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

Cerebral Insights into Olfactory Discrimination: Vanillin, Vanitrope, and Vanillyl Ethyl Ether | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cerebral Insights into Olfactory Discrimination: Vanillin, Vanitrope, and Vanillyl Ethyl Ether Akshita Joshi, Divesh Thaploo, Susanne Weise, Jonathan Warr, Thomas Hummel This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4472205/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract 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. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction 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. Methods 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 mm 2 field of view, voxel size 1 × 1 × 1 mm 3 ). 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 3.5. Results 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 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)). Discussion 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 ). Conclusion 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. Declarations 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. 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N., Han, H., Moscovitch, M., & Grady, C. L. (2009). Event-related fMRI studies of episodic encoding and retrieval: Meta-analyses using activation likelihood estimation. Neuropsychologia , 47 (8–9), 1765–1779. https://doi.org/10.1016/j.neuropsychologia.2009.02.028 Spence, C. (2022). Odour hedonics and the ubiquitous appeal of vanilla. Nature Food , 3 (10), 837–846. https://doi.org/10.1038/s43016-022-00611-x Squire, L. R., Stark, C. E. L., & Clark, R. E. (2004). The medial temporal lobe. Annual Review of Neuroscience , 27 , 279–306. https://doi.org/10.1146/annurev.neuro.27.070203.144130 Vilberg, K. L., & Rugg, M. D. (2008). Memory retrieval and the parietal cortex: A review of evidence from a dual-process perspective. Neuropsychologia , 46 (7), 1787–1799. https://doi.org/10.1016/j.neuropsychologia.2008.01.004 Watanabe, K., Masaoka, Y., Kawamura, M., Yoshida, M., Koiwa, N., Yoshikawa, A., Kubota, S., Ida, M., Ono, K., & Izumizaki, M. (2018). Left Posterior Orbitofrontal Cortex Is Associated With Odor-Induced Autobiographical Memory: An fMRI Study. Frontiers in Psychology , 9 . https://doi.org/10.3389/fpsyg.2018.00687 Welge-Luessen, A., Leopold, D. A., & Miwa, T. (2013). Smell and taste disorders-diagnostic and clinical work-up. Management of Smell and Taste Disorders-a Practical Guide for Clinicians. Stuttgart: Thieme , 49–57. Woolrich, M. W., Behrens, T. E. J., Beckmann, C. F., Jenkinson, M., & Smith, S. M. (2004). Multilevel linear modelling for FMRI group analysis using Bayesian inference. NeuroImage , 21 (4), 1732–1747. https://doi.org/10.1016/j.neuroimage.2003.12.023 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4472205","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":312035458,"identity":"f76c5dab-b9bb-4b74-b770-3c491c67a6d3","order_by":0,"name":"Akshita Joshi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABIklEQVRIie2QMUsDMRTHXzhIlohrjmL9CikH7VLqV0k4uC5VB6EICma6LgeuDuLHcLVQsMvZro69Ja66XaGgL9UuGq2jYH7TPy/58d4LQCDwB6EcKCgMxLhw6mruSDfhK7trRW2UUm5X4sLdvt9RIPkvFFlO7aKqexCNRhhuVtqww6qqh90jYOnYqzwUHalUCqQoO1LfSm34U5LwWXYC3HrbyDmnQqkIyNWACqfcPWa0QfKJNmIgfcrBnFlULlDpW6GvsYvI2HKZv2I4fvYPZtqoTFBRbaHNWqGwk49dl2/WL1HJphx3wXCfJIbbqMFnqc659Q4my76N6+5Zs4U/FtfnzT3DMvJSD3v6kqULb5sPeMt8LtGf3jv2tz0IBAKB/8sbnOJg/uOm6DAAAAAASUVORK5CYII=","orcid":"","institution":"Technische Universität Dresden","correspondingAuthor":true,"prefix":"","firstName":"Akshita","middleName":"","lastName":"Joshi","suffix":""},{"id":312035459,"identity":"7ccc2162-2d24-43ba-ac34-42e6ac01a6da","order_by":1,"name":"Divesh Thaploo","email":"","orcid":"","institution":"Technische Universität Dresden","correspondingAuthor":false,"prefix":"","firstName":"Divesh","middleName":"","lastName":"Thaploo","suffix":""},{"id":312035460,"identity":"26401c25-cd26-4c8e-a53a-8f41967a5f20","order_by":2,"name":"Susanne Weise","email":"","orcid":"","institution":"Technische Universität Dresden","correspondingAuthor":false,"prefix":"","firstName":"Susanne","middleName":"","lastName":"Weise","suffix":""},{"id":312035461,"identity":"e007a453-1b3c-48e2-b8ef-d2611921215b","order_by":3,"name":"Jonathan Warr","email":"","orcid":"","institution":"Takasago","correspondingAuthor":false,"prefix":"","firstName":"Jonathan","middleName":"","lastName":"Warr","suffix":""},{"id":312035462,"identity":"44205038-2fe1-4cf2-ad58-e15cacf0ba42","order_by":4,"name":"Thomas Hummel","email":"","orcid":"","institution":"Technische Universität Dresden","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Hummel","suffix":""}],"badges":[],"createdAt":"2024-05-24 11:39:52","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4472205/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4472205/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":58170082,"identity":"81d45101-ce63-4738-8c36-097cc5836e3d","added_by":"auto","created_at":"2024-06-12 03:36:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":80331,"visible":true,"origin":"","legend":"\u003cp\u003eFamiliarity ratings of odors structurally related to vanilla. Individual data points with box plots of vanillin, vanitrope and VEE, with respective chemical structures.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4472205/v1/172e792a7d0e0c2115e4e7f6.png"},{"id":58171222,"identity":"9fd289dd-5b0a-44ac-8995-76144ca9ad99","added_by":"auto","created_at":"2024-06-12 03:44:38","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":322768,"visible":true,"origin":"","legend":"\u003cp\u003eActivation from conjunction analysis depicted on whole brain\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4472205/v1/0b4fa0384e2557d1c5c93331.png"},{"id":58171223,"identity":"30a142ca-3311-4b4e-a486-adc1abbdeb1f","added_by":"auto","created_at":"2024-06-12 03:44:38","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":554065,"visible":true,"origin":"","legend":"\u003cp\u003eActivations for contrasts between odors depicted as encircled.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4472205/v1/041a30455e640802c0d62469.png"},{"id":58170079,"identity":"72225b1b-8bcd-4e52-8bf8-3de9043d2b47","added_by":"auto","created_at":"2024-06-12 03:36:38","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":33084,"visible":true,"origin":"","legend":"\u003cp\u003eBox plots representing contrast estimates for odorous activation of the right hippocampus with significant differences between Vanillin and VEE.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4472205/v1/5565410c0155507799409e69.png"},{"id":58170080,"identity":"2e2edb0c-6e0c-4154-b396-fd9580ca127f","added_by":"auto","created_at":"2024-06-12 03:36:38","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":105969,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Positive correlation between contrast estimates for right OFC (when perceiving vanillin odor) and familiarity ratings of Vanillin (similar to vanilla). (B) Negative correlation between contrast estimates for right hippocampus (when perceiving vanitrope odor) and familiarity ratings of Vanitrope (similar to vanilla).\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4472205/v1/bcc4e227ce36221d74892dae.png"},{"id":63792028,"identity":"37c2e52a-45ed-40ac-8a11-bd8e74f51611","added_by":"auto","created_at":"2024-09-02 11:46:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1623976,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4472205/v1/70ef5ac6-56ce-4c6f-b774-35c3508c77f4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cerebral Insights into Olfactory Discrimination: Vanillin, Vanitrope, and Vanillyl Ethyl Ether","fulltext":[{"header":"Introduction","content":"\u003cp\u003eVanillin is one of the most popular and flavouring materials, with widespread use in foods, beverages, perfumery, cosmetics as well as pharmaceuticals (Morini et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). 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 \u0026lsquo;vanilla- the sweet smelling odor\u0026rsquo; as a proxy to maintain sweetness of commercial food products, resulting in reduced use of calorific sweetners (Spence, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Due to its synthesis in 1874, by Tiemann and Haarmann, it has become relatively inexpensive.\u003c/p\u003e \u003cp\u003eIn 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.\u003c/p\u003e \u003cp\u003eThese 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., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). This was contradicted by (Meister, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2015\u003c/span\u003e) suggesting dimensionality of odor percepts to be around 20 or less making the number to be much less than claimed.\u003c/p\u003e \u003cp\u003eUsing 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, \u0026ldquo;Can neuroimaging help us in distinguishing odors with subtle differences in smells?\u0026rdquo;.\u003c/p\u003e \u003cp\u003eTo examine the similarity between vanillin and related compounds, apart from intensity ratings and ratings of pleasantness, we focused on the familiarity (\u0026ldquo;the feeling of knowing\u0026rdquo;) 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., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). 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., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2002\u003c/span\u003e; Meunier et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Royet et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Savic et al., \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2000\u003c/span\u003e). True recognition of odors and familiarity processes have been associated with greater activity in hippocampus and parahippocampal gyrus (Royet et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). In addition, thalamus, angular gyrus, and cingulate gyrus are also associated to odor recognition in older subjects (Royet et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). These results show consistency with those of Montaldi et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2006\u003c/span\u003e, 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., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2008\u003c/span\u003e), activity in angular gyrus supports recollection (Vilberg \u0026amp; Rugg, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). 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.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eForty-four healthy volunteers (21 men, 23 women, mean age 27\u0026thinsp;\u0026plusmn;\u0026thinsp;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., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), 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.\u003c/p\u003e \u003cp\u003eHealth status of participants was ascertained by a detailed medical history (Welge-Luessen et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2013\u003c/span\u003e) 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 \u0026ldquo;Sniffin\u0026rsquo; Sticks\u0026rdquo; identification and threshold testing (Oleszkiewicz et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). 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.\u003c/p\u003e \u003cp\u003eFor 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\u0026ndash;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\u0026reg; tubing connected to a portable computer-controlled olfactometer (Sommer et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2012\u003c/span\u003e), 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 \u0026ldquo;odorous stimuli\u0026rdquo; was for 8 seconds followed by OFF or \u0026ldquo;odorless air\u0026rdquo; for 12 seconds. In the MR scanner, after each odor presentation, subjects rated the intensity (scale 0\u0026ndash;10), pleasantness [-5 (extremely unpleasant) to +\u0026thinsp;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 \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eImaging acquisition\u003c/h2\u003e \u003cp\u003eAll images were acquired on 3T MRI scanner (model \u0026ldquo;Trio\u0026rdquo;, 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\u0026thinsp;=\u0026thinsp;1000 ms, TE\u0026thinsp;=\u0026thinsp;38 ms, 58\u0026deg; 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\u0026thinsp;=\u0026thinsp;2000 ms, TE\u0026thinsp;=\u0026thinsp;1.97 ms, 256 \u0026times; 256 mm\u003csup\u003e2\u003c/sup\u003e field of view, voxel size 1 \u0026times; 1 \u0026times; 1 mm\u003csup\u003e3\u003c/sup\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eImage analysis\u003c/h2\u003e \u003cp\u003eAll 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., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2012\u003c/span\u003e), 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, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2002\u003c/span\u003e). 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., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). Results presented were contrasted at \u0026ldquo;odor\u0026thinsp;\u0026gt;\u0026thinsp;baseline\u0026rdquo; and reported at p-FWE corrected\u0026thinsp;\u0026lt;\u0026thinsp;0.05, threshold value\u0026thinsp;\u0026gt;\u0026thinsp;3.5.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAll participants had a normal sense of smell (Oleszkiewicz et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2019\u003c/span\u003e) with mean identification score of 13.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4 and mean threshold score of 8.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3. Odors vanillin, vanitrope and VEE did not differ significantly in their intensity (p\u0026thinsp;=\u0026thinsp;0.07), pleasantness (p\u0026thinsp;=\u0026thinsp;0.34) and familiarity ratings (p\u0026thinsp;=\u0026thinsp;0.92). Based on pleasantness and intensity ratings, all the odors were rated as neutral and isointense. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows descriptive statistics of odor ratings. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e depicts individual data points of familiarity ratings, with depiction of chemical structures.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDescriptive statistics of odor ratings regarding intensity (scale from 0 not intense to 10 very intense), pleasantness (scale from \u0026minus;\u0026thinsp;5 very unpleasant to +\u0026thinsp;5 very pleasant)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStd. Deviation\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntensity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVEE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVANITROPE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.98\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVANILLIN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePleasantness\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVEE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVANITROPE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVANILLIN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFamiliarity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVEE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVANITROPE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVANILLIN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eConjunction analysis:\u003c/h2\u003e \u003cp\u003eConjunction analysis was done to identify consistently activated brain regions using GLM approach for contrast \u0026ldquo;odor\u0026thinsp;\u0026gt;\u0026thinsp;baseline\u0026rdquo; 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\u0026thinsp;\u0026gt;\u0026thinsp;3.5 and cluster level\u0026thinsp;\u0026gt;\u0026thinsp;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.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eBetween group analysis:\u003c/h2\u003e \u003cp\u003eTo better understand the differences between the odors, a whole brain independent 2-sample t-test was done between odor contrasts (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRegions activated for contrast WB associated odors\u0026thinsp;\u0026gt;\u0026thinsp;neutral odors for studies 1 and 2. The effect is seen at FWE p\u003csub\u003ecorrected\u003c/sub\u003e \u0026lt; 0.05 and cluster size k\u0026thinsp;\u0026gt;\u0026thinsp;30 voxels, MNI coordinates presented in x, y, and z; L, left hemisphere; R right hemisphere.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eContrasts\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVoxels\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eZ- value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX Y Z\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRegion\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVanillin\u0026thinsp;\u0026gt;\u0026thinsp;VEE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-13 -34 -36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBrain stem\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-28 -2 -22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLeft amygdala\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-14 -66 -59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSuperior temporal gyrus\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVEE\u0026thinsp;\u0026gt;\u0026thinsp;Vanitrope\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-52 -35 41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLeft supramarginal gyrus\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVanillin\u0026thinsp;\u0026gt;\u0026thinsp;Vanitrope\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e171\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-26 -2 -22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLeft amygdala\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34\u0026thinsp;\u0026minus;\u0026thinsp;9 -34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRight parahippocampal gyrus\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVanitrope\u0026thinsp;\u0026gt;\u0026thinsp;Vanillin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 11 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSubcallosal cortex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eROI-Analysis:\u003c/h2\u003e \u003cp\u003eBased 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)\u0026thinsp;=\u0026thinsp;0.47, p\u0026thinsp;=\u0026thinsp;0.63), left OFC (F(2, 129)\u0026thinsp;=\u0026thinsp;1.05, p\u0026thinsp;=\u0026thinsp;0.35), supramarginal gyrus (F(2, 129)\u0026thinsp;=\u0026thinsp;0.52, p\u0026thinsp;=\u0026thinsp;0.52), left hippocampus (F(2, 129)\u0026thinsp;=\u0026thinsp;2.5, p\u0026thinsp;=\u0026thinsp;0.08), right putamen (F(2, 129)\u0026thinsp;=\u0026thinsp;1.17, p\u0026thinsp;=\u0026thinsp;0.31), left putamen (F(2, 129)\u0026thinsp;=\u0026thinsp;0.90, p\u0026thinsp;=\u0026thinsp;0.40), left thalamus (F(2, 129)\u0026thinsp;=\u0026thinsp;0.09, p\u0026thinsp;=\u0026thinsp;0.91) right thalamus (F(2, 129)\u0026thinsp;=\u0026thinsp;0.39, p\u0026thinsp;=\u0026thinsp;0.67), and left amygdala (F(2, 129)\u0026thinsp;=\u0026thinsp;2.26, p\u0026thinsp;=\u0026thinsp;0.11).\u003c/p\u003e \u003cp\u003eHowever, right hippocampus showed differences between odors (F (2, 129)\u0026thinsp;=\u0026thinsp;3.5, p\u0026thinsp;=\u0026thinsp;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\u0026thinsp;=\u0026thinsp;0.03) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation analysis between ROIs and familiarity ratings:\u003c/h2\u003e \u003cp\u003eExamination 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\u0026thinsp;=\u0026thinsp;0.37, p\u0026thinsp;=\u0026thinsp;0.01) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e(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\u0026thinsp;=\u0026thinsp;0.04) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e(B)).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e 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\u0026rsquo;s mood and arousal (de Wijk \u0026amp; Zijlstra, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). 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 \u0026amp; Petrides, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2002\u003c/span\u003e). Additionally, activation in the right hippocampus suggests a potential role in consolidation of odor- induced memory (Martin et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Silkis, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOlfactory 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., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Masaoka et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2012\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Rolls, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). 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, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). 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, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Previous work by (Sakikawa et al., \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2023\u003c/span\u003e) indicated that amygdala plays an integral role in odor recognition and detection with parahippocampal gyrus acting as support system in memory processing (Naya, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Similar activations in the left amygdala along with brain stem and superior temporal gyrus were found for contrast vanillin\u0026thinsp;\u0026gt;\u0026thinsp;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., \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2000\u003c/span\u003e) in a PET study.\u003c/p\u003e \u003cp\u003eTo 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 \u0026ldquo;reality filtering\u0026rdquo; 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., \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2004\u003c/span\u003e), 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, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2013\u003c/span\u003e), with familiarity being key to separate them (Liverani et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). 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, \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Both the OFC and hippocampus are intricately linked to emotional processing and memory consolidation (Watanabe et al., \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). 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., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2002\u003c/span\u003e). 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., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Spaniol et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2009\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003e In summary, the present study reveals participants\u0026rsquo; 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, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2005\u003c/span\u003e; Spence, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) 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.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgement-\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthor contribution-\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e*A.J.- Data curation and analysis, project administration, writing manuscript; *D.T.- data curation and analysis, review and edit of manuscript; S.W.-\u0026nbsp;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.\u003c/p\u003e\n\u003cp\u003e*A.J. and D.T. contribute equally to the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding source-\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTakasago International Cooperation, Paris, France, supported the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics declarations\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConflict of interest-\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eData availability-\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData generated and analyzed are not publicly available due to subject\u0026rsquo;s confidentiality. It will be available from the corresponding author on request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBird, C. M. (2017). 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Smell and taste disorders-diagnostic and clinical work-up. \u003cem\u003eManagement of Smell and Taste Disorders-a Practical Guide for Clinicians. \u003c/em\u003e\u003cem\u003eStuttgart: Thieme\u003c/em\u003e, 49\u0026ndash;57.\u003c/li\u003e\n\u003cli\u003eWoolrich, M. W., Behrens, T. E. J., Beckmann, C. F., Jenkinson, M., \u0026amp; Smith, S. M. (2004). Multilevel linear modelling for FMRI group analysis using Bayesian inference. \u003cem\u003eNeuroImage\u003c/em\u003e, \u003cem\u003e21\u003c/em\u003e(4), 1732\u0026ndash;1747. https://doi.org/10.1016/j.neuroimage.2003.12.023\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4472205/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4472205/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe 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.\u003c/p\u003e","manuscriptTitle":"Cerebral Insights into Olfactory Discrimination: Vanillin, Vanitrope, and Vanillyl Ethyl Ether","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-12 03:36:33","doi":"10.21203/rs.3.rs-4472205/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5c457697-7323-4822-a50f-84e04b12efb6","owner":[],"postedDate":"June 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-09-02T11:38:47+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-12 03:36:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4472205","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4472205","identity":"rs-4472205","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}