Sensory Science and Chronic Diseases: Clinical Implications and Disease Management 303086281X, 9783030862817

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Sensory Science and Chronic Diseases Clinical Implications and Disease Management Paule Valery Joseph Valerie Buzas Duffy Editors

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Sensory Science and Chronic Diseases

Paule Valery Joseph  •  Valerie Buzas Duffy Editors

Sensory Science and Chronic Diseases Clinical Implications and Disease Management

Editors Paule Valery Joseph National Institute on Alcohol Abuse and Alcoholism and National Institute of Nursing Research Bethesda Bethesda, MD USA

Valerie Buzas Duffy Department of Allied Health Sciences College of Agriculture, Health, and Natural Resources University of Connecticut Storrs, CT USA

ISBN 978-3-030-86281-7    ISBN 978-3-030-86282-4 (eBook) https://doi.org/10.1007/978-3-030-86282-4 © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021 All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

We dedicate this book to the many patients who are afflicted by chemosensory disorders

Introduction

Today, more than ever before, there is recognition of the importance in understanding, researching, and assessing the sensory science for the promotion of health and the prevention of disease. Our world has been challenged with the coronavirus pandemic, with one of the main symptoms of viral infection being the loss and alteration of the chemical senses—smell, taste, and chemesthesis (burn, irritation). Clinicians have paid close attention to these patient-reported symptoms, with greater awareness and appreciation of the need to understand the loss, document the extent of the chemosensory problem, and support recovery of chemosensory function. Sensory Science and Chronic Diseases: Clinical Implications and Disease Management provides clinicians, researchers, public health professionals, and students of multiple disciplines the needed background to improve knowledge of chemosensation and perception, to foster application of this information in practice in a variety of health and community settings, and to stimulate ideas on interdisciplinary research on improving health through advances in sensory science. The book begins with an overview of the basic science of taste and smell sensation by Jaime-Lara, To, and Joseph with clear and informative figures that summarize the current understanding from broad fields of molecular biology, neurology, anatomy, and physiology in a relatively concise and straightforward chapter. Readers can explore further from the reference list that includes a historical work, seminal research, and latest findings. From this necessary foundation, the reader is treated to a most interesting and well-written chapter by Smethers and Mennella on the development of the perception of sweet taste and as importantly how much this sweetness is preferred. We all are born with a preference for sweet taste. Yet, ubiquitous exposure to sweetness in the food supply drives up the desire for sweet taste and challenges the establishment of healthy food preferences early in life. Psychophysics, the oldest branch of psychology, applies rigorous scientific methods to objectively measure perceptual experiences. The next two chapters provide critical information by recognized experts on the measurement of smell and taste function. Parma and Boesveldt report on measures of smell function matched with the clinicians’ and researchers’ goals, testing requirements, and associated health interests. In addition, they provide guidelines for screening measures of olfaction. The taste chapter, written by Duffy, Rawal, and Hayes, covers how to measure variation in the taste related to genetics, lifestyle choices, diseases, and vii

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Introduction

common exposures. The chapter focuses on measures of perceived intensity, how to avoid pitfalls that decrease the ability to compare perceived intensity across individuals, and regional taste perception. The background on measurement of taste is coupled with application to nutrition and public health. Connected with the chapter of Smethers and Mennella, the chapter on taste measurement includes measuring food and beverage preference, including through survey methods as a novel proxy of dietary intake. The brain integrates sensory information from the periphery into an integrated and unique perceptual experience. Linne and Simons provide a thorough overview of this perceptual integration grounded in Gestalt theory (the whole is greater than the sum of its parts) and wonderfully explain through the anatomical processes of chemosensory integration through overlapping sensory pathways. Furthermore, they provide a discussion of why “taste” is the descriptor for the experience of food from the mouth, when clearly the experience is more than true taste (e.g., perception of sweetness). The chapter applies the information of perceptual integration to associative learning and the development of food preferences and to explain alterations with aging and exposures that can damage the separate sensory systems. The last part of the book examines chemosensation in clinical conditions. • Bariatric surgery allows testing of relationships between the chemical senses and body weight loss through a surgery that restricts the size of the stomach, and often, causes macronutrient malabsorption. Carreón, Acevedo, Rowit, and Pepino provide the needed background on the anatomy, physiology, neuroendocrine and gut-brain axis changes with bariatric surgery within the context and extensive animal and clinical evidence to conclude that chemosensory changes are hedonic in nature rather than sensory. • Olfaction is more than detecting an odor. It involves cognitive functions of odor recognition and correctly labeling, odor memory, and emotion. With years of experience in the field, Murphy details the effects of neurocognitive disorders, with focus on olfactory dysfunction as a potential early diagnostic marker of Alzheimer’s disease (AD) and Parkinson’s disease (PD) with implications for understanding healthy aging. • Parallels between substance use disorders and chemosensation are explored by Agarwal, McDuffie, Manza, and Joseph. The mechanisms of addiction are connected with olfactory and taste dysfunction with implications for treating these addictions and potential restoration of chemosensory function. • Chemosensory alterations accompany treatment of cancer, yet there is confusion characterizing this disorder between patients, clinicians, and sensory scientists. Nolden provides an interdisciplinary connection between tools used by clinicians to assess chemosensory alterations, mechanisms of these alterations, and implications for symptom management with challenging treatment regimens. • Phantom oral sensations, including dysgeusia and oral pain syndromes, are complex to diagnose and treat. With years of dental practice experience grounded in sensory science, Gruska and Su review the causes of these oral phantoms and the methods to evaluate with implications for treatment options aligned with the suspected causes.

Introduction

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• Implications of the health of the oral cavity for taste and oral sensations are further explored by Ganesan, Maki, and Kandaswamy within oral diseases/disorders, oral health behaviors, and dental treatments. The chapter delves into emerging science of the oral microbiota and specific taste alterations and potential mechanisms. • The COVID-19 drew attention to the chemical senses with disorders of smell and taste as a prominent sign of infection. Hannum and Reed review the latest evidence on how the viral infection is associated with loss of smell, true taste, and chemesthesis during the acute infection and in those individuals who suffer from losses well past recovery from the acute infection. Covered are implications of the chemosensory losses and alterations in COVID-19 for long-term health and well-being through the ability to restore nutritional health and well-being as well as to prevent additional chronic conditions. Bethesda, MD, USA Storrs, CT, USA

Paule Valery Joseph Valerie Buzas Duffy

Contents

Part I Biology and Development 1 Anatomy, Physiology, and Neurobiology of Olfaction, Gustation, and Chemesthesis��������������������������������������������������������������������   3 Rosario B. Jaime-Lara, Leann To, and Paule Valery Joseph 2 Sweet Taste and Added Sugar Consumption in Infancy and Childhood��������������������������������������������������������������������������������������������  21 Alissa D. Smethers and Julie A. Mennella Part II Measurements of Taste and Smell 3 Measurement of Olfaction: Screening and Assessment��������������������������  45 Valentina Parma and Sanne Boesveldt 4 Measurement of Gustation: From Clinical to Population-Based Methods ������������������������������������������������������������������  65 Valerie Buzas Duffy, Shristi Rawal, and John E. Hayes Part III Taste Smell, Chemesthesis in Clinical Conditions 5 Integration of Taste, Smell, and Chemesthesis: Clinical Implications���������������������������������������������������������������������������������� 105 Brianne M. Linne and Christopher T. Simons 6 Taste and Smell in Weight Loss Surgery�������������������������������������������������� 125 Jessica Nicanor Carreón, M. Belen Acevedo, Blair Rowitz, and M. Yanina Pepino 7 Olfactory Impairment and Neurodegenerative Disorders �������������������� 145 Claire Murphy 8 Taste and Smell Alterations and Substance Use Disorders�������������������� 159 Khushbu Agarwal, Christian McDuffie, Peter Manza, and Paule Valery Joseph 9 Loss of Taste and Smell Function in Cancer Patients���������������������������� 181 Alissa A. Nolden xi

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10 Oral Health and Chemosensory Problems: Clinical Implication and Disease Management ���������������������������������������������������� 203 Miriam Grushka and Nan Su Part IV New Areas and Implications of Taste and Smell 11 Oral Health and Microbiome: Implications for Taste: State-of-the-­Science on the Role of Oral Health and Emerging Science of the Microbiota and its Implications for Taste ���������������������� 227 Sukirth M. Ganesan, Katherine A. Maki, and Eswar Kandaswamy 12 COVID-19-Associated Loss of Taste and Smell and the Implications for Sensory Nutrition���������������������������������������������������������� 245 Mackenzie E. Hannum and Danielle R. Reed

Part I Biology and Development

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Anatomy, Physiology, and Neurobiology of Olfaction, Gustation, and Chemesthesis Rosario B. Jaime-Lara, Leann To, and Paule Valery Joseph

Learning Objectives 1. Define olfaction, gustation, flavor, and chemesthesis. 2. Illustrate basic olfactory and gustatory anatomy. 3. Identify cellular structure and function of olfactory epithelium. 4. Identify cellular structure and function of taste-bud cells. 5. Outline olfactory and gustatory transduction pathways. 6. Differentiate cell-type and receptors specific to each of the five major taste modalities. 7. Describe olfactory and gustatory neuroanatomical pathways. 8. Recognize overlapping pathways in olfaction, gustation, and chemesthesis and their role in flavor perception. 9. Utilize knowledge of anatomy and physiology of olfaction and gustation included in this chapter as a foundation to understanding subsequent chapters. Definitions Chemesthesis GPCRs Gustation

Activation of somatosensory pathways by specific chemicals associated with sensation (e.g., texture, irritation, and temperature). G-protein-coupled receptors that act as binding cites to stimuli (including odorants and tastants). They are plasma membrane proteins that often initiate secondary signaling cascades. The sensory system responsible for taste. Taste perception is initiated in the taste buds and processed in the brain to give rise to our perception of taste.

R. B. Jaime-Lara (*) · L. To · P. V. Joseph National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA National Institute of Nursing Research, Bethesda, MD, USA e-mail: [email protected]; [email protected]; [email protected] © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021 P. V. Joseph, V. B. Duffy (eds.), Sensory Science and Chronic Diseases, https://doi.org/10.1007/978-3-030-86282-4_1

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Flavor Odorant Olfaction Retronasal olfaction (Signal) transduction

1.1

The perceptual integration of smell, taste, and oral-somatosensory signals that arise from foods and beverages in the mouth. An aromatic compound that activates olfaction (a substance that gives off an odor/smell). The sense of smell. Olfaction is initiated in the nasal cavity and processed in the brain to give rise to our perception of smells. When smells, that originate from the oral cavity, reach the nasal cavity behind the sinuses to stimulate olfactory receptors. The process of transferring a physical of chemical signal through an organism. Usually comprises a series of molecular events inside the cell. Signal transduction often leads to a cellular response.

Introduction

1.1.1 Encoding Chemosensory Information All living organisms, including humans and other animals, have the capacity of responding to chemicals in our environment. The term “chemical sense” was first introduced by George H. Parker in 1912 and described senses able to detect chemical substances in the environment [1]. In humans, the chemical senses represented by olfaction (the sense of smell), gustation (the sensory system responsible for taste), and other complimentary senses allow us to monitor our internal and external environments [1–4]. The sense of taste provides us with some information about the nutritional and chemical properties of the foods we consume [5–8]. Similarly, our sense of smell allows the specific identification of what we consume, can detect off notes in spoiled foods, and/or alert us to dangers in our environment, such as the smell of smoke to alert us to the presence of a nearby fire [9–11]. Taste and olfaction impact our food choices [3], mood [2], and the presence of potentially life-­ threatening hazards [4, 9]. Thus, olfaction and taste sensation are intimately intertwined with survival and ultimately impact how we interact and perceive our environment. In this chapter, we will discuss the anatomy and physiology of human taste and olfaction with a focus on eating behavior, including flavor perception. Foods and beverages stimulate more than taste; olfaction plays an important role in flavor perception [12–14] and patients with olfactory deficits report flavor alterations [15, 16]. Stimulation of chemoreceptor cells in both the mouth (e.g., taste bud cells) and nasal epithelium (e.g., olfactory receptor cells) is processed by our central nervous system to give rise to the sensation of flavor. In fact, taste and smell are so closely intertwined in what we perceive as flavor, that it is difficult to discern what is exclusively taste and/or smell [17]. For example, smell impairments induced by inflammation of olfactory tissue following a respiratory infection are often reported as a loss of taste [17, 18]. Thus, it is important to study and understand the anatomy and physiology of both chemical senses, and how they interact and provide us with vital information regarding the composition of substances we encounter, including the foods we consume. In addition to taste and olfaction, other sensory information contributes to our experience of flavor, including somatosensory receptors, such as

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mechanoreceptors, nociceptors, and thermoreceptors, that are responsible for the perception of texture, irritation, and temperature, respectively [19–22]. Chemesthesis refers to the activation of these somatosensory receptors and pathways by specific chemicals and plays an important role in flavor perception. Chemesthesis is discussed in detail in Chap. 6. The multisensory integration of gustatory, olfactory, and somatosensory information into a unitary flavor is discussed in Chap. 7. This chapter will focus on the anatomy and physiology of olfaction and gustation and briefly discuss the integration of these systems and chemesthesis.

1.2

Anatomy and Physiology of Olfaction

1.2.1 Olfactory Anatomy In humans, the primary olfactory apparatus is comprised of the olfactory mucosa situated in the nasal cavity [23]. This olfactory area encompasses the superior turbinate, the sphenoethmoidal recess, the septum, and the lateral and medial regions of the cribriform plate (Fig. 1.1). Odorants reach the olfactory mucosa orthonasally Olfactory bulb

Olfactory tract

Olfactory epithelium Cribriform plate Sphenoethumoidal recess Superior turbinate

Septal Cartilage nt

ra Odo

Fig. 1.1  Nasal cavity

Od

ora

nt

Middle turbinate Inferior turbinate Palate

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through the nasal cavity or retronally, where odorants originating from the oral cavity reach the nasal cavity and stimulate olfactory receptors [24]. The olfactory mucosa is a mucous membrane made up of epithelium and subepithelial lamina propria [23]. In humans, the olfactory epithelium is comprised of four major cell types: olfactory receptor neurons (ORNs), sustentacular cells, microvillar cells, and basal cells [23, 25]. ORNs are the sensory neurons within the olfactory system. ORNs are bipolar cells with circular cell bodies embedded within the epithelial layer. ORN dendrites reach the epithelial surface and cilia project from the dendrites into the mucus layer that lines the olfactory epithelium (Fig. 1.2). The interaction between the odorant and the sensory neuron occurs in the ciliary membrane, initiating olfactory signal transduction. These signals are then carried to the CNS by ORN axons which extend beyond the olfactory mucosa, forming axonal bundles that project to the olfactory bulb. Sustentacular cells and microvillar cells provide support for olfactory neurons [26]. These support cells make up the topmost layer of the olfactory epithelium and play an important role as metabolic and physical support. Due to their proximity to the basement membrane, it has been suggested that supporting cells may regulate the passage of substances between the underlying connective tissue and the epithelial surface. Basal cells are located in the basement membrane and give rise to ORNs [26, 27]. There are two types of basal cells, globose basal cells, and horizontal basal cells. Globose basal cells (GBCs) are immediate precursors of ORNs. Horizontal Olfactory bulb

glomerulus

Bone-cribriform plate Bowman’s gland Lamina propria ORN Axons Basal cell olfactory epithelium

Olfactory receptor neuron (ORN) Sustentacular cell ORN clilia Microvillar cell type 1

Fig. 1.2  Olfactory epithelium and olfactory bulb

Microvillar cell type 2

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basal cells are found below GBCs and lie directly on the basement membrane. Importantly, horizontal basal cells can produce multiple differentiated neuronal and glial cells in the olfactory system [28].

1.2.2 Olfactory Physiology 1.2.2.1 Olfactory Transduction In the ciliary membrane, olfactory transduction is initiated by the binding of an odorant to olfactory receptors. A summary of olfactory transduction is summarized in Fig.  1.3. Odorant receptors [3] belong to a superfamily of G-protein-coupled receptors, first identified by Buck and Axel in 1991 [29]. ORs share a common structure, consisting of seven transmembrane domains [29, 30]. However, ORs vary in amino acid sequence, which may allow for the discrimination of different odorants [31]. The advancement of molecular methods has allowed for the identification of hundreds of ORs (a database of olfactory receptors is available at https://senselab. med.yale.edu/ordb) [32]. ORs have three subunits α, β, and γ. The binding of an odorant to an OR leads to the dissociation of alpha subunit, olfactory-specific excitatory G-protein (Gαolf) (first identified by Jones and Reed in 1989), from the β and γ subunits [33]. This initiates a second messenger cascade. The two secondary messengers involved in olfactory transduction are 1) 3′5′-cycliic monophosphate (cAMP) and inositol 1,4,5-triphosphate (IP3). Olfactory bulb

Olfactory receptor

ORN

Odorant

Adenylyl cyclase (AC)

PLC

PIP2

s

cAMP

cAMP

s

Y

ATP

Activates AC

DAG

Cyclic nucleotide-gated channel (CNG)

cAMP

Inactive Protein kinase A

IP3

Active cAMP Protein kinase A

Ca2+

Endoplastic Reticulum

CI-

2+

Ca

Membrane depolarization

Fig. 1.3  Olfactory transduction

Activated CI- Channel (CaCC)

Na+/Ca2+ Exchanger (NCX)

Plasma Membrane Ca2+ ATPase (PMCA)

Return to baseline

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Cyclic Adenosine Monophosphate (cAMP) A secondary messenger involved in olfactory transduction is cyclic adenosine monophosphate (cAMP). The dissociation of Gαolf from β and γ subunits activates adenylyl cyclase type III (AC III). The catalytic region of AC III converts adenosine triphosphate (ATP) into cAMP, which is a small water-soluble molecule that plays a vital role in the signal transduction of multiple odorants. Subsequently, odorant-­ stimulated cAMP targets cAMP-gated nonspecific cation (CNG) channels. CNG channels are permeable to Ca2+, Na+, and K+ ions. However, Ca2+ permeates slowly through CNG channels excluding other cations. Ca2+ ions entering through the CNG channels increase intracellular Ca2+, [Ca2+]i, and can lead to depolarization. Calcium-Activated Chloride Channels (CaCC) Ca2+ ions, entering through CNG channels, activate chloride channels (CaCCs). The opening of CaCCs leads to an efflux of Cl− ions. This outward movement of Cl− ions further contributes further to the depolarization of ORNs. Unlike in other neurons, where the opening of Cl− channels produce inhibitory responses (e.g., GABAergic synapses), in ORNs, Cl− generates an excitatory current that amplifies the primary transduction current. Another transporter, Na+/K+/2Cl− cotransporter (NKCC1), also contributes to Cl− uptake [34–36]. Sodium Calcium Ion Exchanger (NCX) and Ca2+ ATPase As the concentration of intracellular calcium increases, Ca2+ concentration is restored to basal levels via two mechanisms, Na+/Ca2+ exchanger and Ca2+ ATPase. Na+ drives Ca2+ efflux via Na+/Ca2+ exchanger is the main mechanism by which basal levels are restored. This is supported by studies where current response is prolonged when Na+ is removed/not present [37]. Additionally, Ca2+ ATPase which in olfactory cilia [38, 39] also plays a role in Ca2+ efflux. Studies have found that an absence of intracellular ATP and the blocking of Ca2+ ATPase also significantly prolongs the restoration of Ca2+ concentration to baseline levels. Inositol Triphosphate (IP3) Another secondary messenger that is less understood is IP3. GPCRs activate phospholipase C (PLC) to produce IP3 and diacylglycerol [16]. It is hypothesized that odorant-stimulated IP3 targets IP3-gated channels, and their activation depolarizes the cell, acting as a parallel or alternate excitatory transduction pathway. IP3 increase [Ca2+]i which promotes phosphorylation of protein kinase C-mediated (PKC) channel.

1.2.3 Neuroanatomy of Olfaction 1.2.3.1 Olfactory Pathways After olfactory transduction is initiated at the ciliary membrane of ORNs, this olfactory information travels through the axons of ORNs to the olfactory bulb. The olfactory bulb is in the ventral surface of the frontal lobe. ORN axons projecting from the

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olfactory bulb reach other brain regions. Although the central pathways of the human olfactory system are not fully understood, a few brain regions including cortical and limbic regions (e.g., the olfactory cortex, the hypothalamus, the amygdala, and the hippocampus) have been associated with olfaction. These regions, summarized in Fig.  1.4, highlight the association between olfaction, cognition, emotion, reward, and memory formation. The olfactory cortex receives direct input from the olfactory bulb. In humans, the primary olfactory cortex is the pyriform cortex. It is located on the basal side of the frontal lobe. Pyriform cortex activity is correlated with odor intensity [40]. The secondary olfactory cortex contains the orbitofrontal cortex, which receives olfactory information and is activated by olfactory stimuli. Unlike the pyriform cortex, which is associated with odor intensity, the orbitofrontal cortex conveys the reward value of the odor (e.g., odor pleasantness). Pleasant odors have been associated with medial and unpleasant odors with more lateral regions of the orbitofrontal cortex [40]. In turn, projections from the olfactory cortex reach the frontal lobe, allowing for conscious recognition of odors. The olfactory cortex also sends projection to other areas such as the hippocampus, which is essential for odor-memory formation. The olfactory bulb also projects to the hypothalamus, cortical amygdala, and the hippocampus. The close association between the limbic system and olfaction highlights the importance of olfaction in emotion, including fear (odors indicative of hazards such as smoke/fire) and aversion (spoiled foods). However, we have yet to

Olfactory Pathways Olfactory bulb

Olfactory cortex Hypothalamus Amygdala Hippocampus

Fig. 1.4  Olfactory pathways in the brain

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understand the complex role and exact mechanisms by which these regions impact olfaction.

1.3

Anatomy and Physiology of Gustation

1.3.1 Gustatory Anatomy In humans, the taste bud is the primary taste receptor organ. Taste buds are clusters of taste receptor cells that form an onion-shaped structure composed of 50–100 taste bud cells that is surrounded by stratified epithelium. Taste buds are in multiple regions within the oral cavity, including the tongue epithelium, pharynx, esophagus, and soft palate. In the lingual epithelium, taste buds are present in three gustatory papillae (i.e., fungiform papillae, foliate papillae, and circumvallate papillae) located on the tip, side, and back of the tongue, respectively (Fig. 1.5). Most taste buds are found in circumvallate papillae. Taste buds are composed of three cell types (Type I, Type II, and Type III) [41]. Type I cells are glial-like cells that likely participate in sodium detection [42]. Type II cells express sweet, bitter, or umami taste receptors. Type III cells are presynaptic cells responsible for sour taste sensing. The basal side of the taste buds is connected to afferent nerves. The three nerves associated directly with taste are the facial, glossopharyngeal, and vagus nerves (cranial nerves VII, IX, and X, respectively). The facial nerve innervates the anterior end of the tongue, the glossopharyngeal nerve innervates the posterior end of the tongue, and the vagal nerve carries information from the back of the mouth including the esophagus. The trigeminal nerve (cranial nerve V) transmits somatosensory information related to taste perception, including thermosensation (e.g., temperature of food), mechanoreception (e.g., food consistency), and noxious chemical (pH Circumvallete Papillae

Foliate Papillae

Filiform Papillae

Funglform Papillae Taste Bud

Salivary Glands

Taste Bud

Gustatory Neurons

Fig. 1.5  Gustatory papillae and taste bud

Stratified Epithelium

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changes inducing burning or inflammation) [43]. Gustatory information from these cranial nerves then synapses in the nucleus of the solitary tract [44] (discussed in Sect. 3.3).

1.3.2 Gustatory Physiology 1.3.2.1 Gustatory Transduction There are five accepted taste modalities: salty, sweet, bitter, umami, and sour. More recently, fat-taste has been proposed as a potential sixth taste modality [45–47]. However, there is still controversy regarding whether fat-taste fulfills the minimal properties required to constitute a primary taste. Each of the five accepted taste modalities is characterized by five qualities, including whether it has (1) an effective stimulus, (2) specific receptors and signaling cascades, (3) involvement of peripheral taste pathways, (4) physiological impacts, and (5) regulation of its detection system. Here we discuss gustatory transduction in the tongue epithelium (Fig. 1.6), beginning with the binding of the effective stimulus to specific receptors (Fig. 1.7), and leading to the activation and regulation of complex signaling cascades and their physiological effects. Importantly, taste receptors are also located outside the mouth (e.g., the gastrointestinal tract, the respiratory tract, and sex organs); extraoral taste receptors and related signaling is outside the scope of this chapter but is discussed in Chap. 18. As each primary taste is characterized by its own unique signal

voltage gated sodium channel

Type I

VGSC

ENaC

Suppoting Cell

membrane depolarization

Na+

Y NTs

Salty

Na+ R3

T1R1 T1

3

1R R2 T

Type II

T2Rs

T1

Receptor Cell

et Swe

PLC

Afferent Axons-Cranial Nerves

Sweet Bitter Umami

Umami

Bitter

PIP2 IP3

AC

ch K+ an ne l NTs

ATP DAG

Ca2+ Na+

cAMP Protein kinase A

membrane depolarization

Inactive

Protein cAMP kinase A Active

VGSC

Type III Presynaptic Cell

2L1

Otop1

PKD

Sour

VGSC

NTs

Na+ H+

K+ Chanel

Fig. 1.6  Taste transduction by taste modality

membrane depolarization

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ENaC

T1R2

T1R3

T2Rs

T1R1

T1R3

Otop1

CD36 GPR120

Y

Effective Stimuli (ES)

Receptor(R)

G-Protein Coupled Receptors (GPCRs) R: ENaC

Rs: T1R2 & T1R3

Rs: T2Rs

ION CHANNELS Rs: T1R1 & T1R3

ION CHANNELS GPCRs

Rs: Otop1

Rs: CD36 & GPR120? ES: NaCI

ES:

ES:

ES:

ES:

(lower non-aversive concentrations)

-sugars

-saccharin

-L-glutamate

-acids (e.g. citric

ES: ?

-artificial sweeteners

-quinine

-nucleotide

acid, hydrochlorid

-fatty acids (e.g.

-glycene

-atropine

enhancers

acid)

linoleic acid and

-D-amino acids

-cycloheximide

-other

-denatonium

R: Uknown ES: Sodium salts

oleic acid, etc.)

-salicin -PTC

SALTY

SWEET

BITTER

UMAMI

SOUR

FAT

Fig. 1.7  Taste receptors

transduction, we will discuss each primary taste modality separately. Taste transduction signaling for each taste modality is summarized in Fig. 1.6. Salt Taste Transduction Salt perception relies on at least two pathways, the amiloride-sensitive (AS) pathway and the amiloride-insensitive (AI) [7] pathway. The AS pathway is mediated by the epithelial sodium channel (ENaC) in response to sodium and lithium [48]. The binding of NaCl to ENaC induces the opening of voltage-gated Na+ channels that can depolarize the plasma membrane and may lead to synaptic transmission [49]. In rodents, ENaC is sensitive to amiloride, a drug which selectively blocks this sodium channel at low (below micromolar) concentrations [50]. Thus, amiloride can decrease the response and preference for low sodium chloride concentrations. Although in rodents and other mammals, ENaC’s role in mediating consumption of salt and detection of low-to-medium salt concentrations in humans is not fully understood. In humans, findings regarding the effect of amiloride in reducing salt perception have varied. Some have reported that amiloride decreases the perceived saltiness of salty solution [51–53], while others found little to no effect on salt perception [54–56]. Furthermore, electrophysiological recording of lingual surface potential in response to sodium chloride have also varied in humans [57–59]. While some individuals experienced amiloride-reduced voltage changes induced by NaCl, the effect was highly variable. In humans and other mammals, ENaC is composed of three subunits, α, β, and γ. However, in humans, ENaC is also composed of a δ-subunit. The function of the δ-subunit is analogous to the α-subunit. However, replacement of α-subunit with δ makes the channel 50-fold less sensitive to amiloride, suggesting this subunit may impact amiloride sensitivity.

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The receptor(s) underlying the amiloride-insensitive (AI) pathway remains unknown as well as the response to salts (including sodium and non-sodium salts). TRPV1 receptors have been proposed as potential AI salt receptors. However, TRPV1 KO mice continued to respond to high-salt concentrations [60, 61]. Thus, the role of TRPV1 in AI sensing is not fully understood. High concentrations of AI salt rely on bitter-responsive Type II cells and a subset of sour-responsive Type III cells [62]. AI transduction may involve chloride anions; a recent study found that Cl−, not H+, generates AI salt taste responses. The mechanism underlying the role of Cl− in NaCl transduction remains to be elucidated. Sour Taste Transduction Sour transduction is initiated by an influx of H+ ions into Type III cells in response to sour stimuli, such as substances with an acidic pH. Weak acids can cross the cellular membrane and lower the cytosolic pH, and stronger acids require transporters. This results in decreased intracellular pH that blocks resting K+ channel, Kir2.1., and induces membrane depolarization. Depolarization leads to the opening of Na+gated channels that generate action potentials and activate voltage-gated Ca2+ channels, leading to the release of synaptic vesicles. Multiple receptors have been studied as potential sour receptors, including Polycystin 2 Like 1, Transient Receptor Potential Cation Channel (PKD2L1). In 2016, Huang et al. found that sour taste was dependent on PKD1L1 expressing taste receptor cells. However, sour taste was not affected in PKD2L1 knockouts, indicating PKD2L1 was not the primary receptor. More recently, studies have identified Otopetrin-1 (Otop1) as a sour taste receptor [63, 64]. Zhang et al. showed that a Otop1 knockouts lost sour taste sensitivity [63]. Similarly, Teng et al. found that Otop1 inactivation severely reduced cellular and taste responses to acids [64]. Sweet Taste Transduction Sweet stimuli vary in structure and bind different regions of the complex sweet receptor. Sweet transduction is initiated by the activation of GPCRs in Type II cells. There are two types of second signaling cascades initiated by either the binding of sweet-­tasting compounds or of synthetic sweeteners to their respective GPCRs. Sweet-­tasting compounds bind to GPRCs, which then activate AC III. AC III converts ATP into cAMP.  The increase of cAMP leads to the closing of K+ channels. Synthetic sweeteners activate other GPCRs, which activate PLC to produce IP3 and DAG [65]. IP3 increases [Ca2+]i, which can lead to membrane depolarization and neurotransmitter release. In turn, DAG activates protein kinase A (PKA). PKA leads to the closing of K+ channels and further contributes to membrane depolarization. Bitter Taste Transduction Bitter stimuli vary in structure and include bitter compounds such as coffee or cocoa. Bitter binds to GPCRs in the T2R family [65, 66]. The binding of bitter stimuli to GPCRs activates a second-messenger system similar to that of sweet transduction, where PLC, IP3, [Ca2+]i are increased and trigger the opening of

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TRPM5 channels. However, sweet and bitter stimuli activation occur in different cells and make synaptic contact with axons that are specific to sweet and bitter, respectively. Bitterness often provides a warning about potentially harmful compounds and thus triggers responses at much lower concentrations. Over 25 different types of bitter receptors are believed to vary to recognize a wide array of bitter stimuli. Umami Taste Transduction Bitter and umami taste modalities share the T1R2 receptor. Like bitter taste, umami also triggers similar secondary signaling cascades that initiate with the binding of the stimuli to a GPCR and leads to the activation of PLC and IP3. In turn, this signaling cascade ultimately leads to an increase in [Ca2+]i and the opening of TRPM5 channels. Umami receptors express on bitter cells and connect to specific gustatory axons.

1.3.3 Neuroanatomy of Gustation 1.3.3.1 Gustatory Pathways Gustatory information from the tongue is relayed via cranial nerves to the nucleus of the solitary tract (NTS). The NTS is in the posterolateral medulla within the brainstem. The rostral part of the NTS is known as the gustatory nucleus. The gustatory nucleus receives information regarding taste stimuli and then relays this information to the thalamus. The ventral posteromedial (VPM) nucleus of the thalamus is the main gustatory relay to the gustatory cortex. VPM efferent fibers mostly project the gustatory cortex and amygdala. The gustatory cortex is comprised of the insular cortex and the frontal operculum. The insular cortex has three subdivisions—the granular, dysgranular, and the agranular subdivision. The sensory afferent information distributes differently to the three subdivisions. For example, the afferent input from the VPM targets the granular and dysgranular subdivisions of the gustatory complex. However, these subdivisions are interconnected, suggesting these anatomically distinct regions work together to integrate gustatory information. The gustatory cortex can determine the valance of tastes (discriminating appetitive and aversive cues). In addition to receiving input from the VPM, the gustatory cortex also receives projections from other sensory organs (e.g., olfactory areas) and limbic areas [67]. Importantly, the gustatory cortex’s ability to integrate sensory information from both gustatory and olfactory stimuli suggests it plays a function in flavor recognition. The gustatory cortex outputs then reach many of the same regions that it receives input from (e.g., the amygdala, the thalamus, and the hypothalamus). This interconnectivity suggests these sensory and reward related regions not only work together to mediate gustation but may participate in feedback loops. However, the functional significance of these connections is not fully understood. Gustatory pathways are summarized in Fig. 1.8.

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Gustatory Cortex

(anterior insula & frontal operculum)

Thalamus Amygdala NTS (Nucleus of the Solitary Tract) CNX

Vagus Nerve (CNX) CNV

Glossopharyngeal Nerve (CNV)

CNVII

Facial Nerve (CNVII)

Fig. 1.8  Gustatory pathways

1.3.4 Neuroanatomy Integration 1.3.4.1 Flavor: Integrating Olfaction, Gustation, and Chemesthesis As mentioned in the introduction, what we perceive as flavor encompasses much more than taste. Flavor is mediated by complex multisensory integration, including the perceptual integration of olfactory, gustatory, and somatosensory cues. Importantly, our experience of flavor is much more than the sum of each sensory modality. Rather, each sensory modality interacts and is integrated to give rise to our unique experience of flavor. Olfaction, gustation, and somatosensory systems and their respective neural pathways largely overlap. The somatosensory system underlying chemesthesis is discussed in Chap. 6. The anatomical sites of chemosensory integration are discussed in Chap. 7. In brief, olfactory, gustatory, and somatosensory systems share common anatomical relays, including cortical, and limbic regions (e.g., the amygdala, orbitofrontal cortex, and hippocampus). These neural

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Fig. 1.9  Interconnectivity of olfaction and gustation

pathways are deeply intertwined centrally and peripherally (Fig. 1.9). For example, the orbitofrontal cortex was identified as a region, where olfactory and gustatory inputs converge. In the context of eating behavior, activity in the orbitofrontal cortex is associated with the pleasantness of taste and smell. This is consistent with the representation of flavor which is evoked by both olfactory and gustatory cues.

1.4

Conclusion

Olfaction and gustation are characterized by unique sensory organs, the olfactory epithelium, and the taste bud. Olfactory and gustatory stimuli bind to specific olfactory and taste receptors, respectively. Olfactory receptors belong to a superfamily of GPCRs with shared seven transmembrane domains but with amino acid sequences which vary in order to identify unique odorants. Taste receptors are comprised of both GPCRs and ion channels which are specific to the five primary taste modalities. Although many olfactory and gustatory receptors have been identified and their functions have been defined, many more are still unidentified, or their function is not fully understood. In general, odorant and gustatory stimuli initiate complex signaling cascades which ultimately lead to cell depolarization and neurotransmitter release. These signal transduction pathways allow for the transmission of afferent sensory information to the central nervous system. However, there are overlapping elements within olfactory and gustatory pathways which highlight the high degree

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of integration between these two sensory modalities and cognitive, emotional, reward, and memory centers in the brain. Key Concepts • The main olfactory organ is the olfactory epithelium. • The taste bud is the main gustatory organ. • Olfactory receptors are GPCRs with seven transmembrane domains and vary greatly in amino acid binding cites. • Taste receptors are specific to the five primary taste modalities. • Olfaction and gustation are characterized by transduction signals which transfer chemical and physical information from the environment into cell signals. These cell signals ultimately lead to cell depolarization and neurotransmitter release, which in turn send afferent signals to the brain. • Olfactory and gustatory pathways are comprised of unique (e.g., olfactory bulb and NTS, respectively) and shared neuroanatomical regions (e.g., the amygdala and the orbitofrontal cortex). • Shared neuroanatomical regions between olfaction and gustatory pathways and the high level of interconnectivity in these brain areas suggest that these regions interact to represent sensory information. Funding  This work was supported by the Intramural Research Program of the National Institutes of Health. Dr. Joseph is supported by the National Institute of Alcohol Abuse and Alcoholism (Z01AA000135) and Nursing Research (1ZIANR000035-01), the Office of Workforce Diversity and the National Institutes of Health Distinguished Scholar Award at the National Institutes of Health, and by the Rockefeller University Heilbrunn Nurse Scholar Award. RJL received Intramural Research Training Awards, National Institute of Nursing Research, National Institutes of Health, Department of Health and Human Services. RJL received support from the NIH Center for Compulsive Behaviors Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agencies had no role in the design and conduct of the study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript.

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28. Carter LA, MacDonald JL, Roskams AJ. Olfactory horizontal basal cells demonstrate a conserved multipotent progenitor phenotype. J Neurosci. 2004;24(25):5670–83. 29. Buck L, Axel R. A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell. 1991;65(1):175–87. 30. Ryu SE, Shim T, Yi J-Y, Kim SY, Park SH, Kim SW, et al. Odorant receptors containing conserved amino acid sequences in transmembrane domain 7 display distinct expression patterns in mammalian tissues. Mol Cells. 2017;40(12):954–65. 31. Malnic B, Hirono J, Sato T, Buck LB.  Combinatorial receptor codes for odors. Cell. 1999;96(5):713–23. 32. Crasto C, Marenco L, Miller P, Shepherd G. Olfactory Receptor Database: a metadata-driven automated population from sources of gene and protein sequences. Nucleic Acids Res. 2002;30(1):354–60. 33. Jones DT, Reed RR. Golf: an olfactory neuron specific-G protein involved in odorant signal transduction. Science. 1989;244(4906):790–5. 34. Yang X, Wang Q, Cao E. Structure of the human cation-chloride cotransporter NKCC1 determined by single-particle electron cryo-microscopy. Nat Commun. 2020;11(1):1016. 35. Nickell WT, Kleene NK, Gesteland RC, Kleene SJ. Neuronal chloride accumulation in olfactory epithelium of mice lacking NKCC1. J Neurophysiol. 2006;95(3):2003–6. 36. Reisert J, Lai J, Yau KW, Bradley J. Mechanism of the excitatory Cl- response in mouse olfactory receptor neurons. Neuron. 2005;45(4):553–61. 37. Reisert J, Matthews HR. Na+−dependent Ca2+ extrusion governs response recovery in frog olfactory receptor cells. J Gen Physiol. 1998;112(5):529–35. 38. Castillo K, Delgado R, Bacigalupo J. Plasma membrane Ca(2+)-ATPase in the cilia of olfactory receptor neurons: possible role in Ca(2+) clearance. Eur J Neurosci. 2007;26(9):2524–31. 39. Weeraratne SD, Valentine M, Cusick M, Delay R, Van Houten JL. Plasma membrane calcium pumps in mouse olfactory sensory neurons. Chem Senses. 2006;31(8):725–30. 40. Rolls ET, Kringelbach ML, de Araujo IE. Different representations of pleasant and unpleasant odours in the human brain. Eur J Neurosci. 2003;18(3):695–703. 41. Paran N, Mattern CF, Henkin RI.  Ultrastructure of the taste bud of the human fungiform papilla. Cell Tissue Res. 1975;161(1):1–10. 42. Vandenbeuch A, Clapp TR, Kinnamon SC. Amiloride-sensitive channels in type I fungiform taste cells in mouse. BMC Neurosci. 2008;9:1. 43. Viana F.  Chemosensory properties of the trigeminal system. ACS Chem Neurosci. 2011;2(1):38–50. 44. Monteiro CA, Cannon G, Moubarac J-C, Levy RB, Louzada MLC, Jaime PC. The UN Decade of Nutrition, the NOVA food classification and the trouble with ultra-processing. Public Health Nutr. 2018;21(1):5–17. 45. Running CA, Craig BA, Mattes RD.  Oleogustus: the unique taste of fat. Chem Senses. 2015;40(7):507–16. 46. Keast RSJ, Costanzo A. Is fat the sixth taste primary? Evid Implicat Flav. 2015;4(1):5. 47. Besnard P, Passilly-Degrace P, Khan NA.  Taste of fat: a sixth taste modality? Physiol Rev. 2016;96(1):151–76. 48. DeSimone JA, Lyall V, Heck GL, Phan TH, Alam RI, Feldman GM, et al. A novel pharmacological probe links the amiloride-insensitive NaCl, KCl, and NH(4)Cl chorda tympani taste responses. J Neurophysiol. 2001;86(5):2638–41. 49. Liman ER.  Salty taste: from transduction to transmitter release. Hold Cal Neuron. 2020;106(5):709–11. 50. Shigemura N, Ohkuri T, Sadamitsu C, Yasumatsu K, Yoshida R, Beauchamp GK, et  al. Amiloride-sensitive NaCl taste responses are associated with genetic variation of ENaC alpha-­ subunit in mice. Am J Physiol Regul Integr Comp Physiol. 2008;294(1):R66–75. 51. Schiffman SS, Lockhead E, Maes FW. Amiloride reduces the taste intensity of Na+ and Li+ salts and sweeteners. Proc Natl Acad Sci U S A. 1983;80(19):6136–40. 52. Tennissen AM. Amiloride reduces intensity responses of human fungiform papillae. Physiol Behav. 1992;51(5):1061–8.

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2

Sweet Taste and Added Sugar Consumption in Infancy and Childhood Alissa D. Smethers and Julie A. Mennella

Learning Objectives 1. To review the scientific evidence that revealed that the ability to detect sweet taste and behaviorally respond to sweetness is inborn but changes due to normal aging and dietary experiences. 2. To explain the differences between different dimensions of sweet taste and provide the scientific evidence in how they change during development. 3. To review the dietary guidance recommendations on added sugar intake for infants, toddlers, children, adolescents, and adults.

2.1

Introduction

Technological advances in producing sweeteners, such as the refining of sugar from cane, beets, and corn and the discovery of chemicals that impart sweetness with few or no calories are relatively recent phenomena in human dietary history. However, the biological attraction that humans and other primates have to sweet taste is phylogenically well conserved [1]. While invertebrates and mammals have independently evolved distinct anatomic and molecular pathways for sweet taste sensation [2, 3], there are clear parallels in their organization and the liking for sweet-tasting items in the shared food environments of humans.

A. D. Smethers · J. A. Mennella (*) Monell Chemical Senses Center, Philadelphia, PA, USA e-mail: [email protected]; [email protected] © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021 P. V. Joseph, V. B. Duffy (eds.), Sensory Science and Chronic Diseases, https://doi.org/10.1007/978-3-030-86282-4_2

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2.1.1 History of Sugar During ancient and medieval times, processing raw sugarcane to solid sugar loaves was an arduous task; consequently, sugar was rare, expensive, and a luxury feasted on by aristocracy, many of whom developed obesity [4]. Beginning in the sixteenth century, sugar became the white gold that fueled the barbaric slave trade of millions of Africans to the New World and, in turn, the mass harvesting of raw sucrose from sugarcane by slave-owning sugarcane plantations. The harvesting of sugar beets, viewed as a moral alternative to harvesting of sugarcane by slaves, and technological advances in the refining of raw sugar from beets or cane into white refined sugar led to lower costs and more plentiful supplies of this commodity and, in turn, its enjoyment and overconsumption by the working class [4]. In the mid-twentieth century, the ability to manufacture high-fructose corn syrups by adding the enzyme glucose isomerase to relatively inexpensive corn starch resulted in this liquid sugar replacing cane and beet sugar, particularly in the beverage and manufactured food industries [4]. Such manufactured sources of sugars and syrups met, or perhaps created the increasing demand for and enduring popularity of sweetness by the public.

2.1.2 Dietary Guidance on Sugars in America With increased availability and affordability of sugar, along with the use of high-­ fructose corn syrups in manufactured foods, the American diet changed from one consisting of predominantly home-prepared meals to one of processed foods and beverages, with the intake of soda more than doubling since the 1960s and replacing milk to become the most consumed beverage [5]. Such rapid changes in the American diet did not go unnoticed. The increased production and purchasing of manufactured foods and beverages rich in added sugars were paralleled by increases in sugar intake and the rise of non-communicable diseases such as obesity, diabetes, hypertension, and dental caries—the most prevalent diseases of childhood [6–8]. In 1977, the Senate Committee on Nutrition and Human Needs released the “Dietary Goals of the United States,” a report that emphasized the need for Americans to change their diets to improve the overall health, including the dietary goal of decreasing consumption of refined and other processed sugars [5]. As nutrition sciences evolved with a focus on the role of nutrition on long-term health and disease prevention, the US Department of Agriculture and US Department of Health and Human Services jointly released a set of seven dietary guideline statements, which became the first edition of the Dietary Guidelines for Americans (DGA) [9]. Since 1980, this cornerstone of American nutrition policy and guidance has been updated every 5  years by incorporating the knowledge gained from scientific advances. From the earliest report to the present day, the guidelines have recommended that American adults, and beginning in 1990 children 2 years and older, reduce their intake of added sugars. The reduction of added sugar intake, coupled

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with a healthier eating pattern that includes a variety of nutrient-dense foods, has become a public health priority worldwide [10]. Despite such recommendations, nationwide dietary intake data collected by the National Health and Nutrition Examination Survey (NHANES) reveals that most added sugar in the diet, in both young and old, comes from sugar-sweetened beverages (SSBs), grain-based desserts, dairy desserts, and candy [11]. The percentage of energy from added sugars in one of the most recent NHANES analysis from 2018 was higher than recommended levels for all age groups and highest among adolescents [11]. Deciphering what is a naturally occurring sugar, defined as sugars found in intact fruit, vegetables, and dairy products, and what is an added or free sugar is often difficult for the consumer. Defined by the US Food and Drug Administration (FDA), added sugars are either added during the processing of foods, or are packaged as such, and include sugars (free, mono- and disaccharides), sugars from syrups and honey, and sugars from concentrated fruit or vegetable juices that are in excess of what would be expected from the same volume of 100% fruit or vegetable juice of the same type [12]. In the United States, added sugars typically come from corn or cane sugar and are often found in “empty calorie” manufactured foods and beverages that contain few if any beneficial nutrients. Free sugars, on the other hand, are defined by the World Health Organization to include “mono- and disaccharides added to foods and beverages by the manufacturer, cook, or consumer, and sugars naturally present in honey, syrups, fruit juices, and fruit juice concentrates” [10]. Thus, all added sugars are also free sugars. In other words, added sugars do not include those found in fruits or vegetables, including fruit or vegetable juice concentrated from 100% juices sold to directly consumers (e.g., frozen orange juice concentrate). To help the American public make informed food and beverage choices, the FDA established requirements for nutrient labeling of manufactured foods and beverages and provided guidance to food and beverage manufacturers on labeling requirements [13]. In 2016, the FDA mandated the most recent addition to the nutrient label: the labeling of the added sugar content on all packaged foods and beverages, with labels expected to be changed by 2021 [14]. In this chapter, we take a developmental approach and focus on childhood, highlighting the scientific evidence that provides insight into the strong hedonic appeal of sweet taste and why children are vulnerable to overconsuming sweets. We focus on the ontogeny of sweet taste and the biological mechanisms underlying sweet taste perception. Age-related changes in two distinct psychophysical dimensions— the sensitivity of the taste system to sweet-tasting chemical stimuli and the hedonic valence of that sensation—are reviewed primarily because they can be measured reliably from an early age. We summarize experimental research revealing that both dimensions of sweet taste, sensitivity, and valance, as well as behavioral responses to sweetness, are inborn but change during normal aging and through dietary experience. We highlight the classic experimental studies in the field, along with recent review articles. Because dietary patterns are established early, childhood is an important period for understanding how the biological and psychological factors

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underlying sweet taste sensations shape what children eat—the most important influence on health in modern societies [15].

2.2

Development of the Taste System

The sense of taste is mediated by taste buds, modified epithelial cells comprising aggregates of 50–100 receptor cells that reside in specialized papillae—small, nipple-­like structures located on the tongue’s surface. Taste buds make their first appearance during the seventh to eighth week of gestation [16]; the three types of papillae (i.e., fungiform, foliate, circumvallate) emerge by the tenth week [17], and taste pores, the small epithelial openings on the surface of the epithelium, by the 14th to 15th week of gestation [18]. Upon the appearance of taste pores, taste buds are considered to be functioning, capable of beginning the cascade of events leading to the detection of the myriad taste-active compounds in amniotic fluid in which they are bathed [19, 20]. Beginning around the 12th week, the fetus swallows, and the chemical stimuli in the amniotic fluid provide the first experiences of taste. After birth, the number and shape of taste papillae, along with the size of the tongue, continue to change [21, 22]. Because the anterior portion of the tongue, which typically has the highest density of fungiform papillae, reaches adult size by 8–10 years of age [22], researchers compared fungiform papillae density between children and adults [21]. Using video microscopy to count papillae in defined areas of the anterior region of the tongue, Correa et  al. [21] reported that the average number of fungiform papillae peaked at 7–8 years with ~162 papillae/cm2, a significantly greater number than observed in 9- to 10-year-olds (~146 papillae/cm2), 11to 12-year-olds (~151 papilla/cm2), and adults (~140 papillae/cm2). Further, there are development differences in the shape of papillae, from small and round at 7–8 years of age to the adult-typical, larger, more irregular shape by 11–12 years [21]. Variation in papilla density can be an indicator of oral sensory phenotypes, predicting dietary behavior [23]. Because children have a higher density of papillae [24], it was reasoned that children would be more sensitive to sucrose (i.e., lower detection thresholds), particularly in the anterior tongue region [25, 26]. However, most studies revealed the contrary: children have higher taste detection levels and thus are less sensitive than adults to the taste of sucrose [27, 28]. While variation in papilla density is caused by normal aging, there is perhaps greater variation across individuals and within individuals based on location on the tongue [21, 25]. More research is needed to determine the interplay of anatomical phenotypes with genetic and experiential variation during development.

2.3

Biology of Sweet Taste

The sensation of sweetness begins in the taste buds when sweet-tasting chemicals (both nutritive and non-nutritive low/no-calorie sweeteners) are detected by a heterodimeric, G-protein-coupled receptor that is composed of two subunits, T1R2 and

2  Sweet Taste and Added Sugar Consumption in Infancy and Childhood

25

T1R3 (taste receptor family 1, proteins 2 and 3) on taste cells clustered in the taste buds. The genes that encode for this receptor are referred to as TAS1R2 and TAS1R3 in humans [29], respectively, and the cells that express these genes are located not only in taste buds in the oral cavity but also in other cells throughout the body, such as enteroendocrine cells in the gastrointestinal tract [30]. The taste buds housing these receptor cells in the oral and pharyngeal cavity are innervated by three cranial nerves (i.e., facial [VII], glossopharyngeal [IX], vagus [X]), whose afferent fibers enter the nucleus of the solitary tract, the first central synapse for taste information. Binding of a sweet-tasting chemical ligand to the taste receptors activates neural pathways that stimulate areas in the brain, including those associated with sweet taste, reward, and pleasure. For example, tasting sweet foods and beverages can induce pleasure by stimulating dopamine in reward centers such as the nucleus accumbens and striatum [31].

2.4

Development of Sweet Taste

Research on the development of the taste senses in humans, conducted by an international group of scientists, reveals that the ability to detect and behaviorally respond to sweet taste is inborn but undergoes age-related changes (see Table 2.1). In what follows, we highlight some of the classic studies in the field but acknowledge that we cite some, not all, of the experimental research on sweet taste in children. When appropriate, we reference review articles to lead the reader to the wider literature. Age-related changes in sweet taste occur in two distinct psychophysical dimensions: the sensitivity of the taste system to sweet-tasting chemical stimuli and the hedonic valence of that sensation. Sensitivity is the ability to recognize a taste quality as different from water and is measured by methods including detection thresholds. Hedonic valence refers to the liking or preference for a taste quality or taste concentration and is measured by methods including two-choice comparisons.

2.4.1 Infancy Beginning in the 1970s, the systematic measurement of a variety of phenotypes provided converging evidence that within hours of birth, infants can detect and behaviorally respond to sweet-tasting liquids placed in the oral cavity (Table 2.1).

2.4.1.1 Facial Reactivity In 1973, Jacob Steiner [32] described how newborns displayed distinctive orofacial expressions to three of the five basic tastes (sweet, sour, and bitter, but not salt or umami). When a drop of a 25% (0.73 M) sucrose solution was pipetted onto a newborn’s tongue, the infant relaxed and would occasionally display “smile-like” expressions, followed by protrusion of the tongue and rigorous sucking that was often accompanied by sucking noises. This was in stark contrast to the gaping

26

A. D. Smethers and J. A. Mennella

Table 2.1  Summary of the scientific evidence on a variety of behavioral phenotypes to sweet taste during infancy and childhood Phenotype Facial reactivity

Suckling pattern Ingestion

Pain attenuation

Bitter masking

Most preferred concentration of sweetness Sweet taste detection thresholds

Age group Infants

Behavioral responses to sweet taste Relaxation of facial muscles and “smile-like” expressions accompanied by rigorous suckling when sucrose solution applied to tongue [32, 33] Children Displayed relatively more positive than negative facial expressions when ingesting sweetened liquids [34] Infants Stronger and more frequent suckling while ingesting sucrose solution or with fluidless sweetened nipple in mouth [35, 36] Infants Greater intake of sweetened liquids than water and of sweeter than less sweet liquids [35, 37–39] Children Greater intakes and ratings of liking of sweetened beverages and foods than unsweetened versions [34, 39–43]; greater intakes of sweetened beverage among children fed sugar water early (  PDD  >  DLB  >  DLB/AD  >  AD [40]. Distinguishing between Alzheimer’s disease and dementia with Lewy bodies would be useful for clinical drug trials and subsequent treatment, yet this has been difficult during life. In fact, dementia with Lewy bodies was earlier referred to as the Lewy Body Variant of Alzheimer’s Disease [41].The presence of AD pathology in DLB or vice versa is often detected only at autopsy. A number of areas important for olfactory processing are sites of Lewy body pathology: the olfactory bulb, olfactory tract, piriform cortex, and amygdala. The results of studies that assessed the degree of olfactory impairment in AD and DLB may be informative. Olfactory dysfunction in dementia with Lewy bodies was first reported to be significantly poorer than in AD by McShane et al. [42]. They reported a greater number of anosmics among patients with dementia with Lewy bodies than with AD, using as an operational definition of anosmia the patient’s reporting that he could smell a single concentration of lavender oil. The lack of a blank might have introduced response bias. However, we subsequently used a rigorous psychophysical method, the two-alternative, forced choice threshold test with butanol, to control for response bias [8] and also reported a greater incidence of anosmia among DLB than AD patients [41]. A recent analysis of odor identification data in a large sample

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0.7

FAMILIARITY (%)

0.6 0.5 CONTROL AD LBV

0.4 0.3 0.2 0.1 0

ODORS

FACES

SYMBOLS

Fig. 7.4  Differences in remote memory, operationally defined as rated familiarity, between normal controls, pathologically confirmed Alzheimer’s patients (AD), and patients with the Lewy Body Variant of Alzheimer’s disease (LBV). Participants rated the familiarity of odors, faces, and symbols. (Reproduced with permission from Cambridge University Press, Journal of the International Neuropsychological Society, Gilbert, Barr, and Murphy [27])

of patients with neuropathologically confirmed Lewy Body disease, dementia with Lewy bodies, Alzheimer’s disease dementia, Parkinson’s disease dementia and mixed pathology by Beach et  al. also showed that more severe hyposmia distinguished between dementia with Lewy bodies and AD dementia [43]. In the first study to compare memory for olfactory stimuli in patients with pathologically confirmed LBV and AD, we found that patients with the LBV showed significantly poorer remote odor memory, operationally defined as rated familiarity, than AD patients [27] (See Fig. 7.4). These patients also showed the same pattern of odor threshold impairment described above, patients with LBV had poorer thresholds than AD patients. To ensure that the memory differences were not simply due to threshold differences, we entered threshold as a covariate in analyses. Thus, a number of studies employing different olfactory tasks suggest that the degree of olfactory impairment may provide additional information to facilitate distinguishing between dementia with Lewy bodies and Alzheimer’s disease.

7.4.1 Testing for Olfactory Impairment Because the ability to name odors is profoundly affected in AD and other neurodegenerative diseases, a number of tests have been developed to assess this olfactory function. Odor identification tests can be rapidly administered by non-experts and can be found in the literature (e.g., the San Diego Odor Identification Test [44], Scandinavian Odor Identification Test [45], the Odor Stick Identification Test for Japanese People [46]) or obtained commercially (the Sniffin’ Sticks tests [47] and the UPSIT [48]). The NIH has included an odor identification test in the NIH toolbox, The NIH Toolbox Odor Identification Test. The test is inexpensive, easily

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accessed and administered and has high reliability and validity [49]. A few tests have been developed for specific populations, addressing the fact that experience and culture affect the ability to identify odors. The Scandinavian Odor Identification Test and The Odor Stick Identification Test for Japanese People are good examples of tests that utilize odors that are highly familiar and identifiable to individuals from specific cultures. Odor identification tests are particularly suited for instances when time is of the essence and conducting other tests would be challenging, e.g., in clinical settings, epidemiological and other large-scale studies. As olfactory impairment has been identified as a primary symptom, and often one of the earliest symptoms, of the COVID-19 virus, a number of easily administered, brief, inexpensive olfactory function tests are being or have been developed or modified to further expedite testing. Odor identification impairment is not specific to a single neurodegenerative disease; rather it is affected in a number of diseases. It is possible that better sensitivity to specific neurodegenerative diseases will emerge as olfactory tests that target specific brain areas affected earliest in a disease process are developed and refined, e.g., odor memory tests that target entorhinal cortex or hippocampus in AD. Regardless, the finding of olfactory impairment across a number of neurodegenerative diseases motivates research into the commonalities among these diseases that makes olfaction highly vulnerable. It is important to note that many patients with neurodegenerative disease, certainly those with Alzheimer’s disease and Parkinson’s disease, typically show an unawareness of olfactory dysfunction [50]. Objective assessment with a valid and reliable olfactory test is critical in these patients, as simply asking whether they have noted a change or decrease in smell has not been shown to be an accurate assessment of dysfunction. This is of practical importance as well, as the olfactory system serves as a warning system for the presence of spoiled food, smoke, and natural gas.

7.4.2 Sensitivity and Specificity The sensitivity of a test indicates how well it can detect a patient and the specificity indicates how well it can detect a normal individual. Odor identification shows very good, but not excellent sensitivity for any one neurodegenerative disease, e.g., Alzheimer’s disease. It is important to note that odor identification is limited in its ability to differentiate olfactory dysfunction due to different neurodegenerative diseases or from other causes, such as nasal sinus disease. Further research may reveal differences in sensitivity for different olfactory tasks, or combinations of olfactory tasks [15] to differentiate among diseases. However, it is also very important to highlight the fact that a number of studies have now demonstrated that odor identification testing is highly specific, that is, it can be very useful in ruling out developing dementia. In fact, the data from a number of large studies strongly support the remarkable statement that an older adult who has been objectively tested and demonstrated to have a very good sense of smell is not expected to develop AD in the next 5 years [5, 22, 44].

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Conclusion

In conclusion, it is clear that olfactory impairment is a significant factor in a number of neurodegenerative diseases and often precedes other clinical symptoms. Thus, it may serve as a useful biomarker when included with other early risk factors for disease. Patients with Alzheimer’s disease, Parkinson’s disease, Lewy body disease, among others, show poor performance on a number of measures of olfactory function. Which olfactory tasks are most affected in specific neurodegenerative diseases, at specific points in the disease progression, is a question of interest. Further investigation with both psychophysical and neuroimaging methods may reveal important new insights into disease processes. While olfactory impairment is a risk factor for neurodegenerative disease, we conclude with an important, positive finding that is supported by a number of studies: That an older individual who has been objectively tested and demonstrated to have a very good sense of smell is not expected to develop AD in the next 5 years [5, 22, 44]. Key Concepts • Olfactory dysfunction occurs in Alzheimer’s and other neurodegenerative diseases. • Olfactory dysfunction is an early, preclinical marker of Alzheimer’s and a number of other neurodegenerative diseases. • Different olfactory functions are assessed by olfactory testing: e.g., threshold, identification, recognition memory, familiarity. • Both published and commercial tests are used in assessment of olfactory function in neurodegenerative diseases. • Neuroimaging informs our understanding of olfactory function in Alzheimer’s and other neurodegenerative diseases. • Brain areas that show pathology in a number of neurodegenerative diseases, particularly Alzheimer’s disease and Parkinson’s disease, overlap areas that process olfactory information. Acknowledgements  Supported by NIH grants R01AG004085-26 and R01AG062006-03 (CM), and P50AG005131-28 and P30AG062429 (UCSD ADRC). I have no financial conflicts of interest to declare. I gratefully acknowledge the members of the SDSU Lifespan Human Senses Center and the patients and staff of the UCSD Alzheimer’s Disease Research Center (ADRC), especially Drs. David Salmon, Douglas Galasko, and the late Drs. Leon Thal and Robert Katzman for their assistance in the research described in publications from my laboratory.

References 1. Alzheimer’s Association. 2021 Alzheimer’s disease facts and figures. Alzheimers Dement. 2021;17:3. 2. Braak H, Braak E.  Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:237–59. 3. Christen-Zaech S, Kraftsik R, Pillevuit O, Kiraly M, Martins R, Khalili K, Miklossy J. Early olfactory involvement in Alzheimer's disease. Can J Neurol Sci. 2003;30(1):20–5.

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4. Price JL, Davis PB, Morris JC, White DL.  The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer’s disease. Neurobiol Aging. 1991;12:295–312. 5. Murphy C. Olfactory and other sensory impairments in Alzheimer disease. Nat Rev Neurol. 2019;15(1):11–24. 6. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Pericak-­ Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–3. 7. Doty RL, Reyes PF, Gregor T. Presence of both odor identification and detection deficits in Alzheimer’s disease. Brain Res Bull. 1987;18:597–600. 8. Murphy C, Gilmore MM, Seery CS, Salmon DP, Lasker BP. Olfactory thresholds are associated with degree of dementia in Alzheimer’s disease. Neurobiol Aging. 1990;11(4):465–9. 9. Bacon AW, Salmon DP, Bondi MW, Murphy C. Very early changes in olfactory functioning due to Alzheimer’s disease and the role of the apolipoprotein E in olfaction. Ann N Y Acad Sci. 1998;855:723–31. 10. Djordjevic J, Jones-Gotman M, De Sousa K, Chertkow H.  Olfaction in patients with mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging. 2008;29:693–706. 11. Murphy C, Jinich S. Olfactory function in down syndrome. Neurobiol Aging. 1996;17(4):631–7. 12. Waldton S. Clinical observations of impaired cranial nerve function in senile dementia. Acta Psychiatr Scand. 1974;50:539–47. 13. Serby M.  Olfaction and Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 1986;10:579–86. 14. Morgan CD, Nordin S, Murphy C.  Odor identification as an early marker for Alzheimer’s disease: impact of lexical functioning and detection sensitivity. J Clin Exp Neuropsychol. 1995;17:793–803. 15. Weeler PL, Murphy C. Olfactory measures as predictors of conversion to mild cognitive impairment and Alzheimer’s disease. Brain Sci. 2021;11:1391. 16. Murphy C, Bacon AW, Bondi MW, Salmon DP. Apolipoprotein E status is associated with odor identification deficits in nondemented older persons. Ann N Y Acad Sci. 1998;855:744–50. 17. Graves AB, Bowen JD, Rajaram L, McCormick WC, McCurry SM, Schellenberg GD, Larson EB. Impaired olfaction as a marker for cognitive decline: interaction with apolipoprotein E epsilon4 status. Neurology. 1999;53(7):1480–7. 18. Oleson S, Murphy C. Olfactory dysfunction in ApoE ε4/4 homozygotes with Alzheimer’s disease. J Alzheimers Dis. 2015;46:791–803. 19. Schiffman SS, Graham BG, Sattely-Miller EA, Zervakis J, Welsh-Bohmer K.  Taste, smell and neuropsychological performance of individuals at familial risk for Alzheimer’s disease. Neurobiol Aging. 2002;23:397–404. 20. Serby M, Mohan C, Aryan M, Williams L, Mohs RC, Davis KL. Olfaction in first-degree relatives of Alzheimer’s patients. Biol Psychiatry. 1996;39(5):375–7. 21. Calhoun-Haney R, Murphy C.  Apolipoprotein ε4 is associated with more rapid decline in odor identification than in odor threshold or dementia rating scale scores. Brain Cogn. 2005;58:178–82. 22. Schubert CR, et al. Olfaction and the 5-year incidence of cognitive impairment in an epidemiological study of older adults. J Am Geriatr Soc. 2008;56:1517–21. 23. Devanand DP, Less S, Manly J, et al. Olfactory deficits predict cognitive decline and Alzheimer dementia in an urban community. Neurology. 2015;84(2):182–9. 24. Wilson RS, Schneider JA, Arnold SE, et  al. Olfactory identification and incidence of mild cognitive impairment in older age. Arch Gen Psychiatry. 2007;64:802–8. 25. Yaffe K, Freimer D, Chen H. Olfaction and risk of dementia in a biracial cohort of older adults. Neurology. 2017;88:456–62. 26. Frank C, Murphy C.  The brief form of the California odor learning test 3. Front Neurosci. 2020;14:173. 27. Gilbert PE, Barr, & Murphy, C. Differences in olfactory and visual memory in pathologically confirmed patients with Alzheimer’s disease and the Lewy body variant of Alzheimer’s disease. J Int Neuropsychol Soc. 2004;10:835–42. 28. Dhilla Albers A, Asafu-Adjei J, Delaney MK, Kelly KE, Gomez-Isla T, Blacker D, Johnson KA, Sperling RA, Hyman BT, Betensky RA, Hastings L, Albers MW. Episodic memory of

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odors stratifies Alzheimer biomarkers in normal elderly: POEM: odor memory biomarker in normal elderly. Ann Neurol. 2016;80(6):846–57. 29. Murphy C, Jernigan TL, Fennema-Notestine C. Left hippocampal volume loss in Alzheimer’s disease is reflected in performance on odor identification: a structural MRI study. J Int Neuropsychol Soc. 2003;9:459–71. 30. Haase L, Wang M, Green E, Murphy C. Functional connectivity during recognition memory in individuals genetically at risk for Alzheimer’s disease. Hum Brain Mapp. 2013;34(3):530–42. 31. Kapoulea EA, Murphy C. Older, non-demented apolipoprotein ε4 carrier males show hyperactivation and structural differences in odor memory regions: a blood-oxygen-level-dependent and structural magnetic resonance imaging study. Neurobiol Aging. 2020;93:25–34. 32. Li W, Howard JD, Gottfried JA. Disruption of odour quality coding in piriform cortex mediates olfactory deficits in Alzheimer’s disease. Brain. 2010;33(9):2714–26. 33. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197–211. 34. Goedert M, Spillanti MG, Del Tredici K, Braak H. 100 years of Lewy pathology. Nat Rev Neurol. 2013;9:13–24. 35. Ansari KA, Johnson A. Olfactory function in patients with Parkinson’s disease. J Chronic Dis. 1975;28:493–7. 36. Doty RL, Deems D, Steller S. Olfactory dysfunction in Parkinson’s disease: a general deficit unrelated to neurologic signs, disease stage, or disease duration. Neurology. 1988;38:1237–44. 37. Ross W, Petrovitch H, Abbott RD, et  al. Association of olfactory dysfunction with risk for future Parkinson’s disease. Ann Neurol. 2008;64:167–73. 38. Fullard ME, Tran B, Xie SX, Toledo JB, Scordia C, Linder C, et  al. Olfactory impairment predicts cognitive decline in early Parkinson’s disease. Parkinsonism Relat Disord. 2016;25:45–51. 39. Lee YH, Bak Y, Park C, Chung SJ, Yoo HS, Baik K, Jung JH, Sohn YH, Shin N-Y, Lee PH. Patterns of olfactory functional networks in Parkinson’s disease dementia and Alzheimer’s dementia. Neurobiol Aging. 2020;89:63–70. 40. Jellinger KA, Korczyn AD. Are dementia with Lewy bodies and Parkinson’s disease dementia the same disease? BMC Med. 2018;16:34. 41. Olichney JM, Murphy C, Hofstetter CR, Foster K, Hansen LA, Thal LJ, Katzman R. Anosmia is very common in the Lewy body variant of Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2005;76:134201347. 42. McShane RH, Nagy Z, Esiri MM, King E, Joachim C, Sullivan N, et al. Anosmia in dementia is associated with Lewy bodies rather than Alzheimer’s pathology. J Neurol Neurosurg Psychiatry. 2001;70:739–43. 43. Beach TG, Adler CH, Zhang N, Serrano GE, Sue LI, Driver-Dunkley, et al. Severe hyposmia distinguishes neuropathologically confirmed dementia with Lewy bodies from Alzheimer’s disease dementia. PLoS One. 2020;15(4):e0231720. 44. Murphy C, Schubert CR, Cruickshanks KJ, Klein BEK, Klein R, Nondahl DM. Prevalence of olfactory impairment in older adults. JAMA. 2002;288(18):2307–12. 45. Nordin S, Bramerson A, Liden E, Bende M. The Scandinavian Odor Identification Test: development, reliability, validity and normative data. Acta Otolaryngol. 1998;118(2):226–34. 46. Saito S, Ayabe-Kanamura S, Takashima Y, Gotow N, Naito N, Nozawa T, Mise M, Deguchi Y, Kobayakawa T. Development of a smell identification test using a novel odor stick presentation kit. Chem Senses. 2006;31:3799–391. 47. Kobal G, Hummel T, Sekinger B, Barz S, Roscher S, Wolf S. ‘Sniffin’ sticks’: screening of olfactory performance. Rhinology. 1996;34:222–6. 48. Doty RL, Shaman P, Dann M.  Development of the University of Pennsylvania Smell Identification Test: a standardized microencapsulated test of olfactory function. Physiol Behav. 1984;32(3):489–502. 49. Dalton P, Doty RL, Murphy C, Frank R, Hoffman HJ, Maute C, Kallen MA, Slotkin J. Olfactory assessment using the NIH toolbox. Neurology. 2013;80:S32–6. 50. Nordin S, Monsch A, Murphy C. Unawareness of smell loss in normal aging and Alzheimer’s disease: discrepancy between self-reported and diagnosed smell sensitivity. J Gerontol. 1995;50B:P187–92.

8

Taste and Smell Alterations and Substance Use Disorders Khushbu Agarwal, Christian McDuffie, Peter Manza, and Paule Valery Joseph

Learning Objectives 1. To understand the disturbances of taste and smell in chronic substance users. 2. Do taste and smell disturbances co-occur? 3. To highlight patterns of neural reactivity in response to drug cue (taste/smell) exposure in substance use disorder (SUD).

8.1

Introduction

In this chapter, we define “substance” as any psychoactive compound with the potential to cause health and social problems, including addiction. These substances may be legal (e.g., alcohol and tobacco) or illegal (e.g., heroin and cocaine). According to the 2019 National Survey on Drug Use and Health, 17.2% of adolescents ages 12 to 17 used illicit substances in the past year and 4.5% had a substance use disorder (SUD). Moreover, 9.4% of adolescents consumed alcohol in the past month, 2.3% were cigarette users, and 13.2% were marijuana users during the past year [1]. The Diagnostic and Statistical Manual of Mental Disorders fifth Edition (DSM-5) defines SUD as a behavioral, cognitive, and psychological disorder [2] (Table  8.1). The severity of a substance use disorder is defined based on K. Agarwal · P. V. Joseph (*) National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA Department of Health and Human Services, National Institute of Nursing Research, National Institutes of Health, Bethesda, MD, USA e-mail: [email protected]; [email protected] C. McDuffie · P. Manza National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA e-mail: [email protected]; [email protected] © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021 P. V. Joseph, V. B. Duffy (eds.), Sensory Science and Chronic Diseases, https://doi.org/10.1007/978-3-030-86282-4_8

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Table 8.1  Summary of the diagnosis and adverse effects of substance of abuse Substance Diagnosis Tobacco Inability to quit or lessen the amount of tobacco use despite efforts to do so (due to the nicotine in tobacco) Alcohol Alcohol consumed in larger amounts than intended, and inability to cut down or control use Opiates Opiates used in larger amounts or over a longer period than intended Cocaine Cocaine is used in larger amounts than intended, and inability to cut down or control the use Marijuana Marijuana used in larger amounts than intended, and inability to cut down or control use

Mild SUD

Adverse effects Carcinogenic, and can lead to chronic bronchitis, emphysema, heart disease, stroke, and diabetes It causes damage to the brain and body organs while weakening the immune system Relieves pain and can cause euphoria, confusion, nausea, and slowed breathing Causes “rush” or euphoria with increased breathing, blood sugar, and heart rates Causes a pleasurable high that can impair short-term memory, harm the lungs, and hamper focus and coordination

Moderate SUD

2-3 symptoms

Severe SUD

4-5 symptoms

6 symptoms

1. Hazardous Use

7. Used larger amounts/longer

2. Social problems related to use

8. Repeated attempts to quit/control use

3. Neglected roles to use

9. Physical/Psychological Problems

4. Legal Problems

10. Activites given up to use

5. Withdrawal

11. Craving

6. Tolerance

Fig. 8.1  Outlines the 11 behaviors associated with substance use disorder (SUD) and the severity of occurrence as defined by the DSM-5 criteria (created in Biorender)

symptomology and can range from mild to severe. The presence of two to three symptoms indicates a mild substance use disorder. Moderate SUD is defined by four to five symptoms, and a severe case of SUD is defined by six or more symptoms [2] (Fig. 8.1). Sensory taste and smell information are closely linked as reported in Chap. 2, and these sensory inputs are communicated to different cortical regions in the brain from the mouth and nose. The taste and smell information are integrated in the brain so that different flavors are discriminated and appreciated [3]. Chronic substance abuse can negatively interfere with the feeding process due to gustatory and olfactory impairments caused by continuous exposure. The misuse of these substances alters the capability of the sensory receptors to detect and perceive stimuli. These chemical senses of taste and smell are crucial for conveying information about ourselves and our environment, help identify dangers (for example, the smell of smoke),

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and majorly attribute to the daily enjoyment of food, friends and family, and surroundings. Alterations in these senses are inherently concerning. They may place an individual at risk for being unable or less able to detect smoke, leaking natural gas, and other environmental hazards or to identify an off-taste in spoiled food. The sections below summarized studies reporting the prevalence and severity of taste and smell alterations as a consequence of substance use disorders. We have also discussed the effect of these substances on neural mechanisms associated with chemosensory coding and modulation. Concept check: Substance use disorder (SUD) is the inability to control the use of a drug, and there are nine classes of drugs as identified by the Diagnostic Statistical Manual (DSM-5). Chronic use of these substances alter sense of taste and smell. The brain needs both taste and smell combined to differentiate various flavors; thus disruptions in taste and smell are connected and are often influenced simultaneously.

8.2

Taste and Smell Changes with Substance Use Disorders

8.2.1 Effect of Tobacco on Taste and Smell There are many factors that determine the changes in taste and smell in tobacco users, some of which include (1) the length of time the person has been smoking, (2) number of cigarettes smoked daily, and (iii) the effect of tobacco use in the natural aging process. The exposure of tobacco to the olfactory and gustatory systems causes damage that can be reversible or permanent. The degree of injury is related to exposure time and the concentration and toxicity of tobacco. A preliminary analysis on 17 nonsmoking males (8 smokeless tobacco users and 9 nonusers) revealed that long-term use of smokeless tobacco might reduce taste sensitivity. Moreover, among users the alterations in taste sensation lasted even after 12 h of abstinence [4]. Smokers show significantly elevated detection thresholds for salt, acid, sucrose or quinine [5–7]. In a cross-sectional NHANES study, association of taste perceptions including bitter (quinine), salt with smoking status revealed that current smokers compared to never smokers show enhanced bitter perception for quinine [5]. However, a recent meta-analysis suggest no difference in sweet taste detection thresholds between tobacco smokers and nonsmokers [8]. Gustatory disturbance pertains to the change of form, quantity, and vascularization of the taste buds caused by tobacco consumption. While, tobacco exposure to the olfactory tissue generates a decrease in sensory cell production capacity, causing loss of sensibility to odors and olfactory recognition [9]. Meta-analysis results revealed that the risk for olfactory impairment is higher among the current as compared to never smokers [10, 11]. Although the precise mechanism behind loss of smell is unknown, some commonly postulated mechanisms explored so far involve

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(1) recurring nasal congestion, (2) continuous cold or flu, (3) presence of dry mouth (xerostomia), (4) tonsillectomy, (5) squamous metaplasia of olfactory mucosa (expected to resolve 6  months post quitting), (6) inflammatory effects (likely to resolve in 5 years), and (7) vascular effects (has the chance of returning to the level of nonsmokers in 15–20 years) [12, 13]. Recent reports have identified persistence of olfactory impairment for over 15 years after quitting smoking, which provides evidence towards the involvement of either the vascular mechanism (decreased blood flow) or damage in the microvessels in the olfactory nerve that interrupts the sensory transduction necessary for olfactory processing [10]. Olfactory loss in smokers caused by the vascular mechanism is potentially a sensitive early indicator of risk for neurodegenerative and cardiovascular diseases [13]. Interestingly, however research also shows that cigarette smoking by itself does not cause complete loss of the sense of smell. Individuals who quit smoking typically show improvement in olfactory function and flavor sensation over time; however, the recovery of their olfactory function is dependent on the duration of smoking status [14]. For instance, the recovery of the smell function in a two-pack per-day smoker, to the level observed in nonsmokers need approximately the same amount of time they had been smoking [14]. A randomized controlled trial conducted on a group of daily smokers has shown an improvement in the sense of taste and smell post abstinence [15]. Moreover, quitting smoking relates to rapid recovery of taste sensitivity [16] and an increased sense of taste, thereby leading to increased appetite and weight gain [9] (Table 8.2). Smokers find food high in fat to be relatively less pleasurable than nonsmokers. Oral intake of tobacco can alter salt and sweet taste. Current smokers compared to never smokers are at a high risk of olfactory impairment.

8.2.2 Effect of Alcohol on Taste and Smell Alcohol is a complex and unique component of the human diet, serves as a potential energy source [29 kJ (7.1 kcal) per gram] just after fat [37 kJ (9 kcal) per gram]. Alcohol is also known to have pharmacological potential because it activates γ-aminobutyric acid (GABA) receptors in the brain [17]. Sensory systems, particularly taste and smell, significantly affect the selection and consumption of alcoholic beverages [18]. Humans sense alcohol as a combination of sweet and bitter tastes [19], odors, and oral irritations (e.g., burning sensations) varying on the intake concentration. Likewise, rodents identify the sweet (sucrose-like) and bitter (quinine-­ like) taste and odor volatiles of alcohol and probably the other components detected by humans [20]. The development of preference as well as different consumption patterns for alcohol flavors are associated with (1) activation of peripheral chemoreceptors; (2) central mechanisms that facilitate the hedonics of alcohol flavor; (3) learned associations of alcohol’s sensory attributes, post-ingestive effects, and early postnatal exposure to alcohol flavor; and (4) genetically determined individual

Data from n = 8 cross-sectional studies (Ajmani et al. 2017) [10]

N = 1126 daily smokers N = 3239 Former smokers (Etter et al. 2013) [15]

Population Tobacco N = 17 nonsmoking males—8 smokeless tobacco users (10 h per week for 18 months) and 9 nonusers (Mela et al. 1987) [4] Cigarette smokers: N = 553 males N = 85 females Age 42.97 ± 11.22 years (Frye et al. 1990) [14] Yes

Yes

Yes

No

Yes

No

Olfactory function was assessed using the University of Pennsylvania Smell Identification Test (UPSIT, commercially marketed as the smell identification test, Sensonics Inc., Haddonfield, NJ) Participants answered the original Minnesota withdrawal scale (MWS; nine items), the eight additional symptoms in the revised MWS (MWS-R) and 23 other questions on tobacco withdrawal symptoms. Daily smokers were assigned randomly to either continue to smoke for 2 weeks or to stop smoking, and they answered follow-up surveys 1, 3, and 7 days after their target quit date High quality studies using validated olfactory tests among the generally healthy population were reviewed

No

A systematic review and meta-analysis

An internet survey of daily and former smokers with repeated measurements, followed by a randomized trial among the daily smokers

Association study

Case–control study

Level of Taste Smell evidence

Yes Taste recognition threshold, perceived taste intensities, and hedonic responses (liking or preference) were determined for sucrose, sodium chloride (NaCl), and caffeine solutions

Experiment

Table 8.2  Summary of substance effects on taste and smell

(continued)

Current smokers had substantially higher odds of olfactory dysfunction compared to never smokers (odds ratio [OR] = 1.59, 95% confidence interval [CI] = 1.37–1.85) Former smokers were found to have no difference in risk of impaired olfaction compared to never smokers (OR = 1.05, 95% CI = 0.91–1.21)

Smoking was adversely associated with odor identification ability in a dose-related manner in both current and previous cigarette smokers Among previous smokers, improvement in olfactory function was related to the time elapsed since the cessation of smoking Immediate improvement post abstinence in sense of smell, and taste

Long-term use of smokeless tobacco might reduce taste sensitivity Among users the alterations in taste sensation lasted even after 12 h of abstinence

Findings

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Yes

Yes

No

Comparative study

No influences of ethanol on odor identification, the phenyl ethyl alcohol detection threshold, or the delay interval (memory) component of the odor discrimination/memory test were observed

Findings Smokers showed significantly lower taste sensitivity than nonsmokers—Taste sensitivity was inversely related to nicotine dependence (Fagerström scores) After smoking cessation, progressive increase in EGM thresholds was seen (n = 24 smokers), which reached the taste sensitivity range of nonsmokers depending on locus and time After 2 weeks, recovery was observed on the 3 tip and the 2 edge loci; the recovery in the posterior loci was complete after 9 weeks, and in the dorsal loci recovery was observed only after 2 months or more Compared to never smokers, current smokers A cross-­ reported increased bitter ratings sectional No association was seen between smoking status and analysis on National Health salt taste intensity ratings and Nutrition Examination Survey 2013–2014 data

Level of Taste Smell evidence Yes No 2 phases (1) A case– control phase (2) A follow-up phase

No The subjects underwent two ~4-h-long test sessions, alcohol and non-alcohol, separated from one another by a minimum of 1 week An ethanol odor detection threshold test, a phenyl ethyl alcohol odor detection threshold test, a 40-item smell identification test, and an odor discrimination/short-term odor memory test were conducted

Whole mouth and tongue tip assessments of bitter (quinine) and salty (NaCl) tastes

N = 2808 (51.7% females) Age ≥ 40 years (Chao et al. 2021) [5]

Alcohol N = 8 men N = 8 women Age 24.88 ± 0.67 years (Patel et al. 2004) [31]

Experiment Taste sensitivity measured by electrogustometric (EGM) thresholds from various parts of the tongue (locus)

Population N = 83 smokers N = 48 Nonsmokers (Cheruel et al. 2017) [16]

Table 8.2 (continued)

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Yes

Yes

Cognitive verbal and reflectory facial expressions for pleasant, indifferent and aversive tastes and odors

–

No

Yes

No

Taste threshold was assessed using type 3-alternative forced choice

Opiates Heroin addicts Detoxified former addicts Matching controls (Perl et al. 1997) [36] Opiate users (Mysels et al. 2010) [33]

Yes

Olfactory testing was conducted through Yes the “Sniffin’ sticks test” Gustatory testing was conducted through the “taste strips test”

N = 20 Korsakoff syndrome N = 20 alcohol dependents N = 20 healthy control subjects without past alcohol abuse or dependence (Brion et al. 2015) [30] N = 92 alcoholics in therapy N = 92 Non-­alcoholic volunteers (Silva et al. 2016) [24] Yes

Yes

No

Olfactory testing using Sniffin’ sticks

N = 30 alcohol dependents N = 30 Healthy controls (Rupp et al. 2004) [32]

Literature review

Case–control study

Follow-up study

Case–control study

Case–control study

(continued)

Active addicts interpret sweet taste and savory smells as more pleasant and bitter and sour tastes and a putrid odor as less unpleasant than detoxified former addicts and controls Chronic users reportedly consume more sugary foodstuffs

Alcoholic group reported significant correlation between sweet taste and alcohol consumption, meaning less sensitivity to sweet taste In the salty stimulus, no significant difference was noted in the threshold detection between alcoholic and non-alcoholics

Alcohol dependents showed alcohol-related olfactory deficits with lower scores in odor familiarity No differences between alcohol dependents and healthy controls in odor intensity and pleasantness judgements Impairments in high-level olfaction (odor discrimination) and gustatory deficits in alcohol dependents

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Marijuana N = 2808 (51.7% females) Age ≥ 40 years (Chao et al. 2021) [5]

Cocaine N = 11 cocaine users Average age = 32 years (Gordon et al. 1990) [41] N = 30 crack cocaine users N = 30 nonusers Mean age = 31 years (Chaiben et al. 2014) [38]

Population 48 Addicts (PodskarbiFayette et al. 2005) [37]

Table 8.2 (continued)

Whole mouth and tongue tip assessments of bitter (quinine) and salty (NaCl) tastes

Olfaction was assessed using a butanol threshold test, the UPSIT, and a 7-item discrimination test. Filter paper strips (4 mm) soaked with sterile solutions of the four basic tastes in three different concentrations were placed on the dorsal surface of the tongue and with the mouth closed For flavor identification, strips were moved orally by the subjects No

No

Yes

Yes

Yes

No

A cross-­ sectional analysis on National Health and Nutrition Examination Survey 2013–2014 data

Case–control study

Case study.

Level of Experiment Taste Smell evidence Comparative UPSIT was used for odor identification Yes Yes study Taste measured using method by Krarup in 1985

Current marijuana users were found to have lower tongue tip quinine ratings than never users Among current smokers, current marijuana users had lower whole mouth quinine ratings than never users

Crack cocaine users confused the salty taste as sour or bitter 100% of users while only 76.6% of nonusers were unable to identify the sweet solution less concentrated Hypogeusia was observed in 66.6% crack cocaine users and 23.3% of nonusers

Most cocaine abusers, and chronic users do not develop permanent olfactory dysfunction

Findings Impaired olfactory performance is seen in 52.1% of users (taking drugs intravenously and those who smoked and inhaled drugs), while 16.7% of them were diagnosed with ageusia on testing their sense of taste

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variation in chemosensation. Flavors of alcohol are readily transmitted to amniotic fluid and mothers’ milk during maternal alcohol consumption and are detected by the infant. Animal studies revealed that memories are formed as a result of orosensory experiences during nursing and are retained for a considerable time span acting as reinforcers for early learning. This builds up children’s expectancies about, and the effective disposition towards, hedonic responses to alcohol odors [20]. Quantitative trait loci (QTL) analysis has revealed that genetic differences (pleiotropy in Tas1r3/Sac/Ap3q locus) in the perception of the sweet taste component of ethanol flavor affect vulnerability to alcohol consumption. The genetic variation to alcohol taste has been revealed through psychophysical measures on the bitterness intensity experienced for 6-n-propylthiouracil (PROP). Individuals least able to taste PROP bitterness consumed greater number of beers (most bitter alcoholic beverage) during their first year of drinking than those who tasted PROP as intensely bitter [21]. A positive association between ethanol consumption and sucrose intake has been reported in both preclinical and human studies [22–24]. Overconsumption of ethanol was related to lower sensitivity to bitterness or aversion to sodium chloride (NaCl) [25]. Excessive alcohol drinkers tend to lose appetite as a result of impairment in their sense of taste and reduced sensory pleasure to food. This dysgeusia is a result of zinc deficiency and associated atrophy and keratinization of taste buds as a consequence of excessive alcohol consumption [24]. The sensory signals pertaining to smell are an integral part of human flavor perception, shaping the way tastes and textures are experienced [26]. The presentation of alcohol cues appears to reliably produce activation of neural circuits involved in learning and memory as well as brain regions associated with reward/motivation network such as the ventral (VS) and dorsal striatum (DS) [27], amygdala, prefrontal cortex (PFC), cingulate, precuneus and insula [28]. The presence of alcohol-­ related cues alone can act as a conditioned reinforcer and precipitate instrumental seeking and using behaviors, also described as Pavlovian-instrumental transfer [29]. These cognitive responses may link to reductions in fixed aspects of stimuli-specific inhibitory control. The development of cue reactivity, craving, and diminished (cue-­ specific) inhibitory control may involve and impact neural networks relating to reward processing, executive functioning, salience attribution, and habit formation. Deficits in chemosensory percepts (both gustation and high-level olfaction) have been reported in people with alcohol use disorder (AUD) [30], likely associated with dysfunction in the central neural circuitry of olfaction (including orbitofrontal cortex; OFC and amygdala), also known as alcohol-related brain damage (impaired memory and cognitive functions). This is very interesting to know that alcohol dependence might lead to two olfactory system modifications, consisting of overactivation for alcohol-related cues, but reduced activation for other stimuli [31]. The olfactory deficits in heavy alcohol drinkers impact their ability to enjoy food and may also put them at risk for long-term nutritional or health sequelae. This, in turn, leads them to alter their food choices and intake, resulting in weight loss, challenged immunity, and impaired nutritional status [32]. Therefore, in light of the literature

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reports so far, it is crucial to understand the selective taste and smell alteration experienced by chronic alcohol users and if this alteration renders them with enhanced preference to the smell or taste of alcohol (Table 8.2). Heavy alcohol drinkers can better tolerate bitterness, compared to light drinkers, but they tend to not like salt as much. Two olfactory system modifications are seen in alcohol dependents, consisting of over-activation for alcohol-related cues, but reduced activation for other stimuli. They tend to lose appetite as a result of decreased taste sensitivity and sensory pleasure in food.

8.2.3 Effect of Opiates on Taste and Smell Opiate abuse reportedly affects brain mechanisms responsible for taste and smell of information. Chronic opiate users, either when maintained on opiate agonists or when abstinent, tend to show increased craving, preference for, and intake of sugary foodstuffs, with added sugar contributing ~30% of total caloric intake [33]. The insular cortex (a cortical area associated with taste intensity) shows greater neuronal activation in rats undergoing opiate detoxification, although little evidence is reported in humans. Exogenous opioids reportedly modulate regions in the central nervous system (CNS), which lead to alteration in both the threshold and intensity of taste perception [34]. Brain regions like OFC that are involved in mediating the effects of opiate on eating behavior, and hedonic measures of rewarding taste (for example, sweet), were found to be dysfunctional (as a response to drug-related cues) in opiate, cocaine, and alcohol users [35]. Chronic heroin users rate sweet taste and savory smells as more pleasant, and bitter and sour tastes and putrid odor as less unpleasant than detoxified and healthy individuals [36]. The disruption in the sense of smell is associated with the route of drug administration. Impaired olfactory performance is seen in 52.1% of all drug users (taking drugs intravenously and those who smoked and inhaled various drugs), while 16.7% of them were diagnosed with ageusia on testing their sense of taste [37] (Table 8.2). Interpretation of sweet tastes and savory smells in opiate users is more pleasant compared with non-opiate users. Opiate users tend to show increased craving, preference for, and intake of sugary foodstuffs than nonusers.

8.2.4 Effect of Cocaine on Taste and Smell Crack cocaine users (smoked in the form of rocks using pipes) show a reduced taste perception as well as a high prevalence of hypogeusia with difficulty differentiating salty from sour or bitter flavors [38]. Preclinical studies have shown a loss of

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interest in intake of repeatedly presented palatable taste cues on intravenously administering cocaine. Also, decreased sensitivity to sweet taste was observed in rodents after injection of even moderate doses of cocaine [39]. Adolescents are increasingly using cocaine, and they consume cocaine through rapid insufflation of pulverized cocaine into the nasal vestibule by means of a short narrow drinking straw or roll of paper. During insufflation, the sharp cocaine crystals impinge at high velocity against the delicate nasal mucosa, causing the target area to sting. Hyperemia of the nasal mucosa followed by drug discontinuation is accompanied by edema and rhinorrhea. Some individuals further insult the nasal membranes after the use of sustained-release oxymetazoline hydrochloride nose spray. Rhinitis medicamentosa interferes with the senses of taste and smell and is associated with soreness of the throat and a dry mouth [40]. The chronic and compulsive use of cocaine turns the nasal pathology to impaired olfactory function, although function improves with abstinence [41] (Table 8.2). Notably, olfactory alteration is seen in both intravenous cocaine in humans and intraperitoneal cocaine in rats, which indicates that intranasal cocaine use leads to damage of the nasal septum. It has also been hypothesized that cocaineinduced deficits in olfaction are secondary to decreased subventricular zones (SVZ) proliferation (a sign of altered adult neurogenesis) and the consequential decrease in adult-generated olfactory bulb neurons [42]. The most probable mechanisms for disturbed olfaction in heavy cocaine users pertain to either direct damage to the neuroepithelium from either cocaine or its adulterants or possible obstruction of the olfactory cleft from inflammation and edema of the nasal mucosa. Another proposed mechanism is central olfactory system damage because the olfactory neuron extends from the nasal cavity directly to the brain without synapses, almost as a “drinking straw to the brain” [41]. Repeated intravenous doses of cocaine promote the development of abnormal epileptiform spikes in the olfactory bulb and tubercle. Autoradiographic studies indicate that, relative to many other brain regions, the olfactory tubercle has a particularly high binding affinity for the cocaine ligand [1251]RTI-55 and exhibits more persistent changes in blood flow following intravenous cocaine infusion. Such olfactory alterations may be important for a variety of reasons. For example, there is a possibility that cocaine-induced olfactory alterations promote tolerance for the noxious effects of smoked or inhaled cocaine, and these individuals continue to binge when others would not. Similarly, cocaine-induced deficits in olfactory sensitivity may block the perception of pleasant odors and reduce appetite leading to nutritional deficiencies. EEG measurements show the existence of reduced, as opposed to enhanced, olfactory evoked potentials (OEP) amplitudes among human cocaine abuse possibly associated with deficits in peripheral olfactory structure and function [43]. Cocaine users have difficulty differentiating salty, sour, and bitter flavors with decreased sensitivity to sweet taste.

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8.2.5 Effect of Marijuana on Taste and Smell Marijuana users (whether smoking or ingesting) reportedly show heightened sensitivity or appreciation for the taste (sweet taste) and odor of foods. Tetrahydrocannabinol (THC), which is a key psychoactive ingredient in Marijuana, binds to the cannabinoid CB1 receptors in the tongue, gut, and brain, and activates the reward system (dopamine release) that elicits cravings. Marijuana ingestion reportedly leads to activation of the VS, which assigns hedonic value or increases liking for foods. In particular, CB1 signaling modulates dopaminergic signaling in the nucleus accumbens (NAc) and ventral tegmental area (VTA), a phenomenon that has been directly related to the attribution of salience to food stimuli. However, some also suggest that THC promotes gastric CB1 activation and the production of ghrelin, otherwise known as the “hunger hormone,” increasing the craving for food (hyperphagia). Thus, THC and ghrelin have been proposed in the palliation of chemosensory alterations (dysgeusia) to improve food enjoyment. THC activates the parabrachial nucleus in mice, which presumably leads to their enhanced flavor perception, because mice on THC exposure prefer more sugary and fatty foods than bland items [44]. Marijuana users report decreased quinine (bitter taste) perception (lower intensity ratings) at the tongue tip as compared to individuals who have never used marijuana [5]. Preclinical studies in mice have shown that THC also potentiates the (endo)cannabinoid signaling in the olfactory bulb by binding to CB1 receptors, thereby enhancing odor detection and promoting food intake [45]. However, THC used during analgesic treatment led to subjective reductions in olfactory acuity [46] (Table 8.2). Marijuana users have a high appreciation and flavor perception for sweet taste and food odors.

8.3

Neuroimaging: Taste and Smell in SUD

8.3.1 Taste and Smell Cue Reactivity Gustatory and olfactory cue delivery methodologies are being increasingly incorporated into neuroimaging studies of SUD. Broadly, these cues are presented: (a) subliminally and never enter the subjects’ conscious perception, (b) as task-related targets and the focus of attention, or (c) as task-irrelevant distracters. Reactivity to drug cue exposure, as assessed with functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and related neuroimaging techniques, leads to psychological responses (e.g., craving, urge, or desire to consume), physiologic preparatory responses (e.g., salivation), and neurocognitive responses (e.g., brain activation patterns, allocation of attentional resources). The pathophysiology, and cue reactivity, in particular, have strong learning, and memory components. In this context, taste and smell cue presentations activate neural circuits involved in

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learning and memory, and also brain regions associated with the reward/motivation network, such as the VS and DS, amygdala, PFC, cingulate, precuneus, and insula. The integration of sensory inputs, reward values, and homeostatic signals during drug cue reactivity is mediated by OFC. Sensory cues act as conditioned reinforcers and precipitate instrumental seeking and using behaviors, also described as Pavlovian-instrumental transfer, which thereby manifests as loss of inhibitory control. These cognitive responses [cue reactivity, craving, and diminished (stimulispecific) inhibitory control] may involve networks related to reward processing, executive function, salience attribution, habit formation, and the default mode network (DMN). Both cue reactivity and craving share two prominent theories. The incentive-sensitization theory describes a difference between liking (the hedonic component of a stimulus) and wanting (the attention-grabbing and motivational characteristic of rewards and their craving initiating learned cues). This theory states that wanting develops upon repeated cue exposure and sensitization of the mesocorticolimbic dopamine system (reward network). The dual process theory proposes an enhancement of motivational drive presumably due to hyperreactivity of reward networks. As a consequence, impulsive drive alleviates exposure to addictive cues and overrides control by executive-control networks (reflective system). fMRI studies have shown an increase in the blood oxygen level-dependent (BOLD) activation in brain regions like striatum, anterior cingulate cortex (ACC), posterior cingulate cortex(PCC), inferior/superior parietal lobule, insula, middle occipital gyrus (MOG), and inferior temporal gyrus (ITG) in response to drug (alcohol, cannabis, cocaine, heroin, and nicotine) cues. Cue reactivity is a task essential for understanding substance addiction, relapse rates, and clinical outcomes, where delineating the neural systems involved in cue reactivity plays a crucial role in understanding the mechanism underlying the development and/or maintenance of addictive behaviors [47] (Fig. 8.2). Repeated exposure to cues creates a conditioned response resulting in dopamine release and increased craving. Cue reactivity is important for understanding substance use disorders, relapse rates, and clinical outcomes.

8.3.2 Neural Circuitry Underlying Cue Reactivity 8.3.2.1 Mesocorticolimbic Dopamine System Drug abuse acutely increases extracellular dopamine in the mesocorticolimbic reward system, which is innervated by dopaminergic projections predominantly from the VTA. Drug use precipitates a larger amplitude and longer duration of dopamine signaling than normal physiological responses. Dopamine projections between the PFC and the dorsolateral striatum are critical in the development of habits, and when considering drug use, these projections enhance the conditioned reinforcement mechanisms that promote the habituation of drug-seeking and drug-taking behavior. As for other drugs, alcohol increases dopamine release in the NAc, thereby

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BINGE/INTOXICATION Dorsal Striatum Vental Tegmental Area Cerebellum

PREOCUPATION/ANTICIPATION

Prefrontal Cortex Hippocampus

THE CYCLE OF ADDICTION

WITHDRAWAL/NEGATIVE EFFECT

Basolateral Amygdala Central Amygdala

Fig. 8.2  Illustrates the brain regions involved in the cycle of addiction and the subsequent behaviors each region is responsible for (created in biorender)

stimulating D1 receptors (D1R), which are necessary for reward and conditioning, and for stimulating D2 (D2R) and D3 receptors (D3R). A recent meta-analysis on the dopamine system and sedative drug use have reported lower striatal D2/D3 receptor availability in drug users compared to control individuals. In parallel, drug abuse also induces a gradual shift in dopamine increases (from VS to DS) during the transition from a novel stimulus that is inherently rewarding to that of the associated cues that predict it. This shift from VS to DS activation has been attributed to a change in previous goal-­directed behavior (conscious control; NAc) to compulsive seeking (automatic stimulus-­response habits; DS) of drugs (Fig.  8.3). Drug cues also induce dopamine increases in the nigrostriatal dopamine system, which consists of dopamine projections from the substantia nigra to the DS (caudate and putamen) and globus pallidus. These structures are thought to underlie habit learning and automaticity, and growing evidence suggests that they are also more strongly activated in response to drug cues compared to neutral stimuli [47]. Drugs can induce a gradual shift in dopamine increases from the ventral to the dorsal striatum in the brain. This cue-induced activation has been attributed to the switch from conscious control to compulsive seeking behavior for a substance.

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Fig. 8.3  Illustration of the brain circuitry in drug addiction, and the dopamine signaling on substance cue exposure (taste and smell) (created in biorender)

8.3.2.2 Salience Network (SN) Enhanced drug cue reactivity is associated with increased functional connectivity between dorsal ACC and insula (regions of SN). These regions are associated with orienting attention to internal or external stimuli. The ACC is implicated in cognitive tasks, in particular, tasks involving cognitive control, conflict, or error monitoring. The ACC is also activated by salient stimuli, including those that are reward-related as well as stimuli that elicit pain or negative affect. The insula has been related primarily with interoception, or the awareness of bodily states and internal homeostasis. However, parallel to ACC activation, the insula and the adjacent inferior frontal gyrus are also often engaged during tasks requiring cognitive control and in response to salient external stimuli. Among some, the most important insular function during the stages of the addiction cycle is that it interacts with other brain regions to alter affective states (e.g., irritability), motivation (e.g., cue reactivity), and attention (e.g., goal-directed behavior) [47]. The salience network, which encompasses the insula and the dorsal anterior cingulate cortex (ACC), activates on drug cue exposure and plays a role in the addiction cycle, altering motivation, urge, and attention.

8.3.2.3 Central Executive Network (CEN) The primary nodes of this frontoparietal system are in the dorsolateral prefrontal cortex (dlPFC) and lateral posterior parietal cortex (PPC). This system processes exogenous and attentionally driven cognitive functions [47]. The CEN is more involved in goal-oriented or task-modulated processing that aids decision-making

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and, importantly, response inhibition. Higher activity (in response to cue-reactivity task) in CEN regions was correlated with lower craving in cigarette smokers [48] and cannabis users [49]. Anticipation of drug use has been associated with increased cue-elicited activation of the dlPFC and OFC, which might reflect the explicit representation of this expectancy (by OFC) and the generation and maintenance of behavioral goals aimed at obtaining drug reward (by dlPFC) [50]. Gustatory and olfactory paradigms using alcohol cues test the effect of several drugs for treating patients with AUD. One of these studies determined the effect of naltrexone, ondansetron, their combination, or matched placebo on gustatory and visual alcohol cue reactivity [51]. They observed a reduction in region-specific activation as compared to placebo using the three active drug conditions, while the naltrexone alone condition exhibited an attenuation of primarily frontostriatal activation in response to alcohol cues. In a later study conducted by Lukas et al., an attenuation in the visual and olfactory alcohol cue reactivity was seen on administering an extended-release naltrexone treatment [52]. Schacht and colleagues observed a moderating role of the genetic polymorphisms of the OPRM1 gene and the dopamine transporter gene (DAT1/SLC6A3) on the effects of naltrexone in neural processing on alcohol gustatory and visual cue presentation [53]. These studies suggest the utility of incorporating gustatory and olfactory presentations of various substances in neuroimaging experiments for a better understanding of the pharmacogenetic effects of treatment drugs for SUD. The central executive network is involved in processing attentionally driven cognitive functions, and anticipation of drug use has been associated with increased cue-elicited activation of nodes in this network.

8.3.2.4 Default Mode Network (DMN) The DMN comprises PCC, medial prefrontal cortex (mPFC), medial temporal lobe (MTL), and angular gyrus and is typically deactivated during stimulus-driven cognitive tasks [47]. DMN, which supports self-referential thinking, memory encoding and retrieval, and social reasoning, is disrupted in SUD. Among the mixed findings, deactivation in regions of the DMN [rostral anterior cingulate cortex (rACC), posterior cingulate cortex (PCC)] has been observed in response to nicotine and cocaine cues [54, 55] in some studies, but not all [56]. A full discussion of the DMN activation and deactivation patterns on cue exposure is beyond the scope of this chapter, and the reader is referred to a recent review on this topic by Zhang et al. [57]. The Default mode network (DMN) supports behaviors such as thinking, memory, and social reasoning; however, its activity is disrupted in individuals with substance use disorders.

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Conclusions

There is significant evidence that individuals with SUD are at a higher risk of gustatory and olfactory dysfunction than those without SUD. In general, individuals with SUD show altered taste and smell perception. The chemicals in these substances adversely affect the olfactory receptors; however, it is generally believed that renewal of the olfactory epithelium via regenerative processes, at least in nonhuman mammals, occurs within a matter of weeks. The suppressed sweet sensitivity seen in individuals with SUD has been linked with the brain reward circuitry and is associated with the decreased motivation for a previously rewarding sweet stimulus. The underlying mechanism for the impaired gustatory and olfactory sensation in SUD is unclear; however, this obstruction might serve as an early risk indicator of neurodegenerative diseases. Thus, clinicians treating individuals with SUD-related taste and smell loss should advise patients of the potential negative effects of this substance of abuse and that quitting might improve these chemosensory percepts. Chapter Take-Home Message Substance use disorder (SUD) is the inability to control the use of a drug, and there are 9 classes of drugs as identified by the Diagnostic Statistical Manual (DSM-5). In order to taste and smell, small particles have to bind to their respective receptors (taste cells located within taste buds on the tongue or neurons located in the upper part of the nose’s septum). The brain needs both taste and smell combined to differentiate various flavors; thus, disruptions in taste and smell are connected and are often both influenced simultaneously. Individuals with SUD may be at higher risk of taste and smell dysfunction, so clinicians treating SUD patients should be aware of the potential negative effects. Research shows that quitting the use of substances may be associated with improvements in taste and smell dysfunction. Key Concepts • Substance use disorder (SUD) is the inability to control the use of a drug, and there are nine classes of drugs as identified by the Diagnostic Statistical Manual (DSM-5). • Disruptions in taste and smell are connected and are often influenced simultaneously. • Smokers have a worse sense of smell. Oral intake of tobacco can alter salt and sweet taste. • Alcohol drinkers tend to not like salt and lose appetite as a result of decreased taste sensitivity and sensory pleasure in food. • Interpretation of sweet taste and savory smells in opiate users is more pleasant compared with non-opiate users. They tend to show increased craving, preference for, and intake of sugary foodstuffs. • Cocaine users have difficulty differentiating salty, sour, and bitter flavors with decreased sensitivity to sweet taste.

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• Marijuana users have a high appreciation and flavor perception for sweet taste and thus eat more sugary and fatty foods. • Cue reactivity is important for understanding substance use disorders, relapse rates, and clinical outcomes. • Food and drugs can induce a gradual shift in dopamine increases from the ventral to the dorsal striatum in the brain which has been attributed to the switch from conscious control to compulsive seeking behavior for a substance. • The salience network plays a role in the addiction cycle, altering motivation, urge, and attention. • The central executive network is involved in processing attentionally driven cognitive functions and anticipation of drug use has been associated with increased cue-elicited activation of nodes. • The default mode network (DMN) is disrupted in individuals with SUDs. Funding  This work was supported by the Intramural Research Program of the National Institutes of Health. Dr. Joseph is supported by the National Institute on Alcohol Abuse and Alcoholism (Z01AA000135), the National Institute of Nursing Research (1ZIANR000035–01), the Office of Workforce Diversity, and the National Institutes of Health Distinguished Scholar Award at the National Institutes of Health, and by the Rockefeller University Heilbrunn Nurse Scholar Award. Dr. Agarwal is supported by an Intramural Research Training Award, National Institute of Nursing Research, National Institutes of Health, Department of Health and Human Services. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funding agencies had no role in the preparation, review, or approval of the manuscript.

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threshold: a systematic review and meta-analysis. Compr Rev Food Sci Food Saf. 2020;19(6): 3755–73. 9. Da Ré AF, Gurgel LG, Buffon G, Moura WER, Marques Vidor DCG, Maahs MAP. Tobacco influence on taste and smell: systematic review of the literature. Int Arch Otorhinolaryngol. 2018;22(1):81–7. 10. Ajmani GS, Suh HH, Wroblewski KE, Pinto JM. Smoking and olfactory dysfunction: a systematic literature review and meta-analysis. Laryngoscope. 2017;127(8):1753–61. 11. al. PZe. International consensus statement in rhinology and allergy: olfaction. 2022. in press. 12. Glennon SG, Huedo-Medina T, Rawal S, Hoffman HJ, Litt MD, Duffy VB.  Chronic cigarette smoking associates directly and indirectly with Self-reported olfactory alterations: analysis of the 2011-2014 National Health and nutrition examination survey. Nicotine Tob Res. 2019;21(6):818–27. 13. Siegel JK, Wroblewski KE, McClintock MK, Pinto JM. Olfactory dysfunction persists after smoking cessation and signals increased cardiovascular risk. Int Forum Allergy Rhinol. 2019;9(9):977–85. 14. Frye RE, Schwartz BS, Doty RL. Dose-related effects of cigarette smoking on olfactory function. JAMA. 1990;263(9):1233–6. 15. Etter JF, Ussher M, Hughes JR.  A test of proposed new tobacco withdrawal symptoms. Addiction. 2013;108(1):50–9. 16. Chéruel F, Jarlier M, Sancho-Garnier H.  Effect of cigarette smoke on gustatory sensitivity, evaluation of the deficit and of the recovery time-course after smoking cessation. Tob Induc Dis. 2017;15:15. 17. Yeomans MR. Effects of alcohol on food and energy intake in human subjects: evidence for passive and active over-consumption of energy. Br J Nutr. 2004;92(Suppl 1):S31–4. 18. Bachmanov AA, Beauchamp GK. Taste receptor genes. Annu Rev Nutr. 2007;27:389–414. 19. Lanier SA, Hayes JE, Duffy VB. Sweet and bitter tastes of alcoholic beverages mediate alcohol intake in of-age undergraduates. Physiol Behav. 2005;83(5):821–31. 20. Bachmanov AA, Kiefer SW, Molina JC, Tordoff MG, Duffy VB, Bartoshuk LM, et  al. Chemosensory factors influencing alcohol perception, preferences, and consumption. Alcohol Clin Exp Res. 2003;27(2):220–31. 21. Duffy VB, Peterson JM, Bartoshuk LM. Associations between taste genetics, oral sensation and alcohol intake. Physiol Behav. 2004;82(2–3):435–45. 22. Blizard DA, McClearn GE. Association between ethanol and sucrose intake in the laboratory mouse: exploration via congenic strains and conditioned taste aversion. Alcohol Clin Exp Res. 2000;24(3):253–8. 23. Kampov-Polevoy AB, Garbutt JC, Janowsky DS. Association between preference for sweets and excessive alcohol intake: a review of animal and human studies. Alcohol Alcohol. 1999;34(3):386–95. 24. Silva CS, Dias VR, Almeida JAR, Brazil JM, Santos RA, Milagres MP. Effect of heavy consumption of alcoholic beverages on the perception of sweet and salty taste. Alcohol Alcohol. 2016;51(3):302–6. 25. Pelchat ML, Danowski S. A possible genetic association between PROP-tasting and alcoholism. Physiol Behav. 1992;51(6):1261–6. 26. Small DM, Prescott J.  Odor/taste integration and the perception of flavor. Exp Brain Res. 2005;166(3–4):345–57. 27. Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Childress AR, et  al. Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. J Neurosci. 2006;26(24):6583–8. 28. Noori HR, Cosa Linan A, Spanagel R.  Largely overlapping neuronal substrates of reactivity to drug, gambling, food and sexual cues: a comprehensive meta-analysis. Eur Neuropsychopharmacol. 2016;26(9):1419–30. 29. Dickinson A, Smith J, Mirenowicz J.  Dissociation of Pavlovian and instrumental incentive learning under dopamine antagonists. Behav Neurosci. 2000;114(3):468–83.

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9

Loss of Taste and Smell Function in Cancer Patients Alissa A. Nolden

Learning Objectives • Summarize the impact of taste and smell dysfunction on food behavior. • Compare diagnostic methods for evaluating taste and smell dysfunction in cancer patients. • Evaluate current approaches for supporting cancer patients with taste and smell dysfunction.

9.1

Introduction: Prevalence and Importance

9.1.1 Prevalence of Smell and Taste Loss Cancer continues to have a large burden on societies in the United States (U.S.) and across the world. Based on data from 2015–2017, in the U.S., one in three adults are diagnosed with cancer [1]. Common treatments for cancer include surgery, chemotherapy, and/or radiation, with other therapies including immunotherapy, hormone therapy, or ablation of cancer cells with freezing or high radiofrequency. While treatments work through different pathways to target cancer cells, they can cause unintended side effects, including nausea, vomiting, immune suppression, loss of appetite, and alterations in taste and smell function. While many of these symptoms are well characterized and often have treatments available to reduce their severity, there are few evidence-based strategies or treatments available for patients that experience alterations in taste or smell function. A. A. Nolden (*) Department of Food Science, College of Natural Sciences, University of Massachusetts Amherst, Amherst, MA, USA e-mail: [email protected] © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021 P. V. Joseph, V. B. Duffy (eds.), Sensory Science and Chronic Diseases, https://doi.org/10.1007/978-3-030-86282-4_9

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There is wide variability in the reporting of taste and smell function among cancer patients, with 20–84% of cancer patients suffering from taste alterations [2–4], and 5–60% from smell alterations [4]. Higher prevalence rates are reported for head and neck cancer patients, with 70–100% suffering from taste loss [5]. Even with the large number of patients reporting problems with taste and smell, there are challenges in diagnosing the specific chemosensory disorder and limited care options for managing these symptoms. This chapter will focus on the recent literature on the incidence and severity of taste and smell alterations occurring among cancer patients and the potential management strategies. It is important to first describe the methods for identifying patients with chemosensory alterations. There are challenges in summarizing the original research as there are many inconsistencies among findings. Reviews of the taste and smell assessments attribute these contrasting findings to the large variation in assessment tools used, heterogeneity of the population, and study design (longitudinal vs. cross-sectional and prospective vs. retrospective) [6–9]. Further, these discrepancies in findings have made it problematic for translating findings to clinical support. Below is a brief discussion on these challenges in regard to findings related to chemosensory alterations in cancer patients. A major challenge in diagnosing and identifying problems with taste and smell is attributed in part to the vocabulary we often use to describe the flavor of food.

Clinicians do not always have access to tools to link patient complaints with chemosensory disorders.

It can be difficult to translate reports of differences in perception and hedonic response to a clinical diagnosis.

9.2

 istinct Methodologies, Study Designs, D and Study Populations

9.2.1 Varying Taxonomy: Taste, Smell, and Flavor In terms of chemosensory perception, there is clear and defined terminology to describe and diagnose chemosensory dysfunction. However, this terminology does not translate to everyday use of the vocabulary, making it challenging for clinicians to link patient experience with chemosensory taxonomy. For example, clinicians and patients do not make distinctions between taste and flavor, with taste colloquially describing flavor, both in terms of perception and hedonic response [10]. Thus,

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much of the literature investigating taste and to a lesser extent smell disorders are not characterizing chemosensory disorders appropriately. More work is needed to educate clinicians, such as Boltong’s taxonomy of taste, aimed at linking patient-­ reported problems with chemosensory terminology [11].

9.2.2 Varying Assessment Methods When it comes to subjective or objective measures of cancer patients’ taste loss, no one method is commonly used among researchers and clinicians. However, for smell, Sniffin’ Sticks® are often used to objectively assess smell function. Yet, for both taste and smell, many studies report incidences of taste or smell loss, rather than diagnosing a specific chemosensory disorder. Much of the original research assesses chemosensory function with a survey or questionnaire, relying on patient self-report. There are several validated surveys available to clinicians that ask questions regarding taste and/or smell function (see Table 9.1). However, these provide varying amounts of information, including taste quality (e.g., sweet, bitter, etc.), frequency, duration, severity, direction (i.e., increased or decreased), or persistent off-taste in the mouth. A review recently characterized patient questionnaires that assessed taste changes and related symptoms [12]. This review identified a total of 15 questionnaires that were used to assess taste function in cancer patients, with 12 used in two or fewer studies [12]. Many researchers are concerned with the impact on nutrition and often assess nutrition impact symptoms, including discomfort related to mastication, saliva, nausea, gastrointestinal symptoms, and other oral problems. Fewer questionnaires ask questions related to specific taste qualities (sweet, sour, salty, and bitter; with no survey assessing umami). However, it is not clear whether patients are familiar with these individual qualities. Many involve assessing taste in terms of changes in taste or changes in hedonic response (“unpleasant taste”). Fewer assess the frequency in which they experience taste and smell changes, amount of distress it causes, or its severity. Tools that assess these symptom characteristics may provide important insight into patient distress and influence food behavior and nutritional status. While self-report is an important tool for clinicians, it provides limited information regarding characterizing taste problems experienced by patients. There is a growing body of literature that has employed psychophysical methods to quantify taste function to individual taste sensations. More often, clinical diagnosis of a chemosensory disorder is performed using a combination of self-reported and psychophysical measures, with a disagreement between assessments used as an important characteristic. From a psychophysical standpoint, these methods provide a greater understanding as to the nature of the taste dysfunction; yet, much of the original research using this approach does not define patients in terms of a specific chemosensory disorder. Subjective methods are more widely used throughout the literature, but may not provide researchers and clinicians with all of the information regarding the extent to which taste has been affected or the specific taste qualities. Objective measures are

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Table 9.1  Survey tools to assess patients self-report of smell and taste alterations Survey tool European Organization for Research and Treatment Center (EORTC) H&N35 Taste and smell survey (TSS)

Question(s) •  The trouble with social eating •  Senses impairment (taste/smell) • Comparing my sense of taste now to the way it was before I was diagnosed with cancer: [taste] is stronger, as strong, weaker, or I cannot taste at all. • Have you noticed changes in your sense of taste/ smell? • Have you ever noticed that a food tastes/smells different than it used to? • How has your abnormal taste/smell affected your quality of life? Vanderbilt head and neck symptom •  The severity of alteration of taste survey v. 2.0 •  The severity of alteration of smell • Ability to smell [5 items: Spoiled foods, body Assessment of self-reported olfactory odor, etc.] functioning and olfaction related quality • The extent to which your sense of smell has been of life (ASOF) impaired [6 items: Cooking, eating, etc.] Head and neck symptom checklist • The intensity of taste changes and altered smell (HNSC) • The severity of taste and smell changes in the context of eating Chemotherapy-induced taste alteration • Have difficulty tasting [food, bitter, sour, salt, survey (CiTAS) sweet, umami] •  Everything tastes [bitter, bad] •  Have a bad taste in the mouth •  Food doesn’t taste as it should •  Unable to perceive the smell or flavor or food Patient-generated subjective global •  Smells bother me assessment •  Things taste funny or have no taste Appetite, hunger and sensory perception •  Present smell perception •  Present smell perception compared to the past (AHSP) (also called questionnaire on •  Present taste perception odor, taste, and appetite (QOTA)) Taste change survey (TCS) • How much have you noticed [metallic taste, bitter taste, no sense of taste] • How much does [metallic taste, bitter taste, no sense of taste] bother you? List partially generated based on a recent review [12]

more time-consuming, can be challenging to conduct in a clinical setting, and do not capture hedonic perceptions. Psychophysical methods most often focus on a single dimension, not typical in complex sensations experienced during eating and drinking. Due to large variations in the assessment of patients for taste disorders, examining the literature does not provide a clear understanding of the characteristics of the taste disorder, and is often described as dysgeusia or taste alteration. A recent study characterizing taste and smell loss among advanced cancer patients reported differences in prevalence based on assessment type. This study evaluated patients using the Taste and Smell Survey (TSS), an abbreviated version of the Patient-Generated Subjective Global Assessment, and an objective measure

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which consisted of identification of sweet, sour, salty, bitter using taste strips [13]. There were large differences in prevalence rates based on the use of subjective and objective measures. Almost all the patients’ self-reported taste problems using the TSS (n = 28), while only 16 were identified as having a taste alteration using an objective measure. This meant that over 50% of patients could not correctly identify all four taste sensations. Subjective complaints of the severity of taste loss identified more than half of the patients experienced moderate severity or greater (severe = 5; or incapacitating = 3). For smell, 21 patients report experiencing smell loss, yet only 16 were characterized as having a smell disorder using the Sniffin’ Stick test. Of patients reporting smell changes, 7 reported moderate severity, with one patient describing it as incapacitating. This provides a clear example of how the method can provide very different results for diagnosing a chemosensory disorder. In terms of relationship with food intake, twenty-seven out of 28 patients that had reported taste alterations were identified as being at risk for malnutrition [13].

9.2.3 Study and Methodological Design There are important study design characteristics that are critical for interpreting findings [14]. Some considerations include the length of study, either a single timepoint posttreatment or following patients from baseline. Longitudinal studies that include a baseline measure can provide information on how patients’ taste and smell function changed over the course of treatment and recovery, providing an important understanding of the pathology of chemosensory dysfunction. Alternatively, a single time point for data collection uses a separate group of individuals to serve as a comparison. Without baseline measures, it may be that an individual had altered chemosensory function prior to the start of treatment, either due to illness, age, smoking, or alcohol history [15]. • L  arge variations of prevalence rates are reported across the literature for both taste and smell loss.

• V  ariations are often linked with differences in sample size, homogeneity of the patient population for both for demographic and clinical characteristics, and method of assessment.

9.2.4 T  he Prevalence Varies across Clinical and Individual Characteristics Prevalence or severity of chemosensory alterations is likely to associate demographic and clinical characteristics of cancer patients. In terms of demographics, factors include age, sex, race/ethnicity education level, alcohol use, and smoking

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status [14, 16, 17]. In regard to clinical characteristics, studies found taste or smell loss associated with cancer diagnosis, chemotherapy regimen, time since diagnosis, and prior cancer treatments [14, 17]. However, few studies fail to identify relationships with demographic [18–23] or clinical factors [20, 23]. In summary, there are important considerations when summarizing the literature regarding chemosensory dysfunction among cancer patients. There are several factors that can vary across studies making it challenging to make concise statements regarding these findings, which in turn has led to imprecise conclusions regarding the impact on food behavior, malnutrition, and quality of life. These uncertainties carry into the clinical sector, making it difficult to provide education, assess patient function, and deliver individualized care for those suffering from chemosensory disorders. Considering these barriers, this chapter describes the plausible mechanisms in which cancer treatment results in reduced taste and smell function, other possible treatment-related factors, and symptoms associated with chemosensory disorders. Among cancer patients, taste and smell function likely have a profound negative impact on food behavior and quality of life, which can lead to poor treatment outcomes.

9.3

I mpact on Treatment on Taste and Olfactory Cell Homeostasis

Evidence suggests that cancer treatments, with most research conducted with chemotherapy and radiation therapy, prevent the regrowth of gustatory and olfactory cells. Murtaza and colleagues (2017) have recently summarized the work through which cancer treatments may cause changes in taste perception, including the pathways through which chemotherapy and radiation may alter taste physiology [24]. Here, we briefly review the pathways evidenced to damage the taste and smell pathway.

9.3.1 Cancer and Inflammation Inflammatory markers are known to modulate physiological changes in the perception of taste and smell and have been shown to alter taste bud signaling pathways [25] and can cause neuronal death [26]. This suggests that the growth of cancer cells and the resulting inflammation can result in changes in taste and smell perception. However, there is disagreement among the literature as to whether patients diagnosed with cancer experience changes in taste and smell perception. There is conflicting evidence as to whether treatment-naïve cancer patients experience changes in taste or smell [23]. More studies are needed to understand the relationship between cancer cell growth and inflammation on changes in chemosensory perception and transduction pathways.

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9.3.2 Chemotherapy Treatment Chemotherapy targets rapidly regenerating cells, including cells in the gustatory and olfactory epithelium. See Chap. 2 for a description of the development and renewal of taste and olfactory cells. Chemotherapeutic agents cause apoptosis of cancer cells through several mechanisms, including DNA damage and production of reactive oxygen species, leading to cell necrosis. However, the treatment does not specifically target tumor cells and can cause damage to other regenerating cells. Recent work has provided evidence both in vitro and in vivo that chemotherapeutic agents target the proliferation of new taste cells via the sonic hedgehog and notch pathways [24]. In terms of olfaction, less is known about the pathway that may lead to damaged olfactory cells; however, one chemotherapeutic drug (cyclophosphamide) affected olfactory cell renewal in mice [27]. More work is needed to identify pathways in which chemotherapeutic agents may impair transduction and perception (identification) of odors. It has been suggested that the pathways leading to changes in taste and smell perception are separate from those resulting in the perception of persistent taste sensations. Many patients undergoing chemotherapy complain of a constant or persistent bitter or metallic, often described as a “bad taste” or “metal mouth.” Between 9–78% of chemotherapy patients experience persistent metallic taste or change in metallic taste [28]. The sensation of metallic taste may be due to the transfusion of metallic and/or bitter compounds in chemotherapy agents, antibiotics, and analgesics that activate the taste pathway through plasma or through secretion into the saliva. However, there is no clear pathway for the transduction of metallic sensations, and metallic does not meet the current definition of taste; rather, it is likely integration of taste, smell, and trigeminal sensations [28].

9.3.3 Radiation Treatment Radiation treatment can damage normal tissue surrounding the tumor site and can include both gustatory and olfactory organs in the field of radiation. The severity of taste alterations appears to be associated with radiation dose, and dependent on the radiation field (i.e., oral cavity vs tongue) [29]. In mice, radiation to the head and neck area significantly reduces the number of progenitor cells and can cause damage to the neurons innervating gustatory cells [30]. While there is a lack of evidence regarding the impact of radiation exposure on olfactory cells and neurons, the olfactory bulb often falls in the radiation field and may be damaged as a result of exposure, and likely causes damage to olfactory progenitor cells. While the short-term impact is not known, even after 12 months post-treatment, patients receiving radiation and chemotherapy have reduced olfactory bulb volume, compared to healthy controls, with more than 50% of patients still experiencing reduced olfactory function [31]. However, as patients received both chemotherapy and radiation therapy, it is not clear if the reduced olfactory bulb size is a direct result of radiation therapy, as differences were observed across two different chemotherapeutics (cisplatin and

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cisplatin plus docetaxel). Another pathway that may impact the recovery following radiation, is the reinnervation of the nerve fibers. It is possible that if the synaptic connections follow irregular patterns, taste may be permanently damaged or altered [32]. More work investigating the reinnervation patterns following radiation, accounting for radiation field, dose, and frequency on the regeneration of synaptic connections is needed.

9.3.4 Other Cancer Treatments Other treatments exist for cancer patients, including surgery, hormone therapy, and immunotherapy, among others. However, there is limited research investigating the effects of these treatments on taste and smell function. Moreover, advances in treatments are likely to have different impacts on chemosensory function. For example, proton therapy, a newer type of radiation treatment, has a smaller radiation field and thought to better preserve gustatory and olfactory tissue, reducing the incidence and severity of chemosensory dysfunction [33]. Other medications taken that are taken alongside cancer treatment such as antibiotics and antiemetics are associated with altered taste perception. For example, patients taking an NK-1 antagonist antiemetic with two other antiemetics (most common were 5-HT3 receptor antagonists and a steroid) were more likely to report changes in taste, compared to patients not taking an antiemetic [17]. Both receptors (NK-1 and 5-HT3) and their agonists (substanceP and serotonin, respectively) are involved in the transduction of taste [34–36], while also being involved in gut motility [37, 38].

9.4

Taste Loss and Cancer

9.4.1 Overview of the Findings The prevalence of taste loss among chemotherapy patients varies from 12% to 84% [7, 23, 39]. When considering all cancer patients, both objective and subjective reports suggest that all taste qualities are impacted during or following treatment. Most studies conclude that patients experience a reduction in taste function. Generally, objective studies have reported decreases in suprathreshold intensity ratings, lack of ability to identify a taste sensation, and reduced sensitivity (i.e., increased detection/recognition threshold) [7, 9, 23]. While reduced sensitivity are reported for sweet, salty, bitter, and sour, reduced response to salt and sweet are more common [23]. What does appear across studies, is that in terms of taste problems, not all patients report or experience changes in taste function. Yet, it is not fully understood why some patients do not experience taste changes. There lacks an explanation or exploration as to the characteristics that are associated with patients reporting no changes in taste. More work has been done to identify symptoms that co-occur among patients reporting loss or altered taste function. Investigation of the clinical characteristics and co-occurring symptoms for both patients with and without changes to taste function will help to identify risk factors for patients and potentially point towards treatment strategies.

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Our understanding of taste changes is based on a narrow list of stimuli, including sweet (sucrose), bitter (quinine HCl, urea, caffeine), sour (citric acid), salty (NaCl), and umami (MSG). There is a lack of variety in the stimuli that have been tested, with few studies evaluating umami. While there are differences observed across studies for the specific taste sensations, the majority of studies report decreased function, with few studies reporting increased taste response [9]. Other oral sensations (e.g., texture, fat, chemesthesis) are also lacking from evaluation, which may have unknown yet important consequences for food behavior.

9.4.2 Other Oral Sensations Described above are the taste changes often experienced by cancer patients; however, patients may experience a different classification of taste disorder, known as a phantom taste. This is described as a persistent taste sensation in the absence of stimuli, food, or beverage. The most common is metallic taste, frequently described as a chemical taste, drug taste, blood taste, and bitter taste [40]. Metallic “taste” is not well characterized and can be difficult for patients to report. Not only can metallic be difficult to describe, but many self-reported taste alteration questionnaires also do not specifically ask about metallic taste [28]. While few studies have investigated the prevalence, one study reported that of patients reporting taste changes, 79% described the taste change as metallic [41]. No studies have objectively evaluated a patient’s response to metallic stimuli nor compared the metallic sensations (phantom taste) reported by cancer patients to the metallic sensations experienced from metallic salts. All available data on metallic taste in cancer patients is based on a questionnaire or interview [40]. Only a handful of studies have evaluated metallic taste alteration, therefore it is not surprising to find a large variation in the reported prevalence of metallic taste sensation of 9–78% [28]. One longitudinal study in breast cancer patients reported that of the patients reporting metallic taste during chemotherapy, no longer reported metallic taste sensation six months post-treatment [42]. To date, there is no evidence that chemesthesis or textural perception is altered during or following chemotherapy or radiation. In fact, chemesthetic agents, such as ginger and peppermint are often suggested for increasing enjoyment of foods. This suggests the chemesthetic neurons are stable or less damaged during treatment. However, one study has evaluated sensitivity to hot and cold temperatures in patients undergoing chemotherapy, with 36% and 21% of patients reporting abnormal sensitivity to cold and hot foods, respectively [43]. There is insufficient data to draw conclusions regarding the perception of chemesthetic sensations and more studies are needed to characterize these sensations during and following treatment. Identifying which sensations are intact is just as important as characterizing lost sensations, as both can lead to developing strategies for increasing food enjoyment and maintaining nutrition. Patients do not eat food in isolation, with the complex chemosensory sensations imparting overall sensory experience. To date, other oro-sensory attributes have been largely uninvestigated, such as changes in food texture, chemesthetic sensations (warming and cooling), and drying or astringent sensations. Obtaining a more

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complete representation of patients’ experiences with food and beverages, their changes in chemosensory function, and incidence and severity of symptoms likely to impact food behavior are needed to identify potential interventions and translate information to clinicians in order to provide evidence-based support for patients undergoing cancer treatment.

9.4.3 Non-traditional Testing As discussed above, typical objective testing delivers stimuli using whole-mouth or taste strips; yet one study spiked beverages (e.g., lemonade) with tastant [44]. A similar approach was used to assess hedonic response [45]. These testing methods allow the delivery of targeted stimuli and provide information regarding a single sensation. Moreover, this sample presentation may be more accepted by patients and likely to be appropriate for a clinical setting.

9.4.4 Recovery of Taste Loss Generally, guidance for patients describes that loss of taste function appears early on, with a function returning following the end of treatment (around 1–2 months post-treatment). While several studies report recovery following treatment [6], there is variability in recovery across studies. Many cancer survivors continue to report loss of taste function, with 10% reporting persistent taste problems at 1-year post-­ treatment [42] and a cohort of testicular cancer survivors (between 1–7 years post-­ treatment) had reduced overall taste function compared to controls [46]. For HNC, the duration of taste loss may continue longer, with 52% of HNC patients reporting dysgeusia at 36 months post-treatment [47]. Based on the current evidence on the impact of chemotherapy and radiation on taste bud homeostasis [30, 48], it would suggest that taste bud proliferation is restored following the end of chemotherapy, with a longer recovery period for radiation. Yet, it is not known if taste cells have normal morphology, altered expression of receptors, or have incomplete or distorted reinnervation of the new taste cells following new taste cell renewal. Integrated studies evaluating taste bud morphology, taste cell biology, and psychophysical evaluation will provide a comprehensive understanding of the onset and recovery along with the mechanisms regulating this pathway.

9.5

Smell Loss and Cancer

9.5.1 Overview of the Findings Recent reviews describe the prevalence and factors associated with smell alterations in cancer patients (see [6, 7, 9, 23]. However, some have concluded that changes in smell function are less clear and inconclusive [6, 9]. Cancer patients commonly

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report smell loss, with an estimated 16–49% of chemotherapy patients affected by smell loss [23]. There is greater congruency in methods to assess olfaction. The most common objective method is the Sniffin’ Sticks Olfactory Test®, which can identify increased and decreased function. This test comes with ways to evaluate identification, threshold, or discrimination test; however, some rely on a single method rather than all three. Similarly, to the taste literature, rarely is smell function described in terms of diagnosis of an olfactory disorder; rather, reports the performance of the group. Yet, recent reviews of the psychophysical data assessing smell function of cancer patients, suggest that more information is needed to determine changes in smell function among cancer patients. While several studies report decreased olfactory function [22, 49, 50], many studies report no change in function [51–53], with some reporting increased function [52]. Lack of an association reported could be a result of the method used, the type of treatment received, or the study design. Distorted smell perception is also reported, with changes in the perception of cleaning products, foods while cooking, and fragrances. A qualitative interview study provided an interesting perspective of the challenges faced by chemotherapy patients with an altered sense of smell [54]. One patient described the smell from cleaning detergents as being so strong, smelling of “chemical smells” that these products were thrown out. Another complained that smells typically perceived when cooking or with cleaning products were not able to be detected or identified. Others describe how changes in smell have affected their everyday life, including reduced desire to eat, feeling isolated in social situations, and frustration with the lack of support [54].

9.5.2 Recovery of Smell Loss Few studies have evaluated smell function in long-term cancer survivors. The incidence of smell loss appears to decrease with time following the end of treatment. Among chemotherapy patients that were between 1–7 years post-treatment, there was no evidence of long-term smell dysfunction [46]. Overall, there is limited evidence to conclude the recovery of smell function, with large variations in reports of smell loss. This is likely due to differences in methodologies in evaluating smell loss and with too few studies investigating long-term impact beyond than a year post-treatment.

9.6

Factors that Can Modulate Taste and Smell Function

There are known physiological and personal factors that are known to associate with variability in taste and smell function in healthy adults. Likewise, studies suggest that these and other clinical characteristics are associated with smell and taste function among cancer patients, including incidence, frequency, severity, and duration.

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9.6.1 G  enetic and Biological Variations in Gustation and Olfaction Transduction Pathways Variations in taste sensations are well documented and in some cases, have been linked to genetic polymorphisms in taste receptors [55]. Individual differences in perception and genetic variants are found to associate with variability in liking and intake of foods [56]. This suggests that patients may vary in their baseline perception, making it challenging to compare ratings across groups without accounting for initial baseline variability. It is currently unknown if certain chemosensory genotypes are at greater risk for experiencing taste dysfunction, or whether genotypes are associated with dietary intake, food preferences, or weight loss. One study identified that TAS2R38 diplotype is not associated with cancer risk, and was not associated with intake of bitter fruit or vegetables. However, greater perceived bitterness intensity of phenylthiocarbamide (PTC) may indicate increased cancer risk [57]. Cancer treatment is also thought to alter expression levels for some taste receptors in human fungiform papillae. Patients receiving chemotherapy had altered expression levels of sweet, umami, and bitter taste receptors, with differences in expression levels associated with severity of taste dysfunction [58]. Interestingly not all receptors decreased in expression, which would be expected in the case of reduced taste cells, with some receptors exhibiting increased expression. This suggests that regeneration of new taste cells post-treatment may differentially express taste receptors which can result in continued taste dysfunction and potentially explain persistent taste sensations.

9.6.2 Oral Physiology, Saliva, and Microbiome There is some evidence to suggest that fungiform papillae density is related to taste dysfunction. Radiation treatment appears to cause a significant or complete reduction of fungiform papillae in head in neck patients [59]. This work is supported by recent findings among individuals with taste disorders, reporting a significant reduction in fungiform papillae density compared to healthy controls [60]. However, the study did not report health history of patients diagnosed with a taste disorder, and it is not known if some individuals had previously received cancer treatment. This suggests that individuals with reduced taste function have a lower density of fungiform papillae. This is further supported by evidence in healthy individuals, that shows a relationship between variability in taste function and fungiform papillae density [61]. Both radiation and chemotherapy can damage salivary glands, resulting in reduced saliva production and oral dryness. Dry mouth is a common symptom that can vary in frequency and severity within and across individuals. Radiation can damage salivary glands during treatment, leading to the high prevalence of dry mouth, oral mucositis, and xerostomia. Lower amounts of saliva in the oral cavity are thought to reduce taste perception, as it offers less medium to dissolve food, reducing exposure to taste receptors. Yet, there is conflicting evidence on reduced saliva and taste loss [62]. For head and neck cancer patients receiving radiation, saliva flow is

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significantly reduced shortly after the start of treatment and is not fully recovered even after 12  months post-treatment. However, salivary volume is not associated with patient-reported taste function [29]. Chemotherapy treatment has been shown to alter the salivary constituents. Salivary characteristics such as protein, electrolytes, and metal content significantly differed between chemotherapy patients and healthy individuals and are associated with taste changes [63]. However, it is not clear if taste changes are a result of altered salivary constituents or merely co-occurring. The occurrence and severity of other oral symptoms are often associated with taste loss. This includes poor oral hygiene, infection, post-nasal drip, oral mucositis, oral and the gut microbiome. Chemotherapy alters the microbiome in the mouth and gut [64] and may interact with taste receptors and potentially impact perception and preference. In healthy individuals, there appears to be a relationship between dietary intake, oral microflora, and gustatory function [65]. It is plausible that these changes in microbiota can dysregulate the expression of taste receptors leading to taste changes and altered intake; however, a greater understanding of the pathophysiology regulating expression is needed. It is unknown how these compounds with chemotherapy-induced apoptosis of progenitor cells and the long-term implications on taste bud regeneration following the end of treatment, both in the oral cavity and along the gastrointestinal tract.

9.6.3 Gastrointestinal Symptoms Incidence and severity of taste and smell loss are reportedly associated with gastrointestinal symptoms, such as nausea, vomiting, loss of appetite, constipation, and diarrhea [4, 66]. Incidence of GI symptoms, including constipation, feeling bloated, abdominal cramps, difficulty swallowing, weight gain, weight loss, increased appetite, decreased appetite, mouth sores, dry mouth, vomiting, and nausea were reported more by patients that report changes in taste function, than patients with no changes in taste [17]. There is currently a poor understanding of how chemotherapy may result in these GI symptoms but may be attributed to inflammation and changes in the gut microbiome. This work suggests GI symptoms are experienced more frequently among chemotherapy patients experiencing taste alterations. Additional studies are needed to expand the pathophysiology of these two symptoms and how these symptoms impact food behavior. • I ncidence, frequency, severity, and duration of taste and smell loss may be associated with other factors.

• Individuals with certain genetic differences may be at a greater risk to experience chemosensory dysfunction or may differentially impact food behavior.

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• E  vidence suggests oral physiology impacts chemosensory function but has not been well-studied in the context of cancer-related dysfunction.

• T  here is an association between gastrointestinal symptoms and chemosensory disorders, with a greater incidence of symptoms reported by those experiencing taste alterations.

9.7

 ltered Chemosensory Perception Negatively Impact A Dietary Intake

Alterations in taste and smell function can contribute to patient distress and negatively impact the quality of life. Changes in taste and smell function can result in dietary modifications, such as reduced energy consumption, or reduced intake of individual macronutrients [7, 14], likely due to changes in food preferences [8, 45]. Patients report food tasting bland or has no taste at all, resulting in loss of enjoyment in eating and drinking. Chemosensory changes have been associated with poor appetite, decreased energy and nutrient intake, and changes in food preference [20, 54]. In terms of objective evaluations, taste, rather than smell appears to be important for food intake and dietary preference in cancer patients [7]. For studies that have reported a relationship between taste and intake, taste function has been associated with reduced intake of fat, protein, and overall lower energy consumption; yet several studies have reported no relationship [7]. In regard to altered intake, changes in sweetness followed by bitterness are most often implicated with differences in food behavior and reduced appetite. However, large variability in findings remains, most often attributed to differences in measurements of taste function and evaluation of food liking and intake [7, 14]. While not all studies investigating the link between taste and smell function and food behavior among cancer patients found a relationship, there is growing support that severity of taste and to a lesser extent smell, can have a negative impact on food liking and intake, increasing the risk for malnutrition and poor quality of life [7, 14].

9.8

 iagnosis, Support, and Treatment Options for Cancer D Patients with Taste and Smell Alterations

Diagnosis, treatment options, and clinical care in terms of taste and smell function are inadequate, leaving patients to feel unsupported and unable to seek suitable care. In one study, it was described that patients received the most support from social

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networks and patient communities, rather than from the clinical sector [67]. One reason clinicians may overlook taste and smell complaints is that it is not seen as a life-threatening symptom. Another contributing factor is likely the lack of training and education, diagnostic tools, and treatment options. Without viable and proven solutions for supporting patients suffering from taste and smell problems, it does not seem as pertinent to diagnose chemosensory disorders. Building on these challenges, there are inherent differences in the terminology to describe taste and flavor, adding an additional hurdle for clinicians to overcome in order to support patients experiencing chemosensory alterations [11]. Taste is often used to describe flavor, the act of tasting food, or the hedonic experience. Patients may describe a food or beverage tasting bad, but are not able to describe how the taste changed if it increased in bitterness or decreased in sweetness. Consumers often compare perceptions to prior experiences and can describe if a food or beverage has a similar flavor profile to what they have experienced before. As a clinician, these language barriers and lack of colloquial vocabulary make it difficult to pinpoint the specific sensations and qualities that have been altered for individual patients. To improve patient care and addressing concerns with taste and smell problems, better tools and development of language can facilitate these discussions to document and support patients during short- and long-term consequences of cancer treatment.

9.8.1 B  arriers and Opportunities for Examining Taste and Smell Alterations in Cancer Patients Prior to starting treatment, cancer patients should be informed of the potential changes that may occur to taste and smell function, both in the short- and long term. However, clinicians continue to lack the tools to recommend specific management strategies. Cancer patients suffering from taste and/or smell loss during and following cancer treatment are not receiving support and guidance from clinicians. There is a current need to identify standardized assessment of taste and smell function, evidence-based strategies for patients, and new tools and training for clinicians. There are several reasons why tools have yet to be developed and widely disseminated to clinicians for evaluating taste and smell changes in cancer patients. First, there is no standard for assessing taste or smell function. Standard assessment tools, for both smell and taste, are needed. This will help to identify important symptoms that have an important role in nutrition and health and hopefully open a pathway for communication to describe and understand patients’ experiences. In regard to smell, Sniffin’ Sticks ® are a validated method for identifying smell disorders and can be employed in a clinical setting, yet is not part of routine care for cancer patients. Assessing taste has a few more challenges, with hurdles in access to food grade stimuli and preparation in a food-safe environment for patients. Shelf-­ stable taste assessment tools are needed to more easily assess taste function, such as dissolvable taste strips [68].

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9.8.2 E  xisting Evidence for the Management of Taste and Smell Symptoms There are few evidence-based strategies for managing taste and smell loss. A recent review identified 28 intervention studies for managing taste alterations, with nine enrolling patients undergoing or recently completed treatment for cancer [69]. Six studies evaluated the complaints or sensitivity to taste following intervention with zinc supplementation, with three comparing salivary intervention. Both zinc supplementation and salivary stimulants and substitutes have shown promising results in reducing taste dysfunction, with more work needed to confirm findings in more diverse populations of cancer types and treatments. A recent study observed improvements in taste function among patients who received taste and smell training compared to controls [70]; yet, it is unclear if the repeated familiarity with the compounds among the intervention group impacted their performance at follow-up sessions. Nonetheless, this type of approach may be beneficial to patients as it provides a tool to track symptoms and report changes, providing a common language and start of a conversation for discussing alterations with clinicians and caregivers. This provides a promising first look at the use of this type of treatment for managing taste changes, yet more work is needed to confirm its therapeutic effects. Due to differences in the unique experiences between patients, it is likely that individualized treatment plans will be more successful than blanketed approaches. Proposed strategies to deal with taste changes, such as making dietary changes, may pose hardships and challenges to patients who may not cook their own meals or have the energy or time to try new recipes. Tueros and Uriarte (2018) suggest that the food industry can offer innovative approaches to developing tailored foods and beverages for cancer patients that have unique nutritional needs while also overcoming alterations to taste and smell function [71]. There are opportunities to improve the sensory experience of oral nutritional supplements [72], which are often prescribed by dieticians to help maintain nutrition during treatment. Another approach is by developing novel food products, reducing a patient’s prior familiarity with products, which can help to remove the disappointment patients often experience when encountering foods and beverages which they have prior expectations. Taking into consideration individual needs along with their specific taste and smell changes may lead to more successful interventions to help patients maintain nutrition during chemotherapy and recovery. • In terms of taste and smell evaluation, clinicians do not have adequate tools, leaving clinicians frustrated and patients feeling unsupported.

• There is an immediate need to develop tools for clinicians to support cancer patients to manage their taste and smell dysfunction.

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• Few treatments are available for patients, with even fewer supported by scientific or clinical studies.

9.9

Conclusions and Clinical Implications

Undergoing cancer treatment can be a traumatic experience with many unpleasant side effects. During a period when nutrition can be essential for clinical outcomes, consumption of food and beverages can become a chore, lacking any enjoyment. Cancer patients undergoing chemotherapy and radiation frequently experience changes in smell and taste perception that for a subset of individuals, taking months to years to improve, with some never regaining normal function. Longitudinal studies combining objective and subjective measures to evaluate taste and smell function provide the greatest insight on the timeline of loss and recovery, the extent to which the chemosensory system undergoes changes, and the resulting impact on the patients’ well-being. Changes in smell and taste function are associated with an increased incidence of malnutrition, reduced appetite, weight loss, and poor quality of life. Addressing patient chemosensory symptoms will likely have a positive impact on food behavior, nutritional status, and quality of life. Compared to other problems related to treatment toxicities (e.g., nausea and mucositis), there is a lack of evidence for strategies and treatment options for managing taste and smell alterations. Cancer patients and survivors are in great need of support, as there is currently a lack of information provided to clinicians, and few management strategies and treatments for addressing taste and smell loss during and following cancer treatment. Scientific investigations on quantifying the extent to which treatment impacts taste and smell function throughout treatment are important for advancing our understanding of the impact on chemosensory function. With these advances, along with evidenced-based strategies and improved clinical guidance, cancer patients may experience the enjoyment of foods and beverages and help to promote healthy eating and nutrition during and following cancer treatment. Take-Home Messages • Cancer patients experience reduced taste and smell function during cancer treatment. • Recovery of taste and smell function can occur as soon as 3  months post-­ treatment but some patients may experience a longer recovery period or may never fully return. • Quantifying the extent of altered function has been challenging for clinicians and researchers due to varied methods and diverse patient and clinical characteristics. • A better understanding of the taste and smell loss experienced by cancer patients can help lead to the development of foods and beverages that have desirable flavor profile while meeting essential nutritional requirements.

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63. Mirlohi S, Duncan SE, Harmon M, Case D, Lesser G, Dietrich AM. Analysis of salivary fluid and chemosensory functions in patients treated for primary malignant brain tumors. Clin Oral Investig. 2015;19(1):127–37. 64. Montassier E, Gastinne T, Vangay P, Al-Ghalith G. Bruley des Varannes S, Massart S, et al. chemotherapy-driven dysbiosis in the intestinal microbiome. Aliment Pharmacol Ther. 2015;42(5):515–28. 65. Cattaneo C, Gargari G, Koirala R, Laureati M, Riso P, Guglielmetti S, et  al. New insights into the relationship between taste perception and oral microbiota composition. Sci Rep. 2019;9(1):1–8. 66. Ponticelli E, Clari M, Frigerio S, De Clemente A, Bergese I, Scavino E, et  al. Dysgeusia and health-related quality of life of cancer patients receiving chemotherapy: A cross-sectional study. Eur J Cancer Care (Engl). 2017;26(2). 67. Belqaid K, Tishelman C, Orrevall Y, Månsson-Brahme E, Bernhardson B-M.  Dealing with taste and smell alterations—a qualitative interview study of people treated for lung cancer. PLoS One. 2018;13(1):e0191117. 68. Abarintos RA, Jimenez JC, Tucker RM, Smutzer G. Development of a regional taste test that uses edible circles for stimulus delivery. Chemosens Percept. 2019:1–10. 69. Braud A, Boucher Y.  Taste disorder’s management: a systematic review. Clin Oral Investig. 2020; 70. Von Grundherr J, Koch B, Grimm D, Salchow J, Valentini L, Hummel T, et al. impact of taste and smell training on taste disorders during chemotherapy–TasTe trial. Cancer management and research. 2019;11:4493. 71. Tueros I, Uriarte M. Innovative food products for cancer patients: future directions. J Sci Food Agric. 2018;98(5):1647–52. 72. Galaniha LT, McClements DJ, Nolden A.  Opportunities to improve oral nutritional supplements for managing malnutrition in cancer patients: a food design approach. Trends Food Sci Technol. 2020;

Oral Health and Chemosensory Problems: Clinical Implication and Disease Management

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Miriam Grushka and Nan Su

Learning Objectives 1. To review oral mucosal conditions often seen in the dental office and how these conditions may lead to taste alterations and/or sensory phantoms. 2. To recognize the occurrence of oral chemosensory changes and oral sensory phantoms and review current best management protocols.

10.1 Introduction Taste and sensory changes can result from any insult or injury to the oral mucosa and associated neural tissues (Table 10.1). However, treatment of the mucosal tissue may not be sufficient to resolve a patient’s oral complaints, as taste loss, and the subsequent development of taste and other sensory phantoms, may develop as sequelae of the initial injury. This can be baffling to health care providers due to the lack of clear clinical manifestations. Taste and sensory phantoms, including pain, are often intense [1, 2], and can be very intrusive on day-to-day life, often impacting social and other daily activities. With a better understanding of the sequelae of taste damage at the mucosal level, appropriate treatment is possible and avoids unnecessary and irreversible surgical and dental treatments, which may be done to address inexplicable taste and pain complaints. M. Grushka Toronto, ON, Canada William Osler Health Center, Toronto, ON, Canada Department of Diagnostic Science, Oral Pain and Oral Medicine, Tufts University School of Dental MEdicine, Medford, MA, USA N. Su (*) Toronto, ON, Canada © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021 P. V. Joseph, V. B. Duffy (eds.), Sensory Science and Chronic Diseases, https://doi.org/10.1007/978-3-030-86282-4_10

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Table 10.1  Some possible causes of chemosensory changes Physiological  –  As part of normal aging Oral changes  –  Decreased saliva  –  Mechanical injury to oral mucosa tissue and taste buds  –  Lichen planus  –  Yeast infection  –  Contact sensitivity/inflammation  –  Vesiculobullous disease: Pemphigoid, pemphigus Medication  –  Angiotensin converting enzyme inhibitor  –  Antibiotics  –  Antiarrhythmics  –  Anticholinergics  –  Antidepressants  –  Antihistamine  –  Anti-hyperlipidemic  –  Antimycotic  –  Calcium channel blockers  –  Chemotherapy  –  Diuretics  –  Immunosuppressants  –  Neurologic medication Nerve injury  –  Central changes—Head trauma, tumor, epilepsy  – Peripheral nerve injuries—Chorda tympani injury, glossopharyngeal nerve injury, lingual nerve injury Systemic disorder  –  Sjogren’s syndrome  –  Hypertension  –  Diabetes mellitus  –  Renal disease  –  Liver disease  –  Thyroid disease  –  Anorexia  –  Other  –  Head and neck radiation  –  Smoking  –  Alcohol

10.2 Overview of Taste Anatomy Taste is detected via taste receptor cells in taste buds on the tongue, soft palate, pharynx, larynx, epiglottis, uvula and first one third of the esophagus, and has been identified in other locations including the gastrointestinal tract and the respiratory system [3, 4]. The fungiform papillae at the tongue tip contain only a few taste buds; the foliate papillae at the posterior lateral edges of the tongue contain approximately a dozen taste buds; and the circumvallate papillae located at the posterior tongue contain approximately one thousand taste buds. The filiform papillae do not contain

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taste buds but perceive tactile sensation [4, 5]. Many taste receptors have been identified, including ion channels which are thought to play a role in the detection of sour and salty taste, and G-protein coupled receptors, which detect sweet, bitter and umami taste, with at least 25 bitter taste receptors identified in humans [4]. The integrity of taste buds and taste receptors require the presence of healthy and disease-free mucosal tissue. Damage to taste intraorally can lead to often confusing and unexpected clinical consequences including complaints of taste loss, taste phantoms, as well as other oral sensory phantoms, including burning pain. Taste signals are carried by the chorda tympani and the greater superior petrosal branch of the facial nerve, the lingual branch of the glossopharyngeal nerve, and the superior laryngeal branch of the vagus nerve, and their projections, into the thalamus and cortex. The trigeminal nerves carry somatosensory inputs, i.e., pain, coolness, sharpness, from the tongue and oral cavity [3], with many of these sensation involved in taste perception.

10.3 T  aste, Burning Mouth, and Other Oral Sensory Phantoms Burning mouth syndrome (BMS) is a condition in which patients complain of oral sensory changes, including burning pain, dryness, and taste changes without any obvious clinical findings (Fig.  10.1). It has been classified into primary or idiopathic, and secondary, which can be associated with local or systemic clinical findings, including lesions, allergies, infection, medication, trauma, etc. [6, 7]. It predominantly affect women in greater ratio to men, reported to be 5:1 to 7:1, and occurs in 0.7% of the general population, with some study reporting up to 15% of the population depending on the diagnostic criteria. BMS is reported to occur most Fig. 10.1  Burning Mouth Syndrome (BMS)

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commonly in postmenopausal women in the fifth to sixth decade of life, with prevalence increasing with age [6, 8]. The onset of BMS is often idiopathic but in some patients, local irritation of the tongue and oral mucosa from dental disease, infections, lesions, chemical or mechanical irritation can be present or be reported by patients to precede the onset of BMS [6, 9, 10]. Systemic changes such as vitamin B12 and zinc deficiency, neuropathy, and some classes of medications have also been reported to be linked to development of BMS [7] (Fig. 10.1). Patients frequently present to their dentist or physician with a complaint of severe burning in their mouth, as if they had burnt their mouth on hot tea or coffee. The burning is commonly associated with a feeling of oral pastiness and dryness without a noticeable decrease in salivary flow. Taste complaints are common and have been reported in as high as 70% of patients. These complaints can include loss of taste and/or phantoms tastes, often described as metallic or bitter and has been demonstrated objectively with electrophysiological and psychophysical testing with variable findings of decreased sensitivity to salt, sweet, sour, and bitter, especially at the tongue tip [2, 11–13]. Patients may also describe other odd sensations within the oral cavity such as tingling, numbness, and swelling of their gums, cheeks and/or tongue, a sensation of foreign body in gums or tongue, and globus, a feeling of something stuck in the throat. The burning most often occurs at the tongue tip, the lateral borders of the tongue, anterior hard palate, and mucosal lips, but can occur anywhere in the oral cavity. Symptoms often increase in intensity over the day and can be reduced or entirely suppressed by having intraoral tactile or taste stimulation, such as with food, cold liquids, gum, or candy. For many patients, however, spicy and hot foods may cause more discomfort [1, 2]. Without treatment, pain has been reported by patients to start in the weak to moderate range upon waking up and progressively increase over the day to the very strong to strongest imaginable range by bed time [2]. These constant and intrusive symptoms can be very distressing and BMS patients have been reported to be more depressed, anxious, to have decreased social function, and in some cases, when the pain is severe and disturbing enough, to engage in self-­harm and suicidal tendencies [14]. Bartoshuk et al. [15] proposed that BMS may result from injury to the chorda tympani leading to a central loss of inhibition phenomenon on the trigeminal nerve and the glossopharyngeal nerve. The chorda tympani carries taste to the anterior two-thirds of the tongue in addition to providing parasympathetic innervation to the submandibular and sublingual salivary glands and the minor salivary glands at the floor of the mouth. Local anesthesia of the chorda tympani or injury of the chorda tympani after middle ear surgery can lead to development of BMS symptoms, decreased taste sensitivity, as well as decreased unstimulated flow and normal stimulated flow [16–18]. Oral dryness and decreased unstimulated flow in BMS as well as sialometrical analysis of saliva, which shows elevation of Na, total protein, albumin, IgA, IgG, IgM, and lysozymes similar to those seen in patients with dry mouth [19, 20], suggest that the dryness in BMS may be related to both sensory phantoms, as well as changes in saliva, secondary to parasympathetic innervation to some of the major and minor salivary glands.

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Central and peripheral changes in nerve tissues have also been demonstrated and may lead to an increased sensitization to pain stimuli. Central fMRI of BMS patients demonstrates alterations in cerebral blood flow and gray matter volume in pain-­ related regions of the brain, including the anterior cingulate cortex, medial orbitofrontal cortex, pars orbitalis, insula, and thalamus. Small fiber neuropathy has also been reported in BMS, with reduction in both myelinated and unmyelinated fibers in symptomatic areas on the tongue. In addition, increased transient receptor potential vanilloid channel type 1 (TRPV-1) and voltage gated sodium channel 1 and 8 (Nav 1, 8) associated with nociception, have been found to be elevated in the epithelial nerve fibers in BMS. Diagnosis of BMS, to date, is based on patient history of sensory changes including burning mouth, taste changes, and mouth dryness, and normal clinical examination, after treatment of any tissue changes noted [7] (see below). Often, patients will not have a clear idea on what has happened. Sometimes, the onset can be sudden with no precipitating events. At other times, it can follow dental treatment, with or without injection of local anesthetic, prior to the onset of burning mouth pain. Clinically, salivary flow measurement and spatial taste testing may help in the diagnosis BMS, since unstimulated salivary flow, but not stimulated flow, has been reported to be decreased in BMS. Spatial taste testing may demonstrate decreased taste response often in the area of fungiform papillae and less often at the circumvallate papillae, with increased response to noxious stimuli [2, 20, 21]. More sophisticated testing can include assessment of thresholds to cold, hot, and touch [7], but clinically these are not yet generally used for diagnosis.

10.4 Taste and the Oral Cavity Despite the important association between taste loss or damage and various oral complaints, including burning pain, taste phantoms, and dry mouth, the literature about the impact of specific oral mucosal conditions or diseases on taste perception is sparse. This can leave both patients and their health care providers baffled, when sensory phantoms, including taste phantom, persist once oral mucosal conditions have been successfully treated. Some common oral mucosal changes in dentistry that can lead to the onset of taste loss are reviewed below.

10.4.1 Dry Mouth, Candidiasis (Yeast) Infection, and Taste Salivary flow can be decreased as a result of medication, infection, head and neck radiation, systemic disease such as amyloidosis, untreated diabetes, Parkinson’s disease, and autoimmune conditions such as Sjogren’s syndrome and scleroderma (Fig. 10.2 a–d). Saliva is needed to maintain oral and dental health and is essential in buffering oral pH, engaging in antimicrobial activity, removing residual food particles from teeth, and carrying tastants to taste receptors. Patients with a dramatic loss of salivation, such as patients with severe Sjogren’s syndrome, often complain

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Fig. 10.2 (a) Dry mouth post radiation therapy. (b): Dry mouth in a patient with Parkinson. (c): Sjögren’s Syndrome with oral Candida infection. (d): Sjögren’s Syndrome. (e): Candidiasis. (f–g): Severe Candidiasis

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of chemosensory changes, including metallic, sour, bitter, or unpleasant taste, and burning of the tongue during eating, likely to be the result of inflammatory response that may interfere with normal taste transduction and taste bud cell turnover [22]. Hyposalivation such as in primary Sjogren’s syndrome, results from infiltration of salivary glands by auto-activated B cells leading to salivary gland destruction and can predispose to the onset of oral yeast infection [23]. Candida albicans is part of the normal oral flora and the most frequent cause of infection in patients with decreased salivary flow. It can affect any part of the oral cavity including the tongue. Candida can adhere to host cell surface and penetrate the epithelium and damage to local tissues [24], causing irritation, abnormal sensation, or pain on the tongue, as well as decreased sensitivity to taste. The change in taste is likely associated with structural changes to the taste buds from the inflammation and atrophy of the tongue, or as a result of heavy coating on the tongue leading to a foul taste [25, 26]. Candida lesions can present in different forms (Table 10.2) but lead to similar changes to tongue tissue (Fig. 10.2 e–g). Topical antifungal therapy, such as rinsing with Nystatin oral suspension, can be effective in uncomplicated localized candidiasis. Systemic antifungal Table 10.2  Oral presentation of lesions of yeast infection and oral lichen planus Candidiasis Pseudomembranous Candidiasis

Erythematous candidiasis Chronic erythematous candidiasis Chronic hyperplastic candidiasis Angular Cheilitis Median rhomboid glossitis Chronic Mucocutaneous candidiasis Oral lichen planus Reticular lesions

– White, soft, slightly elevated plaques, which consists of tangled masses of fungal hyphae, epithelial cells, necrotic debris, keratin, leukocytes, fibrin, and bacteria – The plaques can be wiped away, leaving an erythematous area – Result of broad-spectrum antibiotic therapy, corticosteroids, predisposed condition such as diabetes – Constant painful erythematous area along central papillary atrophy of the tongue –  Often associated with dentures –  Reddening of the tissue beneath the denture –  Chronic firm white plaques, homogenous or nodular –  Can be premalignant –  Erythematous lesions at the angles of the mouth –  Chronic condition – Symmetrically shaped lesion on the midline of the dorsum of tongue –  Infection of the mucous membranes, skin, and nails

–  Most common form – Often asymptomatic, multiple papules with small, raised, white-gray, lacy lesions Erosive lesions – Erythema, ulceration or pseudomembrane formation, with reticular keratotic striae surrounding the lesions Plaque oral lichen planus – White, homogenous, slightly elevated, and multifocal smooth lesions –  Commonly affect tongue and buccal mucosa Bullous and papular –  Rare in the oral mucosa lesions

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medication, such as fluconazole, may be indicated in more severe infection [25], or infection resistant to topical therapy. Once the Candida infection is eradicated, the tongue architecture returns to normal and taste often fully recovers [26], despite ongoing oral dryness. However, in patients with chronic dry mouth or other predisposing factors, recurrence of infection is common, and treatment may be required on a longer-term basis to keep the tissue free from infection. In patients with hyposalivation, ideal management when medically feasible with is stimulation of salivary gland tissue with cholinergic medication, including bethanechol, pilocarpine, and cevimeline. If enough salivary gland tissues remain, and if the medications are successful, oral tissues can return to normal, usually with remission of tissue and taste changes. Other treatments to keep the oral mucosa comfortable, including artificial saliva, oral rinses, sugar-free gums and mints, are more palliative in nature but are usually less effective in keeping mucosal tissue and its nerve component healthy [27, 28].

10.4.2 Oral Lichen Planus Oral lichen planus, a T-cell mediated chronic inflammatory oral mucosa disease with idiopathic etiology, is the most common non-infectious oral mucosal disease. It affects women more than men. Lesions of oral lichen planus (Table 10.2) commonly affect the buccal mucosa, tongue, and gingiva (Fig. 10.3). It is considered a premalignant condition with transformation rate reported to be up to 2%. On histology, dense subepithelial lymphohistiocytic infiltration, intra-epithelial lymphocytes and degeneration of basal keratinocytes, parakeratosis, acanthosis, and rete peg formation can be seen. Post-inflammatory pigmentation, diffuse brown, or black pigmentation, can occur in areas of lesions [29, 30]. Clinically, patients complain of roughness of mucosal tissue, sensitivity to hot or spicy food, oral mucosal pain, red or white patches, or oral ulceration [30]. Suter et al. [31] assessed taste in patients with oral lichen planus and found the ability to detect tastants was decreased, especially for sour. In hyperkeratotic plaque lesions, taste change may occur when the hyperkeratotic lesions cover the dorsal surface of the tongue, including the fungiform papillae. Topical corticosteroids are first-line treatment for oral lichen planus; however, long-term use may lead to adrenal suppression and secondary candidiasis, oral dryness, bad taste, and mucosal atrophy. Topical calcineurin inhibitors such as tacrolimus and retinoids are alternatives to steroids. Systemic steroids and immunosuppressive drugs such as mycophenolate mofetil (CellCept), azathioprine, and methotrexate have been suggested to treat widespread and severe oral lichen planus. Reticular lesions that are asymptomatic generally require only monitoring for changes [30]. Successful treatment of lichen can lead to return to normal of taste. Clinically, patients with reticular forms of oral lichen planus can present with oral burning, taste disturbance, xerostomia, oral itching, sialorrhea, and a feeling of globus, symptoms that respond to treatment for BMS (see below) [32].

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Fig. 10.3 (a, c, d) Oral Lichen Planus. (b) Oral Lichen Planus with BMS

10.4.3 Oral Contact Sensitivity Contact sensitivity is a delayed hypersensitivity reaction (type IV hypersensitivity reaction) that is primarily T-cell medicated. It occurs when patients become sensitized to a specific antigen. T-cell mediated macrophage infiltration of tissues may cause damage and necrosis of the tissue, leading to erythema and edema. In the oral cavity, reactions can manifest 24–72  hours after antigen introduction and can be localized or diffuse. Contact sensitivity reaction can occur to medication, chemicals and compounds in cosmetics, dental materials such as amalgam, composite, dental acrylic, and metals including cobalt and nickel, fragrances, food additive and ingredient in toothpaste. Generalized erythema and edema is common, and some reactions can present lichenoid like lesions, vesicles, and bullae (Fig.  10.4). Dental prosthesis contact sensitivity can present with changes in areas where the prosthesis contacts the oral mucosa [9, 30, 33].

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Fig. 10.4 (a–d) Contact Sensitivity

Contact sensitivity can manifest clinically with taste complaints, burning pain, dryness of mucosa, and numbness on the sides of tongue [34]. Delayed contact sensitivity reaction has been found to be present in up to 67% of burning mouth syndrome patients with the most common allergens found to be foods/flavor and metals in dental material or restorations [9]. Diagnosis of contact sensitivity is done with patch testing and therapy is by topical steroid preparations [33]. Avoidance of antigens may also help to reduce or resolve any oral discomfort [9]. The diagnosis of a contact sensitivity causing BMS complaints, including taste changes or phantoms, can be made only if removal of the allergen also leads to remission of the oral complaint; the findings may otherwise be incidental.

10.4.4 Geographic Tongue (Benign Migratory Glossitis) Geographic tongue (GT) can present as annular oral lesions with atropic centers and white margin ranging between 0.5 and 1.5 cm on the tongue and oral mucosa and is associated with infiltration of inflammatory cells and found in 1.8% up to 8.5% of the general population. These lesions heal and recur in the same or different locations, giving it a “migratory” pattern [35–37]. Fissured tongue is a normal variant presenting with fissures and grooves at the central and lateral aspects of the tongue. It is often more commonly found in patients with geographic tongue [5] (Fig. 10.5).

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Fig. 10.5 (a, c) Geographic tongue. (b) Geographic tongue with BMS

On histopathology, subepithelial infiltration of neutrophils, epithelial acanthosis with elongation of rete ridges, acantholysis, parakeratosis, necrotic cells in the surface layer in the white margin, with predominantly T-cell lymphocyte infiltration, suprapapillary hypertrophy and vascular ectasia in the atropic center are seen [38]. Geographic tongue is typically benign and asymptomatic and an incidental finding during dental visits, and usually requires no treatment; however, some patients may report burning pain or sensitivity to foods, especially in areas of atrophy [5, 39] or constant burning pain and taste changes in the absence of eating [10]. Geographic and fissured tongue have been found in up to 27% of patients with BMS [10], and is thought to be a risk factor to the development of BMS [21], perhaps through local tissue changes as a result of inflammation and epithelial nerve injury [35]. GT patients often complain of burning pain similar in intensity with patterns of increased pain intensity over the day as seen in BMS. The location of the lesions often does not correspond to location of burning pain. GT patients with BMS compared to BMS patient without GT demonstrated better perception on spatial taste testing for salt, sweet, and bitter at the fungiform papillae for salt, sweet, sour, and bitter at the circumvallate papilla. Despite similar reports of burning pain through the day, they also showed a significantly higher response to ethanol, at both

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the fungiform and circumvallate papillae, which may be due to the presence of tongue inflammation in GT [21]. In patients with geographic tongue, asymptomatic lesions do not require any treatment. If symptomatic, some efficacy has shown with topical corticosteroids, antihistamines, cyclosporine, vitamin A, zinc, acetaminophen, and topical tacrolimus. Avoidance of irritating agents has been recommended to avoid exacerbation of symptoms [38]. If the treatment of the inflammation is associated with geographic tongue is not successful in pain reduction, the use of the medication for BMS (see below) may be more effective.

10.4.5 Viral Infection Viral infection may damage the cells in the tongue directly (Fig. 10.6). The inflammatory cytokines may be responsible for damaging the taste receptors and altering their transductions or expression and taste bud cell turnover rate. Upper respiratory tract infection has been associated with both smell and taste loss, and more than 200 viruses, that can cause upper respiratory tract infection, have been shown to impact chemosensation [4]. Several viral infections of the tongue may have a more specific presentation which may help facilitate diagnosis [40] (Table 10.3). Treatment with a

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Table 10.3  Oral viral infection presentation Virus HIV Epstein–Barr virus with immunosuppression Herpes simplex virus

Varicella zoster virus

Human papillomavirus

Coxsackievirus

Condition Oral hairy leukoplakia

Presentation Hyperkeratotic white plaques on lateral aspect of tongue. Do not wipe off. No malignant potential Often asymptomatic Acute herpetic Grouped vesicles that rupture Gingivostomatitis and form shallow red ulcer Often accompanied by signs of systemic infection (i.e., fever, tender adenopathy) Herpetic Tenderness and pain in geometric glossitis fissured areas Varicella zoster Involvement of mandibular infection branch of trigeminal can cause blisters and ulcers of the tongue, floor of mouth, mandibular gingival and buccal mucosa. Can be accompanied by odontalgia, dysgeusia, ageusia Oral verruca Commonly on lips, tongue, vulgaris gingiva. Exophytic, sessile or pedunculated lesions Condyloma Can occur on lips, tongue. Acuminata Presentation same as other HPV lesions

Herpangina

Hand-foot-mouth disease

Oral lesion can occur on palate, uvula, posterior pharyngeal wall, tonsils Clusters, progress to macular, popular, and vesicular stage Then diffuse erythema and punctate erosion in posterior oral cavity Highly transmissible Vesicular sores that coalesce into symptomatic lesion on tongue, palate, and buccal mucosa

Treatment None required Topical retinoids, podophyllin, acyclovir Systemic antiviral Systemic antiviral with 72 hours of onset

Non required Removal by cryosurgery, electrosurgery, carbon dioxide Excision is suspicious presentation Self-limited and generally need supportive therapy Anesthetic rinse for oral discomfort

antiviral medication including acyclovir, famciclovir, and valacyclovir may be effective for some viral infections in the herpetic family. For many others, e.g., Coxsackie virus, no specific treatment is available. This topic in the age of Coronaviridae infection (COVID 19) has demonstrated the profound impact that viral infection may have on chemosensation.

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10.4.6 Post-Dental Nerve Injury Injuries to the inferior alveolar nerve, the trigeminal nerve, and especially the lingual nerve, as well as the chorda tympani, which travels with the lingual nerve, can occur with endodontic treatment, local anesthetic, and dentoalveolar surgery such as implants. Nerve injury related to implants is reported in the literature to range from 0 to 13% [41]. In dentistry, nerve injury typically occurs due to nerve compression or stretching, which have the potential to recover. If the injury causes the nerve to be cut or severely damaged, such as during drilling and/or placement of implants, there may be permanent injury [41]. Lingual/chorda tympani nerve injury is well documented with mandibular third molar extraction because of the close proximity of the course of the lingual nerve and the tooth, especially when distobuccal bone must be removed to extracted tooth [42]. Lingual nerve injury can result in the loss of sensation, including taste, to the ipsilateral anterior tongue and lingual mucoperiosteum [42]. Although in most cases, the sensory disturbance is temporary, persistent sensory changes have been reported in up to 0.37% of cases [43]. Damage to nerve tissue can lead to very debilitating and distressing sensory phantoms including burning, dryness and taste changes and taste phantoms amongst others.

10.5 Diagnosis of Taste Change and Oral Sensory Phantoms Examination for patients with complaints of taste or sensory changes includes assessment of the mucosal tissue for disease and inflammation, infection or dryness, taste and trigeminal perception and smell perception. Inflammation can cause taste changes by disrupting cell turnover in taste buds and interfere with signal transduction and transmission. To differentiate between a subjective feeling (i.e., sensory phantom) of dry mouth, and dry mouth due to a decrease in salivary flows, daytime chairside salivary flow measurement can be carried out. Oral pH can be measured with pH-indicator strips to assess for proper function of salivary, which includes buffering oral pH. Unstimulated flow can be measured by asking patients to expectorate into a test tube for 5 min at rest. The same process is repeated to measure stimulated flow, but patients are asked to expectorate while they chew or hold a piece of unflavored gum or in their mouth as stimulation. Accepted unstimulated flow rates above 0.1 ml/min and simulated flow rates above 0.2 ml/min are considered within the range of normal [44] (Fig. 10.7). Taste testing can be carried with a number of validated assessments. Clinically, spatial taste testing is done with application of suprasaturated solutions of salt (1 M NaCl), sweet (1 M sucrose), sour (0.032 M citric acid), and bitter (0.001 M quinine hydrochloride) applied as a droplet to the fungiform papillae at the tongue tip for chorda tympani function, and to the circumvallate papillae on the posterior for glossopharyngeal function, to determine the presence, location, and pattern of taste loss.

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Fig. 10.7 Measuring salivary flows

Fig. 10.8  Spatial taste testing

Other areas, including the foliate papillae, the soft palate and whole mouth testing with swallowing, can also be done. Patients are asked to rate taste intensity on a gLMS scale [45] with the descriptors “barely detectable,” “weak,” “moderate,” “strong,” “very strong,” and “strongest imaginable” at semi-logarithmic distance corresponding to a scale of 1–100 [46]. Trigeminal sensation which carries noxious stimuli, is done with application of 50% ethanol to the same areas (Fig. 10.8). Other methods for clinical testing are also available, including taste strips that can be saturated with salt, sweet, sour, and bitter solutions at different concentration to test for both taste detection and taste threshold [47]. For assessing taste in a clinical setting,

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Fig. 10.9  Sniffin’ sticks

testing must be relatively straightforward and employable. Electrogustometry testing can be used to determine electrical taste threshold; however, these are usually only performed for research studies [11, 48, 49]. Patients with taste changes also benefit from having smell testing carried out to determine if the loss of taste or taste phantom derive from the inability to detect the five main tastants or also include smell loss, resulting in the loss of ability to detect flavor. Several validated smell testing kits exist, including The Smell Threshold Test and University of Pennsylvania Smell Identification Test, Odor Memory/ Discrimination Test and Sniffin’s Sticks test which can be used to test for orthonasal olfaction [50, 51] (Fig. 10.9). Retronasal olfaction can be tested by using flavored agents such as Jelly Beans or candy and asking patient to first pinch their nose and chew the stimulus, followed by unplugging the nose to allow the odorants to reach the olfactory mucosa. Other clinical diagnostic aids may be indicated to help assess and diagnose other cause of taste changes, including patch testing used to identify type IV allergic reaction and contact hypersensitivity. Allergen preparations are applied onto patches which are placed on the skin of the back. The results of the patch is read at 48 hours and then at 96 hours [9]. Patch testing can test for sensitivities to foods additives, cosmetic ingredients, dental material amongst others, which can cause changes to mucosal tissue and are usually carried out by dermatologist or allergists.(Fig. 10.10). Swabs can be done to look for fungal or bacterial infection. Biopsy may be performed for diagnosis when clinical presentation of oral lesion does not yield a clear diagnosis. If systemic factors are suspected in causing taste loss or taste changes, laboratory test and imaging studies such as MRI or CT may be helpful to rule out central and peripheral pathology causing mucosal changes may be of benefit. Blood tests can include tests for nutritional changes and autoimmune panel such as antibodies to Ro/SSA or La/SSB antigens, can help to diagnose systemic disorders such as scleroderma, systemic lupus, Sjogren’s syndrome, all of which may cause oral dryness and impact mucosa tissues and taste.

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Fig. 10.10  Patch testing for delayed contact sensitivity (a) material trays (b) preparation of patches (c) patient with patches applied

10.6 Treatment of Taste and Sensory Changes If examination of the oral cavity and medical history show mucosal changes that may account for the taste and oral sensory changes, then treating these mucosal changes often leads to resolution of symptoms. However, even when primary oral changes are treated and have resolved, some patients can be left still with burning pain, taste phantoms, taste confusion, and other oral sensory changes. Currently, the medication of choice for taste, burning, and other oral sensory phantoms are topical or systemic medications that enhance the inhibitory effect on neurons, including clonazepam, GABA analogues such as pregabalin or gabapentin, and tricyclic antidepressants [52]. Medications that have been reported in literature to be effective in treating BMS and associated taste phantoms include clonazepam, gabapentin, pregabalin, tricyclic antidepressants, selective serotonin reuptake inhibitors, zinc, alpha lipoic acid [7, 53, 54] (Table 10.4). Topical and systemic clonazepam have been reported to be most efficacious single drug treatment in symptoms reduction, but combination therapy with clonazepam was the most effective in reducing symptoms of BMS [2, 52].

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Table 10.4  Treatment modalities for BMS Topical treatment

Systemic treatment

Others

- Artificial sweeteners - Benzydamine hydrochloride - Hot pepper and water (1:1 solution) - Local anesthesia - Low-level laser therapy - Salivary substitutes - Sucking on clonazepam tablet - Tabasco in water (1:2 solution) for burning pain - Topical aloe vera and tongue protector/tactile stimulation - Topical antidepressant: Doxepin as analgesic - Topical antifungals - Topical capsaicin cream - Alpha lipoic acid - Anticonvulsants: Gabapentin, pregabalin, topiramate - Antihistamine: Lafutidine - Antipsychotic: Amisulpride, levosulpiride - Anxiolytics: Clonazepam, diazepam - Dopamine agonist: Pramipexole - Monoamine oxidase inhibitor: Moclobemide - Salivary stimulant: Pilocarpine, cevimeline - Systemic capsaicin 0.25% capsule - Serotonin reuptake inhibitor (SSRI): Sertraline, paroxetine, duloxetine - Serotonin-norepinephrine reuptake inhibitor (SNRI) - Tricyclics antidepressants (TCA): Amitriptyline nortriptyline - Vitamin B, folic acid, iron, zinc - Natural remedies: Catuama, St. John’s wort - Acupuncture - Cognitive behavior therapy - Bruxism appliance

Clonazepam is a benzodiazepine. It primarily binds γ-aminobutyric acid (GABA) receptor centrally and enhances GABA activity on the brain. Both topical and systemic clonazepam are effective in reducing symptoms of BMS. Topical clonazepam can be absorbed by the oral mucosa and the levels can rapidly build up and exert similar adverse effects as patients on systemic clonazepam, the most common being sedation [53], suggesting that topical clonazepam may also act centrally. A low dose of clonazepam of 0.25–0.5 mg per day can be effective in reducing symptoms in BMS including taste and taste phantoms complaints [2]. Some studies suggest that even in patients with normal zinc levels, supplementing with zinc can improve symptoms in BMS, because of its role in intercellular signaling and in proper development of oral tissues, with reports of improvement of taste function in dysgeusic patients. Alpha lipoic acid has also been reported to be effective in improving taste alterations and BMS, which may be due to its antioxidant effect; however, results have been mixed. Even without treatment, the literature reports that 28% of patients will eventually have spontaneous improvement over a number of years in their symptoms, 19% will report worsening of their symptoms, and half will report no changes in their symptoms [55]. With successful treatment, pain reduction is significant for both for

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minimum (usually in the morning) and maximum pain intensity (usually by late afternoon). Overall, pain reduction can occur “relatively” quickly once an optimal medication protocol is found, averaging approximately 5 months for significant reduction in pain and likely associated taste phantoms and oral dryness. In BMS patients with pain reduction, taste, especially salt and bitter perception at the tip of the tongue and salt perception at the circumvallate papillae have been found to improve significantly, although the mechanism of repair is unclear [2].

10.7 Conclusions Taste changes can occur as a result of normal aging or from injury to taste buds or their innervation, hyposalivation such as in Sjogren’s syndrome, medication, inflammation, or trauma that may damage the oral tissues. Lingual nerve and chorda tympani damage can occur from dental surgery or local anesthetic injections, middle ear surgery and less frequently, glossopharyngeal injury, from tonsillectomy or dental surgeries. Damage to the taste system at the level of taste buds and taste receptors may lead to the development of phantom sensations such as bitter, salty, or metallic taste, burning, or dryness as seen in BMS. The origin of these changes secondary to taste loss may be due to a loss of inhibition phenomenon centrally on trigeminal activity, without affecting mechanosensation of the tongue or oral cavity. Treatment of primary oral conditions can often lead to resolution of taste alterations and phantoms sensation in some patients. However, other patients may continue to complain of oral discomfort including pain, taste alterations and taste phantoms, even after successful mucosal treatment. In these patients, treatment with medications for BMS, especially clonazepam, and additional adjunctive medications, can reduce or even resolve complaints of taste and other oral sensory changes. Key Concepts • Burning mouth syndrome (BMS) is a condition in which patients complain of oral sensory changes, including burning pain, dryness, and taste changes without any obvious clinical findings. • Oral lichen planus is a T-cell mediated chronic inflammatory oral mucosa disease with idiopathic etiology, is the most common non-infectious oral mucosal disease. • Contact sensitivity is a delayed hypersensitivity reaction (type IV hypersensitivity reaction) that is primarily T-cell medicated occurring when patients become sensitized to a specific antigen. • Geographic tongue (GT) can present as annular oral lesions with atropic centers and white margin ranging between 0.5 and 1.5 cm on the tongue and oral mucosa and is associated with infiltration of inflammatory cells and found in 1.8% up to 8.5% of the general population.

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References 1. Grushka M, Sessle BJ, Miller R. Pain and personality profiles in burning mouth syndrome. Pain. 1987;28(2):155–67. 2. Su N, Poon R, Liu C, Dewan C, Darling M, Grushka M.  Pain reduction in burning mouth syndrome (BMS) may be associated with selective improvement of taste: a retrospective study. Oral Surg Oral Med Oral Pathol Oral Radiol. 2020;129(5):461–7. 3. Bromley SM.  Smell and taste disorders: a primary care approach. Am Fam Physician. 2000;61(2):427–36, 38. 4. Risso D, Drayna D, Morini G. Alteration, reduction and taste loss: main causes and potential implications on dietary habits. Nutrients. 2020;12(11). 5. Mangold AR, Torgerson RR, Rogers RS III.  Diseases of the tongue. Clin Dermatol. 2016;34(4):458–69. 6. Coculescu EC, Tovaru S, Coculescu BI. Epidemiological and etiological aspects of burning mouth syndrome. J Med Life. 2014;7(3):305–9. 7. Klasser GD, Grushka M, Su N. Burning mouth syndrome. Oral Maxillofac Surg Clin North Am. 2016;28(3):381–96. 8. Kolkka-Palomaa M, Jaaskelainen SK, Laine MA, Teerijoki-Oksa T, Sandell M, Forssell H. Pathophysiology of primary burning mouth syndrome with special focus on taste dysfunction: a review. Oral Dis. 2015;21(8):937–48. 9. Lynde CB, Grushka M, Walsh SR. Burning mouth syndrome: patch test results from a large case series. J Cutan Med Surg. 2014;18(3):174–9. 10. Ching V, Grushka M, Darling M, Su N. Increased prevalence of geographic tongue in burning mouth complaints: a retrospective study. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114(4):444–8. 11. Nasri-Heir C, Gomes J, Heir GM, Ananthan S, Benoliel R, Teich S, et al. The role of sensory input of the chorda tympani nerve and the number of fungiform papillae in burning mouth syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;112(1):65–72. 12. Just T, Steiner S, Pau HW. Oral pain perception and taste in burning mouth syndrome. J Oral Pathol Med. 2010;39(1):22–7. 13. Grushka M. Clinical features of burning mouth syndrome. Oral Surg Oral Med Oral Pathol. 1987;63(1):30–6. 14. Kontoangelos K, Koukia E, Papanikolaou V, Chrysovergis A, Maillis A, Papadimitriou GN.  Suicidal behavior in a patient with burning mouth syndrome. Case Rep Psychiatry. 2014;2014:405106. 15. Bartoshuk LM, Snyder DJ, Grushka M, Berger AM, Duffy VB, Kveton JF.  Taste damage: previously unsuspected consequences. Chem Senses. 2005;30(Suppl 1):i218–9. 16. Pellegrino R, Hummel T. Chemical, electrical and tactile sensitivity changes after middle ear surgery. Ann Otol Rhinol Laryngol. 2020;129(6):572–7. 17. Schobel N, Kyereme J, Minovi A, Dazert S, Bartoshuk L, Hatt H.  Sweet taste and chorda tympani transection alter capsaicin-induced lingual pain perception in adult human subjects. Physiol Behav. 2012;107(3):368–73. 18. Mandel L.  Hyposalivation after undergoing stapedectomy. J Am Dent Assoc. 2012;143(1):39–42. 19. Nagler RM, Hershkovich O. Sialochemical and gustatory analysis in patients with oral sensory complaints. J Pain. 2004;5(1):56–63. 20. Poon R, Su N, Ching V, Darling M, Grushka M. Reduction in unstimulated salivary flow rate in burning mouth syndrome. Br Dent J. 2014;217(7):E14. 21. Su N, Poon R, Liu C, Dewan C, Darling M, Grushka M.  Taste and pain response in burning mouth syndrome with and without geographic tongue. J Oral Facial Pain Headache. 2020;34(3):217–21. 22. Šijan Gobeljić M, Milić V, Pejnović N, Damjanov N.  Chemosensory dysfunction, oral disorders and oral health-related quality of life in patients with primary Sjögren’s syndrome: comparative cross-sectional study. BMC Oral Health. 2020;20(1):187.

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23. Serrano J, López-Pintor RM, Ramírez L, Fernández-Castro M, Sanz M, Melchor S, et al. Risk factors related to oral candidiasis in patients with primary Sjögren’s syndrome. Med Oral Patol Oral Cir Bucal. 2020;25(5):e700–5. 24. Lewis MAO, Williams DW.  Diagnosis and management of oral candidosis. Br Dent J. 2017;223(9):675–81. 25. Patil S, Rao RS, Majumdar B, Anil S. Clinical appearance of oral candida infection and therapeutic strategies. Front Microbiol. 2015;6:1391. 26. Sakashita S, Takayama K, Nishioka K, Katoh T.  Taste disorders in healthy “carriers” and “non-carriers” of Candida albicans and in patients with candidosis of the tongue. J Dermatol. 2004;31(11):890–7. 27. Ramos-Casals M, Brito-Zerón P, Bombardieri S, Bootsma H, De Vita S, Dörner T, et al. EULAR recommendations for the management of Sjögren’s syndrome with topical and systemic therapies. Ann Rheum Dis. 2020;79(1):3–18. 28. Al Hamad A, Lodi G, Porter S, Fedele S, Mercadante V.  Interventions for dry mouth and hyposalivation in Sjögren’s syndrome: a systematic review and meta-analysis. Oral Dis. 2019;25(4):1027–47. 29. Kurago ZB. Etiology and pathogenesis of oral lichen planus: an overview. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;122(1):72–80. 30. Alrashdan MS, Cirillo N, McCullough M. Oral lichen planus: a literature review and update. Arch Dermatol Res. 2016;308(8):539–51. 31. Suter VG, Negoias S, Friedrich H, Landis BN, Caversaccio MD, Bornstein MM. Gustatory function and taste perception in patients with oral lichen planus and tongue involvement. Clin Oral Investig. 2017;21(3):957–64. 32. Adamo D, Mignogna MD, Pecoraro G, Aria M, Fortuna G.  Management of reticular oral lichen planus patients with burning mouth syndrome-like oral symptoms: a pilot study. J Dermatolog Treat. 2018;29(6):623–9. 33. Bakula A, Lugović-Mihić L, Situm M, Turcin J, Sinković A. Contact allergy in the mouth: diversity of clinical presentations and diagnosis of common allergens relevant to dental practice. Acta Clin Croat. 2011;50(4):553–61. 34. Syed M, Chopra R, Sachdev V. Allergic reactions to dental materials—a systematic review. J Clin Diagn Res. 2015;9(10):ZE04–9. 35. Darling MR, Su N, Masen S, Kwon P, Fortino D, McKerlie T, et al. Geographic tongue: assessment of peripheral nerve status, Langerhans cell, and HLA-DR expression. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017;124(4):371–7.e1. 36. Kullaa-Mikkonen A.  Geographic tongue: an SEM study. J Cutan Pathol. 1986;13(2):154–62. 37. Gonzalez-Alvarez L, Garcia-Pola MJ, Garcia-Martin JM.  Geographic tongue: predisposing factors, diagnosis and treatment. A systematic review. Rev Clin Esp. 2018;18(9):481–8. 38. Shareef S, Ettefagh L. Geographic tongue. 2020. 39. Assimakopoulos D, Patrikakos G, Fotika C, Elisaf M.  Benign migratory glossitis or geographic tongue: an enigmatic oral lesion. Am J Med. 2002;113(9):751–5. 40. Fatahzadeh M. Oral manifestations of viral infections. Atlas Oral Maxillofac Surg Clin North Am. 2017;25(2):163–70. 41. Steinberg MJ, Kelly PD.  Implant-related nerve injuries. Dent Clin North Am. 2015;59(2):357–73. 42. Rapaport BHJ, Brown JS. Systematic review of lingual nerve retraction during surgical mandibular third molar extractions. Br J Oral Maxillofac Surg. 2020;58(7):748–52. 43. Shintani Y, Ueda M, Tojyo I, Fujita S. Change in allodynia of patients with post-lingual nerve repair iatrogenic lingual nerve disorder. Oral Maxillofac Surg. 2020;24(1):25–9. 44. Humphrey SP, Williamson RT. A review of saliva: normal composition, flow, and function. J Prosthet Dent. 2001;85(2):162–9. 45. Green BG, Dalton P, Cowart B, Shaffer G, Rankin K, Higgins J.  Evaluating the ‘Labeled Magnitude Scale’ for measuring sensations of taste and smell. Chem Senses. 1996;21(3): 323–34.

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46. Bartoshuk LM, Duffy VB, Green BG, Hoffman HJ, Ko CW, Lucchina LA, et al. Valid acrossgroup comparisons with labeled scales: the gLMS versus magnitude matching. Physiol Behav. 2004;82(1):109–14. 47. Landis BN, Welge-Luessen A, Brämerson A, Bende M, Mueller CA, Nordin S, et al. “Taste Strips”—a rapid, lateralized, gustatory bedside identification test based on impregnated filter papers. J Neurol. 2009;256(2):242–8. 48. Braud A, Descroix V, Ungeheuer MN, Rougeot C, Boucher Y.  Taste function assessed by electrogustometry in burning mouth syndrome: a case-control study. Oral Dis. 2017;23(3): 395–402. 49. Eliav E, Kamran B, Schaham R, Czerninski R, Gracely RH, Benoliel R.  Evidence of chorda tympani dysfunction in patients with burning mouth syndrome. J Am Dent Assoc. 2007;138(5):628–33. 50. Hwang BY, Mampre D, Penn R, Anderson WS, Kang J, Kamath V. Olfactory testing in temporal lobe epilepsy: a systematic review. Curr Neurol Neurosci Rep. 2020;20(12):65. 51. Özay H, Çakır A, Ecevit MC. Retronasal olfaction test methods: a systematic review. Balkan Med J. 2019;36(1):49–59. 52. Khawaja SN, Bavia PF, Keith DA. Clinical characteristics, treatment effectiveness, and predictors of response to pharmacotherapeutic interventions in burning mouth syndrome: a retrospective analysis. J Oral Facial Pain Headache. 2020;34(2):157–66. 53. Grushka M, Epstein J, Mott A.  An open-label, dose escalation pilot study of the effect of clonazepam in burning mouth syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998;86(5):557–61. 54. Heckmann SM, Kirchner E, Grushka M, Wichmann MG, Hummel T. A double-blind study on clonazepam in patients with burning mouth syndrome. Laryngoscope. 2012;122(4):813–6. 55. Coculescu EC, Radu A, Coculescu BI. Burning mouth syndrome: a review on diagnosis and treatment. J Med Life. 2014;7(4):512–5.

Part IV New Areas and Implications of Taste and Smell

Oral Health and Microbiome: Implications for Taste: State-of-the-­Science on the Role of Oral Health and Emerging Science of the Microbiota and its Implications for Taste

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Sukirth M. Ganesan, Katherine A. Maki, and Eswar Kandaswamy

Learning Objectives 1. Recognize the role of oral health in taste perception. (a) Identify the differences in alterations in taste perceptions with different oral conditions. (b) Understand the effects of dental treatment in causing reversible and irreversible alterations in the taste perception. 2. Appreciate the complexity and specificity of the microbiome in different parts of the oral cavity. (a) Acknowledge the existence of taste-specific microbiome. (b) Identify the potential mechanism(s) linking oral microbiome and taste perception.

S. M. Ganesan (*) Department of Periodontics, The University of Iowa College of Dentistry and Dental Clinics, Iowa City, IA, USA e-mail: [email protected] K. A. Maki Nursing Department, Nursing Research and Translational Science, National Institutes of Health Clinical Center, Bethesda, MD, USA e-mail: [email protected] E. Kandaswamy Department of Periodontics, School of Dentistry, Louisiana State University Health Sciences Center, New Orleans, LA, USA e-mail: [email protected] © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021 P. V. Joseph, V. B. Duffy (eds.), Sensory Science and Chronic Diseases, https://doi.org/10.1007/978-3-030-86282-4_11

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11.1 Introduction Oral health is an integral part of an individual’s general health and well-being. The definition of oral health transcends beyond the mere absence of disease. The most recent definition from the FDI World Dental Federation General Assembly defined three core elements of oral health: 1) disease and condition status, 2) physiological function, and 3) psychosocial function, recognizing the multifaceted and comprehensive nature of oral health [1]. The oral cavity is the first part of the digestive tract and houses accessory organs such as the tongue, teeth, and salivary glands involved in a number of physiological functions such as mastication, speech, swallowing, and taste sensation. Even a minor disorder in any of these functions or organs can affect nutrition and overall well-being. Health in the oral cavity is associated with positive systemic health and is important for well-being throughout the lifespan. Decades of research have revealed the association of taste perception with nutrition and the individual’s systemic health. The role of taste perception extends beyond the evolutionary rejection of bitter substances as a protection or survival mechanism (toxic substances are bitter in taste). Several oral and systemic conditions including dental caries and periodontitis, upper respiratory tract infections, systemic viral infections such as HIV, and several autoimmune and inflammatory disorders such as Sjogren’s syndrome, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, and neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases are associated with altered taste perceptions. Additionally, altered taste perception is associated with chronic disorders such as obesity, and diabetes, leading to over-nutrition or malnutrition. A multitude of factors, including host genetics and the microbiome, have been proposed to influence the associations between the altered taste perception and oral and systemic diseases. In this chapter, we will discuss the impact of oral health on taste and vice-versa. Additionally, we will also examine the implications of the oral microbiome on taste perception.

11.2 Oral Health and Taste Perception: A Two-Way Street? The tongue and the taste buds are part of the oral cavity. Therefore, a direct relationship exists between oral health and taste perception. A plethora of oral conditions, including dental caries, periodontitis, salivary dysregulations, and dental rehabilitation, affect taste sensation (Fig. 11.1). Additionally, elevated threshold or sensitivity to certain tastes can increase the risk for developing dental caries. The following section will discuss the implications of oral health on taste perception.

11.2.1 Dental Caries and Taste Perception Dental caries (commonly known as “tooth decay”) is the most common non-­ communicable disease worldwide. The complex interaction between acid

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Fig. 11.1  Outlines the various oral conditions, practices, and treatments that potentially affect taste perception

producing tooth-adherent bacterial biofilms and fermentable carbohydrates results in dental caries [2]. Free sugars and sugar-sweetened diets are the principal contributing factors for dental caries [3]. The consumption of a sugary and cariogenic diet are associated with an increased taste threshold phenotype to sugar/sweet. Increased sugar taste

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threshold has been associated with a higher risk for developing dental caries—however, the evidence is equivocal [4–10]. While many investigations have shown that caries-free adults have a lower threshold for sweet taste when compared to the caries-­prone cohort [6, 7], one of the pilot studies reported the opposite trend [11]. A small but significant correlation between sweet taste perception (sucrose sensitivity) and occlusal caries/caries index was reported in children of different ethnicities. A weak negative correlation between salty taste perception to caries has also been reported [12]. Using the 6-n-propylthiouracil (a bitter-tasting substance) threshold, a study reported that there was a significantly greater caries prevalence in the non-­ taster group (a group with heightened taste threshold) even after controlling for other variables (such as age, oral hygiene) [13]. However, no such associations were identified in the United States (US), Saudi Arabian, Brazilian, and Japanese cohorts [4, 5, 10, 14]. The complexity of taste perception, variable demographics, cultural differences, non-standardized research methods, and smaller sample sizes may contribute to the equivocal evidence that associates taste perception and dental caries.

11.2.2 Is there a Genetic Link between Caries and Taste Perception? Findings from twin studies reveal that the inter-individual variations in the taste sensitivity may partly be explained by genetic polymorphisms of genes involved in the taste perception of the basic taste qualities [15]. Studies have identified associations between several taste receptor genes, such as TAS1R1, TAS1R2, TAS1R3, TASR38, and GNAT3, and dental caries. Genes TAS1R1 and TAS1R3 code for umami, and TAS1R2 codes for sweet perception. TASR38 codes for bitter taste perception (specifically, glucosinolate, a pungent bitter-tasting substance found in cruciferous vegetables) [16, 17]. Several polymorphisms related to the TAS2R38 gene and TAS1R2 gene have been associated with dental caries in primary and mixed but not permanent dentitions [18]. Three single nucleotide polymorphisms (SNPs; rs713598, rs1726866, rs10246939) at positions encoding amino acids 49, 262, and 296 encode for two major forms of distinct taste perception: 1) PAV (Proline, Alanine, Valine) and 2) AVI (Alanine, Valine, Isoleucine) haplotypes. The PAV haplotype (represented by the nucleotides GGC) is associated with increased sensitivity to the bitter taste. The PAV haplotypes are considered “supertasters,” while the AVI haplotypes (represented by the nucleotides CAT) are associated with bitter insensitivity and are considered non-tasters. The PAV haplotype has been associated with caries protection in primary dentition, and the AVI haplotype has been associated with an increased risk for dental caries [18]. While the “supertasters” are associated with reduced caries risk, other studies on pre-school children (3.5–4.5 years) [19] and children (5–10 years) [20] identified associations between the PAV haplotype and increased sweet likening. In the TAS1R2 gene, analysis of the 2 SNPs revealed a significant association of the C allele with dental caries in mixed dentition only and not in primary or permanent dentition. These associations vary between the age groups and the

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demographics [18]. In a healthy female cohort GNAT3, SCL2A2, SCL2A4, TAS1R1, and TAS1R2 but not TASR1R3 were associated with increased caries risk [21]. Among the 175 people recruited for an oral microbiome associated with sugar intake study, 23.8% of subjects of the high sugar/sucrose intake group had the TAS1R1 (rs731024) polymorphism and 6.8% of subjects in the low sugar/ sucrose intake group had the TAS1R1 (rs731024) polymorphism [22]. This increased sugar/sucrose intake group is potentially linked with a higher risk for developing caries. The differences in the taste threshold to certain foods determined by the genetic polymorphisms have been proposed to influence dietary habits (potentially, an increase in the consumption of a highly cariogenic diet). However, there is a lack of consensus on the exact mechanisms linking genetic changes to dental caries susceptibility. Besides taste being a complex phenomenon and dental caries a multifactorial disease, the variation in the population’s age, demographics, and sample size in these investigations contribute to the heterogeneity in the findings.

11.2.3 Periodontal Disease, Halitosis, and Taste Perception Periodontitis (aka irreversible gum disease) is a microbially induced chronic inflammatory disease that destroys the structures that anchor the tooth to the jawbone leading to tooth loss. Periodontitis is the sixth most prevalent disease globally, and the severe form of the disease severe periodontitis affects 9% of US adults [23]. Periodontal disease is associated with altered taste perception [24]. A placebo-­ controlled trial administering professional oral hygiene three times a day improved taste perception in elderly individuals [25]. Additionally, untreated periodontal disease is associated with halitosis (aka bad breath). The abundance of the gram-­ negative bacteria associated with periodontal disease degrades the amino acids in the oral cavity into volatile sulfur compounds. These volatile sulfur compounds are associated with halitosis [26]. The olfactory sensation and taste perception are responses to chemoreceptors, and their functional response is entwined. Changes in olfactory cues (for example, in halitosis) impact the subjective perceptions of taste [27]. Besides an altered taste sensation, halitosis is also associated with phantom taste sensations (phantogeusia) [28]. In the absence of periodontal disease, tongue coating is another key contributing factor for halitosis intra-orally. Tongue brushing is advised to improve halitosis. A handful of interventional trials have also explored the relationship between tongue coating, halitosis, and taste perception. After 14 days, regular use of tongue cleaning aid has been shown to improve objective and subjective taste perceptions in smokers and non-smokers aged 45 years and above and in a hospitalized elderly population [29]. A pilot investigation on 44 older adults showed that tongue brushing improved subjective taste perceptions in 74% of people with a reduction in taste threshold for sour and bitter in the posterior tongue and sweet and salty perception in anterior and posterior tongue surfaces [30]. In several ways, the literature demonstrates the role of oral hygiene for optimal taste perception.

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11.2.4 Sjogren’s Syndrome and Altered Taste Perceptions Sjogren’s syndrome, a systemic autoimmune disorder that affects salivary and tears production, is also associated with altered taste sensations [31]. Reduced taste perception (hypogeusia) is reported in 26% of patients with primary Sjogren’s syndrome and 10% of patients with sicca syndrome (patients who fulfill some but not all the diagnostic criteria of Sjogren’s syndrome) [32]. The absence of taste perception, also known as ageusia, is prevalent in 15% of this population. Despite a relatively high prevalence of altered taste sensation in patients with Sjogren’s and sicca syndrome, the exact mechanism by which taste sensation is altered remains unknown [31].

11.2.5 Burning Mouth Syndrome (BMS) and Associated Alterations in Taste Sensation Burning mouth syndrome is a chronic condition that affects the tongue and oral mucosa, causing a burning sensation of the oral structures. BMS is accompanied by reduced salivary flow and 70% of the patients with BMS report dysgeusia or altered taste perceptions [33–35]. Several studies have investigated the whole mouth versus tongue taste perceptions using both gustatory and electrical stimulation. Whole mouth taste sensations for patients with BMS were reported to be similar to the healthy controls except for sour taste. The sour taste threshold was higher in BMS patients [33, 36–38]. However, electrical taste stimulation of the “tongue-only” revealed measurable taste disturbances in the tongue. This altered taste perception in the tongue could be attributed to: 1) hypofunction of chorda tympani peripheral nerve fibers (such as A-delta) and 2) compensatory mechanism for the loss of the tongue’s sensitivity by the other oral structures [33, 35–37]. There are also reports that the intensity of taste perception is higher in patients with BMS and altered taste related to bitter, metallic, or both [35].

11.2.6 Head and Neck Cancer Therapy and Taste Perception Head and neck cancer patients often report changes in taste sensation following treatment [39, 40] with reported prevalence up to 100% [41]. This altered taste sensation could be either due to: 1) direct damage to the oral mucosal tissues in conditions such as oral mucositis following chemotherapy or radiotherapy, surgery or radiotherapy related damage to the oral tissues (including damage to the taste buds); 2) damage to the salivary gland and resulting in altered salivary composition and flow; 3) chemotherapy and medications that can cause xerostomia (dry mouth) because of the indirect effect of the salivary flow; 4) immunosuppression in these patients lead to increased occurrence of oral infections and thus leading to changes in the taste sensation. Radiation therapy is associated with a loss of sweet sensation followed by bitter, umami, and salt taste, ultimately resulting in phantogeusia or

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hypogeusia [42–45]. Patients undergoing chemotherapy often complain of metallic or “medicine-like taste sensations”. These alterations in taste sensation tend to linger, and 10% of patients report these alterations even a year after their treatment [46, 47]. The loss of acuity to taste and altered taste sensations affect the quality of life and nutrition of patients’ post-cancer therapy. It has been reported that less than 30% of patients go back to a normal diet following head and neck cancer therapy, primarily because of taste and texture changes in their food [48].

11.2.7 Aging and Associated Changes in Taste Perceptions Aging has been significantly associated with a diminished sense of taste [24, 49, 50]. Hospitalized elderly patients showed an increased taste sensitivity and threshold to sour taste. Atrophy of the tongue in this population altered sweet taste sensitivity and these taste disturbances were significantly associated with dental caries, oral hygiene, and xerostomia in this cohort [51]. It was also reported that sweet and salty taste perception was diminished in the aging population and was associated with xerostomia and hyposalivation [51]. Dysgeusia in older patients leads to poor nutritional status, and in turn, deficiency in certain vitamins and minerals was found to be inversely related to the extent of dysgeusia [52]. Interventions using flavor enhancers in older patients with dysgeusia result in the maintenance of nutritional status and weight gain compared to the cohort that did not receive the flavor enhancement, showing the close association between olfactory and taste sensation [53].

11.2.8 Dental Prosthesis and Taste Perceptions Missing teeth and replacement prostheses have been shown to alter taste sensations. The taste acceptance tends to decrease with an increasing degree of edentulous states (aka the number of missing teeth). The lowest taste acceptance was identified in completely edentulous patients and patients rehabilitated with dental prosthetics, while the highest taste acceptance was in completely dentate individuals [54]. Rehabilitation of completely edentulous patients with removable maxillary dentures results in an altered flavor, smell, and taste perception [55, 56]. When similar methods were used in a study measuring subjective changes in perceived taste after fabrication of new dentures (replacing old dentures), conventional removable dentures and implant-supported overdentures resulted in declining taste perception with a greater change in the conventional removable complete denture patients. Interestingly, the replacement of old dentures with new removable dentures (with or without implants) did not significantly alter food choices (overdenture and taste) but were associated with deterioration of taste and texture perception [57]. Dental materials used in the fabrication of prostheses such as denture bases and metallic restorations have altered the taste perception [55]. In rare instances, subjects who develop an allergy to dental and prosthetic materials (such as dental implants) can experience a transient taste loss [58].

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11.2.9 Dental Treatment and Taste Sensations In rare instances, injury to the chorda tympani nerve secondary to dental procedures (either directly or as a result of post-operative inflammation) can lead to taste changes, including hypogeusia and ageusia [59]. The use of topical agents such as chlorhexidine, hydrogen peroxide, and delmopinol can cause transient but reversible changes in taste perception [60–62].

11.2.10  Effects of Behavioral Factors (Tobacco and Nicotine Use) on Taste Sensations Smoking and tobacco use has both direct and indirect effects on the oral cavity, including taste. Cigarette smoking reduces the vascularity of the tongue and alters taste sensation. In addition, smoking increases the risk of developing periodontitis and halitosis and impacts salivary flow, affecting the taste perceptions [55]. Nicotine, a major component of cigarettes, is a bitter-tasting substance, and there is evidence that genetic variations in bitter taste are related to smoking in some populations [63]. While there are no original investigations yet, electronic (e)-cigarette use has been reported to xerostomia and “vapor’s tongue,” characterized by loss of taste sensation. These patients experience “flavor fatigue” where they cannot taste or smell the differences in e-cig flavors. No studies are examining the olfactory and taste disturbances in e-cigarette users at this time. The exact mechanism behind tobacco and nicotine use and altered taste sensation is not yet clarified in the scientific literature.

11.3 T  he Oral Microbiome: A Major Determinant of the Oral Health The oral cavity is an open ecosystem with hundreds of bacterial species colonizing the oral cavity in complex communities called biofilms. These microbial communities are in continual interface with the host immune system through the epithelial barrier surface. The homeostatic interactions and equilibrium within and between the microbial communities (aka microbiome) and the host immune defenses determine health in this environment. The oral microbiome plays an important role in several local and systemic physiologic processes [64]. Disruptions or dysbiosis leads to disease. The anatomy of the oral cavity is complex, with several distinctive microenvironments. For example, the mucosal surfaces with high cellular turnover versus non-­ mucosal teeth remain in close proximity [65]. Despite the proximity, these microenvironments (e.g., the keratinized gingiva, tongue dorsum, subgingival plaque, teeth, buccal mucosa) possess large differences in environmental conditions, including pH, temperature, oxygen, and cellular properties [66]. The oral microbiome is specific to each of these niches and exhibits remarkable specificity

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and temporal stability. Differences between health and disease in any of these niches are identified by species richness and evenness (measured by diversity indices) and relative abundances of health-associated and pathogenic microbial taxa. Contrary to the healthy gut microbiome [67], oral community health and homeostasis are not necessarily associated with increased bacterial diversity. Unlike the reduced microbial diversity associated with inflammatory bowel disease, periodontal disease, a microbially induced chronic inflammatory disease in the oral cavity, is characterized by a stark increase in bacterial diversity [68].

11.3.1 The Tongue Microbiome The tongue dorsum and saliva are two oral microbiome niches that are especially pertinent to taste due to their proximity to the taste buds. Compared to other oral niches, the tongue dorsum and saliva have high bacterial loads [69] with higher relative abundances of species belonging to Prevotella, Veillonella, Actinomyces, Oribacterium, and Fusobacterium, and lower relative abundances of species belonging to Streptococcus, Gemella, and Haemophilus as compared to the buccal mucosa, keratinized gingiva, and hard palate [65, 70, 71]. The characteristic crypts in the tongue dorsum are a favorable environment for anaerobic bacteria, and the ratio of anaerobic/aerobic microorganisms is higher in tongue biofilm samples than saliva [72]. Importantly, the proximity of the bacteria in the mouth to taste buds on the posterior tongue dorsum support the role of oral bacteria on the influence and modulation of taste perception [73].

11.3.2 Bacteria Associated with Altered Taste (Fig. 11.2) 11.3.2.1 Total Taste Sensitivity Published studies examining taste and the oral microbiome have used samples from the posterior tongue [72–74], whole tongue [75, 76], whole mouth [77], and saliva [22, 51, 72, 78]. Total taste sensitivity examined in obese and non-obese adolescent subjects clustered into groups with high and low Bacteroidetes abundances revealed that the group with the highest relative abundance of Bacteroidetes in saliva correctly identified fewer taste strips [78]. Conversely, in elderly patients, high growth of Streptococcus mutans and Lactobacillus (belonging to the Firmicutes phylum) had significantly lower total taste scores than patients with low bacterial growth [51]. 11.3.2.2 Salty and Sour Oral microbiome and salty taste threshold comparisons have been published using whole tongue [75] and saliva [72] samples. An increased relative abundance of Actinobacteria in saliva and Rothia in tongue dorsum samples was associated with lower salt taste sensitivity in healthy subjects [72, 75]. An increased relative abundance of Peptococcus, Parvimonas, Peptostreptococcus, and Prevotella in tongue dorsum samples was associated with higher salt sensitivity [72]. Increased

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abundance of Bergeyella, Peptostreptococcus, and Lachnoanaerobaculum in whole tongue samples were associated with lower taste thresholds and increased sour sensitivity [75]. High colony-forming units of Lactobacillus in saliva were associated with significantly lower sour taste identification scores, indicating lower sour sensitivity [51].

11.3.2.3 Bitter Metrics that quantify overall bacterial community (alpha/beta diversity) were similar between “supertaster” (high taste sensitivity) and “non-taster” groups (low taste sensitivity, defined by N-Propylthiouracil [PROP], Sect. 11.2.2), but differences between groups were found when individual taxa were analyzed at the genus level [76]. The increased relative abundance of Bacteroidetes in the tongue film was

Salty

Sour

Lower Sensitivity

Lower Sensitivity

Actinobacteria Rothia

Lactobacillus

Higher Sensitivity

Higher Sensitivity

Peptococcus, Parvimonas, Peptostreptococcus, Prevotella

Bergeyella, Peptostreptococcus, Lachnoanaerobaculum

(Cattaneo 2019; Feng, 2018)

(Cattaneo 2019; Soldemal, 2012)

Bitter

Sweet Higher Sensitivity Colstridiales Family XIII

Higher Sensitivity

Oral Microbiome

Actinomyces, Oribacterium, Campylobacter, Solobacterium, Catonella, Bulleidia (Cattaneo 2019; Mameli, 2019)

(Esberg, 2020)

Lipid Lower Sensitivity Enterorhabdus, Bacteriodaceae Lactobacillaceae, Helicobacteraceae, Tepidomonas

Higher Sensitivity Barnesiella, Lachnospiraceae, Flavonifracor, Barnesiella, Porphyromonadaceae, Deltaproteobacteria, Lactobacillus (Besnard 2018; Besnard, 2020)

Fig. 11.2  Summarizes the oral microbial composition specific to each taste as presented in the literature. There is a varying degree of strength in the evidence for these associations

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associated with increased bitter sensitivity in one study [72], and increased relative abundance of Bacteroidetes in saliva was associated with decreased bitter sensitivity in another [78]. Both studies are from cohorts with small sample sizes, so additional confirmatory research is needed. The increased relative abundance of Actinomyces, Oribacterium, Campylobacter, Solobacterium, Catonella, and Bulleidia in the tongue dorsum were present in the “supertaster” (high taste sensitivity) group, compared to the low bitter taste sensitivity group [76].

11.3.2.4 Sweet Burcham et  al. [77] found no differences in oral microbiome community (alpha/ beta) or differential abundance measures between sucrose preference groups in adults or youth subjects. This study performed whole mouth (teeth, tongue, cheek, etc.) sampling, which may have masked community differences versus sampling in specific oral niches since oral bacterial communities can vary greatly. With site-­ specific sampling, increased Clostridiales Family XIII relative abundance in whole tongue samples associated with increased sweet taste sensitivity [75]. Esberg et al. clustered bacterial taxa in the saliva oral microbiome into four groups and compared differences in sugar intake and genotypes associated with taste preference. The group with the highest sugar intake had the highest alpha diversity, a higher abundance of Streptococcus and Prevotella genera, and a lower abundance of Fusobacterium in saliva samples when compared to the other clustering groups [22]. The group with the lowest sugar/sucrose intake had a higher abundance of Fusobacterium and Neisseria in saliva samples [22]. 11.3.2.5 Lipid-Linoleic Acid With the alarming increase in rates of obesity and metabolic syndrome globally, the fat taste is gaining much significance and is considered the sixth taste primary. Besnard et al. performed taste sensitivity to fat taste using linoleic acid (LA) in studies comparing obese and normal-weight subjects and obese-only cohorts with differing levels of LA taste sensitivity [73, 74, 79]. There was a large variance in LA tasting sensitivity in both obese and normal-weight patients. When all patients were compared between high and low LA sensitivity, no differences in alpha diversity were found, but when the obese patient cohort was stratified, reduced LA sensitivity was associated with higher alpha diversity at the posterior tongue dorsum. When patients were not stratified by weight, increased abundance of Enterorhabdus in posterior tongue dorsum samples was associated with lower LA sensitivity, and increased Barnesiella abundance was associated with higher LA sensitivity [73]. Lower Helicobacteraceae and Lactobacillaceae and increased Bacteroidaceae abundances in the posterior tongue dorsum are associated with low LA sensitivity (non-tasters) in taste group comparisons of all weights and the obesity-only phenotype group [73]. In obese-only LA taste groups compared, increased abundance of Tepidomonas in posterior tongue dorsum associated with low LA sensitivity, and increased Lachnospiraceae, Flavonifractor, Barnesiella, Porphyromonadaceae, Deltaproteobacteria, and Lactobacillus associated with higher LA sensitivity [73, 74].

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11.4 I nteraction between Taste and Oral Microbiome: Potential Mechanisms 11.4.1 Metabolites Understanding mechanisms and direction of influence between the oral microbiome and taste modulation is an evolving field of inquiry. In determining the biological underpinnings of association between the microbiome and the taste perception, it will be crucial to identify beyond compositional alterations in the microbiome. Investigating the microbial gene abundances, associated pathways, and the downstream end-stage small molecules (metabolites) will be essential to determine the functional attributes behind the associations. Either through the consumption or synthesis of sensory-influencing metabolites, the oral microbiota can influence taste perception and sensitivity. Additionally, these microbial metabolites can regulate the bacterial community interactions, and thus one microbial taxon can influence the activity of neighboring taxa [80]. These metabolites can also influence the host metabolism and influence the immune system through cell signaling [81]. These metabolites or the end products contribute to the microbiome’s highly interactive nature that influences community stability and important physiologic processes such as taste perception. Oral bacteria that consume sugars and amino acids reduce their availability around the taste buds and taste receptors. Conversely, bacteria including Veillonella, Lactobacillus, and Actinomyces synthesize organic acids and short-chain fatty acids, which increase availability near the taste buds and influence taste perception and sensitivity [66]. When investigators quantified short-chain fatty acid production in tongue biofilm versus saliva inoculums, tongue dorsum biofilms produced significantly higher acetate, butyrate, and propionate [82]. Higher metabolite production by tongue biofilm-metabolite production in close proximity to taste receptors suggests metabolite production and processing is an essential mechanism for taste modulation. Metabolite production by bacterial protein consumption is another potential mechanism in which oral bacteria may influence taste. Samples inoculated with tongue dorsum biofilms had significantly increased protein loss than saliva samples [82]. Therefore, bacteria inhabiting the tongue dorsum may need to consume protein for normal functioning, and decreased consumption could be a future marker for altered tongue bacteria dynamics. Finally, glycolysis-associated and pyruvate-­ derived metabolites potentially drive sugar processing and taste sensitivity metabolites. After research subjects consumed sucrose, glycolysis-related metabolites (lactate, pyruvate, and succinate) and pyruvate-derived metabolites (acetoin, alanine) were increased in saliva samples [82]. Sweet and bitter taste sensitivity are mediated by G-protein coupled receptors (TAS1R and TAS2R taste receptor genes), and glutamate, inosine monophosphate, and guanosine monophosphate are ligands that can activate these receptors. Actinomyces and Streptococcus metabolize endogenous and/or food sugars through the glycolysis pathway to produce adenosine triphosphate, which is subsequently converted into lactate, acetate, ethanol, and formate in anaerobic conditions [66].

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In studies evaluating relationships between oral metabolites and taste, propionate saliva levels had a significant moderate association with increased salt taste sensitivity [72]. Salivary short-chain fatty acid levels had moderate (but non-significant) associations with taste sensitivity, including lactate and butyrate with increased sweet taste sensitivity and acetate and butyrate with increased salt taste sensitivity. Moderate (non-significant) associations between tongue dorsum metabolite levels and taste were all simple sugars: sucrose was associated with increased sweet sensitivity, glucose and fructose were associated with decreased bitter sensitivity, and fructose was associated with decreased umami sensitivity [72].

11.4.2 Influence of Oral Environment by Diet Differences in taste perception levels among subjects were associated with diet differences, including vegetables, bakery/sweets, and fats [75]. Understanding if differences in taste sensitivity and food choices drive the relative abundance of bacteria or if the relative abundance in bacteria influences taste sensitivity and subsequent food choices is a current research topic. Food consumption can influence the oral environment by several mechanisms modulated through the bacteria in the mouth. For example, Actinomyces and Veillonella convert nitrate from green vegetables to nitrite, which inhibits bacterial acid production and contributes to caries prevention [83]. Conversely, sugars are metabolized to acids by saccharolytic bacteria (including Streptococcus, Actinomyces, and Lactobacillus), and increased acid production can have a negative effect on the oral environment and bacterial homeostasis. Streptococcus and Actinomyces are usually present in tongue dorsum samples [69], but Lactobacillus genera are usually localized to supragingival oral niches [84]. In published research evaluating the oral microbiome, taste sensitivity, and food consumption, some bacteria were associated with both taste sensitivity differences and food choice differences, while others only influenced taste sensitivity. Some taxa were positively associated with vegetable-rich diets (Prevotella), and others were associated with protein/fat-rich diets (Clostridia) [75, 76]. Increased relative abundance of Rothia in tongue dorsum samples was associated with lower salt sensitivity, lower fat intake, and higher protein intake [75]. An increased relative abundance of Peptococcus, Parvimonas, Peptostreptococcus, and Prevotella in tongue dorsum samples was associated with higher salt sensitivity and lower carbohydrate intake [72]. An increase in Clostridiales Family XIII relative abundance in whole tongue samples was associated with an increased sweet taste sensitivity and lower carbohydrate intake [75]. Subjects with high and low bitter taste sensitivity had differential consumption of oil intake [76], which may influence the oral microbiome community. In addition to lower taste thresholds, increased relative abundance of Peptostreptococcus in whole tongue samples associated with higher protein intake and lower carbohydrate and total fiber intake [76]. Host and bacterial genetics also were associated with food

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consumption patterns [22]. When patients were stratified by sugar/sucrose intake, the group with the highest sugar consumption had both a higher percentage of the TAS1R1 (rs731024) taste preference gene polymorphism (23.8% vs. 6.8%) and a specific bacterial profile compared to the lowest sugar intake group [22].

11.5 Implications for Health and Future Directions Evidence is emerging to show a strong and synergistic relationship between the oral microbiome and taste sensitivity. Disruption of oral microbiome communities with insults such as antibiotics [85], tobacco and nicotine use [23, 86], or periodontal disease [87] could have significant implications for taste perception, metabolic health, and quality of life. Oral bacteria and food associations may influence systemic host systemic physiology and modulation of the mouth and oral microbiome environment. Actinomyces, Neisseria, Rothia, and Veillonella are capable of nitrate reduction and modulate nitric acid production through dietary sources such as green vegetables [66]. Nitric oxide is a potent vasodilator, and increased systemic availability may have implications for cardiovascular and metabolic health. However, future research is needed to clarify these mechanisms [88]. Finally, the synergistic interactions of the oral microbiome with taste perception and modulation poise microbial taxa as possible future biomarkers for sensory disorders, and manipulation or restoration of the oral microbiome may have future therapeutic benefit to improve patient health. Key Concepts • The oral microbiome plays an important role in several local and systemic physiologic processes. • The human microbiome is composed of communities of bacteria (and viruses and fungi). The microbiome consists of 10–100 trillion symbiotic (where both the human body and microbiota benefit) microbial cells and some, in lesser numbers, are pathogenic (promoting disease). • Several oral conditions, including dental caries, periodontitis, salivary dysregulations, and dental rehabilitation, affect taste sensation. • Specific oral microbiota is found to be associated with each taste sensation. • End products (metabolites) and gene polymorphisms (eg. TAS1R1 (rs731024)) maybe mediating the potential interactions between the oral microbiome and the taste sensations. • Periodontitis (aka irreversible gum disease) is a microbially induced chronic inflammatory disease that destroys the structures that anchor the tooth to the jawbone leading to tooth loss. • Sjogren’s syndrome, a systemic autoimmune disorder that affects salivary and tears production, is also associated with altered taste sensations. • Burning mouth syndrome is a chronic condition that affects the tongue and oral mucosa, causing a burning sensation of the oral structures.

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COVID-19-Associated Loss of Taste and Smell and the Implications for Sensory Nutrition

12

Mackenzie E. Hannum and Danielle R. Reed

Learning Objectives • Understand the prevalence of chemosensory loss in COVID-19 patients. • Theorize on the impact COVID-19-related chemosensory loss on food intake and nutritional health. • Discuss future implications of molecular studies on the manifestation of smell/ taste loss in COVID-19 patients to help plan clinical research.

12.1 Overview People choose what and how much to eat in large part because they like the taste of some foods more than others [1]. However, taste has one meaning to consumers and another to scientists; often when consumers refer to the “taste” of food, they mean its flavor, which is the integration of all the sensory aspects of food: taste sensations that arise from specialized cells in the tongue, smell sensations that arise from a different type of specialized cell in the nose, and chemesthesis, which arises from nerve endings in the tongue and mouth and conveys sensations like the cool of menthol or the tingle of carbonation [2]. Many patients infected with SARS-CoV-2, the virus responsible for the current COVID-19 pandemic, experience lost or changed flavor perception. Here we review the prevalence of chemosensory loss of COVID-19, its known and expected effects on food intake and food choice, and future implications of molecular studies to help plan clinical research and research gaps in our current knowledge.

M. E. Hannum (*) · D. R. Reed Monell Chemical Senses Center, Philadelphia, PA, USA e-mail: [email protected] © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021 P. V. Joseph, V. B. Duffy (eds.), Sensory Science and Chronic Diseases, https://doi.org/10.1007/978-3-030-86282-4_12

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12.2 COVID-19 and Loss of Chemosensory Ability Smell loss and COVID-19. We start with the sense of smell because its loss is a cardinal feature of infection with SARS-CoV-2. In this review, when we use the phrase “smell loss” we mean the loss of normal sense of smell; thus, smell loss could include reduced ability to smell (hyposmia), distortion of smell (parosmia; e.g., a normally pleasant odor now smells like garbage), inability to smell anything (anosmia), and/or perception of an odor that is not there (phantosmia; e.g., smelling garbage when none is near). Many early studies of COVID-19 smell loss did not distinguish among these four components, so we refer broadly to “smell loss” except where reports make the distinction. Understanding the full range of human olfactory experience is crucial to identify future directions of research; for example, having anosmia (inability to smell) may have fewer consequences than having persistent parosmia [3, 4] (e.g., food smells like garbage). Defining smell loss broadly, on average more than half of the people with symptoms of the viral illness COVID-19 will have smell loss (at least transiently); more sensitive methods of odor assessment (direct measures as opposed to self-report) reveal smell loss nearing 70% (Table 12.1) [5]. More sensitive methods may detect more cases of loss of smell because some people don’t notice mild smell loss. Direct measures detect smell loss better but require that people smell a defined stimulus and report on such aspects as its intensity or identity. Table 12.2 lists several types of validated direct measures of smell. Taste loss and COVID-19. Taste loss is also common in COVID-19 (Table 12.1), which was unexpected because taste loss rarely arises when people are ill with ordinary colds and flu. Like “smell loss,” we use the term “taste loss” broadly to mean the loss of the normal sense of taste, such as diminished taste (hypogeusia), distorted or phantom taste (dysgeusia), or complete taste loss (ageusia) [6]. In the past, patients complaining of post-viral taste loss almost always actually had a loss of smell but mistakenly thought it was taste (e.g., [7]). With COVID-19, however, reports of taste loss appear to be valid. Taste loss is confirmed when measured directly using sensory stimuli, such as tasting a sugar solution. Investigators using such measures found that, on average, nearly half of people with COVID-19 have taste loss [8–24]. People with COVID-19 seem to self-report their taste loss accurately, and more accurately than they report smell loss, as demonstrated by similar results of studies of self-reported versus objectively measured taste loss, in contrast Table 12.1  Prevalence of smell and taste loss in COVID-19 patientsa Chemical Sense Tested Smell Taste

Method Objective Subjective Objective Subjective

N Studies 28 149 17 169

N People 3090 66,140 2153 61,797

Updated March 4, 2021. Data are from an ongoing online analysis [5] Significant difference between methods (α 35,000 participants), revealed increased adherence to a healthier diet [64], this information was collected within the first month of lockdown, and more research is needed to establish the sustainability of these new dietary changes. Within a similar timeline (within 1–2 months of the onset of the COVID-19 pandemic), in a survey distributed throughout the United Kingdom many participants expressed more barriers to weight management—issues with motivation and control surrounding food—than before lockdown, a trend especially pronounced among those with higher BMI [65], suggesting BMI might be a mitigating factor in dietary choices and weight management. Sex may also play a role: results from a randomized clinical control trial revealed that energy density of purchased foods, calculated from grocery store trips before and during the COVID-19 pandemic, increased for females yet decreased for males [66]. It is also important to consider the compounding impact of additional factors (e.g., mental health challenges, isolating environments, lower physical activity, lack of motivation, and increased desire for comfort) present during the COVID-19 crisis, and their evolution over time as the COVID-19 pandemic continues, on our patients who suffer from chemosensory loss. Generic pandemic-related changes in food habits will affect people with COVID-19-related taste and smell loss, too.

12.5 Future Directions for Research Molecular studies to help plan clinical research on post-COVID smell recovery. While it is clear that chemosensory loss is a feature of COVID-19, how this loss occurs at the molecular level is unclear. We know that the SARS-CoV-2 virus enters cells though the ACE2 receptor and that this receptor is found rarely, if at all, on olfactory receptor neurons in the olfactory epithelium; rather, it appears on supporting (sustentacular) cells [67]. Through some mechanism as yet unknown, this

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infection causes olfactory receptor neurons to shut down gene expression for proteins necessary for signal transduction, including olfactory receptors [68]. There are two types of human olfactory receptors, called class 1 and class 2, distinguished by their ability to bind hydrophilic versus hydrophobic ligands [69]. It appears that with COVID-19 class 1 receptors are less downregulated than class 2 receptors. These observations suggest that olfactory tests might be devised to measure smell loss using ligands for class 1 and class 2 receptors to gauge whether smell loss is complete for all ligands or for only those that bind to class 2 receptors. It is possible that perception of hydrophilic ligands like carboxylic acids (e.g., sweaty odors) would remain in mild cases of COVID-19, while hydrophobic ligands like musk would be lost; this might explain why recovery from anosmia tends to start with bad odors [51, 70], involving the re-emergence of class 1 receptor function. Hints that some odorants are better than others at distinguishing people with and without COVID-19 come from smell tests done at home using a range of uncontrolled odorants [34]. Evaluating more odorants can help us better understand whether all ligands are affected equally or whether certain odorants, such as some food flavors, are more affected than others. Chemosensory receptors: postoral or atopic expression and COVID-19 ramifications. Although there is much about the effect of SARS-CoV-2 infection on taste and smell that we do not understand, what we do know suggests that chemosensory receptors, which are also found elsewhere in the body [71], may be affected with COVID-19. For example, investigators have suggested that downregulation of bitter taste receptors, known to have a role in innate immunity (e.g., [72]), may occur through the same pathways during an immune response to SARS-CoV-2 [73]. Whether the downregulation of chemosensory receptors occurs in other cell types outside the tongue and olfactory epithelium, such as in the pancreas, is not currently known and will require careful study, because these receptors are expressed in rare cell types and with low abundance. We do not know how much the postoral pathways involved in food digestion, such as the gut, rely on chemosensory receptors—COVID-19 effects may extend to those tissues and further affect food intake and preferences.

12.6 Conclusion and Take Home Message Most studies of people with chemosensory losses prior to COVID-19 report negative effects on their appetite, body weight, and psychological well-being [7]. For people with sustained loss with COVID-19, these negative effects may be intensified due to multiple chemosensory losses (e.g., loss of both smell and taste). We need to focus on better describing the experiences of people with smell, taste, and chemesthesis loss, perhaps through text analysis or focus groups, which are useful in studying new forms of illness, better capture patient experiences, and improve research engagement (e.g., patient-centered research). We also need to find ways to better quantify the severity of these losses, so we can better classify patients, study their diet, including food preferences and intake, and measure their recovery, to better describe the impact and pave the way for treatment.

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Key Concepts • Chemosensory perception refers to smell, taste, and chemesthesis (e.g., burn from chili peppers). • Smell loss refers to a reduced ability to smell (hyposmia), distortion of smell (parosmia; e.g., a normally pleasant odor now smells like garbage), inability to smell anything (anosmia), and/or perception of an odor that is not there (phantosmia; e.g., smelling garbage when none is near). • Taste loss encompasses the loss of the normal sense of taste, such as diminished taste (hypogeusia), complete taste loss (ageusia), and/or distorted or phantom taste (dysgeusia). • Some people with COVID-19 are experiencing co-occurring smell, taste, and chemesthetic loss (triple whammy) and these losses might be permanent. • More research is needed to underscore the effect of COVID-19-related chemosensory loss on overall nutrition for patients.

Acknowledgments  Pamela Dalton provided feedback on the assessment of food intake in chemosensory patients. We acknowledge the comments provided by Michael Tordoff during the development of this manuscript. We thank Joel Mainland, who contributed ideas discussed here, especially details about the class 1 vs. class 2 olfactory receptors. MEH is supported by the by the National Institutes of Health T32 funding (DC000014), and DRR is supported in part through NIH U01DC019578.

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