Thesis
Reference
Emotion elicitation by odors and their influence on behavior and cognitive performance
PICHON, Aline
Abstract
Because of technical constraints associated to odor delivery, odor-borne emotions have often been understudied in comparison to other sensory modalities. The understanding of these emotions and their links with other cognitive processes remains at a nascent stage, in spite of the strong affective power of smells. This work aims at decoding the complex mesh of odor-born feelings and their underlying mechanisms at the behavioral, physiological and neural level in humans. In particular, this manuscript presents three studies; one of them describes the representation of complex odor-specific emotions in the brain, beyond odor pleasantness only. The second study assesses the influence of endogenous attentional modulation on the neural processing of odor valence. The third evaluates the influence of an affective olfactory context on learning processes at the behavioral and psychophysiological levels. The manuscript also includes the description of a new MRI-compatible olfactometer that was implemented during this doctorate work.
PICHON, Aline. Emotion elicitation by odors and their influence on behavior and cognitive performance. Thèse de doctorat : Univ. Genève et Lausanne, 2015, no. Neur. 150
URN : urn:nbn:ch:unige-754114
DOI : 10.13097/archive-ouverte/unige:75411
Available at:
http://archive-ouverte.unige.ch/unige:75411
Disclaimer: layout of this document may differ from the published version.
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DOCTORAT EN NEUROSCIENCES des Universités de Genève
et de Lausanne
UNIVERSITÉ DE GENÈVE FACULTÉ DES SCIENCES
Professeur Vuilleumier, directeur de thèse Professeur Sander, co-directeur de thèse
TITRE DE LA THÈSE
Emotion elicitation by odors and their influence on behavior and cognitive performance
THESE Présentée à la Faculté des Sciences de l’Université de Genève
pour obtenir le grade de Docteure en Neurosciences
par
Aline PICHON
de Nancy, France
Thèse N° 150
Genève
Editeur ou imprimeur : Université de Genève
2015
1
Table of Contents
Tables and Figures list 9
Abbreviations 12
Acknowledgements 14
Abstract (english version) 16
Abstract (version française) 18
Theorethical part 20
What is an odor? ... 21
1 Olfaction and the brain ... 23
2 2.1 Odors and emotions: a specific link through neural overlap ... 23
2.2 Two systems working together for odor perception ... 25
2.3 Peripheral transduction of odors ... 26
2.3.1 Trigeminal chemosensation ... 26
2.3.2 The olfactory epithelium and odor receptor neurons ... 26
2.4 Central transduction of odors ... 28
2.4.1 Trigeminal central relays ... 28
2.4.2 The olfactory bulb and overview of the central olfactory system ... 30
2.4.3 The piriform cortex ... 33
2.4.4 The amygdala ... 34
2.4.5 The anterior olfactory nucleus and the olfactory tubercle ... 37
2.4.6 The entorhinal cortex ... 38
2.4.7 The orbitofrontal cortex ... 38
2.4.8 The insula ... 41
2.4.9 Other brain areas associated to odor stimulation ... 43
Odor-borne emotions ... 45 3
2
3.1 General considerations on emotions ... 45
3.2 Describing odor-borne emotions: familiarity, intensity, hedonicity ... 45
3.3 The importance of valence ... 48
3.4 Valence and beyond: odors and theories of emotions ... 49
3.4.1 Odors and bidimensional theories of emotion. ... 49
3.4.2 Odors and basic emotions theory ... 51
3.4.3 Odors, appraisal theories and the component process model ... 52
3.4.4 The olfactory feeling appraisal component and the (G)EOS model ... 56
3.5 The complex functions of odor-borne emotions ... 59
3.6 How are odor-borne emotions generated? ... 61
3.6.1 Odor perception and chemistry ... 61
3.6.2 The plasticity of odor-borne emotions: differential influences ... 62
3.6.2.1 Overview ... 62
3.6.2.2 Inner state, motivations and expectations ... 63
3.6.2.3 Contextual influences on olfactory processing ... 64
3.6.2.4 Preference formation: influence of choice and learning ... 65
3.7 Olfactory deficits and emotions ... 66
3.7.1 Overview and etiology of olfactory disorders ... 66
3.7.2 Olfactory disorders and neurological diseases ... 67
3.7.3 Olfactory disorders alter quality of life ... 67
3.8 Summary... 68
Modulation of behavioral and cognitive processes by odor-borne emotions ... 69
4 4.1 General overview ... 69
4.2 Olfaction and attention ... 69
4.2.1 Attention (and emotion) influence perception ... 69
4.2.2 Attentional effects in olfaction ... 70
4.2.3 Affectively relevant stimuli are processed outside of attentional focus... 72
4.3 Olfaction and learning ... 75
3
4.3.1 The importance of acquisition of preferences and affective context ... 75
4.3.2 Odors as contextual stimuli ... 76
4.3.3 Odors and associative learning... 77
Research questions ... 78
5 5.1 Validation of the MRI compatible olfactometer. ... 78
5.2 Study 1: how are complex odor-borne emotions are represented in the brain: neural correlates of GEOS. ... 79
5.3 Study 2: how does attention modulate the emotional response to odors in the brain? ... 81
5.4 Study 3: how do odors contextually influence associative aversive learning processes? .... 83
Research methodology ... 85
6 6.1 Functional MRI ... 85
6.1.1 The physical basis of MRI ... 85
6.1.2 Principles of functional MRI: BOLD and HRF ... 86
6.1.3 fMRI data statistical analysis ... 87
6.1.3.1 Preprocessing ... 87
6.1.3.2 Statistical analysis: 1st and 2nd levels. ... 88
6.2 Specific constraints for the study of olfaction in MRI ... 89
6.2.1 Imaging parameters ... 89
6.2.2 Respiratory patterns and experimental design ... 90
6.2.3 Odor delivery: the MRI compatible olfactometer. ... 90
Experimental part 94
Prestudy: validation of the MRI compatible olfactometer ... 95
1 1.1 Air flow detection ... 95
1.2 Influence of air debit on flow latency ... 96
1.3 Odor detection ... 97
1.3.1 Methods ... 97
1.3.1.1 Participants ... 97
1.3.1.2 Stimuli ... 97
4
1.3.1.3 Odor Delivery ... 98
1.3.1.4 Experimental Procedure ... 98
1.3.1.5 Behavior Ratings: Hedonicity, Familiarity, Intensity, and GEOS ... 100
1.3.1.6 Physiological Recordings ... 100
1.3.1.6.1 Respiratory activity ... 100
1.3.1.6.2 Heart rate ... 100
1.3.1.7 MRI data acquisition ... 100
1.3.1.8 fMRI Analysis ... 101
1.3.1.8.1 Preprocessing ... 101
1.3.1.8.2 Analysis of odor-evoked activity ... 101
1.3.1.8.3 FIR analysis and time course extraction ... 102
1.3.2 Behavioral results ... 102
1.3.3 fMRI results ... 103
1.3.3.1 Sequence parameters: F map ... 103
1.3.3.2 Odor perception ... 104
1.3.3.3 Influence of stimulus repetition on the olfactory signal ... 105
1.3.3.4 Influence of physiological parameters ... 106
1.3.3.5 FIR & Time courses of activation ... 106
Study 1: how are complex emotions are represented in the brain: neural correlates of GEOS 2 108 2.1 Material and Methods ... 108
2.1.1 Participants ... 108
2.1.2 Olfactory Emotional Scale ... 109
2.1.3 Stimuli ... 109
2.1.4 Odor Delivery ... 109
2.1.5 Experimental Procedure ... 109
2.1.6 Behavior Ratings: Hedonicity, Familiarity, Intensity, and GEOS ... 109
2.1.7 Physiological Recordings ... 110
5
2.1.7.1 Respiratory activity ... 110
2.1.7.2 MRI data acquisition ... 110
2.1.8 fMRI Analysis ... 110
2.1.8.1 Preprocessing ... 110
2.1.8.2 Analysis of odor-evoked activity... 110
2.1.8.3 Parametrical analysis of post-scan ratings ... 110
2.2 Results ... 111
2.2.1 Behavioral and Physiological Results ... 111
2.2.2 fMRI Results ... 114
2.2.2.1 Main effect of olfactory stimulation and positive and negative odors ... 114
2.2.2.2 Parametrical effects of emotions: hedonicity, intensity, and familiarity ... 116
2.2.2.3 Parametrical effects of GEOS categories ... 119
2.2.2.4 Comparison of GEOS categories with Hedonicity ... 122
2.3 Discussion ... 124
2.3.1 Valence and Beyond in the Olfactory Brain: Pleasantness feeling and Disgust ... 126
2.3.2 Sensory pleasure: Eating Proust’s madeleine ... 127
2.3.3 Desire and sensuality ... 128
2.3.4 Relaxation: Self-related thoughts and emotional regulation ... 128
2.3.5 Familiarity and Intensity Assessments Complement Hedonicity but do not Capture the Full Emotional Complexity of Odors ... 129
Study 2: how does attention modulate the emotional response to odors in the brain? ... 130
3 3.1 Material and Methods ... 130
3.1.1 Participants ... 131
3.1.2 Stimulus material & delivery ... 131
3.1.2.1 Odors ... 131
3.1.2.2 Sounds ... 132
3.1.3 Experimental Procedure ... 133
3.1.4 Localizer task ... 134
6
3.1.5 Memorization ... 135
3.1.6 Main task ... 135
3.1.7 Control task ... 136
3.1.8 Physiological Recordings ... 136
3.1.8.1 Respiratory activity ... 136
3.1.8.2 Heart rate ... 137
3.1.8.3 MRI data acquisition ... 137
3.1.9 fMRI Analysis ... 138
3.1.9.1 Preprocessing ... 138
3.1.9.2 Physiological noise modeling... 138
3.1.9.3 Analysis of emotion and attention evoked-activity in the main task ... 138
3.1.9.4 Control task ... 139
3.1.9.5 Localizer task ... 139
3.2 Results ... 140
3.2.1 Behavioral Results ... 140
3.2.2 fMRI Results ... 141
3.2.2.1 Olfactory pathways identified in the localizer scan ... 141
3.2.2.2 Main effect of attention ... 141
3.2.2.3 Main effects of odor valence ... 148
3.2.2.4 Valence effects in different attention conditions ... 150
3.2.2.5 Amygdala response to odor presence, unchanged by attentional manipulation ... 153
3.3 Discussion ... 154
3.3.1 Olfaction as a special, intrinsically affective sense ... 155
3.3.2 Valence effects with and without attention... 156
Study 3: how do odors contextually influence associative aversive learning processes? ... 159
4 4.1 Material and Methods ... 159
4.1.1 Participants ... 159
4.1.2 Stimuli ... 160
7
4.1.2.1 Faces ... 160
4.1.2.2 Odors ... 160
4.1.3 Experimental procedure ... 160
4.1.4 Subjective ratings ... 162
4.1.5 Physiological recordings ... 162
4.1.5.1 Heart rate, electrodermal activity, respiratory activity ... 162
4.1.5.2 Pupil diameter ... 162
4.1.6 Data Analyses ... 162
4.1.6.1 Behavioral data and reaction times ... 162
4.1.6.2 Electrodermal activity, Heart and Respiratory rate ... 163
4.1.6.3 Pupil diameter ... 164
4.1.7 Statistical analyses ... 164
4.1.7.1 Odor ratings (Odor_M) ... 164
4.1.7.2 Respiratory activity (Resp_M) ... 164
4.1.7.3 Other measurements ... 165
4.1.7.3.1 Non odor controls (Control_M) ... 165
4.1.7.3.2 Odor context measurements (General_M): baseline corrected scores ... 165
4.2 Results ... 165
4.2.1 Odor ratings ... 165
4.2.1.1 Hedonicity ... 165
4.2.1.2 Familiarity ... 165
4.2.1.3 Intensity ... 165
4.2.2 Anger level ratings ... 166
4.2.3 Reaction times ... 167
4.2.4 Skin conductance responses (SCRs) ... 168
4.2.5 Heart rate ... 169
4.2.6 Respiration Rate ... 170
4.2.7 Respiration Amplitude ... 170
8
4.3 Discussion ... 170
4.3.1 Results summary ... 170
4.3.2 Relationship to previous work ... 171
4.3.3 Partial invalidity of affective congruence ... 171
4.3.4 Pleasant context: generalized facilitation of attention or contrast effect? ... 173
4.3.5 On trigeminality ... 174
General Discussion 175
Summary of the main findings ... 176
1 Cerebral regions involved in the processing of odor-borne emotions ... 177
2 2.1 Amygdala, intensity & arousal ... 177
2.2 OFC, pleasantness and beyond ... 180
2.3 Insula ... 182
2.4 Dissociating consciousness and attention ... 186
2.5 Putative neural candidates for olfactory attention ... 187
2.6 Other areas involved in olfactory processing ... 189
2.6.1.1 Hippocampus ... 189
2.6.1.2 Motor areas ... 189
Limitations & Perspectives ... 191
3 3.1 MRI experiments ... 191
3.1.1 Study 1 ... 191
3.1.2 Study 2 ... 192
3.2 Behavioral experiment: study 3 ... 193
3.3 Perspectives ... 193
General conclusions ... 195
4 Citations 198 Bibliography 200
9
Tables and Figures list
Table 1.The common neural substrates of olfaction and emotion. ... 25
Table 2. Relationships between the functions and the components of emotions, and the organismic subsystems that subserve them. ... 53
Table 3. The six GEOS categories and their representative terms. ... 57
Table 4. Odorant stimuli with respective dilutions in dipropylene glycol (DIPG). ... 98
Table 5. Odorant dilution. ... 109
Table 6. Odorant detection. ... 112
Table 7. Item Reliability ... 113
Table 8. Average of individual participants correlations for the different emotional scales across all odors ... 113
Table 9. Paired t-tests comparing odors to control intensities ... 114
Table 10. Activation coordinates for the odor>non-odor (O>NO), pleasant>unpleasant (P>U), and unpleasant>pleasant (U>P) contrasts ... 116
Table 11. Areas correlating with hedonicity... 118
Table 12. Parametric brain activations correlating with individual ratings of specific category- specific>others, and vice versa... 122
Table 13. Areas correlating with individual ratings of categories>HEDO or HEDO>categories ... 124
Table 14. Olfactory stimuli ... 131
Table 15. Auditory stimuli ... 132
Table 16. Activation coordinates for the Odor>Sound contrast in the olfactory localizer task (iO>iS loc) and the Odor + Sound>Sound in the control task (OS>S control). ... 143
Table 17. Activation coordinates for the Sound>Odor contrast in the main and the auditory localizer tasks (S>O main and S>O loc, respectively). ... 146
Table 18. Activation coordinates for the Unpleasant>Pleasant (U>P all) and the Pleasant>Unpleasant (P>U all) contrast in main task. ... 149
Table 19. Activation coordinates for the Odor Unpleasant>Odor Pleasant (OU>OP), the Odor Pleasant>Odor Unpleasant (OP>OU) and the Sound with Odor Unpleasant>Sound with Odor Pleasant (SU>SP) contrasts in the main task ... 152
Table 20. Sensory pleasure and food, taste, hunger in the lateral orbitofrontal cortex ... 181
Table 21. Sensory pleasure and food, taste, satiation in the anterior ventral insula. ... 185
Table 22. Anterior insula and active odor detection. ... 185
10
Figure 1. Schematic outline of neural areas involved in emotional processes. ... 24
Figure 2. Olfactory transduction. ... 28
Figure 3. The trigeminal nerve. ... 29
Figure 4. Central Processing of trigeminal stimulus. ... 30
Figure 5. The olfactory brain. ... 32
Figure 6. An overview of the olfactory system’s interconnections in Mammals. ... 32
Figure 7. Categorization of odor quality in the posterior piriform cortex. ... 34
Figure 8. Combined encoding of odor valence and intensity in the amygdala. ... 37
Figure 9. The orbitofrontal encodes olfactory valence. ... 40
Figure 10. The OFC as a high order and integrative area. ... 41
Figure 11. The insula is involved in the processing of olfactory unpleasantness... 43
Figure 12. Hippocampus and olfactory memory. ... 44
Figure 13. Non-linear relation between pleasantness and familiarity evaluations. ... 46
Figure 14. Affective circumplex and basic emotions theories. ... 51
Figure 15. The component process model of emotion. ... 54
Figure 16. Venn diagram of three hypothetical types of central representation of the emotion component and the emergence of feeling. ... 55
Figure 17. GEOS refines the odor-borne emotional perception beyond the binary pleasantness ... 58
Figure 18. Odor-borne emotions: description and discrimination. ... 59
Figure 19. Chemistry and subjective olfactory experience. ... 62
Figure 20. Sensory specific satiety effect in the orbitofrontal cortex. ... 64
Figure 21. Influence of verbal labeling on olfactory perception and processing. ... 65
Figure 22. Choice-induced change of preference for odors. ... 66
Figure 23. Attentional modulation of olfactory cortices. ... 72
Figure 24. Example of attention vs. emotional manipulation. ... 74
Figure 25. Effects of attention and emotion on face processing in the brain. ... 74
Figure 26. The influence of unattended pleasant or unpleasant odors. ... 75
Figure 27. Schematic diagram of the 28 odor MCO. ... 92
Figure 28. Air flow detection. ... 96
Figure 29. Influence of air debit on latency. ... 97
Figure 30. Time course of the experiment task and odor delivery. ... 99
Figure 31. Odor detection. ... 103
Figure 32. Subjective pleasantness. ... 103
Figure 33. F map for all the 13 conditions, p = 1. Sagittal ( X = -6,left) and horizontal (z = -18, right) views. ... 104
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Figure 34. Prestudy: fMRI data. ... 105
Figure 35. Effect of stimulus repetition on olfactory signal. ... 106
Figure 36. Dynamic time course and FIR. ... 107
Figure 37. Subjective ratings of olfactory stimuli for study 1. ... 114
Figure 38. Main Odor effect. ... 115
Figure 39. Regression analysis for hedonicity (a), intensity (b) and familiarity (c). ... 118
Figure 40. Regression analysis for individual categories compared with the rest of GEOS at the second level. ... 121
Figure 41. Regression analysis for GEOS categories compared with hedonicity at the second level. 123 Figure 42.Time course of the experiment task and odor delivery. ... 134
Figure 43. Memorization of stimuli names into separate, random categories. ... 135
Figure 44.Behavioral results. ... 141
Figure 45. Attention, Localizer and Control contrasts. ... 143
Figure 46. Main valence effect. ... 149
Figure 47. Valence x attention interaction. ... 152
Figure 48. The amygdala does not respond to attentional manipulation... 154
Figure 49. Experimental design. ... 161
Figure 50. Biphasic heart rate trace. ... 163
Figure 51. Mean subjective ratings of (A) pleasantness, (B) familiarity and (C) intensity. ... 166
Figure 52. Mean Baseline Corrected Scores (BASc) for anger level ratings as a function of the olfactory context. ... 167
Figure 53. Mean BASc of reaction times as a function of the olfactory context in ms. ... 168
Figure 54. Mean BASc of Electrodermal response amplitude as a function of the olfactory context in micro Siemens (µS). ... 169
Figure 55. Coronal brain sections displaying differential activity in the amygdala related to the different paradigms used in this thesis work. ... 179
Figure 56. Horizontal brain sections displaying differential activity in the orbitofrontal cortex (OFC) related to the different paradigms used in this thesis work. ... 181
Figure 57. Sagittal brain sections displaying differential activity in the insula related to odor detection, identified with the different paradigms used in this thesis work. ... 184
Figure 58. Sagittal brain sections displaying differential activity in the insula related to odor valence and novelty processing, as well as sensory-pleasure and desire GEOS categories, identified with the different paradigms used in this thesis work. ... 185
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Abbreviations
ACh: Acetylcholine
ACC: Anterior Cingulate Cortex
aMCC: anterior Middle Cingulate Cortex AD: Alzheimer Disease
AMP: Adenosine mono Phosphate ANOVA: Analysis of Variance ANS: Autonomic Nervous System AON: anterior Olfactory Nucleus APC: anterior Piriform Cortex ASICs: Acid-sensing Ion Channels BASc: Baseline Corrected Score
BOLD: Blood-oxygenation-level Dependent CBV: Cerebral Blood Volume
CNS: Central Nervous System CR: Conditioned Response CS: Conditioned Stimulus
CT: X-ray Computed Tomography DD: Double Debit
DE: Desire dl: dorsolateral
DMN : Default Mode Network DPG: Dipropylene Glycol EC: Entorhinal Cortex F: Familiarity
FCR : Fear Conditioned Repsonse FDR: False Detection Rate FIR: Finite Impulse Response
fMRI: functional Magnetic Resonance Imaging
FWE: Family-wise Error GCs: Granule Cells
(G)EOS: (Geneva) Emotion Odor Scale GLM: General Linear Model
GABA: Gamma Aminobutyric Acid H: Hedonicity
I: intensity
IADS: International Affective Digital Sounds database
IFG: Inferior Frontal Gyrus ITG: Inferior Temporal Gyrus ISI: Inter Stimulus Interval ITG: Inferior Temporal Gyrus HD: Huntington Disease Hipp.: Hippocampus
HRF: Hemodynamic Response Function LAI: Left Anterior Insula
lat: lateral
LC: Locus Coeruleus LN: Left Nostril m: medial ms: millisecond
MANOVA: mixed models analyses of variance MCs: Mitral Cells
MCIES: MRI-compatible insert earphones system
MCO: MRI-compatible Olfactometer MD: mediodorsal nucleus (thalamus) MFG: Middle Frontal Gyrus
13 MTG: Middle Temporal Gyrus
MVPA: Multi-Voxel Pattern Analysis NES: Neuroendocrine System NMR: Nuclear Magnetic Resonance NO: No Odor
n.s.: nonsignificant NS: No Sound
O: Odor or attention to Odor Occ.: Occipital
ON: Attention to Neutral Odor OP: Attention to Positive Odor OU: Attention to Unpleasant Odor OB: Olfactory Bulb
OFC: Orbitofrontal Cortex
ORNs: Olfactory Receptor Neurons OTu: Olfactory Tubercle
pACC: pregenual ACC PC: Principal Component PCC: Posterior Cingulate Cortex PD: Parkinson Disease
PET: Positron Emission Tomography PF: Pleasant Feeling
PFC: Prefrontal Cortex PHC: Post-Hoc Comparison PHG: Parahippocampal Gyrus PTFE: polytetrafluoroethylene PirC: Piriform Cortex
PirF: frontal Piriform Cortex PirT: temporal Piriform Cortex PPC: posterior Piriform Cortex
PostCG: Posterior Central Gyrus PreCG: Precentral Gyrus
RAI: Right Anterior Insula RF: Refreshing
RN: Right Nostril RX: Relaxation s: second s.: sulcus
S: Sound or attention to Sound SECs: Stimulus Evaluation Checks SCRs: Skin Conductance Response SFG: Superior Frontal Gyrus SMA: Supplementary Motor Area SNR: Signal-to-noise Ratio SNS: Somatic Nervous System
SON: Attention to Sound, Neutral Odor SOP: Attention to Sound, Pleasant Odor SOU: Attention to Sound, Unpleasant Odor SP: Sensory Pleasure
SPL: Superior Parietal Lobule
SPM: Statistical Parametric Mapping STG: Superior Temporal Gyrus TE: Echo Time
TR: Repetition Time UF: Unpleasant Feeling US: Unconditioned Stimulus VGA: Valve Generated Airstream vm: ventromedial
VPM: Ventroposteromedial nucleus(thalamus)
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Acknowledgements
I would like to express my deepest gratitude to the great number of people who contributed to this work, as it would not have been possible to finalize this thesis without their help and support. The last five years have been very intense and fulfilling, and I have had the great luck to spending them surrounded by accomplished and generous colleagues and friends.
Je tiens à remercier en premier lieu mes superviseurs, les professeurs Patrik Vuilleumier et David Sander pour m’avoir accueillie et m’avoir permis de mener à bien cette thèse avec un constant soutien. Patrik, merci de m’avoir donné accès à cette opportunité incroyable, et d’avoir su rester disponible et enthousiaste en toutes circonstances pour me guider tout au long de ces années. Merci d’avoir partagé vos nombreuses connaissances avec moi, nos discussions m’ont beaucoup apporté. David, merci pour ton implication, tes encouragements constants, et la limpidité de tes explications dans de nombreux domaines, elles m’ont énormément aidé. Merci aussi de m’avoir fait une place à part entière dans ton laboratoire.
Je voudrais aussi remercier tout particulièrement le Dr. Delplanque et le Dr Corradi-dell’Acqua pour leur contribution essentielle à ce travail de thèse. Sylvain, merci infiniment pour m’avoir patiemment initiée au monde merveilleux de l’olfaction, et aux arcanes de la psychophysiologie et de l’écriture. Merci pour ton soutien sans faille, tes relectures minutieuses, tes commentaires judicieux et ton enseignement (que ce soit en cht’i ou en japonais), ils ont été vitaux pour mon doctorat. Grazie tanto Corrado per avermi imparato ad analizzare i dati IRM dall’A alla Z, per il tuo aiuto invalutabile sui segreti degli script matlab, per la tua pazienza, il tuo appoggio, il tuo ottimismo e per avere sempre una risposta precisa alle mie numerose domande, in particolare sui misteri dell’insula. Sopratutto, grazie per la tua amicizia.
I would like to thank Dr. Jane Plailly, Dr. Basile Landis and Prof. Thomas Hummel for accepting to be my jury members, and Prof. Christoph Michel, for being my jury president. Jane, je te remercie sincèrement pour la qualité des échanges que nous avons eus et la pertinence de tes commentaires lors de l’examen théorique, ainsi que pour avoir accepté de revenir deux fois à Genève. Basile, merci beaucoup de m’avoir fait partager une part de ton vaste savoir pour mieux appréhender les troubles de l’olfaction et leurs répercussions, et pour ton apport théorique lors de mon examen. Thomas, thank you for kindly accepting to come to Geneva, and for sharing your vast knowledge on olfaction with me on various occasions (Dresden, Bertinoro, Champéry).
Christoph, thank you for your kindness, your availability, and for your help in finding this PhD position.
Je remercie également le service de Recherche et Développement de Firmenich, en particulier Christian Margot, Isabelle Cayeux, Christelle Porcherot, Nadine Gaudreau, Alain Hugon et Maria Inés Velazco, pour leur gentillesse et leur disponibilité. Christian, merci pour tes explications passionnantes sur la chimie organique des odeurs et tes conseils avisés pour le choix de fragrances (je pense notamment au transpirol). Isabelle, Christelle, Nadine, merci pour vos conseils et réponses à mes questions, ainsi qu’à votre tolérance olfactive les
15 jours de fabrication de mèche. Merci à Alain Hugon pour avoir développé cet incroyable outil de travail, l’olfactomètre IRM-compatible, et à Maria Ines d’avoir rendu cette collaboration possible.
I also want to thank all my colleagues and friends at the Campus Biotech (Labnic, E3lab, CISA), CMU, Unimail and outside the University of Geneva: Alain, Alessia, Alexis, Bruno, Cristina, Christian, Dan, David R., Didier, Fabien, Federico, Gil, Katja, Karsten, Konnie, Kim, Ilaria, Jonas, Judith, Leo, Marcello, Marcel, Marcin, Naëm, Nico, Petra, Roberta, Sascha, Simon, Sonia, Ulrike T., Tobias, Wiebke… and all the members of the Labnic. A special thanks goes to the E3 Lab members for welcoming me in my new ‘home’ during the last year of my PhD, in particular to Chiara, Eva, Matthieu, Ryan, Tiffany, Vanessa and Yoann for the daily mix of science, giggles, and coffee. Thanks to Sebastian for his help on MRI matters and his incredible Gravlax, Christophe Mermoud pour ses prouesses informatiques, Rémi pour ses éclaircissements en statistiques, Christoph H. pour avoir toujours été là quand j’avais des questions, Ben M. for his R skills and for being able to talk about any subject, Fabien pour son sourire contagieux et ses efforts pour me faire chanter, Mihai for his beer Thursdays and all his parallel knowledge, Ewa & Despina, for the fun and laughter in every situation possible, Kallia, pour sa bonne humeur infatigable lors de nos week-ends de scans, Kim-Crystie, for being the funniest chat buddy possible, Elena, for being so kind and generous, мою подругу, Hamdi & Panos for being great long-distance friends and for proving wrong that there is no nightlife in Geneva, Lore pour me faire autant rire, Caroline pour nos apéros au Mandarin Oriental, Alison pour nos bavardages existentiels autour d’un café, Daniela, Marion et Marie- Ange, pour leur pêche et sans qui rien ne tournerait au CISA ou au Labnic, Manu pour toujours être là quand il faut.
Géraldine et Laure: merci pour votre indéfectible soutien transatlantique / outre Rhin dans les nombreux moments de ras le bol. Flonflon, merci pour notre amour commun des belles choses (Louboutins, Bradley C. et Chaource), et nos inoubliables pérégrinations nippono-chinoises. GG, merci pour ton endurance à toute épreuve durant nos marathons olfacto-imagerie sur fond de tubes 90s, ta compréhension métaphysique de l’état de Faim et nos crises de fous rires (mes abdominaux s’en souviennent encore).
Thanks also to Professor Egbert Welker from the University of Lausanne and Marco Valente for believing in me and for their support throughout my career.
Finalement, je remercie ma famille, et surtout mes parents et ma sœur pour leur affection, leur présence et le support moral dont ils m’ont toujours entourée durant l’ensemble de mes études. Leur soutien a contribué pour beaucoup à la réalisation de ce travail. Merci enfin à Marius, pour TOUT de ces trois dernières années merveilleuses en ta compagnie.
16
Abstract (english version)
“He who ruled scent ruled the hearts of men.”
Patrick Süskind.
Olfaction stands out in the sensory landscape for its peculiar and intimate connection with the world of emotions. Odors surround us in the everyday life and affect our behavior, our mood and our well- being in a crucial way, as attested by the importance of perfumery since the earliest civilization and the significantly impoverished quality of life observed in individuals suffering from olfactory impairment.
Because of technical constraints associated to precise odor delivery, and the lack of attention, odor- borne emotions have often been understudied in comparison to other sensory modalities such as vision or audition, especially at the neural level. Olfaction-related literature in experimental psychology and brain imaging is undergoing an unprecedented boom, along with the development of MRI-compatible olfactometers (Gottfried, O'Doherty, et Dolan, 2002; Ischer et al, 2014; Lorig, Elmes, Zald, & Pardo, 1999; Vigouroux, Bertrand, Farget, Plailly, et Royet, 2005). These technical achievements have enabled the emergence of studies characterizing the processing of olfactory stimuli at the brain level. Nevertheless, the understanding of odor-borne emotions and their links with other cognitive processes remains at a nascent stage, in spite of the strong affective power of smells. Thus, my work aims at decoding the complex mesh of these odor-born feelings and their underlying mechanisms at the behavioral, physiological and neural level in humans. In particular, this manuscript presents three studies; one of them describes the representation of complex odor- specific emotions in the brain, beyond odor pleasantness only. The second study assesses the influence of endogenous attentional modulation on the neural processing of odor valence. The third evaluates the influence of an affective olfactory context on learning processes at the behavioral and psychophysiological levels. The manuscript also includes the description of a new MRI-compatible olfactometer that was implemented during this doctorate work.
The following theoretical background is divided into 6 parts. The first one briefly defines the concept of odor. The second one describes the sense of olfaction, its neural representation and connection with emotions. The third part overviews the importance of valence in olfaction, the characterization of odor-borne emotions and their plasticity. The fourth part sums up the current experimental knowledge in terms of behavioral and cognitive processes modulation by olfactory stimuli. The fifth
17 part outlines the three main research questions explored in the subsequent experimental section, and the sixth and last part introduces MRI physics and data analysis, as well as the apparatus used for the delivery of odors, an MRI compatible olfactometer.
The experimental part presents the methodology used and discusses the results obtained for each of the three experiments performed in this doctorate. This section also includes a description of the preliminary psychophysical, behavioral and fMRI results obtained for validating the functioning of the MRI-compatible olfactometer.
The final part, the general discussion, examines the general significance of the results obtained in the thesis, their theoretical relevance and limitations. This part also explores the prospective research questions arising from our experimental findings.
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Abstract (version française)
L’olfaction se démarque dans le paysage sensoriel en raison de sa connexion si particulière avec le monde des émotions. Les odeurs qui nous entourent dans la vie de tous les jours affectent notre comportement, notre humeur et notre bien-être d'une manière cruciale, comme en témoignent l'importance de la parfumerie dans toutes les civilisations, des plus anciennes à nos jours; et l’appauvrissement significatif de la qualité de vie des personnes souffrant de déficiences olfactives.
En raison de contraintes techniques liées à l’envoi d’une stimulation olfactive contrôlée et précise, ainsi que le manque d’attention qui est prêté aux odeurs en général, les émotions d’origine olfactive ont été souvent peu étudiées par le passé en comparaison d'autres modalités sensorielles comme la vision ou de l'audition, en particulier au niveau cérébral. Le développement récent d’olfactomètres IRM-compatibles (Gottfried, O'Doherty, et Dolan, 2002; Ischer et al, 2014; Lorig, Elmes, Zald, &
Pardo, 1999; Vigouroux, Bertrand, Farget, Plailly, et Royet, 2005) a permis un développement sans précédent de la recherche sur le sujet, et la littérature correspondante en psychologie expérimentale et imagerie cérébrale est en pleine expansion, avec l'émergence d'études qui caractérisent le traitement cognitif des stimuli olfactifs. Néanmoins, en dépit de la puissance affective des odeurs, la compréhension des émotions d’origine olfactives et de leurs liens avec d'autres processus cognitifs en est encore à ses commencements.
Le travail présenté dans cette thèse de doctorat a cherché à décoder ces émotions complexes et leurs mécanismes sous-jacents odeurs aux niveaux comportemental, physiologique et cérébral chez l'Homme. Trois études sont présentées dans ce manuscrit; l'une d'entre elles caractérise la représentation cérébrale des émotions complexes évoquées par les odeurs, au-delà de leur simple côté plaisant ou déplaisant. La deuxième évalue les effets de l’attention endogène sur le traitement cérébral de la valence olfactive. Enfin, la troisième étudie l'influence d’un contexte affectif olfactif ces sur les processus d’apprentissage aux niveaux comportemental et psychophysiologique. Le manuscrit comprend également la description d'un nouvel olfactomètre compatible avec l’imagerie par résonance magnétique (IRM) dont l’utilisation été mise en place au cours de ce doctorat.
Le contexte théorique est divisé en 6 sections. La première section définit brièvement le concept d’odeur. La seconde décrit la modalité sensorielle olfactive, sa représentation cérébrale et sa connexion avec les émotions. La troisième section résume l'importance de la valence dans l'olfaction,
19 la caractérisation des émotions d’origine olfactives ainsi que leur plasticité. La quatrième section reprend les connaissances actuelles en termes de modulation des processus cognitifs et comportementaux par les stimuli olfactifs. La cinquième section décrit les trois principales questions de recherche explorées dans la partie expérimentale. Enfin, la sixième et dernière section pose les bases de la physique liée à l’IRM et de l'analyse des données, ainsi que l'appareil utilisé pour la stimulation olfactive contrôlée, un olfactomètre IRM-compatible.
La partie expérimentale présente la méthodologie utilisée et analyse les résultats obtenus pour chacune des trois expériences réalisées dans ce doctorat. Cette section comprend également une description des résultats psychophysiques, comportementaux et d’imagerie cérébrale ayant permis la validation fonctionnelle de l'olfactomètre IRM.
Finalement, la discussion générale examine la signification générale des résultats obtenus dans ce travail thèse, ainsi que leur pertinence théorique et leurs limites. Cette section explore également les questions de recherche potentielles découlant de nos résultats expérimentaux.
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Theorethical part
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What is an odor?
1
“Perfumes are the feelings of flowers.” Heinrich Heine
“Odor” or “smell” usually designates the perceived sensation elicited by one or several volatile chemicals – odorants – stimulating the olfactory organ. However, the hedonic hue of its many synonyms – perfume, fragrance, scent, aroma, malodor, reek, stench – also reflects its application to the quality of the sensation, namely, to one of its most salient attributes: its valence, or pleasantness (see section 3.3). A third definition, related to the word “smell”, indicates an action: the ability to notice, recognize or sense the odor of things. It has been recently estimated that Humans could discriminate at least 1 trillion olfactory stimuli (Bushdid, Magnasco, Vosshall, & Keller, 2014). Another notion that has been defined is that of olfactory object (Gottfried, 2010; Stevenson & Wilson, 2007):
“(…) olfactory sources (objects that produce odors, such as a lion) and olfactory events (odors that emanate from objects, such as a musky lion smell) can be thought of as olfactory objects.” p 628, (Gottfried, 2010) These descriptions combine three aspects that appear to match the perspectives under which odors are apprehended by Humans: chemistry, emotion and cognition. We will focus on the reciprocal links uniting the last two (see section 2).
Odors are to be distinguished from pheromones. Although both of them are involved in the regulation of social behaviors in the animal kingdom (see section 3.5, and Doty, 2003 for a review), pheromones can be defined as “isolated chemicals shown to be relatively species-specific which elicit a clear and obvious behavioral or endocrinological function which produce effects involving a large degree of genetic programming, influenced little by experience” (Martin, 1980). Although mice urine pheromones are known for inducing a series of behavioral and physiological changes within the species (e.g. aggression, individual recognition, ovulation, see Bronson, 1979 and Hurst et al., 2001), pheromone effects in mammals are mostly established through learning and not stereotypically, in combination with other sensory cues (see Doty, 2003 for a review). Pheromones are sensed by a specific structure, the vomeronasal organ (VNO), present in most amphibians, reptiles and mammals (Trotier et al., 1998). Although some studies advocate for a functional VNO in humans (for a review see Monti-Bloch, Jennings-White, & Berliner, 1998), the organ is thought to be vestigial in adult humans (for a review, see Evans, 2003), developing at the prenatal stage in humans (Moran, Jafek, &
Rowley, 1991), before regressing at the time of birth (Humphrey, 1940). Additionally, human behavior being extremely flexible, complex and subject to various sensory regulations, it is highly unlikely that the VNO exerts a tangible chemosensory influence on it (see Brennan & Keverne, 2003;
22 Doty, 2003 for reviews). We will thus not address the pheromonal question in humans, and rather concentrate on the olfactory and trigeminal systems.
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Olfaction and the brain 2
2.1 Odors and emotions: a specific link through neural overlap
Olfaction has an outstanding status among sensory modalities when it comes to emotional elicitation, illustrated by the extensive experimental evidence of the influence odors have on mood (Alaoui-Ismaïli, Robin, Rada, Dittmar, & Vernet-Maury, 1997; Rétiveau, Chambers, & Milliken, 2004;
Warrenburg, 2005). Pleasant and unpleasant odors induce differential responses at the behavioral (Bensafi, Rouby, Farget, Vigouroux, & Holley, 2002) and physiological (Bensafi, Rouby, Farget, Bertrand, et al., 2002b; Delplanque et al., 2009) levels. The use of certain smells can result in improved mood (Rétiveau et al., 2004), reduced anxiety (Lehrner, Eckersberger, Walla, Pötsch, &
Deecke, 2000), enhanced alertness (Heuberger, Hongratanaworakit, Böhm, Weber, & Buchbauer, 2001), or profound aversion or disgust (Alaoui-Ismaïli et al., 1997), thoroughly affecting behavioral and cognitive processes, such as learning (Gottfried and Dolan 2004), memory (Herz, Eliassen, Beland, & Souza, 2004; Yeshurun, Lapid, Dudai, & Sobel, 2009), or social preferences (Leppanen &
Hietanen, 2003; Li, Moallem, Paller, & Gottfried, 2007). It thus appears that, similarly to emotional cues, odors modulate motivational states in a powerful fashion through their relevance. They are thus prone to induce behavioral adaptations to changes in the environment (Pause et al., 2003), resulting in approach or avoid action tendencies (Frijda, 1987) for pleasant and unpleasant odors respectively.
This unique affective power of olfactory stimuli proceeds from the peculiar anatomical overlap between olfactory and emotion related neural structures. The olfactory system displays several particularities at the anatomical and functional level, and shares common neural substrates with emotion (Figure 1 and Table 1). The specific brain anatomy of olfaction features a close overlap with the limbic system, embodied by a direct connection between the primary olfactory cortex and the amygdala (Carmichael, Clugnet, & Price, 1994; Gottfried, Deichmann, Winston, & Dolan, 2002). The neural olfactory network also comprises memory related areas, such as the anterior olfactory nucleus, the EC, and the hippocampus, as well as valence-related structures, either primitive, reward (see section 3.3 for a definition) focalized loci such as the olfactory tubercle, or integrative and associative loci such as the OFC or the disgust-sensitive insula, that can be thus considered as being part of emotional circuits in the brain (see Adolphs, 2009; Rolls, 2004a, 2004b for review). We will now review the neural circuits underlying the processing of odors, and functioning specificities of olfactory areas – processing of relevant odor and global emotional value, affective memory, hedonic value and disgust (for a definition of relevance, see section 3.5)
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Figure 1. Schematic outline of neural areas involved in emotional processes.
The yellow and red boxes (left) highlight structural and cognitive processes related to emotion and empathic simulation. Among the mentioned areas, many are also belong and play a predominant role in the olfactory circuit. Taken from Adolphs, 2009.
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Table 1.The common neural substrates of olfaction and emotion.
Comparison of anatomy of olfactory and emotion-linked systems, and in two pathologies possibly related to olfaction (depression and schizophrenia). Taken from Soudry et al., 2011.
2.2 Two systems working together for odor perception
Two systems are at stake for the perception of odors in Humans: the olfactory system, carried out by the cranial nerve I, and the trigeminal system, sensed by nociceptive fibers of cranial nerve V, mostly stimulated by chemical irritants (Kleemann et al., 2009) which can produce a burning or stinging (Cometto-Muniz, Cain, & Hudnell, 1997), or a cooling or freshness sensation (Laska, Distel, & Hudson, 1997). As most odorants stimulate both systems, the olfactory and trigeminal systems work together and influence each other despite their partial physical separation (Boyle, Heinke, Gerber, Frasnelli, &
Hummel, 2007; Lombion et al., 2009). For example, the perception of an artificially mixed olfactory and trigeminal stimulus leads to higher cortical activations compared to the sum of its parts (Boyle, Frasnelli, Gerber, Heinke, & Hummel, 2007), and the presence of a trigeminal stimulus during odor encoding alters its neural representation (Bensafi, Frasnelli, Reden, & Hummel, 2007); while evidence from olfactory dysfunction patients shows that the processing of trigeminally mediated information differs in the presence or absence of smell (Frasnelli, Schuster, & Hummel, 2007, 2010; Iannilli, Gerber, Frasnelli, & Hummel, 2007). The two systems also share overlapping neural networks for stimulus concentration encoding (Bensafi, Iannilli, Gerber, & Hummel, 2008), and trigeminal stimuli activate the common olfactory network as shown in a recent metananalysis (Albrecht et al., 2010).
Additionally, olfactory perceived valence is a key feature of the smell (Engen & McBurney, 1964, see also section 3.3 and Mohanty & Gottfried, 2013 and Yeshurun & Sobel, 2010 for reviews), but it is complemented by the information conveyed by trigeminality (Kobal, Van Toller, & Hummel, 1989), that also signals potential chemical threats. Thus, both olfactory and trigeminal systems are responsible for rendering essential characteristics of odors, and their neural organization will be overviewed in the next paragraphs.
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2.3 Peripheral transduction of odors 2.3.1 Trigeminal chemosensation
The trigeminal system is considered to be a defense mechanism against irritants and poisonous substances, eliciting multiple sensations – described as burning, stingy, itchy, tingling or cold (Viana, 2011), and protective responses (e.g. tear, sneeze) upon activation. It responds to chemical irritants such as CO2, Ethanol, acetic acid, menthol, capsaicin, garlic or even atmospheric pollutants such as NH3 or SO2 (Doty, 1995; Petrova, Diamond, Schuster, & Dalton, 2008). These molecules activate a wide set of ion channel receptors, expressed mostly in the respiratory epithelium at the middle septum level (Scheibe, van Thriel, & Hummel, 2008), and in the oral cavity (Viana, 2011). The signaling mechanism directly acts on the gating of the ion channel, enabling cation influx and intracellular depolarization. The ion channels involved either respond to an agonist chemical signal (e.g. protons or capsaicine), temperature or mechanical stimulation, but many of them have combined sensitivity. For instance, the V1 subtype of transient receptor potential (TRPs) has an extended thermal, mechanical and chemical sensitivity that could account for the polymodality of the reported sensations (Viana, 2011). Other channel types include TRPV2, V3, A1 and M8, with sensitivity to varied agonists such as tetrahydrocannabinol, camphor, mustard oil or menthol, acid sensing ion channel (ASICs) sensitive to protons (lowering of pH) and purinic receptors (for a detailed review of receptor sensitivity and functioning mechanisms, see Viana, 2011).
2.3.2 The olfactory epithelium and odor receptor neurons
Olfactory stimuli interact with olfactory receptor cells or neurons (ORNs) from the olfactory epithelium, which can be considered as the key sensory organ for smell, since its damage can lead to anosmia (Reiter, DiNardo, & Costanzo, 2004, see also section 3.7). ORNs are embedded in the olfactory mucosa which is mostly located in the upper nasal ceiling, superior and posterior part of the olfactory cavity, but also on the midline nasal septum and its roof, and the lateral wall of the nose (Figure 2). The ORNs are short lived bipolar neurons that project axons to the olfactory bulb (OB) though the cribriform plate, while, on their apical surface, they carry olfactory cilia that express one or two out of the 1000 mammalian odorant receptor genes (Buck & Axel, 1991; Firestein, 2001;
Gaillard, Rouquier, & Giorgi, 2004), according to populations differential patterns in the human olfactory repertoire (Gilad & Lancet, 2003). A study characterizing the expression of the human olfactory receptor gene determined that around 76% of these genes are expressed in the olfactory epithelium, and that expressed olfactory receptor genes differ by at least 14% between each individual (Zhang et al., 2007), providing a putative basis for specific anosmia and inter-individual differences in odor perception.
27 These odorant receptors are intermembrane proteins belonging to the G-protein coupled receptor family (Buck & Axel, 1991). Odorants bind to a specific receptor molecule embedded in the cell membrane. This association activates a specific olfactory G protein which in turn triggers the production of cyclic AMP through adenylyl cyclase. The intracellular increase of cyclic AMP enables the opening of a target cation-channel, resulting in a massive extracellular Ca2+ influx into the cell, which an intracellular depolarization (for a detailed review on calcium signaling and regulation in ORNs, see Menini, 1999). This neuronal depolarization then extends from the cilia to the axon, where an action potential is generated and transmitted to the OB.
Although the ORNs of one particular type converge in the same glomerulus (Mombaerts et al., 1996) where they establish synaptic connections with mitral and tufted cells (Figure 2), they are scattered randomly in the nasal mucosa. Additionally, a single odorant can bind to multiple receptor subtypes and a single receptor can bin to multiple odorants (Firestein, 2001). The apparent lack of clear pattern is a specific feature of the olfactory system, although this has recently been challenged by a study that managed to intranasally record odorant induced evoked responses in humans (Lapid et al., 2011). They found that olfactory epithelial locations responding maximally to a given odorant were likely to respond strongly to another odorant of corresponding pleasantness, suggesting the presence of a putative valence-related organization in the olfactory receptor surface.
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Figure 2. Olfactory transduction.
The odorant receptor neurons located in the upper nasal epithelium express one to two odorant receptors. When activated by an olfactory stimulus, the odorant receptor neurons convey the neural signal through the cribriform plate to the glomeruli in the olfactory bulb, where they form synapses with mitral cells which relay the signal to higher central areas. Each glomerulus receives axons from neurons expressing a single odorant receptor gene. Taken from Rinaldi, 2007.
2.4 Central transduction of odors 2.4.1 Trigeminal central relays
The trigeminal nerve, or cranial nerve V, is responsible for the trigeminal sensation. Its three branches radiate from the trigeminal ganglion to innervate the face (Figure 3), and the chemosensitive information of the nasal respiratory epithelium is mainly conveyed by the maxillary (V2) and the ophthalmic branches (V2). Glossopharyngeal (IX) and vagal (X) endings in the oropharynx and the nasal cavity also contribute to chemosensation (see also Kirchner et al., 2004).
The elicited sensation is carried through both myelinated (A delta) and unmyelinated (C) fibers. While a fraction of the trigeminal information is relayed to the amygdala via the lateral parabrachial complex (Bernard, Peschanski, & Besson, 1989), the majority chemosensory fibers project from the nasal cavity to the superficial laminae of the spinal trigeminal nucleus. From there, the information is relayed to the ventral posteromedial nucleus (VPM) of the thalamus. Finally, the projections from the VPM nuclei terminate in the primary (Figure 4a, for a review, see Hummel & Livermore, 2002) and
29 the secondary olfactory cortices (Figure 4a)(Hummel, Iannilli, Frasnelli, Boyle, & Gerber, 2009;
Hummel, Oehme, et al., 2009). Along with the latter, trigeminal stimuli are known to recruit an ensemble of structures associated with nociceptive stimuli (Albrecht et al., 2010, Metanalyise, Bensafi et al., 2008; Boyle et al., 2007; Hari et al., 1997; Hummel et al., 2005, 2009b; Huttunen et al., 1986; Iannilli et al., 2007, 2008), including the thalamus, the anterior cingulate cortex, the insula, the superior parietal lobule and the precentral gyrus.
Most ascending fibers to the thalamus decussate towards the contralateral side, but some ascend ipsilaterally, thus enabling a monorhinal stimulation to generate activation in both hemispheres (Boyle, Frasnelli, et al., 2007). Unlike the olfactory system, the trigeminal system is lateralized and allows directional detection of the stimuli (Berg, Hummel, Huang, & Doty, 1998; Croy et al., 2014;
Hummel, Futschik, Frasnelli, & Hüttenbrink, 2003; Kleemann et al., 2009; Kobal et al., 1989). Given the stinging or burning sensation they elicit, trigeminal stimuli are also known for activating neural structures constituting a pain network (see section 2.4.1 and metanalysis Albrecht et al., 2010).
Figure 3. The trigeminal nerve.
The three branches of the trigeminal nerve innervating the face are shown here. The maxillary nerve is responsible for the chemosensory sensitivity brought by volatile chemicals in the nose. Taken from Purves et al., 2003, Neurosciences 2nd Edition, De Boeck, Chap. 15 Chemical Senses.
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Figure 4. Central Processing of trigeminal stimulus.
a) Activation of the piriform and primary and secondary bilateral somatosensory cortices in response to a CO2 vs. baseline (odorless air) stimulation. b) Activation of the anterior cingulate cortex and the right anterior insula in response to isoamylacetate (trigeminal) vs.
phenylethyl ethanol (non-trigeminal). Taken from Hummel et al., 2009 (PET) and Lombion et al., 2009 (fMRI), respectively.
2.4.2 The olfactory bulb and overview of the central olfactory system
Once arrived in the glomeruli, the olfactory information undergoes a synapse at mitral and tufted cells and is then conveyed though the lateral olfactory stria to the primary olfactory cortex, which consists of the amygdala, the entorhinal and piriform cortex, the anterior olfactory nucleus and the olfactory tubercle (Figure 5 and Figure 6). The information is then further relayed to the orbitofrontal cortices, the insula, the hippocampus, the thalamus, the hypothalamus and basal ganglia (Carmichael et al., 1994, for review see Mohanty & Gottfried, 2013, for metanalysis see Seubert, Freiherr, Djordjevic, & Lundström, 2012). The OB thus encodes the primary olfactory information from the ORNs and transmits it to frontal and temporal areas in the brain. In turn, these central areas send back projections to GABA neurons in the OB (Strowbridge, 2009; Wachowiak & Shipley, 2006),
31 suggesting that these numerous cortical efferents can exert an early top-down influence on odor processing (Kay & Freeman, 1998, for reviews see Mackay-Sim & Royet, 2006; Mohanty & Gottfried, 2013). Given its small size – 60-100 mm2 in healthy humans – (Kavoi & Jameela, 2011; Mueller et al., 2005) and location (near bone and air sinuses), the OB is difficult to study functionally with brain imaging techniques, mostly because of the current unresolved compromise between resolution and imaging artifacts, both function of the strength of the magnetic field. Nevertheless, anatomical studies in humans and in vivo studies in animals enable us to deduce functions of the OB regarding odor processing. The OB appears to have a key role in olfactory processing in humans, since an underdeveloped OB is associated with anosmia (MacColl, Bouloux, & Quinton, 2002). Reduced OB is also linked to poor olfactory detection (Buschhüter et al., 2008), whether this originates from trauma or infection (Mueller et al., 2005). Conversely, olfactory training results in increased OB volume in both healthy subjects and patients with olfactory loss (Damm et al., 2002; Hummel & Pietsch, 2014), which has led to the suggestion that attentional selection in olfaction could occur in the OB (Kay &
Laurent, 1999; Kay & Sherman, 2007; Keller, 2011) through cholinergic signaling (D’Souza &
Vijayaraghavan, 2014). In rodents, the glomeruli are considered to constitute a form of primary stereotyped odor map in the OB, where the odor identity can be represented by differential spatio- temporal patterns of glomerular activation (Bathellier, Buhl, Accolla, & Carleton, 2008; Mombaerts et al., 1996). Glomeruli are attuned to detect molecular features (Rubin and Katz, 1999) and play a role in concentration coding (Rubin & Katz, 1999; Vincis, Gschwend, Bhaukaurally, Beroud, & Carleton, 2012), and could even underlie the alteration of the perception of some odorants as a function of their concentration (Johnson & Leon, 2000). The OB thus appears to be able to discriminate odorants, and data from the Zebrafish suggest that this faculty could arise from the classification of odor evoked inputs into discrete output patterns, though coordinated response changes among small neuronal ensembles (Niessing & Friedrich, 2010). These animal models should be translated with caution to Humans, as important anatomical differences arise in the organization of the human OB. Humans express less intact olfactory receptors and have more glomeruli, resulting in a convergence ratio of 16:1 compared to 2:1 in mice (Maresh, Rodriguez Gil, Whitman, & Greer, 2008).
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Figure 5. The olfactory brain.
The afferent outputs from the olfactory bulb (OB) are represented from a ventral view: anterior olfactory nucleus (AON), olfactory tubercle (OTUB), anterior and posterior piriform cortex (APC and PPC), amygdala (AM), entorhinal cortex (EC). Secondary projections from the piriform and entorhinal cortices are also shown: orbitofrontal cortex (OFC) and hippocampus (HP). Taken from Gottfried, 2010.
Figure 6. An overview of the olfactory system’s interconnections in Mammals.
Some connections were omitted for simplicity. The olfactory tubercle also projects to several basal nuclei and to the orbitofrontal cortex in rodents and monkeys respectively. These connections, along with the ventral tenia tecta and the indusium griseum which are additional olfactory structural efferents of the olfactory bulb, were omitted for simplicity. Adapted from Cleland and Linster, 2003, and Mackay-Sim and Royet, 2006.
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2.4.3 The piriform cortex
As part of the primary olfactory cortex, the piriform cortex (PirC) is an essential step of olfactory processing: it is sensitive to odorant perception (Gottfried, Deichmann, et al., 2002; Savic, Gulyas, Larsson, & Roland, 2000; Seubert et al., 2012; Sobel, Khan, Hartley, Sullivan, & Gabrieli, 2000;
Zatorre, Jones-Gotman, Evans, & Meyer, 1992), recognition (Plailly et al., 2005); and even olfactory mental representation (Arshamian et al., 2013; Bensafi, Sobel, & Khan, 2007). The PirC is reciprocally connected with most of the other primary olfactory cortex constituents (Carmichael et al., 1994;
Haberly, 2001; Johnson, Illig, Behan, & Haberly, 2000; Kay & Freeman, 1998, for a review see Gottfried, 2010) and projects directly to the orbitofrontal cortex (Gottfried, Deichmann, et al., 2002), but also indirectly through a mediodorsal thalamic relay (Carmichael et al., 1994) that possibly reflects an involvement of both structures in olfactory attention (Murakami, Kashiwadani, Kirino, &
Mori, 2005; Plailly, Howard, Gitelman, & Gottfried, 2008; Seubert et al., 2012; Zelano & Sobel, 2005, see also section 4.2.2). Finally, as many other regions of the olfactory system, the PirC is also sensitive to trigeminal stimulation (Figure 4a)(Hummel, Iannilli, et al., 2009; Hummel, Oehme, et al., 2009)
A seminal review (Gottfried, 2010) reassembled the evidence showing the critical implication of the PirC in most aspects of odor object perception. These aspects are listed as odor background segmentation (Stevenson & Wilson, 2007), which is the ability to disentangle irrelevant background odors from new and relevant ones through habituation (Kadohisa & Wilson, 2006; Sobel et al., 2000);
odorant feature analysis, which can be defined as the synthesis of different odor components into a
“perceptual whole” odorant constancy and categorization, defined as the ability to recognize an object across sensory or stimulus variability; and its reciprocate counterpart, odor object discrimination.
The PirC is divided into an anterior (APC) and a posterior part (PPC), sometimes approximated by a frontal / temporal distinction (Bensafi, Sobel, et al., 2007; Zelano & Sobel, 2005). These two anatomical subdivisions (see Gottfried, 2010 for a review) process complementary facets of the odor object perception mechanism listed below, as they differ by the neuronal networks they belong to:
the APC constitutes the main efferent of the OB, whereas the PPC receives more associative projections (Schwob & Price, 1978, for reviews see Gottfried, 2010 and Haberly, 1985), which contribute to integrate contextual information. These differences in connectivity are reflected by the relative functional partition of the two structures.
Interestingly, the APC is modulated both by valence (Zelano, Montag, Johnson, Khan, & Sobel, 2007) – responding particularly to unpleasant odors (Bensafi, Sobel, et al., 2007; Gottfried, Deichmann, et
34 al., 2002; Zelano et al., 2007), and odorant chemical identity (Gottfried, Winston, & Dolan, 2006).
Although the chemical nature of the odorant sometimes plays a role in its pleasantness, the link between the two is not straightforward and pleasantness perception in odors depends on many additional factors (see section 3.6). Additionally, the frontal PirC is less responsive to odor imagery - compared to other portions of the olfactory circuit (Bensafi, Sobel, et al., 2007). Thus as suggested by Gottfried (2007), the APC seems to supports the reconstruction of an odorant’s identity, based on the elemental molecular and valence features stemming from the perceived stimulus.
Conversely, the PPC appears to integrate associative inputs to modify odorants’ representation (Howard, Plailly, Grueschow, Haynes, & Gottfried, 2009; Margot, 2009). Contrary to the APC’s coding of odor chemical identity, the PPC encodes an odor object quality (Gottfried et al., 2006), enabling its categorization through a specific pattern representation (Figure 7) (Howard et al., 2009). This quality representation in the PPC is flexible, and can be altered by incorporating external factors, such as sensory experience or associative learning (Li, Howard, Parrish, & Gottfried, 2008; Li, Luxenberg, Parrish, & Gottfried, 2006; Mouly, Fort, Ben-Boutayab, & Gervais, 2001).
Figure 7. Categorization of odor quality in the posterior piriform cortex.
The flattened PPC maps of two participants display unique categorical patterns in response to differentially perceived odorants. Taken from Howard et al., 2009.
2.4.4 The amygdala
The amygdala is central to the cognitive processing of novel (Blackford, Buckholtz, Avery, & Zald, 2010), or emotionally significant events (Anderson & Phelps, 2001; Cahill, Babinsky, Markowitsch, &
McGaugh, 1995; Grandjean et al., 2005; E. a Phelps & LeDoux, 2005; Vuilleumier, Armony, Driver, &
Dolan, 2001). The role of the amygdala is too complex and vast to be overviewed in detail here, but as described previously, it has been shown to be involved in many emotional related processes (e.g.
35 emotional elicitation, responses, regulation), and to mediate prioritized neural processing in various systems (e.g. perception, learning, memory, attention, see Sander, 2009 for a review). For instance, the amygdala is considered to be crucially involved in the processing of fear or threat related stimuli (Öhman & Mineka, 2001), and more generally, to emotional arousal (Hamann, 2003, see section 3.2 for a definition of arousal).
However, because the amygdala is sensitive to other types of information: negative, positive and reward related (Sergerie, Chochol, & Armony, 2008), or low arousal affect (Fine & Blair, 2000), it has been proposed that it may be broadly specialized in the processing of emotionally significant events and involved in relevance detection, according to individual goals needs and concerns (Sander, Grafman, & Zalla, 2003; Sander, Grandjean, & Scherer, 2005), such as food-related stimuli for hungry participants (LaBar et al., 2001). Its sensitivity to affectively salient stimuli is so acute, that it can occur at low level perceptual levels (Vuilleumier, Armony, Driver, & Dolan, 2003; Whalen et al., 2004), and outside of the attentional focus (Vuilleumier & Schwartz, 2001; Vuilleumier, 2005, see also section 4.2.3). Finally, the amygdala plays a key role in emotional memory (Hamann, 2001;
Pouliot & Jones-Gotman, 2008), interacting with memory systems in the prefrontal cortex (PFC), Hippocampus and Entorhinal cortices (for a review see LaBar & Cabeza, 2006).
The amygdala is also considered to be part of the primary olfactory cortex given the reciprocal connection of the periamygdaloid cortex and the amygdalar cortical nuclei to the OB (Carmichael et al., 1994, for reviews see Cleland & Linster, 2003 and Mackay-Sim & Royet, 2006). In fact, the amygdala is recruited early in the processing stream upon olfactory stimulation (Lascano, Hummel, Lacroix, Landis, & Michel, 2010), and responds to odorant detection (Savic et al., 2000; Seubert et al., 2012). It is also highly sensitive to habituation (Li et al., 2006), along with the PPC and the hippocampus.
In mammals, amygdalar sites project to the piriform, entorhinal and insular cortices, as well as the hypothalamus (Paxinos & Watson, 1986; Price, 1973; Scott & Leonard, 1971, Haberly, 1985, 1998, 2001; for reviews see Cleland & Linster, 2003 and Mackay-Sim & Royet, 2006). This particular neural configuration places the olfactory system in a unique position among sensory modalities, since it is the only system possessing such a direct connection to the emotional neural network. Such a specificity is reflected in the role amygdala appears to play in the processing of odors. Indeed, in line with its mediating role of the emotional arousal on memory (for a review, see LaBar & Cabeza, 2006), the amygdala is also recruited for various learning processes related to olfaction, such as aversive conditioning of odors (Li et al., 2008), odor-picture association recall (Yeshurun et al., 2009), and olfactory information retrieval through repetition-suppression (Jung et al., 2006).
