Cerebral Insights into Olfactory Discrimination: Vanillin, Vanitrope, and Vanillyl Ethyl Ether

doi:10.21203/rs.3.rs-4472205/v1

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Cerebral Insights into Olfactory Discrimination: Vanillin, Vanitrope, and Vanillyl Ethyl Ether

https://doi.org/10.21203/rs.3.rs-4472205/v1

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The study investigates neural processing underlying the perception of vanillin and structurally similar odorants, vanitrope, and vanillyl ethyl ether (VEE), aiming to discern subtle differences in odor perception using functional magnetic resonance imaging (fMRI). Despite similar psychophysical ratings of intensity, pleasantness, and familiarity for the odors, fMRI analysis with 44 individuals revealed distinct activation patterns in brain regions associated with olfactory processing, memory retrieval, and odor recognition. Specifically, increased activations were observed in the parahippocampal gyrus and left amygdala during the perception of vanillin compared to vanitrope and VEE. This indicates a link between emotional responses and familiarity; particularly during vanillin's resemblance to the familiar scent of vanilla. Results from further analysis could imply that the orbitofrontal cortex is involved in the diffentiation of odors, especially in linking vanillin to the the familiar aroma of vanilla, while the hippocampus might be involved in consolidating odor-induced memories. The findings underscore the intricate interplay between olfactory perception, emotional processing, and memory consolidation within the human brain. The study demonstrates the utility of fMRI in elucidating subtle perceptual differences in similar odorants and sheds light on the underlying neural mechanisms governing odor discrimination and recognition.

Vanillin is one of the most popular and flavouring materials, with widespread use in foods, beverages, perfumery, cosmetics as well as pharmaceuticals (Morini et al., 2021). Originating from the natural essence of vanilla beans or pods, vanillin, chemically represented as C8H8O3, is also one of the most liked smells cross culturally. Food scientists are becoming interested in ‘vanilla- the sweet smelling odor’ as a proxy to maintain sweetness of commercial food products, resulting in reduced use of calorific sweetners (Spence, 2022). Due to its synthesis in 1874, by Tiemann and Haarmann, it has become relatively inexpensive.

In the world of scents, vanillin stands out alongside the structurally similar odorants vanitrope and vanillyl ethyl ether (VEE), both echoing the familiar notes of vanilla. Vanitrope with molecular formula C11H14O2 has an intensely sweet, vanilla-like olfactory profile with similar application in culinary creations, beverages and cosmetics. Additionally, it serves as a plausible substitute for vanillin in certain contexts. On the other hand, VEE, characterized by molecular formula C10H14O3, imparts a subtle vanilla note predominantly utilized in alcohol free beverage flavorings like mouthwash and energy drinks due to its heating sensation, underscored by faint smoky undertones.

These aromatic counterparts, united by shared functional groups including aldehydes, hydroxyls, and ethers, offer parallels to vanillin while carving out distinct olfactory identities. Olfactory stimuli are typically mixtures of a large number of diverse components present at different ratios. Bushdid et al., used psychophysical testing with odor mixtures to conclude that humans can discriminate at least one trillion odor mixtures of shared components (Bushdid et al., 2014). This was contradicted by (Meister, 2015) suggesting dimensionality of odor percepts to be around 20 or less making the number to be much less than claimed.

Using vanillin and structurally related odorants, we aimed to find out if humans can differentiate between odorants with similar percept, that is vanillin, vanitrope and VEE. By perceiving odors evoking vanilla-like perceptions, the aim was to illuminate objective and subjective measures of differentiation. The research uses functional magnetic resonance imaging (fMRI) to objectively decipher the neural substrates underpinning odor discrimination with similar odor percept, in other words, “Can neuroimaging help us in distinguishing odors with subtle differences in smells?”.

To examine the similarity between vanillin and related compounds, apart from intensity ratings and ratings of pleasantness, we focused on the familiarity (“the feeling of knowing”) of odors similar to vanilla. Familiarity involves remembering having encountered a stimulus in absence of confirmatory contextual information, and has been associated with hippocampal and perirhinal activity (Shrager et al., 2008). Regions involved during mental processing of recognizing familiar odors include activation of piriform cortex, amygdala, entorhinal cortex, hippocampus, anterior cingulate cortex, thalamus, insula, and orbitofrontal cortex (Dade et al., 2002; Meunier et al., 2014; Royet et al., 2011; Savic et al., 2000). True recognition of odors and familiarity processes have been associated with greater activity in hippocampus and parahippocampal gyrus (Royet et al., 2011). In addition, thalamus, angular gyrus, and cingulate gyrus are also associated to odor recognition in older subjects (Royet et al., 2011). These results show consistency with those of Montaldi et al., 2006, demonstrating that as strength of familiarity increases, activity in the left dorsomedial thalamus, left ventrolateral, and anteromedial frontal cortex, posterior cingulate gyrus and left parietal neocortex increase linearly. Where thalamic activation is associated with olfactory attentional processing (Plailly et al., 2008), activity in angular gyrus supports recollection (Vilberg & Rugg, 2008). We hypothesized that since vanillin is a natural extract closely associated with vanilla, it would likely be more recognized and trigger activity in memory and recognition areas of the brain compared to vanitrope and VEE (the least nuanced vanilla note). Our aim was to explore the mechanisms underlying the potential distinctions in how the brain processes these three similar yet distinct odors.

Forty-four healthy volunteers (21 men, 23 women, mean age 27 ± 3 years) participated in the fMRI study. The study design was approved by the ethics committee of the medical faculty, the Technical University of Dresden (approval number BO-EK-451092021). All participants provided written informed consent and the experiments were conducted according to declaration of Helsinki. The sample size was estimated by the effects measured in previous studies (Joshi et al., 2023), with alpha level of 0.05 and power set to 0.95 and effect size of 0.5 for t-tests (a-priori power analysis) in order to produce reliable results with minimum of 42 sample size.

Health status of participants was ascertained by a detailed medical history (Welge-Luessen et al., 2013) with exclusion criteria of olfactory dysfunction, clinically assessed physical or mental illness, regular consumption of alcohol, regular intake of medications (apart from pharmacological contraception), and family history of any major neurological disorders brain responses to stimulation with three vanilla-like compounds were assessed. Normal sense of smell was ascertained using the “Sniffin’ Sticks” identification and threshold testing (Oleszkiewicz et al., 2019). All testing was performed in a well-ventilated room. Odor identification test includes a forced choice paradigm where subjects are asked to choose an option from a flash card with four descriptors each. Threshold test is a staircase test procedure of 16 triplet pen sets with one odorized and two odorless pens, prepared by diluting the odor 2-phenyl ethanol starting from a concentration of 4% in a ratio of 1:2.

For odor stimulation three odors with vanilla-like perceptual characteristics were selected. These were: vanillin, vanitrope, and VEE. The odors were diluted at 1:10 ratio in propylene glycol. Odors were tested to be isointense in a pilot of 15 subjects, where odors were presented at interval of 2 minutes each and participants were asked to rate the odors for intensity on a scale of 0–10; 0 being not at all intense to 10 being highly intense. During fMRI measurements (see below), the selected odors were delivered bi-rhinally using Teflon® tubing connected to a portable computer-controlled olfactometer (Sommer et al., 2012), in a room next to the scanner room. Odorous stimuli were embedded in a 2L/min constant airflow. Each subject underwent four sessions with one type of odor presentation per session. The order of sessions were pseudo-randomized among subjects. The stimuli were presented in a block design format with 10 alternating ON/OFF blocks. ON or “odorous stimuli” was for 8 seconds followed by OFF or “odorless air” for 12 seconds. In the MR scanner, after each odor presentation, subjects rated the intensity (scale 0–10), pleasantness [-5 (extremely unpleasant) to + 5 (extremely pleasant)] and familiarity of the vanilla-like odors [0 (not at all familiar) to 10 (very familiar)]. Participants communicated through the scanner intercom system. Statistical analysis was done using IBM SPSS version 27 (SPSS Inc., Chicago, Ill., USA). The significance level for statistical tests including ANOVA and Pearson correlations was set at p value of less than 0.05 (Table 1).

Imaging acquisition

All images were acquired on 3T MRI scanner (model “Trio”, Siemens Medical Systems, Erlangen, Germany) using a 32-channel head coil. A total of 248 functional images were collected using a T2 single-shot echo-planar imaging (EPI) sequence: TR = 1000 ms, TE = 38 ms, 58° flip angle, no interslice gap, 210 X 210 mm field of view. A high-resolution structural T1 image was acquired using a 3D magnetization prepared gradient rapid acquisition gradient echo (MPRAGE) sequence (TR = 2000 ms, TE = 1.97 ms, 256 × 256 mm² field of view, voxel size 1 × 1 × 1 mm³).

Image analysis

All image analysis was carried out in FSL, a FMRIB software from the Oxford center for functional magnetic resonance imaging of the brain version 6.0.2 (Jenkinson et al., 2012), using FMRI Expert Analysis Tool (FEAT). Standard preprocessing pipeline was set on the data. Brain extraction was performed to each structural and functional data using brain extraction toolbox (BET) (Smith, 2002). At first level analysis, parameter estimates were extracted from each subject per run, which were then modelled in second level analysis with fixed effect models. Group level analysis was carried out using FLAME1 (Woolrich et al., 2004). Results presented were contrasted at “odor > baseline” and reported at p-FWE corrected < 0.05, threshold value > 3.5.

All participants had a normal sense of smell (Oleszkiewicz et al., 2019) with mean identification score of 13.3 ± 1.4 and mean threshold score of 8.5 ± 1.3. Odors vanillin, vanitrope and VEE did not differ significantly in their intensity (p = 0.07), pleasantness (p = 0.34) and familiarity ratings (p = 0.92). Based on pleasantness and intensity ratings, all the odors were rated as neutral and isointense. Table 1 shows descriptive statistics of odor ratings. Figure 1 depicts individual data points of familiarity ratings, with depiction of chemical structures.

Table 1

Descriptive statistics of odor ratings regarding intensity (scale from 0 not intense to 10 very intense), pleasantness (scale from − 5 very unpleasant to + 5 very pleasant)
	Mean	Std. Deviation
Intensity
VEE	4.82	2.37
VANITROPE	5.84	1.98
VANILLIN	5.14	2.01
Pleasantness
VEE	0.89	2.33
VANITROPE	0.18	2.20
VANILLIN	0.61	2.30
Familiarity
VEE	3.95	2.63
VANITROPE	3.86	2.28
VANILLIN	4.07	2.49

Conjunction analysis:

Conjunction analysis was done to identify consistently activated brain regions using GLM approach for contrast “odor > baseline” across different odor perceptions. Using FSL, we modelled the hemodynamic response to each task and estimated the level of activation for each voxel at threshold value > 3.5 and cluster level > 20 voxels. The regions that showed significant conjunction across different odor delivery and common to all conditions were bilateral thalamus, bilateral precentral gyrus, part of OFC (Fig. 2).

Between group analysis:

To better understand the differences between the odors, a whole brain independent 2-sample t-test was done between odor contrasts (Table 2, Fig. 3).

Table 2

Regions activated for contrast WB associated odors > neutral odors for studies 1 and 2. The effect is seen at FWE p_corrected < 0.05 and cluster size k > 30 voxels, MNI coordinates presented in x, y, and z; L, left hemisphere; R right hemisphere.
Contrasts	Voxels	Z- value	X Y Z	Region
Vanillin > VEE	99	3.92	-13 -34 -36	Brain stem
	93	3.52	-28 -2 -22	Left amygdala
	33	3.48	-14 -66 -59	Superior temporal gyrus
VEE > Vanitrope	33	3.3	-52 -35 41	Left supramarginal gyrus
Vanillin > Vanitrope	171	3.6	-26 -2 -22	Left amygdala
	51	3.5	34 − 9 -34	Right parahippocampal gyrus
Vanitrope > Vanillin	53	3.5	2 11 1	Subcallosal cortex

ROI-Analysis:

Based on the whole brain results, using data-driven approach we did region of interest (ROI) analysis. ROIs chosen were bilateral OFC, supramarginal gyrus (SMG), hippocampus, angular gyrus, putamen, amygdala, thalamus. We extracted the beta estimates for each subject per odor for the respective ROIs. ANOVA was done to explore potential differences across different odors. The analysis revealed no significant differences between the odors for right OFC (F(2, 129) = 0.47, p = 0.63), left OFC (F(2, 129) = 1.05, p = 0.35), supramarginal gyrus (F(2, 129) = 0.52, p = 0.52), left hippocampus (F(2, 129) = 2.5, p = 0.08), right putamen (F(2, 129) = 1.17, p = 0.31), left putamen (F(2, 129) = 0.90, p = 0.40), left thalamus (F(2, 129) = 0.09, p = 0.91) right thalamus (F(2, 129) = 0.39, p = 0.67), and left amygdala (F(2, 129) = 2.26, p = 0.11).

However, right hippocampus showed differences between odors (F (2, 129) = 3.5, p = 0.03). Post hoc analysis with a Bonferroni adjustment revealed a significant difference between vanillin and VEE (0.37 [95% CI, 0.028 to 0.719] p = 0.03) (Fig. 4).

Correlation analysis between ROIs and familiarity ratings:

Examination of correlation between β estimates for each ROI and familiarity ratings was done to assess if any association exists between brain activity and the familiarity of the odors structurally related to vanilla. Correlation analysis revealed a statistically significant positive correlation (Pearson's correlation coefficient, r = 0.37, p = 0.01) (Fig. 5(A)) specifically within the right OFC for vanillin. However, no statistically significant correlations were detected for the other odors, namely, Vanitrope and VEE. Additionally, a negative correlation existed between the right hippocampus and familiarity ratings of vanitrope (r=-0.31, p = 0.04) (Fig. 5(B)).

In the present study, using neuroimaging it was shown that participants can objectively differentiate between odors of similar percept. This was based on a detailed comparison of neural processing underlying the perception of vanillin, vanitrope and vanillyl ethyl ether (VEE). Initial psychophysical assessments indicated no significant differences among the odors in terms of intensity, pleasantness, or familiarity. However, upon closer examination of central processing mechanisms using fMRI, similar and overlapping activation patterns were observed across the olfactory, reward, memory evoked, feeling of pleasantness, and attentional processing regions of the brain when participants perceived the odors. Subsequent analysis employing independent sample t-tests highlighted a significant increase in activation within the parahippocampal gyrus and left amygdala specifically during the perception of vanillin compared to vanitrope and VEE. Further investigation through post-hoc tests on the regions of interests, revealed a significant difference between vanillin and VEE for right hippocampus, suggesting specific emotional responses during memory retrieval and a sense of familiarity towards vanillin, likely due to its resemblance to the familiar scent of vanilla and the potential influence of repeated exposure to the most common, popular odor with various applications, vanillin, also documented to influence people’s mood and arousal (de Wijk & Zijlstra, 2012). Also, familiarity ratings of vanillin correlated positively with the contrast estimates of activations in the right OFC when perceiving vanillin odor. Neuroimaging, as hypothesized, assisted in identifying vanillin's familiarity, which resembles vanilla more closely than vanitrope and VEE. This was supported by activation in regions associated with olfactory discrimination, recognition of retrieved memory, as well as controlling judgments, specifically the right OFC (Frey & Petrides, 2002). Additionally, activation in the right hippocampus suggests a potential role in consolidation of odor- induced memory (Martin et al., 2007; Silkis, 2023).

Olfactory information ascends directly to the olfactory-related limbic structures, including piriform cortex, entorhinal cortex, amygdala, hippocampus, OFC, and thalamus. These areas overlap with the emotional, and recognition memory region. Involvement of these brain regions in human olfaction has been confirmed by several neuroimaging studies, sharing common substrates of the olfactory and emotional system (Gottfried et al., 2004; Masaoka et al., 2012, 2014; Rolls, 2004). Entorhinal cortex and amygdala, part of primary olfactory regions, converge information to the OFC, where higher-order processing including smell identification and emotional labelling takes place (Rolls, 2011). In this study, results from conjunction analysis showed activation of these regions, explaining the olfactory processing with its identification and interpretation. Interestingly, our findings from between odor contrasts indicated increased activation in the left amygdala and right parahippocampal gyrus when participants perceived vanillin compared to vanitrope, hinting the importance of amygdala towards assocative learning accounting for the likelihood of a familiar odor, vanillin, based on previous experiences (Spence, 2022). Previous work by (Sakikawa et al., 2023) indicated that amygdala plays an integral role in odor recognition and detection with parahippocampal gyrus acting as support system in memory processing (Naya, 2016). Similar activations in the left amygdala along with brain stem and superior temporal gyrus were found for contrast vanillin > VEE. This might reflect the role of brain stem and part of the temporal cortex towards the systematic and hierarchical processing of the perception, discrimination, and recognition of odors ; as reported by (Savic et al., 2000) in a PET study.

To delve deeper into the neural mechanisms underlying odor perception, beta estimates of these regions were extracted and compared between the different odors. The present results suggested an involvement of the right OFC in associating vanillin odor with the familiar scent of vanilla, highlighting its role in distinguishing between olfactory stimuli with similar perceptual qualities. Interestingly, despite consistent activation patterns of the OFC for the various vanillin-related compounds, it stood out in the processing of the familiarity of vanilla-related aroma. This can be explained by the concept of orbitofrontal “reality filtering” which is a memory control mechanism, allowing one to filter memories and thoughts in relation to ongoing reality. Limbic system has its contribution to the memory control. While hippocampus along with the posterior limbic system is necessary in encoding long term and episodic memories (Squire et al., 2004), posterior medial OFC along with anterior limbic system is involved in the sense whether an activated memory relates to the present task or not (Schnider, 2013), with familiarity being key to separate them (Liverani et al., 2020). Furthermore, a negative correlation was observed between contrast estimates of the right hippocampus and vanitrope familiarity ratings, indicating that the hippocampus does not evoke memories when perceiving vanitrope, indicating its unfamiliarity with vanilla. This negative correlation can explain decreased activity in the hippocampal regions which contributes to the ability to judge whether or not an item has been previously experienced based on familiarity-like processes (Bird, 2017). Both the OFC and hippocampus are intricately linked to emotional processing and memory consolidation (Watanabe et al., 2018). These results are in line with previous literature where the right OFC associates with odor discrimination, identification, and recognition of experienced memory, with the elicitation of pleasant emotions in response to odors (Gottfried et al., 2002). While the hippocampus, as part of the limbic system, shares neural networks with the OFC, contributing to the binding of contextual information and retrieval of odor-induced memories (Levy et al., 2004; Spaniol et al., 2009).

In summary, the present study reveals participants’ capability to cerebrally differentiate between similar odors, namely vanillin, vanitrope and VEE. Despite initial psychophysical assessments indicating no significant differences in intensity, pleasantness, or familiarity, participants displayed distinct neural responses. Specifically, increased activations in the parahippocampal gyrus and left amygdala were observed during the perception of vanillin compared to structurally similar odorants, suggesting a connection between emotional responses and familiarity, likely due to vanillin's resemblance to the widely recognized scent of vanilla. The popularity of vanilla, attributed to its multifaceted roles in food, beverages, medicine, and anxiety relief, (Bythrow, 2005; Spence, 2022) underscores its significance. Further analysis indicated the involvement of the OFC in distinguishing odors, particularly in associating vanillin with the familiar aroma of vanilla. Meanwhile the hippocampus contributed to recognizing and consolidating odor-induced memories, as suggested by decreased activity during perception of the unfamiliar vanitrope. These findings highlight the intricate interplay between olfactory perception, emotional processing, and memory consolidation within the human brain. Importantly, fMRI allows the delineation of subtle perceptual aspects of similar vanilla-like odorants.

Acknowledgement-

We would like to thank all subjects for showing their keen interest in the study. Also, many thanks to the lab members for their guidance and contribution.

Author contribution-

*A.J.- Data curation and analysis, project administration, writing manuscript; *D.T.- data curation and analysis, review and edit of manuscript; S.W.- project administration, review and edit of manuscript; J.W.- conceptualization, review and edit of manuscript; T.H.- conceptualization, project administration, supervision, validation, review and editing manuscript.

*A.J. and D.T. contribute equally to the manuscript.

Funding source-

Takasago International Cooperation, Paris, France, supported the study.

Ethics declarations

Ethical approval and consent to participate

The study design was approved by the ethics committee of the medical faculty, the Technical University of Dresden (approval number BO-EK-451092021). All participants provided written informed consent and the experiments were conducted according to declaration of Helsinki.

Consent for publication

Not applicable.

Conflict of interest-

The authors declare no conflict of interest.

Data availability-

Data generated and analyzed are not publicly available due to subject’s confidentiality. It will be available from the corresponding author on request.

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No competing interests reported.

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Cerebral Insights into Olfactory Discrimination: Vanillin, Vanitrope, and Vanillyl Ethyl Ether

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Abstract

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Introduction

Methods

Imaging acquisition

Image analysis

Results

Conjunction analysis:

Between group analysis:

ROI-Analysis:

Correlation analysis between ROIs and familiarity ratings:

Discussion

Conclusion

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References

Additional Declarations

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