Methods for measuring responses to olfactory stimuli

Abstract

The present invention relates to a method for screening aromas or flavors using functional magnetic resonance imaging to assess the ability of the aroma or flavor to induce a "well-being" effect.

Description

[Technical field]

[0001] The present invention relates to the use of a mapping technique, quantitative functional Magnetic Resonance Imaging (fMRI), to discern human responses to stimuli, specifically stimuli resulting from fragrance ingredients, accords, perfectly formulated fragrances or flavors that induce well-being effects. [Background technology]

[0002] Traditional consumer research techniques have only limited success in predicting whether a product will be a commercial success. It would be desirable to have a technique that measures the brain's response to a stimulus without the time and deliberation required to verbally express an opinion in response to a question. Magnetic resonance imaging techniques offer a way to consider how consumers respond to a stimulus in a non-verbal manner while the brain interprets the stimulus. It allows for visualization of both the primary response (e.g., in the piriform cortex PC) and further processing of the sensory signal (e.g., in the orbitofrontal cortex OFC). The consumer must use or experience the product in order to respond to it, and in the context of measuring brain responses by MRI, this can be difficult for many products. However, it is possible to introduce olfactory stimuli to a subject in a precise and accurate manner while measuring the brain's response using a particular form of olfactometer.

[0003] An olfactometer is a device designed to provide a number of olfactory stimuli to a subject in a controlled and reproducible manner. The requirements of MRI scanning technology impose constraints on the design of olfactometers suitable for use with MRI scanners. One major constraint is the exclusion of magnetic materials from within the vicinity of the scanner. Due to the availability of olfactometers that can be used with MRI scanners, interest in measuring the brain's response to olfactory stimuli by MRI has increased significantly in the past few years. With regard to olfaction, most of the interest in MRI measurements has focused on hedonic responses to stimuli (see for example Zatorre RL, Jones-Gottman M, Rouby C, Neural mechanisms involved in odor pleasantness and intensity judgements, NeuroReport 11, 2711-2716 (2000) or Kobal G, Kettenmann B, International Journal of Psychophysiology 36(2), 157-163 (2000)).

[0004] The angular gyrus (AG), part of the temporoparietal junction (TPJ), has attracted attention because of its association with the integration of signals from other brain areas, specifically its link with the social context (see e.g. Seghier, Neuroscientist, 2013, v19, p43 or Carter and Huttel, Trends in Cognitive Sciences, 2013, v17, p32).

[0005] The studies used to draw such conclusions used a variety of stimuli, such as words (Thakral et al., The Journal of Neuroscience, 2017, v37, p8142), text (Uddin et al., Cerebral Cortex, 2010, v20, p2636), or pictures (Apperly et al., Cognition, 2007, v103, p300).

[0006] Other brain areas associated with the interpretation of social cues include the inferior frontal cortex, which encompasses the inferior frontal gyrus, and the middle frontal cortex, which encompasses the middle frontal gyrus. See, for example, Henco et al., Cortex, 2020, v131, p221-236 or Mainieri et al., NeuroImage, 2013, v81, p294-305.

[0007] The idea of ​​"well-being" has become increasingly widely used, and many people naturally consider it to be what can determine their state of "well-being." While there is no single definition, for the purposes of this disclosure, we refer to the interpretation provided by the Centers for Disease Control and Prevention (CDC) Division of Population Health's Health-Related Quality of Life (HRQOL) Program, which provides expert opinion and support in population HRQOL and well-being assessment to CDC, states, communities, and other public health partners. In summary, they state the following (https: / / www.cdc.gov / hrqol / wellbeing.htm-accessed 2021 / 11 / 04): - Although there is no consensus on a single definition of well-being, there is general agreement that, at a minimum, well-being encompasses the presence of positive emotions and moods (e.g., contentment, happiness), the absence of negative emotions (e.g., depression, anxiety), a sense of life satisfaction, fulfillment, and positive functioning. Simply put, well-being can be described as positive judgments of life and feeling good. - Well-being is a meaningful positive outcome for people and many sectors of society because it tells us that people perceive their lives as going well. Good living conditions (e.g. housing, employment) are fundamental to well-being. Tracking these conditions is important for public policy. However, many indicators that measure living conditions fail to measure what people think and feel about their lives, for example the quality of their relationships, their positive emotions and resilience, the realization of their potential, or their overall life satisfaction - that is, their "well-being". Well-being generally encompasses a global judgment of life satisfaction and feelings ranging from depression to joy. - Well-being integrates mental health (mind) and physical health (body), providing a more holistic approach to disease prevention and health promotion.

[0008] A literature review describing how ambient odors can be used to enhance well-being in multisensory built environments was published by Charles Spence in 2020 (Frontiers in Psychology, November 2020, Volume 11, Article 598859). In his conclusion, the author points out that there is a growing awareness that odors associated with our indoor salience can have a significant impact on our mood and well-being, and that new evidence is also revealing the potentially positive impact that pleasant ambient odors, at least when properly managed, can have on our social, emotional, and cognitive well-being.

[0009] We found that subjects who smelled the aromas / accords identified as inducing well-being effects associate them with one or more of the following attributes: sweet, soft, light, pleasant.We further surprisingly found that the aromas and flavors identified by the respondents as having such high "well-being" associations compared to those with lower "well-being" associations show activation of the angular gyrus (AG) and optionally also activation of the inferior frontal cortex and / or middle frontal cortex.We interpret this activation as being linked to the complex and rich associations of the respondents with these aromas or flavors.In this disclosure, no distinction is made between whether the right or left hemisphere or both are activated. Summary of the Invention

[0010] In one aspect, the present invention provides a method for identifying an aroma or flavoring that induces a "well-being" effect, the method comprising determining whether the angular gyrus is activated in a subject smelling said aroma or flavoring. In some embodiments, the method further comprises determining whether the inferior frontal cortex and / or middle frontal cortex are also activated in said subject. In some embodiments, determining activation of the angular gyrus, and optionally the inferior frontal cortex and / or middle frontal cortex, comprises taking an fMRI brain scan of the subject.

[0011] In another aspect, the present invention provides an aroma or flavoring identified by the above-described method.

[0012] In another aspect, the present invention provides a method of preparing a fully formulated fragrance or accord, which comprises identifying a fragrance that induces a "well-being" effect by the method described above, and formulating said fragrance into a fully formulated fragrance or accord. The present invention also provides a method of preparing a flavor preparation, food product, oral care product, or beverage, which comprises identifying a flavor that induces a "well-being" effect by the method described above, and formulating said flavor into a flavor preparation, food product, oral care product, or beverage.

[0013] In another aspect, the present invention provides the use of a "well-being" effect inducing fragrance identified by the above-mentioned method in a consumer product. The present invention also provides the use of a "well-being" effect inducing flavor identified by the above-mentioned method in a flavor preparation, food product, oral care product, or beverage.

[0014] definition In this disclosure, well-being is given its commonly accepted meaning, namely, a sense of health and vitality resulting from thoughts, feelings, actions, and experiences. There are five main types of well-being: - emotional well-being, which may be defined as the ability to practice stress management techniques, be resilient, and generate feel-good emotions; - physical well-being, which may be defined as the ability of the body to function better through healthy eating, good exercise habits, and other healthy habits; - social well-being, which can be defined as the ability to communicate, develop intimacy with others, and create support networks that help overcome loneliness; - Workplace well-being, which can be defined as the ability to pursue work interests, skills, and goals in order to gain meaning, happiness, and enrichment in life; - Social well-being, which can be defined as the ability to actively participate in creating thriving communities, cultures and environments.

[0015] The term "brain activity" as used herein refers to the physiological and biochemical activity in the human brain or brain regions associated with mental activity, including, but not limited to, increased blood flow to the active brain region, changes in blood oxygen levels, increased metabolic activity (e.g., glucose consumption), changes in neuronal electrical potential, and release of neurotransmitters.Brain activity can be measured non-invasively, for example, by measuring changes in electric and magnetic fields emanating from the skull, or by the Blood Oxygen Level-Dependent (BOLD) method, which is a recognized technique for measuring brain activity that correlates with increased energy consumption by the brain and the contrast between oxyhemoglobin and deoxyhemoglobin.

[0016] As used herein, the term "brain field" refers to a volume of tissue within the human brain that can be of any shape and that can be characterized anatomically or spatially.

[0017] As used herein, the terms "frontal," "anterior," "posterior," "superior," and "inferior" have their conventional meaning in anatomy. See, e.g., Stedman's Medical Dictionary.

[0018] A particular intracerebral location or intracerebral volume can also be described by reference to a three-dimensional coordinate system. One such system is that described by Talairach and Tournox ("Stereotaxic Coplanar Atlas of the Human Brain", Thieme, 1988, ISBN 9783137117018), which is based on a single brain considered by the authors to be representative. Images or maps of individual subjects' brains can be compared to such template brains by visual comparison, or computer software programs can be used to map individual brains onto the template brain. For example, the Statistical Parametric Mapping (SPM) software described below performs automatic spatial registration and normalization of individual brains onto the MNI (Montreal Neurological Institute) template. Software to determine correspondence between MNI and Talairach coordinates is also available (e.g., MRIcro, available at www.cla.sc.edu / psyc / faculty / rorden / mricro.html; see also Rorden and Brett (2000), Behavioural Neurology, 12:191-200).

[0019] The term "voxel" as used herein refers to a multidimensional data point corresponding to a particular volume in space, specifically such data point obtained from brain imaging and corresponding to a particular volume in the brain. The voxel size depends on the experimental procedure and the resolution of the equipment, particularly the fMRI machine. In this application, a 3.0 Tesla machine was used, but machines up to 7 Tesla are commercially available today. It should be noted that the two types of "voxels" referred to in this disclosure in relation to fMRI experiments are voxels from functional sequences and voxels from anatomical sequences. Unless explicitly stated, all references to voxels refer to voxels from functional sequences.

[0020] The term "brain activation map" as used herein means an array or set of data where each data point corresponds to a point or volume in the human brain. Each data point may consist of a single datum associated with a brain coordinate or may consist of a multi-dimensional array of data associated with a brain coordinate. A brain activation map may be displayed as a two or three dimensional diagram or may be stored as a data set without being graphically displayed.

[0021] As used herein, the term "fragrance" is understood to mean: any individual ingredient, such as a "fragrance ingredient" (which is synonymous with the terms "fragrance ingredient" and "fragrance material"); - a mixture of individual materials as defined above, such as an accord or a fully formulated fragrance. A mixture of individual materials may contain at least 5, at least 10, at least 20, at least 30, or at least 40 fragrance ingredients. An accord typically has less than 25 individual materials and has a singular or simple odor description, e.g. apple accord, musky accord. A fully formulated fragrance may be made from an accord, or one or more accords and individual ingredients, or a combination of multiple individual ingredients, and will typically have 50-75 individual materials and a more complex odor description, e.g. fruity-floral-woody.

[0022] Those skilled in the art will understand that a fragrance ingredient may itself contain many individual chemical compounds and possess a pleasant odor. This distinction is understood by those familiar with the field of fragrance creation. A fragrance ingredient or fragrance material may be any natural oil or extract or chemical compound used in a fragrance composition. Natural oils and extracts are described in "The Essential Oils" by E. Guenther, published by Van Nostrand, and may include extracts and distillates from any part of a suitable plant: roots, rhizomes, bulbs, corms, stems, bark, heartwood, leaves, flowers, seeds, and fruits. Examples of such extracts and distillates include citrus fruit oils, such as orange or lemon oil, woody oils, such as pine oil or cedarwood oil, herbal oils, such as peppermint oil, thyme oil, rosemary oil, clove oil, or flower extracts, such as rose oil or geranium oil. A wide variety of synthetic odoriferous materials for perfumery use are also known, including materials bearing various chemical functional groups, such as acetals, alkenes, alcohols, aldehydes, amides, amines, esters, ethers, imines, nitriles, ketals, ketones, oximes, thiols, thioketones, etc. Without wishing to be limited, in most cases the odoriferous ingredients will be odoriferous compounds with a molecular weight between 70 and 400 mass units to ensure sufficient volatility. The odoriferous ingredients will not contain functional groups with a strong tendency to ionize, such as sulfonates, sulfates, or quaternary ammonium ions.

[0023] "Flavor" is taken to mean any individual ingredient or mixture of from a few to more than 40 individual ingredients that are taken in by the mouth and perceived primarily by the senses of taste and smell as well as the general pain and touch receptors in the mouth, and received and interpreted by the brain. Flavors can lead to singular or simple flavor directions, such as apple flavors and meat flavors, or more complex flavor directions, such as apple pie and BBQ flavors. The perception of flavor is a property of the flavor.

[0024] "Flavours" are products added to food to impart, modify or enhance the flavour of the food (see Guidelines for the Use of Flavourings CAC / GL66-2008, a document prepared by the Joint FAO / WHO Expert Committee on Food Additives (JECFA)). Flavourings may consist of flavouring substances (which include natural flavouring substances and extracts as well as synthetic flavouring substances), complexes of natural flavours, heat-treated or smoked flavours, and mixtures thereof, and may further contain non-flavouring food ingredients. Flavourings may consist of a few to more than 40 components listed above. Flavourings are not intended to be consumed as such and may be incorporated into flavour preparations, food products, oral care products, or beverages. Flavourings may also contain additives (e.g. solvents or solubilisers, e.g. surfactants) that are compatible with the products in which they are incorporated.

[0025] A more expanded explanation of some of the above terms can be found in the above-mentioned guidelines, Regulation (EC) No 1334 / 2008 on flavourings, and Regulation (EC) No 1333 / 2008 on food additives. An additional useful reference is the International Organization of Food and Flavor Industries (IOFI) Code of Practice, April 2020 Revision (https: / / cdn2.assets-servd.host / erratic-warthog / production / Documents / iofi-code-of-practice-5th-revision.pdf, accessed 2021 / 07 / 15), which explains the regulatory context and ingredients for flavourings in more detail. It should be noted that oral care products are considered cosmetic products and not food products, requiring that flavors used in oral care products meet both the International Fragrance and Flavor Association (IFRA) standards and the requirements for flavors in food products (see IFRA, Guidance for the Use of the IFRA Standards, May 4, 2020, 1.6.2, https: / / ifrafragrance.org / docs / default-source / ifra-code-of-practice-and-standards / 49th-amendment / ifra-49th-amendment-(att-01)---guidance-for-the-use-of-ifra-standardsa7006c445f36499bbb0eb141e8c0d4be.pdf?sfvrsn=7fb244c8_2, accessed 2021 / 07 / 15).

[0026] The perception of flavour from a food product, oral care product or beverage involves a combination of taste and olfactory stimuli resulting in descriptors such as "fruity", "meaty", "floral" or "herbal". A distinction is made between anterior nasal smells when sniffing (which give the aroma of food, the bouquet of wine) and retronasal smells when air is expelled from behind the nose during the act of swallowing. It is the retronasal aromas or scents that combine with the taste cues to give rise to flavour (Spence, Cell, 2015, vol. 161, p24-35). Thus, smell perception is key to both aroma and flavour evaluation.

[0027] Fragrance and flavor ingredients are described in more detail in S. Arctander, Perfume Flavors and Chemicals, Vol. I and II, Montclair, NJ, The Merck Index 8th Edition, Merck & Co., Rahway, NJ, Allured's Flavor and Fragrance Materials, 2013, Allured Publishing Company, ASIN: B01FKWD33S, and Surberg and Panten, eds., Common Fragrance and Flavor Materials: Preparation, Properties & Uses, 6th Edition, Wiley-VCH (2016) ISBN-10: 3527331603, all of which are incorporated herein by reference.

[0028] As used herein, the expression "oral care product" is intended to mean a product that cleanses the oral cavity, freshens the breath, and / or maintains good oral hygiene. Examples of oral care products include toothpaste, mouthwash, and breath fresheners. [Brief description of the drawings]

[0029] [Figure 1] FIG. 1 represents the design of an fMRI experimental block used in the method of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] In one embodiment, the invention provides a method of identifying an aroma or flavoring that induces a well-being effect, the method comprising determining whether the angular gyrus is activated in a subject that smells said aroma or said flavoring.

[0031] In some embodiments, the method further comprises determining whether the inferior frontal cortex and / or the middle frontal cortex are also activated in said subject.

[0032] In some embodiments, determining activation of the angular gyrus and, optionally, the inferior frontal cortex and / or the middle frontal cortex comprises taking an fMRI brain scan of the subject.

[0033] In some embodiments, the method comprises: a) - exposing each subject in the control group to a control odor; and - capturing a functional magnetic resonance imaging (fMRI) brain scan of each subject smelling the control odor to detect brain activity of each subject; subjecting a subject group to a first protocol, b) - exposing each subject of said group to the aroma or flavoring substance to be tested; and - capturing an fMRI brain scan of each subject who smelled the aroma or flavoring to be tested in order to detect brain activity of each subject; subjecting the same subject group to a second protocol, comprising: c) averaging the brain activities of all subjects obtained in the first protocol and the second protocol; and d) contrasting the resulting averaged brain activity obtained in the second protocol with the resulting averaged brain activity obtained in the first protocol and determining from this contrast the number of adjacent activated voxels in the angular gyrus; If the number of adjacent activated voxels (from the contrast) thus determined is equal to or greater than a threshold, then the tested aroma or the tested flavor induces a well-being effect.

[0034] In some embodiments, step d) further comprises determining from the contrast a number of adjacent activated voxels in the inferior frontal cortex (FIC) and / or middle frontal cortex (FMC), where if the determined number of adjacent activated voxels in the FIC and / or FMC (from the contrast) is equal to or greater than the same threshold used for the angular gyrus, further confirmation is obtained that the tested aroma or the tested flavor induces a well-being effect.

[0035] Sniffing any odor induces brain activity due to odor processing, which is detected by fMRI as described below. The present invention is based on the surprising finding that activation of the angular gyrus and optionally the inferior and / or middle frontal cortex in response to sniffing a fragrance or flavoring is evidence that odor is associated with a state of "well-being".

[0036] The method of the present invention comprises a first step step a), in which each subject in a subject group smells a control odor, and the brain activity of each subject is determined using fMRI. The subject group typically comprises at least 5 subjects, preferably at least 10 subjects. The control odor is preferably air or a solvent diluted with air. Any odorless solvent commonly used in aroma or flavor creation, such as dipropylene glycol, propylene glycol, MCT (medium chain triglyceride) oil, or triethyl citrate, can be used in the method of the present invention. In some embodiments, the control odor can also be the above-defined aroma or flavor that has been shown (using fMRI) not to activate the angular gyrus (e.g., an individual material, such as coffee extract, or an accord or existing aroma or flavor against which the new aroma or flavor is tested).

[0037] In a second step, step b), the same group of subjects smells the test aroma or flavor and the brain activity of each subject is determined again using fMRI.

[0038] The control odor and the fragrance or flavoring are infused into one of the subject's nostrils by the olfactometer. To avoid drying out the nasal passages, the control odor and the fragrance or flavoring are preferably humidified before being introduced into the nose.

[0039] In the third step, step c), the brain activity of all subjects who smelled the control odour is averaged and also the brain activity of all subjects who smelled the test aroma or flavouring is averaged.

[0040] In step d) of the fourth step, the averaged brain activity in step c) is contrasted for the test aroma or flavor and the control odor. As a result of the contrast, the number of adjacent activated voxels in 3D space, i.e. adjacent voxels with significantly different blood flow (or activity), i.e. voxels that pass the Student's t-test (p<0.005 or more preferably p<0.001) in the brain area studied is determined. Voxels are typically cubes or rectangular prisms, with a size of, for example, about 0.5 mm to about 7 mm per side. When voxels are adjacent to each other, they typically form what is known as a cluster. The number of voxels in a cluster is referred to as the cluster size. The number of adjacent activated voxels obtained from the contrast is compared to a threshold value to determine whether a brain area is activated. A threshold of 10 is commonly used in fMRI research, see for example Liebermann and Cunningham, Social Cognitive and Affective Neuroscience, December 2009, vol. 4(4), p. 423.

[0041] Thus, in some embodiments, the threshold is 10. In some embodiments, the threshold is 20. In some embodiments, the threshold is 30. In some embodiments, the threshold is 50.

[0042] If the number of adjacent activated voxels in the angular gyrus from the contrast of the test aroma or flavor with the control odor is above a threshold, then the tested aroma or flavor induces a well-being effect.

[0043] Further confirmation that the test aromas or flavors induce well-being effects can come from conducting the same analysis in the inferior and middle frontal cortex.

[0044] In some embodiments, steps c) and d) are replaced by steps c1) and d1), respectively: c1) for each subject, comparing the brain activity obtained in the second protocol with the brain activity obtained in the first protocol, thereby determining the number of adjacent activated voxels; d1) Averaging the resulting contrasted brain activity across all subjects.

[0045] A typical example of the overall experimental approach used is described below.

[0046] Selecting a target Subjects are required to be literate and capable of providing informed consent. Potential subjects will be excluded if they have the following: current or past psychiatric disorders other than simple phobias but including substance abuse / dependence as determined by the Structured Interview for DSM-IV axis I Disorders (SCID-I) (First et al., Structured clinical interview for DSM-IV axis I disorders - patient edition, SCID-I / P, version 2.0, New York, Biometrics Research Division: New York State Psychiatric Institute, 1995), history of neurological disease, currently unstable medical condition, psychotropic medications used within 5 half-lives from the time of procedure, any metallic implants or pieces that would make the MRI procedure unsafe, non-removable medical devices such as pacemakers or fixed hearing aids, previous inability to tolerate MRI procedures, or claustrophobia severe enough to induce substantial anxiety in enclosed spaces. Other exclusion criteria included age under 9 years, history of any disease known to have an effect on olfactory function (e.g. diabetes, Parkinson's disease, renal failure, etc.). A complete ENT (ear, nose and throat) examination ruled out pathologies that may interfere with olfactory ability: acute or severe chronic rhinitis or sinusitis, severe nasal septum deviation, history of trauma, nasal polyps, etc. Subjects also completed a handedness test for participation in the study. It is preferable to avoid variations due to gender or handedness. Thus, subjects are selected to constitute panels or groups of a single gender and with the same preferred hand.

[0047] Only normal olfactory subjects who passed the above selection criteria were selected for testing. A variety of tests are available commercially to ensure that subjects have a normal sense of smell. These tests range from odor identification tests to more sophisticated threshold and discrimination tests. Any suitable test should be validated and reliable. In the example given below, the "sniffing stick" test was used to evaluate olfactory function. Further information on sniffing sticks can be found in T. Hummel et al., "Sniffin Sticks: Olfactory Performance Assessed by the Combined Testing of Odor Identification, Odor Discrimination and Olfactory Threshold", Chemical Senses, 1997, vol 22, pp 39-52 or T. Hummel et al., "Screening Olfactory Function with a Four Minute Odor Investigation Test Reliability Normative Data and Investigations in Patients with Olfactory Loss", Annals of Otology, Rhinology & Laryngology, 1997, pp 39-52. See Journal of Laryngology, 2001, vol 110, pp 976-981. Sniffing sticks are available from Burghardt Gmbh, Wedel, Germany. For odor presentation, the cap is removed by the experimenter for approximately 3 seconds and the tip is placed approximately 2 cm in front of both nostrils. The odor identification test involves the evaluation of 12 common odors (cinnamon, banana, lemon, licorice, pineapple, coffee, clove, rose, leather, fish, orange, peppermint).A multiple-choice task was used to identify individual odorants from a list of four descriptors per odor. The interval between odor presentations was 20–30 s. All measurements were performed in a quiet, air-conditioned room. At least 10 correct responses were required for participation in the subsequent experiment.

[0048] Preparation of test samples The test fragrances and test flavors were prepared using an expert panel to have approximately equal odor intensities.

[0049] fMRI Scanner Any suitable MRI device may be used to achieve the desired fMRI images, which may be operated using a spin-echo-echo planar imaging (SE-EPI) sequence. This EPI protocol has been optimized to detect subtle changes in cerebral blood oxygen levels over time. EPI scans are a valid way to measure changes in blood oxygen level-dependent (BOLD) signal, which have been shown to reliably correlate with changes in neural activity. Scans covering the whole brain were performed, allowing for continuous monitoring of the whole brain throughout each evaluation. Suitable MRI scanners are available from Siemens AG, Philips, GE Healthcare, Varian, Toshiba, and Hitachi.

[0050] Olfactometer Any olfactometer suitable for use in an fMRI scanner may be used. Suitable olfactometer designs are reported by Kobal (Electroencephalography and Clinical Neurophysiology, Vol. 71, p241-250, 1988), Sobel (Journal of Neuroscience Methods, Vol. 78, p115-123, 1997), and Sommer et al. (Journal of Neuroscience Methods, Vol. 209, p189-194, 2012). A suitable commercial olfactometer is available from Burghart Medezintechnik GmbH, Wedel, Germany. To minimize head movements, odorants are applied intranasally through a cannula with an internal diameter of 2-3 mm. This cannula is inserted ~1 cm into the nostril so that its opening is located beyond the nasal valve. Presentation of odorants does not simultaneously activate mechanical or thermoreceptors on the nasal mucosa, because odor pulses are incorporated into a constant flow of thermostatically controlled (36°C) humidified (80% RH) air (typically 1-8 l / min), which quickly becomes undetectable after a few minutes. Thus, subjects do not perceive any change when the olfactometer switches from unstimulated to stimulated conditions and vice versa, and subjects do not experience any interference from mechanical or thermal stimuli. The airflow rate is determined by a mass flow controller, which is computer controlled in conjunction with a switching valve. Hence, the instrument allows the setting of sequences of stimuli with different quality, intensity, duration, or stimulus interval, and multiple repetitions to achieve the highest accuracy and precision in sample presentation.

[0051] Statistical Data Analysis Methods for statistical analysis of changes in brain activity are well known in the art, and for some brain activity measurement devices, computer software packages are commercially available that are specifically adapted to analyze the data. For example, SPECT, PET, or MRI data can be analyzed using the Dot or EMMA (Extensible MATLAB Medical Image Analysis) packages, both available for free from the MNI, or the Statistical Parametric Mapping (SPM) software package (www.fil.ion.ucl.ac.uk / spm / ), available for free from the Functional Imaging Laboratory, Wellcome Department of Imaging Neuroscience, University College London, UK. The EMMA and SPM software are based on the MATLAB programming language (MathWorks, Natick, Mass), with additional routines in the C programming language. The SPM module is integrated into the commercially available MEDx software (Medical Numerics, Stirling, Va, USA).

[0052] The SPM software uses parametric statistical models for each voxel, using a general linear model to describe the variability of the data in terms of experimental and confounding effects as well as residual variability. Hypotheses expressed in terms of model parameters are evaluated at each voxel by univariate statistics. Temporal convolution of the general linear model of fMRI allows the application of results from regression with serial correlation, allowing the construction of statistics images from fMRI time series. The multiple comparison problem of simultaneously evaluating all voxel statistics is addressed using continuous random field theory, assuming the statistics image to be a well-formed lattice diagram of the underlying continuous stationary random field. The Euler characteristic results in a corrected p-value for each voxel hypothesis. In addition, the theory allows the calculation of corrected p-values ​​for clusters of k voxels above a given threshold, leading to more powerful statistical tests for the entire set of clusters above the threshold, at the expense of some localization power (see Friston et al., Magnetic Resonance in Medicine, vol. 35, p. 346-355, 1996, and citations therein).

[0053] The statistical approach used to evaluate a typical set of fMRI data is a time series variant of the analysis of variance (ANOVA) form of the general linear model. For each subject, the statistical analysis tests each voxel of the brain against the null hypothesis that the rise and fall of the BOLD signal from that voxel over the duration of the trial is not correlated with the onset and offset of the odor presentation cycle. For the single task variables of interest, a weighted model is created starting from a simple square wave type model of on-off timing events.

[0054] ANOVA model takes into account the use of regressors to model disturbance variables. In the present invention, the global signal intensity of the whole brain is used as such a regressor. The global signal intensity of the brain will account for the fluctuations in the brain caused by breathing cycles, cardiac blood flow cycles, blinking, etc. These signal fluctuations occur throughout the whole brain and can often be larger in magnitude than the localized changes in the BOLD signal resulting from olfactory signals. These signal fluctuations occurring throughout the brain can be subtracted from the measured fMRI signal to show the signal resulting from odor stimulation.

[0055] The resulting product of an ANOVA computation on one person's fMRI data is a three-dimensional matrix of t-values ​​that can be represented as a three-dimensional map. This t-value map can then be converted into a probability map (a map of corresponding p-values), and the results can be displayed graphically at any threshold desired (e.g., p<0.005). The results can be overlaid onto higher resolution MRI images to facilitate identification of finer-grained cortical structures.

[0056] To combine data from more than one subject, each subject's brain is first normalized into a common 3D stereotaxic space before each individual's t-map is calculated. Then, the value of the sum of contrast weights for each voxel from each subject calculated during the ANOVA (essentially the numerator of the t-statistic) is entered as a single data point in a new "second-level" t-statistic calculation. In this second-level calculation, the mean value of each voxel across subjects is modeled as the effect term, and the variance across subjects as the error term. An important consequence of this approach to keep in mind is that unless substantially all of the subjects show activation in a voxel, it is highly unlikely that that voxel will show significant activation on the group-level map. Also, a brain area is considered activated only if several adjacent voxels (from the contrasts) show statistical significance above a given probability standard.

[0057] For the purposes of statistical analysis and graphical display, raw data on brain activity is usually grouped into voxels, which correspond to fixed volumes of the subject's brain. Voxel size may vary depending on the resolution of the brain activity measuring device or the degree of desired accuracy in identifying brain regions. However, it should be noted that due to partial volume effects, smaller voxels have a worse signal-to-noise ratio and larger susceptibility artifacts. Functional voxels are cubes or rectangular prisms, with dimensions of, for example, 0.5 mm to 7 mm per side (e.g., 2.4 × 2.4 × 3.0 mm). 3 ) The data can then be displayed graphically by coloring the voxels according to some statistical value and showing cross sections along which the level of activity or changes in level of activity are mapped in two dimensions. By producing a series of such coplanar cross sections, the entire brain volume can be mapped.

[0058] When performing statistical analysis of brain images, the researcher may select an appropriate probability value for assessing statistical significance. The specific value selected may vary depending on the purpose of the statistical analysis and the level of certainty required. In the study described in the examples, the level of statistical significance was selected to be p<0.001.

[0059] The method described above makes it possible to identify aromas or flavors that induce a well-being effect by stimulation of the angular gyrus and, optionally, the inferior and / or middle frontal cortex.

[0060] Thus, in another aspect, the present invention relates to aromas and flavors identified by the above method.

[0061] Such fragrances may be accords or fully formulated fragrances or may be used to formulate accords or fully formulated fragrances, which in turn, when smelled or worn, will induce a well-being effect by activation of the angular gyrus and optionally the inferior and / or middle frontal cortex.

[0062] Therefore, another aspect of the present invention relates to a method for preparing an accord or fully formulated fragrance comprising: a) identifying at least one aroma that induces a well-being effect by the method described above; b) blending said at least one fragrance sample thus identified into an accord or fully formulated fragrance.

[0063] The fragrances identified as inducing well-being effects by the methods described above can be used in consumer products such as household products, candles, laundry products, personal care products, and cosmetic products (including alcohol-based fragrances and colognes). Such products include cleaning products such as laundry detergents, laundry softeners and finishes, air care, toilet care, shampoos, hair conditioners, skin lotions, body oils, deodorants, and sunscreen products.

[0064] In some embodiments, the fragrance comprises one or more of orange oil, citrus oil, ethyl vanillin, and nonalactone gamma.

[0065] Another aspect of the present invention relates to a method for producing a consumer product as defined above, the method comprising: a) identifying at least one aroma that induces a well-being effect by the method described above; b) incorporating said at least one fragrance thus identified into a consumer product.

[0066] In some embodiments, at least one identified fragrance is formulated into an accord or fully formulated fragrance prior to incorporation into a consumer product.

[0067] Flavors identified as inducing a well-being effect by the methods described above may be used in flavor preparations, food products, oral care products, or beverages.

[0068] Therefore, another aspect of the present invention relates to a method for preparing a flavor preparation, a food product, an oral care product, or a beverage comprising: a) identifying at least one flavoring that induces a well-being effect by the method described above; b) formulating said at least one flavoring thus identified into a flavor preparation, a food product, an oral care product, or a beverage.

[0069] In some embodiments, the flavorings include one or more of orange oil, citrus oil, ethyl vanillin, and nonalactone gamma.

[0070] The present invention is illustrated by the following non-limiting examples. EXAMPLES

[0071] Example 1 An initial panel of 100 subjects was asked to rate intensity, well-being, and (hedonic) valence using a Likert-type scale. Intensity was rated on a scale of 1 to 10 (1=not at all strong, 10=very strong), well-being was rated on a scale of 1 to 10 (1=no association, 10=strong association), and valence was rated on a scale of -5 to +5 (-5=very unpleasant, +5=very pleasant). Subjects were asked to smell a series of 14 odors of approximately equal odor intensity (neat oil from a bottle with an opening of 6 cm in diameter). These were presented in a randomly selected order, and each of these odors was either strongly or weakly associated with well-being. Subjects rated "white flower" (6.96 ± 2.09) and "orange" (7.22 ± 1.90) as strongly associated with well-being, and "coffee" (4.81 ± 2.85) as weakly associated with well-being.

[0072] The white flower scent - fragrance formulation IMP234647C - was created with a focus on vanilla effects (ethyl vanillin) and coconut effects (nonalactone gamma).

[0073] The citrus scent - fragrance / flavoring formula FJJ232836D - was created based on cold pressed orange oil, fractionated orange oil, so-called folded orange oil, and other cold pressed citrus oils.

[0074] Coffee odor - Coffee C'less CI-1020 - is a natural coffee extract purchased from Robertet, SA, France, suitable for use in aroma and flavoring. It was selected as it does not have strong associations with well-being.

[0075] From this initial panel, 44 subjects (23 males and 21 females) were recruited to participate in the fMRI study. They rated the odors "white flower", "citrus", and "coffee" as reported in the table below.

[0076] [Table 1]

[0077] The 44 subjects recruited had a mean age of 25 years. Data from one subject were excluded from the fMRI analysis due to excessive movement. Subjects underwent a structured medical history (Welge-Luessen and Hummel, eds., 2013, Management of Smell and Taste Disorders-A Practical Guide for Clinicians, Thieme, ISBN 9783131545213, p49-57, DOI: 10.1055 / b-002-89586). This included questions about demographics, smoking and drinking habits, medications, current disorders, family history of any neurodegenerative diseases, and general nasal health.

[0078] All subjects reported a normal sense of smell, which was confirmed using the odor identification test from the "sniffing stick" olfactory test battery (with a maximum score of 16) (Oleszkiewicz et al., 2018, The Laryngoscope, vol. 128(7), p1518-1522, https: / / doi.org / 10.1002 / lary.26985). The test is performed in a forced-choice format and subjects must identify 16 odors at suprathreshold concentrations using flash cards with four descriptors each (Kobal et al., 2000, European Archives of Oto-Rhino-Laryngology: Official Journal of the European Oto-Rhino-Laryngological Society (EUFOS): Affiliated German Societies of Otorhinolaryngology and Head and Neck Surgery, Vol. 257(4), p205-211, https: / / doi.org / 10.1007 / s004050050223). Participants reached a mean score of 13.6 ± 1.4 (mean ± SD).

[0079] The experiments were carried out in accordance with the Declaration of Helsinki. The ethical committee of the Medical Faculty of the TU Dresden approved the study design. Subjects were recruited by distributing flyers on campus. They provided written informed consent.

[0080] Then, fMRI experiments were performed as follows.

[0081] Odor stimuli were infused bilaterally into both nostrils of the subject under the scanner by an air-dilution computer-controlled olfactometer (Sommer, JU, W. Maboshe, M. Griebe, C. Heiser, K. Hormann, BA Stuck, and T. Hummel, "A Mobile Olfactometer for FMRI-Studies", Journal of Neuroscience Methods, vol. 209, no. 1 (30 July 2012): p189-94, https: / / dx.doi.org / 10.1016 / j.jneumeth.2012.05.026). This allowed for alternation between olfactory (on) and non-olfactory (off) stimulation conditions. Odors were incorporated into a constant airflow of 2 L / min. Each functional run consisted of 11 off or "baseline" blocks (14 scans each) and 10 on blocks (9 scans each). Odors were infused intranasally for 8 seconds during the on sessions, and odorless air was infused intranasally for 12 seconds during the off sessions. Each subject underwent four functional runs, with one type of odor presented per run. Odors were presented randomly to subjects positioned on the scanner. Between subjects, the sequence of these runs was randomized using a Latin square. If necessary, subjects could communicate verbally through the scanner intercom system. After the functional runs, an anatomical scan was acquired. A 2-minute rest period was included between runs. Overall scan time was approximately 50 minutes. Results of three stimuli are reported.

[0082] Participants were trained to use the velopharyngeal closure technique (breathing only through the mouth by lifting the soft palate) during the scan. This technique allows olfactory stimulation to be independent of breathing patterns. This procedure also prevents participants from sniffing odors that would cause sensory-irrelevant activation in olfactory eloquent structures (Mainland and Sobel, 2006, Chemical Senses, vol. 31, p181-196).

[0083] Figure 1 shows the design of the fMRI experimental block showing the odor presentation method, where on-session = 9 scans (10 blocks) and off-session = 14 scans (11 blocks), for a total of 244 scans.

[0084] Data acquisition was performed by a 3T-MRI scanner (Siemens Medical Systems, Erlangen, Germany) using a 32-channel head coil at the Neuroimaging Center, Dresden, Germany. A total of 248 functional images were collected on an individual basis using a T2 single-shot echo planar imaging (EPI) sequence (TR = 869 ms, TE = 38 ms, 58° flip angle, no interslice gap, 210 × 210 mm field of view). High-resolution structural T1 images were acquired using a 3D magnetization-prepared gradient rapid imaging gradient echo (MPRAGE) sequence (TR = 2000 ms, TE = 1.95 ms, 256 × 256 mm field of view). 2 Field of view, (anatomical) voxel size 1×1×1mm from anatomical sequence 3 ) was used to obtain the

[0085] A task-driven general linear model approach (GLM) using statistical parametric mapping (SPM) software (Penny et al., 2006, Statistical parametric mapping: The analysis of functional brain images, Elsevier, ISBN: 9780123725608) was used to analyze the fMRI data. Neuroimaging data were pre- and post-processed using SPM12 (Wellcome Department of Cognitive Neurology, London, UK. Implemented in MatlabR2018b, MathWorks, Natick, MA, USA). Functional image volumes were pre-processed starting from realignment and distortion correction. Voxel size from the functional sequence was 2.4 × 2.4 × 2.4 mm. 3 Functional data were registered and realigned to correct for motion issues and then coregistered to the corresponding structural images. Furthermore, spatially normalized (stereotaxically transformed into the MNI-ICBM152 space of the MNI template provided by SPM12) and smoothed images (by means of a 8 × 8 × 8 mm3 FWHM Gaussian filter) were analyzed.

[0086] From the main block design (Figure 1), 10 blocks of on and off phases were used to increase the BOLD signal related to the stimuli. We compared the on phase vs. off phase (air) and on phase (air) of the presented stimuli. ウェルビーイング vs. On ウェルビーイングでないwere compared with N=43. In other words, adding further details, each functional run consisted of alternating ON and OFF periods. In total there were 10 ON periods of 8 s each and 11 OFF periods of 12 s each, each period consisting of several scans. In the analysis we discarded the last OFF block and used 10 OFF and 10 ON blocks. Scans: per period (or phase or block), for OFF we chose the last 9 scans out of 14 (12 periods of 12 / 0.869-0.869 s) scans, for ON we chose the last 5 scans out of 9 (8 / 0.869) scans. Since there is a delay in BOLD, we chose the last scans from ON and OFF with a TR (temporal resolution) of 0.869 s. In a simplified way we may suggest the following: On average is based on 4 runs x 10 blocks x 5 scans (8 samples of 0.869 seconds) The off average is based on 4 runs x 10 blocks x 9 scans (12 samples in 0.869 seconds).

[0087] Significant whole-brain activations (from contrasts) are reported with a family-wise error (FEW) correction < 0.05 and uncorrected p < 0.001 for cluster sizes (k) ≥ 10 voxels. For clusters with multiple peaks, the one with the highest t-value was chosen. MNI coordinates are presented in x, y, and z, L - left hemisphere, R - right hemisphere. Significant brain regions were labeled by the AAL3 toolbox - Automated Analytical Labelling Atlas (http: / / www.gin.cnrs.fr / en / tools / aal-aal2 / ) (Rolls et al., 2020, NeuroImage, vol. 206, p116189, https: / / doi.org / 10.1016 / j.neuroimage.2019.116189).

[0088] In other words, when contrasting scented test samples with control odors, a cluster k of a minimum of 10 adjacent activated voxels in 3D space was set as the threshold for experiments based on SPM analysis (uncorrected p<0.001). "Yes" means that at least 10 adjacent voxels were activated. The contrasts were determined first for odors associated with well-being (scented test samples) versus air (considered to be odorless) as the control odor, and then for odors associated with well-being (scented test samples) versus odors not associated with well-being as the control odor. The results are shown below in Tables 2 (on vs. off) and 3 (on vs. off). ウェルビーイング vs. On ウェルビーイングでない ) to

[0089] [Table 2]

[0090] The results show that the citrus and white flower odors activated the angular gyrus, inferior frontal cortex, and middle frontal cortex, while the coffee odor did not activate any of these brain areas.

[0091] From the results in Table 2, consistent with Table 1, we can assign the citrus and white flower smells as associated with well-being and the coffee smell as not associated with well-being.

[0092] [Table 3]

[0093] The results show that the odors citrus and white flower activated the angular gyrus when compared to the odor of coffee.

[0094] In conclusion, both odors associated with well-being activated the angular gyrus.

[0095] Example 2 A further separate sniffing test was carried out in Germany (Cologne) with a normal representative population of n=80. Subjects were asked to sniff the odor samples blindly (without odor identifier) ​​and answer the question "To what extent do you think or do not think this odor conveys well-being?". A scale of 1 to 5 was used (1=strongly disagree, 2=somewhat disagree, 3=neutral, 4=somewhat agree, 5=strongly agree). The white flower odor (4.1 / 5) and the citrus odor (3.4 / 5) were rated as strongly associated with well-being. In addition, subjects were also asked to give three words that they naturally associate with these two odors. The words sweet, soft, light and pleasant were associated to a greater extent. It was also noted that odors rated as high well-being were also rated as good (preferred) by the respondents.

[0096] Aspects of the present disclosure are further illustrated with reference to the following non-limiting embodiments.

[0097] 1. A method for identifying an aroma or flavoring that induces a well-being effect, the method comprising determining whether the angular gyrus is activated in a subject that smells the aroma or flavoring. 2. The method of paragraph 1, further comprising determining whether the inferior frontal cortex and / or the middle frontal cortex is activated in a subject who smells said aroma or said flavoring. 3. The method of paragraph 1 or paragraph 2, wherein determining the well-being effect comprises taking an fMRI brain scan of the subject. 4. The method of paragraph 1, including: a) - exposing each subject in the control group to a control odor; and - capturing a functional magnetic resonance imaging (fMRI) brain scan of each subject who smells the control odor to detect brain activity of each subject; subjecting the subject group to a first protocol comprising: b) - exposing each subject of said group to the aroma or flavoring to be tested; and - capturing an fMRI brain scan of each subject who smells the aroma or flavor to be tested in order to detect brain activity of each subject; subjecting the same group of subjects to a second protocol, comprising: c) averaging the brain activities of all subjects obtained in the first protocol and the second protocol; and d) comparing the resulting averaged brain activity obtained in the second protocol with the resulting averaged brain activity obtained in the first protocol and determining from the comparison a number of adjacent activated voxels in the angular gyrus; If the number of adjacent activated voxels thus determined is equal to or greater than a threshold value, then the tested aroma or the tested flavor induces a well-being effect. 5. The method of paragraph 4, wherein step d) further comprises determining from the contrast a number of adjacent activated voxels in the inferior frontal cortex and / or the middle frontal cortex, whereby if the number of adjacent activated voxels thus determined is equal to or greater than the threshold, further evidence is obtained that the tested aroma or the tested flavor induces a well-being effect. 6. The method of paragraph 4 or paragraph 5, wherein steps c) and d) are replaced by steps c1) and d1), respectively: c1) for each subject, comparing the brain activity obtained in the second protocol with the brain activity obtained in the first protocol, thereby determining the number of adjacent activated voxels; d1) Averaging the resulting contrasted brain activity across all subjects. 7. The method of any one of paragraphs 4 to 6, wherein the control odor is air or an odorless perfume solvent diluted with air. 8. The method of any one of paragraphs 4 to 7, wherein the subject group comprises at least 5, preferably at least 10 subjects. 9. The method of any one of paragraphs 4-8, wherein the threshold number of adjacent activated voxels is 10. 10. A method for preparing an accord or fully formulated fragrance, comprising: a) identifying at least one aroma that induces a well-being effect by any one of the methods of paragraphs 1 to 9; b) formulating said at least one fragrance thus identified into an accord or a fully formulated fragrance. 11. The use of fragrances to induce well-being effects in household products, laundry products, candles, personal care products, or cosmetic products. 12. The use of paragraph 11, wherein the fragrance comprises one or more of orange oil, citrus oil, ethyl vanillin, and nonalactone gamma. 13. A method for preparing a flavor preparation, a food product, an oral care product, or a beverage, comprising: a) identifying at least one flavouring that induces a well-being effect by the method of any one of paragraphs 1 to 9; b) formulating said at least one flavoring thus identified into a flavor preparation, a food product, an oral care product, or a beverage. 14. Use of flavourings in flavour preparations, food products, oral care products or beverages to induce a well-being effect. 15. The use of paragraph 14, wherein the flavoring comprises one or more of orange oil, citrus oil, ethyl vanillin, and nonalactone gamma. 16. A method or use according to any of the preceding paragraphs, wherein the well-being effect is associated with one or more of the following attributes: sweet, soft, light, pleasant. ***

[0098] Although the subject matter of the present disclosure and its advantages have been described in detail, it should be understood that various changes, substitutions, and modifications can be made herein without departing from the spirit and scope of the present application as defined by the appended claims. Moreover, the scope of the present application is not intended to be limited to the specific embodiments of the processes, machines, manufacture, compositions, means, methods, and steps described herein. As one skilled in the art would readily appreciate from the disclosure of the subject matter of the present disclosure, any existing or later developed process, machine, manufacture, composition, means, method, or step that performs substantially the same function or achieves substantially the same result as the corresponding embodiment described herein may be utilized in accordance with the subject matter of the present disclosure. Thus, the appended claims are intended to encompass such processes, machines, manufacture, compositions, means, methods, or steps within their scope.

[0099] In addition to the various embodiments described and claimed, the subject matter of the present disclosure is also directed to other embodiments having any other possible combinations of the features disclosed and claimed herein. Thus, the specific features presented herein may be combined with each other in other ways within the scope of the subject matter of the present disclosure. As a result, the subject matter of the present disclosure encompasses any suitable combination of the features disclosed herein. Thus, the foregoing description of specific embodiments of the subject matter of the present disclosure is presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the subject matter of the present disclosure to the disclosed embodiments.

[0100] It will be apparent to those skilled in the art that various modifications and variations can be made to the devices, methods, and systems of the presently disclosed subject matter without departing from the spirit or scope of the presently disclosed subject matter. Thus, it is intended that the presently disclosed subject matter cover modifications and variations that come within the scope of the appended claims and their equivalents.

[0101] Any patents, patent applications, publications, product descriptions, and protocols cited in this application, the entire disclosures of which are incorporated herein by reference in their entirety for all purposes.

Claims

1. A method for identifying an aroma or flavor that induces a well-being effect, the method comprising determining whether the angular gyrus is activated in a subject who has smelled the aroma or the flavor, the determination comprising performing a functional magnetic resonance imaging (fMRI) brain scan of the subject.

2. The method according to claim 1, further comprising determining whether the inferior frontal cortex and / or the middle frontal cortex is activated in a subject who has smelled the aroma or the flavor.

3. a) - having each subject in a subject group smell a control odor, and - capturing a functional magnetic resonance imaging (fMRI) brain scan of each subject who has smelled the control odor to detect the brain activity of each subject, whereby the subject group is subjected to a first protocol; b) - having each subject in the group smell an aroma or flavor to be tested, and - capturing an fMRI brain scan of each subject who has smelled the aroma or flavor to be tested to detect the brain activity of each subject, whereby the same subject group is subjected to a second protocol; c) averaging the brain activity of all subjects obtained in the first protocol and the second protocol; d) comparing the averaged brain activity resulting from the second protocol with the averaged brain activity resulting from the first protocol, and from this comparison, determining the number of adjacent activated voxels in the angular gyrus; and, if the number of adjacent activated voxels thus determined is equal to or greater than a threshold value, the tested aroma or the tested flavor induces a well-being effect. The method according to claim 1.

4. Step d) further comprises determining the number of adjacent activated voxels in the inferior frontal cortex and / or the middle frontal cortex from the comparison, and if the number of adjacent activated voxels thus determined is equal to or greater than the threshold value, additional confirmation is obtained that the tested aroma or the tested flavor induces a well-being effect. The method according to claim 3.

5. Steps c) and d) are c1) For each subject, comparing the brain activity obtained in the second protocol with the brain activity obtained in the first protocol, thereby determining the number of adjacent activated voxels; d1) Averaging the compared brain activities resulting from all subjects; The method according to claim 3 or 4, respectively replaced thereby.

6. The method according to claim 3 or 4, wherein the control is air or an odorless perfume solvent diluted with air.

7. The method according to claim 3 or 4, wherein the subject group includes at least 5, preferably at least 10 subjects.

8. The method according to claim 3 or 4, wherein the threshold number of adjacent activated voxels is 10.

9. a) Identifying at least one fragrance that induces a well-being effect by the method according to any one of claims 1 to 4; b) Formulating the at least one fragrance thus identified into an accord or a fully formulated fragrance; A method for preparing an accord or a fully formulated fragrance, comprising.

10. Use of a fragrance that induces a well-being effect in household products, laundry products, candles, personal care products, or cosmetic products.

11. The use according to claim 10, wherein the fragrance comprises one or more of orange oil, citrus oil, ethyl vanillin, and gamma nonalactone.

12. a) Identifying at least one flavoring agent that induces a well-being effect by the method according to any one of claims 1 to 4; b) Formulating the at least one flavoring agent thus identified into a flavoring preparation, a food product, an oral care product, or a beverage; A method for preparing a flavoring preparation, a food product, an oral care product, or a beverage, comprising.

13. Use of a flavoring agent that induces a well-being effect in a flavoring preparation, a food product, an oral care product, or a beverage.

14. The use according to claim 13, wherein the flavoring agent comprises one or more of orange oil, citrus oil, ethyl vanillin, and gamma nonalactone.

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