulation module via a pressure regulator. In order to send the low pressure flow to one of the three jars, the tube was connected to two valves that were controlled by a high pressure flow produced by a compressor inside the control room. The output of the compressor went inside the control module, and was switched to two of a set of four tubes that went from the control module to the
two valves inside the stimulation module. Two computer-steered solenoid valves inside the control module controlled the switching. 2.3. Experimental procedures The olfactory system habituates rapidly. For instance, Sobel et al. (2000) demonstrated that a prolonged odorant stimulus induces a sharp blood-oxygenation level-dependent (BOLD) increase in the primary olfactory cortex that returns to baseline level after 25–30 s, despite continuous stimulation. One way to bypass habituation is to reduce the actual stimulation time. Tabert et al. (2007) reported that odorant stimulation lasting 6 s is optimal to induce activation in primary olfactory cortex and its projection areas. For this reason, we used an event-related fMRI design. Each participant underwent three fMRI runs with 16 stimulus presentations per run, resulting in a total of 48 stimulus presentations. Half of the stimuli were the odorants phenylethyl alcohol and butanol and the remaining were odorless (propenediol) control stimuli, presented in a semi-random fashion. The 6-s stimuli were separated by fixed inter-stimulus intervals of 29 s (Tabert et al., 2007). This design allows for physiological refreshment and prevents the overlap of hemodynamic responses. The first stimulation was preceded by a 15 s blank, and the last one was followed by a 30 s blank. The total duration of one run was 581 s. Prior to the scanning session, participants were trained in the odor detection task. They were instructed to breath normally and to maintain a constant depth of breathing throughout stimulus delivery and not to sniff, as sniffing can elicit signal changes in primary olfactory cortex even in the absence of odorant stimulation (Sobel et al., 1998). Participants performed an odor detection task that is a simple cognitive task that does not involve the recruitment of stored representations of odors (Royet et al., 2001). Participants indicated whether they had perceived an odor or not by clicking one of two buttons (YES/NO) of a response pad. A tone, announcing the stimulation epochs, was presented through a headphone 2 s prior to the stimulus onset. A second tone was presented at the end of the stimulus delivery period, indicating participants to press one of the response buttons. The number of correctly identified stimuli was monitored throughout the scanning session to ensure that the odorants were perceived. After the experiment, participants rated intensity and pleasantness of the odors using a 5-point rating scale, with “0” as not perceptible or neutral and “5” very strong or very pleasant. The number of correct answers was analyzed using a 2 by 3 mixed analysis of variance (ANOVA), with group (blind versus sighted) as fixed effect factor and the fMRI runs (1–3) as random effect factor. The subjective perception of odorants was analyzed by a Student t-test for independent samples. Cardiac and respiratory motion were recorded throughout scanning with respectively an MR-compatible pulse oximeter and a respiration belt, both sampled at 50 Hz. Respiration was measured to make sure that BOLD differences between blind and sighted participants cannot be explained by group differences in sniffrelated respiration patterns (Bensafi, Sobel, & Khan, 2007; Sobel et al., 1998). We measured both respiration frequency and depth, defined respectively as the number of breathes per minute and the amount of air moved between each breath. 2.4. MRI data acquisition Images were acquired on a 3T scanner (Siemens Magnetom Trio, Erlangen, Germany) with an 8-channel head coil. Prior to the functional runs, a T1weighted MR image was obtained with the following parameters: TR/TE/TI/FA 1.55 s/3.04 ms/800 ms/9◦ , 256 × 256 matrix, spatial resolution of 1 mm × 1 mm × 1 mm. Single-shot gradient-echo echo-planar images (EPI) with BOLD contrast and whole-brain coverage (45 slices; 3 mm slice thickness; no gap) were collected in an oblique orientation, 30◦ to the commissural plane, with the following parameters TR/TE/FA: 2.95 s/30 ms/90◦ , total readout time, 38.4 ms, matrix, 64 × 64 and a field of view of 192 mm. In each of the 3 functional sessions, 197 dynamic scans were acquired. Head motion was restricted with a forehead strap and placement of comfortable padding around the participant’s head. Each fMRI session was followed by a short FLASH sequence for field mapping estimation (TR/TE1-TE2/FA: 500 ms/5.19 ms–7.25 ms/60◦ , matrix, 64 × 64, 3 mm × 3 mm × 3 mm voxel size, 45 slices) using the same orientation as the functional acquisitions. 2.5. Processing and statistical analyses of the fMRI data Image processing and statistical analyses were performed using SPM8 (statistical parametric mapping 8; www.fil.ion.ucl.ac.uk/spm/) and percent signal changes were visualized using rfxplot (Gläscher, 2009). The first two brain volumes of each run were discarded from further analysis to eliminate effects of non-equilibrium magnetization. In order to address the susceptibility-by-movement interaction, we used the FieldMap Toolbox of SPM8 and the reconstructed phase and magnitude images of the FLASH sequence described above. An unwarped field map was calculated and then converted into a voxel displacement map (VDM) (Hutton et al., 2002) that was coregistered to the first EPI volume of each fMRI session. EPI time-series were corrected for head movements and unwarped using the VDMs (Andersson, Hutton, Ashburner, Turner, & Friston, 2001). The resulting images were spatially normalized to MNI standard space as implemented in SPM 8, thereby resampled to 3 mm isotropic voxel, and smoothed with an 8 mm full width at half maximum isotropic Gaussian kernel.
R. Kupers et al. / Neuropsychologia 49 (2011) 2037–2044 Table 1 Stereotactic coordinates ROIs. Side L/R
Primary olfactory areas Piriform cx Amygdala Entorhinal cx
R L R L R L
Higher order olfactory areas Anterior insula R L Posterior insula R L Medial orbitofrontal cx Lateral orbitofrontal cx R L Anterior cingulate cx Posterior cingulate cx Mediodorsal thalamus R L Hippocampus R L Visual areas V1 R L V2 R L V3 R L V4 R L MT R L
Radius (mm)
MNI coordinates x
y
z
5 5 8 8 5 5
22 −22 21 −21 39 −39
3 3 −4 −4 −1 −1
−17 −17 −17 −17 −17 −17
5 5 5 5 8 5 5 8 8 5 5 5 5
33 −33 36 −36 3 22 −22 3 3 12 −12 30 −30
23 23 −10 −10 41 30 30 23 −43 −8 −8 −10 −10
4 4 −2 −2 −17 −14 −14 37 25 9 9 −14 −14
8 8 8 8 8 8 8 8 8 8
9 −9 30 −30 51 −51 41 −41 51 −51
−97 −97 −80 −80 −67 −67 −84 −84 −64 −64
7 7 8 8 −8 −8 4 4 4 4
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tory processing (ROIs in the primary and higher olfactory cortex) and cross-modal plasticity in congenital blindness (occipital ROIs). Next, as proposed by Bensafi et al. (2007), we used the activation maps of our odorless control condition in the sighted control group to specify the exact x, y, z coordinates that were used for the final analysis. Within each our preliminary ROIs, we selected the voxel showing regional peak activation and defined its x, y, z coordinates as center of mass for the spherical ROIs that were used for small volume correction (SVC). Results were thresholded at P < 0.05, corrected for multiple comparisons, using the family wise error (FWE) method implemented in SPM8. SVC was performed within the pre-defined ROI, whereas for all voxels outside the ROIs, correction for multiple non-independent comparisons considered all voxels in the brain.
3. Results 3.1. Behavioral results Fig. 1 shows the behavioral results acquired during scanning. As can be seen, blind and sighted participants detected the odor stimuli equally well (F1,23 = −0.50, ns; mixed ANOVA). Mean percentage of correctly detected odor stimuli during the fMRI scans were 92.6% for the blind and 94.3% for the sighted controls, indicating that both groups attended and responded to the stimuli throughout the entire scanning session (Fig. 1A). There was no significant difference in odor detection between male and female participants (F2,46 = 0.63, ns) nor did we find a main effect of runs (F2,46 = 0.36, ns), suggesting that the stimuli were equally well detected throughout the study and that no habituation occurred. There was also no significant interaction effect between groups and runs (F2,46 = 2.20, ns). The intensity and pleasantness ratings also did not reveal significant group differences, suggesting similar perception of the stimuli in the scanner (Fig. 1B).
3.2. fMRI results Statistical analysis was performed separately for each voxel using a general linear model. At the individual level (fixed effects), we defined separate regressors for the experimental conditions of interest, i.e. odor (both odors combined) and odorless, respectively, and one for the responses. Epochs with incorrect answers (<10%) were modeled in a separate regressor (irrespective of condition). The condition regressors were modeled by convolving a 6-s boxcar function at stimulus onset with the canonical hemodynamic response function (HRF), and the responses were modeled by convolving delta functions (representing each button press) with the canonical HRF. A high-pass filter with a cut-off period of 128 s removed low frequency drifts in BOLD signal. The individual contrast images for the comparison of “odor > baseline” and “odorless > baseline” were then entered into a random-effects analysis at the group level. The design matrix was configured as a full factorial model including the factors group (blind/sighted) and condition (odor/odorless). Fifteen spherical regions-of-interest (ROIs) with a diameter of 5 or 8 mm, depending on the size of the structure, were selected a priori (see Table 1) based on their implication in olfactory processing (Gottfried, 2006) and occipital areas recruited in the blind by cross-modal plasticity (Matteau, Kupers, Ricciardi, Pietrini, & Ptito, 2010; Ptito, Moesgaard, Gjedde, & Kupers, 2005). ROI analysis used the first eigenvariate of the voxels surviving a P < 0.05 (uncorrected) within the ROI. We determined the stereotactic coordinates of the center of each spherical ROI using a 2-step procedure. In a first step, we identified a range of stereotactic coordinates for each of our regions of interest, based on existing results from the literature on olfac-
The main effect of odor was examined by a conjunction analysis of the contrast “odor > odorless” in both groups of subjects. This analysis revealed that compared to the odorless condition, odors evoked significantly stronger BOLD responses in the piriform cortex bilaterally, and in the left orbitofrontal cortex. A borderline significant BOLD response increase (P = 0.052; SVC) was found in the left hippocampus. Fig. 2 shows the increased BOLD response in the left and right piriform cortex together with the peristimulus time histograms of the evoked BOLD responses in both groups. We examined the main effect of group with a conjunction analysis based on the contrast “blind > controls” for the odor and odorless condition (Fig. 3 and Table 2). Compared to normal sighted subjects, congenitally blind participants showed significantly larger BOLD response increases throughout the entire extent of the occipital cortex (areas V1–V4, MT). The group comparisons for the contrasts “odor > rest” and “odorless > rest” yielded similar results (data not shown).
Fig. 1. Odor perception within the fMRI scanner for blind and control subjects. (A) Odor detection performance scores. N refers to the number of correctly detected odors. The maximum possible score is 16. (B) Rating scores for odor intensity and pleasantness. Error bars indicate the standard error of the mean.
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Fig. 2. Increased BOLD responses in bilateral piriform cortex in the odor compared to the odorless condition. The statistical activation maps to the left show the results of the conjunction analysis of blind and sighted participants for the contrast “odor > odorless”. The visualization threshold is set to P < 0.05, FWE- corrected, and activation maps are displayed on the average structural image of all participants. The graphs to the right show peristimulus time histograms of evoked BOLD responses in left (Pir L) and right (Pir R) piriform cortex within each group (SC = sighted control, CB = congenital blind). The graph represents the average group response, rescaled to 0 at stimulus onset, together with the standard error of the mean. Responses to the odor and odorless condition are shown in red and blue colors, respectively.
Table 2 Main effect of group “CB > SC”. Anatomical area
Visual areas V1 V2 V3 V4 MT a
Coordinates x
y
9 −9 30 −30 51 −51 42 −42 51 −51
−97 −97 −79 −79 −67 −67 −85 −85 −64 −64
Cluster size
Pa
T
34 62 52 34 32 17 54 55 46 17
0.040 0.045 0.047 0.021 0.027 0.040 0.012 0.011 0.027 0.029
2.92 2.87 2.85 3.22 3.11 2.93 3.48 3.49 3.11 3.07
z 7 7 7 7 −8 −8 4 4 4 4
Corrected for multiple comparisons.
Table 3 BOLD signal increases “odor > odorless”. Anatomical area
Primary olfactory areas Piriform cortex Amygdala Entorhinal cortex Higher order olfactory areas Medial orbitofrontal cortex Lateral orbitofrontal cortex Anterior cingulate cortex Posterior cingulate cortex Mediodorsal thalamus Hippocampus Visual areas V2 V3 a
Corrected for multiple comparisons.
Congenitally blind
Sighted controls
Side
Cluster size
Pa
T
Cluster size
Pa
T
R L R L L
15 12 18 15 6
0.010 0.002 <0.000 0.002 0.031
3.19 3.88 4.47 3.92 2.70
12 12 18 15
0.007 <0.000 0.004 <0.000
3.35 4.66 3.55 4.66
R R L
30
0.025
3.15
15 14
0.009 0.002
3.24 3.89
R L R L
17 19 19 19
0.033 0.037 <0.000 <0.000
2.65 2.51 5.19 4.93
R L L
73 72 28
0.022 0.004 0.020
3.21 3.94 3.25
R. Kupers et al. / Neuropsychologia 49 (2011) 2037–2044
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Fig. 3. Increased occipital activation during the odor condition in congenitally blind compared to sighted subjects. The visualization threshold is set to P < 0.01, uncorrected, and activation maps are displayed on the average structural image of all participants. Blind subjects showed significant odor-related BOLD responses throughout the whole extent of the occipital cortex. The numbers (mm) next to the slices refer to the dorso-ventral (z-dimension) positioning of the slices in stereotactic (Montreal Neurological Institute, MNI) space.
Table 3 lists the within group results of the contrast “odor > odorless”. Both groups showed significant BOLD response increases in piriform cortex and amygdala bilaterally. Blind subjects showed additional bilateral activations in the mediodorsal thalamus, hippocampus, area V2, and left entorhinal cortex and area V3. Fig. 4 and Table 4 show the results of the group × condition interaction “(blind > controls) × (odor > odorless)”. Blind subjects showed larger BOLD signal increases than the sighted in the odor relative to the odorless condition in the right amygdala and right orbitofrontal cortex, and bilaterally in the hippocampus and visual area V2. We explain the absence of a significant group × condition interaction effect in the other visual ROIs by the prominent BOLD response increase in the odorless condition in the blind participants. A subsignificant increase was found in the left orbitofrontal cortex (P = 0.052; SVC). Only blind but not sighted
control subjects showed significantly increased BOLD activity in the right mediodorsal thalamus in the odor versus odorless contrast, but this difference did not reach significance in the direct group × condition interaction. In contrast, we found no brain areas where BOLD increases to odor relative to odorless stimulation was larger in sighted than in blind participants. Not unexpectedly, the odorless condition also yielded increased BOLD responses in several areas that were activated by odor detection (data not shown). As there were no significant group differences in either respiration frequency (blind: 17.9; sighted controls: 16.5; P = 0.20) or respiration depth (blind: 1.83; sighted controls: 1.68; P = 0.09) during fMRI data acquisition, the observed group differences in BOLD responses cannot be attributed to differences in breathing patterns.
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Odor
0 -0.05 -0.10 -0.15
Amygdala (R)
0.10
***
0.05 0 -0.05 -0.10 -0.15
Hippocampus (L)
** 0.15
***
0.10 0.05 0 -0.05 -0.10 -0.15
0.10 0.05 0 -0.05 -0.10 -0.15
0.15 0.10 0.05 0 -0.05 -0.10 -0.15
Orbitofrontal (L)
*
0.30 0.20 0.10 0
Thalamus (R)
* % signal change
% signal change
% signal change
0.15
**
0.40
Hippocampus (R)
* **
% signal change
**
0.10 0.05
0.15
0.20
*
**
% signal change
% signal change
% signal change
***
% signal change
*
* 0.15
Odorless
0.10 0 -0.10 -0.20
Orbitofrontal (R)
V2 (L)
0.20
*
0.10 0 -0.10 -0.20
V2 (R)
Fig. 4. Percent BOLD changes in primary (amygdala) and higher order (mediodorsal thalamus, hippocampus, lateral orbitofrontal cortex) olfactory brain areas and visual cortex (V2) of congenitally blind and blindfolded sighted controls. Data of the blind subjects are shown to the left in each graph. Abbreviations: L = left; R = right. Asterisks indicate the levels of statistical significance (*P < 0.05; **P < 0.01; ***P < 0.001). Error bars indicate standard error of the mean.
4. Discussion Compared to normal sighted control subjects, congenitally blind subjects more strongly activate a subset of the primary and higher order olfactory areas as well as the occipital cortex during a simple odor detection task. Since blind and sighted participants did not differ in terms of odor detection rate, odor intensity and valence ratings, this finding cannot be attributed to perceptual differences per se. Our data add new evidence to the supramodality of the visually deprived occipital cortex in congenital blindness by showing that in addition to tactile and auditory stimuli, odorants effectively activate the occipital cortex when vision is lacking from birth.
workers demonstrated an intensity-by-valence interaction in the amygdala. Specifically, the amygdala responded more strongly to high compared to low intensity odors for (un)pleasant but not for neutral odors. Along the same line, de Araujo et al. (2005) reported positive correlations between odor pleasantness and BOLD responses within the amygdala. Since our blind and sighted participants rated the odors as equally pleasant, it is unlikely that the observed group difference in amygdala response is mediated by differences in hedonic coding of the stimuli. In view of our earlier finding of a lower odor detection threshold in congenitally blind subjects (Beaulieu-Lefebvre et al., 2011), we rather attribute the increased amygdala response to an upregulation of odor intensity processing in congenital blindness.
4.1. The amygdala 4.2. The mediodorsal thalamus Together with the olfactory nucleus, olfactory tubercle and piriform cortex, the amygdala forms part of the primary olfactory cortex (Price, 2004). Although both groups showed increased responses in the amygdala during the odor as compared to the odorless condition, the magnitude of BOLD signal increase in the right amygdala was significantly larger in blind subjects. The involvement of the amygdala in olfactory processing has been documented in several previous neuroimaging studies (de Araujo, Rolls, Velazco, Margot, & Cayeux, 2005; Gottfried, Deichmann, Winston, & Dolan, 2002; Royet et al., 2003; Sobel et al., 2000; Winston, Gottfried, Kilner, & Dolan, 2005). For instance, a study by Winston and co-
Congenitally blind but not sighted control subjects showed a significant BOLD response increase in the odor compared to the odorless condition in the right mediodorsal thalamus. The thalamus plays an atypical role in olfactory processing. Neurons from the lateral olfactory tract project directly to the primary olfactory cortex and various components of the limbic system, thereby bypassing the thalamus. The mediodorsal thalamus receives olfactory inputs from the piriform cortex and sends information to the orbitofrontal cortex. Plailly, Howard, Gitelman, and Gottfried (2008) suggested that the mediodorsal thalamus is involved in olfactory attention.
Table 4 Interaction group × condition “(CB > SC) × (odor > odorless)”. Anatomical area
Coordinates x
Primary olfactory areas Amygdala Higher order olfactory areas Lateral orbitofrontal cortex Hippocampus Visual areas V2 a
Corrected for multiple comparisons.
Cluster size
Pa
T
y
z
24
−10
−14
6
0.047
2.72
18 −21 27 −33
26 32 −13 −10
−14 −14 −14 −17
14 10 16 13
0.050 0.052 0.003 0.019
2.45 2.43 3.63 2.93
30 −24
−79 −79
7 7
78 77
0.029 0.003
3.07 4.06
R. Kupers et al. / Neuropsychologia 49 (2011) 2037–2044
We previously demonstrated that congenitally blind subjects score higher on the odor awareness scale (Beaulieu-Lefebvre et al., 2011), a measure of attention to environmental smells. The current finding that blind subjects show a BOLD signal increase in the odor compared to the odorless condition in the right mediodorsal thalamus and right orbitofrontal cortex (OFC) may provide a neurobiological basis for this increased odor awareness. As the olfactory system is highly plastic (Li et al., 2006; Plailly et al., in press; Wilson et al., 2004), increased conscious analysis or awareness of odors may lead to changes in neural networks such as the strengthening of the connectivity between the thalamus and higher order olfactory areas.
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Blind participants also showed stronger activation of the right lateral OFC during the odor condition. Earlier brain imaging studies demonstrated that the right OFC is more strongly activated by odorants than the left (Malaspina, Perera, Lignelli, Marshall, & Esser, 1998; Zatorre, Jones-Gotman, Evans, & Meyer, 1992), suggesting that it is more involved in the encoding of olfactory information. Royet et al. (2001) demonstrated that the right OFC is implicated in familiarity judgments and in the evaluation of odor quality. Even though our participants only had to perform a simple odor detection task, it is possible that due to their higher degree of odor awareness (Beaulieu-Lefebvre et al., 2011), the blind subjects engaged in more complex assessment of the odorant stimuli, resulting in a stronger activation of the right OFC. The OFC has been implicated in the conscious perception of aromas and the processing of higher-order olfactory information (Rolls, 2001). Furthermore, the OFC is also involved in multisensory integration of visual and olfactory inputs as it receives direct projections from the anterior infero-temporal region and the piriform cortex (Barbas, 1988). We have shown previously that there is an increased structural connectivity between inferior temporal visual areas and the prefrontal cortex (Ptito et al., 2008). Therefore, the stronger OFC activation might be due to increased structural and or functional connectivity between inferior temporal visual areas and the prefrontal cortex.
during the processing tactile and auditory stimuli (Pietrini et al., 2009). The direct group comparison of the contrast “odor > rest” revealed significantly increased BOLD responses in the congenitally blind subjects throughout the whole extent of the occipital cortex. A similar but slightly less strong BOLD response increase was also observed in the group comparison of the contrast “odorless > rest”. Sighted individuals showed a trend towards deactivation of the occipital cortex during the odor and odorless conditions. A limited number of previous brain imaging studies however did show that certain odorant tasks may activate the occipital cortex even in normal sighted subjects (Cerf-Ducastel & Murphy, 2006; Plailly et al., 2008; Royet et al., 2001). The absence of visual cortex activation in normal sighted control subjects might be explained by the low level cognitive complexity of our detection task. The occipital activation found in normal sighted subjects in some studies has been attributed to mental imagery related to the olfactory task (Royet et al., 2001). Anatomical tracing studies in the primate revealed that the visual cortex sends afferents to the OFC where they converge with olfactory input (Carmichael & Price, 1995). Interestingly, visuoolfactive convergence is even present in species with reduced visual pathways such as the blind mole rat (Cooper et al., 1994). Moreover, electrophysiological studies in awake monkeys showed the existence of bimodal visual-olfactory neurons in the orbitofrontal cortex (Rolls and Bayliss, 1994). These findings may explain the influence that vision can exert on the processing of odors and also supports recent results showing that olfaction can directly affect visual processing (Zhou, Jiang, He, & Chen, 2010). Therefore, the increased activation of the occipital cortex during olfaction may reflect the unmasking of olfactory inputs caused by the absence of visual afferent information from birth (Kupers et al., 2006; Ptito et al., 2008). In conclusion, our results indicate that blind and sighted participants process olfactory stimuli differently. The stronger activations in the right amygdala, right orbitofrontal cortex, bilateral hippocampus and visual cortex in congenitally blind participants may provide a neurobiological substrate for their increased odor awareness (Beaulieu-Lefebvre et al., 2011).
4.4. The hippocampus
Acknowledgments
Olfactory information is relayed from the amygdaloid complex and the entorhinal cortex to the hippocampus (Carmichael, Clugnet & Price., 1994), a brain structure with known functions in memory and emotional processing. The hippocampus is also involved in olfactory processing. Results of functional brain imaging studies in normal human subjects suggest that the hippocampus is a site of cross-modal visual and semantic facilitation of odor perception (Cerf-Ducastel & Murphy, 2006; Gottfried & Dolan, 2003). The hippocampus is also involved in odor discrimination (Kareken, Mosnik, Doty, Dzemidzic, & Hutchins, 2003) and in olfactory imagery (Plailly et al., in press). As our behavioral task was a very low-level odor detection task, we explain the increased hippocampal activity in the congenitally blind participants by a stronger evocation of odorinduced mental imagery or memory processes.
The Danish Medical Research Council (M.P., R.K.), the Harland Sanders Foundation (M.P.) and The Lundbeck Foundation (R.K.) supported this study. M.B.L. received a student fellowship from the National Science and Engineering Research Council of Canada (NSERC). The authors are indebted to D.R. Chebat and L. Gagnon for their help during testing and to M. Melillo and F. Richard for building the olfactometer.
4.3. Right lateral orbitofrontal cortex (OFC)
4.5. Visual areas The present fMRI data show that blind participants also activate their visual cortex during odor detection, providing the first demonstration for the role of the visual cortex of the blind in olfactory processing. This adds new evidence to the notion that the visual cortex in the blind acquires a multimodal function, extending previous findings showing recruitment of visual cortex in the blind
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Contents lists available at ScienceDirect
Neuropsychologia journal homepage: www.elsevier.com/locate/neuropsychologia
Neural correlates of olfactory processing in congenital blindness R. Kupers a,∗,1 , M. Beaulieu-Lefebvre b,c,1 , F.C. Schneider d,e,f , T. Kassuba g , O.B. Paulson g,h , H.R. Siebner g , M. Ptito b,g a
Institute of Neuroscience and Pharmacology, Panum Institute, University of Copenhagen, Blegdamsvej 3B, 2300 Copenhagen, Denmark Chaire de Recherche Harland Sanders, School of Optometry, University of Montreal, Montreal, Canada Psychology Department, University of Montreal, Montreal, Canada d Université de Saint Etienne, Jean Monnet, F-42023 Saint Etienne, France e Radiology Department, University Hospital of Saint-Etienne, France f CNRS UMR 5229, Centre de Neurosciences Cognitives, Bron, France g Danish Research Center for Magnetic Resonance, Copenhagen University Hospital, Hvidovre, Denmark h Neurobiology Research Unit, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark b c
a r t i c l e
i n f o
Article history: Received 7 October 2010 Received in revised form 15 March 2011 Accepted 22 March 2011 Available online 30 March 2011 Keywords: Blindness Olfaction Cross-modal plasticity Behavior fMRI
a b s t r a c t Adaptive neuroplastic changes have been well documented in congenitally blind individuals for the processing of tactile and auditory information. By contrast, very few studies have investigated olfactory processing in the absence of vision. There is ample evidence that the olfactory system is highly plastic and that blind individuals rely more on their sense of smell than the sighted do. The olfactory system in the blind is therefore likely to be susceptible to cross-modal changes similar to those observed for the tactile and auditory modalities. To test this hypothesis, we used functional magnetic resonance imaging to measure changes in the blood-oxygenation level-dependent signal in congenitally blind and blindfolded sighted control subjects during a simple odor detection task. We found several group differences in taskrelated activations. Compared to sighted controls, congenitally blind subjects more strongly activated primary (right amygdala) and secondary (right orbitofrontal cortex and bilateral hippocampus) olfactory areas. In addition, widespread task-related activations were found throughout the whole extent of the occipital cortex in blind but not in sighted participants. The stronger recruitment of the occipital cortex during odor detection demonstrates a preferential access of olfactory stimuli to this area when vision is lacking from birth. This finding expands current knowledge about the supramodal function of the visually deprived occipital cortex in congenital blindness, linking it also to olfactory processing in addition to tactile and auditory processing. © 2011 Elsevier Ltd. All rights reserved.
1. Introduction The sense of smell is critical for almost all species since it contributes to basic vital needs such as finding the right food, choosing a mate or avoiding predators. Smells may evoke strong emotions and vivid memories, and influence social interactions (Gottfried, 2006). Although it is believed that humans have a less refined sense of smell than animals, they are nonetheless able to distinguish thousands of different odors. Notwithstanding, the human sense of smell is not always reliable, especially not when it comes to odor identification. Psychophysical studies have shown that humans are only able to name about one third of the odors when they are presented without other sensory cues (Cain, 1979; Engen & Ross, 1973), suggesting that other modalities provide associative cues
∗ Corresponding author. Tel.: +45 35456890; fax: +45 3545 3989. E-mail address: [email protected] (R. Kupers). 1 These authors contributed equally to this work. 0028-3932/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2011.03.033
that contribute to odor identification. For instance, there is evidence that vision may aid in odor identification. Thus, Gottfried and Dolan (2003) showed that odor recognition is faster and better when odors are paired with semantically congruent visual cues. The cross-modal facilitation of olfactory processing by visual information is mediated by pathways linking olfactory and visual brain areas (Cooper, Parvopassu, Herbin, & Magnin, 1994; Rolls & Bayliss, 1994; Rolls, Critchley, Mason, & Wakeman, 1996). Another example is that identification of odors improves when they are presented with a semantically congruent color combination (Zellner, Bartoli, & Eckard, 1991). Previous psychophysical studies revealed differences in olfactory performance between sighted and congenitally blind individuals. Cuevas, Plaza, Rombaux, De Volder, and Renier (2009) reported that blind individuals are better than sighted controls in the free identification of odors. In addition, a recent study by BeaulieuLefebvre, Schneider, Kupers, and Ptito (2011) demonstrated that blind subjects have a lower odor detection threshold and are more aware of their olfactory environment. This raises the question of
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how the olfactory system is influenced by the absence of vision from birth. Adaptive neuroplastic changes in congenitally blind individuals have been well documented for the processing of tactile and auditory information. Congenitally blind individuals outperform their sighted counterparts in a variety of sensory and cognitive tasks, and thereby recruit their visual cortex (reviewed by Kupers, Pietrini, Ricciardi, & Ptito, 2011; Merabeth & Pascual-Leone, 2010). These cross-modal responses have been attributed to brain reorganization, in particular to an increase in cortico-cortical projections (Ptito, Schneider, Paulson, & Kupers, 2008). Behavioral, imaging and anatomical studies therefore suggest that the so-called “visual” cortex of the blind has acquired multimodal functions (Pietrini, Ptito, & Kupers, 2009). To the best of our knowledge, no published reports exist on how olfactory information is processed following visual deprivation. Since the olfactory system is very plastic (Li, Luxenberg, Parrish, & Gottfried, 2006; Plailly, Delon-Martin, & Royet, in press; Wilson, Best, & Sullivan, 2004), it is highly susceptible to crossmodal changes similar to those observed for the tactile and auditory modalities. Here we used functional magnetic resonance imaging (fMRI) to study the purported role of olfactory brain areas and the occipital cortex in olfactory processing in subjects lacking vision from birth. In light of previous findings on cross-modal plasticity in early blindness (Pietrini et al., 2009), we hypothesized that besides the primary and higher order olfactory brain areas, blind subjects will also recruit their visual cortex during odor detection. 2. Materials and methods 2.1. Participants Eleven congenitally blind subjects without light perception (4 females; mean age: 32 ± 14 years; mean education: 13 ± 2 years) and fourteen sighted controls (8 females; mean age: 30 ± 9 years; mean education: 16y ± 2 years) participated in this study. Origin of blindness was peripheral in all cases: retinopathy of prematurity (N = 8), glaucoma (N = 1), congenital cataract (N = 1) and one whose cause of blindness was unknown. Ten subjects were blind from birth and the remaining became blind before the age of 6 months. None of the participants had a documented history of psychiatric disorders, nor did they suffer from any allergies or from nasal deformities, fractures or obstruction. The local ethics committee of the county of Copenhagen approved the study and all subjects gave informed consent.
2.2. Stimuli and stimulation equipment To prevent odorant-specific habituation during the fMRI data acquisition period, we used two different odors: phenylethyl alcohol 5% (v/v) in propenediol and butanol 5% (v/v) in propenediol (Sigma–Aldrich). These odors are widely used in olfactory testing and their detection thresholds are known to be the same (Croy et al., 2009). At the used concentration, they mainly activate the olfactory nerve with minimal co-activation of the trigeminal nerve (Doty et al., 1978). We used a custom-made, fMRI-compatible, computer-controlled olfactometer to present the odors. The device allows rapid delivery of odors without accompanying thermal, tactile or auditory stimulation. The olfactometer consisted of a control and a stimulation module. The control module was placed in the scanner control room, while the stimulation module was positioned close to the subject. The stimulation module comprised three 125-ml large glass jars, two of them contained 60 ml of odorant liquids and one 60 ml of odorless propenediol. The jars were tightly sealed with a rubber cap. Two 2-m long TeflonTM tubes with an inner diameter of 4 mm, one for the inlet and another for the outlet, entered the jars through a small hole in the rubber seals. A constant airflow of 4 l/min was injected into the jar where it was mixed with the liquid before leaving the bottle. This permits a rapid delivery of odor in the absence of tactile or auditory confounds (Li et al., 2006). The three outlet tubes, coming from each jar, merged into a single tube that ended 2 cm in front of the subject’s nose. Subjects were asked whether they felt any tactile sensation from the tube or odor presentation and none did so. The low-pressure flow was generated by a pump, located in the control module. The output of the pump was sent through an 8 m long tube to the stimulation module via a pressure regulator. In order to send the low pressure flow to one of the three jars, the tube was connected to two valves that were controlled by a high pressure flow produced by a compressor inside the control room. The output of the compressor went inside the control module, and was switched to two of a set of four tubes that went from the control module to the
two valves inside the stimulation module. Two computer-steered solenoid valves inside the control module controlled the switching. 2.3. Experimental procedures The olfactory system habituates rapidly. For instance, Sobel et al. (2000) demonstrated that a prolonged odorant stimulus induces a sharp blood-oxygenation level-dependent (BOLD) increase in the primary olfactory cortex that returns to baseline level after 25–30 s, despite continuous stimulation. One way to bypass habituation is to reduce the actual stimulation time. Tabert et al. (2007) reported that odorant stimulation lasting 6 s is optimal to induce activation in primary olfactory cortex and its projection areas. For this reason, we used an event-related fMRI design. Each participant underwent three fMRI runs with 16 stimulus presentations per run, resulting in a total of 48 stimulus presentations. Half of the stimuli were the odorants phenylethyl alcohol and butanol and the remaining were odorless (propenediol) control stimuli, presented in a semi-random fashion. The 6-s stimuli were separated by fixed inter-stimulus intervals of 29 s (Tabert et al., 2007). This design allows for physiological refreshment and prevents the overlap of hemodynamic responses. The first stimulation was preceded by a 15 s blank, and the last one was followed by a 30 s blank. The total duration of one run was 581 s. Prior to the scanning session, participants were trained in the odor detection task. They were instructed to breath normally and to maintain a constant depth of breathing throughout stimulus delivery and not to sniff, as sniffing can elicit signal changes in primary olfactory cortex even in the absence of odorant stimulation (Sobel et al., 1998). Participants performed an odor detection task that is a simple cognitive task that does not involve the recruitment of stored representations of odors (Royet et al., 2001). Participants indicated whether they had perceived an odor or not by clicking one of two buttons (YES/NO) of a response pad. A tone, announcing the stimulation epochs, was presented through a headphone 2 s prior to the stimulus onset. A second tone was presented at the end of the stimulus delivery period, indicating participants to press one of the response buttons. The number of correctly identified stimuli was monitored throughout the scanning session to ensure that the odorants were perceived. After the experiment, participants rated intensity and pleasantness of the odors using a 5-point rating scale, with “0” as not perceptible or neutral and “5” very strong or very pleasant. The number of correct answers was analyzed using a 2 by 3 mixed analysis of variance (ANOVA), with group (blind versus sighted) as fixed effect factor and the fMRI runs (1–3) as random effect factor. The subjective perception of odorants was analyzed by a Student t-test for independent samples. Cardiac and respiratory motion were recorded throughout scanning with respectively an MR-compatible pulse oximeter and a respiration belt, both sampled at 50 Hz. Respiration was measured to make sure that BOLD differences between blind and sighted participants cannot be explained by group differences in sniffrelated respiration patterns (Bensafi, Sobel, & Khan, 2007; Sobel et al., 1998). We measured both respiration frequency and depth, defined respectively as the number of breathes per minute and the amount of air moved between each breath. 2.4. MRI data acquisition Images were acquired on a 3T scanner (Siemens Magnetom Trio, Erlangen, Germany) with an 8-channel head coil. Prior to the functional runs, a T1weighted MR image was obtained with the following parameters: TR/TE/TI/FA 1.55 s/3.04 ms/800 ms/9◦ , 256 × 256 matrix, spatial resolution of 1 mm × 1 mm × 1 mm. Single-shot gradient-echo echo-planar images (EPI) with BOLD contrast and whole-brain coverage (45 slices; 3 mm slice thickness; no gap) were collected in an oblique orientation, 30◦ to the commissural plane, with the following parameters TR/TE/FA: 2.95 s/30 ms/90◦ , total readout time, 38.4 ms, matrix, 64 × 64 and a field of view of 192 mm. In each of the 3 functional sessions, 197 dynamic scans were acquired. Head motion was restricted with a forehead strap and placement of comfortable padding around the participant’s head. Each fMRI session was followed by a short FLASH sequence for field mapping estimation (TR/TE1-TE2/FA: 500 ms/5.19 ms–7.25 ms/60◦ , matrix, 64 × 64, 3 mm × 3 mm × 3 mm voxel size, 45 slices) using the same orientation as the functional acquisitions. 2.5. Processing and statistical analyses of the fMRI data Image processing and statistical analyses were performed using SPM8 (statistical parametric mapping 8; www.fil.ion.ucl.ac.uk/spm/) and percent signal changes were visualized using rfxplot (Gläscher, 2009). The first two brain volumes of each run were discarded from further analysis to eliminate effects of non-equilibrium magnetization. In order to address the susceptibility-by-movement interaction, we used the FieldMap Toolbox of SPM8 and the reconstructed phase and magnitude images of the FLASH sequence described above. An unwarped field map was calculated and then converted into a voxel displacement map (VDM) (Hutton et al., 2002) that was coregistered to the first EPI volume of each fMRI session. EPI time-series were corrected for head movements and unwarped using the VDMs (Andersson, Hutton, Ashburner, Turner, & Friston, 2001). The resulting images were spatially normalized to MNI standard space as implemented in SPM 8, thereby resampled to 3 mm isotropic voxel, and smoothed with an 8 mm full width at half maximum isotropic Gaussian kernel.
R. Kupers et al. / Neuropsychologia 49 (2011) 2037–2044 Table 1 Stereotactic coordinates ROIs. Side L/R
Primary olfactory areas Piriform cx Amygdala Entorhinal cx
R L R L R L
Higher order olfactory areas Anterior insula R L Posterior insula R L Medial orbitofrontal cx Lateral orbitofrontal cx R L Anterior cingulate cx Posterior cingulate cx Mediodorsal thalamus R L Hippocampus R L Visual areas V1 R L V2 R L V3 R L V4 R L MT R L
Radius (mm)
MNI coordinates x
y
z
5 5 8 8 5 5
22 −22 21 −21 39 −39
3 3 −4 −4 −1 −1
−17 −17 −17 −17 −17 −17
5 5 5 5 8 5 5 8 8 5 5 5 5
33 −33 36 −36 3 22 −22 3 3 12 −12 30 −30
23 23 −10 −10 41 30 30 23 −43 −8 −8 −10 −10
4 4 −2 −2 −17 −14 −14 37 25 9 9 −14 −14
8 8 8 8 8 8 8 8 8 8
9 −9 30 −30 51 −51 41 −41 51 −51
−97 −97 −80 −80 −67 −67 −84 −84 −64 −64
7 7 8 8 −8 −8 4 4 4 4
2039
tory processing (ROIs in the primary and higher olfactory cortex) and cross-modal plasticity in congenital blindness (occipital ROIs). Next, as proposed by Bensafi et al. (2007), we used the activation maps of our odorless control condition in the sighted control group to specify the exact x, y, z coordinates that were used for the final analysis. Within each our preliminary ROIs, we selected the voxel showing regional peak activation and defined its x, y, z coordinates as center of mass for the spherical ROIs that were used for small volume correction (SVC). Results were thresholded at P < 0.05, corrected for multiple comparisons, using the family wise error (FWE) method implemented in SPM8. SVC was performed within the pre-defined ROI, whereas for all voxels outside the ROIs, correction for multiple non-independent comparisons considered all voxels in the brain.
3. Results 3.1. Behavioral results Fig. 1 shows the behavioral results acquired during scanning. As can be seen, blind and sighted participants detected the odor stimuli equally well (F1,23 = −0.50, ns; mixed ANOVA). Mean percentage of correctly detected odor stimuli during the fMRI scans were 92.6% for the blind and 94.3% for the sighted controls, indicating that both groups attended and responded to the stimuli throughout the entire scanning session (Fig. 1A). There was no significant difference in odor detection between male and female participants (F2,46 = 0.63, ns) nor did we find a main effect of runs (F2,46 = 0.36, ns), suggesting that the stimuli were equally well detected throughout the study and that no habituation occurred. There was also no significant interaction effect between groups and runs (F2,46 = 2.20, ns). The intensity and pleasantness ratings also did not reveal significant group differences, suggesting similar perception of the stimuli in the scanner (Fig. 1B).
3.2. fMRI results Statistical analysis was performed separately for each voxel using a general linear model. At the individual level (fixed effects), we defined separate regressors for the experimental conditions of interest, i.e. odor (both odors combined) and odorless, respectively, and one for the responses. Epochs with incorrect answers (<10%) were modeled in a separate regressor (irrespective of condition). The condition regressors were modeled by convolving a 6-s boxcar function at stimulus onset with the canonical hemodynamic response function (HRF), and the responses were modeled by convolving delta functions (representing each button press) with the canonical HRF. A high-pass filter with a cut-off period of 128 s removed low frequency drifts in BOLD signal. The individual contrast images for the comparison of “odor > baseline” and “odorless > baseline” were then entered into a random-effects analysis at the group level. The design matrix was configured as a full factorial model including the factors group (blind/sighted) and condition (odor/odorless). Fifteen spherical regions-of-interest (ROIs) with a diameter of 5 or 8 mm, depending on the size of the structure, were selected a priori (see Table 1) based on their implication in olfactory processing (Gottfried, 2006) and occipital areas recruited in the blind by cross-modal plasticity (Matteau, Kupers, Ricciardi, Pietrini, & Ptito, 2010; Ptito, Moesgaard, Gjedde, & Kupers, 2005). ROI analysis used the first eigenvariate of the voxels surviving a P < 0.05 (uncorrected) within the ROI. We determined the stereotactic coordinates of the center of each spherical ROI using a 2-step procedure. In a first step, we identified a range of stereotactic coordinates for each of our regions of interest, based on existing results from the literature on olfac-
The main effect of odor was examined by a conjunction analysis of the contrast “odor > odorless” in both groups of subjects. This analysis revealed that compared to the odorless condition, odors evoked significantly stronger BOLD responses in the piriform cortex bilaterally, and in the left orbitofrontal cortex. A borderline significant BOLD response increase (P = 0.052; SVC) was found in the left hippocampus. Fig. 2 shows the increased BOLD response in the left and right piriform cortex together with the peristimulus time histograms of the evoked BOLD responses in both groups. We examined the main effect of group with a conjunction analysis based on the contrast “blind > controls” for the odor and odorless condition (Fig. 3 and Table 2). Compared to normal sighted subjects, congenitally blind participants showed significantly larger BOLD response increases throughout the entire extent of the occipital cortex (areas V1–V4, MT). The group comparisons for the contrasts “odor > rest” and “odorless > rest” yielded similar results (data not shown).
Fig. 1. Odor perception within the fMRI scanner for blind and control subjects. (A) Odor detection performance scores. N refers to the number of correctly detected odors. The maximum possible score is 16. (B) Rating scores for odor intensity and pleasantness. Error bars indicate the standard error of the mean.
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Fig. 2. Increased BOLD responses in bilateral piriform cortex in the odor compared to the odorless condition. The statistical activation maps to the left show the results of the conjunction analysis of blind and sighted participants for the contrast “odor > odorless”. The visualization threshold is set to P < 0.05, FWE- corrected, and activation maps are displayed on the average structural image of all participants. The graphs to the right show peristimulus time histograms of evoked BOLD responses in left (Pir L) and right (Pir R) piriform cortex within each group (SC = sighted control, CB = congenital blind). The graph represents the average group response, rescaled to 0 at stimulus onset, together with the standard error of the mean. Responses to the odor and odorless condition are shown in red and blue colors, respectively.
Table 2 Main effect of group “CB > SC”. Anatomical area
Visual areas V1 V2 V3 V4 MT a
Coordinates x
y
9 −9 30 −30 51 −51 42 −42 51 −51
−97 −97 −79 −79 −67 −67 −85 −85 −64 −64
Cluster size
Pa
T
34 62 52 34 32 17 54 55 46 17
0.040 0.045 0.047 0.021 0.027 0.040 0.012 0.011 0.027 0.029
2.92 2.87 2.85 3.22 3.11 2.93 3.48 3.49 3.11 3.07
z 7 7 7 7 −8 −8 4 4 4 4
Corrected for multiple comparisons.
Table 3 BOLD signal increases “odor > odorless”. Anatomical area
Primary olfactory areas Piriform cortex Amygdala Entorhinal cortex Higher order olfactory areas Medial orbitofrontal cortex Lateral orbitofrontal cortex Anterior cingulate cortex Posterior cingulate cortex Mediodorsal thalamus Hippocampus Visual areas V2 V3 a
Corrected for multiple comparisons.
Congenitally blind
Sighted controls
Side
Cluster size
Pa
T
Cluster size
Pa
T
R L R L L
15 12 18 15 6
0.010 0.002 <0.000 0.002 0.031
3.19 3.88 4.47 3.92 2.70
12 12 18 15
0.007 <0.000 0.004 <0.000
3.35 4.66 3.55 4.66
R R L
30
0.025
3.15
15 14
0.009 0.002
3.24 3.89
R L R L
17 19 19 19
0.033 0.037 <0.000 <0.000
2.65 2.51 5.19 4.93
R L L
73 72 28
0.022 0.004 0.020
3.21 3.94 3.25
R. Kupers et al. / Neuropsychologia 49 (2011) 2037–2044
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Fig. 3. Increased occipital activation during the odor condition in congenitally blind compared to sighted subjects. The visualization threshold is set to P < 0.01, uncorrected, and activation maps are displayed on the average structural image of all participants. Blind subjects showed significant odor-related BOLD responses throughout the whole extent of the occipital cortex. The numbers (mm) next to the slices refer to the dorso-ventral (z-dimension) positioning of the slices in stereotactic (Montreal Neurological Institute, MNI) space.
Table 3 lists the within group results of the contrast “odor > odorless”. Both groups showed significant BOLD response increases in piriform cortex and amygdala bilaterally. Blind subjects showed additional bilateral activations in the mediodorsal thalamus, hippocampus, area V2, and left entorhinal cortex and area V3. Fig. 4 and Table 4 show the results of the group × condition interaction “(blind > controls) × (odor > odorless)”. Blind subjects showed larger BOLD signal increases than the sighted in the odor relative to the odorless condition in the right amygdala and right orbitofrontal cortex, and bilaterally in the hippocampus and visual area V2. We explain the absence of a significant group × condition interaction effect in the other visual ROIs by the prominent BOLD response increase in the odorless condition in the blind participants. A subsignificant increase was found in the left orbitofrontal cortex (P = 0.052; SVC). Only blind but not sighted
control subjects showed significantly increased BOLD activity in the right mediodorsal thalamus in the odor versus odorless contrast, but this difference did not reach significance in the direct group × condition interaction. In contrast, we found no brain areas where BOLD increases to odor relative to odorless stimulation was larger in sighted than in blind participants. Not unexpectedly, the odorless condition also yielded increased BOLD responses in several areas that were activated by odor detection (data not shown). As there were no significant group differences in either respiration frequency (blind: 17.9; sighted controls: 16.5; P = 0.20) or respiration depth (blind: 1.83; sighted controls: 1.68; P = 0.09) during fMRI data acquisition, the observed group differences in BOLD responses cannot be attributed to differences in breathing patterns.
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Odor
0 -0.05 -0.10 -0.15
Amygdala (R)
0.10
***
0.05 0 -0.05 -0.10 -0.15
Hippocampus (L)
** 0.15
***
0.10 0.05 0 -0.05 -0.10 -0.15
0.10 0.05 0 -0.05 -0.10 -0.15
0.15 0.10 0.05 0 -0.05 -0.10 -0.15
Orbitofrontal (L)
*
0.30 0.20 0.10 0
Thalamus (R)
* % signal change
% signal change
% signal change
0.15
**
0.40
Hippocampus (R)
* **
% signal change
**
0.10 0.05
0.15
0.20
*
**
% signal change
% signal change
% signal change
***
% signal change
*
* 0.15
Odorless
0.10 0 -0.10 -0.20
Orbitofrontal (R)
V2 (L)
0.20
*
0.10 0 -0.10 -0.20
V2 (R)
Fig. 4. Percent BOLD changes in primary (amygdala) and higher order (mediodorsal thalamus, hippocampus, lateral orbitofrontal cortex) olfactory brain areas and visual cortex (V2) of congenitally blind and blindfolded sighted controls. Data of the blind subjects are shown to the left in each graph. Abbreviations: L = left; R = right. Asterisks indicate the levels of statistical significance (*P < 0.05; **P < 0.01; ***P < 0.001). Error bars indicate standard error of the mean.
4. Discussion Compared to normal sighted control subjects, congenitally blind subjects more strongly activate a subset of the primary and higher order olfactory areas as well as the occipital cortex during a simple odor detection task. Since blind and sighted participants did not differ in terms of odor detection rate, odor intensity and valence ratings, this finding cannot be attributed to perceptual differences per se. Our data add new evidence to the supramodality of the visually deprived occipital cortex in congenital blindness by showing that in addition to tactile and auditory stimuli, odorants effectively activate the occipital cortex when vision is lacking from birth.
workers demonstrated an intensity-by-valence interaction in the amygdala. Specifically, the amygdala responded more strongly to high compared to low intensity odors for (un)pleasant but not for neutral odors. Along the same line, de Araujo et al. (2005) reported positive correlations between odor pleasantness and BOLD responses within the amygdala. Since our blind and sighted participants rated the odors as equally pleasant, it is unlikely that the observed group difference in amygdala response is mediated by differences in hedonic coding of the stimuli. In view of our earlier finding of a lower odor detection threshold in congenitally blind subjects (Beaulieu-Lefebvre et al., 2011), we rather attribute the increased amygdala response to an upregulation of odor intensity processing in congenital blindness.
4.1. The amygdala 4.2. The mediodorsal thalamus Together with the olfactory nucleus, olfactory tubercle and piriform cortex, the amygdala forms part of the primary olfactory cortex (Price, 2004). Although both groups showed increased responses in the amygdala during the odor as compared to the odorless condition, the magnitude of BOLD signal increase in the right amygdala was significantly larger in blind subjects. The involvement of the amygdala in olfactory processing has been documented in several previous neuroimaging studies (de Araujo, Rolls, Velazco, Margot, & Cayeux, 2005; Gottfried, Deichmann, Winston, & Dolan, 2002; Royet et al., 2003; Sobel et al., 2000; Winston, Gottfried, Kilner, & Dolan, 2005). For instance, a study by Winston and co-
Congenitally blind but not sighted control subjects showed a significant BOLD response increase in the odor compared to the odorless condition in the right mediodorsal thalamus. The thalamus plays an atypical role in olfactory processing. Neurons from the lateral olfactory tract project directly to the primary olfactory cortex and various components of the limbic system, thereby bypassing the thalamus. The mediodorsal thalamus receives olfactory inputs from the piriform cortex and sends information to the orbitofrontal cortex. Plailly, Howard, Gitelman, and Gottfried (2008) suggested that the mediodorsal thalamus is involved in olfactory attention.
Table 4 Interaction group × condition “(CB > SC) × (odor > odorless)”. Anatomical area
Coordinates x
Primary olfactory areas Amygdala Higher order olfactory areas Lateral orbitofrontal cortex Hippocampus Visual areas V2 a
Corrected for multiple comparisons.
Cluster size
Pa
T
y
z
24
−10
−14
6
0.047
2.72
18 −21 27 −33
26 32 −13 −10
−14 −14 −14 −17
14 10 16 13
0.050 0.052 0.003 0.019
2.45 2.43 3.63 2.93
30 −24
−79 −79
7 7
78 77
0.029 0.003
3.07 4.06
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We previously demonstrated that congenitally blind subjects score higher on the odor awareness scale (Beaulieu-Lefebvre et al., 2011), a measure of attention to environmental smells. The current finding that blind subjects show a BOLD signal increase in the odor compared to the odorless condition in the right mediodorsal thalamus and right orbitofrontal cortex (OFC) may provide a neurobiological basis for this increased odor awareness. As the olfactory system is highly plastic (Li et al., 2006; Plailly et al., in press; Wilson et al., 2004), increased conscious analysis or awareness of odors may lead to changes in neural networks such as the strengthening of the connectivity between the thalamus and higher order olfactory areas.
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Blind participants also showed stronger activation of the right lateral OFC during the odor condition. Earlier brain imaging studies demonstrated that the right OFC is more strongly activated by odorants than the left (Malaspina, Perera, Lignelli, Marshall, & Esser, 1998; Zatorre, Jones-Gotman, Evans, & Meyer, 1992), suggesting that it is more involved in the encoding of olfactory information. Royet et al. (2001) demonstrated that the right OFC is implicated in familiarity judgments and in the evaluation of odor quality. Even though our participants only had to perform a simple odor detection task, it is possible that due to their higher degree of odor awareness (Beaulieu-Lefebvre et al., 2011), the blind subjects engaged in more complex assessment of the odorant stimuli, resulting in a stronger activation of the right OFC. The OFC has been implicated in the conscious perception of aromas and the processing of higher-order olfactory information (Rolls, 2001). Furthermore, the OFC is also involved in multisensory integration of visual and olfactory inputs as it receives direct projections from the anterior infero-temporal region and the piriform cortex (Barbas, 1988). We have shown previously that there is an increased structural connectivity between inferior temporal visual areas and the prefrontal cortex (Ptito et al., 2008). Therefore, the stronger OFC activation might be due to increased structural and or functional connectivity between inferior temporal visual areas and the prefrontal cortex.
during the processing tactile and auditory stimuli (Pietrini et al., 2009). The direct group comparison of the contrast “odor > rest” revealed significantly increased BOLD responses in the congenitally blind subjects throughout the whole extent of the occipital cortex. A similar but slightly less strong BOLD response increase was also observed in the group comparison of the contrast “odorless > rest”. Sighted individuals showed a trend towards deactivation of the occipital cortex during the odor and odorless conditions. A limited number of previous brain imaging studies however did show that certain odorant tasks may activate the occipital cortex even in normal sighted subjects (Cerf-Ducastel & Murphy, 2006; Plailly et al., 2008; Royet et al., 2001). The absence of visual cortex activation in normal sighted control subjects might be explained by the low level cognitive complexity of our detection task. The occipital activation found in normal sighted subjects in some studies has been attributed to mental imagery related to the olfactory task (Royet et al., 2001). Anatomical tracing studies in the primate revealed that the visual cortex sends afferents to the OFC where they converge with olfactory input (Carmichael & Price, 1995). Interestingly, visuoolfactive convergence is even present in species with reduced visual pathways such as the blind mole rat (Cooper et al., 1994). Moreover, electrophysiological studies in awake monkeys showed the existence of bimodal visual-olfactory neurons in the orbitofrontal cortex (Rolls and Bayliss, 1994). These findings may explain the influence that vision can exert on the processing of odors and also supports recent results showing that olfaction can directly affect visual processing (Zhou, Jiang, He, & Chen, 2010). Therefore, the increased activation of the occipital cortex during olfaction may reflect the unmasking of olfactory inputs caused by the absence of visual afferent information from birth (Kupers et al., 2006; Ptito et al., 2008). In conclusion, our results indicate that blind and sighted participants process olfactory stimuli differently. The stronger activations in the right amygdala, right orbitofrontal cortex, bilateral hippocampus and visual cortex in congenitally blind participants may provide a neurobiological substrate for their increased odor awareness (Beaulieu-Lefebvre et al., 2011).
4.4. The hippocampus
Acknowledgments
Olfactory information is relayed from the amygdaloid complex and the entorhinal cortex to the hippocampus (Carmichael, Clugnet & Price., 1994), a brain structure with known functions in memory and emotional processing. The hippocampus is also involved in olfactory processing. Results of functional brain imaging studies in normal human subjects suggest that the hippocampus is a site of cross-modal visual and semantic facilitation of odor perception (Cerf-Ducastel & Murphy, 2006; Gottfried & Dolan, 2003). The hippocampus is also involved in odor discrimination (Kareken, Mosnik, Doty, Dzemidzic, & Hutchins, 2003) and in olfactory imagery (Plailly et al., in press). As our behavioral task was a very low-level odor detection task, we explain the increased hippocampal activity in the congenitally blind participants by a stronger evocation of odorinduced mental imagery or memory processes.
The Danish Medical Research Council (M.P., R.K.), the Harland Sanders Foundation (M.P.) and The Lundbeck Foundation (R.K.) supported this study. M.B.L. received a student fellowship from the National Science and Engineering Research Council of Canada (NSERC). The authors are indebted to D.R. Chebat and L. Gagnon for their help during testing and to M. Melillo and F. Richard for building the olfactometer.
4.3. Right lateral orbitofrontal cortex (OFC)
4.5. Visual areas The present fMRI data show that blind participants also activate their visual cortex during odor detection, providing the first demonstration for the role of the visual cortex of the blind in olfactory processing. This adds new evidence to the notion that the visual cortex in the blind acquires a multimodal function, extending previous findings showing recruitment of visual cortex in the blind
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