Other areas involved in olfactory processing

2.6.1.1 Hippocampus

Although not considered part of the olfactory brain per se, we found a certain variety of central areas that were responsive to an odorant stimulation or to its emotional aspects. For instance, both odorant stimulation (OS>S control contrast from study 2), and familiar odors (F+, study 1) resulted in hippocampal activations, in its anteromedial and lateral posterior aspects respectively. As previously mentioned in the introduction, the hippocampus features connections to the EC and the OB, is implicated in odor perception (Abele et al., 2003; Mainland et al., 2005) and in olfactory crossmodal association and retrieval (Bensafi et al., 2008; Yeshurun et al., 2009). It could thus be speculated that the hippocampal involvement in the processing of familiar odors might reflect particular episodes associated with a specific smell, according to each participant’s memories. Given the specific the specific neural link between odors, emotion and memory (Gottfried et al., 2004; Yeshurun et al., 2009), it would be interesting to test whether olfactory familiarity differs in its hippocampal representation, compared to that of other modalities.

2.6.1.2 Motor areas

Odor stimulation consistently elicited activation in posterior aspects of the cerebellum (O>S localizer and OS>S control contrast in study 2), while odor intensity was positively correlated with enhanced activities in the putamen and the globus pallidus. Along with their well-known role in motor control (see Koziol et al., 2014, for a review), cerebellar activities have also consistently been observed in response to trigeminal and olfactory stimulation (Boyle, Heinke, et al., 2007; Cerf-ducastel & Murphy, 2001; Small et al., 1997; Sobel et al., 1998; Zatorre, Jones-Gotman, & Rouby, 2000, for a metanalysis see Albrecht et al., 2010), while patient studies revealed olfactory impairments following cerebellar lesions or atrophy (Abele, Riet, Hummel, Klockgether, & Wüllner, 2003; Mainland, Johnson, Khan, Ivry, & Sobel, 2005). Moreover, it appears that the olfactory sensitivity of the cerebellum diminishes with age, probably as a result of decreased olfactory abilities (Ferdon & Murphy, 2003). In turn, putamen and globus pallidus are associated with a variety of functions, including the control of motor skills (DeLong, Alexander, et al., 1984; DeLong, Georgopoulos, et al., 1984; Kimura, Kato, &

Shimazaki, 1990; Marchand et al., 2008; Tsang et al., 2012). These combined motor oriented responses to odor stimulation and increasing intensity could potentially reflect a role in olfactomotor control and sniffing (see Mainland et al., 2005 for a discussion) during odor detection.

Additionally, negative valence (H-, UF>H, UF>GEOS and U>P contrasts of study 1) also correlated with cerebellar activations, but more anteriorly. The cerebellum also contributes to affective processing (for a review, see Schmahmann & Caplan, 2006), and it has been shown to be differentially sensitive

190 to aversive sounds, or pictures eliciting disgust vs. happiness, in the vermis and cerebellar hemispheres, and the posterior cerebellum, respectively (Schienle & Scharmüller, 2013; Zald &

Pardo, 2002). The combined sensitivity of cerebellum to visually and auditory induced emotions and olfactory stimulation calls for a more systematic investigation of this structure in the context of odor borne emotions. Interestingly, cerebellar activations linked to odor stimulation were almost systematically co-activated with other motor-related areas, such as the SMA (see study 2 Table 16, section 3.2.2.2, experimental part) and the anterior/medial cingulate cortices (H-, UF>H, UF>GEOS and U>P contrasts of study 1). Moreover, although not together with the cerebellum, pallidal activations were also observed in study 2 in response to an unpleasant odor context (U>P contrast, study 2).

Although not part of the olfactory brain, the ACC is steadily activated during a series of processes linked to trigeminal and olfactory processing, such as odor stimulation (Albrecht et al., 2010;

Gottfried & Dolan, 2003; Lombion et al., 2009; Savic et al., 2002), retronasal smell (Small et al., 2004), odor familiarity judgments (Royet et al., 1999), top down, verbal or hunger state modulation of odor response (de Araujo et al., 2005; Gottfried et al., 2003; Hillert, Musabasic, Berglund, Ciumas, & Savic, 2007). Moreover, among many other functions, the ACC is also involved in the networks supporting the processing of negative emotional stimuli (for a review, see Etkin & Schatzberg, 2011), as well as in motor planning (Hanakawa, Dimyan, & Hallett, 2008), given its connections with premotor areas (Bates & Goldman-Rakic, 1993; Morecraft et al., 2013). It has thus been suggested that the ACC could be a probable site for behavioral control, selection and preparation (Schulz, Bédard, Czarnecki, & Fan, 2012, see Craig, 2009, for a review).

Therefore, the preparatory behavioral and motor response pattern combining ACC, cerebellum, SMA and/or pallidum that we observed in both studies to unpleasant olfactory could reinforce the suggestion formulated in section 2.3.1 of the experimental part according to which odor elicited disgust could result in the recruitment of motor planning networks, in order to induce physical withdrawal away from an unpleasant smell. Given the privileged connections of the ACC and the SMA with the anterior and ventral insula (Deen et al., 2011), both involved in olfactory and disgust perception, and the central function of olfaction for chemical threat detection (see section 3.5 of the theoretical part), the motor-planning of odor induced avoidance might be different compared to that of other sensory modalities.

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Limitations & Perspectives 3

We will now review the limitations encountered across the studies performed during this thesis, along with the prospective questions they bring for future investigation.

3.1 MRI experiments 3.1.1 Study 1

The aim of this study was to explore the neural correlates of complex odor-borne feelings beyond valence only, measured by a specifically design scale (GEOS). It is important to note that none of our GEOS categories was saturated completely by one particular odor, with the exception of PF and UF that accounted for the valence component. Instead, for most odorants, we obtained rather composite emotional profiles, reflecting the fact that odor-borne feelings are complex and that some emotion categories did not elicit a distinct neural profiles on their own (RF, for example). Despite the subtleness of differences in olfactory profiles, the identified neural correlates of GEOS were specific and distinct from each other, and they reveal selective modulations of distributed brain areas in response to odor-specific emotions. Since we studied a specific subset of the French-speaking population in Geneva, for whom the GEOS questionnaire and terms have previously been validated (Chrea et al., 2009; Porcherot et al., 2010), it would be interesting to conduct intercultural comparisons in other areas in the world. Nevertheless, it is important to stress that most of the categories used here appear to be universally observed in the general EOS model (Ferdenzi, Delplanque, et al., 2013).

Such a universal scale is a tool of choice for exploring whether the differences in odor-borne feelings observed across cultures are rooted in the brain, and could be the object of an experiment in the future.

One of the greatest technical limitations we encountered throughout these two experiments was the simultaneous impossibility of presenting the participants with a wide variety of odors (13) while judging the subjective experience these odors elicited in the scanner according to all 6 GEOS categories, familiarity, hedonicity and intensity, after each trial, in order to get immediate, precise, event-related individual scores for parametric modulation. The experiment was already longer than usual (2 hours, separated sessions), because of the number of trial repetition per condition (20) necessary for obtaining a reliable and detectable signal; and because of the rapid habituating nature of the olfactory stimulation, which requires long ISI times (>20s). Thus, additional ratings over 9 scales (6 GEOS + F,H,I) or even 12 (9 EOS, + F,H,I) for each trials would have elongated the experiment even more. One way to overcome this for future studies would be to perform the

192 experiment with less odors, previously chosen on a basis of intensity and familiarity evaluation, with less trial repetitions (15). As our data suggests, hedonicity assessment is already included in the GEOS / EOS scale (Pleasant and Unpleasant feeling), and could thus be dropped, so that only the GEOS / EOS categories would remain.

3.1.2 Study 2

The aim of study 2 was to assess whether attentional modulation would affect the processing of odor valence in the related sensory cortices. We already addressed the dissociation that could be made between consciousness (or awareness) and top down attentional modulation, and how these could be manipulated separately (see section 2.4 of the general discussion). One of the other limitations encountered in study 2, regards the manipulation of endogenous attention per se. Experimental settings – MRI in particular – do not constitute ecological environments in general, with stimuli being presented in a controlled but artificial fashion (e.g. odors through a nasal cannula). For instance, we deliberately chose to send the stimulation in a cued-breathing fashion, in order to maximally control the delivery of odors at regular intervals. This procedure presents the advantage of minimizing respiratory activity intra and inter individual and potential confounds that could be caused by pleasant versus unpleasant odors, since participants are requested to breathe in evenly after the 3 second expiration, regardless of stimulus valence, while taking into account the “sniffing” part of the olfactory experience (Mainland & Sobel, 2006). However, it places the participant in an artificial

“sniffing” state, which is not ideal to assess passive detection, in a design where endogenous attention is manipulated – in particular when attention has to be diverted away from the olfactory stimulus, given that sniffing will constantly remind the participant that a smell might be present. One way to circumvent this problem would be to synchronize odor delivery on the basis of breathing patterns – inspiratory and expiratory phase, as this has been done in several experiments (e.g. Plailly et al., 2008).

Finally, attentional manipulation did not appear to induce a corresponding sensory amplification in olfactory cortices. Because of time constraints, we chose not to manipulate the affective value of our competing modality of attention, audition – all sounds were neutral, contrary to odors, that could be pleasant, neutral or unpleasant. Although odors possess a particularly strong affective power compared to other modalities, we cannot exclude that the attentional competition between odors and sounds could be influenced by the affective value of the stimuli. A follow-up experiment with neutral odors and valenced sounds could clarify this issue.

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