Epilepsy & Behavior 37 (2014) 184–190

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Epilepsy & Behavior

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Lateralization of olfactory processing: Differential impact of right and lefttemporal lobe epilepsies

Julie Hudry a, Philippe Ryvlin b,c,d, Anne-Lise Saive a, Nadine Ravel a, Jane Plailly a, Jean-Pierre Royet a,⁎a Olfaction: From Coding to Memory Team, Lyon Neuroscience Research Center, INSERM U1028, CNRS UMR 5292, University of Lyon, Franceb Department of Functional Neurology and Epileptology, Hospices Civils de Lyon, Lyon, Francec TIGER, Neuroscience Research Center of Lyon, INSERM U1028, CNRS 5292, Lyon-1 University, Lyon, Franced Department of Clinical Neurosciences, CHUV, Lausanne, Swizterland

⁎ Corresponding author at: Olfaction: From Coding toMNeurosciences de Lyon (CRNL), CNRS UMR 5292, INSERMAvenue Tony Garnier, 69366 Lyon Cedex 07, France. Tel.4 37 28 76 01.

E-mail address: royet@olfac.univ-lyon1.fr (J.-P. Royet)

http://dx.doi.org/10.1016/j.yebeh.2014.06.0341525-5050/© 2014 Elsevier Inc. All rights reserved.

a b s t r a c t

a r t i c l e i n f o

Article history:Received 16 June 2014Revised 26 June 2014Accepted 29 June 2014Available online xxxx

Keywords:OlfactionTemporal lobe epilepsyLateralization

Olfactory processes were reported to be lateralized. The purpose of this study was to further explore this phe-nomenon and investigate the effect of the hemispheric localization of epileptogenic foci on olfactory deficits inpatientswith temporal lobe epilepsy (TLE). Olfactory functioningwas assessed in 61 patients and 60 healthy con-trol (HC) subjects. The patients and HC subjects were asked to rate the intensity, pleasantness, familiarity, andedibility of 12 common odorants and then identify them. Stimulationswere deliveredmonorhinally in the nostrilipsilateral to the epileptogenic focus in TLE and arbitrarily in either the left or the right nostril in the HC subjects.The results demonstrated that regardless of the side of stimulation, patients with TLE had reduced performancein all olfactory tasks compared with the HC subjects. With regard to the side of the epileptogenic focus, patientswith left TLE judged odors as less pleasant and had more difficulty with identification than patients with rightTLE, underlining a privileged role of the left hemisphere in the emotional and semantic processing of odors. Final-ly, irrespective of group, a tendency towards a right-nostril advantage for judging odor familiarity was found inagreement with a prominent role of the right hemisphere in odor memory processing.

emory, Centre de Recherche enU1028, Université Lyon 1, 50

: +33 4 37 28 74 95; fax: +33

.

© 2014 Elsevier Inc. All rights reserved.

1. Introduction

The importance of the temporal lobes in human olfactionwas recog-nized as early as the 1890swith the observation that patients with tem-poral lobe epilepsy (TLE) were prone to olfactory auras and olfactorydysfunctions [1–4]. Patients with TLE typically have normal olfactorysensitivity but impaired complex olfactory function, as assessed by stan-dard tests of odor discrimination, recognition memory, identification,and naming [5–13]. These olfactory deficits are thought to reflect thepresence of several abnormalities of temporal lobe structures and func-tions underlying seizure disorders [for review, see [14,15]]. However,the specific neural networks altered in patients with TLE with olfactorydeficits are still unknown.

Based on cognitive psychology concepts [16,17], we previously hy-pothesized that the ratings of intensity, pleasantness, familiarity, andedibility represent different olfactory judgments requiring activationfrom perceptual to semantic representation [18–20]. This assumptionwas supported by functional neuroimaging data showing the

involvement of distinct neural networks – in terms of both structureand hemispheric specialization – in these olfactory judgment tasks[18,19,21]. For example, the left hemisphere is dominant in the judgmentof odor pleasantness, and the right hemisphere is dominant during the fa-miliarity judgment, emphasizing the roles of these hemispheres in emo-tional and memory processing, respectively [22]. These olfactory taskshave also been used to detect impaired olfactory abilities in patientswith Alzheimer's disease, those with schizophrenia, or those withParkinson's disease and show patterns of disturbance specific to each pa-thology [23–25].

A unique feature of olfactory system anatomy is that the olfactorynerve is the only cranial nerve with primarily ipsilateral central projec-tions to the piriform cortex, amygdala, and entorhinal cortex, although afew contralateral projections have been noted via the lateral olfactorytract and the anterior commissure [26,27]. Secondary projectionsreach the hippocampus, ventral striatum, thalamus, and orbitofrontaland insular cortices. As several areas involved in olfactory processingare localized to the temporal lobes [for review, see [28–30]], it followsthat unilateral TLE can offer new insights to better understand thedifferential temporal hemispheric contributions to the perceptual andsemantic processing of odors. Using monorhinal stimulations and stan-dard olfactory tests, previous studies have shown that olfactory deficitsare restricted to the nostril ipsilateral to the epileptogenic region [9,10]and indicated that in commissurotomized patients, each hemisphere is

185J. Hudry et al. / Epilepsy & Behavior 37 (2014) 184–190

independent and sufficient for perceiving and recognizing familiarodors [31]. The purpose of the present study was twofold: to com-pare olfactory performances between patients with TLE and healthycontrol (HC) subjects using the olfactory-specific tasks of intensity,pleasantness, familiarity, and edibility judgments and of identificationand to examine whether right and left TLEs are associated with distinctperformances in olfactory processing. The patients performed the testinterictally, and odorants were administered monorhinally in the nos-tril ipsilateral to the suspected epileptogenic focus. Based on our previ-ous findings, we predicted that the olfactory performances of patientswith right TLE and those with left TLE would be differentially alteredfor these olfactory tasks.

2. Materials and methods

2.1. Participants

A total of 61 patients with intractable TLE (33 left, 28 right) and 60HC subjects participated in the study (Table 1). Patients with TLE wereinvestigated while undergoing presurgical evaluation of their epilepsyand were on therapeutic levels of antiepileptic medication. All partici-pants with the exception of 3 patients with TLE were right-handed;however, all but 1 patient had a predominantly left-sided speech repre-sentation based on a preoperative intracarotid sodium amytal procedurefor assessing hemispheric language dominance [32,33]. No patientsexhibited any nasal pathology, complained of any disturbance in theirsense of smell, or had olfactory ictal symptoms. The patients weredistributed into four subgroups based on the side of the epileptogenicfocus and gender. The epileptogenic focus location was determinedusing video-scalp-electroencephalographic monitoring, magneticresonance imaging (MRI), fluorodeoxyglucose positron emission to-mography, and ictal blood flow single-photon emission computer-ized tomography when available. Illness duration (F3, 57 = 0.159, p =0.924) did not differ among the groups. The patients were seizure-freefor at least 12 h prior to the experiment. The most common abnormalitywas hippocampal sclerosis/atrophy present at least unilaterally in 32patients. Other abnormalitiesweremalformation of cortical development(7 patients), cavernoma of the amygdala (1) or temporal lobe(1), dysembryoplastic neuroepithelial tumors of the temporal lobe(3), and hamartoma of the hypothalamus (1). Eleven patients pre-sented with normal MRI.

The 60 HC subjects were right-handed (with the exception of 3 left-handed) volunteers with no history of chemosensory, neurological, orpsychiatric disorders. The HC subjects were relatives of the patients orrecruited from the surrounding community. The HC subjects were dis-tributed into four subgroups of 15 subjects depending on the side ofnostril stimulation and gender. The eight subgroups of patients andHC subjects were balanced for age (F7, 113 = 0.740, p = 0.638) andgender (χ2

1, 3 = 1.537, p = 0.674).

Table 1Subject demographic and disease-related variables.

Subjects

Group Nostril Gender N Age

Years (range)

Right TLE Right Men 10 35.4 (23–47)Women 18 36.4 (23–60)

Left TLE Left Men 15 34.7 (19–56)Women 18 33.2 (17–56)

Total or mean 61 34.9 (17–60)HC Right Men 15 34.2 (18–51)

Women 15 38.0 (21–50)Left Men 15 31.2 (23–48)

Women 15 32.6 (20–47)Total or mean 60 30.4 (18–50)

TLE, temporal lobe epilepsy; HC, healthy control; N, number; SD, standard deviation; HS, hippo

General instructions about the experimentwere given to all subjects,and fully informed consent for study participation was obtained.

2.2. Odorants

Twelve familiar odorantswere used (Table 2). As in previous studies,these odors were selected in such a way that they were perceived asfamiliar, with variations in the intensity, pleasantness, and edibilityratings. Odor mixtures were furnished by Givaudan (Argenteuil,France) or by International Flavors & Fragrances (Colombes, France),and simple chemical compounds were provided by manufacturers ofchemical products (Aldrich or Sigma, France).

Odorants were stored in 20-ml yellow glass bottles with polyethyl-ene screw lids (Fisher, Elancourt, France). The bottles were opaque tomask any visual cues of the odorant's identity. The odorants were dilut-ed inmineral oil to prepare 5ml of odorous solution (10%) and absorbedby compressed polypropylene filaments. Tetrahydrothiophene (gas),acetic acid (vinegar), and ether were diluted 100 times as they releasea very strong odor. The odorants were refrigerated when not in useand removed prior to the experiment to reach room temperature beforeuse. The odorants were changed every three months and were neverused more than ten times.

2.3. Experimental procedure

As described previously [23–25], the experimental procedureincluded two sessions during which subjects received the same 12odorant stimulations. The odorants were presented only once duringeach session, with a presentation time not exceeding 5 s andwith an in-terstimulus interval of 60 s long enough to prevent sensory adaptation[34–36]. In the first session, the subjects were asked to successivelyrate the odor intensity, pleasantness, familiarity, and edibility usinglinear rating scales segmented at regular intervals and numbered from1 to 10. The scale extremities were marked ‘very weak’ and ‘verystrong’, ‘very unpleasant’ and ‘very pleasant’, ‘very unfamiliar’ and‘very familiar’, and ‘very inedible’ and ‘very edible’, for intensity, pleas-antness, familiarity, and edibility, respectively. In the second session,the subjects had to identify each odor by selecting a name from a writ-ten list of five alternative proposals comprising the veridical label, thename of a similar odor, and three names evoking more distinct edibleor inedible odors (Table 2). The stimulations were administeredmonorhinally, with subjects holding the contralateral nostril closedwith one finger. The patients were stimulated in the nostril ipsilateralto the epileptogenic focus so that patients with right TLEwere stimulat-ed in the right nostril and patients with left TLE were stimulated in theleft nostril. Half of the HC subjects were arbitrarily stimulated in theright nostril and half in the left nostril.

Abnormalities

Smoker Illness duration HS Others No

(N) (Years ± SD) (N) (N) (N)

2 21.0 ± 9.1 3 4 33 21.6 ± 14.7 12 4 22 23.7 ± 13.4 5 6 41 20.8 ± 11.3 12 5 28 21.8 ± 12.4 32 19 111 – – –

2 – – –

1 – – –

1 – – –

5

campal sclerosis.

Table 2List and order of the odorants presented for the olfactory test.

No. Veridical label Chemical name Dilution Distractor names

1 2 3 4

1 Mushroom 1-Octen-3-ol 10% Mold Camphor Licorice Lilac2 Lemon Mixture 10% Hyacinth Grapefruit Vanilla Apricot3 Vinegar Acetic acid 1% Orange Mustard Gardenia Cider4 Lavender Mixture 10% Incense Caramel Mothballs Thyme5 Citronella Mixture 10% Banana Lychee Tar Verbena6 Clove Eugenol 10% Grass Garlic Chocolate Cinnamon7 Ether Diethyl ether 1% Chloroform Lily Pizza Nail varnish8 Strawberry Mixture 10% Biscuit Raspberry Petrol Passion fruit9 Gas Tetrahydrothiophene 1% Carnation Petroleum Cheese Turpentine10 Mint Mixture 10% Bitter almond Rose Licorice Anise11 Pine Mixture 10% Eucalyptus Wax Tobacco Gingerbread12 Smoked salmon Mixture 10% Prawn Ham Glue Jonquil

186 J. Hudry et al. / Epilepsy & Behavior 37 (2014) 184–190

2.4. Statistical analyses

The scores for intensity, pleasantness, familiarity, and edibility weredetermined directly from the rating scale values. The odor identificationscores were determined by attributing a value of ‘1’ when the veridicallabel was selected and a value of ‘0’ for an alternate choice.

Judgments of intensity, pleasantness, familiarity, and edibility andodor identification were considered different olfactory tasks involvingdifferent olfactory processes. However, these tasks have previouslybeen shown to be closely related [19,37]. Therefore, amultivariate anal-ysis of variance (MANOVA) with group (patient vs. control), gender(male vs. female), nostril (left vs. right), and task (intensity, pleasant-ness, familiarity, edibility, and identification) factors was performedwith repeated measurements for the odor factor. Five-way analyses ofvariance (ANOVAs) with repeated measurements [38] were then usedto separately analyze the scores relative to each olfactory judgmenttask. Given that the judgment of pleasantness is bipolar, ranging fromunpleasant to neutral and fromneutral to pleasant [39,40], an additionalANOVA was performed to distinguish pleasant and unpleasant ratings.Thus, a two-way ANOVA was performed for group and pleasantnessfactors. The differences between pairs or groups ofmeanswere assessedby multiple orthogonal contrasts. Sample normality and homogeneityof variance were controlled with the Lilliefors [41] and Hartley [38]tests, respectively.

3. Results

All subjects provided all required ratings; no data were missing. Thescores obtained for intensity, pleasantness, familiarity, edibility, andidentification as a function of subject groups (TLE vs. HC), stimulatednostril (right vs. left), gender, and the twelve odorants were first ana-lyzed by MANOVA. The results showed a significant effect for group(Roy's Greatest Root11, 55 = 3.79; p b 0.001), task (Roy's GR11, 558 =177.87; p b 0.001), odorant (Roy's GR11, 555 = 90.69; p b 0.001), andgender (Roy's GR11, 555 = 2.38; p = 0.007) but not for nostril (p =0.582). Significant group × task (Roy's GR11, 558 = 5.33; p b 0.001),group × nostril (Roy's GR11, 555 = 2.93; p b 0.001), gender × task(Roy's GR11, 558 = 4.14; p b 0.001), and group × gender (Roy'sGR11, 555= 2.37; p= 0.007) effects were noted, but no gender × nostril(p = 0.342) and task × nostril (p = 0.611) effects were observed.Only the group × nostril × task (Roy's GR11, 558 = 2.66; p =0.003) and group × gender × task (Roy's GR11, 558 = 1.81; p =0.049)interactions were significant. The group × gender × nostril × task in-teraction (Roy's GR11, 558 = 1.80; p = 0.051) was almost significant.Post hoc Bonferroni testing showed significant pairwise differencesamong the different olfactory tasks (intensity, pleasantness, familiarity,edibility, and identification) (p b 0.005 at least). This result means that

the scores obtained for the five tasks were independent. Thus, we didnotmeasure the same performanceswith the different tasks. Univariatetestswith four-way (group× gender × nostril × odorant) ANOVAwerethen performed for the five olfactory tasks.

For the intensity judgment, ANOVA revealed a significant effect ofgroup (F1, 113 = 10.27, p = 0.002), with scores significantly lower inthe patients with TLE than in the HC subjects and a significant effect ofodorant (F11, 1243 = 51.89, p b 0.001) (Fig. 1A).

For the pleasantness judgment, there was a significant effect of odor(F11, 1243 = 112.86, p b 0.001), and there were significant interactionsbetween group × nostril (F1, 113 = 3.77, p = 0.055), group × odor(F11, 1243 = 6.00, p b 0.001), and gender × odor (F11, 1243 = 2.23,p = 0.011). Mean comparisons indicated that patients with leftTLE rated odors as less pleasant than patients with right TLE (p =0.033) and than HC subjects stimulated on the right or the left side(p = 0.015 and p = 0.043, respectively) (Fig. 1B). Mean compari-sons further showed that vinegar was judged as less unpleasant(p = 0.019) and lavender, strawberry, mint, and pine as less pleas-ant (p = 0.004, p = 0.053, p = 0.029, and p = 0.019, respectively)by patients with TLE than by HC subjects. To determine whetherTLE could have an overall impact on the judgment of odors as a func-tion of hedonic valence, we grouped odors according to an a prioriselection of pleasantness or unpleasantness, calculated themean rat-ings for each hedonic condition, and performed a two-way ANOVA(group × pleasantness) with repeated measurements for pleasant-ness factor. The results showed a significant group × pleasantnessinteraction (F1, 119 = 17.50, p b 0.001) (Fig. 1C). Multiple meancomparisons showed that pleasant odors were rated as less pleasant(p b 0.001) and unpleasant odors as less unpleasant (p b 0.001) inpatients with TLE than in HC subjects.

For the familiarity judgment (Fig. 2A), the ANOVA showed a signifi-cant effect of the group factor (F1, 113 = 18.00, p b 0.001) with lowerscores in patients with TLE than in HC subjects and a significant effectof the odor factor (F11, 1243 = 40.36, p b 0.001). The nostril factorapproached significance (F1, 113 = 3.39, p = 0.068), showing that re-gardless of the group, odors tended to be less familiar when perceivedby the left than by the right nostril.

For the edibility judgment (Fig. 2B), the rankings were significantlylower in the group with TLE (F1, 113 = 5.60, p = 0.020) than inthe HC subjects, and there was also a significant effect of the odorfactor (F11, 1243 = 77.83, p b 0.001). These factors (F11, 1243 =4.62, p b 0.001) also had significantly interacted. Post hoc compar-isons showed that mushroom, strawberry, mint, and salmon werejudged as significantly less edible by the patients with TLE thanby the HC subjects (p = 0.006, p = 0.024, p = 0.046, and p =0.009, respectively). These differences were only found in the pa-tients with left TLE, as revealed by a significant group × nostril ×odor interaction (F11, 1243 = 2.14, p = 0.016). Mean comparisons

Fig. 1. A)Mean intensity scores in HC subjects and in patients with TLE and mean pleasantness scores as a function of B) group and nostril factors and C) group and pleasantness factors.Horizontal bar, neutral value; vertical bar, standard error of the mean; *p b 0.05, **p b 0.01, and ***p b 0.001.

187J. Hudry et al. / Epilepsy & Behavior 37 (2014) 184–190

then showed that the scores were significantly lower in the patientswith left TLE than in the left controls for 7 of 12 odors (p b 0.05 atleast).

For the identification test, the ANOVA revealed that the patientswith TLE had a lower performance compared with the HC subjects(F1, 113 = 56.67, p b 0.001) and revealed a significant effect of theodor factor (F11, 1243 = 7.33, p b 0.001). The group × nostril interac-tion was significant (F1, 113 = 4.55, p = 0.035). Mean comparisonsindicated that the performances of the patients with left TLE werelower than those of the patients with right TLE (p = 0.008) andthat performances of the patients with left TLE and those with rightTLE were significantly lower than their respective controls (p b 0.001and p b 0.001) (Fig. 2C). The gender × nostril interaction approachedsignificance (F1, 113 = 3.66, p= 0.058), thus, showing that the identifi-cation scores for males using the left nostril tended to be lower thanthe scores for males using the right nostril (p = 0.036) and lowerthan the scores for females using either the right (p = 0.014) or theleft (p = 0.017) nostril.

4. Discussion

Consistent with our expectations and previous findings, the presentclinical investigation demonstrates that TLE is associatedwith significantimpairments in olfactory function. Our data revealed that seizure-freepatients with TLE have impaired evaluation of odor intensity, pleasant-ness, familiarity, and edibility and corroborated previous findings indi-cating impaired odor identification in patients with TLE [6,9,10]. Withregard to the side of the epileptogenic focus, significant differenceswere observed for the judgments of odor pleasantness and edibilityand for odor identification, with lower performances in patients withleft TLE than in those with right TLE. In both HC subjects and patients,

Fig. 2.Mean A) familiarity scores and B) edibility scores as a function of HC subjects and patientbar, standard error of the mean. *p b 0.05 and ***p b 0.001.

a tendency for a right-nostril advantage was found for odor familiarityprocessing.

4.1. Influence of TLE on olfactory functioning

The present results showed that TLE is associatedwith deficits for allthe olfactory tasks, suggesting that the analysis of the olfactory signalwas disturbed from its perceptual to its more semantic level. Consider-ing the olfactory judgments requiring the most semantic processing,patients with TLE rated odorants as being less familiar and less edibleand identified themwith less accuracy than HC subjects. These findingsare consistent with previously reported data indicating impairment ofthe olfactory functions of discrimination, recognition memory, identifi-cation, and naming in TLE [5–12]. For olfactory judgments involving themost perceptual processes, we further found that patients with TLErated odorants as being less intense and less emotional than HC sub-jects. These observations could be attributed to peripheral dysfunctionor to general cognitive deficits as impaired performances were foundfor all tasks. However, with the exception of one recent study [42], noimpairment in the ability to detect odors has been reported in patientswith TLE [6,8,10,11,13]. Additionally, although significant, the decreasein the intensity scores in the present study was relatively small (8.5%of HC scores) compared with decreases in the scores of familiarity andidentification (12.4 and 24.0%, respectively), suggesting that olfactoryprocesses were differentially altered in patients with TLE. Moreover,these data confirmed that different olfactory processes were investigat-ed, findings consistent withmultivariate analysis results demonstratingthat measures recorded for the five olfactory tasks differed according tothe type of task.

Although the patients with TLE in the current experiment wereseizure-free during the olfactory tests, interictal perceptual function

s with TLE. C)Mean identification scores as a function of group and nostril factors. Vertical

188 J. Hudry et al. / Epilepsy & Behavior 37 (2014) 184–190

has been well established to also be potentially affected [43]. Therefore,the dysfunction of an olfactory region could be responsible for the olfac-tory deficits in patients with TLE. The site of the epileptogenic focus inTLE is most often located in the mesial temporal structures, includingthe amygdala and hippocampus [44]. Several studies of patients withfocal epilepsies of the temporal and frontal lobes have further providedevidence for the involvement of the piriform cortex in the epileptogenicnetwork [45,46]. The piriform cortex could act as a generator and ampli-fier of seizure activity and account, at least in part, for the susceptibilityof the limbic lobe to develop epilepsy [44]. Because patients with TLEfound odors less intense and rated pleasant and unpleasant odors asmore neutral than HC subjects and because the amygdala is stronglyinvolved in the processing of the emotional intensity of odors [47,48],we speculate that the deficits observed in the patients with TLE forodor intensity and pleasantness judgments could result from an amyg-dala dysfunction. Ciumas et al. [49] observed that patients with TLE failto activate the amygdala in response to odor stimuli. Pouliot and Jones-Gotman [50] found that both healthy individuals and patients withmedial temporal lobe resection including the amygdala had similar sub-jective emotional reactions to odors and memory for odors, but unlikehealthy individuals, patients did not have a bettermemory for emotion-ally arousing odors compared with nonarousing ones. The patients lostthe specific memory advantage caused by odors that induce strongemotional reactions.

Hippocampal dysfunction might also explain some of the olfactorydeficits of the patients with TLE. The hippocampal region is reportedlyrecruited in odor familiarity judgment [51,52]: encoding and retrievalof odor–object [53,54], odor–name [55–57], or odor–place [58] associa-tions: odor recognitionmemory [59]: and successful odor identification[60]. Thus, the observation of lower scores during the familiarity judg-ment task in patients with TLE is consistent with the fact that 50% ofthemhad at least unilateral atrophy of the hippocampal region. Becausethe additive conception hypothesis stipulates that cognitive operationsincluded in familiarity judgments are also involved in those of edibilityjudgments and identification [20], it is further logical to observe that theedibility and identification scores are lower in patients with TLEcompared with HC subjects.

4.2. Hemispheric lateralization of olfactory processing

We observed task-specific lateralization of olfactory processes, boththrough the analysis of differential performances in HC subjectsdepending on the side of the stimulated nostril and through the inter-pretation of altered judgments in patients dependent on the side ofthe TLE focus.

The familiarity judgment was the only olfactory task to demonstratean effect of the stimulation side on performance in HC subjects. Weobserved a right hemispheric advantage in HC subjects, corroboratingprevious observations and hypotheses [22,51,61]. In contrast, we didnot observe right–left differences for ratings of pleasantness and edibil-ity or for odor identification. However, previous behavioral findingsregarding lateralization for the pleasantness judgment [62–64] andfor odor identification [61,63] are inconsistent. For example, odorshave been rated as more pleasant when sniffed through the rightnostril [62,63], or no difference has been observed between nostrilsfor hedonic estimates [64]. This inconsistency of results emphasizesthat multiple uncontrolled factors are involved. Thus, complexity in-creases as gender and handedness may interact with hemisphericlateralization [62,65] and as airflow periodically reverses betweenboth nostrils because the turbinates alternatively swell and congestfrom side to side [66,67].

We found that patients with TLE, on average, judged odorants to besignificantly less pleasant when they were stimulated on the left thanon the right side (pleasantness scores of 5.31 vs. 5.73), suggesting thatthe impact of emotionally arousing odors was affected by left TLE. Thisresult would be consistent with previous findings showing a prominent

role of the left hemisphere in emotional processing [22,68,69]. We alsoobserved a greater impairment of identification scores in patients withleft TLE compared with patients with right TLE. In split-brain patients,odor identification has been tied to left hemisphere functioning [31].Furthermore, several functional MRI studies of patients with TLE[70–73] or of healthy subjects [74–78] have shown left–right hemi-spheric lateralization of verbal and nonverbal memory performance.Our data indicated that greater identification deficits in patients withleft rather than right TLE and this may reflect specific hemispheric def-icits for semantic–verbal processing. Although our observations suggestthat processes for pleasantness and identification are lateralized, no lat-eralization of familiarity and edibility judgmentwas apparent in the pa-tientswith TLE. However, the edibility judgment task activates semanticrepresentations [18,19], and the familiarity judgment can reportedlyautomatically engage semantic circuits [19,51,52,79]. Therefore, the fa-miliarity task results may serve as evidence for a greater impact of leftTLE on a semantic judgment task than of right TLE on the perceptualjudgment task. In addition to the possible effects of interference be-tween judgment tasks, it is important to note that other factors couldaccount for the absence of any significant effect of the epileptogenicfocus on olfactory ratings. First, in partial epilepsy, the precise locationand extent of the epileptogenic focus differ from one patient to another.Consequently, the olfactory areas are unlikely to be equally affected inall patients with TLE, potentially masking specific deficits. Second, epi-lepsy has been reported to constitute an example of neural plasticity,exemplifying the remarkable capacity of the brain to change its basicstructure and function due to seizure activity [80]. For example, usingfMRI, Banks et al. [77] recently observed that activation patterns repre-sent an effective adaptation to the presence of an unhealthy hippocam-pus. In this study, patients with unilateralmedial temporal lobe damagepresented enhanced activation in the contralateral hemisphere and re-organization of activation ipsilateral to the epileptogenic focus. Thus,as Scharfman [80] described for language and speech functions, thebrain areas responsible for olfactory function in patients with epilepsycan alter position or undergo functional reorganization, particularly ifseizures occur in childhood.

4.3. Conclusion

In conclusion, in this study, the decreased performance in patientswith TLE in the odor intensity, familiarity, pleasantness, and edibilityratings and in odor identification is evidence for global olfactory impair-ments. These cognitive olfactory deficits are likely due to dysfunction ofolfactory neural networks in the temporal lobes. This study alsohighlighted the lateralization of olfactory processing. Weaker olfactoryperformance in patients with left rather than right TLE suggests prefer-ential involvement of the left hemisphere for the pleasantness judg-ment and for the identification of odors, consistent with previousstudies. Additionally, differences in the ratings of odor familiarity inHC subjects as a function of the stimulation side depicted a right-nostril advantage, which may reflect a right hemispheric dominancein odor memory processing.

Conflict of interest

There is no conflict of interest.

Acknowledgments

We are grateful to the staff of the Functional Neurology andEpileptology Unit (Neurological Hospital of Lyon) for providing infor-mation about the patients. This work was partly supported by the Cen-tre National de la Recherche Scientifique (CNRS) and the LABEX Cortex(NR-11-LABX-0042) of Université de Lyon within the program“Investissements d'Avenir” (ANR-11-IDEX-0007) operated by theFrench National Research Agency (ANR).

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