Discovering Odors 9781119687474, 1119687470

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Discovering Odors

Series Editor Marie-Christine Maurel

Discovering Odors

Gérard Brand

First published 2019 in Great Britain and the United States by ISTE Ltd and John Wiley & Sons, Inc.

Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms and licenses issued by the CLA. Enquiries concerning reproduction outside these terms should be sent to the publishers at the undermentioned address: ISTE Ltd 27-37 St George’s Road London SW19 4EU UK

John Wiley & Sons, Inc. 111 River Street Hoboken, NJ 07030 USA

www.iste.co.uk

www.wiley.com

© ISTE Ltd 2019 The rights of Gérard Brand to be identified as the author of this work have been asserted by him in accordance with the Copyright, Designs and Patents Act 1988. Library of Congress Control Number: 2019947394 British Library Cataloguing-in-Publication Data A CIP record for this book is available from the British Library ISBN 978-1-78630-521-3

Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

ix

Chapter 1. Dr. Følling’s Flair: Discovery of Phenylketonuria by Smell . . . . . . . . . . . . . . . . . . . . . . . . . .

1

Chapter 2. A Nobel Prize for the Nose and Retraction in Science . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5

Chapter 3. Sperm and Lily of the Valley . . . . . . . . . . . . . . . .

9

Chapter 4. Vibrational Theory and the Astonishing Story of Researcher Luca Turin. . . . . . . . . . . . . . . . . . . . . .

13

Chapter 5. The Famous Madeleines: The Proust Phenomenon, a Scientific Spoliation? . . . . . . . . . . . . . . . .

17

Chapter 6. The Smell of Rain . . . . . . . . . . . . . . . . . . . . . . . .

21

Chapter 7. The Neanderthal Nose . . . . . . . . . . . . . . . . . . . .

25

Chapter 8. Mr. and Mrs. Kallmann Have a Son: When Losing Your Nose and Losing Your Gonads Go Hand in Hand. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

29

Chapter 9. Whiplash, or Losing Your Sense of Smell Following a Head Injury . . . . . . . . . . . . . . . . . . . . . . .  

33

vi Discovering Odors

Chapter 10. Phantom Odors . . . . . . . . . . . . . . . . . . . . . . . .

37

Chapter 11. These Odors That Make Your Head Hurt . . . . . .

41

Chapter 12. The Sleeper’s Nose . . . . . . . . . . . . . . . . . . . . .

45

Chapter 13. Surströmming: The Worst Odor in the World? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

49

Chapter 14. It Smells Like Cheese . . . . . . . . . . . . . . . . . . . .

53

Chapter 15. What Fennel Reveals to Us . . . . . . . . . . . . . . . .

57

Chapter 16. Mustard Goes Up My Nose and Onions Make Me Cry: Discovering a Third Unknown Chemical Sense . . . . . . . . . . . . . . . . . . . . .

61

Chapter 17. Lavender at the Dentist: Aromatherapy, a Myth or a Reality? . . . . . . . . . . . . . . . . .

65

Chapter 18. Catnip and Pregnant Women: Some Variations in Sensitivity to Odors . . . . . . . . . . . . . . .

69

Chapter 19. If You Eat Too Much Fat, You Will Lose Your Sense of Smell . . . . . . . . . . . . . . . . . . . . . . . . . .

73

Chapter 20. Experts’ Noses . . . . . . . . . . . . . . . . . . . . . . . . .

77

Chapter 21. Filled with Smells . . . . . . . . . . . . . . . . . . . . . . .

81

Chapter 22. Obesity and Chocolate . . . . . . . . . . . . . . . . . . .

85

Chapter 23. The Nose on the Plate: A Difficult Scientific Consensus . . . . . . . . . . . . . . . . . . . . .

89

Chapter 24. The Smell of a Hot Croissant: When Our Sense of Smell Nibbles Away at Our Free Will . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

93

Chapter 25. The Dog That Sniffs Out Cancer . . . . . . . . . . . .

97

Contents vii

Chapter 26. Smells to Cure Cancer? . . . . . . . . . . . . . . . . . .

101

Chapter 27. A Depressed Patient’s Nose . . . . . . . . . . . . . . .

105

Chapter 28. Gogol’s Nose or “Empty Nose” Syndrome . . . .

109

Chapter 29. She Smells Parkinson’s . . . . . . . . . . . . . . . . . .

113

Chapter 30. And What Does Parkinson’s Smell Like? . . . . .

117

Chapter 31. Alzheimer’s Nose: Losing Sense of Smell and Losing Memory, the Same Story? . . . . . . . . . . . .

121

Chapter 32. The Smell of Old People . . . . . . . . . . . . . . . . . .

125

Chapter 33. The Smell of Death . . . . . . . . . . . . . . . . . . . . . .

129

Chapter 34. Red Meat, Garlic and Sex Appeal . . . . . . . . . . .

133

Chapter 35. Tears and Desire: Stop Crying, it Doesn’t Turn Me On Anymore . . . . . . . . . . . . . . . . . . . . .

137

Chapter 36. With a Bad Nose, Comes a Poor Flirt . . . . . . . .

141

Chapter 37. It’s All in the Sweat . . . . . . . . . . . . . . . . . . . . . .

143

Chapter 38. The Smell of Fear . . . . . . . . . . . . . . . . . . . . . . .

147

Chapter 39. What Epigenetics Owes to the Nose: How Fear Learned From an Odor can be Transmitted to Offspring . . . . . . . . . . . . . . . . . . . . . . . . . . .

151

Chapter 40. Odor and Pain . . . . . . . . . . . . . . . . . . . . . . . . .

155

Chapter 41. Odorology . . . . . . . . . . . . . . . . . . . . . . . . . . . .

159

Chapter 42. On the Trail of Odors . . . . . . . . . . . . . . . . . . . .

163

Chapter 43. The Electronic Nose . . . . . . . . . . . . . . . . . . . . .

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Chapter 44. The Plane Nose: The Methods of the Fraunhofer-Institut für Bauphysik to Get Up in the Air . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

171

Chapter 45. The Gender of the Nose . . . . . . . . . . . . . . . . . .

175

Chapter 46. The Newborn’s Nose . . . . . . . . . . . . . . . . . . . .

179

Chapter 47. The Smell of a Handshake . . . . . . . . . . . . . . . .

183

Chapter 48. The Nose and Perfumes . . . . . . . . . . . . . . . . . .

187

Chapter 49. Odors… A Hobby? . . . . . . . . . . . . . . . . . . . . . .

191

Chapter 50. Tell Me What You Smell, I’ll Tell You Who You Are, But Not Where You Come From: On Genetic Variations in Odor Perception . . . . . . . . . . . . . .

195

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

199

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

201

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

223

Preface

It is common to read that smell is an unknown sense, that it is a primitive or archaic sensorial modality, and that the human species is not very efficient with the use of the nose. If we consider that it is one of the first senses to appear during evolution, then yes, it is primitive, but considering the human nose as mediocre is a false belief based on 19th-Century scientific considerations. In biology, there are three states of knowledge, obviously closely interconnected, relating to questions of structure, functioning, and functional potential. Today, although there are still some problematic areas, the structure of the olfactory system(s) is known. The same applies to functioning, although there are more questions than there are about structure (e.g. perireceptor space, influence of the metabolism, and cortical information processing). However, there are still many questions about the functional aspects of the human species, in other words, “what is the point?”. This book, while it naturally sometimes refers to aspects of structure and functioning, is mainly concerned with functional aspects. Obviously, and to a large extent, there are hypotheses in the process of being verified, but from all the research conducted in recent years, it seems that the sense of smell will never cease to surprise us. What it is used for is not always directly apprehended by consciousness, but olfaction undeniably maintains a considerable place in our relationship with the world, with others, and in the regulation of our physiological and psychological states. Above all, it greatly influences our most fundamental behaviors (nutrition, sexuality, emotional responses, etc.).

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Paul Broca (1824–1880) remains forever recognized in the history of medical science for putting his name to the area of language production in the brain. What is less well known is that his curiosity about neuroanatomy also led him to become interested in the olfactory system (Broca 1879). He was the first to publish the idea that smell is an inferior sense in humans due to the ratio of the volume of olfactory bulbs to the volume of the brain1. This ratio is indeed very disadvantageous for the human species compared to other species such as dogs or rodents. Then Freud came onto the scene, interested in and influenced by Broca’s work, and postulated that smell was mainly linked to sexuality and that because of its regression in humans, it was at the origin of psychosexual developmental disorders, psychological conflicts, and all mental illnesses! The scientific fame of Broca and Freud led to a scientific disaffection with the sense of smell for most of the 20th Century and many biologists and psychologists today persist in their belief that humanity has an impaired sense of smell (McGann 2017). Smell is, therefore, minor from a functional point of view. However, from the end of the 20th Century, scientific work in many fields – physiology, genetics, molecular biology, neuroanatomy, psychophysics, etc. – gradually explained the complexity of the structure and functioning of the olfactory system, its uniqueness, and its interactions with other systems (including and beyond sensory systems). However, it is only in recent years that scientists from all four corners of the globe have embarked on the investigation of functional issues. The growing literature on the subject makes it clear that we often move from genial experiences to general works, we witness debates which are as constructive as they are heated and pointless, and we are as excited about this as much we find the situation ironic. Being interested in the functional aspects of olfaction – mainly in humans – is inevitably combined with some scientific stories that challenge us. The purpose of this book is to try to combine these two considerations in order to better understand the current state of knowledge about all these “strange odors” that surround us. In the coming years, research work will undoubtedly close in on a few major axes and many will probably not appear in the future. Before that day comes, this book provides a non-exhaustive overview of how we perceive these strange odors and how they influence our relationship to the world.                                         1 Today, this report is no longer considered relevant. Other more appropriate data are retained such as the number of cells, the number of projections to other areas, and so on.

Preface

xi

“Of the five senses that man possess, the most precious is common sense” (Alphonse Karr). Gérard BRAND University of Burgundy September 2019

1 Dr. Følling’s Flair: Discovery of Phenylketonuria by Smell

Asbjørn Følling (1888–1973), a Norwegian doctor and specialist in metabolism, is famous for his flair – in the literal sense – for discovering a previously unknown disease, phenylketonuria (PKU), still called Følling’s disease in Scandinavia. Phenylketonuria is a genetic disease that inhibits the body’s ability to naturally metabolize phenylalanine, a substance that is widely present in our diets since it is found in virtually all animal and plant proteins. Our body needs phenylalanine even though it cannot produce it. It is, therefore, an essential part of our diet. People with phenylketonuria do not have the enzyme that transforms phenylalanine, which then accumulates before being transformed into toxic substances by the liver (phenylketones). The prevalence of this metabolic disease varies from one country to another. Estimated numbers are 1/10,000 in Europe, including high numbers in Turkey, for example, with 1/4,000 but the disease is almost absent in Finland (1/100,000), without any real explanation for these differences. Until Følling’s discovery (Følling 1934), no one knew anything about this serious condition, which results in developmental problems in childhood characterized by motor and intellectual difficulties that can lead to severe intellectual disabilities. One day, Dr. Følling welcomed a mother and her 6-year-old daughter into his office. The child was born without any particular problems, but over time the mother realized that her daughter was not developing normally and that she was showing increasing signs of motor and intellectual disabilities. At 6 years of age, she walked with a lot of pain and could say only a few words. In addition, this woman had given birth to a

Discovering Odors, First Edition. Gérard Brand. © ISTE Ltd 2019. Published by ISTE Ltd and John Wiley & Sons, Inc.

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son two years after her daughter. Problems linked to his development were even more noticeable; at 4 years of age, he could not speak, could not walk, and could not eat alone. The mother of these children had seen many specialists, but at that time, medicine did not have many answers to questions about developmental disability or intellectual disability. Følling, like his colleagues, used the usual tests and diagnostic tools without detecting anything that could explain a deterioration in the health of the two children. However, one particular element – at first sight insignificant – caught his attention. The children emitted a strong odor, similar to the smell of mold. It emanated from both their skin and urine. Urine tests carried out before and then by the other doctors had not revealed anything in particular and Følling decided to carry out another test, the Gerhard test. The aim was to look for the presence of a compound called acetylacetic acid, a potential marker of diabetes. No link between diabetes and developmental and intellectual disability could be found so Følling decided to follow a simple observation (“something common is present in the urine of both children”) and carry out an experimental trial (“I use all the tools at my disposal and we will see what comes out of it”). In the Gerhard test, ferric chloride is mixed with urine and if acetylacetic acid is present, then the urine turns purple. In this case and to the doctor’s great surprise, the urine of the two children turned green! The conclusion that an unknown molecule was present in the urine of the two children was certain, so all that remained was to identify it (although, at this stage, it was not certain that there was a link between the molecule and the children’s deficient state). After many months of analysis, he finally discovered that the substance in question was phenylpyruvic acid, normally absent in the urine. He wondered whether this substance had a role in the children’s motor and intellectual disabilities. To answer this new question and in a sensible approach, Dr. Følling applied Gerhard’s test to 400 children in specialized institutions in Norway. In about 10 of them, the urine turned green, and it was concluded that it was probably a metabolic dysfunction of genetic origin. Since phenylpyruvic acid is normally absent in the urine, it had to come from the transformation of another molecule. Starting from the proximity of the molecular structure, he suspected phenylalanine, an amino acid that is common in our diets. This was a bold statement at the time as it amounted to considering that the intellectual and motor disabilities observed in the children could be due to a substance naturally present in certain foods. Consistent in his approach, he decided to take a certain number of children with green urine and subject

Dr. Følling’s Flair

3

them to a strict diet without phenylalanine. The problem was significant since this molecule is present in most food products, particularly in milk, eggs, meat, and so on. However, with this strict diet, the urine quickly lost its characteristic musty odor, no longer turned green following the Gerhard test, and, therefore, no longer contained phenylpyruvic acid! Following Dr. Følling’s exemplary exploratory work, it took several years to develop processes to eliminate phenylalanine from foods and to provide alternative foods for patients with phenylketonuria. It was only in 1953 (Bickel et al. 1953) that the first complete diet treatment was offered and in 1963 (Guthrie and Susi 1963) that a routine screening test was developed for newborns. Currently, the mechanisms involved in this disease are well understood (Ghozlan and Munnich 2004), from the genetic dysfunction that underlies the process to the metabolic dysfunctions that result from it and to the neurological disorders that cause motor and cognitive disorders. Thanks to screening and a suitable diet low in phenylalanine, children can develop normally and no longer show any kind of disability. There is no doubt that the citizen of Oslo, Asbjørn Følling, would have deserved a Nobel Prize in Medicine and Physiology for this major discovery due to his observational skills and sense of smell that helped to improve the lives of thousands of children around the world.

2 A Nobel Prize for the Nose and Retraction in Science

On December 10, 2004, American researchers Linda Buck and Richard Axel received the Nobel Prize in Physiology and Medicine from the Karolinska Institute in Stockholm. This prize was awarded in recognition of their work on the discovery of olfactory receptors, first published on April 5, 1991, in the journal Cell, a prestigious journal in cell biology. At that time, the interest of the scientific community was immediately aroused by the discovery of a new gene family coding olfactory receptors. This discovery finally confirmed the molecular basis for odor recognition. Until then, no one had been able to explain how the olfactory system detected the thousands of odors we are likely to perceive (see Chapter 4). In the study of sensory mechanisms, that of the sense of smell, therefore, proved to be very delayed compared to other modalities such as hearing (the Nobel Prize was awarded to Von Bekesy in 1961 for his work on the cochlea) or vision (the Nobel Prize was awarded to Wald in 1967 for his work on the retina). Four decades thus separate discoveries relating to transduction in the eye and inner ear from discoveries based on the sense of smell. However, while the publication of Buck and Axel’s paper improved the understanding of odor decoding mechanisms, many subsequent questions remain open on integrative and treatment processes in the central nervous system, on the impact of odors on behavior, and on psychological processes – questions that are addressed in this book. These are receptors coupled with a specific type of protein (G proteins already known to be involved in the recognition of certain neurotransmitters and hormones) which, when activated, cause a series of chain reactions inside the cell leading to the activation of nerve impulses. Perhaps the most

Discovering Odors, First Edition. Gérard Brand. © ISTE Ltd 2019. Published by ISTE Ltd and John Wiley & Sons, Inc.

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surprising result following the American researchers’ discovery was the considerable number of genes coding olfactory receptors in humans. In the initial article published in the Cell journal in 1991, only 18 genes were mentioned. It should be noted that, in an animal with a high-performing sense of smell like mice, about a thousand genes have been inventoried. In humans, 862 olfactory genes have been identified, with the knowledge that many of them (56%) are actually pseudogenes, which means that they are not (or no longer) functional1. A decline in smell is often noted when discussing evolution in the human species (although this issue is controversial – see Chapter 7), while there are almost no pseudogenes in some mammals such as mice. But Linda Buck’s story does not end with her Nobel Prize. In fact, it constitutes an illustrated case of retractions in science. In 2001, she published an article in the renowned journal Nature with Zhihua Zou, one of her post-doctoral students in her Harvard laboratory (Zou et al. 2001), for which she had to sign a retraction in 2008. The results initially published could not be replicated, with replication being – as everyone can agree – the best guarantee of validity. The first author of the publication, Zou, refused to sign the retraction in a deleterious atmosphere where Linda Buck apparently blamed him. In any case, this raised questions about Ms. Buck’s role: holding her responsible suggests that she did not “control” (or only from a very far distance) her student’s work. Worse still, two and a half years later, she had to make two further retractions for articles published in 2005 in the journal PNAS (Proceedings of the National Academy of Sciences) and in 2006 in the journal Science. Before their retraction, these two articles had been widely cited in the scientific literature. Linda Buck was in no way disconcerted by these retraction cases. She continues to travel to international conferences and receive applause. A little like the current policy, caught with their hand in the cookie jar, the guilty party apologizes flatly2 (or not) and continues on their way as if nothing or almost nothing had happened. These excesses in research have become a real scourge, a depressing gangrene. Every week, the Retraction Watch website created in 2010                                         1 Recent studies (notably Prieto-Godino et al. 2016) suggest that some pseudogenes in the olfactory modality may actually be functional. 2 “It is disappointing, of course”, said Buck: “The important thing is to correct the literature. I sincerely apologize for any confusion that its publication may have caused”.

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announces the retraction of scientific literature from several publications, with a total of between 500 and 600 per year! The changes in researchers’ activities in recent years are undoubtedly not unconnected to this phenomenon: the hunt for fame, the race for contracts and funding, etc., are in the image of the conflicts of interest that are today flourishing everywhere. Withdrawal or retraction means that the publisher considers that the data are no longer considered reliable and the article should no longer be cited. There are many reasons for the loss of reliability. Historically, the most well-known fraud is outright plagiarism, which persists despite the verification tools put in place by the major scientific publishing houses. Another barely believable but very real case of fraud is for an author to be their own reviewer. Indeed, scientific journals are said to be peer-reviewed and each paper submission is generally critically analyzed by two or three experts in the field, not having any relationship of interest with the team that wishes to publish. Many publications have, therefore, been retracted in recent years simply because the reviewers were the authors themselves. Of course, there is still the widespread possibility of tampering with or even simply inventing experimental data. The biggest counterfeiters are undoubtedly the Japanese anesthetist Yoshitaka Fujii and the German Joachim Boldt, whose dozens of articles have been removed. Other incredible stories are told in labs, such as that of the Czech biochemist who had to retract an article after he was, surprised by video surveillance in the process of manipulating samples to verify his controversial initial results! Obviously, the list of scientific misdeeds on the Retraction Watch website is growing faster than Pinocchio’s nose!

3 Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg. Until the early 2000s, the process by which they progress and orient themselves to reach and fertilize the egg was not known, and many teams of researchers were working on this issue. However, it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates. In this context, Marc Spehr’s German team working on reproductive biology focused on a new hypothesis: the potential presence of olfactory receptors (ORs) in sperm. In the journal Science (Spehr et al. 2003), the team published its work, which sent shockwaves through the scientific community. Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm, code name OR1D2 (alias hOR17-4). Not knowing the nature of the odorant that could bind to this receptor, the researchers proceeded by experimental trial and error using several molecules. They discovered that, by using the fluorimetric method, that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro. This molecule was indeed present in the fluid surrounding the egg, but no one knew where it came from, from the egg itself or from other elements of the female reproductive system. Once this discovery was published, a large number of popular articles appeared with catchy titles such as: “sperm have a nose”, “the egg smells like lily of the valley”, “the sperm’s favorite fragrance”, and so on. It has been popularized that sperm travel using their sense of smell to reach the egg, which, in turn, emits an attractive smell. This misunderstanding continued until the 1990s, reaching its peak with the publication (Sinding et

Discovering Odors, First Edition. Gérard Brand. © ISTE Ltd 2019. Published by ISTE Ltd and John Wiley & Sons, Inc.

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al. 2013) of another German team from the University of Dresden, aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent. The idea was relevant, but the results were unconvincing despite the researchers’ peremptory conclusions. Infertility affects a significant proportion of the population. A study conducted in France in 2007–2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24% and 11% after 24 months. The logic of shared responsibility is respected since in about 50% of cases, it is the man who is infertile. A number of causes are well-identified, such as a lack of sperm mobility, as in the case of varicocele1 for example, or a deficiency in sperm composition. However, for 25% of infertile men, there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility). It has, therefore, been known since 2003, with the discovery of the OR1D2 receptor, mentioned above, that olfactory receptors are present in regards to sperm, particularly in the middle part of the flagella, and that they play a role in mobility. The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent). Assuming that bourgeonal is an attractive chemical agent for human sperm, the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal. Without this activation mechanism, the lack of response to bourgeonal could be responsible for fertility problems2. Two groups of men were compared: a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group, and a group of 15 men (average age of 34.5 years) with idiopathic infertility. Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile, did not take any contraceptive methods, and had not reported pregnancy in the past 2 years. Sensitivity was self-assessed for three odorants: bourgeonal, helional (green smell, wet grass type, and close to the smell of melon)                                         1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord. 2 Interestingly, it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men. This result is all the more interesting because, in general, women are more sensitive to odors than men.

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retained for its structural proximity to the bourgeonal, and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal. Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men, while no difference was found for the other two odors. The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor. They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal, which is known to inhibit the OR1D2 receptor. However, these conclusions had to be qualified because, in the same study, the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men, and this for the three odors, including bourgeonal3. The physiological reality is probably more complex. Indeed, progesterone, a female sex hormone, is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm; in context, not to be mistakenly spelled CatSpehr...). Progesterone opens these channels and modifies the calcium level in the sperm and, consequently, the mobility of the flagellum. The men whose gene regulating the function of CatSper is defective are, therefore, infertile. We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly, without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells. Moreover, bourgeonal can only be active at concentrations a thousand times higher than that of progesterone. The initial study of Spehr in vitro approached this criterion, which is, therefore, very far from the physiological reality. The poetic Lily of the Valley phenomenon would, therefore, ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley. In addition, there are olfactory receptors elsewhere than in the nose and on sperm cells. In 2014, a biomedical team in Washington discovered                                         3 Recently, an Italian team (Ottavio et al. 2015) determined bourgeonal detection thresholds in 37 men (aged 20–36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function – IIEF – scale). The results showed that the lower the detection threshold for bourgeonal (better sensitivity), the higher the intensity of sexual desire.

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olfactory receptors in the lungs (Gu et al. 2014). They were found in the membranes of specific pulmonary neuroendocrine cells4 (PNECs). These olfactory receptors respond to external chemical agents (such as air pollutants) and trigger the release of hormones that can induce contraction of the respiratory system. They therefore contribute directly to the protection of the body against irritating or toxic substances present in the atmosphere. Knowing that the contraction of the respiratory system is a process that occurs in people who are hypersensitive to certain external volatile agents (exhaust fumes, cigarette smoke, perfumes, etc.) and suffer from chronic respiratory diseases, it can be considered that the olfactory receptors of PNECs become interesting therapeutic targets in classical diseases such as asthma, emphysema, or obstructive pulmonary disease. Other more recent studies have reported the existence of olfactory receptors in the blood, heart, and even skin. Strangely, like a fable by La Fontaine, the protocols are based on the same principle as the one that prevailed in Spehr’s initial study on sperm and lily of the valley.

                                        4 These are neural cells that respond to signals from other neurons, not by transmitting a nerve impulse as a conventional nerve cell can, but by releasing hormones into the bloodstream.

4 Vibrational Theory and the Astonishing Story of Researcher Luca Turin

Chandler Burr’s book The Emperor of Scent1 should be one of the mandatory texts for doctoral school lessons. This will remind PhD students and future researchers that they require a little bit of madness, but that stubbornness is also a significant trait to have... a fantastic one, depending on the context. This book reads like a novel and is a true story, recounting Luca Turin’s work. This passionate researcher in physiology and biophysics was born in 1953. He is a great traveler who has taught in London, worked at the CNRS in France, and who also worked in the United States, Greece, and Germany. He is first of all passionate and very knowledgeable about perfumes, on which he has written a reference guide. He is also interested in how our sense of smell works, mainly with regard to transduction, i.e. the mechanism that triggers a potential for action (or nervous impulses) at the receptors located in the nasal cavity. Unlike almost all researchers in the late 1980s, he is a follower of the vibrational theory2 first developed by Dyson (1938) and then taken up by Wright (1964, 1972). Until the publication of Buck and Axel (1991; see Chapter 2), although many researchers suspected a shape recognition mechanism, other hypotheses were possible, including vibration theory. The theory is based on Dyson’s idea that our body has a biological spectroscope and that human cells act as conductors of electrons                                         1 Burr Chandler, The Emperor of Scent: A Story of Perfume, Obsession, and the Last Mystery of the Senses. Random House, New York, 2002. 2 He is also a strong personality. In 1988, he denounced H. Korn on the subject of data tampering. Since Korn was an important scientific figure, and in order not to damage the reputation of the CNRS, Luca Turin had 1 week to change laboratories. Korn recounts this episode in his book published in 2016 (Korn 2016).

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by the tunnel effect3 through the proteins they contain. However, despite the discovery by Buck and Axel (which won them a Nobel Prize a few years later), Luca Turin would continue to develop, argue and try to disseminate his theory. This was a time, not so long ago, when researchers had free reign to work on one subject or another, or even in one discipline or another without having to be accountable... today, this would be considered a Utopia! Turin first considered the obstacles of pattern recognition theory and pointed out that two molecules very close in a configuration such as enantiomers4 can induce very different odor sensations, while two extremely distinct molecules can generate the same odor perception. He also pointed out that the number of receptors is much lower (at the time estimated at about a thousand) than the number of odors perceived by humans (estimated at about 10,000). In 1995, Axel proposed a solution to this flaw by explaining that it is not the entire molecule that coincides with a receptor but only a part of it and that, in addition, the same molecule can, therefore, be linked to several receptors. The pattern recognition theory becomes combinatorial but, consequently, makes it even more complex to associate the characteristics of a molecule with a percept... a complexity that is still relevant today (see Chapter 13). With determination, Turin finally succeeded in showing that two very different molecules, sulfur and borane, vibrate at the same frequency (~2,500) and present the same odor. By chance or in terms of proof, vibration theory linked to olfaction could not be proven. The following problem remained (or rather it was against him): the problem of enantiomers vibrating at the same frequency but not having the same odor! This was a good way of getting a theory straight, but like Axel with combinatorics in pattern recognition, Turin found a way through: if the vibrations are identical, it is necessary because the “reader” is different... depending on the shape of the molecule (the usual metaphor here being that of a pair of righthanded scissors being used with the left hand, the tool is the same, the hands similar but the orientation different). Then began a battle for Turin with the publishers of scientific journals, including the famous Nature, which rejected the submission. It was finally accepted in Chemical Senses in 1996. The                                         3 The tunnel effect is an emblematic phenomenon of quantum physics. It occurs when a quantum object crosses a potential barrier when it does not have enough energy to cross it. 4 Enantiomeric molecules are the two forms (right and left, like two hands) that cannot be superimposed on the same molecule. We also talk about chiral molecules.

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personality as well as the results of Turin were then denigrated while the work of Buck and Axel obtained the Nobel Prize in 2004. For almost 15 years, only a few scattered articles questioned vibration theory in olfaction. But from 2010 onward, unresolved questions about the perception of odors rekindled the research controversy. In the prestigious PNAS journal (Franco et al. 2011), Turin, with a Greek team, based his theory on results obtained in Drosophila and then in PLOS ONE (Gane et al. 2013) in humans. In 2015, again in the PNAS journal, the fierce debate on vibration theory, which was more than 30 years old by that point, resurfaced (Block et al. 2015; Turin et al. 2015; Vosshall 2015). Luca Turin’s determination over so many years raises a smile among us, but the history of science reminds us how many people have fought to finally be right, so we must be careful! Without returning to Galileo, one of the recent famous discoveries – after being widely criticized – is probably that of Barry Marshall (Marshall and Warren 1984). With his colleague, he supported the idea that most stomach ulcers were caused by a bacterium (Helicobacter pylory), while for many decades, the medical world had argued that the causes were related to stress, a too spicy diet, or excessive acidity. Marshall’s hypothesis was mocked by the guardians of orthodoxy who claimed that bacteria could not survive in an environment as acidic as that of the stomach. Bravely, for an experiment, Marshall swallowed the contents of a test tube for culturing this bacterium and very quickly developed an ulcer, which he then treated with an antibiotic course of treatment. This daring and sardonic demonstration was immediately and unanimously welcomed by the scientific community. Marshall and Warren were awarded the Nobel Prize in Physiology and Medicine in 2005 for this discovery. Today, beyond the strict field of olfaction, the general question of the role of molecular vibration is still very acute in molecular biology and physiology (e.g. Chee et al. 2015; Hoehn et al. 2017).

5 The Famous Madeleines: The Proust Phenomenon, a Scientific Spoliation?

Marcel Proust is currently very popular among scientists. To mention only two books: Proust Was a Neuroscientist by Johan Lehrer published by Houghton Mifflin (2012, originally published in 2011) and La Madeleine and Le Savant1 by André Didierjean published in Le Seuil (2015). Everyone is familiar with the very specific phenomenon of memories linked to smells, illustrated by Proust in the first volume, Swann’s Way, from In Search of Lost Time (2016, originally published between 1913–1927), popularized under the expression “Proust’s famous (little) madeleines”. References are everywhere and even Woody Allen recently mentioned this phenomenon in one of his films (Midnight in Paris 2011). However, do we really know what this means beyond the appearance of ancient memories revived by a particular smell, whose evocative power is suspected? First, we must take a detour through how our memory generally works. The proper functioning of this prodigious capacity is based on three pillars: encoding, storage and recovery. In traditional memory, good encoding is often based on the repetition of information; like now students cram information in order to face an exam. Surprisingly, smells can be encoded in memory without repetition, especially if the context accompanying the smell is emotionally charged. Most of the time, they are encoded alone, i.e. without names, without visual reference – this is obviously what makes it difficult to retrieve them from memory. When you try to locate a smell in your memory, to have a representation of it, the exercise is almost always a failure and what appears to the mind is often a visual representation instead.                                         1 This book has not been translated into English. Its title means: The Madeleine and the Scholar.

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Let us take an example: if you close your eyes and try to imagine the Eiffel Tower or Big Ben... no problem, you get a mental image. If you try to sing the Star-Spangled Banner, no problem either, but if you try to imagine the smell of coffee or that of bananas, the task is very difficult or even impossible for most of us. Usually, it will be the image of the coffee maker or coffee cup, or of the banana that will appear to you. This phenomenon has been verified by fMRI studies that show that when the task required is to mentally represent the smell of coffee or that of bananas, it is the visual brain areas (e.g. cup, coffee maker, fruit, etc.) that are preferentially activated. This does not mean that smells are not encoded in memory, because if you smell lily of the valley, you agree that it is a scent known to you; what is difficult is, therefore, recovery. However, when the odor is associated during encoding with a particular context (often emotionally charged), its perception even years later will suddenly reactivate old memories that seemed totally forgotten (childhood memories, a first love encounter, etc.)2 Metaphorically, we can say that odor acts as a key to opening the drawers of episodic3 memory. However, the reading or interpretation that scientists can make of this famous phenomenon is subject to intense, if not heated, debate (Bray 2013). Among the first researchers to have scientifically addressed the phenomenon of the famous shell-shaped cake4, we should mention Chu and Downes (2002). They compared the autobiographical memories initiated with the name of an odor, with those initiated by the smell itself, a non-congruent smell, or a visual indication. In the case of odor indication itself, subjects evaluate their memories as being of better quality and the amount of detail reported is greater than the initial condition (only with the name of the odor). The opposite is observed with a non-congruent odor or visual indication. This study is less controversial than the study by Herz and Schooler, published in the same year. The authors compared reported autobiographical                                         2 “Memory can revive everything but odors, although nothing brings the past to life more completely than an odor that was once associated with it” – Vladimir Nabokov. 3 Of course, there are other types of memory that do not fit into this schema, such as procedural memory: learning to ride a bike and remembering it all your life even if you do not practice for several years. 4 Let us recall that Proust originally considered the idea of a slice of toasted bread dipped in tea... perhaps less noticeable as a result!

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narratives when they were initiated by visual and olfactory stimuli. They concluded: “Results revealed that memories recalled in the context of odors were significantly more emotional than those recalled in the context of the same cue presented visually and by the verbal label for the cue… This work is the first unequivocal demonstration that naturalistic memories evoked by odors are more emotional than memories evoked by other cues”. This conclusion was strongly criticized, particularly by Jellinek (2004) who pointed out that in the case of Proust’s story, the stimulation is multisensory and involves sight, taste, and texture as well as smell when soaking the madeleine in tea. Recent studies conducted in Lyon by AnneLise Saive’s team5 seem to confirm Herz’s initial conclusions that the more emotionally charged an odor is, the more memorized the context to which it is attached (Saive et al. 2013, 2014). However, the debate here is also due to a more prosaic cause frequently encountered in the scientific world, namely, fierce competition between laboratories working on the same themes! This tragicomedy was perfectly recounted by Lambert in 2009 in the excellent journal Épistémocritique. However, some people continued to explore the subject. Thus, in 2012, a Dutch team was investigating whether this phenomenon also worked for the recall of negative or very unpleasant events, as could be the case in patients suffering from post-traumatic stress disorder (see Chapter 38). In this study (Toffolo et al. 2012), 70 participants watched horrible film scenes (road accidents, surgery, genocide, etc.) and were simultaneously exposed to simultaneous stimuli: olfactory, auditory, and visual. A week later, participants were divided into three groups exposed to one of the three indications. They had to recount the story of the film they saw and their impressions. The results indicated that the retellings reported for the associated odor were more detailed and described as more unpleasant than those reported for the auditory or visual indications. Thus, Proust syndrome works regardless of the hedonic valence of the memory episode, which seems logical overall. For a long time, neurobiologists have been looking for potential biochemical supports for memory. Their main challenge is the plasticity of the nervous system where synaptic connections are constantly made and broken:                                         5 This team has developed an experimental protocol to demonstrate this phenomenon in laboratory conditions.

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how then do we explain the persistence of memories in such a pattern? In the early 2000s, a student of Indian origin, Kausik Si, joined Eric Kandel’s laboratory (Nobel Prize in Physiology and Medicine) to work on the molecular basis of memory based on the highly prized model of aplysia, which neurophysiologists have been very fond of. Aplysia is a marine mollusc that has very few neurons (a few thousand) and whose main characteristic is their large size, which naturally facilitates work on the lab bench. It is based on the idea that any synaptic marker must be able to activate messenger RNA (mRNA) since it is essential for protein synthesis, which is a priori essential in the neuronal activity of memory formation. It logically focuses on the dendritic ends of neurons, involved in synaptic combinations and whose characteristics are constantly changing. He soon discovered (Si et al. 2003) a molecule called CPEB (cytoplasmic polyadenylation element-binding protein) present in all dendritic branches of aplysia neurons and decided to block it selectively. This blockage then led to the disappearance of the cellular changes that underlie long-term memory: the aplysia was unable to remember anything! On the strength of this discovery, Si and Kandel explored the structure of the CPEB and found that it had the unusual characteristics of prion. The specificities of prion6 (many of which remain to be discovered!) seem appropriate to the mechanism of memory. Si and his collaborators continued their investigations and discovered that CPEB is widely expressed in the hippocampus (a key brain structure in the memorization process) of mice and that a blockage of CPEB induces specific long-term memory problems. In his book Proust was a Neuroscientist, Jonah Lehrer links the discoveries described above to Proust’s narrative and proceeds, by analogy, to assert that biology only explains what the French author had already described at the beginning of the 20th Century. This way of proceeding is very bankable but, nevertheless, constitutes a prodigious shortcut: it should be remembered that Si and Kandel never alluded to Proust’s writings and that the “prion theory” in explaining the memory process remains very controversial, even if it was supported by the results of a Swiss team (Papassotiropoulos et al. 2005), and that it was most recently taken up by S. Lindquist (a member of the original team of Si and Kandel) to explain memory in plants (Chakrabortee et al. 2016). We must stay tuned, then!

                                        6 Prion is often responsible for serious diseases such as Creuzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker syndrome, or fatal familial insomnia. Prion occurs in two functional states, active or inactive, and can autonomously change conformation and change proteomic structure without DNA modification. It is also very resistant to the effects of time.

6 The Smell of Rain

Figure 6.1. Images of the impact of a drop of water on the ground, taken 1 by a very high-resolution camera (Gariepy et al. 2015)

Everyone has experienced a country walk in the summer after a rain shower where a characteristic smell floats in the air, pleasant, familiar, earthy, fresh, light, and almost evanescent. Where does this specific smell of rain, or more precisely the smell after a rainfall, come from? This is a relevant question: the smell of rain refers to profound existential concerns of the human species. In 1964, Bear and Thomas, two Australian geologists, were the first to address the topic by publishing an article in the prestigious scientific journal Nature. To designate this specific smell, they proposed the term petrichor                                         1 Available at: news.mit.edu/2015/rainfall-can-release-aerosols-0114.

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derived from the Greek terms petra meaning “stone” and ichor meaning “blood or fluid”. Petrichor is the result of a complex work of nature as a whole and is mineral. Petrichor is first of all an oily substance secreted by plants and absorbed by soil and rocks during the dry season. It also impregnates plant seeds before germination to allow them to adapt better in the event of drought. During a shower or storm2, wind, leaves, rain, and soil mix together, and this dispersed oily substance then emits a characteristic smell. Today, the term geosmin is used to describe this smell, which is the result of the mixture of these oils, the activity of bacteria (actinomycetes) that produce spores and sediment compounds in contact with water drops. After a long period of drought, the smell of geosmin is often perceived more intensely because the bacteria have produced a greater quantity of spores. The human nose is very sensitive to geosmin (threshold of about 5 ppb), and qualitative assessments reveal that, in the “after rain” context, it is unanimously considered to be rather pleasant. In her anthropological research on Pitjantjatjara Aboriginal populations, Australian Diana Young (again!) from the University of Queensland reports in the journal Etnofoor that the smell of rain after a long drought is integrated into the collective consciousness of this community because it is directly related to cultivation and livestock conditions (Young 2005). Survival (and thus cultivation and animal husbandry) depends largely on these rainfall events. The positive hedonic valence associated with the smell of rain seems logical and is probably anchored in the collective memory of humanity. However, for those living in 21st Century cities, the smell of rain falling on asphalt is not quite the same and may not be as pleasant. We have, therefore, one more object for research. Until recently, the process by which this emanation occurred was unknown. Rather, the commonly accepted assumption was based on complex chemical reactions. However, this is not the case and this is what engineers from the famous MIT (Massachusetts Institute of Technology) discovered and published in their work in the journal Nature Communication                                         2 In the event of a storm, ozone (which etymologically means “exhaling an odor”) composed of three oxygen atoms (O3) may also be produced. Unlike odorless oxygen (O2), ozone has a pleasant, slightly bleached smell, perceptible at very low concentrations by the human nose (0.01 ppm). The electricity generated by the lightning strikes divides the oxygen and nitrogen molecules in the atmosphere, which then reform into nitric oxide (NO). The latter, in interaction with other chemical elements in the atmosphere, then produces ozone. This smell can be found in confined areas with a strong electric field.

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(Gariepy et al. 2015). They filmed the impact of water droplets on the ground using very high-performance cameras (speed and image accuracy). Since Americans never do things by halves, they filmed more than 600 drops of water falling on 28 different types of surfaces (16 portions of natural soil and 12 artificial materials), with several drop heights to vary the speed and force of the impact (Figure 6.1). From these observations, it appears that when a drop of water hits the ground, it traps impact of tiny air bubbles underneath. These then rise into the liquid (as in any gaseous drink) and eventually burst on the surface of the “bouncing” drop of water. In doing so, they disperse a large number of aerosols in the air, including odorous molecules. It is, therefore, a physical (not chemical) mechanism that is responsible for the smell of rain. To be more precise in their description, the researchers compared the amount of aerosols dispersed according to the nature (especially porosity) of the soil and the falling speed. When the soil was rather porous (they used campus lawns for their experiments, e.g. clay) and the drop of water was low or moderate, then the release of aerosols (and therefore odors) was significant. On the other hand, when the rain was intense, the drops fell too violently on the ground to form air microbubbles, thus preventing the dispersion of aerosols and therefore odors. Passionate about their work, MIT engineers continued their investigations by modeling the impact of drops of water on surfaces covered with fluorescent ink. They were able to observe the dispersion of the microparticles after the impact over the drop of water, which then naturally depended on the direction and strength of the winds. These observations are not as crucial in explaining the smell of rain as they are in explaining the spread of certain diseases. Indeed, if the odorous molecules are thus tossed around by the winds, so are many viruses and bacteria present at ground level, and the rainfall could be an important vector for the act of spreading. Will we soon have to give cautionary advice to the hiker, who innocently inhales the smell of rain with delight?

7 The Neanderthal Nose

Neanderthals occupied a large part of continental Europe and the Middle East between 250,000 and 30,000 years before our time. First considered as a subspecies of Homo sapiens, they were then recognized as an independent species called Homo neanderthalensis. Today, the relationship between Neanderthals and modern humans remains a subject of debate, particularly in light of several recent genetic studies. From a morphological point of view, Neanderthals present significant differences compared to Homo sapiens, particularly concerning the face. As early as 1996, two Americans, Schwartz and Tattersall, showed that their sinuses were much larger than ours. They also observed that the nasal region was larger and therefore probably had a more extensive olfactory epithelium. Does this observation lead us to believe that Neanderthal noses were more efficient than those of modern humans? In any case, this seems to be consistent with the widespread hypothesis of a phylogenetic decline in the olfactory capacities of human species compared to the first hominids, a hypothesis supported by the most recent studies in evolutionary genetics (Pierron et al. 2013). But this would be without taking into account the genius of science which, with each new discovery, questions, if not the established certainties, at least the many presumptions present. This was the case in the following study (Bastir et al. 2011). A group of European paleoanthropologists (Spanish, English, German, and Italian) worked on the comparative anatomy of fossilized skulls of three species: Homo erectus, Homo neanderthalensis, and Homo sapiens. To measure head volumes and different specific regions, the researchers used 3D scanning technology. The two major observations

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revealed significant differences in internal structures. These concerned the temporal lobes and olfactory bulbs, which are more developed in Homo sapiens by about 12% compared to Homo neanderthalensis. Some authors also postulate that the increase in brain volume and olfactory information processing areas could somehow compensate for the observed decrease in the number of functional olfactory receptors during the evolution of Homo sapiens. Bastir and his group of paleoanthropologists recalled the crucial role of not only the temporal lobe in memory processes but also language and more generally cognition and sociability. They suggested that this difference in the brain could have been an evolutionary advantage over other hominids and in particular Homo neanderthalensis. Is the same true for the olfactory system, which, more developed in Homo sapiens, could also have been an evolutionary advantage? To the extent that the disappearance of Neanderthals remains an enigma, all hypotheses promoting the survival of Homo sapiens are admissible. For the team of paleoanthropologists, a better nose could have contributed to better mutual recognition, especially at the level of kinship, and helped to improve group cohesion and social learning. In short, a more efficient nose marks the progress of modern humans in enabling adaptation. This was conversely less efficient in Homo neanderthalensis and responsible for their extinction. However, and as in the case of language where there is no consensus as to whether Homo neanderthalensis was gifted with the act of speaking or not, it is difficult to conclude on the actual differences in olfactory capacities between Neanderthals and modern humans. Getting lost in conjecture about evolution in the nasal cavities is a typical story. Following the observations of Schwartz and Tattersall in 1996, it was commonly accepted for many years that Neanderthals had disappeared because they had sinuses (to warm the inhaled air) that were smaller than those of Homo sapiens and had not been able to acclimatize to the cold. This hypothesis, which has now been abandoned, is fundamentally similar to the one formulated on the sense of smell and described earlier. Both reflect the scientific trap of giving immediate meaning to observation. A scientific truth does not exist; it is always fragmented and transient. The most common error is to conclude de facto from the observation, but most of the time the observation data must be analyzed, interpreted and compared to be understood. For biologists, the truth never appears directly under the microscope, on the MRI image, or in the Petri dish. If a young child watches the sunset, they see the sun go down and then disappear over the horizon. From this observation, it can be

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deduced that it is the sun that is mobile and not the earth. To understand the phenomenon, we must move away from what is seen and consider an abstract reality. In the case of Neanderthals, the question that focuses attention is why they disappeared. From this point on, any new observation of a difference with Homo sapiens becomes a source of possible hypotheses about the causes of extinction. The observations made by Bastir and his collaborators are structural data (the brain is more voluminous); they only provide very imperfect information – if at all – on how things work (odor is better). From there to imagining functional consequences in terms of the survival of the species is at the very least a daring leap! Hypotheses, and there are already a lot of them, are most of the time the only thing that results from scientific observations and studies. Paradoxically, they are the very essence of scientific thought. Some, such as Edgar Morin (2014), continue to warn about the current teaching, which dispenses knowledge only as established facts by only too rarely questioning “the knowledge of knowledge” or, more prosaically, by “looking no further than the tip of one’s nose”. Therefore, like Bastir’s team, let’s stay inspired!

8 Mr. and Mrs. Kallmann Have a Son: When Losing Your Nose and Losing Your Gonads Go Hand in Hand

The parents of Nathanaël, a 14-year-old boy, consulted the endocrinology department. Nathanaël was not showing the usual signs of puberty and a clinical examination revealed a micropenis and the absence of testicles in the scrotum (technical term: cryptorchidism). Nathanaël did not report any sense of smell disorders, but an odor detection test revealed almost total anosmia. An MRI scan confirmed the olfactory disorder by lack of visualization of the olfactory bulbs. His pituitary gland, on the other hand, appeared normal. Genetic investigations showed that Nathanaël had a mutation of the Kal1 gene, one of the genes involved in a pathology that combines congenital gonadotropic deficiency with olfactory deficiency. In 1856, Aureliano Maestre de San Juan was the first to publish, in the journal El Siglo Médico, the observation of a patient with the same symptomatic configuration as Nathanaël, namely, suffering from both olfactory deficiencies and testicular atrophy. However, it would take almost another century for this syndrome to be finally identified by Franz Joseph Kallmann, who described this genetic disease in 1944. This illness, characterized by hypogonadism due to pituitary gonadotropic hormone deficiency associated with anosmia, has since become known as Kallmann syndrome. In the 1950s, De Morsier and Gauthier (1963) described the atrophy or absence of olfactory bulbs – and corresponding axons – in people suffering from this pathology, hence the name sometimes given:

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Kallmann–De Morsier syndrome1. The discovery (Schwanzel-Fukuda et al. 1989) in several animal species that neurons synthesizing GnRH (gonadoliberin) migrate during embryonic life following the path of olfactory nerves has made it possible to understand the specific pathophysiology of this disease. In Kallmann syndrome, during embryonic development, the lack of maturation of the olfactory system (epithelium and bulb) prevents the migration of GnRH neurons to the hypothalamus and consequently prevents the production of pituitary hormones (produced by the pituitary gland) LH (luteinizing hormone) and FSH (follicle-stimulating hormone). This explains the fact that two systems that seem very distinct from each other are associated within the same pathology. Kallmann syndrome is a rare condition with a prevalence of 1/8,000 to 1/29,000 for men and 1/40,000 to 1/130,000 for women, according to studies. In general, the risk is, therefore, five times higher for men than women. It may be accompanied by other disorders such as blindness or deafness, abnormal movements or obesity. Due to the aforementioned embryonic developmental dysfunctions, it is usually the delayed onset of puberty that alerts and serves as a starting point for diagnosis. From a genetic point of view (Kim 2015), things are particularly complex: there can be sporadic cases or family forms in dominant autosomal mode, autosomal recessive mode or X-linked recessive mode. Kallmann syndrome is part of the larger group of hypogonadic pathologies due to insufficient pituitary gonadotropic hormones (CHH, Congenital Hypogonadotropic Hypogonadism). Currently, consensus is being reached on a list of six genes involved only in Kallmann syndrome, including the famous Kal1 (now, following a change of nomenclature by The Human Genome Organization, ANOS1) linked to the X chromosome and for which only men are affected, 14 genes involved in CHH outside Kallmann syndrome and 11 genes involved in both Kallmann syndrome and other CHH. It is also not uncommon for the mutation of one gene to contribute to pathogenesis through synergistic effects on other genes. Given the genetic complexity and the various possible symptomatic forms, diagnosis is not always easy and Kallmann syndrome may not be easily distinguishable from other rare diseases such as CHARGE syndrome (Coloboma, Heart anomalies, choanal Atresia, Retardation of growth and/or development, Genital and/or urinary defects, and Ear anomalies and/or deafness) for example or Bardet-Biedl syndrome (CHH with multiple                                         1 Also called “olfacto-genital dysplasia”.

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symptoms including obesity). A thorough examination of olfactory function – including olfactory bulb imaging (Figure 8.1) and psychophysical sensitivity tests – can, therefore, be crucial, as in the case of Nathanaël.

Figure 8.1. Comparative radiographs of olfactory bulbs 2 in a healthy person and in a patient with Kallmann syndrome . For a color version of this figure, see www.iste.co.uk/brand/odors.zip

The disorder can be managed with hormone treatments, testosterone in boys, estrogen/progesterone in girls or the pulsatile administration of exogenous GnRH that can restore puberty and fertility. The success rate has recently been estimated at 22% (Sidhoum et al. 2014). In conclusion, it should be emphasized that Kallmann syndrome reveals the complex intertwining of genetic, hormonal, and physiopathological factors contributing to a wide variety of functional disorders. For example, the mutation of a gene encoding prokineticin-2 in Kallmann syndrome (Prok2) is also linked to obesity problems. This protein is strongly expressed in the central nervous system, particularly in the olfactory bulb, and is also an anorectic hypothalamic neuropeptide. Several research teams are                                         2 Available at: radiopaedia.org/cases/kallmann-syndrome.

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therefore working to determine the exact role played by this protein since – apart from its involvement in Kallmann syndrome – it could also be an interesting target in the treatment of obesity.

9 Whiplash, or Losing Your Sense of Smell Following a Head Injury

Route 57, September 22, 2009, 11:17 p.m. Lydia was tired, sleepy, and especially eager to go home to rest. She drove at an average speed but was surprised by the sudden crossing of a deer in front of her car. She made a sudden action with her steering wheel that sent her into a tree below the roadway. After a few days of observation in the hospital and a few bruises, Lydia was doing very well but would soon receive a scare. Time passed, to the point that she rarely thought about this accident again, but she confusedly perceived that something had changed in her perception of the world. Wishing to discover why, she finally understood that these changes mainly concerned meals and bathing. And one morning, she realized... she no longer perceived odors. She did not immediately make the connection with her accident or even when she consulted her general practitioner. He remained doubtful and referred her to an ear, nose and throat specialist. During the routine discussion with Lydia, he understood that her anosmia was most likely due to her car accident, even though she had no other sequelae. Loss of sense of smell in the case of head or facial trauma is common. Prevalence is estimated at between 5% and 8%, but estimating is difficult and some authors even put forward the figure of 20%. In some very specific populations, such as boxers, the percentage can reach 28% (Vent et al. 2010). Three main mechanisms (Figure 9.1) can explain olfactory disorders after a trauma: (A) lesions in the nasal cavities that can be found preferentially in facial shocks; (B) lesions in the olfactory nerves that can be found preferentially in occipital shocks, i.e. whiplash; (C) central lesions for which the location of the trauma can be very variable. In Lydia’s case, and due to the absence of other neurological sequelae, the most likely hypothesis

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was olfactory nerve shear. Olfactory neurons are so-called bipolar neurons, classic in sensory systems and composed of a dendrite, a cellular body, and an axon. Dendrites and cellular bodies are located in the olfactory epithelium that lines the ceiling of the nasal cavities. The axons, for their part, pass through the cribriform plate of the ethmoid bone (skull bone with small holes in it) in clusters to form a synapse in the olfactory bulb, the first relay of olfactory information in the brain. Thus, during a rear impact to the head, the entire brain mass is shaken with a back and forth and forward and backward movement that causes the axons to shear. Despite the presence of olfactory stem cells in the epithelium, which normally differentiate into mature cells to replace the neuronal loss (whether natural death by apoptosis or accidental death, toxicological aggression occurs, for example), it is impossible to restore the integrity of the system. For some traumas, the olfactory bulbs themselves are damaged and the transmission of sensory information is compromised. In this case, the MRI assessment generally reveals the damage to the olfactory bulbs. Nevertheless, total loss of smell (anosmia) is obviously not observed in all cases of head trauma. In addition to reduced sensitivity (Coelho and Costanzo 2016), parosmia (deformation of the olfactory perception that does not correspond to stimulation) and phantosmia (olfactory hallucinations) are also frequently observed. A recent meta-analysis1 on the subject (Proskynitopoulos et al. 2016) clearly points out that there is a significant correlation between the severity of the trauma2 and the severity of olfactory loss. In a number of cases (variable according to the studies, but generally estimated at around one-third), functional recovery may occur within 6–24 months after the trauma. Beyond a period of 2 years post-trauma, the chances of recovery are minimal. However, if detected early, it may be possible to medically remedy these specific olfactory disorders. This potential medical breakthrough is not anecdotal when we recognize the impact of anosmia on quality of life and its etiopathogenic role in certain depressions (see Chapter 27). Thus, the lesion of olfactory nerves, as in the case of Lydia, causes a local inflammatory response and the formation of                                         1 A meta-analysis is a scientific work on a given subject that uses a statistical approach from a large number of publications (and therefore a large number of cases or subjects tested) to try to identify the most obvious trends. 2 The most commonly used scale to assess the severity of a head injury is the Glasgow Coma Scale (GCS). It is used to describe a patient’s condition at a given time and to monitor their state of consciousness. It combines three indicators: opening of the eyes (E), verbal response (V), and motor response (M).

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healing tissue that will constitute an obstacle to the regeneration of neurons and their connection to olfactory bulbs. In mice, the Kobayashi team demonstrated that dexamethasone treatments (2009) and other treatments interfering with the functioning of interleukin (2013) improved post-traumatic neural recovery of olfactory nerves by modulating the inflammatory response. To date and to our knowledge, there are no similar works published on humans. With a weak guarantee of success at present, what remains possible at this time and which depends mainly on the nature of the brain lesions involved in olfactory disorders (extremely numerous lesions as demonstrated by the observations of Lötsch et al. 2016), is the possibility of encouraging repeated and varied olfactory stimuli, in order to try to reactivate a sensory system whose plasticity is recognized. A 

B

C

  Figure 9.1. Mechanisms that can induce post-traumatic olfactory disorders: (A) lesions in the nasal cavities that will be found preferentially in facial shocks; (B) lesions in the olfactory nerves that will be found preferentially in occipital shocks, i.e. whiplash; (C) central lesions for which the location of the trauma may be variable (adapted from Coelho and Costanzo 2016). For a color version of this figure, see www.iste.co.uk/brand/odors.zip

10 Phantom Odors

Sandra consulted the neurology department on the advice of her general practitioner. For some time now, she has experienced hallucinations: “I don’t see ghosts, but I’m not fooled by invisible odors... For example, I’m sitting quietly watching television or reading and suddenly it smells like burnt bread... as if I’d left a brioche in the oven... I look everywhere to try to identify the source (there’s no brioche in the oven) even among the neighbors but I have to admit, this odors don’t exist outside my brain!” In this book, the great variability in the perception of odors has been mentioned many times. In most cases, the variations observed can be explained logically, but sometimes it must be admitted that they are either distortions of perception, generally called parosmia (from the Greek term para, alongside), or sometimes troposmia (from the Greek term tropo which implies a change, a modification), or hallucinations called phantosmia (Hong et al. 2012). In the case of distortions, we can distinguish by far the most numerous cacosmia (from the Greek term kakos meaning bad)1 that evoke unpleasant odors and, exceptionally, euosmia (from the Greek term eu, meaning good) that evoke pleasant odors (Landis et al. 2006). The distortion of perception suggests the presence of an odorous stimulus, which is not the case for phantosmias2 for which no molecule activates the olfactory receptors.                                         1 The literature also distinguishes torquosmias (metallic, chemical, or burnt sensations). 2 Specialists distinguish phantosmias, which last over time, from olfactory hallucinations, which last only a few seconds. In this chapter, both terms will be considered as synonyms.

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The prevalence of phantosmia is difficult to assess, initially estimated between 0.8% and 2.1%. It is probably even underestimated. In addition, it increases with age, as shown by a Swedish team (Sjölund et al. 2017) that conducted an epidemiological survey of 2,569 people aged 60–90 years of age. For the entire cohort, the prevalence was 4.9%, which is not negligible, especially since other factors influence risk such as gender (prevalence was higher in women than in men), vascular or genetic vulnerability. While idiopathic phantosmias are rare, olfactory hallucinations have been described in many nervous system disorders. They may occur in cases of a migraine (see Chapter 11), epilepsy, depression, head injury, nervous system infection, tumor, or stroke (see Coleman et al. 2011; Croy et al. 2013). They may also occur in neurodegenerative diseases such as Parkinson’s disease (Landis and Burkhard 2008). Finally, they can occur after exposure to toxic products, after the consumption of certain substances or drugs, or after radiotherapy or chemotherapy. The neurophysiological or metabolic bases that cause hallucinations, whether olfactory, visual, auditory, gustatory, somato-sensory, and viscerosensory are not established. Only the differences in the activation of brain areas according to each modality have been demonstrated. In the event of recurrent phantom odors, long-term harmful effects on quality of life, mood or personality are to be feared. Also, treatments are possible that depend mainly on the origin – peripheral or central – of phantom odors. When the peripheral origin is proven, surgical treatment by excision of the olfactory mucosa can be performed (more rarely, the removal of an olfactory bulb). Either the patient is anosmic and this will relieve them without functional consequences, or they are not anosmic but – like patients suffering from tinnitus – they will prefer to lose the use of the sense rather than endure hallucinations. The latter solution is generally reserved for cases where the hallucinations are clearly unilateral in origin. Thus, the problem is solved and some of the odor provided by the other nostril is preserved. There are also drug treatments such as the use of haloperidol (a neuroleptic) or the application of a cocaine solution (first described in 1966 by Zilstorff), but whose effect is only temporary (Leopold and Hernung 2013). Other drugs may occasionally be associated with improved phantosmias, as reported for example for venlafaxine (an antidepressant) (Landis et al. 2012). In the case of a central origin, the improvement occurs according to the type of condition involved and its management. Thus, Sandra’s general practitioner had a good intuition, because, while hallucinations can occur in mild cases of the upper respiratory tract or sinus infections, they can be a sign of more significant problems in the nervous system, as mentioned

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earlier. In Sandra’s case, the neurologist did discover a tumor in the temporal lobe, with no other apparent signs other than phantosmia. Following a neurosurgical operation on the tumor, the phantosmia disappeared. According to an article in the International Journal of Biometeorology (Aiello and Hirsch 2013), the doctor could also have asked Sandra about the possible impact of the weather on the intensity of her hallucinations. Indeed, the authors report the case of a 64-year-old Parkinson’s patient who had been suffering from phantosmia for several years and who systematically transcribed meteorological data and the intensity of his hallucinations. These observations were not baseless – the problem emerged only two to three hours before a storm, and during the whole stormy episode, the phantosmia clearly intensified going from “almost absent” to “extremely present”. Predicting the weather with phantom odors... how unexpected!

11 These Odors That Make Your Head Hurt

A migraine is a very common disease, affecting an estimated 10–15% of the population. Overall, it affects women twice as much as men. They can be a source of considerable discomfort and have a bad reputation. Some consider them a pretext for many unjustified days off work, while others believe that many migraine sufferers would not consult anyone. The cause(s) of migraines is/are poorly understood. A genetic factor seems undeniable because, in 80% of cases, migraine patients are parents. It seems that migraines are the result of complex neurovascular changes. This would be a decrease in cerebral blood microcirculation of about 5–10% of blood flow. Once the process has been triggered (stress, emotions, hyperluminosity, etc.), a momentum change is observed in the brain – in the way of a closed circuit – which crescendo into a paroxysmal state. Migraines differ from a classic headache or neuralgia: it can last from several hours to several days, it is frequently associated with effects such as nausea or vomiting, and its pain is classically amplified by noise, light, movement, and so on. At the beginning of an attack, transient neurological deficits often appear – corresponding to an inhibition phenomenon in the cerebral cortex – and which, in many patients, serves as a warning when a migraine occurs. These warning signs, also called an aura, generally disturb the vision (with deformations in the visual field, for example) and general sensitivity. Sensitive auras consist of numbness sensations and tingling of the face or limb which will slowly spread over all or part of the hemi-body, with the migraine attack appearing on the other side of the brain. Curative or preventive treatments against migraines are not always effective, and all migraine sufferers know that the best way to avoid the attack is to avoid the triggering factors. These are very diverse: they can be

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the consumption of certain food products (white wine or chocolate are sometimes incriminated), insufficient sleep, changes in lifestyle or stressful events1, and sometimes specific sensory stimuli such as in the case of odors. In a first Brazilian survey (Lima et al. 2011) following 98 migraine sufferers aged 18–82 years old, odor appeared to be the most frequent trigger (48%) after stressful situations (59%). In addition, odors appeared to be the most significant aggravating factor (73%) like hyperluminosity (74%). While hypersensitivity and intolerance to odors in migraine sufferers are known, the question of the specificity of certain odors has not been studied until recently. In this study (Lima et al. 2011), it appears that the most frequent odors involved in migraines are perfumes, cigarette smoke, household products (containing bleach or ammonia), and, to a lesser extent, gasoline and air pollution. Brazilian researchers seem very concerned about the migraine issue because another team from this country (Silva-Néto et al. 2014) published a study based on questionnaires. However, it was much more complete because it compared a group of 200 migraine patients with a group of 200 patients with tension headaches. The results are irrefutable since migraine sufferers cited odors as a trigger in 70% of cases (140/200) while no subject with a tension headache mentioned them (0/200). However, the categories of odors involved are identical to ones mentioned in the former study, and the pain occurs rapidly, within a time frame estimated by migraine sufferers at 25 min after exposure to odors. Although odor avoidance, called osmophobia in specialist jargon, is well-known to migraine sufferers, the interest of these two studies is to show that it is, in fact, a particular group of odors that cause the irritation. Thus, the odors mentioned activate not only the olfactory system but also the other chemosensitive system called the trigeminal system (see Chapter 16). It is therefore not the unpleasant nature of the odor that is the issue, as evidenced by the presence of perfumes in the list of incriminated odors, but its irritating nature. From a neurophysiological point of view, this relationship between trigeminal system activation and migraine onset is quite logical. To date,                                         1 It is becoming more and more common for patients to suffer a “weekend migraine”. All week long, they work without any particular worries and when Friday evening arrives, the migraine settles in for the whole weekend. The crisis ends on Sunday evening or Monday morning. These observations reveal that it is the change in stress level (here a decrease) which causes the migraine attack, not just an increase.

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however, the question of odor intensity required to trigger migraines has not been studied, but for those affected, the best way to reduce attacks is to avoid exposure to the odors in question, regardless of their intensity. However, as this remains to be scientifically verified, it would seem that certain odors (green apple, peppermint, etc.) could be effective in reducing migraine pain.  

   

12 The Sleeper’s Nose

The legislation has made it mandatory to have smoke detectors to prevent fires based on the activation of a piercing siren; this means of alerting is ineffective in the case of deaf people, especially if the fire occurs at night. There are hearing impaired detectors on the market which send flashes of light or vibrations (a device placed under the pillow), but their effectiveness remains relative. Based on this observation, Japanese researchers at Shiga University have developed an original fire alarm system – in the event of smoke detection, the device emits a strong smell of wasabi (also known as Japanese horseradish or Japanese mustard). Japanese scientists and engineers tested about 100 odors, including the odor of rotten eggs, before stopping to take a look at the favorite condiment of sushi lovers. The wasabi plant is widely used in Japanese cuisine for its spicy properties – properties that have burned some people’s taste buds! The smell of wasabi is indeed a powerful stimulant of the trigeminal system (see Chapter 16), whose active ingredient acts as an irritant in the nose, effective enough to wake a person in Morpheus’ arms. The “wasabi” alarm system was tested on 14 sleeping people, where one of them was deaf. People with no hearing problems woke up within about 2 min after the odor was released, while one deaf person woke up after only about 10 s. This system has a bright future ahead, because even if the proportion of deaf people in the general population is not very high – this is the same principle as the accessibility of people with reduced mobility in public places – the law could require places welcoming the public, hotels in particular, to be equipped with such devices. In 2011, the Ig Nobel Prize in Chemistry was awarded to Shiga’s Japanese researchers for this invention and for determining the required

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density of wasabi in the air to wake up people from their sleep in an emergency situation. The Ig Nobel Prize is an annual prize awarded to researchers whose inventions “make people laugh first and then think”. These are the inventions that will generally not change the face of the world, such as defeating major epidemics, but which are sometimes interesting in their ability to solve specific problems that are not necessarily a priority. A kind of ironic Nobel Prize for unusual or improbable research, we could say. Among the achievements in recent years which have been rewarded are of an American team in 2009 with a bra that can be converted in no time at all into a pair of effective gas masks and an Australian team in 2015 with the invention of a method to partially uncook eggs. True! The name “Ig Nobel” is a pun because it is pronounced approximately like the word “ignoble”. In 2017, a French team (Royet et al. 2016) from the CNRS in Lyon was awarded the Ig Nobel Prize for Medicine for their work on stinking cheese. The researchers studied by imaging the brain mechanisms at work in aversion to the odor of cheese (the food for which aversion is most frequent), and therefore in food disgust. And in 2018, this prize once again rewarded the work on olfaction to a team of French researchers (Becher et al. 2018). The results of the study showed that if a female fly falls into a glass of wine, the odor and taste of the wine will be significantly altered, whereas this will not be the case if the fly is male. The explanation lies in the fact that, unlike the male, the female deposits a very odorous pheromone that is perceived by humans even at very low concentrations. On a more serious note, some teams have focused on the effect of odors on sleep and, in particular, on the processes of memory consolidation. In 2005, Goel and his collaborators observed the sleep of 31 participants aged 18–30 for three consecutive nights: one night of adaptation, one night with an odorous stimulus, and one night of control, whereas the latter two followed a counterbalanced order between the participants. A lavender scent was used, delivered for 2 min for every 10 min between 11:10 p.m. and 11:40 p.m. Subsequent polygraph recordings showed an increase in the percentage of deep sleep phases (stages 3 and 4), correlated with selfassessed vigor upon awakening, better than in the absence of a scent. They also showed an increase in stage 2 phases (light sleep) and a decrease in REM sleep1 (stage 5). This first study based on electrophysiological recordings of sleep, and no longer only on subjective assessments, confirmed                                         1 During this stage, brain activity is intense, quite close to that of awakening, and very rapid eye movements (REM) are observed, in saccades. Paradoxically (hence its name), the body is completely inert, a muscular inertia that contrasts with the intensity of brain activity.

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the improvement in sleep quality through the lavender scent known for its relaxing properties (see Chapter 17). At the same time, in the early 2000s, several studies demonstrated the crucial role of sleep in memory consolidation processes, particularly in the knowledge acquired the day before. This is the case with the work of neurologists at the University of Lübeck published in the journal Science (Rasch et al. 2007). They were interested in declarative memory, also called explicit memory, which concerns the encoding and retrieval of information that can be consciously brought to light and expressed verbally. In this process, the role of the hippocampus (a key brain structure in memory processes) is very important because it is known to spontaneously reactivate during deep slow sleep phases. The researchers had the original idea of stimulating volunteers with the scent of roses (note that the authors did not explain why they chose this particular smell) while they trained to memorize the location of pairs of cards on a computer screen. Then, during sleep, on the following night, some of them were again exposed to the scent of roses during the phases of deep sleep. The next morning, participants exposed to the scent at night passed the memory test in 97.2% of cases compared to only 85.8% for the others, a statistically significant difference. Naturally, upon waking up, subjects were unable to say whether or not they were exposed to the scent during the night. The researchers then replicated the experiment without subjecting the participants to the odor during the learning phase, but only during sleep. In this configuration, memory test results were not improved the next day (82.9% success rate for odor-exposed participants versus 85.9% for others). This shows the importance of the presence of odor during the learning phase, which will then serve as a reinforcement during deep slow sleep. In this very comprehensive study, Rash and colleagues conducted a new odor-coupled trial during learning, but exposed participants to odor during REM sleep phases and not during deep slow sleep phases. In this case, the next day’s memory tests were no better for participants who had been subjected to the scent of roses (88.3%) than for others (89.5%). This part of the study thus confirms the crucial role of deep slow sleep in strengthening the memory trace, unlike REM sleep. Finally, while the results of this work all focused on explicit memory, in a final trial, the researchers wanted to know what would happen under the same conditions in a procedural memory test. Procedural memory essentially concerns motor skills and gestural skills. The example usually cited in the

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case of procedural memory was “cycling skills”, whose great singularity is to be reliable, resist time, and last even if memories or practices are not reactivated. In the study by Rash et al. (2007), it was a question of learning to type a series of keys on a computer keyboard as quickly as possible. The results did not show any specific effect on odor because, the next morning, they were improved by all the participants, both the control subjects and those who were subjected to the scent of roses. The reinforcing effect of the odor therefore only concerns declarative memory. More recently, an Israeli team from the Weizmann Institute (Arzi et al. 2012) investigated the role of odors during sleep, suggesting that learning can be efficient though strictly during sleep. Once the subjects had fallen asleep, they carried out a kind of conditioning by odor/sound association using either pleasant or unpleasant odors. It is well-known that pleasant odors induce a prolonged and powerful sniffing behavior while unpleasant odors induce a short and light sniffing. The day after the night of conditioning, the subjects were subjected only to sound and their sniffing was measured. Those who had been conditioned with a pleasant odor had a prolonged characteristic sniff and their sniffs were different from those who had been conditioned with an unpleasant odor that, when listening to the sound, produced only a brief sniff. This publication was thus the first to demonstrate that the sleeping person can learn (more precisely here, to be conditioned) without their knowledge (when they woke up, the participants declared that they could not remember either the odors or the sounds to which they had been subjected) of new information.

13 Surströmming: The Worst Odor in the World?

Swedish specialties include herring in all its forms and, for a novice, discovering surströmming is a daunting culinary experience. The most difficult thing is not tasting the product but opening a can of this longfermented herring. The odor is so strong and repulsive that the Swedes themselves recommend opening it at the bottom of the garden or, better still, in a basin of water to limit odors and splashes! Fermentation must last at least for 6 months, but it seems that a box over a year old is a real fragrant “caviar”. The fermentation process is so intense that the can is usually bulging as if it were ready to explode. Its origin dates back to the 16th Century and legend has it that Swedish fishermen, who lacked salt, sold high-meat to their Finnish neighbors. Surprised the following year to see them come back to ask for more, the Swedes tasted their “recipe” and enjoyed it. The method consists of using the strict minimum of brine necessary to avoid the decomposition of the product and to let it ferment. In Sweden, millions of cans of surströmming are sold every year. It can be enjoyed on a slice of bread with potatoes, onions, and so on, and visitors who survive the initial putrid odor find the taste more than acceptable. The problem is that this culinary discovery can only be made in Sweden: the European Commission prohibits the export and sale of surströmming outside the country. This anecdote raises the question of the definition of bad odors: are they universal? Are they constructed through experience or would it be more accurate to say through inexperience? Do they have specific molecular properties in common? And even then, are there any odors worse than others? The answer to this last question is yes. This is evidenced by the

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now-famous competition for the most stinking shoe... which therefore assumes that others would be less stinky1. In the United States, in the state of Vermont, this amazing competition is held every year to choose the most nauseating trainer. In 2015, the National odor-eaters rotten sneaker contest – that’s its name – celebrated its 40th anniversary. A 14-year-old teenager, Kane Young-Hiss, won the award with a cheque for $2,500 and a trip to New York City. What a way to encourage smelly feet! The most extraordinary thing in this story is that the members of the jury are not common noses but real big names! There is Rachel Herz, a renowned expert on odor, author of a reference book, The Scent of Desire (2008), and Georges Aldrich, nicknamed NASA’s nose, a chemical specialist and a meticulous checker of the odor of everything that is on board the shuttles. Leaving nothing to chance in olfactory matters is crucial for space expeditions. It should be recalled that in 1976 the Soyuz 21 mission had to return urgently to Earth after a very unpleasant pungent odor – whose source could not be identified by the astronauts – had spread into the cabin. For specialists, it is neither surströmming nor Kane Young-Hiss’ sneakers that can claim the title of the worst odor in the world, but a molecule resulting from the cracking of trithioacetone. In 1889, German chemists working in Freiburg on this molecule caused such an unbearable odor that the authorities had to evacuate the city entirely. Naturally, the horrible odor was accompanied by nausea, headaches, fainting... but scientifically speaking, the most interesting thing in this test was that the compound responsible was not identified. And in 1967, British researchers, as unlucky as their German counterparts, repeated the trithioacetone cracking experiment. As the odor had spread accidentally, and in response to the inconvenience caused in the neighborhood, the chemists decided not to isolate the molecule responsible for the worst odor in the world. In comparison, hydrogen sulfide (H2S; see Chapter 26), which evokes the odor of rotten eggs (on a less serious note, who has actually smelled rotten eggs in real life?), is almost like a subtle fragrance! Moreover, sulfur is

                                        1 With regard to pleasant odors, it has been demonstrated (Brand et al. 2012) that everyone can classify a large number of odors according to a strict order of preference, even for odors that are very similar from a perceptual point of view. This hedonic classification is individual and does not allow generalization over a large population. In addition, this transitivity of olfactory preferences is perfectly stable over time.

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found in many odorous molecules2, most of which are unpleasant, but the odor of sulfur compounds when they are very diluted can be perceived pleasantly. This is the case in garlic or grapefruit, for example. Everything depends on the binding capacities of sulfur with other molecules and, in particular, with hydrogen. This question of the relationship between molecular structure and hedonic appreciation of odors is old but still relevant3 (Keller et al. 2017). A team from Lyon (Kermen et al. 2011) tested a large number of odorants, chosen from the standardized Arctander atlas, which lists more than 3,000 odorants and their complete olfactory descriptions, produced by expert noses4. From the list of 74 odors considered most relevant, the team examined the number of olfactory notes of each substance according to the complexity of the corresponding molecule. The results showed that the more complex the molecular structure, the higher the number of notes evoked (floral, woody, etc.) and, conversely, the less complex the structure, the more unpleasant the odor was considered. This is a conclusion that obviously does not apply to the odor from the cracking of trithioacetone in Freiburg, since the supposed compounds would be propanedithiol (C3H8S2) and 4-methylsulfanylpentan-2-one (C6H12OS), nor probably to that of surströmming.

                                        2 But many molecules with unpleasant odors do not contain S. This is the case, for example, with trimethylamine (C3H9N), which has a strong fishy odor. 3 The relationship between molecular structure and odor is complex. Thus, molecules that are very similar from a structural point of view can evoke very different odors and, conversely, molecules with very different structures can induce the same odor perception. 4 In the 1950s, John Amoore suggested that all odors could be grouped into seven categories. This theory did not last very long and Amoore himself recognized its limitations. However, some have obviously not abandoned the idea. Castro et al. (2013), based on a complex analytical technique, suggested that all odors could be divided into ten categories.

14 It Smells Like Cheese

A team of Oxford scientists (De Araujo et al. 2005) conducted a judicious experiment on perception and demonstrated that it was sufficient to give different names to the same odor to impact the interpretation of what is conveyed by smell. They chose to work on the only famous British pressed cheese, cheddar cheese. They compared six experimental conditions: (1) with a pleasant odor (ά-ionone) for which the information given to participants was “floral odor”; (2) with an unpleasant odor (octanol) for which the information given was “burnt plastic”; (3) and (4) with an odorless air stream for which the given information was either “cheddar cheese” or “body odor”; (5) and (6) with a mixture of isovaleric acid1 and cheddar flavoring for which the given information was again either “cheddar cheese” or “body odor”. The results are shown in the graph plotted in Figure 14.1. The pleasant/unpleasant assessment was rated as follows (+2 very pleasant; +1 pleasant; 0 neutral; 1 unpleasant; 2 very unpleasant). Logically, the floral odor was considered pleasant and the odor of burnt plastic unpleasant. When an odorless airflow was proposed in association with the information “cheddar odor”, the judgment was neutral, while in association with “body odor”, it was unpleasant. Finally, when a cheesy odor was proposed with the                                         1 Isovaleric acid has a characteristic rancid butter odor. It has been demonstrated by microbiology researchers (Ara et al. 2006) that foot odor comes largely from isovaleric acid produced when Staphylococcus epidermidis, a bacterium from normal skin microflora, degrades leucine (an amino acid) present in sweat. Practical information: the researchers also identified fragrance agents such as citral or geraniol that can inhibit isovaleric acid production at low concentrations. Isovaleric acid is also known for its presence in cat urine, acting as a pheromone and used for territory marking.

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information “cheddar cheese”, it was considered slightly unpleasant, while in association with “body odor”, it was considered much more unpleasant. 1

Pleasantness ratings Pleasant 

0

-0.5

  Unpleasant

-1.5 Stimulus

alpha-ionone Octanol Test odor

Label Cheddar cheese

Clean air Body odor

Cheddar cheese

Body odor

Floral odor

Burnt plastic odor

Figure 14.1. Pleasure/displeasure assessment according to stimulus and label (information given) (adapted from De Araujo et al. 2005)

These results show that cognitive inputs, in this case, semantic labels, influenced subjects’ subjective reactions, including emotional reactions to olfactory stimuli and even when the stimulus was absent (in this case, the odorless specialties). We are therefore unconsciously deceived by the nature of the messages delivered and researchers have continued their investigations to describe the processes involved in this phenomenon through fMRI. It appears first of all – as has been published many times – that the activation of certain specific brain areas is correlated with the hedonic estimation of the odorant (floral and burned plastic odor conditions). More surprisingly, this correlation exists in the case of odorless airflow, i.e. without olfactory stimuli. In this case, it must be noted that it is the message that activates olfactory areas differently. Finally, cognitive regulation plays a key role in processing the appreciation of the stimulus when it is present since the activations are different for the same odor associated with a

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message likely to produce a pleasure anticipatory effect (cheddar cheese) or, on the contrary, a repulsion effect (body odor). To clarify, it should be added that the researchers took care to measure inspiratory flows and did not detect any variations between experimental conditions that could explain the differences in brain activation. This study confirms the empirical research work previously conducted by Herz and Von Clef in 2001. These researchers used five odors (a mixture of isovaleric acid – again! – and butyric acid, odors of menthol, patchouli, violet, and pine). Each odor was associated with two labels, one positive and one negative: – mixture → parmesan cheese/vomit; – menthol → minty breath/pharmacy odor; – patchouli → incense/musty odor; – violet → fresh cucumber/mold; – pine → Christmas tree/disinfectant. Study participants were asked to complete three evaluation grids (scales 0–9) on hedonic appreciation, familiarity and perceived intensity. In all the cases, odors were considered more unpleasant with the negative label, but this difference was much more pronounced in the case of mixing. Similarly, odors were generally considered more intense in association with a negative label. However, the level of familiarity was not affected by the label, except in the case of the mixture (considered less familiar with the negative label). For the sense of smell, this cognitive influence on perception is relevant in many areas and, in particular, in the case of food. The information given on a product is likely to modify its perception, appreciation and ultimately its consumption. Laurence Jacquot from the Neuroscience Lab of Besançon coordinated a study (2013) on Comté cheese (AOC, protected designation of origin, renowned for the variety and richness of its aromas, more than 66 listed). He used two common labels in the field of food advertising, the “good taste” label and the “good for health” label and asked several participants to evaluate the perceived intensity of the 10 most prominent flavors of Comté cheese such as walnuts, mushrooms and boiled milk. Compared to the results of a control group (which evaluated the intensity of flavors without any information given on the product), it appeared that the “good taste” label significantly increased the intensity of perceived flavors,

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while the “good for health” label significantly reduced it. Thus, labels activate mental representations of the type, if the product tastes good, has many aromas, or if it is good for your health. For example, the words “it is not too rich in...” insinuates that it is less tasty. Naturally, these cognitive influences can become stronger or create dilemmas: if the product tastes good and is also good for your health, you can easily afford to eat it (see Chapter 21), but if it tastes good and is considered too fatty, too sweet, or too salty, for example, you may need to adopt a restrictive attitude.

15 What Fennel Reveals to Us

Figure 15.1. Retronasal pathway modeling (Ni et al. 2015)1. For a color version of this figure, see www.iste.co.uk/brand/odors.zip

Let’s do a little sensory experiment: take a plump piece of fennel, remove the outer part, cut it into pieces and rinse. Fennel can be eaten raw or cooked, but in the proposed experiment, it will be raw. If you put it in your mouth normally, you will inevitably perceive its aniseed aromatic characteristics. If, however, you chew with your mouth closed and you pinch your nose at the same time, apart from its crunchy texture, it will then seem so bland that you will not be able to tell which food it is. Now that you have chewed it well and crushed it in your mouth, clear your nose, and you will instantly experience the characteristic aniseed sensation of fennel. This little culinary experiment enables us to understand the importance of flavors in the overall perception of food. Indeed, a very important part of sensory perception when                                         1 Available at: www.ncbi.nlm.nih.gov/pmc/articles/PMC4664350/figure/fig02/.

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consuming a certain food concerns the sense of smell. The tongue (mainly) perceives the so-called fundamental tastes (sweet, salty, sour, bitter, umami and fatty), but fennel activates few of the corresponding receptors (a little sweet and a little bitter but only very slightly noticeable). Pinched nostrils prevent air circulation and the rise of odorous molecules through the back of the throat (also called the palatal canal, which communicates with the oral and nasal cavities). As soon as the nostrils are opened, airflow rises in the nose, which is why the odorous molecules released in the mouth play a major role in the appreciation of food. Of course, you can do this experiment with other products (e.g. cardamom) as long as they have sufficient aromatic power. There are therefore two ways for volatile odorous molecules to access the olfactory receptors: through the nostrils in a direct pathway called the orthonasal pathway and through the back of the throat in an indirect pathway called the retronasal pathway. The fennel experiment helps to explain that when people lose their sense of smell, they frequently and logically experience a loss of taste. Also, since there are two distinct pathways in the olfactory system, many researchers have questioned the possible existence of differences between the two types of perception, orthonasal and retronasal. The main evidence is that, in the case of nostril perception, molecules are transported to the receptors upon inhalation, while in the case of oral cavity perception, molecules are transported by exhalation. Under these conditions, it is easily understandable that the airflows are different (moreover, in some people, one pathway may be functional while the other is not; this may be the case with nasal polyps, for example). Due to these flow differences, detection thresholds are generally better in orthonasal measurement than in retronasal measurement. Typically in the elderly, it has long been recognized (Voirol and Daguet 1986) that retronasal measurement performance is more affected by age-related sensory decline than orthonasal measurement. A recent study (Gagnon et al. 2015) indicates that in blind subjects, olfactory performance (particularly odor identification) is better than that of control subjects with normal vision in the orthonasal pathway, and that this is not the case with retronasal performance. Another study (Salihoglu et al. 2014), which focuses on the effects of sleep apnea on olfactory performance, concluded that there is a significant decrease in orthonasal pathways (sensitivity, discrimination and identification) without modification of

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retronasal outcomes in patients with OSA (obstructive sleep apnea) syndrome. Given the existence of two pathways for molecules to olfactory receptors, it is natural to question their relative importance in terms of diet. The work conducted by Bender et al. (2009) shows that, depending on the type of odors, the signals using the orthonasal and retronasal pathways are not similar. Thus, when a type of food’s odorant stimulation is repeated by the same pathway, the induced salivary response decreases regularly as the stimulation progresses. As soon as the food odor changes, the saliva response is again at its maximum, which is in line with what is generally observed in sensory physiology. Bender’s study shows that after the adaptation of the salivary response to a dietary odorant stimulation by one pathway, if one stimulates with the same odor by the other route, the salivary response is again at the maximum. Conversely, this phenomenon also works, which proves that the two pathways are in fact two different sub-modalities, notwithstanding the fact that this phenomenon only works with food odors. The importance of these two routes is also crucial in the determination of the organoleptic properties of wines. Botezatu and Pickering (2012) compared detection thresholds with the molecule called methoxydimethylpyrazine (MDMP)2 in two groups of subjects, one orthonasally and the other retronasally. This molecule is one that contributes to one of the most well-known flaws of wine, the famous “cork taste”. MDMP evokes moldy, corky, earthy type aromas. In an orthonasal pathway, the threshold is obtained at 31 ng/L and in a retronasal pathway at 70 ng/L, a very significant difference in favor of the direct pathway through the nostrils and a reminder of the need to smell the wine swirling in the glass before tasting. While all researchers interested in olfaction agree that the flows of the two pathways are different, no one has so far attempted to accurately describe how volatile molecules travel in the retronasal pathway3. However, a multidisciplinary team of researchers in engineering, materials science and neuroscience carried out remarkable modeling work (Figure 15.1). Ni et al. (2015) first scanned the entire naso-bucco-pharyngeal region of a subject by tomography and then, using a 3D printer, obtained an identical mold of this region. All that remained was to circulate airflows, record their trajectories,                                         2 To be exact: 2-methoxy-3,5-dimethylpyrazine. 3 In 1953, Proetz attempted to describe the flow differences by circulating air through these two routes with corpses.

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and quantitatively evaluate their efficiency. The results were surprising: they showed that, when inhaled, an anatomical cavity in an oropharyngeal position creates an air stream that prevents volatile molecules from leaving directly into the lungs, while, when exhaled, this cavity causes an air stream that causes the molecules to rise through the retronasal pathway. In addition, the results show that these two phenomena work optimally in the case of calm breathing. For those interested in what fennel reveals, the complexity of orthoretronasal olfaction raises the question of its implementation over time. In a journal of highly documented literature, Rowe and Shepherd (2016) explained the congruences between the stages of the structural development of the orthoretronasal olfactory system and cortical evolution in mammals, particularly in humans. They also remind us that aromas as such do not exist, but are the perceptual result of the integration of multiple sensory signals.

16 Mustard Goes Up My Nose and Onions Make Me Cry: Discovering a Third Unknown Chemical Sense

At 18 years old and penniless, I remember my first backpacking trip to Morocco. After an exhausting journey in a Renault 4L of more than 2,000 km, a crossing on a crowded ferry between Algeciras and Tangier and formalities that dragged on at customs, our group of friends was starving. The first restaurant seen on arrival at the port did the trick. First a little surprised that it was serving soup in the middle of the hot summer, we allowed ourselves to be tempted. Lured by the aroma and in a hurry to fill our stomachs, everyone went from shoving spoonfuls to suddenly stopping a few moments later, their mouths on fire. The soup was undoubtedly excellent, but above all, it was extremely spicy and nothing had prepared us for such oral aggression. Some had water, which did not reduce burning sensations, others had soft drinks, which increased taste discomfort, all under the amused gaze of native customers. We were thinking of giving up emptying our bowls when the boss, in a jovial tone, explained to us that before giving up, we must first wait a few minutes, without eating and drinking, and then quietly resume eating the soup, which will cease any burning sensation. With confidence in this wise advice, we applied the protocol and were surprised by the absence of a burning sensation as we finished our soup. A few days later, we began the ascent of Jebel Toubkal, the summit of the Atlas Mountains. We left for 2 days and 1 night, with the bare minimum. After a day of walking, exhausted but amazed by what surrounded us, we waited for our chef to finish cooking a huge pot of pasta – the only hiking

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dish – and to pour two cans of tomato sauce into it. Unfortunately, these boxes bought locally and labeled in Arabic turned out to be harissa... the real stuff. For a moment, tempted to rinse the sauce off with water, we gave up, because we had too little of this precious liquid left for our return. We then recalled our previous experience with Moroccan soup and decided to apply the same principle to pasta with harissa, with a surprisingly similar result! Taste and smell are not the only two chemical senses we possess, there are others that are less known, including the one we are concerned with here, called the trigeminal system. Present on the face, it is called trigeminal because three branches, ophthalmic, maxillary and mandibular innervate these three regions, respectively. The nasal cavities are mainly concerned by the ophthalmic branch, while the buccal region is concerned by both the maxillary and mandibular branches. It is a very rudimentary system from the point of view of reception because it is composed of free nerve fibers present in the skin and mucous membranes. Its role is mainly protective, protecting the upper respiratory tract and digestive tract. It informs the nervous system of the presence of pungent, irritating, and toxic substances and contributes to the perception of temperature. Onions make you cry when you peel them, because irritating volatile molecules reach the cornea, activating the trigeminal system and triggering a protective reflex by activating the tear glands. A mint candy causes a feeling of freshness in the throat, also due to the activation of this system. Some molecules are powerful activators of the trigeminal system, such as piperine or capsaicin, but most odorous molecules activate this system to varying degrees. NOTE.– In 1912, Wilbur Scoville designed an intensity scale relative to the effect of different peppers. This scale (Table 16.1), rated from 0 to 10, has the great benefit of qualifying each level (an exercise that is all the more difficult if you want to add nuance). For clarification, 1 g of the strongest chili pepper diluted in a 10,000-L pool is enough for it to be noticeable!

A major feature of this chemical sensoriality is the variability of response with respect to the temporal aspect of stimulation, particularly following initial receptor stimulation (Brand 2006). Indeed, for common irritants such as capsaicin (the molecule most commonly used in research in this field, mainly English-language research), we observe that a second application of the same concentration, separated from the first by a restricted time interval (less than 1 min), causes a stronger sensation, as if it were a summation of the stimuli. However, if the second stimulation occurs after a sufficient delay of at least 3 min, it does not cause any sensation. This is a desensitization

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phenomenon that is due to the inactivation of the related stimulated fibers. The Moroccan cook is a fine connoisseur of the role of the trigeminal system! Degree 0 1 2 3 4 5 6 7 8 9 10

Assessment Neutral Soft Warm Spicy Hot Strong Intense Burning Torrid Fiery Explosive

Scoville units 0–100 100–500 500–1,000 1,000–1,500 1,500–2,500 2,500–5,000 5,000–15,000 15,000–30,000 30,000–50,000 50,000–100,000 100,000 and over

Example Pepper Sweet paprika Anaheim pepper Ancho pepper Espelette pepper Chimayo pepper Strong paprika Cascabel pepper Cayenne pepper Tabasco pepper Habanero pepper

Table 16.1. Scoville scale

When the same molecule is used, it is called self-sensitization and selfdesensitization. When, following initial stimulation (e.g. with capsaicin), another molecule with similar observed effects to those described earlier is used, it is called cross-sensitization or desensitization. Recent work has shown that mustard oil (allyl isothiocyanate) activates many of the same receptors as capsaicin, so work on this molecule is needed. While mustard oil is not particularly popular with English-speaking researchers, it seems that French research finds it particularly interesting to study the molecule that gives one of their favorite condiments its character. In this context, observations made at the University of Besançon (Brand and Jacquot 2002) have shown that the sensitization and desensitization properties described for capsaicin are identical for mustard oil, particularly in terms of time. The method consists of recording variations in psychophysiological parameters (electrodermal activity) as well as the intensity perceived by participants in response to stimuli of the same concentration, separated by variable time differences. It has thus been shown that a second stimulation with mustard oil (of the same intensity) within 30 s caused a more intense sensation (sensitization) while a delay of 3–4 min causes an almost total absence of sensation (desensitization). Also at the University of Besançon

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(Jacquot et al. 2005), it has been shown that initial stimulation with acetic acid (vinegar) desensitizes the subsequent response to mustard oil. However, initial stimulation with mustard oil does not cause any change in the subsequent response to acetic acid. All that remains is to find out what happens with the salad dressing when the two ingredients are mixed.

17 Lavender at the Dentist: Aromatherapy, a Myth or a Reality?

It is inconceivable to write a book on odors, a book discussing the nose, and not mention lavender. The plethora of current publications on aromatherapy naturally leads to an interest in the most famous of essential oils (here we examine its effects via inhalation), in particular its renowned soothing, relaxing and anxiolytic effects (Koulivand et al. 2013) (nevermind the many others...) A classic anxiety-provoking situation is being in a waiting room before a dental appointment, even if advances in dental hygiene take us there less often (and for procedures that are generally less painful). In 2010, Metaxia Kritsidima, who works at King’s College London, published a study in which she compared the results of two questionnaires1 completed by 340 patients in a dental clinic waiting room: half of them were exposed to the scent of lavender and the other half were waiting under normal conditions. The average anxiety score obtained on the STAI-6 scale was reduced by one-third for the lavender-scented group compared to the control group (7.4 vs. 10.7). In addition, the effect was valid regardless of the nature of the appointment (i.e. its anxiety level): descaling, filling of cavities, tooth extraction, etc. The authors recall that if the relaxing effect is important for the patient, it is also important for the medical team, who can thus work under better conditions. These results confirm those of an earlier study conducted by Lehrner and colleagues in 2005 that found similar effects not only with lavender but also with the smell of orange.                                         1 These were the State Trait Anxiety Indicator (STAI-6) and the Modified Dental Anxiety Scale (MDAS).

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The question is whether the relaxing effect produced by inhaling lavender has a physiological substrate or not. To test this hypothesis, Toda and Morimoto (2008) of Osaka University measured the level of cortisol and chromogranin A (CgA), two stress markers in saliva. Thirty students between the ages of 21 and 26 years were required to perform an arithmetic task about 10 min long. 16 of them worked in a lavender-scented environment and 14 in an odorless one. Saliva samples were taken just before the test (t0), at the end of the 10 min (t10) exercise and 10 min after the end of the exercise (t20). For chromogranin A2 (Figure 17.1), the rate increased quite logically at t10 compared with t0 similarly for both groups. However, at t20, while the control group remained at the same rate, the group that worked in the ambient smell of lavender saw its rate decrease significantly, to be practically at the rate raised at t0. From a neurochemical point of view, lavender acts on many levels. For example, it occurred at the post-synaptic level with modulation of cAMP activity3, knowing that a reduction in cAMP activity may be associated with sedation. Similarly, linalool, one of the main compounds in lavender, is known to inhibit glutamate binding sites, which also leads to sedative effects. Lavender also has an objective effect on pain (see Chapter 40) and sleep (see Chapter 12). In their study, Lillehei et al. (2016) formed two groups of students who slept five consecutive nights with a patch. For one group, it was a lavender patch and for the other, a placebo. At the end of the experiment, participants completed a quality of life questionnaire. The results were better (energy, dynamism and quality of sleep) for students whose sleep had been surrounded by the lavender scent, thus confirming, by a self-assessed measure, the work of Goel et al. (2005) demonstrating the positive effects of lavender on sleep. However, the results concerning the effects of lavender on memory were less clear. In humans, there does not appear to be any measurable impact, whereas, in laboratory rats, it has been shown that spatial memory can be improved by inhaling lavender (Hritcu et al. 2012). The effects of lavender on performance are generally less convincing than the effects on mood or anxiety. The most tangible result seems to be that                                         2 This change is not observed with cortisol, but cortisol measurement is considered less reliable than CgA after a stressful situation. 3 Cyclic adenosine monophosphate (cAMP) is a member of the so-called second messenger family. This means that it acts as an intermediary in the action of neurotransmitters or hormones.

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lavender slows down the decline in performance that is typically observed during weariness (Sakamoto et al. 2005). It is interesting to note that the effects of inhaling lavender are often more significant than those obtained by oral ingestion, even though bioavailability is much higher by an oral route. Therefore, there is no need to drink lavender syrup or to inject it intravenously to calm yourself down! And for stressed readers, it must be noted that the scientific literature is almost as prolific with chamomile4. However, for readers looking for stimulating inhalations, it seems that peppermint shares the spotlight with lemon scents.

Level of salivary CgA (pmol/ml) 

Arithmetic task 

Time (min)  Figure 17.1. Salivary CgA levels (pmol/mL) measured during an arithmetic task in two groups of participants (adapted from Toda and Morimoto 2008). The continuous line represents a group affected by a lavender scent and the dotted line, a control group without an associated odor

                                        4 Curiously, there are very few studies on incense, even though the fumigations of this resin have been used for thousands of years by most religions. However, it seems (Lijima et al. 2009) that incense modifies brain activity and induces inhibition of motor responses.

18 Catnip and Pregnant Women: Some Variations in Sensitivity to Odors

Cats love certain odors that produce an exciting or even euphoric effect on them, especially catnip (Nepeta cataria). Biologists and veterinarians were very interested in the catnip response associated with the odor of this plant in the 1960s and 1970s (Figure 18.1). In particular, they were very intrigued by the conditions under which this behavioral response appeared in cats: (1) the plant is very attractive to some animals while others seem totally indifferent to it; (2) in cats attracted by the odor, the response manifests itself for a few minutes (5–15 min) then disappears for an hour or more before it can be initiated again; (3) in some cases, the odor is repellent. The emanations of catnip are naturally stable and it must be admitted that changes in perception and hedonic reaction depend on factors intrinsic to the animal, in particular, genetic and physiological factors. Sensory systems transmit information to the brain, but all receptors are influenced by feedback to adapt their functional properties in order to regulate inputs, especially in terms of intensity. This is the case, for example, in adaptation to light and darkness in the visual system and adaptation to excessively loud sounds in the auditory system. The olfactory system is no exception, and sensitivity to odors varies according to certain physiological conditions in cats, such as in the human species (see Chapters 21–23). Most studies in this area probably concern women’s sensitivity to odors according to their hormonal status: during pregnancy1, according to the time of the menstrual cycle or according to the type of contraception they use. However,                                         1 Dedicated solely to changes in olfaction during pregnancy, Cameron’s (2014) literature review includes no less than 69 references.

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the variations in olfactory sensitivity in women – when they exist – are less spectacular than in cats! For many years, the increase in olfactory sensitivity during pregnancy – especially during the first trimester – was considered a certainty. The functional justification for this hyperosmia in pregnant women was based on the protective role played by the sense of smell with respect to potentially teratogenic substances, particularly in the first 3 months of pregnancy when the fetus is most vulnerable. However, this scientific “truth” was initially based on studies using self-assessed measures of olfactory sensitivity. Until recently, Cameron (2007) recalled that approximately two-thirds of pregnant women in early pregnancy considered their olfactory acuity to be better than normal and believed that this increased perception of odors was – at least in part – responsible for the commonly reported effects such as nausea and vomiting. However, studies based on standardized measures of detection limits do not support this fact (Cameron 2014). To explain this, a Turkish team from Kirikkale University (Simsek et al. 2015) suggested that, in reality, it would be a distortion of olfactory perception rather than a change in sensitivity. The researchers used the Brief Smell Identification Test (BSIT; Doty et al. 1996) among approximately 120 women in four groups: first, second, and third trimesters of pregnancy and a control group (non-pregnant women). The results showed that the odor identification score was altered only for the “first trimester” group compared to all other groups, and that this alteration was more specific to certain odors (leather, pine, soot, etc.). Let us be reassured, the strawberry smell that was part of the 12 items was successfully identified! Knowing all the same that among the choices offered were garlic and chocolate... Let’s agree that a pregnant woman’s sense of smell would really have to be very altered to confuse strawberry with garlic or chocolate! With regard to the modulation of olfactory sensitivity according to the phase of the menstrual cycle in women, not all research work is convergent. Nevertheless, a trend seems to be emerging toward an increase in sensitivity around the ovulation period, unlike the menstruation period where the results differ (an increase, decrease, or no change in sensitivity, as the case may be). The Navarrete-Palacios team (2003) working on this question showed a correlation between the cytological characteristics of nasal and vaginal cells according to the cycle phase.

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This observation could have been extremely relevant in understanding sensitivity changes according to hormonal status, but the results are unfortunately questionable from a methodological point of view. Some work has also focused on the hedonic appreciation of certain odors during the menstrual cycle. It appears that androstenone, one of the components of male odor (see Chapter 32), is perceived as more pleasant by women during the ovulation period, which is not the case for other smells such as nicotine or roses. In the United States, 82% of women aged 15–44 have used oral contraceptives at some point in their lives (Mosher and Jones 2010). In the wake of the previous observations, it is legitimate to question the impact of this contraceptive method on a person’s sense of smell. In their study, Renfro and Hoffman (2013) compared detection thresholds (with androstenone, androsterone and musk) in two groups of women: one with a natural cycle and the other on oral contraceptives. It appeared that during the ovulation period, women with a natural cycle were more sensitive to these three odorous compounds than those on oral contraceptives. A previous study suggested that this decrease in sensitivity associated with oral contraceptive use may be specific to social odors (Lundström et al. 2006) and may be accompanied by an increase in sensitivity to environmental odors. Research on postmenopausal women is rare. Among them, it is worth mentioning the study by Savovic et al. (2002) which compared women of the same age, menopausal or not, and indicated that menopausal women have a significant decrease in olfactory capacities compared to women who are still fertile. The observers of cats had very early noticed that a cat’s behavior related to the inhalation of the catnip odor was surprisingly similar to that observed in cats during the estrus cycle. It was even considered for a time that the odor of catnip could act as a pheromone, but subsequent studies did not confirm this hypothesis. This should not deter gentlemen from offering their favorite lady a déjeuner sur l’herbe (a plant-based lunch)...

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A

B

C

D

Figure 18.1. Typical behavioral reactions of cats in the presence of the odor of catnip: (A) placing item in in their mouth and chewing a ball of catnip, characteristic of palatability behavior; (B) rubbing and rolling into a ball, characteristic of the receptive female’s sexual behavior; (C) hitting the ball of catnip, characteristic of play and predation behavior; (D) carrying and hitting the ball with hind legs, characteristic of play and predation behavior

19 If You Eat Too Much Fat, You Will Lose Your Sense of Smell

A high-fat diet has many health consequences and the associated pathologies are well-known. Mentioned less often are the impacts on the functioning of the central nervous system, such as reduced neural plasticity or cognitive deficits. There is also much to explore on the repercussions on sensory systems and, in particular, the olfactory system (Aimé 2010). This question has been addressed from a perceptual point of view (see Chapter 22), but what about from a physiological point of view? This is what researchers at the University of Florida attempted to highlight in a study edited by Nicolas Thiebaud et al. (2014) in the Journal of Neuroscience. They worked with several mouse strains, mice normally prone to obesity (C57BL/6), mice resistant to obesity (whose Kv1.3 gene has been invalidated)1, and mice predisposed to obesity (whose MC4R gene had been invalidated)2. The first two strains were subdivided into three subgroups in relation to diet, normal food (13.5% fat), a moderate-fat diet (32%), and a high-fat diet (60%). The third strain was fed with normal food. The diets lasted for a period of 6 months. The results showed that the mice on a fat diet were slower to learn the association between an odor and a reward than                                         1 In 2004, it was shown in mice that the inactivation of the Kv1.3 gene, which plays a role in nerve cell communication – particularly in areas related to smell – leads to a significant improvement in olfactory abilities (these mice are “super-smellers”). At the same time, they stay slim even with a diet increased by 30% fat and are therefore considered resistant to obesity. 2 Conversely, the mice whose MC4R gene (melanocortin receptor 4, present in particular in the hypothalamus) has been invalidated, become hyperphagic and rapidly obese.

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control mice on a regular diet. They were also slower to adopt this association when researchers changed the type of odor. Surprisingly, this reduction in olfactory capacity was maintained even after a return to a normal diet (and therefore a return to a normal weight and consistent blood results). Even more surprisingly, these changes in olfactory performance were not correlated with weight gain and fat level. Indeed, MC4R mice that gained weight with a normal diet did not have significant changes in smell while Kv1.3 mice that did not gain weight following a moderately increased diet (32%) had the same olfactory loss as normal mice (C57BL/6) with this same diet (32%). In this study, olfactory loss can be explained by different neurophysiological mechanisms. In the olfactory bulb, the frequency of neuronal discharge in mitral cells is reduced and, in the olfactory epithelium, the measurement of the amplitudes of nerve responses (by electroolfactogram) in neuroreceptors shows a significant reduction. In addition, cell proliferation, so specific to the olfactory system, is also strongly affected, as is the normal apoptotic cycle. In total, researchers are measuring a very significant loss of functionality in the order of 50%. So far, there is no evidence that the same mechanisms are involved in humans. However, a study by Guthoff et al. (2009) revealed the role played by the polymorphism of the Kv1.3 gene on olfactory performance (assessed with Sniffin Sticks3) which allows measurements of odor identification or an odor detection threshold. Nevertheless, the results are questionable, particularly because the comparison of independent groups, although agematched, remains difficult in this type of test. What is less debatable, however, is the role played by insulin in olfactory functions. Indeed, the insulin receptor is widely expressed in the olfactory bulb. The application of insulin to a primary culture of olfactory bulb neurons causes a decrease in the amplitude of the current on the voltage-gated potassium channel Kv1.3. In transgenic mice with a Kv1.3 channel deletion, insulin no longer has an effect on the Kv1.3 current. From a behavioral point of view, these mice showed great performance on different olfactory tasks (were faster at finding food hidden in the litter, took more time to explore new odors and could detect odors at lower concentrations than control mice). Thus, when insulin cannot play its role in the Kv1.3 channel of olfactory bulbs, the sense of smell improves significantly. Tests have also been carried out in mice with                                         3 With Sniffin Sticks, an identification score is established from 16 common fragrances. For each, the subjects had the choice between four proposals. Maximum score: 16.

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intranasal insulin administrations (olfactory neuroreceptors in the nasal cavity also have insulin receptors), but the results are not very convincing. Indeed, while some performances improve (e.g. distinction), others do not show any change (sensitivity, in particular). Moreover, the increased “curiosity” for novelty is not limited to odors but applies to any unknown object. Therefore the use of insulin sniffing kits to improve our olfactory performance is not ready yet... It should also be recalled that lipid receptors (CD36, GPR120) have been identified in the taste buds (present for the most part on the tongue) and that the “fat taste” constitutes a sixth gustatory quality (after sweet, salty, bitter, acid and umami). Numerous studies on animals and humans have shown that there is a spontaneous preference for lipids. Obese people often have an increased preference for fatty foods, which seems to be the result of a poor taste perception of dietary fat. People with low lipid perception would be those who consume the most lipids (and have the highest BMI; Stewart et al. 2010). This may be a looming vicious cycle (still not the only one!), a failure in the perception of fat by the tongue that leads to the over-consumption of fat. This over-consumption of fat, in turn, leads to a decrease in smell, which generally leads to over-consumption... We are not sure whether the instruction “eat five fruits and vegetables a day” is sufficient!

20 Experts’ Noses

In a number of areas (wines, cheeses, etc.), labels (AOP, AOC1, etc.) are awarded to products according to strict criteria, and the quality of these products is generally judged by a panel of experts. As in the case of perfumery, the experts’ noses are the reference instrument, an instrument whose reliability must be assessed. In the case of wines, for example, many studies have compared the perceptions of experts and novices. Performance needs to be examined differently depending on whether it is sensitivity or identification, differentiation and recognition capabilities. Contrary to popular belief, the sensitivity of experts is no better than that of novices (Parr et al. 2002; Royet et al. 2013), and sometimes it is even worse. However, the main issue with sensitivity measurement in experts is that it is frequently determined from odors usually used in olfaction – such as n-butanol, for example – even though sensitivity to butanol does not reflect general sensitivity. Thus, an expert may have a correct detection threshold for butanol (and obtain their expert title) while at the same time, they may be hyposmic (or frankly anosmic) to other molecules present in wines. Indeed, there is a very large inter-individual variability of detection (not to mention the average age of the groups of experts, often quite high) and it is not uncommon to notice that some experts detect very poorly certain molecules of wines such as geosmin for example, responsible for one of the defects of wine having a “mouldy earthy” character... to say the least, troublesome. Equally problematic is the fact that many molecules exhale odors that differ qualitatively according to concentration. At low                                         1 The AOP (Appellation d’origine protégée – Protected designation of origin) and the AOC (Appellation d’origine contrôlée – Controlled designation of origin) are French labels granting a status to particular food products.

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concentrations, 4MMP (4-mercapto-4-methylpentan-2-one), specific to some white wines, such as Sauvignon, evokes a pleasant note of flowers and citrus fruits, while at high concentrations, it is similar to the unpleasant odor of cat urine. Thus, for a given concentration, if two people have a different sensitivity to 4MMP, one will find it delicate while the other will find it repulsive! Alcohol is easily diluted in water, and a comparative study (Brand and Brisson 2012) between experts and novices measured the detection thresholds of three wines (Savagnin, Morgon, and Riesling) according to the type of nostril used. The results showed that whatever the wine, novices got better results with the left nostril than experts. This is probably related to the fact that experts usually work in a birhinal way (with their noses in the glass) while novices – as in any sniffing act – prefer one of two nostrils. This observation questions the effects of training on perception. It is possible to hypothesize that experts who regularly work with their noses have better skills than untrained novices. While this clearly does not apply to the sensitivity of experts2, it seems to be accepted that experts have better identification, differentiation and recognition skills (Marino-Sanchez et al. 2010). Training and learning develop cognitive skills that go well beyond the ability to name perceived flavors, detect them in mixtures, or determine typicity since other parameters such as intensity estimation are also better judged. However, it is mainly in the vocabulary used that the differences are significant. The experts have a broader, more specific vocabulary (red fruit note, vanilla, toasted bread, etc.) that can even be metaphorical3, but, above all, their vocabulary will be more related to odorous sources than that of novices, who prefer qualitative descriptive terms (pleasant, harsh, delicate, etc.). From a semantic point of view, acting like a nose is not innate. Moreover, a study by two Dutch researchers (Croijmans and Majid 2016) revealed that the skills of experts in a particular field cannot be transferred to another field. They compared wine and coffee experts in descriptive tasks of scents and flavors (1) related to wines, (2) related to coffee, and (3) others. Although wine experts presented better descriptive performances in their field, they were                                         2 This observation is in contradiction with studies that show that olfactory training can in some cases improve detection. 3 Tasting note, about a Château Meyney: “Beautiful bottle, excellent state of preservation, very classic nose of spices and musk, lots of character, elegant body, distinguished tannin, no dilution, wine of civilization and a spirit of sensuality and voluptuousness”.

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no different from novices in the descriptive performances of coffees, nor from those of coffee experts... who would therefore only be an expert by name. The three groups had similar performances for the so-called “everyday” (other) smells and flavors. The myth of the big nose (or tasting gurus, as some call them) was somewhat shaken by the revelations of these studies. As a result, the average consumer should not be ashamed of their tasting skills or the subjectivity of their assessments.

21 Filled with Smells

At Greuze’s1, there was an odor. It took you in with your taste buds, like a zephyr from Olympus. The reduction of white wine and shallots, hot butter, meringue in gestation, profiteroles in pursuit of hot chocolate. Cooking is all about the smell. No smell, no cooking. We surround ourselves with olfactory agents, we enjoy what hits the nostril. Gourmet is like having a little friend in our nostril: he takes over the nose, the nasal passage, the schnozz, the hooter, the snoot. He’s a Cyrano of pleasure... (Cérésa 2010) Yes, but not just that...! The regulation of food intake is mainly ensured by the hypothalamus, a key structure of the central nervous system which also participates in the management of many other functions such as reproduction, thermoregulation, stress, and so on. From the early stages of food intake, the hypothalamus receives information from the digestive system that will gradually lead to satiation, and then follows a more or less long period of satiety before the feeling of hunger reappears. However, everyone experiences this daily. During the pre-ingestive and ingestive phases, food intake is also modulated by sensory factors (Rolls 2005): sight, taste, texture, and smells2. Normally, it increases if the food is palatable (which provides a pleasant sensation when consumed) and decreases logically if the sensation is unpleasant. With regard to the element to be ingested, the perceived                                         1 Gourmet restaurant in Tournus, France. 2 To a lesser extent, it is possible to add hearing, such as in the case of the specific sound of the food being browned in the pan.

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sensations and previous experiences are generally compared, relating to its organoleptic qualities, its nutritional properties, and its energy value. In some cases, following a conditioning phenomenon, an aversion may occur if during a previous experience the sensory signals related to a particular food have been coupled with a negative context (common in children). Sensory information and mainly food smells (before food being placed in the mouth) and during chewing (aromas developed in the mouth stimulate olfactory receptors through the retro-nasal pathway – see Chapter 15) directly and immediately stimulate the hypothalamus and another key brain region, the orbitofrontal cortex (Rolls 2006). The pleasant and therefore attractive nature of food smells will then gradually decrease, from the moment a food is sniffed and eaten for a certain period of time until a phenomenon called sensory-specific satiety (SSS) appears. Specific to food, it’s why you’ll probably order a dessert even if you’re full after the main course (and especially if the scent of the dessert reaches your nostrils). This phenomenon logically induces the approach of other foods and favors food variety, a guarantee of good health for an omnivorous species like us. However, a variety of food must be available. SSS is a phenomenon that does not work when you have no choice but to eat cassava three times a day! On the other hand, in our societies where overabundance and extreme diversity prevail, SSS could play a harmful role and ultimately contribute to an increase in obesity. This issue is crucial for young children for whom diversification of diet is very important and for whom SSS would be particularly active. On the one hand, it is not clear that forcing a child to finish the spinach on their plate is relevant. On the other hand, be careful with the choices offered if they only concern sweet products, for example. From a functional point of view, SSS is all the more effective when the congruence between the smell and the food is strong (Stafford 2016). For example, it will be optimal in the case of “banana smell and banana consumption”, less effective in the case of “apple smell and banana consumption”, and ineffective in the case of “pizza smell and banana consumption”. However, the relationships between smells and food intake are complex (see Chapter 23) since it was shown in the previous chapter that smells sharpen our appetite and can “short-circuit” our free will (see Chapter 24). It may all come down to time, as Dutch researchers suggest (Ramaekers et al. 2014b). A food smell could initially stimulate appetite over an estimated period of 1–3 min and then induce SSS over an estimated period of 5–20 min. The authors also link these two phenomena to the two molecular pathways: direct pathway (orthonasal) in the first stage and

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indirect pathway (retro-nasal) in the second stage. For Greuze, it is not only the pleasure aroused by the smells (in a direct way) in all their variety (damn extractor hoods that deprive us of them!), but it is also the anticipation of the pleasure to come from tasting and aromas (in an indirect way). The richness and finesse of the aromas give pleasure but they also contribute to slowing down the rate of ingestion (the measured times taken to eat the same quantity in Greuze’s work and in a fast-food restaurant are incomparable!), allowing the digestive system to stimulate the physiological satisfaction of the hypothalamus within a reasonable period of time. QED, “eating less” means “eating well”... and smells play a key role.

22 Obesity and Chocolate

Excess weight and obesity have become public health problems in recent decades. Trivially, obesity can be defined as the result of energy consumption exceeding the energy expended. The consequences are multiple and not only concern congruent diseases such as cardiovascular diseases and diabetes but can also concern psychological or social aspects. On another level, the consequences are not simply trivial for public finances. For example, in 2007, in the United Kingdom, a study on the management of obesity-related conditions estimated the cost at £4.2 billion, or €5.46 billion. These obesity problems occur predominantly in some developed countries, and many studies have focused on identifying the factors involved, integrating lifestyles, genetic and metabolic specificities, and of course the nature of diet. Knowing the role played by the sense of smell in food intake, it seems relevant to question the specificities existing between this sensory modality and obesity. A study by Richardson et al. (2004) indicated that olfactory dysfunctions were more significant in an obese population (BMI > 45) compared to moderately obese people (BMI < 45). This suggested that a weakened sense of smell could lead to overeating. However, the hypothesis that an obese person is more sensitive to food smells and therefore more attracted to food also arose. An observation using fMRI (Bragulat et al. 2010), which has since been confirmed (Sun et al. 2016), shows that cortical activations – with the same odorous stimuli – are different between obese and non-obese subjects. The authors compared the results obtained in five subjects of a normal weight (mean BMI = 22) and five obese subjects (mean BMI = 41.6). They were exposed to four diet-related odors (two sweet and two fatty) and four non-diet-related odors after a 24-h fast. First, it appeared,

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independently of the group of subjects, that the activations were different according to the type of odorant, and – a particularly interesting observation – the areas of the brain activated by food odors were partly similar to those activated by potentially addictive substances. Second, it appeared that differences between obese and non-obese subjects existed for food odors, particularly for certain brain areas involved in the processes of regulating food intake. No one had ever had the idea to test the reactivity of obese people to the smell of a specific food. This is what Stafford and Whittle (2015) from the University of Portsmouth in the United Kingdom did by using chocolate, for which 15% of men and 30% of women admit to having compulsive desires. Naturally, chocolate falls into the category of “fat/sweet” foods. Forty people participated in the experiment, 20 obese (11 male and 9 female – average BMI = 31.3) and 20 non-obese (5 males and 15 females – average BMI = 20.3). The liquid flavor of dark chocolate was used for successive dilutions (dilution factor ½), 15 in total. The results were clear: obese people had a lower detection threshold, so they were more sensitive to the smell of chocolate than non-obese people (four dilutions of difference on average!). Incidentally, obese people considered the smell of chocolate to be much more pleasant than non-obese people. In addition, a correlation analysis clearly showed that the more their weight increased, the more sensitive the subjects were and the more they appreciated the smell of chocolate. A truly vicious cycle! This is the first “ecological” study on the subject and deserves to be replicated with other products with strong odorant properties and high sugar and/or fat content (e.g. cheese). Obesity can be considered as a consequence of a form of addiction (as shown by fMRI studies of the brain areas involved) and drug sensitization mechanisms are well-known (gradually increasing the quantities or frequency of doses for the same result). As early as 2006, Getchell et al. in a behavioral study showed that obese mice were faster in a test to find food than non-obese mice, whereas under normal circumstances, they were less fast. From a functional point of view, the question of causality reminds us of the classic chicken or the egg dilemma – which came first: obesity or chocolate? Concerning chocolate specifically, odor is not the only factor involved; studies on the addictive potential of sugar, for example, are multiplying and other substances can play this role. Chocolate is a complex product in which hundreds of substances have been identified, some of which could cause addictive effects, but whose concentration seems too low for a real impact. In 1996, a neurotransmitter naturally produced by the

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brain, anandamide, was isolated from chocolate. The anandamide neuronal receptors are the same as those to which THC (the active ingredient in cannabis) is bound. Researchers estimated that about 30 kg of chocolate would have to be eaten to have the same effect as smoking a joint!

23 The Nose on the Plate: A Difficult Scientific Consensus

All sensory systems play a role in food intake, and smell plays a major role. It contributes to the identification and recognition of food or food products, to their appreciation (pleasant/unpleasant), to the associated pleasure/displeasure and desire to eat, and therefore to the evaluation of their qualities (freshness, healthy character, caloric level, etc.). The sense of smell is also involved in overall perception – in particular, by aromas developed in the mouth that activate olfactory receptors through the retro-nasal pathway (see Chapter 15) – and in other functions such as sensory-specific satiety (see Chapter 21). However, one of the most enigmatic properties of the sense of smell is undoubtedly the variation of its sensitivity according to our state of hunger or satiety (see Chapter 18). This question of the variation of olfactory capacities according to state of hunger is still relevant, despite the considerable number of studies published since Glaze’s first observation in 1928. John Arthur Glaze reported an increase in sensitivity to different odors during a period of fasting for a few days. This observation does not meet current standards for experimental protocol because it covered only two subjects, including Glaze himself. However, it can be confirmed with another experiment during which olfactory sensitivity was tested before and after a meal. This problem has become even more acute in the context of food/health research since the demonstration was made (Richardson et al. 2004; Sun et al. 2016) that adult obesity is associated with changes in olfactory sensitivity (see Chapter 22). Since the vast majority of what we perceive from food depends on odorous sensations (more than on flavors themselves), it is not uncommon to think

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that a change in smell can interfere with the mechanisms regulating food intake. Intuitively, one might think that odor detection could be improved in periods of intense hunger, and less so in periods of satiety, but the results of studies on this subject are contradictory. As Ramaekers et al. (2016) point out, while many studies show an increase in odor sensitivity during a hunger state, many do not show such a change in sensitivity and, perhaps more surprisingly, some studies conclude that sensitivity increases with satiety. The next logical question is to question the hypothesis that the sensitivity changes could be related to odors tested. In this perspective, most protocols compare olfactory performance before and after a meal. This was the case study by Albrecht et al. (2009), which measured the detection threshold of a food smell, isoamyl acetate (banana odor) and a non-food odor in 24 participants. The authors found no difference in the pre- and post-meal threshold for butanol and a decrease in the threshold (corresponding to greater sensitivity) for isoamyl acetate after meals, i.e. in a state of satiety. Two years later, Stafford and Welbeck (2011), with an almost identical protocol, came to diametrically opposed conclusions: they found a threshold difference for butanol before and after meals, the detection threshold being higher (corresponding to a lower sensitivity) in a state of satiety. As a result, another question that reasonably emerged was whether the kind of meal (light vs. copious, for example) could have influenced olfactory sensitivity. This is what Ramaekers et al. (2016) undertook to test the case where odors used for the detection thresholds were congruent with the meal (in the case of congruence, for example, vanilla odor with a sweet meal) and highlighted a better sensitivity to odors during hunger, regardless of the type of meal1. Finally, the question of the characteristics of the subjects included in the studies naturally arose. In addition to the classic inter-individual differences in olfactory sensitivity, the body mass index (BMI) – as discussed elsewhere in this book – plays an important role in odor sensitivity. Sun’s team (2016) demonstrated that overweight participants perceive odors as more intense in a state of hunger, unlike subjects of a “normal weight”. According to the authors, these                                         1 In Drosophila (Beshel and Zhong 2013), it has been shown that certain nerve cells are specifically activated in response to food odors, an activation modulated by the state of hunger. In mice (Soria-Gómez et al. 2014), it appears that the relationships between hunger, odor perception and food intake involve a specific type of receptor, cannabinoid type 1 (CB1) receptors.

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differences could be explained by different metabolic regulation, specifically for ghrelin. The fMRI results collected by Sun et al. support the idea that some brain structures are unequally activated according to BMI in response to odors. In recent years, another inter-subject comparison has often been carried out, distinguishing between the so-called restricted participants (who pay attention to what they eat) and the so-called unrestricted participants (several validated assessment scales exist). The magic and beauty of science – the less consensus there is, the more studies there are! Obviously, smell is not the only sensory modality involved in food intake. Hanci and Altun (2016) jointly compared the olfactory and gustatory sensitivities of 123 participants before and after meals. With their method, they found a decrease in olfactory capacities as well as a lower sensitivity to sweet, sour and salty flavors in a state of satiety compared to a state of hunger. However, in a state of satiety, sensitivity to bitterness was better than in a state of hunger. And to complicate matters further, the relationship between hunger and odor perception is not one-sided. Thus, smells can increase hunger and increase appetite, especially if they are pleasant food smells (Ramaekers et al. 2014a; Yeomans 2006), a phenomenon easily measured by the induced stimulation of saliva. However, hedonicity, like sensitivity, is not a stable assessment: after consuming a banana, for example, the estimation of hedonicity with respect to bananas as much as with respect to banana odor decreases, while the estimation of hedonicity with respect to other odors is not modified. This phenomenon, which also works with the consumption of chicken and the odor of gallinacean (Rolls and Rolls 1997), or any other similar combination, contributes to a subtle satiating mechanism (see Chapter 21).

 

24 The Smell of a Hot Croissant: When Our Sense of Smell Nibbles Away at Our Free Will

It’s 11 o’clock in the morning and we have hunger pangs as we pass by a bakery. Aromas of hot croissants... what a dilemma, indeed! On the one hand, an almost irresistible attraction, on the other hand, the reason that reminds us that mealtime is near and that we should abstain. According to the established formula, smells lead us by the nose, consciously and unconsciously. Psychologists call this process “priming”. The priming effect is defined as the influence of the presentation of an event (the priming) on the processing of a consecutive event (the target). This influence generally results in easier processing when there is a link between the primer and the target. This facilitation can be measured by comparing, for example, the processing time and/or accuracy of the responses made to the target according to the nature of their relationship with the primer; it can also be measured by the decision made in a choice situation. This paradigm has been used in different fields, but curiously enough rarely in the field of food and with little olfactory priming. Holland and Aarts (2005) were the first to use olfactory priming. This study, which is widely cited in the scientific literature, showed that a lemony odor of detergent activated the concepts of household and cleanliness among participants. First, participants had to perform a lexical decision task where a series of letters that appeared on a screen was a real word or a non-existent word. They had to answer as quickly as possible “yes” or “no” to the question “is this a real word?”. The series consisted of 20 non-words and 20 real words. Of these, six were clearly related to cleanliness and the

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household (cleaning, tidying, etc.), and the others served as controls. The results indicated that in an atmosphere with a lemon detergent odor, the response time to words related to cleanliness and the household was significantly faster, while participants reported not being aware of the purpose of the experiment. In a second step, the experimental conditions were the same and participants had to write five activities they planned to carry out before the end of the day. In the fragrant atmosphere of lemon detergent, 36% of participants included an activity related to the household or cleanliness compared to only 11% of the control group1. Third, participants at a table were invited to enjoy biscuits that crumbled easily while completing a questionnaire. They were filmed without their knowledge, and with the air filled with a lemon detergent odor, significantly more of them cleaned the crumbs before leaving their seat than the control group. This was a behavioral assessment of the priming effect, considered by psychologists to be the most conclusive. Concerning eating habits, several studies have studied the impact of priming, including in restaurants. Jacob et al. (2010) compared two decorative configurations in a restaurant based on the choice of the main course. They observed that with a decoration linked to the sea (visual priming), customers preferentially choose fish dishes. In the same vein, Gaillet et al. (2013, 2014) and Chambaron et al. (2015), from the Centre des sciences du goût et de l’alimentation (CSGA)2 in Dijon, showed that a fruity pear smell impacted the intentions of dessert choice and guided participants preferentially toward the so-called low energy density (LED) desserts (compote rather than waffles, for example), compared to unprimed participants. Conversely, when the olfactory primer was a pain au chocolat smell, the participants mainly chose desserts called high energy density (HED; e.g. waffles), or when the primer was a pizza smell, they mainly chose a main dish with HED (hamburger/fries rather than fried salmon/steamed vegetables, for example). The value of this work in the potential prevention of excess weight and obesity can be easily understood, especially when it is known that advertising campaigns on preventing obesity and food hygiene are very limited in terms of scope. Applied research could be carried out among children to encourage them (in the context of school canteens, for example)                                         1 Both sexes participated in the experiments, but the authors did not include gender results in their publication. Would this information be excessive or would it reveal anything? 2 Center for Taste and Food Science.

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to prefer the so-called LED dishes. Similarly, olfactory priming could be used in the case of eating disorders (obesity or anorexia) to direct patients to one or the other category of dishes. Naturally, we must admit that with these smells that influence our eating habits, our free will takes a serious blow, as it is so difficult to resist the scents of temptation. However, we must resolve ourselves to this, by reading this book: we understand that it is not only our food choices that are influenced by smells but most of our fundamental behaviors, such as a pre-eminence of the nose over reason... or in other words “the nose has its motives that motive does not know!” (Schaal et al. 2013).

 

 

25 The Dog That Sniffs Out Cancer

Beyond hunting game or truffles, dogs’ well-known flair is used in many fields: the detection of drugs or explosives; searching for people buried under an avalanche, following an earthquake; or in the pursuit of runaways. These detection and differentiation performances have recently been extended to the medical field. Indeed, researchers have shown that properly trained dogs are able to detect cancers. As is often the case, it all started with anecdotal information published in the prestigious magazine The Lancet. It concerned a woman whose dog – a Dalmatian in this case – was constantly sniffing a mark on her leg. Later, doctors discovered that it was a malignant melanoma, a very aggressive type of cancer. Based on this finding, Michael McCulloch et al. (2006) in California conducted and published a prospective study with five dogs, trained to identify breath samples from people diagnosed with lung or breast cancer. It was a classic training exercise with rewards during the successful tests. In a second step, healthy people and cancer patients had to blow strongly and several times into a tube containing a tissue that could retain the volatile organic compounds (VOCs) contained in their breath. For the tests, the dogs were each presented with five samples, only one of which was from a cancerous donor and which they had to mark (sit next to), as dogs trained in drug detection can also do (one in five chances for the dog to succeed at random). The results were astounding as the success rate was 99% for lung cancer and 95% for breast cancer. In addition, dogs detected both cancers regardless of the stage of the disease, recently discovered or advanced. The authors also reported that the sample of healthy people actually included three subjects who had received cancer treatment and were

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therefore in advanced remission. The dogs marked two of these people as healthy controls and one as part of the cancer group. The 18-month followup then showed that this last person initially marked by dogs was suffering a recurrence of his cancer. This could mean that the dogs would have detected the cancer cells during the experiment even though conventional diagnostic tests did not detect anything abnormal at that time. In addition to breath, urine is another interesting revealing source. In 2011, Olivier Cussenot’s team, a Parisian urologist/oncologist, carried out enlightening work on prostate cancer screening (Cornu et al. 2011). Prostate cancer is one of the most frequently diagnosed (in France, it is estimated that there are more than 50,000 new cases each year) and the means of diagnostic investigation are limited1. The team trained a Malinois dog to identify urine samples from prostate cancer patients during daily training over a period of more than 16 months. The actual experimental phase was then carried out. In this experiment, 66 urine samples (33 sick patients and 33 healthy controls) were double-blind tested, and for each test, the dog had to mark the urine of one of six cancerous subjects proposed (five controls). The dog correctly detected 30 of 33 samples from prostate cancer patients. For the three unrecognized cases (false negatives), new tests with other urine controls then allowed the dog to correctly identify the urine of these three patients. For the three cases of marked control subjects (false positives), a biopsy diagnosis showed that one of the three people had prostate cancer. This innovative initial work was replicated by an Italian team in 2015 on a very large number of subjects (362 men with prostate cancer and 540 female and male controls2). Gianluigi Taverna et al. trained two German shepherd dogs for 5 months and the tests were performed in the same way as in the previous study, namely, a cancerous sample and five controls. One dog recognized 100% and the other 98% of urine samples from prostate cancer patients. This method – which at least is non-invasive! – is therefore much more reliable than conventional medical screening tests. In response to these results, several studies are currently being conducted on other types of cancer such as ovarian cancer and thyroid cancer.                                         1 The commonly used marker known as PSA (Prostate Specific Antigen) may be indicative of cancer but it is not specific and may also reveal inflammation or infection. A biopsy (as in the case of the study) will confirm or invalidate this. 2 The control group consisted of not only healthy subjects but also people suffering from various pathologies.

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These studies show that there are volatile and odorous molecules specific to cancer in the breath and urine that can be detected by highly skilled animals such as dogs. At this stage, it is not possible to say whether they are cancer markers in general or whether there may be specific marking for each type of cancer. Based on these findings, it is now a question of identifying the metabolites responsible for the recognition performed by dogs. It is unlikely that a single metabolite is responsible for the odor of cancer, and it is likely a combination of factors. Indeed, the cancer cell emits several biomarkers, among which it will be necessary to determine which ones have an odorous potential for the dog. From a practical point of view, it is not possible to generalize canine sense of smell screening for at least three main reasons: a dog can only be trained for one type of recognition, it is really only operational over a relatively short period of its life, and finally, it cannot perform chain tests! However, these scientific advances due to the dog’s sense of smell can be applied, particularly to electronic noses. Indeed, current research is working to program detection devices (see Chapter 43) that can be easily used in clinical routines from a urine sample or a patient’s breath. Like the results obtained with a dog’s sense of smell, the reliability of detection with an electronic nose is just as good. In fact, some teams are working on prototypes that could diagnose other pathologies such as infection or septicemia. However, dogs are not lacking in resilience, they are versatile and will not find themselves unemployed, even in the health sector. For example, we know that some of them, properly trained, are able to detect the imminent arrival of an epileptic seizure. There is even an association in Great Britain, “Medical Detection Dogs”, whose purpose is to promote research for diagnostic assistance provided by our canine friends.

 

 

26 Smells to Cure Cancer?

“Rotten egg gas holds key to healthcare therapies”. Following this catchy title in newspapers announcing that the gas produced by rotten eggs could be a therapeutic tool, many newspapers – particularly Time – took a leap forward (see Chapter 3) by proclaiming that “pet odors were an anti-cancer weapon” or that “smelling flatulence was good for your health”. The proclamations were so many that the authors of the initial research had to publish a clarification to remind everyone that there was no point in inhaling H2S for treatment! Even if it is indeed this molecule that the researchers worked with. Matt Whiteman’s team at the University of Exeter studied the effects of hydrogen sulfide, usually known for its unpleasant odor, on cell function. Firstly, they discovered that cells stressed by the disease activated enzyme systems to produce small amounts of H2S (Le Trionnaire et al. 2014). This molecule helps to maintain the functioning of mitochondria (cellular organelle that plays an important role in energy metabolism) and to regulate inflammation. Everything is natural in terms of the dosage since at high concentrations hydrogen sulfide is particularly toxic and can be fatal, as in the case of the famous green tides where large quantities of decomposing algae are produced. Preventing and/or repairing mitochondrial damage is a leading research strategy currently used to treat and manage many diseases as diverse as cancers, strokes, heart failure and age-related dementias. The researchers then used the observed natural biological process to develop a compound called AP391 that could release minute amounts of hydrogen sulfide, specifically to the mitochondria. The published results show that if AP39 is                                         1 AP39: for the complete and very poetic name [10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol5yl)phenoxy)decyl) triphenylphosphonium bromide].

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used in stressed cells, mitochondrial activity is protected and cell survival is maintained. As it is a mechanism common to many diseases, this discovery is undoubtedly of major therapeutic interest in many conditions. In their euphoria, the researchers wanted to spread their discovery by popularizing it. However, the press immediately and extensively relayed the idea that sniffing the odor of flatulence or rotten egg was effective in fighting diseases, so they had to carry out a necessary backpedaling exercise. False beliefs in science can prove difficult: some still believe that spinach is much richer in iron than other vegetables, even though it was a misplaced comma in the 19th Century that gave rise to this misconception! The Exeter researchers in collaboration with a team from Texas (Szczesny et al. 2014) also demonstrated in vitro that at a selected dose, AP39 maintained the integrity of mitochondrial DNA in stressed endothelial cells (here, by glucose-oxidase). Still based on animal models (Zhao et al. 2016), current results seem to indicate in an increasingly credible way that AP39 plays a protective role in the development of Alzheimer’s disease (after cardiovascular disease). The challenge now is to move from animals to humans. It is stated in Chapter 3 that there are olfactory receptors elsewhere than in the nose which obviously have a different role than allowing us to perceive odors. Neuhaus et al. (2009) discovered that an olfactory receptor present in the prostate (OR51E2) was activated by beta-ionone (a subtle fruity and woody odor). In the case of cancer cells, exposure to beta-ionone has been shown to inhibit cell proliferation and induce apoptosis (programmed cell death) of prostate cancer cells (Jones et al. 2013). Hans Hatt’s team (Maßberg et al. 2015) worked with citronellal on liver cancer cells. Citronellal activates the olfactory receptor (OR1A2) and increases the concentration of intracellular calcium, as in the previous example. This phenomenon contributes to stopping the cell proliferation observed in cancer and also induces apoptosis mechanisms. Still, under the direction of Dr. Hatt (Manteniotis et al. 2016), other researchers studied the impact of an odorant from sandalwood on the cells of a rare but particularly aggressive cancer, chronic myeloid leukemia (CML). The odorant activates an olfactory receptor (OR51B5) and leads to the same processes as those seen above. These mechanisms undoubtedly offer possible therapeutic options in the future, which are particularly relevant, especially in the case of cancers that are considered difficult to treat or even incurable, such as CML.

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These latest scientific developments are reminiscent of René-Maurice Gattefossé’s story, who is considered to be the founding father of aromatherapy. Seriously burned during an explosion in his laboratory, he suffered from gangrene that nothing seemed to prevent. He then decided to apply lavender essential oil to the wounds, the effects of which were spectacular.

 

 

27 A Depressed Patient’s Nose

At the pub with a friend recently, I told him that I was writing a literature review on the links between olfaction and depression (Brand and Schaal 2016). In particular, I explained to him that I was embarrassed because the journal did not allow more than 80 bibliographical references and that I had to make a drastic choice among several hundred publications. He was really captivated because he had no idea that science could be interested in the links between olfaction and depression, so from there to imagine hundreds of scientific articles, it was unthinkable! As a result, he wondered: what can be said about the relationship between olfaction and depression? Because of the close connections between olfactory pathways and the brain areas involved in regulating mood and emotions (especially the limbic system and prefrontal areas), olfaction is an interesting research pathway in several respects. First, olfactory disorders that occur in the case of depression can help in diagnosis and especially in understanding the underlying mechanisms. Second, and conversely, it is known that deficiencies in the sense of smell are sometimes the cause of depressive symptoms. Third, many studies show a positive impact of odors on the improvement of depressive and anxious states. Being depressed generally leads to distortions of smell rather than a net loss of sensitivity. A decrease in olfactory acuity sometimes exists but is not systematically found. However, depressed patients are less able to distinguish the different levels of odor intensity, less able to identify those present in the mixture, and respond differently to the pleasant nature of odors. This last aspect is undoubtedly the most indicative for the clinician. Those suffering from depression are not very sensitive to odors that are

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supposed to be pleasant (such as vanilla or cinnamon, for example) and – compared to non-depressed controls – they generally perceive unpleasant odors as more unpleasant and pleasant odors as less pleasant. This is known as “negative olfactory alliesthesia1”. Smell disorders can lead to a depressive state, because, in general, they have consequences on the quality of life, especially with regard to food intake with a reduced appetite. It is legitimate to believe that the repercussions on the quality of life due to smell disorders have a secondary depressant impact. The most commonly accepted mechanism is that the reduction of olfactory inputs has an impact on the limbic system. This hypothesis has been tested for many years in laboratories on rodents. Indeed, a depression model has been developed in rats called olfactory bulbectomy (OBX). OBX is a bilateral destruction of olfactory bulbs that induces behavioral and neuroendocrinological changes similar to those observed in depressed patients. OBX causes severe changes in several brain areas (amygdala, hippocampus, etc.) due to the disappearance of connections between olfactory bulbs and these areas. It also causes neurochemical changes similar to those observed in depressed patients, such as dopamine and serotonin. However, the exact mechanisms by which OBX induce depressive states via interactions (which have become deficient) between olfactory bulbs and different brain areas remain poorly understood. In this context, a recent publication (Oral et al. 2013) shows the probably crucial role played by the habenula2. The nuclei of the habenula are indeed involved in the regulation of psychomotor and psychosocial behavior under the major influence of inputs from olfactory bulbs. In addition, the role of the lateral habenula in depression is currently at the center of research on the mechanisms involved in depression. Projections from habenula nuclei are mainly directed toward areas known to be involved in the etiology of depression. Thus, the histopathological study conducted in rats by Oral et al. (2013) shows that OBX induces structural degeneration of habenula by neuronal apoptosis, leading to the appearance of the main symptoms of depression.

                                        1 The term “alliesthesia” is used to refer to the differences in sensations felt on the pleasant/unpleasant side following external stimulation (e.g. an odor). 2 The habenula is a very small structure of the brain made up of two nuclei. It is located above the mesencephalon and close to the thalamus.

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Odors can help to improve depression... However, it’s not easy! In this book, it is mentioned several times that exposure to odors can have multiple influences at different levels: psychological, behavioral, cognitive, and emotional. The two main functional explanations are pharmacological and psychological. The pharmacological effect induced by odors is based on the fact that volatile molecules entering the nasal cavity enter the bloodstream at the level of the nasal mucosa and thus have an impact on the neuronal activity of the autonomic nervous system and the central nervous system, as well as on neuroendocrine activity. Through the transdermal application, it has been established that a period of about 20 min is required for molecules integrated into the bloodstream to pass through the blood–brain barrier and have an effective role at the central level. However, the amount of active compounds entering the bloodstream by inhalation is relatively small – i.e. at trace levels – compared to other modes of entry such as ingestion, for example. Thus, it has long been shown in animals that long-term exposure inducing prolonged inhalation is necessary for traces of odorous molecules to be found in the bloodstream. The psychological hypothesis suggests that odors may have effects on factors such as attention or mood, but physiological correlates are difficult to obtain and there is no clear consensus from the many studies in this area. Yet, the progress of science in this field is undeniable. As evidence, a recent study (Xu et al. 2015) confirmed that in depressive rat models (under chronic stress conditions), exposure to vanilla odor induced an improvement in the depressive state at the behavioral level, associated with a change in neurotransmitter concentrations and in particular an increase in dopamine and serotonin levels. However, in the model of rats depressed following bulbectomy (OBX), exposure to vanilla odor did not produce therapeutic effects. This observation is extremely important because it suggests that the integrity of the olfactory system is necessary for a therapeutic effect and that the action of the molecules via the blood circulation is, in fact, inoperative or at least insufficient. This observation is crucial because it jointly hypothesizes a possible dual mechanism, which would add the pharmacological (via the blood circulation) and psychological (via the olfactory system) effect. This complexity of the interactions between olfaction and depression is well-illustrated in terms of possible neurochemical functioning presented below. Numerous studies in animals and humans have shown that certain scents such as rose, orange, lemon, lavender and vanilla have relaxing and soothing properties. One of the fundamental mechanisms by which the body reacts to

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stress is the activation of the hypothalamic-pituitary axis. The study by Xu et al., discussed above, suggests that vanilla odor may act at this level since the concentration of corticosterone is different between animals under chronic stress with and without exposure to this it. In addition (and for those enlightened), the activation of the amygdala and mesocorticolimbic pathway by odors could lead to an increase in the level of monoaminergic neurotransmitters with proven clinical effect on depression. If a sense of smell seems important to not be (or be less) depressive, other parts of the nose seem essential to maintaining a good mood balance. Indeed, the subject of turbinate bone removal is associated with certain severe depressive processes, and this topic deserves more than a footnote (see Chapter 28).

 

28 Gogol’s Nose or “Empty Nose” Syndrome

It is difficult to write a book on odors without mentioning the associated organ! It is, of course, possible to mention the famous noses of Cleopatra, Cyrano and Pinocchio, but following on from Chapter 27, logic dictates that we should rather talk about Gogol’s nose. In 1836, Nicolas Gogol published a fantastic story in which, one morning, a character named Yvan Yakovlevich discovered a nose in his bread. At the same time, another character, Major Kovaliov, noticed when he woke up that his own had disappeared. The latter, fatally terrified, then did everything possible to find it. In the first half of the 19th Century, the Russian writer probably did not suspect that surgery, a century and a half later, would then produce a frightening syndrome close to the misadventure of his noseless hero, “empty nose” syndrome! To demonstrate, our contemporary Kovaliov was called Brett Helling (he died in 2015), a 36-year-old man living in Ohio, who suffered from allergies and therefore from colds and a permanently blocked nose. To overcome this discomfort, the ear, nose and throat (ENT) doctor on duty recommended a fairly common procedure called turbinectomy, which consists of removing the turbinates from the nose. There are three turbinate bones in the nasal cavity (lower, middle, and upper) and they play an important role in breathing and smelling (Figure 28.1). They can inflate according to temperature (more or less congested to heat the air), act as a filter (in the presence of allergens, for example), secrete moisture and direct the airflow (while causing a turbulent flow of air). In the case of chronic congestion, many doctors recommend removing these bones (lower and/or middle in general). This was the case for Mr. Helling who, in the months following the operation, became a shadow of himself. He locked himself away at home

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and no longer participated in his usual social activities, had trouble sleeping and was always exhausted. After a medical consultation, he was diagnosed with depression (the doctor did not know about “empty nose” syndrome), but he was convinced that it came from his nose operation, and he spoke of nothing else. Refusing to take antidepressant medication, he continued to decline, his marriage broke up, and he eventually threw himself off a bridge. Following his operation, Mr. Helling was a victim of this famous syndrome, empty nose syndrome (ENS), a name given in 1994 by American ENT physician Eugene Kern from Rochester. Patients with ENS often experience severe pain, nasal dryness (with scabbing in the nose), hyperventilation and odor disorders. More surprisingly and paradoxically, patients often have a feeling of nasal obstruction! This is due to the fact that because the airways are clearer, the airflow suffers a loss of pressure, and the feeling of obstruction comes from this lack of pressure on the sensory receptors present in the mucous membranes. Finally, patients with ENS often develop severe depression. The prevalence of “empty nose” syndrome is not precise; some studies estimate that 2–5% of patients undergoing turbinectomy go on to suffer from it, while others put the figure at 14%. An association of patients suffering from ENS was created in France in 2011; it participates in legal proceedings and has questioned congressmen on this subject. The testimonies on the website of this association are striking and some members of this young association have commit suicide. Naturally, after turbinectomy, the turbinate bones do not grow back. Antidepressant and anxiolytic treatments often prove to be ineffective for the simple reason that the disorders previously described (hyperventilation, nasal dryness, fatigue, etc.) persist. However, reconstructive surgery can be considered with implants. This surgery is not the perfect solution as the implants do not have the properties of natural turbinate bones and, in particular, the fact they have to adapt the volume according to external conditions. However, it appears that this surgical treatment in the case of ENS has a positive impact on anxiety and depressive disorders. This is revealed by a study published in The Laryngoscope (Lee et al. 2016). Researchers used the BDI (Beck Depression Inventory) and BAI (Beck Anxiety Inventory) depression scales in 20 patients with ENS before and 12 months after biosynthetic implant transplantation. It appeared that depression and anxiety were improving in all patients regardless of the initial severity level, which was encouraging. Gogol may have liked to know if the same doctors performed the initial turbinectomy and subsequent implant placement. He would probably have mainly sought to understand the

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neurofunctional mechanism that leads ENS patients to lose their taste for life! There are few studies on this subject. A study by Freund et al. (2011) compared brain activations by MRI between control subjects and ENS patients. The study demonstrated different activations at the temporal level, at the cerebellum level and at the level of the cerebral amygdala. Some of these areas are directly involved in emotional processing processes. More specifically, the activations of resting ENS patients correspond to brain activations normally found in non-ENS subjects, but in respiratory distress or during experiments involving respiratory stress such as CO2 inhalation. In Gogol’s story, the unfortunate Kovaliov finds his nose again one fine morning, in good and due form, and with it his jovial warmth. Whether it is a Roman, Greek, or snub nose, in due form, its simple presence in the middle of the face is reassuring, but it must not be dented!

Figure 28.1. Schematic section representing the turbinates in the nasal cavities. For a color version of this figure, see www.iste.co.uk/brand/odors.zip

 

 

29 She Smells Parkinson’s

In late 2015, a Scottish woman made the headlines for claiming to have detected a change in the body odor of her husband with Parkinson’s disease, long before he was diagnosed with this neurodegenerative disorder. Joy Milne perceived a subtle change in her husband’s odor (more musky according to her) 5 or 6 years before the usual symptoms of this disease appeared. At the time, she simply thought that he was sweating more than usual, a situation related to his work. It was only much later, when her husband attended the Parkinson’s Foundation in the United Kingdom, that she realized that other Parkinson’s patients she met had the same odor as her husband. While we are surprised by this anecdote, she said that she has always had a very good sense of smell, even finding it strange that no one has made this observation before! Researchers involved in the Parkinson’s Foundation decided to verify Joy Milne’s statements and asked her to go through T-shirts worn for 1 day by six sick and six healthy people. By carrying out a blind test and detecting only with smell, she identified five of the healthy people and seven people with Parkinson’s disease. One might have thought it was a mistake, but 8 months after the test, it turned out that the allegedly healthy person was diagnosed as having Parkinson’s disease. Body odor (see Chapter 25) could, therefore, be used as a diagnostic marker and humans, like dogs, could be able to use their noses as a tool for pathological determination. This is not new or surprising because: “Odors were a preferred aid in the establishment of medical diagnosis in previous centuries. Doctors did not neglect the study of breath, vomit and feces and descriptions are not

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lacking, the pungent breath of diabetic ketones, the putrid odor in the case of scurvy or the more pleasant odor of fresh bread in the case of typhoid fever” (Brand 2001). Hippocrates himself stated that the odors of some patients could be used as a diagnostic tool1. A broader research project was launched with more than 200 healthy and Parkinson’s odor donors and several sharp noses (including Joy Milne) from sensory analysis and agri-food. At the same time, analyses at the molecular level sought to isolate the elements contained in sweat that may be at the origin of Parkinson’s odor. Shirasu and Touhara (2011) proposed a relatively comprehensive literature review, specifying the disease, odor characteristics, source, where known, the pathogen responsible and the volatile organic compound related to the odor (Table 29.1). From an evolutionary and adaptive point of view, it seems relevant at the species level that the odor of certain diseases – communicable diseases in particular – can alert congeners/partners in order to avoid spread within the population. In the study of the mechanisms involved, work in rats using lipopolysaccharides (LPS)2 – to activate the immune system and induce an inflammatory response – showed that the body odor of the injected animals was altered and that these animals were avoided by the congeners. This hypothesis that the immune response may play a role in body odor changes has recently been tested in humans (Olsson et al. 2014)3. Researchers compared subjects receiving LPS with control subjects receiving a saline solution. An additional 40 people (28 women and 12 men) were enrolled in the study to smell the T-shirts worn by the subjects within 4 h of the injection. From the rating scales, it appears that the odor of “LPS T-shirts” was perceived as more unpleasant, more intense and less healthy. The question was whether it was a quantitative difference (the same compounds but in higher concentrations) or a qualitative difference (other                                         1 The study by Kimball et al. (2016) postulates that Alzheimer’s disease (AD) may soon be diagnosed through the odor of urine. In mice, urine odor is altered by metabolic processes associated with AD precursors and specific changes detectable by gas chromatography. 2 Technically, LPS bind to a receptor that activates the release of pro-inflammatory cytokines. 3 In another register (Sundelin et al. 2015), volunteers receiving LPS injections were compared to controls receiving a placebo in a situation where they had to walk freely. They were filmed and observers who were not aware of the purpose of the study had to rate the level of health, fatigue and sadness. Subjects who received LPS injections moved less quickly and were perceived to be less healthy, more tired and more sad compared to control subjects.

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types of compounds emitted). At that stage, there were no evidence to conclude, but surprisingly, it appears that in subjects treated with LPS, the amount of sweat excreted was less than in control subjects, which would be more in line with the production of new inflammation-specific compounds. An analysis according to the type of cytokine seems to support this hypothesis. Through a mediation analysis4, the researchers showed that some cytokines – IL-6 (for interleukin 6) and TNF-α (for tumor necrosis factoralpha) – are related to changes in body odors while another – IL-8 (for interleukin 8) – is not. If these results were to be confirmed, it was then necessary to agree on major adaptive inequalities – perhaps at the origin of some selections – between those who had a super nose and could, therefore, protect themselves against certain diseases carried by those around them and the mediocre noses, capable of being contaminated! Pathology

Source

Odor

Pathogen element

Volatile compound

Cholera

Feces

Sweet

Vibrio cholerae

Dimethyldisulfide p-menth-1-en-8-ol

Breast cancer

Infected area

Rotten

Not determined

Dimethyltrisulfide fatty acids

Throat cancer

Infected area

Rotten

Not determined

Dimethyltrisulfide fatty acids

Gynecologica l tumors

Tumor

Rotten

Not determined

Volatile fatty acids

Diphtheria

Body odor

Sweet/putrid

Corynebacterium diphteria

Not determined

Scarlet fever

Skin, breath

Foul

Streptococcus bacteria

Not determined

Smallpox

Skin

Sweet/acrid

Variola virus

Not determined

 

 

                                        4 Trivially, in statistics, a mediation analysis seeks to determine whether when A influences B and B influences C, if A influences C.

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Pneumonia

Breath

Foul

Bacteria, viruses, etc.

Not determined

Tuberculosis

Breath

Foul

Mycobacterium tuberculosis

Not determined

Scrofula

Skin

Fermented beer

Mycobacterium tuberculosis

Not determined

Typhoid fever

Body odor

Must/fresh bread

Salmonella typhi

Not determined

Yellow fever

Skin

Butcher’s odor

Yellow fever virus

Not determined

Table 29.1. Disease and characteristics of the associated odor, the source and, where known, the pathogen responsible and the volatile organic compound related to odor (Shirasu and Touhara 2011)

 

30 And What Does Parkinson’s Smell Like?

Olfactory disorders in Parkinson’s disease were first described in 1975 by Ansari and Johnson. They affect nearly 90% of patients and therefore occur with a higher frequency than the main motor symptom, namely, a rest tremor (which occurs in about 70% of cases). Olfactory deficiencies are clearly objective from the early stages of the disease because, in reality, they exist before diagnosis, sometimes for several years. This was revealed by an 8-year longitudinal study of 2,267 men (Ross et al. 2008) who, at the beginning of the follow-up, had no clinical signs of Parkinson’s disease and dementia. The conclusions are obvious, when initial olfactory deficiencies are observed, the risk of the disease occurring is five times higher, within a period of up to 4 years. Parkinson’s disease is a slow neurodegenerative pathology that progresses “discretely”. By the time the first symptoms appear, more than half (sometimes 60–80%) of the dopaminergic neurons1 of the substantia nigra (one of the brain areas mainly involved) have already disappeared. Olfactory damage is both peripheral and central and can be detected by all types of tests (detection, identification, discrimination, memory, etc.). Since motor activity is the first to be affected in Parkinson’s disease, it has long been recognized that olfactory deficiencies in Parkinson’s patients are aggravated by a poor ability to sniff (Sobel et al. 2001). As the disease is severe from the outset, olfactory deficiencies remain logically stable over time, with little influence from the severity of the disease or treatments. In a meta-analysis based on 81 published works (Rahayel et al. 2012), it is clear that unlike Alzheimer’s disease, where high-level tasks (identification,                                         1 Dopamine is the main neurotransmitter involved in Parkinson’s disease and most treatments aim to improve its bioavailability.

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discrimination, recognition, etc.) are mainly affected, Parkinson’s disease is also affected by significant deficiencies in odor detection thresholds. The question of the causes of Parkinson’s disease – as with many neurodegenerative diseases – remains complex. However, research hypotheses are based on two main axes: genetic factors and environmental factors. In the latter case, the olfactory system could suffer a double impact, direct and retrograde, responsible for significant deficiencies in odor perception. Indeed, environmental toxins (pesticides, insecticides, etc.) partially penetrate the body directly through the olfactory system with a deleterious effect, to alter the neurons of the nigrostriatal pathway (the dopaminergic neurons of the substantia nigra project onto the striatum). At the same time, olfactory dysfunction also results from the neurodegenerative process of Parkinson’s disease, which leads to retrograde degradation of olfactory bulbs and epithelium. In Parkinson’s disease, a protein called α-synuclein is considered to be primarily responsible for the destruction of neurons. One of the functions of α-synuclein is to control the release of certain neurotransmitters, including dopamine. In Parkinson’s disease (as in other generative neurodegenerative diseases), this misfolded protein forms aggregates in neurons that lead to their destruction. From the early stages of the disease, and as in other brain structures, deposits of α-synuclein are found in olfactory bulbs. Moreover, pathologies related to dysfunctions involving α-synuclein (Lewy body dementia, for example) have often severely associated olfactory disorders, while pathologies linked to dysfunctions preferentially involving tau protein (tauopathies: progressive supranuclear paralysis2 or corticobasal degeneration3, for example) have relatively preserved olfactory capacities. In the initial assessment phase, sometimes long and difficult, during the possible development of a neurodegenerative pathology, olfactory disorders can thus play a definite role in the differential diagnosis.

                                        2 Progressive supranuclear paralysis (also known as Steele-Richardson-Olszewski disease) is characterized by lesions in several regions such as brain stem, striatum, and reticular formation, and affects many functions such as balance, vision, mobility, swallowing, speech, and so on. 3 Corticobasal degeneration is a rare condition that mainly affects the subcortical cerebral areas and is characterized by motor and practical disorders – generally asymmetric – to which, as the disease progresses, cognitive disorders are added.

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It should be noted, however, that deposits of α-synuclein in olfactory bulbs do not affect dopamine neurons, but they do affect other types such as glutamatergic neurons. At OB level, it has long been recognized that dopamine inhibits olfactory transmission and several studies (Huisman et al. 2004; Ubeda-Banon et al. 2010) have shown that in Parkinson’s disease patients’ olfactory bulbs the number of dopamine neurons was significantly increased, by almost twofold compared to a healthy age and sex-matched control population. It is therefore easy to understand that anti-Parkinson’s treatments based on increasing the bioavailability of dopamine (L-Dopa and dopaminergic agonists in particular) do not have any tangible effects on olfactory performance. In addition to drug treatments, other therapeutic methods are used in Parkinson’s disease, in particular, deep brain stimulation (DBS). It involves stimulating a specific brain area (the subthalamic nucleus) with surgically implanted electrodes. This method gives good results not only on motor symptoms but also on non-motor symptoms. Some studies have attempted to identify the effect of DBS on olfactory performance; some note an improvement (see, for example, Hummel et al. 2005) while others observe no effect, either at the detection thresholds or at the level of cognitive identification tasks (Breen et al. 2015; Fabbri et al. 2015). Although the number of patients included is systematically low, it seems that this will have to be resolved. Parkinson’s does not smell like much and there’s not much we can do about it...

 

31 Alzheimer’s Nose: Losing Sense of Smell and Losing Memory, the Same Story?

The prevalence of olfactory disorders in Alzheimer’s disease (AD) is estimated at between 85% and 90% of patients tested. These disorders occur at an early stage and worsen as the disease progresses. As with other symptoms of this condition, patients generally do not complain about odor deficiencies, although they are actually present. Only 6% of surveyed patients reported discomfort (possibly related to other factors). In Alzheimer’s patients, olfactory disorders result from both peripheral and central deficiencies, as evidenced by failing detection, discrimination, identification or memory tests. However, the qualitative judgments of odors (intensity, hedonicity, familiarity, edibility, etc.) seem to be preserved. The presence of olfactory disorders should be compared with the results of anatomopathological studies. Histologically, specific lesions of AD, namely, senile plaques and neurofibrillary degeneration lesions, are found in all peripheral and central olfactory structures, the most prominent being neurofibrillary degeneration in olfactory bulbs, described in 85–100% of patients in the studies. The early onset of olfactory disorders in AD raises the question of their presence in pre-symptomatic forms and their interest as a predictive factor. With regard to detection thresholds, the difference between healthy subjects and subjects with cognitive decline diagnosed de novo is difficult to perceive. Matching these two populations is difficult (apart from gender, age and smoking habits). However, it has been found that differential

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threshold measures1 are much more indicative of olfactory decline than absolute threshold measures2 (Hidalgo et al. 2011). In fact, the vast majority of the work is based on tests involving identification, discrimination and memorization. In this respect, Graves et al. (1999) carried out a princeps study (confirmed in 2009 by Robert Wilson’s team) as part of a large prospective study. They administered a CrossCultural Smell Identification Test and a Cognitive Abilities Screening Instrument to 1,836 participants who did not have a mental illness. Two years later, they were able to retest 1,604 of them and determine (in 69% of these 1,604 people) whether or not the ApoE-4 gene (apolipoprotein E epsilon4 on chromosome 19)3 significantly (although this is not mandatory) increases the risk of developing Alzheimer’s disease. In ApoE-4 carriers, they then observed a significant correlation between the deficient initial olfactory capacities and the risk of cognitive decline. This risk was five times greater4 in subjects with initially impaired olfactory performance than in initially normosemic participants. In 2010 (Devanand et al. 2010), a study conducted with 1,092 participants confirmed the hypothesis of the predictive role of olfactory deficiencies in the evolution of healthy subjects with MCI5 and MCI subjects with Alzheimer’s disease. Olfactory scores (measured with UPSIT – University of Pennsylvania Smell Identification Test) were correlated with the volume of hippocampi (key structures in memory                                         1 The differential threshold determines the smallest perceptible difference between two concentrations, necessary for a subject to be able to recognize the two stimuli as different. 2 In 2013, researchers at the University of Florida (Stamps et al. 2013) developed an olfactory test based on the odor of peanut butter, which only activates the olfactory system and not the trigeminal system (see Chapter 16). The originality was that it tested the two nostrils separately: individuals gradually approached the pot and measured the distance to the nostril when the subject said they perceived the odor. They compared several populations and, in the case of Alzheimer’s patients, they found a large disparity between the two nostrils, with the left nostril detecting the odor only when the pot was much closer (10 cm) than the right nostril. The explanation lies in the fact that, in this pathology, the left hemisphere is more affected than the right and the olfactory pathways are ipsilateral (on the same side). 3 However, a carrier of ApoE-2 provides a significant level of protection against AD. 4 This is an average and there is, in fact, a large gender disparity since the risk is almost 10 times higher for women and only about 3 times higher for men. 5 MCI stands for Mild Cognitive Impairment. This represents a nosographic category intermediate between age-related cognitive changes and degenerative pathologies responsible for progressive cognitive disorders, in particular Alzheimer’s disease. The conversion rate of MCI to Alzheimer’s disease is extremely high, in the order of 50% within 5 years of MCI diagnosis (although this figure varies widely from one study to another).

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function) evaluated on an MRI scan. The recent work of Woodward et al. (2017), which specifically targets a population of MCIa (amnesic MCI, to be distinguished from MCIna – non-amnesic), validates the role of olfactory deficiencies as a predictor of AD. This link between olfactory deficiency, alteration of episodic memory and the presence of the ApoE-4 gene is at the heart of the concerns of researchers and practitioners (e.g. Dhilla Albers et al. 2016; Oleson and Murphy 2015; Olofsson et al. 2016), whose results are all congruent. At the biochemical level, the contiguity between Alzheimer’s disease and olfaction has been known for some years now (Wilson et al. 2004). Acetylcholine is a neurotransmitter involved in AD, which plays an important role in learning and memory processes. In hippocampi, for example, there is a prolific death of acetylcholine neurons in Alzheimer patients, giving way to the famous senile plaques. Acetylcholine is also involved in olfactory learning processes. Cholinergic projections on olfactory structures such as the olfactory bulb, the piriform cortex and the olfactory tubercle are well–established and a cholinergic deficiency appears to be largely responsible for the olfactory disorders observed in AD. In 2011, research teams from Marseille and Montpellier, France, carried out an original study that received a lot of media coverage (Nivet et al. 2011). In mice that lost memory due to hippocampus damage, the researchers grafted human olfactory stem cells. One month after transplantation, conventional behavioral tests revealed that the transplanted mice had regained their ability to learn and memorize (searching for the location of an object, association of a reward and an odor), with performance even similar to that of normal control animals. Naturally, the injured and non-grafted mice remained totally incompetent 1 month after the lesion. This functional recovery was confirmed by histological analyses, which showed that human olfactory stem cells have effectively implanted themselves in damaged areas, differentiated into mature neurons, and have made it possible to restore the long-term potentiation processes underlying memory mechanisms. These observations were confirmed by Marei et al. (2015) in rats and paved the way for potential cellular therapies in Alzheimer’s disease and other neurodegenerative diseases.

32 The Smell of Old People

Our body odor can reveal – usually without our knowledge – our state of health, our physiological and our emotional states, but no one had previously been interested in whether body odor could also be a witness to our age. In other words, is there a specific odor for children, middle-aged people and elderly people1? Above all, are we able to discern them? Johan Lundström is a researcher at the Monell Chemical Senses Center2 in Philadelphia, USA, and, having often visited senior citizens’ homes, he realized that there was an odor common to all of them and that it was the same odor as that of a senior citizens’ home his mother ran in Sweden when he was young. Logically, he then wondered whether this odor was not characteristic of the elderly themselves. To investigate the issue (Mitro et al. 2012), Johan Lundström’s team first collected axillary odors from volunteers of different ages. The researchers attached underarm absorbent pads to t-shirts that subjects had to wear for five consecutive nights. During the day, the t-shirts were kept in waterproof plastic bags to avoid possible odorous contamination. In addition, subjects participating in the study could not consume spicy foods, smoke or drink alcohol and could not take certain medications such as antidepressants during this period. Finally, in terms of personal hygiene, it was inconceivable to leave the “odor donors” 5 days without taking a shower and knowing that the usual toiletries strongly                                         1 The term used in the title of this chapter, “old people”, can be read in an eniantosemic way, either pejoratively or affectionately. It is obviously this last interpretation that we refer to here. 2 Insiders say “the Monell”. It is probably the most important chemical sensory research center in the world, the most up-to-date facility in sensory research!

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impregnate clothes with their perfume, an odorless shampoo and soap were provided for them for the duration of the experiment. Three age groups were formed of young people aged 20–30 (7 men and 8 women), middle-aged people aged 45–55 (7 men and 8 women), and those aged 75–95 (6 women and 5 men). It should be noted that for the latter group and to obtain a sufficient number of “donor” subjects, the authors tolerated the use of certain drugs (hypertension, cholesterol, etc.). From a practical point of view, in order to avoid a possible prominent individual odor, the researchers mixed pads from several donors of the same age and sex in each jar used in the sniffing tests. Following the collection and constitution of the body odor jars, a homogeneous sample of 41 testers aged 20–30 years (21 women and 20 men) blindly noted the pleasant or unpleasant nature, the intensity, and tried to determine the age to which the odors belonged. The results showed that the “noses” described the elderly odor as less strong and unpleasant than that of other age groups. This contradicts a commonly held belief that – according to Johan Lundström – reflects social prejudice rather than physiological reality. By contrast, the body odor of middle-aged men scored the highest for intensity and unpleasantness. Finally, the testers easily identified odors as those of the elderly compared to the other two age groups, and the odors of the elderly were often instantly recognized. A publication in PLOS ONE (2012) was the first to show that an age group can be recognized by odor in the human species. This has already been demonstrated in several very different animal species such as mice, otters, owls and rabbits. Body odors change with age because they are mainly derived from the secretions of certain glands present in the skin (notably the sebaceous and sweat glands), and these glands are not uniformly functional throughout life (baby stage, adolescent, middle age, old age), either in terms of the nature of the substances produced or the amount excreted. Body odors are mainly due to the degradation by bacteria of these secretions, which will persist all the more if the region is hairy (compared to hairless, low-odor areas). Thus, the areas of the body most affected by odors are located at the axillary and inguinal levels. The pleasant nature of the odor depends largely on concentration, and men emit more concentrated odors than women – which is why the study reveals significant differences between middle-aged men and women – but this difference disappears at an older age when men and women produce less concentrated and probably less varied body odors. According to the authors of the study, this last characteristic leads to a more easily identifiable form of the uniqueness of odor among the elderly.

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What is surprising about the results of this study is that there is no evidence of any difference in perception (i.e. from the point of view of sniffers) between men and women. It should be recalled that in the perception of odors – including body odors – there are great inter-individual variations: some people may not be able to perceive certain odors and may present specific anosmias. For example, one of the components of male odor is called “androstenone”, and it has long been known that many men are themselves anosmic to this odor, while women are not. This suggests that some men may not be aware of their own odor. Compounds other than androstenone may play a role in age determination by body odor. An old study published in a renowned dermatology journal (Haze et al. 2001) studied the compounds present in body odor (more than 20!) using chromatography. The authors then compared two age groups, a 26- to 40year-old group and a 40- to 75-year-old group. They identified a new molecule (2-nonenal) with the particularity (unlike all the other molecules identified) of being detectable only in the 40–75 age group and, therefore, totally absent in people under the age of 40. 2-nonenal is similar to the odor of beer and buckwheat, and it is also found in orris roots (the roots of certain species of irises) and cucumbers. Since Lundström’s study focused on a group of people over 75 years of age, it is not known what happens to 2-nonenal in this age group and its potential role in helping to determine age using odor.

33 The Smell of Death

Mr. Abel has been a forensic doctor in a provincial university hospital for about 15 years. He loves his job while being perfectly aware of the special notoriety that surrounds him. He performs autopsies daily and, inevitably, must deal with corpses whose death is more or less recent. In addition to the usual indicators, which are repeated in police TV films, he claims, on the strength of his years of experience, to be able to determine the date of death from the outset and fairly accurately. He believes that he cross-references two indicators: the nature of odors and their intensity. However, he acknowledges that this is made difficult by the conditions in which the corpse remained: indoors or outdoors, in dry or wet weather, and so on. More surprisingly, he admits that he has long since lost his repulsion for this odor. Knowledge and habituation to odors are, therefore, limitless because for the average person (if we can say so!), the odor of a rotting carcass (not everyone discovers a human corpse in the forest) is immediately recognized as such and invariably appears to be very repulsive. It should be noted that for some animal species (scavengers), this odor is, on the contrary, particularly attractive. The decomposing corpse releases volatile molecules, at least two of which are detectable by the human nose: putrescine and cadaverine (part of the large group of diamines, i.e. chemical signals that cause specific behavioral responses without the need for prior exposure and, therefore, without learning). Researchers at the forensic toxicology laboratory in Leuven, Belgium, have recently proven Mr. Abel’s nasal abilities. Eva Cuypers and her team have highlighted a cocktail of volatile molecules characteristic of a decomposing human body. The results published in PLOS ONE (Rosier et al. 2015) are important because they could help to guide dog training more

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specifically in the search for corpses and assist in the design of electronic noses for this purpose. The protocol used by the researchers is ultimately quite simple. They placed samples of human corpses and many other animal species in jars (rabbit, turtle, mole, etc.) and carried out analyses of the gases released during putrefaction over a period of 6 months. A long list of molecules had already been compiled in previous studies but none had been as complete. The Belgian researchers isolated 452 different compounds and, among them, 8 appeared common to humans and pigs, to the exclusion of all other species tested. Similarities such as the percentage of body fat or the microbial flora of the digestive system between the human body and that of pigs are well-known and, therefore, persist after death. The researchers mainly showed the existence of five molecules (esters) specifically released by the human body in decomposition. There may, therefore, be a specific odor of the decomposing human body. But where Mr. Abel’s nose is more efficient, it is that he evaluates the condition of the corpse under any condition of residence (e.g. wet or in direct sunlight), while Eva Cuypers et al. carried out the experiment under standardized conditions of identical jars and on only certain parts of the corpse. The smell of death would have inspired scientists a lot during 2015. Indeed, while the Belgians were working with their jars, Arnaud Wisman and Ilan Shira from the University of Kent in Great Britain were testing the reaction of subjects when they perceived putrescine, trying to describe the mechanisms induced by this odor. In a first experiment, they showed that the smell of death increases alertness, through a faster reaction time in response to simple stimuli delivered on a computer (compared to an odorless condition). However, the reaction time was no faster than in the case where an ammonia odor was used. This change in vigilance was, therefore, not specific to putrescine and actually corresponded to an activation of the trigeminal system (see Chapter 16). In a second experiment, to measure the level of fight or flight, subjects had to run 80 m after smelling the putrescine, and guess what! The time taken by these subjects to travel the distance was shorter (56.4 s on average) than that of subjects who smelled ammonia (59.93 s) or who smelled nothing (60 s). The smell of death could improve the 100-m record, stimulating yourself without the use of drugs! In a third experiment, to measure the level of motivation for fight or flight, subjects had to complete words that were missing letters. In the list provided, two groups were formed: the so-called neutral group and a group of words referring to the threat. The results showed that the latter was better identified when the odor of putrescine was used, which tends to suggest activation by the odor of an implicit cognitive mechanism related to the threat and its

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avoidance. The authors also showed that, at very low concentrations (below the threshold of conscious perception), subjects stimulated by putrescine exhibited characteristic avoidance behaviors, particularly in relation to an unknown person. The study by Wisman and Shira, therefore, reveals that it is possible to objectify the instinctive and universal reaction (except for the forensic scientist) to the smell of death. What if the loss of sense of smell heralds death? More surprising is the study by Jayant Pinto and his American colleagues in Chicago published in October 2014 in PLOS ONE. They conclude that a significant loss of smell after 57 years of age can predict the subject’s death within 5 years. This question of predicting the occurrence of death remains a concern that has difficulty in finding reliable indicators, a predictive factor that does not mean certainty. Age and sex are naturally the two main criteria, in addition to which are many risk factors such as smoking, inadequate nutrition, physical inactivity and so on; however, trends in the general population are not always consistent with individual life courses. As a result, doctors and biologists are working to find indicators to best prevent the risk of death. The researchers worked with a sample of five fragrances (orange, leather, rose, fish and peppermint). They classified subjects into three categories according to the identification score (normosmic 0–1 error, hyposmic 2–3 errors, and anosmic 4–5 errors) and recorded the number of deaths for each of the three age groups retained (57–64 years, 65–74 years, and 75–85 years). While only 10% of people with a normal sense of smell (according to the criteria used in the study) died within 5 years, about 40% of those considered anosmic died, regardless of age. For normosmic and hyposmic subjects, the number of deaths increased gradually and logically with age. These results are both disturbing and questionable. They are disturbing because, presented in this way, they tend to prove that loss of smell is indeed and significantly an indicator of death, except that 60% of people without the ability to detect odors did not die within 5 years! In addition, the measurement performed was a brief identification test, i.e. a cognitive measurement and not a measure of loss of sensitivity (subjects may well have perceived the odor without being able to identify it). If the study was valid, then it would have to be concluded that cognitive loss (but how to extrapolate from such a simplistic test?) is predictive of death within 5 years. The following year, another team (Devanand et al. 2015) with UPSIT (University of Pennsylvania Smell Identification Test) reached the same conclusions. The problem with this type of publication is that it is likely to unnecessarily worry many people, even though doctors will sometimes carry out, at the request of the patient, superfluous tests. Finally, the loss of smell is rarely

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underlying a more significant pathology, except in the case of certain neurodegenerative pathologies and, therefore, it is not very informative from a medical point of view. Let us be totally reassured: losing your sense of smell does not kill you!

34 Red Meat, Garlic and Sex Appeal

Researchers at the University of Prague (Havlicek and Lenochova 2006) had the funny idea of testing the effect of red meat consumption on the quality of body odors collected from the armpits. Axillary body odors have individual characteristics that constitute a true odorous signature. This individual body odor is partly due to genetic factors but may also be influenced by other factors such as the use of certain medications or eating habits. The importance of body odors is revealed very early in life. It has long been known that newborns, in the weeks following birth, recognize their mother’s body odor (breast odor and axillary odor). Similarly, it has been seen that mothers recognize the odor of their child within 2 days of birth. Fathers themselves, from 3 weeks after birth, can distinguish the odor of their child from that of another child. Body odor recognition is not limited to parent–child relationships and it has long been known that we are able to recognize the odor of a sexual partner when the relationship is wellestablished. The personal odorous signature is partly determined genetically and several studies provide proof of this. First, the odors of parents and their children can be matched by strangers who, however, cannot differentiate the odors of spouses (of both members of the parental couple) from to each other (genetically different). However, it is still possible in some cases that this coupling may correspond to a “common house odor”. Second, it has been shown that it is more difficult to distinguish the odor of monozygotic twins (whether they live together or not) from the odor of heterozygotic twins.

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Third, body odor preference is correlated with MHC genes (major histocompatibility complex1) whose productions are crucial in the immune system. It appears that women note the odor of men, which is all the more attractive because the MHC is different from their own, which would contribute to genetic mixing. However, everyone’s body odor, although specific, changes with age (see also Chapter 32) and depends not only on genetic factors but also on physiological and ecological factors. For example, female body odors change according to the menstrual cycle and are more attractive around the ovulation period. It is also known that our current mood influences the pleasant/displeasing perception of our own body odor. Concerning eating habits, and somewhat surprisingly, few studies have focused on the impact of the consumption (or not) of a particular food on body odor. Based on an ethnological observation that vegetarian Hindus find the odor of meat-eating people unpleasant, Havlichek and Lenochova compared 17 odor donors over two different periods. First, participants were randomly assigned a carnivorous or vegetarian diet for 2 weeks. During the last 24 h of dieting, they wore axillary pads to “harvest” their body odor. Thirty women who did not use hormonal contraceptives had to evaluate the odor samples for hedonicity (pleasant/unpleasant), attractiveness (attractive/repellent), and intensity (weak/strong). The same experiment was repeated 1 month later with the same donors, each participant then following the opposite diet to that of the first experiment (those who had followed a vegetarian diet followed a carnivorous diet and vice versa). In the vegetarian phase, participants had to avoid consuming certain products (onion, garlic, chilli, cabbage, etc.). In the carnivorous phase, participants had to consume 100 g of red meat with each meal. The results were unambiguous; the odor of donors following an exclusively vegetarian period was assessed as more pleasant, more attractive and less intense. This suggests that red meat consumption has a negative effect on women’s perception of male body odor. This effect is found regardless of the phase of the sniffers’ menstrual cycle. The question that naturally comes to mind is what, in the consumption of red meat, can qualitatively change body odors. The authors hypothesized a change in the level of aliphatic acids known to be abundant in axillary sweat.                                         1 The major histocompatibility complex (MHC) is a part of our genetic code that plays a key role in the body’s defense system.

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Axillary odor is mainly due to the degradation of secretions by bacteria, whereas bacteria of the genus Corynebacterium metabolize fatty acids into aliphatic acids. Thus, the fat content – increased in the case of meat consumption – would be responsible for modifying odor and reducing sex appeal. The macho side of the carnivorous man takes a hit... It remains to be seen what happens if a steak is served with red wine or still water. And if we reverse the roles. And if we replace beef with lamb. And what if... The same team came back 10 years later (Fiavola et al. 2016), this time asking about the effect of garlic consumption on body odor. Its influence on breath is easily verifiable, but it is widely believed that garlic also alters body odor. Garlic is widely used in cooking for its taste and aromatic properties. It is also associated with a wide range of health benefits. Some claim that the pyramid builders in Egypt were doped with garlic (garlic cloves were found in Tutankhamun’s tomb). In ancient times, it was prescribed to treat problems as diverse as gastrointestinal disorders, asthma and “madness”. The antibacterial properties of garlic have been proven by Louis Pasteur and during the two World Wars; it was even used as an antiseptic in the absence of other products and in the prevention of gangrene, in particular. Today, it is recognized as having antioxidant, immunestimulant, cardiovascular and oncological benefits. The consumption of garlic by women is also accompanied by changes in amniotic fluid and breast milk, which will induce a differentiated behavior of the baby toward this odor. Strangely, the potential effect on body odors has not really been studied. In their work, the Havlichek team tested a group of men consuming garlic combined with fresh cheese (6 g of garlic in accordance with daily recommendations) compared to another group of men consuming the same garlic-free cheese. The researchers also tested a potential dose effect, in comparison with another group, with a daily consumption of 12 g of garlic. The protocol conditions were similar to the initial study with red meat and body odors collected on axillary pads, assessed by a large number of women. The first observation was that there was no difference in hedonicity, attractiveness and intensity between the group that did not consume garlic and the group that consumed 6 g. However, the body odors of the group of men who swallowed 12 g of garlic were noted as less intense, more pleasant and more attractive by women. The seducer has not finished refining his diet... but with garlic, breath and underarms to consider, odor will have to choose!

35 Tears and Desire: Stop Crying, it Doesn’t Turn Me On Anymore

A team of scientists from the Weizmann Institute in Israel (Gelstein et al. 2011) showed that men confronted with women’s tears felt less desire toward their counterparts. It was not the sight of the crying woman – an event that some might say is more likely to cause irritation rather than sadness in men(!) – that was responsible for the decrease in libido observed in the study, but the fact that tears contain chemical signals that may influence sexual arousal. It was first necessary to collect tears, and for this purpose, the women watched sad films in an isolated cabin. They had a mirror and a test tube for collection (about 1 mL each time). Then, a sample of 24 men aged 23–32 years found themselves wearing a cotton pad taped under their nostrils containing either women’s tears or a saline solution (as a control). While sniffing either of these solutions, they had to evaluate women’s faces presented on a computer according to two criteria: the sadness they expressed and the physical attraction they felt for them. The results did not show any difference in the assessment regarding the sadness expressed between sniffing tears and sniffing saline. If we extrapolate a little, we could say that the odor of tears did not change men’s empathy with the proposed women’s faces. However, there was a significant difference in physical attractiveness. Indeed, with real tears under their noses, men had less desire for women than the control situation (i.e. with the saline solution under their nose). This could mean that the tears contained a chemical signal that could induce such an effect. To test this hypothesis, the researchers then carried out two other experiments. First, they measured the level of testosterone (the male hormone, whose level varies – in particular – according to the state of

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sexual interest) using a simple saliva sample. After exposure to tears, testosterone levels decreased significantly from the basic level, while after exposure to saline, no difference was recorded. Second, they performed fMRI measurements of hypothalamic activity (the hypothalamus being a brain region highly involved in regulating emotions and sexual behavior) in men in the two configurations already stated (true tears and saline solution) and during three film screenings (sad, happy and neutral). In the case of the sad film, hypothalamic activity was significantly less with real tears under the nose than with saline solution. Breathing women’s tears in a sad context would, therefore, have a powerful cumulative effect that kills love! This research is ultimately only anecdotal even if our culture did not bring us into regular contact with the tears of others. The authors of the study point out that, when a person cries, they are often cuddled or kissed. As a result, our nose, through which the message is probably perceived, is then close to another person’s face, so the test performed here could be relevant in many other everyday situations. Thus, can women’s tears cause effects other than a decrease in libido in men? Do they have any effect on other women? Are the effects different depending on the hormonal state of the weeping woman? And moreover, are women’s tears different from those of men, especially those of children? But what scientists are most interested in is discovering the chemical compound(s) present in the tears and responsible for the potential effects. The composition of tears is complex: they contain proteins, fats, enzymes, various metabolites, electrolytes and other elements such as traces of drugs. There are two main categories of tears: those resulting from a reflex protective mechanism (dust, airflow, toxic products, etc.) and those produced during an emotional event such as sadness. This distinction is important because the composition is not identical in both cases. In the Israeli study and on a preliminary basis, the researchers tested whether the two types of tears had a different or discriminatory odor, which was not the case. This then raised the question of the nature of the chemical signal contained in the “emotional tears”; is it an odor of too low an intensity to be consciously perceived or is it another type of chemical signal that does not pass through the olfactory system? In mice (who sometimes cry!), the tears contain identified chemical signals. They are pheromones that activate the vomeronasal system (a system different from the main olfactory system), sometimes referred to as the “sexual nose”, and are responsible for specific behavioral responses in

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congeners. For example, it has been shown (Thompson et al. 2007) that tears from a male mouse stimulate aggression in other males. This could certainly another interesting human experiment for the team at the Weismann Institute, one in which something other than tissues may have to be used!

36 With a Bad Nose, Comes a Poor Flirt

Smell is expected to play a role in food intake, in the identification of toxic substances in the environment and in social relationships, including the recognition of certain emotional states in others, and in the choice of sexual partners. Concerning the latter aspect, in many animal species, the importance of the “nose” is recognized, but it is often a different system to olfaction, called the “vomeronasal system”, which includes specific molecules called pheromones. In adult humans, the vomeronasal system is not functional, and it is not customary to sniff each other as many animal species do. It remains to be seen whether our human nose does indeed play a “sexual” role or whether it is a conjecture. When asked (Herz and Inzlicht 2002), women say that they consider men’s body odor as a more important criterion in their choice than physical appearance, while the opposite is true for men. To approach the topic, German researchers at the University of Dresden (Croy et al. 2013) have turned the problem around. They wanted to know if living without a sense of smell (being anosmic) could have an impact on the quality of life, in particular on sex life. They recruited 32 people aged 18–46 (10 men and 22 women) with total congenital anosmia, who they compared to 36 control subjects with a normal functioning sense of smell (normosmic) in the same age group. All responded to an extensive questionnaire on daily living activities regarding eating habits, personal hygiene practices, domestic accidents and social relationships. In the latter case, the questions focused on social ease, age at first intercourse, number of children, number of sexual partners, or degree of satisfaction and security in the relationship. Respondents were also asked to complete a questionnaire on their attachment to their mother and a depression rating scale.

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While the results do not show a tangible effect of anosmia on food and hygiene practices, the lack of smell results in greater social insecurity for both women and men. Above all, it appears that anosmic men had five times fewer adventures than men in full possession of their olfactory capacities. In anosmic women, however, there was no decrease in the number of conquests, which may seem surprising given that male body odor was rated as an important criterion for them in Herz and Inzlicht’s study. However, the results of the questionnaires show that anosmic women who lived together as a couple had a significantly lower sense of security toward their partners than normosmic women. A man without a sense of smell would, therefore, be a poor flirt, not because he is less concerned by the situation (which has already been demonstrated1) but probably because he is less socially comfortable (difficulty in evaluating others, mistrust of his own body odor, etc.) and, therefore, he is less daring, which the authors of the study prosaically summarize as “sexual behavior less oriented toward exploration”. A woman with or without smell is just as seductive. However, from an evolutionary point of view, what she is looking for from her partner is above all security, which seems to be lacking for anosmic women. Without a sense of smell, they are not sure that they have made the right choice, especially with regard to motherhood and the partner’s investment in children. Incidentally, they also do not know how to recognize his alcoholic breath, or the perfume of another person... enough to fuel suspicion! This study is not so much valid (only 10 anosmic men, perhaps men with a normal sense of smell play Pinocchio more easily and exaggerate the number of their conquests...) as it is valid from a research point of view. Even if the idea may seem crazy at first, it is still interesting in that it seeks to understand the importance of a mechanism (odor) by looking at what happens when it malfunctions. Modest in the approach, it still shows that the researcher took a step back or maintained distance, a basic principle that is not always scrupulously followed (see Chapter 2).

                                        1 A study (Gudziol et al. 2009), conducted with anosmic, hyposmic and normosmic individuals found that olfactory impairment is not correlated with decreased sexual appetite, reinforcing the previous conclusion that anosmic patients are less daring. However, among people without a sense of smell, those who are the most depressed are also those who are the least influenced by sex.

37 It’s All in the Sweat

Concerning the sense of smell, the 2010s will probably go down in history as that of sweat. The importance of chemosignals has already been mentioned in several chapters of this book (see, e.g. Chapters 32, 34, 36 and 38) and faced with the inflation of studies that make us sweat (Lübke and Pause 2015); here is a small collection that might give us cold sweats... Can happiness be measured in sweat? Happiness is communicative and everyone has been able to experience it through visual or auditory signals. The question asked by De Groot et al. (2015) was whether, after the demonstration of the communication of negative emotions by body odors (see Chapter 38), emotional contagion was also possible for positive emotions. In this study, 12 healthy, non-smoking, drug-free men provided their sweat samples after viewing video clips that could induce an emotional state related to happiness; 36 women were then exposed to the sweat samples while electromyographic facial activity was recorded. In this situation and for many of them, the muscles involved in the production of smiles were activated. However, when they were exposed to the sweat collected when viewing emotionally neutral video clips, no particular muscle activity was recorded at the facial level. If exposure to sweat, produced in a context of feelings of happiness, induces contagion of this emotional state, it is necessary to stock it again in jars for those rainy days. Could sweat promote cooperation? Two Finnish researchers (Huoviala and Rantala 2013) investigated the effects of androstadienone – one of the compounds found in male sweat (1) known to influence women and (2) known to interact with emotional processes (Hummer and McClintock 2009) in decision-making in other men. The researchers based their research on the

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ultimatum game used in experimental economics and often used by psychologists. In this game, player A receives a sum of money (10 euros in the experience of Huoviala and Rantala) and must give some of it to player B who can refuse this sum if they consider it insufficient, but in this case, neither of the two players receive asks that money. The logic is simple and any player B accept any amount proposed by player A since this solution will always be more lucrative than not winning anything. Player A, however, has an interest in offering the lowest possible amount. Strangely, these two logical predictions are rarely found in practice, and many factors can influence the decisions made by players on either side. Finnish researchers recruited 40 men, of which 20 were exposed to androstadienone and 20 served as controls. The former offered on average 50 cents more (or 5 euros on average) than the subjects in the control group and accepted lower offers of around 50 cents also (or 3 euros on average). Both the researchers are evolutionary biologists and naturally interpreted these data in terms of “adaptive advantage”. They translated these decision biases into the idea of greater cooperation between individuals (see the title of their article), which is already debatable, but above all, they concluded by formulating the hypothesis that the cooperation of same-sex individuals is more interesting from the point of view of survival rather than aggression (which can be understood but is far from being verified!), and that the influence of androstadienone that they observe would thus be linked to our evolutionary history. As such, the results are indisputable (although it should also be mentioned that the concentrations of androstadienone used are very far from the ecological reality). However it is probably necessary to replicate this type of experiment before taking certain phylogenetic shortcuts. Why not start by testing the changing rooms of sports clubs? In their work, the researchers also took saliva samples to measure testosterone levels and found a positive correlation between testosterone levels and the level of “cooperation”. Another avenue to pursue, then. Does sweat influence social judgments? In an attempt to answer this question, Pamela Dalton et al. (2013) of the Monell Chemical Senses Center in Philadelphia collected the axillary odors of 44 women in several situations, one of which was sweating in the case of physical exercise and the other in a stressful situation1. One hundred and twenty men and women                                         1 In this study, the authors used the Trier Social Stress test (TSST) (Kirschbaum et al. 1993), one of the most widely used validated methods for inducing moderate psychosocial stress in laboratory situations. It consists of a task of verbal expression and mental calculation in front

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then observed other women in video clips and made personality judgments (warm, competent, etc.) and generally found them more stressed when the judgment was associated with the axillary odor collected during the stressful situation. For the rest (confident, trustworthy, competent, etc.), the results were not very convincing. In 2014, Lübke and his colleagues asked the opposite question. They collected the axillary odors of eight men and eight women following a night’s sleep, which they combined for analysis. During fMRI sessions where axillary odors were delivered, they then compared two groups of women according to their degree of social openness (high or low) using a specific scale published in the German language called Inventar Sozialer Kompatenzen (ISK)2. Brain activations in response to axillary odors did vary according to the degree of social openness. The higher the latter, the more activated the right lower frontal gyrus and the right caudate nucleus were. This did not surprise the authors, who recalled the role played by the lower frontal gyrus in the mirror neuron system3, on the one hand, and, on the other hand, the involvement of the caudate nucleus4 in the social reward. Thus, axillary odors could have a more or less important meaning depending on this personality trait. Is aggressiveness found in sweat? In the animal world, the ability to detect congeners that represent a potential hazard is naturally an adaptive advantage. In humans, this ability to perceive aggression in others requires a combination of verbal and non-verbal signals. Smiljana Mutic’s team (2016) questioned whether body odors could also contribute to providing information about the aggressiveness of others and, if so, what types of responses could result therefrom. The researchers recruited 16 men and collected their axillary odors in two situations. In the first situation, it was a boxing match characterized by a specific and repeated attitude of induction of aggression on the part of his opponent (a provocative experimenter... but also courageous, in terms of the blows). In the second case, it was a sporting                                         of an audience. This test activates the usual pathways of stress and results in a change in heart rate, skin conductance, cortisol levels, and axillary production. 2 Meaning “Inventory of Social Competency”. In fact, they only used a part of ISK (Kanning 2009) called “Openness” with eight items such as “I always approach people if I want to get to know them”, rated from 1 (absolutely false) to 4 (absolutely true). 3 An important aspect of social interactions is everyone’s ability to understand the mental state of others. Mirror neurons play a key role in this process. 4 The caudate nucleus participates in a sort of reward system. It can detect and collect a reward and distinguish between multiple rewards and set preferences. In addition, it participates in planning out the steps required to obtain this reward.

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exercise with an ergometer used as a control situation. It was first verified that the self-assessment of the level of aggressiveness, the motivation to harm or inflict pain and anger, increased with the experimental induction of aggression. It was then assessed whether aggressive odors could be contagious and whether it was rather an emotional contagion as seen elsewhere (in this case anger) or a reciprocal contagion (i.e. anxiety). The participants (10 men and 12 women) exposed to these odors performed an emotional recognition task and an emotional Stroop task5. The results indicated that they preferred to focus on anxiety-related responses. The question remains as to what would happen in a situation of real danger. And, in general, for all these studies, what is the ecological reality?

                                        5 In the emotional Stroop task, words of emotional meaning and neutral words are printed in various colors and presented instead of color names. The time taken to name the color of emotional stimuli (often negative) and the time taken to name the color of control stimuli (neutral or positive) reflect the emotional interference effect of Stroop.

38 The Smell of Fear

Take a laboratory mouse, which has never seen a cat or fox before, and spread the odor of cat urine or fox feces in its cage and you will immediately obtain characteristic fearful behaviors such as flight behavior or freezing (total immobility). This genetically programmed behavioral response is fundamental to adaptation in many species, particularly with regard to predators. Some odors and other sensory stimuli – including in humans – can cause fear. Conversely, can a fearful situation cause a specific smell? Everyone knows very well how to identify (and from an early age) the so-called primary emotions (joy, sadness, fear, anger, surprise and disgust) in others, mainly through facial expression. In the case of fear, eyes are wide open, eyebrows raised and mouth tightened. If the person speaks in fear, intonations and vocal characteristics will also be distinguished, which will be easily recognized as showing fear (even if the facial expression is not visible). The first study proving the ability to differentiate the smell of fear in humans dates back about 10 years (Prehn et al. 2006). The authors had student volunteers wearing t-shirts to collect their axillary odors in two situations: a physical activity and an oral academic exam situation. Participants who volunteered to smell the t-shirts were able to discriminate against them according to both situations. Using an olfactometer, they then proposed the classical acoustic startle reflex to the subject (here 100 dB!). Using electromyography (EMG), the researchers measured the amplitude of the reflex at the ocular level. They discovered that the reflex was more significant when the subjects found themselves exposed to the odor of fear rather than when they were exposed to the odor of the athlete’s sweat.

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In 2009, two separate studies corroborated this observation and found that body odor could be characteristic of fear and influence others. The first study was carried out by the same team as before (Prehn-Kristensen et al. 2009). Men watched a horror film and, at the end of the session, their sweat was removed. They then filmed women (without their knowledge) who had to perform vision tests. When the male “fear” odor was diffused simultaneously with the vision test, the women’s facial expression and eye movements were similar to those expressing fear, even though they had no information about the odors they were exposed to and the tests to which they were subjected did not cause fear1. The second study (Zhou and Chen 2009) proposed another experimental paradigm (except for the collection of odors, carried out as part of the horror film screening). Subjects had to evaluate different emotions expressed in photographs: some images were perfectly explicit, while others were ambiguous. The results showed that when the image clearly expressed fear, the associated odor did not change the judgment. However, when the image was ambiguous, participants who were exposed to the smell of fear together rated it as more fearful than participants who were not exposed to the smell or those who were exposed to a different smell. While multisensory interactions (e.g. vision and hearing) were known in the appreciation of emotions, the role of the sense of smell had not yet been grasped. The results of these two studies may logically leave some room for doubt: for the most skeptical, it should be pointed out that in the context of odor collection, a large number of subjects were involved and many self-assessed (scales and questionnaires) and psychophysiological (heart rate) measurements recorded and that, in the end, only a few donors were able to be selected... because these studies also confirmed that one can very well watch a horror film without becoming afraid! In the field of the smell of fear, neurobiologists are not to be outdone. Recently, a team from the University of New Jersey (Kass et al. 2013) focused on learning fear through smell. The researchers used a conventional conditioning system with a neutral odor for mice, acetophenone (see Chapter 39) coupled with an electric shock to the paw. Logically, after conditioning,                                         1 Another study (De Groot et al. 2012) worked in the same way on the smell of fear and on the body odor produced in a disgusting situation. As with fear, the smell of disgust leads to responses – especially facial expressions – that are characteristic of disgust in those who perceive it. This hypothesis of a possible emotional “contagion” by odors is very popular at the moment. It undoubtedly deserves thorough studies and inspection.

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the mouse showed fear when presented with acetophenone alone. There was a suspicion of greater sensitivity to odor once the learning was completed, and the researchers’ innovative idea was to work on the peripheral system, i.e. the receptors in the nasal cavities and the first relay in the brain, namely, the olfactory bulb. They used genetically modified mice to make acetophenone neuroreceptors produce a specific compound that binds to vesicles containing neurotransmitters (i.e. at the synapse between peripheral receptor neurons and olfactory bulb nerve cells) and becomes fluorescent when released into the synapse. Thus, the greater the fluorescence observed, the greater the amount of neurotransmitters released. The results were spectacular because, at the same delivered concentration, the odor learned in a context of fear induced a more intense response of olfactory neuroreceptors to acetophenone corresponding to four times the initial concentration (in unconditioned mice). This discovery shows an increase in the sensitivity to odor attached to the danger, the adaptive interest of which is obvious. It would seem logical that such a mechanism exists in the human species. It can, therefore, be assumed that this phenomenon may play a role in certain dysfunctions related to anxiety or post-traumatic stress disorder, for example, in which odor may play a role (see Chapter 27). The physiological mechanism described by Kass’ team led to inappropriate focus and hyperresponsiveness in connection with odorant stimulation. This is echoed in studies of SPT veterans. Unlike the control subjects, they considered the odor of diesel fuel (related to the traumatic memory of combat) to be much more unpleasant and, above all, exposure to this odor significantly increased SPT symptoms and anxiety in them (Dileo et al. 2007; Vasterling et al. 2000). In another area (Kondoh et al. 2016), American researchers have just demonstrated the existence of a specific cerebral area in the olfactory cortex in animals, involved in the hormonal response to predator odors. This is the amygdala–piriform transition area that contains neurons (upstream of CHR neurons, for corticotropin-releasing hormones) specifically activated by the predator odor and which trigger the hormonal response leading to instinctive fear behavior. When researchers prevented these neurons from functioning (we will skip the technical details here), the hormonal response was drastically reduced. However, the behavioral response (measured here by freezing in particular) was not affected, again reminding us of the complexity of the relationship between hormonal response and behavioral response (see Chapter 39).

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Finally, in today’s world where fear is omnipresent – fear of failure, fear of unemployment, fear of tomorrow, fear of disease, fear of the other, fear of eating badly and fear of aging – it may be necessary to start blocking your nostrils if you want to become more serene...

39 What Epigenetics Owes to the Nose: How Fear Learned From an Odor can be Transmitted to Offspring

To protect themselves from danger, many animal species use the odor of their potential predators as a warning signal. In mice, for example, cat urine and fox feces contain odorous chemical signals that trigger an appropriate response behavior, which can be summed up briefly in two possibilities: escape or a characteristic immobility posture (crouching, lying low) called freezing. In fox feces, the molecule responsible for mouse avoidance behaviors has been identified as TMT (for 2, 4, 5-trimethylthiazoline) and, in cat urine, as L-feniline. The behavioral response is part of the genetic heritage of rodents since laboratory mice react with fear and demonstrate stress even if they have never encountered a fox or cat nor have their previous generations1. It is the same process that governs fear at the sight of snakes in humans, a phylogenetic memory that is part of the hereditary heritage. Brian Dias and Kerry Ressler, from Emory University in Atlanta, USA, performed olfactory conditioning in male mice (this coupling conditioning                                         1 However, this genetic predisposition is not immutable. Very recently, a team of Russian researchers showed that early exposure (during the first 2 weeks of life) of mice to L-felinine led them in adulthood to not run away from the perception of this odor (at the risk of being eaten!). It should be noted that this is only a behavioral adaptation because, when measuring the level of corticosterone (stress hormone), it is equivalent to that of unconditioned mice, which Haquemand et al. (2010) have already shown with the odor of TMT contained in fox feces. In a way, the body is stressed but the behavioral response does not follow.

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mechanism has long been known) by combining an acetophenone odor (a very aromatic molecule similar to almonds) with electric shocks (Dias and Ressler 2014). In mice, acetophenone has no ecological value and, therefore, does not induce a particular response. However, after conditioning, simple exposure to this odor induces remarkable stress levels. In their study, Dias and Ressler tested the reactivity of the progeny of the conditioned mice and, surprisingly, found that the first generation of mice reacted to the odor of acetophenone with fear and stress responses when they had not been conditioned. To avoid any doubts about the transmission of this fear learned from one generation to the next, the researchers repeated the experiment in mice in the next generation obtained through in vitro fertilization to avoid any potential behavioral effects on the progeny, and they obtained the same results. The fear of an odor can, therefore, be passed on from one generation to the next. How then can we explain such a transmission phenomenon that leaves the scientific community perplexed? Once again, the sense of smell is at the heart of a remarkable advance in biological knowledge. It should be recalled, for example, that it was at the level of the olfactory system that it was first shown that nerve cells could regenerate (whereas for a very long time neurobiologists considered this impossible). This time, the sense of smell provides tangible evidence that epigenetic changes can be passed on to subsequent generations. Epigenetics has become, in recent years, a kind of Holy Grail in biology and medicine. After analyzing the entire genome, it was necessary to admit that not everything is written in DNA sequences and that gene expression is partly subject to external conditions or constraints that encompass both nutrition (consumption of fat, carbohydrates, variety, etc.) and pollution (air, water, food, etc.), culture and education, as well as stress and many other factors. This influence of the environment explains why two individuals carrying the same DNA sequence may present differences in the expression of the characteristic concerned. However, until then, epigenetic effects seemed to be confined to the individual, without the changes being passed on to subsequent generations. However, the observations of Dias and Ressler show the opposite for the first time and thus open up very important perspectives. Indeed, considering that such phenomena occur in humans, it is possible to consider that certain mechanisms related to traumas experienced by parents may affect certain behaviors of their children who have not experienced these traumas. Therefore, and as a first step, it is possible to imagine that many neuropsychiatric disorders related to stress or phobias

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could be better understood in a multigenerational approach. Second, it is possible to assume that other conditions such as certain cancers, diabetes, and even certain malformations could also depend on epigenetic transmission. The question is to determine how such a transmission can take place. In a previous study, Ressler observed that conditioning by coupling acetophenone–electric shock odor modified the structure of olfactory receptor neurons for this odor in mice as well as the corresponding glomeruli in the olfactory bulb (first relay of olfactory information in the brain). But this neurophysiological data did not explain the transmission of fear to the acetophenone odor in the progeny. The researchers then came up with the idea of analyzing the sperm of stressed males and discovered that the part of the DNA sequence responsible for acetophenone sensitivity was more predominant than in controls, a change found in the offspring. This difference may have been due to less methylation in the region of the DNAencoding acetophenone. Methylation is a typical epigenetic process that blocks the expression of a gene, while hypomethylation can lead to overexpression. This hypothesis seems to be true because other studies have since been published on other models that show that changes related to environmental effects can not only be transmitted to progeny but can also be transmitted over a few generations and then erased. It is, therefore, easy to understand the adaptive value of epigenetic transmission, both rapid and selective, which is superimposed on traditional genetic transmission. Thus, the work of Dias and Ressler is not only remarkable because it is the first to suggest the possibility of epigenetic transmission but also because it is based on three concomitant approaches: behavioral, neuro-cellular and genetic. This methodological complementarity makes it possible to better understand complex phenomena such as the fear of an odor learned and transmitted to the offspring. A congruent study (Debiec and Sullivan 2014), published at the same time, demonstrates the role of certain brain structures in these mechanisms, particularly the amygdala cortex.

40 Odor and Pain

Figure 40.1. Examples of images from the “mouse grimace scale”1. For a color version of this figure, see www.iste.co.uk/brand/odors.zip

The Alan Edwards Research Center at McGill University in Montreal is working on the topic of pain. They still have a lot of work to do, as do all teams dedicated to this subject, because the mechanisms involved are extremely complex. Indeed, it is well-known that some people subjected to intense stimulation of nociceptors (pain receptors) may experience only a weak painful sensation (or even no pain at all in some cases), while others will suffer greatly while nociceptor stimulation is low or almost nonexistent. Similarly, some are highly sensitive to placebo relief, while others see no improvement, even after very high doses of morphine! There is a high inter- and intra-individual variability in pain perception due to the fact that many mechanisms (sensory, pharmacological, genetic, psychological, etc.) act together. The advantage for pain researchers is that once ethical issues have been overcome (there always comes a time when it is necessary to                                         1 Available at: research.unc.edu/files/2012/11/CCM3_022603.pdf.

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cause harm in order to advance our understanding of pain!), there is no shortage of ways to stimulate them: high temperature (therefore, burning!), high pressure (or crushing!), electric shocks, various injections and so on. In a completely subjective way, the staff at Alan Edwards made a curious observation – when the workers were male, the animals seemed to suffer less than when the women were in control of maneuvering. Obviously, it is difficult to get a mouse to fill out an evaluation scale from 0 to 10 on the intensity of perceived pain... but in their great inventiveness, the researchers developed (and validated) a “mouse grimace scale” (MGS). Genuinely! The interested reader (or a slightly sadistic voyeur) can refer to the link in footnote 1 of this chapter. The document explains the procedure and provides photos of the famous faces, including the example inserted at the top of this chapter (Figure 40.1). Using this scale (Sorge et al. 2014), they administered intraperitoneal injections of zimosan A (an inflammatory agent), which induced rapid pain within the first 30 min after the injection and gradually faded away over the next 30 min. They compared three conditions, namely a male or female experimenter 50 cm from the animal and also without an experimenter. The MGS score decreased significantly in the presence of a man, while the presence of a woman did not change anything compared to the situation “without an experimenter”. They obtained the same results with cotton pads worn under t-shirts in the armpits during the night before the measurements, which proved that the effect was due to odor. For completeness, it should be noted that the analgesic effect of male odor works in male and female mice (although the effect is stronger in female mice). Curiously, while the cotton pads of both sexes were presented simultaneously, the analgesic effect was not visible. Continuing their investigations, Jeffrey Mogil’s collaborators logically sought to determine whether the effect depended on the intensity of the pain caused. They then performed a conventional test called a “formalin test”2 in which diluted formalin is subcutaneously injected into one of the animal’s                                         2 The formalin test makes it possible to measure the animal’s behavioral response as a function of the intensity of the pain caused (level of dilution), particularly in the first phase (5–10 min) resulting from the direct activation of nociceptors. The rating is as follows: 0 = normal posture; 1 = the injected leg remains on the ground without supporting the animal; 2 = the injected leg is clearly raised (protective posture); 3 = the paw is licked, chewed, shaken, and so on.

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front legs. They compared behavioral responses with injections at 1% and 5%. It appeared that the analgesic effect of male axillary odor worked in the case of mild to moderate pain (formaldehyde 1%) and not in the case of more intense pain (formaldehyde 5%). The molecules responsible for this analgesic effect were identified, including hexanoic acid, androstenone and androstadienone. These chemical signals are relatively invariant in mammals, so the researchers were able to demonstrate that the effects observed with human male odor were also observed with odors from other male animals (e.g. rats, dogs and cats). However, the analgesic effect was not observed with odors from castrated males (the human species did not participate in this part of the experiment), which underlines the essential role played by androgens in this effect. The explanation proposed by the Montreal researchers is based on a stress-induced analgesia (SIA) process generated by the downward modulatory pathways of pain in the spinal cord. They confirmed this assertion by measuring corticosterone levels (a stress hormone) and neuronal activation measures (c-Fos marker) in the spinal cord. The comprehensive study by Mogil’s team particularly highlights the possible connections between pain and olfaction. There are multiple connections and they occur at several levels. It is known, for example, that interactions exist at the molecular level for a pain insensitive phenotype associated with a loss (or very marked decrease) in smell due to a specific genetic mutation (Goldberg et al. 2007). As early as 1959, the link between lack of pain perception and anosmia was mentioned in a child, and today, the common genetic basis is identified; it concerns a dysfunction of the Nav1.7 sodium channels. Nociception and olfaction also meet at the central level where several areas process both nociceptive and olfactory information. Finally, the role of odors in pain management and relief, and even in the clinical treatment of pain, is scientifically supported. Unpleasant odors result in higher pain scores in comparison to pleasant odors that can induce a positive mood contributing to the perception of less intense pain (Bartolo et al. 2013; Prescott and Wikie 2007). Several recent studies, which would take too long to mention here, have used the scent of lavender or Damask rose (it probably also works with other varieties), producing proven analgesic effects with different types of pain. These studies confirm the initial work of Chantal Villemure in 2003. It was based on the observation that positive stimuli such as music or humorous films reduce painful sensations. Odorants also modify mood with the advantage of a rapid effect of only 2 to 3 min after being perceived. The interest of Villemure’s work is to have established an individual threshold

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for pain. To do this, she obtained a moderate pain score by gradually increasing the temperature (between 36°C and 48°C) of a small heating plate placed on the inner side of the forearm. Then, for each subject, she delivered a temperature of 2°C above the individual threshold, with and without odor. She showed that modulating mood through odor reduces the painful sensation, and also that focusing attention on odors helps to reduce it. However, it is naturally not advisable, if necessary, to focus on pain. This chapter is not intended to raise false hopes and its conclusion will be lexical. While odor can have a partly analgesic effect (which reduces pain), it is far from having a complete analgesic effect, one that removes all pain.

41 Odorology

Figure 41.1. Dog performing an identification session (Marchal et al. 2016)1

An identity parade, or a lineup, is a well-known police technique that consists of presenting several people (called “distractors” – usually of similar size and morphology) to a victim or witness of a crime alongside the suspect for recognition. The same method can be used with photographs. The main problem is that this method is not always very reliable. This is why another technique based on the same principle has been developed in recent years, namely, odorology. As its name suggests, it is a technique for identifying human odors using trained dogs. It was first initiated in Hungary, one of the only countries to use this practice as evidence, although a few others (e.g. Germany or Belgium) use it in some of their investigations. Naturally, the recognition of people by dogs through body odor has long been known (Romanes 1887). The police traditionally use the method to track down a runaway, for example, but criminals do not necessarily leave                                         1 Available at: www2.cnrs.fr/presse/communique/4405.htm.

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their scarves, let alone their t-shirts2, at a crime scene. The first step is to collect body odors where the perpetrator is supposed to have deposited them using strips of special fabric (on the handle of a door, on the steering wheel of a car, etc.). These strips are then stored in sterile jars and it is estimated that, under these conditions, the fabric can remain impregnated with the odor for about 10 years! However, the sampling itself must be carried out quickly because the odorous molecules are volatile: 90% of positive results occur within 24 h and almost no results occur beyond four days after the deposit. If a suspect is stopped, he or she must then rub a cloth in both hands for several minutes to soak it with their odor. This cloth, also kept in a sterile jar, will be used as a reference and our friends the dogs can start working. The problem with the use of dogs’ smelling abilities in the identification of people implicated by the courts is first and foremost a lack of international standards for dog training. Indeed, it is well known that the accuracy of identification depends largely on the quality of the dog’s training! This is why a Lyon-based team has worked for many years to validate a protocol that can serve as a reference in training and in “olfactory tapering” exercises (Figure 41.1) for the police and, consequently, for the courts. In the work of Marchal et al. (2016), German Shepherd and Belgian Shepherd dogs were trained for five days a week, from Monday to Friday (they rested on weekends!), by positive reinforcement (food rewards or games given by the handler following each successful interaction). Five identical pots were arranged on a 20-cm-wide and 9-m-long line on the ground. Body odors were collected according to forensic standards. It should be noted that, in France, if a suspect refuses to give his scent, they may be sentenced to imprisonment, with reference to article 55-1 of the French Code of Criminal Procedure. Of course, control samples are collected in the same way, except that the participants are voluntary and do not risk imprisonment if they refuse. During each daily session, the training consisted of six to eight trials in a row with a reward of 10 g of Knacki sausage3. First, the dog had to be taught to sniff in the pots for a minimum of 5 s. Then, several steps followed one after the another. In step 1, all the jars contained a piece of cotton and a piece of sausage. In step 2, all jars contained a piece of cotton but only two                                         2 With reference to the many studies cited in this book that work on body odors using t-shirts worn by voluntary odor donors. 3 In the following steps, the reward can also be a game (ball).

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(randomly arranged) contained the reinforcement. The dog was rewarded if it kept its nose in these two pots only. In step 3, only one pot contained the reinforcement. The dog was rewarded when it kept its nose in the pot and then sat in front of it. When dogs got 100% correct answers, they could move on to step 4 and human odor recognition. In this step, only one out of five jars contained the human body odor, which is called an odorant sample (OS). At this stage, several donors were used and, as before, the dog was rewarded when it kept its nose close for at least 5 s and sat in front of the correct pot. Only animals that achieved a 95% success score in 20 successive trials could proceed to step 5. This last step consisted of identifying the odorous trace (OT) taken from a crime scene from the odorous sample (OS), and was divided into three parts. In step 5.1, one jar contained one odorous sample to be identified (OSi), and the other four contained samples from four different people. The dog sniffed the OSi and then performed the test (OSi configuration presented/OSi recognized). In step 5.2, one jar contained the odorous trace to be identified (OTi), and the other four jars contained odorous traces from four different people. The dog sniffed the odorous sample to be identified (OSi) and then carried out the test (OSi configuration presented/OTi recognized). In step 5.3, one jar contained the odorous sample to be identified (OSi), and the other four jars contained samples from four different people. The dog sniffed the odorous trace to be identified (OTi) and then carried out the test (OTi configuration presented/OS recognized). Training was considered satisfactory at this stage if the dog made 100% correct identifications on a minimum of 100 consecutive tests (which corresponded to 12 sessions and was equivalent to 2–3 weeks of work), but only dogs that did not give false alarms (sitting in front of the wrong pot, to be distinguished from not sitting at all, including in front of the right pot) on 200 consecutive tests entered the judicial program! The entire training procedure lasted between 18 and 20 months. This method was validated over a period of more than 10 years, from 2003 to 2014, with spectacular results since it has led to 120 criminal identifications in 435 cases where it has been used (from 2003 to 2016, 162 identifications in 522 cases). As mentioned above, this “on-the-spot” validation confirmed the importance of rapid sampling of body odors since, in 86.5% of cases of successful identification, this sampling took place within 24 h of the crime, and only 13.5% of cases beyond 24 h. The researchers noted that training not only improves scores but also improves the sensitivity of dogs, which reminds us – as has already been proven – that olfactory training improves the sense of smell. Finally, German Shepherds are more efficient than Belgian Shepherds, perhaps due to the fact that they are more disciplined and attentive. Dogs’ sense of smell

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remains significantly more efficient than that of humans since for the same odor (Krestel et al. 1984), the sensitivity can be up to 10,000 times higher. Judicial authorities that easily validate a visual lineup by human identification should perhaps now favor an olfactory lineup with canine identification.

42 On the Trail of Odors

As in any field, scientific ineptitude exists and can also be legitimized in prestigious journals. This is the case in the journal Nature Neuroscience, which has an impact factor of 16, considered to be a very good rating. The impact factor is a value calculated from the number of times articles published in the journal are cited, compared to the number of articles published. In recent years, the impact factor has become the standard for scientific publication fame, but it does not always reflect the quality of published results. As a result, this standard is sometimes contested because questionable data may be published in high-profile journals, while highly relevant data may well be published in low-impact journals. The journal Nature Neuroscience published the joint work (Porter et al. 2007) of two teams of researchers – one American from the University of Berkeley and the other Israeli from the Weizmann Institute – whose objective was to find out if a human being could, like a dog, follow a scent trail in a meadow with their nose to the ground and... necessarily on all fours. To do this, the researchers created a scent trace in a meadow about 10 m long by spreading a chocolate aroma (the smell of truffles or game being considered incongruous here). Thirty-two student volunteers (without sciatica problems, which are not mentioned in the article but can be assumed!) were recruited to follow this trail in the grass, only with their noses. Participants wore blindfolds and headphones to avoid any interference with the other senses. The maximum time allowed was 10 min and, on the first attempt, two-thirds of the four-legged volunteers (21/32) managed to complete the task within the time limit. According to the researchers, their way of proceeding appeared very similar to that used by dogs, with a zigzag progression. This technique was based on the analysis of the intensity of the

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odor; when the concentration gradient was decreasing, one moved logically away from the source odor and vice versa. To prove that it is indeed the odorous trace that guides the participants, the trial was repeated with the nostrils blocked, and the authors concluded: “none of the subjects were able to follow the scent trail under these conditions, assuring the olfactory nature of the task”. That said, it is difficult to see what else could have made it possible to carry out this task, the relevance of which in everyday life is fully appreciated! In a second experiment, four participants underwent training for the same task, several times a day and over a few days. As the trials progressed, it appeared that the deviation from the trace decreased and the velocity improved. However, for these two parameters, the progression was not similar. Concerning the deviation from the trace, from the second day of training, the participants obtained results that no longer improved (from an average deviation of about 25–30 cm to an average deviation of about 15 cm that it seems difficult to reduce). On the other hand, regarding velocity, on the fourth day of training, performance continued to improve linearly, which led the authors to suggest long-term training. But since this was a serious study, researchers carried out other types of analyses. In situations involving odor, there is active air uptake behavior in the nostrils (sniffing), which is absent in normal breathing situations. Researchers therefore counted the number of sniffs and discovered that as the velocity increased, the number of inhalations increased, which seems logical considering that each sniff is a form of information gathering. The average number of sniffs thus increased from 0.3 to 0.7 sniff/s among study participants. It should be noted that this figure remains far below that of the dog, which has long been known (Thesen et al. 1993) to achieve a remarkable frequency of 6 sniffs/s in odorous conditions. More interestingly, the researchers also studied the path of the air inhaled by each nostril. The two airflows inhaled by each nostril were not parallel due to their anatomy but slightly offset toward the periphery, which implied different spaces involved and different airflows. As a result, one nostril could carry odorous molecules to the receptors, while the other draws up the air without odor or at different concentrations. This feature exists for vision and hearing; with odors, it is called stereo olfaction and plays a crucial role in odor detection navigation. In another experiment, on the same principle, 14 subjects followed the odor trace twice in monorhinal conditions (with only one nostril, the other being blocked) and bi-hinal (with both nostrils) conditions. To avoid the learning effect mentioned above, the execution was

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counterbalanced. The results show that the performance (accuracy and velocity) was much lower in monorhinal conditions and underlined the need for stereo olfaction to orient oneself using an odorous trace. In a final experiment, the researchers invented a device that would carry the same airflow through both nostrils. They confirmed, with this device preventing stereo olfaction, the worst tracking performance. From an adaptive point of view, following an odorous trace on the ground is useless to humanity, while it is crucial for many animal species. During evolution, by standing up and moving nostrils away from the ground, humans have abandoned this method of gathering information. However, one can imagine that this stereo olfactive process is still at work in the standing position. It would probably have been more appropriate to use a protocol to assess the extent to which an odorous trace on the ground or at half-height could be followed by humans in a habitual bipedal situation. Can we imagine experiments where dogs would have to move on their hind legs?

43 The Electronic Nose

At the beginning of the 20th Century, in one of the volumes of his Souvenirs entomologiques, Jean-Henri Fabre devoted a chapter to the sense of smell (series VII, Chapter 25), in which the intelligence of observation, experimentation and deduction fascinated us. J.-H. Fabre ends this chapter with these sentences: “Like light, odor has its X-rays. That science, instructed by the beast, will one day provide us with the radiographer of odors, and this artificial nose will open up a whole world of wonders for us” (author’s translation). It was not until 1961 that R.W. Moncrieff developed a mechanical nose and then until 1964 that Wilkens and Hartmann proposed a first attempt at an electronic nose. In the 1980s, many prototypes were developed and, from the following decade, commercial devices were available on the market. Their design involves very different disciplines (chemistry, physics, electronics, modeling, signal processing, etc.) and the operating principle varies from gas chromatography techniques to models that approach the configuration of the mammalian olfactory system. The e-nose includes a sampling system for gaseous substances to be analyzed, sensors capable of detecting very low gas concentrations (in the order of ppm and in a number of cases in the order of ppb), a signal processing system, and an analysis system that ultimately identifies molecules and determines their respective concentrations. The challenge of developing an electronic nose is considerable given the complexity of gas mixtures, the interactions between molecules, and their permanent evolution according to many factors (humidity, temperature, pressure, etc.). In addition, the system must allow the elimination of molecules in order to avoid contamination during the subsequent analysis sequences.

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Of course, an electronic nose is not universal1; each device is relatively specific and its sensors are selective for the molecules relevant to its use. Currently, they are used in many sectors of activity, such as the environment (pollution measurement, detection of toxic substances, etc.), explosives detection, the food industry (e.g. to test new products, to evaluate the quality of products such as fruit and vegetables2 and their degree of ripeness, etc.), perfumery, pharmacy or the medical world (see Chapter 25). A new generation of electronic noses has recently emerged which uses biosensors (referred to as bioelectronic noses) using enzymatic reactions (Wasilewski et al. 2017). These detectors, also called nanobiosensors, have a bright future. They are divided into two categories according to whether they use receptor cells (from dogs or humans, in particular) grown in yeasts or in proteins. The interest is that by using all the receivers, the system should one day make it possible to detect all the odors in our repertoire. In the meantime, here are some specimens of electronic noses that can be used in very different fields of application. A German team (Voss et al. 2014) has developed an electronic nose capable of differentiating a cannabis smoker from an ordinary tobacco smoker by simply analyzing body odor collected from the forearm: simpler and faster than urine analysis, less restrictive than blood sampling. The researchers conclude that a wide eNoses range (market?) is opening up with regard to the variety of illicit substances consumed (Lorwongtragool et al. 2014). The HERACLES electronic nose by Alpha Mos (France) is based on a gas chromatography technique. It is used in a wide variety of contexts such as quality control of dog food, detection of diacetyl3 in orange juice, analysis of bad odors in rinsing water, or authenticating the origin of a Cognac. Hossam Haick’s Israeli team has developed an electronic nose called “Na-Nose” that detects several forms of cancer from patients’ breath. Tested                                         1 Some companies are trying to create devices that could be similar to a human nose, such as an olfactory prosthesis for anosmic people, but we are still far from a device reimbursed by Social Security! One of the most advanced companies is Aryballe Technologies based in Grenoble, France. It has developed “NeOse”, which makes it possible to detect more than a hundred olfactory signatures. 2 Electronic noses have already been used in some supermarkets to detect the odor of the fruit or vegetable purchased, a kind of olfactory scanning. 3 Diacetyl is a by-product of fermentation. It is widely used in the food industry to give a buttered aroma. It is also found in electronic cigarette liquids. Over the past decade, synthetic diacetyl has given rise to serious health concerns.

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on several thousand patients worldwide, its effectiveness is around 95%. In the long term, and at a modest cost, preventive tests could be considered for the entire population. In a broader context, where gadgets can be used instantaneously, an Israeli team has developed a smartphone application to determine the composition of objects and food products from a photograph. The tool, called Unispectral, is based on the principle of hyperspectral imaging to identify the electromagnetic fingerprints specific to each object. The information is then sent to a database for analysis and comparison. All we have to do now is wait for the response! But there is still a big difference between the electronic nose and the human nose. With the latter, in fact, the first response obtained is hedonic (pleasant/unpleasant) before any identification (often very difficult), while the eNose identifies very well but does not provide any information on the potential pleasure brought by the molecule.

 

44 The Plane Nose: The Methods of the Fraunhofer-Institut für Bauphysik to Get Up in the Air

SNCF1 sandwiches have long been denigrated because of their uncertain appearance, their spongy texture, and their lack of taste. Over the past two or three decades, air transport has grown at a rate of 6% per year, low-cost airlines have multiplied, and aircraft use has become more widespread. The debate of food on transport, initially discussed exclusively in the context of rail travel, now also includes the meal trays served in flight. Many travelers find the meals tasteless, but more surprisingly, drinks of any kind (soft drinks, beer, wine, strong alcohols, etc.) are also considered less aromatic or of unusual taste in flight. Manufacturers have, for some time, already integrated this observation and do not hesitate to increase the quantities of salt and sugar and serve more spicy dishes in order to get closer to the perception on Earth. Environmental conditions in flight therefore influence our perception, and Andrea Burdack-Freitag’s team at the Fraunhofer Institute in Germany has been working on this issue (Burdack-Freitag et al. 2011). The Fraunhofer Institute has no shortage of resources, and researchers were able to use the so-called FTF (Flight Test Facility) system for their work. It is a fuselage part of an Airbus A310 (15.5 m long) installed in a huge metal tube (30 m long and 9.6 m in diameter), which allows most of the parameters in flight to be reconstructed (vibrations, background noise, humidity, pressure, temperature, etc.). In their study, the researchers wanted to know the influence of pressure changes on olfactory and gustatory perception independently of other parameters, particularly the humidity                                         1 SNCF: Société Nationale des Chemins de Fer, a French railway company.

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level. We know that in the cabin, even before take-off, the humidity level drops by more than 10%, which obviously has the effect of drying out the mucous membranes, increasing nasal resistance, and contributing to lower odor performance2. Burdack-Freitag et al. therefore conducted tests in two situations, at normal atmospheric pressure (934 hPa) and at low atmospheric pressure (753 hPa), corresponding to the conditions of a pressurized cabin. In flight, atmospheric pressure decreases and oxygen pressure (pO2) is similar to the pressure on Earth at an altitude between 2,000 and 2,500 m or about 70% of that measured at the sea level. The other parameters were similar, namely, a temperature of 23°C and a humidity level of 15%. In the FTF system, the environment was realistic, giving the impression of a real flight and respecting the usual times of boarding (15–20 min), ascent (20–30 min), descent, and disembarkation. Two different flight times were tested: a short flight of about 2 h and a long flight of about 8 h. First, they assessed the participants’ olfactory thresholds of five odorants. The thresholds were higher (corresponding to a poorer perception) in three out of five cases, and above all, the quality of what was perceived was different at low pressure. For example, methoxybenzene, with its characteristic aniseed odor, lost this property in the pressurized cabin. They then evaluated the taste thresholds for the five basic flavors and caffeine. As with the sense of smell, the taste thresholds were higher, but there were large variations depending on the substances tested (low for sweet and salty and high for savory). Variations for caffeine were minimal. They also varied the level of salt in food preparation (tomato soup and bread) and the level of sugar (vanilla cream and red fruit gelatin) and tested preferences. It was quite clear that at low atmospheric pressure, subjects preferred foods with a higher salt or sugar content (a significant increase, in the order of 20–50%!). Finally, they evaluated the subjects’ perception of real food (starters, main courses, and desserts) and real drinks (white wines: Pinot, Chardonnay, Riesling and red wines: Bordeaux “Château Belgrave” and Valpolicella... only good ones, of course! For dishes, it is generally the sauces that differed in terms of perception. Again, the study shows that these differences depend on the products tested: for example, mango cream lost all                                         2 Changes in perception are not only due to olfactory and gustatory changes, since noise, radiation, or changes in magnetic field can induce different perceptions. For example, according to a 2011 study by scientists at the University of Manchester (Woods et al. 2011), when eating with a permanent background noise, there is a perception that the food is less sweet or less salty than when eating in silence. Something to be considered at the next meal in the canteen.

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its flavor in flight, while the taste of red fruit gelatinous cream remained unchanged. These differences between products are reflected in the appreciation of wines, sometimes unchanged, sometimes better, and sometimes worse. In total, the significant resources implemented by the Fraunhofer Institute team confirm: (1) that there are changes in perception due to the decrease in air pressure in flight and (2) that the observed changes are highly dependent on the type of product consumed. If you do not have the resources of the Fraunhofer Institute, it is possible to carry out relevant studies under natural conditions and at a lower cost. Thus, in 2013 (results published in 2014), a Turkish team (Altundag et al. 2014) studied the changes in olfactory perception in natural altitude conditions and at an altitude comparable to pressurized cabin conditions3, i.e. at 2,200 m above sea level. They worked in the Ordu region of northern Turkey, near the Black Sea. Forty-one volunteers (31 male and 10 female, average age 38 years) were assessed using Sniffin Sticks. The subjects did not reach altitude during the two weeks preceding the test and stayed for two days in a mountain village before reaching the chosen altitude. The air temperature at the seaside was 32°C, and the humidity level was 58%. The temperature at altitude was 20°C, and the humidity level was 20%. In both cases, the wind force was almost zero. The authors concluded that there was a slight decrease in the identification score at altitude (mean of 12.4–2,200 m and 13.6 at sea level). On the other hand, the detection thresholds carried out with butanol showed a very significant increase in the upper threshold (and therefore a decrease in sensitivity) of around 2.5 concentrations (the dilution ratio here was ½). The author of these words would have liked to be able to give the cost ratio (probably very high) between the two studies, but this is traditionally the type of data that is missing in publications...

                                        3 Another study (Cingi et al. 2011) carried out olfactory perception measurements at very high altitude (3,900 m), which showed a very significant decline in smell, but the temperature difference and hypoxia (compensated by faster ventilation) at this altitude are not comparable to the environment of a pressurized cabin.

 

 

45 The Gender of the Nose

It is generally accepted that women have a better sense of smell than men. This fact has been established for a long time (Brand 2001) and concerns all types of odor tasks. Women have better sensitivity (measured by lower detection thresholds) to most odors, as well as better identification, discrimination, and memorization skills. This superiority is almost systematically confirmed by indirect measurements, electrophysiology, or brain imaging, for example. The reasons for this female superiority remain largely unclear. There are naturally subtle genetic and hormonal differences, and hypotheses focus on women’s greater attention and interest in this type of task or a benefit conferred by the social organization of the human species during its evolution (e.g. tasks involving odor more frequently performed by women than men). Among the hundreds of studies dealing with olfactory differences according to sex, that of Diamond et al. (2006) of the Monell Chemical Senses Center in Philadelphia is particularly enlightening and corroborates the idea that repeated exposure to odors and/or training in odor perception improves sensitivity and thus reveals the flexibility of the olfactory system1. Precisely, Diamond’s observation is only valid for women and thus supports the phylogenetic hypothesis of exposure to odors, which differs according to gender.                                         1 The flexibility of the olfactory system concerns several dimensions and men can also benefit from it. In the study by Wysocki et al. (1989), men anosmic to androstenone trained over a long period of time (3 min, three times a day, for six weeks) to smell this molecule. Of the 20 subjects initially anosmic to androstenone, 10 managed to perceive it at the end of the training period.

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In the Monell study, men and women aged 20–32 years were tested using a conventional method to determine their detection threshold with benzaldehyde, an aromatic molecule with an odor similar to bitter almond. The originality of the protocol is based on the repetition (the article does not mention the details) of the threshold determination. We could almost talk about stress since the participants performed the detection test 30 times! In routine experiments, each test of this type lasted about 30 min, i.e. about 15 h of sniffing. However, it was worth it because, in the first tests, the results were similar between men and women, but as the test sessions progressed, it appeared that detection thresholds improved in women and remained almost stable in men (Figure 45.1). After 30 sessions, the difference in perceived concentration between men and women was about 1/11. The researchers then wondered whether the phenomenon could be systematic or whether it was specific to certain odors. Using a molecule with a similar odor to benzaldehyde (5-methylfurfural) and the same protocol, they effectively observed an improvement in sensitivity in women and not in men. However, using a molecule with a very different odor (isoamyl acetate), they did not observe any improvement in sensitivity, regardless of sex. To summarize, it seems that this ability to improve sensitivity according to exposure is specific to women but cannot be generalized to all odors. With regard to functional hypotheses, it is difficult to determine what is related to cognitive mechanisms (attention, learning, etc.) and what is related to biological mechanisms. However, a recent study presented below provides new insights. Few studies to date have found real olfactory dimorphisms at the neurocellular level. This has been done, however, thanks to a Brazilian team (Oliveira-Punto et al. 2014) who focused on the first relay of olfactory information in the brain, called the olfactory bulb (OB)2. Oliveira-Pinto et al. studied post-mortem olfactory bulbs from seven men and eleven women aged 55–94 years of age. The age distribution for both sexes was similar, which from a neurocellular point of view is crucial, given the changes due to aging at this level. The causes of death were also similar and, for the most part, it was the result of a pulmonary edema. They first weighed the olfactory bulbs, with great precision in dissection because the variability is measured in milligrams! The average weight of the OBs for women was 0.132 g and that of men was 0.137 g, not a significant difference. They then                                         2 Scientists always talk about the olfactory bulb, but this can lead to misunderstanding because, in reality, there are two olfactory bulbs, right and left, each connected to the ipsilateral nostril.

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Concentration thresholds (mM) 

evaluated the cell count using a fast and reliable method (isotropic fractionator). The average number of cells of all types was 16.2 million for a female OB and only 9.2 million for a male OB, which represented a considerable difference of 43.2%. Concerning the neurons themselves (relating to olfactory information), the average number was 6.9 million for women and 3.5 million for men, a difference of 49.3%. Finally, for nonneural cells, the average number was 9.3 million for women and 5.7 million for men with a difference of 38.7%. In total, this represented a cellular advantage of between 40% and 50% for women. This study first reminds us that the size or weight of the brain or its specific structures is not very correlated with functional reality and there are many examples: Einstein’s brain weight was about 10% lower than the average and he is not remembered as an idiot; in Parkinson’s disease, 60–80% of neurons in the main area affected by degeneration (called substantia nigra) are already destroyed when the first symptoms appear. But as far as the number of cells is concerned, it is difficult not to hypothesize a functional impact on the sense of smell of this numerical superiority of cells in female OBs, the equipollence of “the function creates the bulb”... At this stage, and as the authors rightly indicate, the important thing is now to look, among the many areas receiving afferences of the olfactory bulb, at whether some are quantitatively more connected in women than in men.

Men Women

Test sessions Figure 45.1. Evolution of olfactory sensitivity as tests are repeated; comparison between men and women (adapted from Diamond et al. 2005)

 

 

46 The Newborn’s Nose

The olfactory system is one of the most mature sensory modalities at birth. This system develops early in utero since receptor cells begin to appear between the 6th and 7th weeks of pregnancy and potentially functional ciliated receptors are visible as early as the 11th week. Observation of premature babies suggests that reactivity to odors can be efficient between 29 and 30 weeks’ gestation and ultimately quite close to the olfactory sensitivity of a newborn. The fetus is alongside odorous molecules present in the amniotic fluid. At birth, the baby is not only able to distinguish between the amniotic fluid in which it was bathed and a foreign amniotic fluid, but it also appears reactive after birth to specific odors present in this fluid during the last trimester of gestation (Varendi et al. 1996). Many and varied molecules are found in the amniotic fluid, depending on the mother’s diet. It has been shown (Mennela et al. 2001) that regular consumption of carrot purée by the mother during the later stages of pregnancy induces different behavioral responses in children of around six months of age when carrot purée is introduced into their diet, depending on whether or not they have been exposed to this flavor in utero. Thus, if it were still necessary, the functioning of the olfactory system demonstrates the effective existence of prenatal learning, which lasts well beyond a few days after birth. In addition, the baby is able to discriminate because they have preferences for the smell of breast milk a few minutes after birth, this smell being the only one capable of inducing a preferential orientation of the head that will guide them toward the nipple. In general, the infant is very reactive

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to maternal scents. At six days old, breastfed newborns preferentially turn their heads to cotton impregnated with their mother’s smell for a longer period of time than cotton impregnated with the smell of another woman. The most commonly used and recognized odors in experimental studies are those of the breast, neck, and armpits. In this context, skin-to-skin contact at birth is crucial in the baby’s recognition of the mother. All early childhood practitioners agree that the recognition of the mother by smell is an essential element in the development of the mother–child bond and the attachment process. Vaglio et al. (2009) confirmed the existence of a mother’s odor at the end of pregnancy and after childbirth. Five specific molecules have been isolated (1-dodecanol, 1-1'-octane Oxybis, isocurcumenol, ð-hexylcinnamic, aldehyde, and isopropyl myristate), which participate in the mother’s individual chemical signature. From a functional point of view, the mother’s odor plays a role in managing fear, stress, and physical suffering. Several studies have experimentally shown that the presence of a baby’s mother odor (unlike that of another mother) or breast milk helps to reduce crying and relieve the baby (e.g. in the case of a medical procedure), with physiological parameters such as heart rate, cortisol level, or oxygenation of the blood corroborating these observations1. Among the most frequently selected volatile compounds are indeed milk and colostrum. However, in recent years, research has focused on the different structures of the breast. Apart from the nipple, the Montgomery glands present in the areola, formed by sebaceous and lactiferous units, produce volatile compounds, some of which are identical to those of milk while others are specific to these glands. The latter participate in chemical sensory communication between mother and child; they are able to produce an effect in sleeping children, stimulate appetite, and increase certain behaviors. All this work reminds us of the importance of maternal odor even when skin-to-skin contact is not possible for medical reasons. Therefore, in the case of children in incubators, for example, the use of clothing worn by the mother to maintain the olfactory bond is recommended. However, the infant’s olfactory faculties are not limited to maternal odors. Several studies have shown that newborns have the ability to finely discriminate against odors. Goubet et al. (2002), for example, used a habituation paradigm (repeated presentation of the same odorous stimulus led to a progressive decrease in response) and subsequently stimulated with a new odorant. After                                         1 It has also been shown that odors reduce apnea in newborns, especially premature babies.

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the gradual extinction of facial movements during habituation, a renewed facial expressiveness appeared following the presentation of the second stimulus, confirming the discrimination. The authors performed the experiment with vanilla and aniseed and produced the same results in the case of “vanilla followed by aniseed” and in the case of “aniseed followed by vanilla”. In addition, this variation in reactivity was found to be similar in full-term and premature infants, suggesting identical discrimination abilities. On the other hand, the question of the hedonic appreciation of odors by infants was not really settled. Hedonic appreciation is largely constructed through experiential learning about a particular odorant (as is the case with breast milk, which contains similar odor indices to amniotic fluid) and work that shows facial expressions and oral movements expressing spontaneous negative appreciation in infants (such as the disgust pattern) is frequently obtained when using odorants that jointly activate the trigeminal system (see Chapter 16). The results obtained would, therefore, not be within the scope of the fragrant evocation. And what about the baby’s own smell as understood by the mother? Attachment is logically a two-way process and the baby’s smell plays an important role for the mother. In general, babies’ odor is considered pleasant, and mothers naturally recognize their own offspring by odor, but what has recently been demonstrated (Lunström et al. 2013) is that maternal status involves different neural activations in response to the baby odor in general. Women who had recently given birth and women who had never had children were compared using brain imaging. Differentiated activations of dopaminergic activity, particularly in striatal areas, suggest that baby odor may be involved in activating the reward circuit in mothers (and not in women who have not had children) and thus contribute to the behavioral regulation of mother–child interactions.

 

 

47 The Smell of a Handshake

In 2010, the Chevrolet brand published, with the help of a psychology professor from the University of Manchester, a manual for the correct handshake for its sales representatives1. No less than 12 criteria were listed, which had to be mastered in order not to make any mistakes and to convince the partner, whoever they are: customer, boss, partner and so on. This funny anecdote reveals the importance of this ritualistic gesture, which is nevertheless banal. The handshake among the human species has a long history since representations dating back to several centuries BC illustrate this behavior, mainly related to entering (and leaving) in communication with others. First, it involves establishing physical contact with the person encountered, a contact that gives multiple somesthetic information: temperature, humidity, strength, duration, and so on, and can reveal certain aspects of personality. Of course, it has long been known (Given 1929) that shaking hands is also a privileged opportunity to share remarkable quantities of germs and all kinds of bacteria with our fellow creatures, even when we wash our hands regularly. But what we did not know until then was that a handshake also makes it possible to feel who you are talking to. This was demonstrated by an Israeli team from the Weismann Institute (Frumin et al. 2015; and for a summary of the study: Semin and Farias 2015).                                         1 According to Professor Geoffrey Beattie, an ideal handshake should have the following characteristics: “The rules for men and women are the same: a right hand, a complete grip, a firm squeeze (but not too strong), in a mid-point position between yourself and the other person, a cool and dry palm, approximately three shakes, with a medium level of vigour, held for no longer than 2 to 3 s, with eye contact kept throughout and a good natural smile with a slow offset with, of course, an appropriate accompanying verbal statement, make up the basic constituent parts for the perfect handshake”. Simple as pie.

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The researchers recruited 271 participants who did not know the true purpose of the study. Three minutes after their arrival in the experiment room, they were greeted individually by a person who delivered a standard text of about 20 seconds, either only orally or by shaking hands. This contact phase and the next 80 seconds were filmed. From the video recordings, the number of times each participant brought their hands toward their nose or near area (to be precise, above the upper lip and below the eyes) and the contact time was counted. The result was that participants who had their hands shaken spent twice as much time then placing their hands in the nasal area as others. However, touching your nose does not mean sniffing (behavior necessary for the proper delivery of volatile odorous molecules to the receptors) and the researchers wanted to verify that participants with their hands held toward their faces did for the purpose of smelling. Also, in a second experimental session, they equipped volunteers with catheters in the nostrils to measure the flow of inhaled air. The results confirmed that inhalation was much more important than normal breathing and that sniffing led to the hand being smelled. The next logical question was to know which chemical compounds were likely to provide potential information during sniffing. The researchers then shook hands with sterile gloves and analyzed the collected chemicals. They mainly noted the presence of squalene and decahexaenoic acid2. Squalene is a complex formula lipid, produced naturally by many mammals (including humans) and found in sebum. It owes its name to its strong presence in shark liver oil and has a slight floral odor. Decahexaenoic acid, also known as caproic acid, is a derivative of hexane. It is a fatty acid found in mammals and insects, which has a cheese or even goat odor (hence its name). These substances are known for their role as chemosignals in inter-individual communication in dogs or rats, for example. In these species, they participate in the determination of the congener’s status and, consequently, in the regulation of interactions (Stockley et al. 2013). More discreet than dogs sniffing each other’s rear-ends, smelling the other’s odor through the handshake could be a behavioral relic of the social animal inside us. Of course, there are other ways to connect. Kissing, for example, is an alternative in the greeting sequence. Let us, therefore, wager that the researchers at the Weismann Institute, in their great inventiveness, should soon equip volunteers with nasal catheters during kissing or hongi                                         2 There is an individual olfactory signature of the traces left by the hands (see Chapter 41).

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sessions, a traditional Maori greeting that consists of pressing noses together! In the very recent evolutionary history of the human species, a new greeting behavior has appeared – the fist bump or fist to fist greeting – which would not have escaped anyone’s notice. Celebrities like Barack Obama have made it their trademark, a cooler and more egalitarian gesture according to anthropologists who also predict that this behavior will continue to gain ground, at the expense of the traditional handshake. In the United Kingdom, Sara Mela and David Whitworth (2014) compared the number of bacteria exchanged during a handshake and a fist bump. The results, although predictable, are irrefutable: in the latter case, due to the characteristics of the touch zone and the brevity of the contact, the number of bacteria exchanged is divided by 10. The authors even suggest that this mode of greeting should become mandatory in some cases, such as in hospitals. But, as a result, what about the transmission of chemical information? That being said, holding your hand to your nose after shaking another person’s hand may well be an ancestral behavior with no real functional meaning today, such as dogs that turn several times on themselves before lying on the carpet in the living room...

 

 

48 The Nose and Perfumes

While the use of perfumes dates back to the dawn of time, it seems that in recent decades, in industrialized countries, cosmetic production and perfumery have exponentially grown. Therefore, we can wonder about the possible significance of the choice of fragrances worn, beyond wanting to mask/modify one’s own body odor or to be a simple indicator of cleanliness. In some cases, this can help to provide information on social status and personality, and increase sexual attractiveness. For the latter, it seems that the use of a clearly identifiable male/female fragrance and its congruence with the gender of the person wearing it is necessary (Marinova and Moss 2014). One of the questions that arise is whether perfume actually masks body odor or whether the mixture of body odor + perfume results in a new compound. Jan Havlicek’s team at the University of Prague has conducted several experiments about this. Initially (Lenochova et al. 2012), this team showed that the association “body odor and a person’s usual perfume” is perceived as different from each of the two compounds, a kind of specific mixture. In addition, this combination was perceived as more pleasant than body odor alone. Very interestingly, the researchers then compared the perception of this usual mixture with another combination of “body odor and unusual fragrance” in 12 male donors. The samples were evaluated by 21 women and the results were significant in that they evaluated the mixtures “body odor and usual perfume” as more pleasant than the mixtures “body odor and unusual perfume.” This suggests that the choice of fragrance is made – at least in part – on the basis of a good interaction with one’s own body odor, which can enhance the pleasant perception of the cocktail in the nose of others. To go further, researchers from the above-mentioned team

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(Allen et al. 2015) wondered whether this mixture could also help to discriminate against the odors of others. To do this, they collected axillary odors from six male and six female donors under three conditions: fragrancefree, usual fragrance, and unusual fragrance. The experiment consisted in detecting intrusion using a triangular test1. For this purpose and under each condition, two samples of the same person and one sample of another (of the same sex) were presented2. In a triangular test, the probability of answering just by chance is obviously 1/3. The results obtained with a large population of both sexes (238 participants for male odors and 189 participants for female odors) clearly indicate that in the presence of body odors alone, the intrusion is significantly better identified than in the presence of a “body odor + perfume” mixture, which is logical. But more interestingly, the results also indicated that the intrusion was significantly better identified in the case of “body odor + usual perfume” than in the case of “body odor + unusual perfume”. Clearly, this supports the conclusions of previous research (Lenochova et al. 2012) that the choice of fragrance is partly based on a certain adequacy of what it produces in interaction with body odor. This hedonic adequacy also proves to be valid from the point of view of discrimination, in essence a kind of personal olfactory signature. Body odor alone can provide information on certain personality traits such as extroversion, neuroticism3, or dominance (Sorokowska et al. 2012). Based on this observation, Sorokowska et al. (2016) compared personality judgments between the condition “body odor alone” and the condition “body odor + usual perfume”. The impact of the presence of perfume seemed to depend on the type of personality trait. For example, neuroticism assessment was poorer in the “body odor + usual fragrance” condition (compared to the “body odor alone” condition) while it was unchanged for dominance. These observations were corroborated by another team (with a different experimental protocol), which effectively shows that social judgments based on olfactory knowledge differ, depending on whether one is confronted with the body odor alone of others or their body odor associated with their usual perfume or deodorant (Gaby and Zayas 2017). Enough to feed the reflections of social psychology!                                         1 In a triangular test, three samples were presented, two of which were identical, and it was a question of determining which of the three was different from the other two. 2 For the “body odor + perfume” mixtures, it was naturally the same perfume both in the “usual perfume” condition and in the “unusual perfume” condition. 3 Neuroticism is a personality trait that leads to a tendency to experience negative emotions on a continuous basis.

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This research [which Jean-Baptiste Grenouille, the hero of the book Le Parfum by Patrick Süskind (1986), would not have denied] makes it possible to imagine perhaps an à la carte future for perfumes. There could be an individualized service where each person would provide their own body odor from which perfumers would create a personalized fragrance most appropriate in terms of hedonism, attractiveness, or even several fragrances depending on the circumstances (date, job interview, etc.). A nice market with potential for growth4, if we remember that body odor changes according to age (see also Chapter 32), physiological condition, or disease (see also Chapters 25 and 27).

                                        4 A team of Irish researchers (Gunaratne et al. 2015) has developed a product (it is not known whether to call it “perfume,” researchers call it “fragrant ionic liquid”) with self-regulating properties: the higher the level of perspiration, the more the product acts. This is an important point; it is not a question of masking the odor of sweat but making it odorless.

 

 

49 Odors… A Hobby?

The perception of time and estimation of duration are crucial data in our adaptation to different environments in which we operate. There are many factors that can change our perception of time. Thus, it is well-known that during boredom, time passes slowly, while in pleasant situations, time “passes quickly.” Similarly, if the task requires a lot of attention and has a high cognitive load, time will flow faster than if the situation is simple or repetitive. However, the nature of the task is not the only parameter that can change the perception of time. External stimuli (e.g. noise) can also play an important role, and odors are not to be neglected. From an experimental point of view, there are two main categories of measures, the so-called prospective measures for which subjects are informed that they will have to evaluate the time elapsed during one or more tasks and the so-called retrospective measures for which subjects are not informed before the task and must then estimate the time a posteriori. Thus, the perception of time is a complex phenomenon that involves both the level of attention and the mnemonic or information processing aspects, and emotional aspects (related to the pleasant/displacing nature of the task or the environment associated with the task). Most explanatory models concerning the perception of time are based on the existence of a pacemaker (which generates pulses) controlled by an internal clock. In this model, external stimuli can influence both the internal clock and the pacemaker. For example, with negatively judged auditory stimuli, time seems longer than if they are judged positively. It is, therefore, legitimate to believe that odors known for their strong pleasant or unpleasant connotations can produce the same effects. A study (Schreuder et al. 2014) using rosemary scent showed that time estimates were shorter in the presence of this odor than in odorless control conditions. Recently (Brand et al. 2016), research on the perception of time in a

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retrospective way (this is what is most used in everyday life) compared time estimates with two very different odors: one pleasant and non-irritating phenyl ethyl alcohol, close to the floral scent of rose, and the other pyridine, unpleasant and irritating (the study also included an odorless control condition). Participants were required to perform three types of tasks. The first task consisted in classifying 10 landscape photographs in the order of their preference without time limit and the experimenter recorded the time taken by each participant to do this. This task did not require any prerequisites and did not aim at any performance to be achieved. The second task was to point with a pen to a page full of circles as quickly as possible. This was an exercise in speed and precision. The experimenter stopped the task after 137 seconds. The third task was to perform more or less difficult mathematical operations. This was an exercise where concentration and cognitive effort were important. The experimenter stopped the task after 202 seconds. After each task, the subject had to complete a short questionnaire (difficulty level, pleasant character, duration, stress, and concentration level) in which the duration assessment was inserted without the subject knowing that the objective of the study was the evaluation of time. In the first task, the estimated time was always longer than the actual time and the time taken to complete the task was much longer in the presence of the odor (whatever it may be) than in the absence of one. In the second task, the estimated time was systematically lower than the real time with or without odor. This was probably due to the fact that the concentration of subjects in the execution of the exercise gave them the impression that it was shorter than in reality. In this case and due to the cognitive load, the presence of the odor did not influence the duration estimate. In the third task, the estimated time was systematically longer than the real time and in an equivalent way with or without the odor. In total, it appears: (1) that the influence of odors on the perception of time was highly dependent on the type of task performed; (2) that it was the presence of an odor that seemed to be acting, regardless of its characteristics; and (3) that the impact of odor on the perception of time was only efficient in tasks where the attention or cognitive load was low. From a marketing point of view, it is possible to imagine a use of smell so that consumers stay longer in a store. Few studies have attempted measurements in real situations, and the results are contradictory. Gueguen and Petr (2006) chose to scent a restaurant with lavender or lemon. It appeared that with lavender, customers stayed longer in the restaurant than without a particular odor or that of lemon. In 2014, Bouzzabia scented a

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store with different pleasant odors (mint, citrus fruits, ylang-ylang, etc.). Several parameters were measured, some of which were found to be very dependent on the presence of odors, but there was no influence of odors on the time spent inside the store. At the present time, while it is reasonable to assume that odors influence the perception of time, there is still a long way to go to elucidate the complexity of the mechanisms... and to know if odors can save or waste our time!

 

 

50 Tell Me What You Smell, I’ll Tell You Who You Are, But Not Where You Come From: On Genetic Variations in Odor Perception

There is a very wide diversity of odor perception from one person to another, which is not limited to whether or not we perceive a particular molecule (specific anosmia). Diversity is also found in the detection thresholds (and, therefore, perceived intensity) and in terms of hedonic quality. To address this diversity, Leslie Vosshall’s team at Rockefeller University (Keller et al. 2012) conducted a demographic survey of New York City among 391 different people in terms of gender, age, ethnicity, habits, and so on. The researchers used a large number of odors and a large number of tests. While known trends were found (influence of gender, age, eating habits, smoking, etc.), the fact remained that what predominated was very high inter-individual variability. In an original modeling study (Secundo et al. 2015), a team of Israeli researchers used a sample group of 28 odors and 54 descriptors evaluated by 89 participants. The results showed – as in the previous study – that each person had their own nose (a unique olfactory fingerprint) and the analyses revealed that only seven odors and 11 descriptors would have been sufficient for a clear inter-individual differentiation. By extrapolation, they deduced that with a sample group of 34 odors and 35 descriptors, it would be possible to identify the seven billion human beings on Earth! Naturally, differences in perception are based on genetic variations that the scientific community is beginning to understand better. The human

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species has just under 400 different functional olfactory receptors1 (for about 107 sensory neurons in the olfactory epithelium), the largest family after the immune system. Each person has a unique repertoire of variations and, on average, two random individuals have a functional difference of about 30% (Mainland et al. 2014); these phenotypic variations correspond to variations in genotype that can affect perceived intensity as well as hedonic valence (Keller et al. 2007). The latter are particularly important in the case of food smells and, by working specifically on this type of odor, New Zealand researchers led by RD Newcomb (Jaeger et al. 2013; McRae et al. 2013) have shown that phenotypic variations in perceived intensity, quality (floral, fruity, etc.) and hedonic appreciation (pleasant/unpleasant) correspond to genotypic variations. In a genome-wide association study2, conducted with 200 people and 10 odors tested, they found genetic differences for four odors: heptanone-2, one of the main constituents of blue cheeses such as Roquefort, isobutyraldehyde found in malt, β-damascenone with a fruity apple or prune aroma, and β-ionone with a floral rose aroma. Concerning βionone, the researchers succeeded in precisely locating the mutation of the gene associated with sensitivity to this odor. Thus, these inter-individual differences explain, to a certain extent, the selection and choice of a particular food according to the perception of the odor that each person may have of it. By contrast, comparative genetic studies (see, e.g. Abecassis et al. 2012) do not highlight characteristics specific to a given ethnic group or population, either in terms of sensitivity or hedonic appreciation. Only the large inter-individual variability of perception is found within each group. Since this observation is valid for all types of odors, including food odors, there is, therefore, no genetic specificity at the olfactory level that could explain the differences and food preferences of a given human group, thereby referring primarily to a cultural reason related to the availability of the food resource. On the other hand, the question arises regarding body odors (Hoover et al. 2015). Indeed, a comparative study on the perception of androstenone and androstadienone (see Chapter 37) conducted with 2,224 people from 43                                         1 The genes encoding olfactory receptors are distributed on all chromosomes except chromosomes 20 and Y. 2 A genome-wide association study consists in analyzing a large number of genetic variations within a large sample, in order to study existing correlations with objectifiable phenotypic traits.

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different populations and on variations in the OR7D4 gene (selectively activated by androstenone and androstadienone) suggests subtle differences. Thus, for five of the 43 populations studied and from a statistical point of view, the variations were significantly different. These may be possible modifications related to evolution and which remain to be explained: could they depend on body odors that would be different according to the populations? The work of Prokop-Prigge et al. (2016), which compared African Americans, Caucasians, and Asians, showed that for axillary body odors, there are no qualitative differences in production but only quantitative differences. Therefore, from the olfactory point of view, nothing is ever simple: I differ from all others but nothing differentiates us from each other!

 

 

Conclusion

These olfactory snippets are only an open discussion on a land of infinite knowledge. Barely a chapter completed that additional information deserves to be added, barely a closed chapter that another one opens. And much lays by the wayside... Perhaps, the chapters could have been: – considering progress on the use of “odors instead of pesticides”; – evoking “strawberry essence” and congruence issues; – talking about “bad breath” and its implications; – speaking ironically on “the odor of teenagers’ bedrooms that keep them up at night”; – considering the role of “the experimenter’s odor” in some results; – informing about “the smoker’s nose”; – making the link between odors and “the major histocompatibility complex”; – summarizing knowledge on “age and olfaction”; – coming back to the story about Grenouille in Perfume and “hyperosmia”; – being surprised about the chorus of “sniffing and mirror neurons”; – fantasizing about “the smell of panties”; – meditating on “the smell of churches” and the role of incense;

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– thinking with “a philosopher’s nose”; – being nostalgic about “the smell of old books”; – considering “a world without smells”; – always remembering the importance of “having a hollow nose”; – and “feeling good just to feel good”; – and... “Learning is experience, everything else is just information” (Albert Einstein).

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Index

A

K, L, M

Alzheimer’s, 102, 114, 117, 121–123 memory, 17–19, 22, 26, 47, 62, 66, 121, 123, 149, 151 androstenone, 71, 127, 157, 175, 196 aromatherapy, 65, 103 Axel, 13, 14

Kallmann syndrome, 29–31 lily of the valley, 9–12, 18 memory, 17–19, 22, 26, 47, 62, 66, 121, 123, 149, 151 menstrual cycle, 70, 71, 74, 134 migraine, 38, 41, 42

B, C, D Buck, 13, 15 cancer, 97–99, 101, 102, 115 dog, 97–99, 159–161, 164, 168, 184 death, 34, 102, 123, 129–131 depression, 38, 105–108, 110, 142 E, F, H electronic nose, 99, 130, 167, 168 epigenetics, 151–153 fear, 147–153, 180 food intake, 81, 82, 85, 89–91, 106, 141 head injury, 33, 34, 38

N, O Neanderthals, 25, 26 newborn, 133, 179, 180 Nobel Prize, 14, 15, 19, 46 obesity, 30, 31, 73, 82, 85, 94 odorology, 159 orthonasal, 58, 59, 82 pathway, 58, 59 P, R pain, 42, 43, 66, 155–158 Parkinson’s disease, 38, 113, 114, 117–119, 177 priming, 93, 94 olfactory, 93, 94 Proust phenomenon, 17–20 rain, 21–23 retronasal pathway, 57–59, 82, 83, 89

Discovering Odors, First Edition. Gérard Brand. © ISTE Ltd 2019. Published by ISTE Ltd and John Wiley & Sons, Inc.

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  S satiation/satiety, 81–83, 89, 91 sleep, 42, 46–48, 58, 66, 110, 145 sperm, 9–12 stress, 15, 19, 41, 42, 66, 81, 107, 108, 111, 144, 149, 151, 152, 157, 180 sweat, 53, 114, 115, 134, 143–145, 148, 189

T, V trigeminal system, 42, 45, 62, 63, 122, 130, 181 Turin, 13–15 vibrational theory, 13–15 vomeronasal, 138, 141

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