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Christopher H. Hawkes , Richard L. Doty
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Smell and Taste Disorders

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Christopher H. Hawkes , Richard L. Doty
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Smell and Taste
Disorders
Christopher H. Hawkes, MD FRCP
Honorary Professor of Neurology and Honorary Consultant Neurologist, Neuroscience Centre, Blizard Institute,
Barts and the London School of Medicine and Dentistry, London, UK

Richard L. Doty, PhD FAAN
Professor, Department of Otorhinolaryngology: Head and Neck Surgery, and Director, Smell and Taste Center,
Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

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978-0-521-13062-2 — Smell and Taste Disorders
Christopher H. Hawkes , Richard L. Doty
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978-0-521-13062-2 — Smell and Taste Disorders
Christopher H. Hawkes , Richard L. Doty
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Contents
Preface vii
Acknowledgments ix

1 Anatomy and Physiology of
Olfaction 1

7 Neurodegenerative Chemosensory
Disorders 293

2 Anatomy and Physiology of
Gustation 46

8 Assessment, Treatment, and
Medicolegal Aspects of
Chemosensory Disorders 387

3 Measurement of Olfaction 80
4 Measurement of Gustation 138
5 Non-neurodegenerative Disorders of
Olfaction 182

Index

6 Non-neurodegenerative Disorders of
Gustation 248

Color plates are to be found between
pp. 214 and 215.

406

v

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978-0-521-13062-2 — Smell and Taste Disorders
Christopher H. Hawkes , Richard L. Doty
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Preface
This smell and taste disorders aims to provide neuroscientists, physicians, dentists, and
psychologists with concise, practical, and authoritative information for understanding,
testing, and managing disorders of taste and smell. Nearly 3 percent of Americans under
the age of 65 suffer from some form of chronic olfactory or gustatory dysfunction –
a percentage that rises to more than 50 percent of those over 65 years of age and is likely
much higher in areas of the world where air and water pollution are prevalent. Despite such
statistics, the chemical senses remain neglected by the majority of medical practitioners.
Such oversight stems from a number of sources, not least of which is the lack of understanding or trivialization of these senses and the belief that their accurate assessment cannot
be made in the clinic. Less-than-total dysfunction is rarely brought to the attention of the
physician and, when aberrations are found, many are unsure of how to proceed.
Although practical quantitative tests of smell function are now widely available, the
majority of neurologists test only cranial nerves II through XII. This continues, despite the
fact that olfactory testing has been recommended by the Quality Standards Committee of
the American Academy of Neurology for inclusion in the diagnostic criteria for Parkinson’s
disease (Suchowersky et al., 2006). Similar suggestions have been made for inclusion of smell
testing as an aid in the diagnosis of Alzheimer’s disease (Foster et al., 2008). There is evidence
that smell tests can be useful in differential diagnosis of several disorders (e.g., depression vs.

Alzheimer’s disease; Parkinson’s disease vs. progressive supranuclear palsy and essential
tremor). Moreover, they may assist the detection of malingering. Loss of smell or taste has
considerable medico-legal importance, commanding major financial compensation for those
who are victims of head injury or exposure to toxic agents, particularly for the young and
persons whose livelihoods depend upon chemosensation. As this book emphasizes, there are
no longer excuses for neglecting the chemical senses in medical practice.
Smell and taste are regularly lumped together, particularly by lay people. While both are
chemical senses and contribute to the flavor of foods and beverages, in the embryo these two
systems develop independently and are completely separate at subcortical level and merge
only at the anterior insula. Olfaction is seemingly more ancient, developing first phylogenetically; taste, as an oral chemosensory system, is a relatively new thalamic-dependent
system. It is important to recognize, however, that both olfactory and gustatory receptor
proteins are found outside of the nose and oral cavity, suggesting that these proteins are
ubiquitous and have functions beyond those of transducing the conscious perception of
tastes and smells. For example, olfactory receptor proteins have been found in the tongue,
brain, prostate, enterochromaffin cells, pulmonary neuroendocrine cells, and spermatozoa.
Taste receptors have now been reported in the epiglottis, larynx, respiratory epithelium,
stomach, pancreas, and colon, where they influence such processes as digestion, chemical
absorption, insulin release, and protection of the epithelium from xenobiotic agents.
Olfaction is more plastic than taste, and it is damaged more readily from head trauma,
viruses, and exposure to xenobiotics. Inborn mechanisms largely determine the meaning of
taste experiences, whereas learning plays a much greater role for the sense of smell.
Nonetheless, these primary sensory modalities intermingle both with each other and
other sensory systems at the cortical level – interactions that in some cases are influenced
greatly by learning. Such interplay is only just beginning to be understood.
vii

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viii

Preface

Many chemosensory systems have evolved in mammals, including the vomeronasal
system, but the senses of taste and smell are the most prominent in humans. In Chapters 1
and 2 we emphasize the anatomy and physiology of these two modalities, beginning with
olfaction, which as noted above is typically more compromised than taste by injury and
disease. In subsequent chapters we review methods to measure smell (Chapter 3) and taste
(Chapter 4), what factors influence these modalities, and, from a clinical perspective, the
nature and major causes of their dysfunction with an emphasis on neurological disorders
(Chapters 5, 6, and 7). Our goal is to provide up-to-date information about these senses in
health and disease, and to guide the practitioner in the assessment, treatment, and management of patients with chemosensory disturbances (Chapter 8).
We express our gratitude to the editors of Cambridge University Press who agreed to an
update of our earlier work The Neurology of Olfaction (2009) and to include taste complaints. We hope that this compendium will serve the needs of a broad array of clinicians
and scientists who recognize the unique role that the chemical senses play in medicine and
everyday life.

References
Foster, J., Sohrabi, H., Verdile, G. and Martins, R.,
2008. Research criteria for the diagnosis of
Alzheimer’s disease: Genetic risk factors, blood
biomarkers and olfactory dysfunction.

International Psychogeriatrics 20(4), 853–855.
Hawkes, C.H., Doty, R.L., 2009. The Neurology of
Olfaction. Cambridge, UK: Cambridge University
Press.

© in this web service Cambridge University Press

Suchowersky, O., Reich, S., Perlmutter, J.,
Zesiewicz, T., Gronseth, G., Weiner, W.J., 2006.
Practice parameter: Diagnosis and prognosis of
new onset Parkinson disease (an evidence-based
review). Report of the quality standards
subcommittee of the American Academy of
Neurology. Neurology 66(7), 968–975.

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978-0-521-13062-2 — Smell and Taste Disorders
Christopher H. Hawkes , Richard L. Doty
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Acknowledgments
We owe a debt of gratitude to the following who have helped with various sections of this
volume:
Professor Kailash Bhatia, National Hospital for Neurology and Neurosurgery, Queen
Square, London
Professor Jay Gottfried, Perelman School of Medicine, University of Pennsylvania,

Philadelphia, Pennsylvania
Professor John Hardy, National Hospital for Neurology and Neurosurgery, Queen Square,
London
Dr. Isabel Ubeda-Banon, Universidad de Castilla-La Mancha, Avda. de Moledores s/n, 13071,
Ciudad Real, Spain.
Professor Jason Warren, National Hospital for Neurology and Neurosurgery, Queen
Square, London

ix

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Chapter

1

Anatomy and Physiology
of Olfaction

Introduction
The evolution of life required organisms to sense chemicals suspended or dissolved in water.
Some of these chemicals provided nourishment, whereas others were destructive and had to
be avoided. Single-celled organisms, such as Escherichia coli, developed multiple chemical
receptors critical for such survival. The rotatory direction of their flagellae – whip-like
appendages used to propel them through their environment – is altered by the type of
chemical encountered. Thus, chemicals important for sustenance induce a counterclockwise rotation of the flagella, facilitating a smooth and somewhat linear swimming path,
whereas toxic chemicals provoke a clockwise flagellar rotation, resulting in tumbling and

turning away from the offending stimulus (Larsen et al., 1974).
The sense of smell is one of nature’s true wonders, being ubiquitous within the animal
kingdom and capable of detecting and differentiating thousands of diverse odorants at very
low concentrations. Humans possess far more odorant receptor types than any other sensory
system, which explains, in part, their ability to perceive such a large number of stimuli. It is
now well established, as described in subsequent chapters of this book, that the olfactory
system provides a unique probe into the general health of the brain. Thus, smell loss is among
the first signs of neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease and
provides insight into elements of brain development. Importantly, smell loss is one of the
best predictors of future mortality in older populations, being a stronger predictor than
cognitive deficits, cancer, stroke, lung disease, or hypertension even after controlling for the
effects of age, sex, race, education, socioeconomic status, smoking behavior, alcohol use,
cardiovascular disease, diabetes, and liver damage (Wilson et al., 2011; Gopinath et al., 2012;
Pinto et al., 2014; Devanand et al., 2015). In the future, screening for a range of neurological
disorders by olfactory biomarkers may be commonplace and may encourage the development of protective measures that delay or prevent central nervous system (CNS)
degeneration.
We now describe the detailed anatomy, physiology, and pharmacology of the olfactory
pathway, followed by factors that influence olfactory input and its interpretation.

Nasal Cavity
During normal inspiration, only 5–10 percent of inhaled air reaches the olfactory epithelium. This specialized pseudostratified neuroepithelium harbors the olfactory receptors. It is
found high within the nasal vault, lining sectors of the upper nasal septum, cribriform plate,
superior turbinates, and, to a lesser extent, the anterior aspect of the middle turbinates
1
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Smell and Taste Disorders

Olfactory bulb
Cribriform
plate
Olfactory epithelium

Superior

Inferior
l
sa
na
nt
tro
a
nx
or
Re
ary
ph
so
Na

Turbinates

Od

O
Od

r th
or
on
a
No
as
nt
str
al
il

Middle

Palate

Figure 1.1 This figure shows the human nasal cavity and extent of the olfactory epithelium. Note the extension of
the epithelium onto the anterior part of the middle turbinate. Odorants access the olfactory epithelium either
directly through the orthonasal route (anterior arrow) or indirectly through the retronasal route as in chewing or
swallowing (posterior arrow). Reproduced with permission from Rawson, N. (2000), Chapter 11, Human olfaction.

(Figure 1.1). The existence of olfactory receptor neurons (ORN) on the middle turbinate is a
useful aspect of applied anatomy for those wishing to biopsy olfactory receptor cells (ORC)
for culture, histology, or patch clamp studies, as it is more accessible and less risky to sample
than the main olfactory area.
Sniffing. Although sniffing assists smell recognition and identification, the first awareness of a
new odor can be passive; sniffing then follows in an attempt to analyze the odor further and
assess its behavioral significance. Sniffing redirects up to 15 percent of the inhaled air through
the olfactory meatus, a ~1 mm-wide opening leading to the uppermost sector of the nose that
contains most of the olfactory epithelium. Sniffing helps to increase the number of odorous
molecules that ultimately reach this region. However, molecules must absorb into the mucus

that forms across the nasal mucosa to make contact with the olfactory receptor cells. In some
cases – particularly in the case of hydrophobic odorants – stimuli may be carried through this
mucus by specialized “odorant carrier” proteins to the receptors (Pelosi et al., 1990). It should
be emphasized that without a moist mucosal surface, detection of odors is largely impossible.
As mentioned in Chapter 5, diseases with excessive nasal dryness such as Sjögren’s syndrome
are often accompanied by smell dysfunction.
Nasal Turbinates. The nasal turbinates are highly vascularized structures that extend into the
nasal cavity from its lateral wall (Figure 1.2). They can rapidly expand or contract, depending
upon autonomic nervous system tone and stimulation. Exercise, hypercapnia, and increased
sympathetic tone constrict their engorgement, whereas cold air, irritants, hypocapnia, and
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Anatomy and Physiology of Olfaction

3

Figure 1.2 Coronal T1–weighted MRI scan to show the main structures around the nose.

increased parasympathetic tone can induce such engorgement. Turbinate engorgement can
be influenced by pressure on sectors of the body, body position, or ambient temperature. Leftto-right fluctuations in relative engorgement, termed the nasal cycle, occur in many people
over time, although these change with age and reciprocity is frequently the exception rather
than the rule (Mirza et al., 1997). These fluctuations relate to changes in lateralized blood flow
to various paired organs, including the two brain hemispheres, and belong to the basic restactivity cycle, a continuation of the REM/non-REM sleep cycle that occurs during the
daytime. Although the turbinates have never been thought relevant to the clinical neurologist,
this concept may need to change given the recent suggestion that rhinorrhea, secondary to
relative parasympathetic overactivity, may be a prodromal sign of Parkinson’s disease (see
Chapter 7 and Bower et al., 2006).
Innervation of the Nasal Cavity. In common with the nasal and oral mucosae, the olfactory

epithelium also contains free nerve endings from the trigeminal nerve (CN V). Nonolfactory elements of nasal chemosensation, e.g., sharpness, coolness, warmth, and pungency, are mediated via free nerve endings of this nerve (Figure 1.3). These free nerve
endings are supplied to the upper part of the nasal cavity by the anterior and posterior
ethmoid nerves – branches of the nasociliary nerve which come from the ophthalmic (first
division) of the trigeminal nerve. The nasopalatine nerve, a branch of the maxillary nerve
(second division of the trigeminal nerve) is the source of the CN V fibers innervating the
posterior nasal cavity. Most odorous compounds stimulate CN I and CN V, at least at higher
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Smell and Taste Disorders

Long ciliary
Nasociliary
Ophthalmic

Ethmoid
Maxillary
Mandibular

Buccal
Posterior palatine

Nasopalatine

Lingual

Figure 1.3 Schematic diagram of the branches of the trigeminal nerve that innervate the nasal, oral, and ocular

epithelia. From Bryant & Silver (2000). Copyright © 2000, Wiley-Liss.

concentrations and/or volumes. Vanillin is one of few compounds that appear to have no
perceptible CN V activity. This contrasts with ammonia, for example, which strongly
stimulates the olfactory and trigeminal nerves. Thus, patients with anosmia can readily
detect, via trigeminal sensation, several “impure” odors, such as menthol or camphor.
Vomeronasal Organ (VNO) and Nervus Terminalis. The VNO is a bilaterally symmetrical
tubular structure located just above the palate at the base of the anterior nasal septum. This
pouch-like structure is enclosed in a bony capsule and, depending upon the species, has a
single opening into either the nasal or the oral cavity via the vomeronasal or nasopalatine
duct, respectively. In the case of humans, the VNO is clearly vestigial and non-functional. In
the developing human fetus there is a VNO which stains for gonadotropin-releasing hormone
(GnRH), but its connections with the olfactory bulb disappear or become displaced and hard
to locate at about 19 weeks of gestational age. In the adult human the vestigial VNO is present
bilaterally on the anterior third of the nasal septum and opens through a pit about 1–2 cm
behind the posterior margin of the nostril. However, VNO cells do not react to olfactory
marker protein – a stain for functional olfactory neurons – and there is no neural connection
to the CNS. Adult humans lack an accessory olfactory bulb, to which functional VNOs
project. Moreover, most human VNO receptor genes are vestigial (pseudogenes) and the
VNO-specific TRP2 cation channel critical for VNO function is lacking.

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6

Smell and Taste Disorders

b

(a)
fs

(d)

ob
cp
ns

ns

et

(b)

(e)
on
ob

sas
on
cp

ns

(c)

cp

(f)

on

Figure 1.5 Lymphatic drainage through the nasal cavity. Silicone (Microfil) injection distribution patterns in the
head of a human (a-f). All images are presented in sagittal plane with gradual magnification of the olfactory area
adjacent to the cribriform plate. Reference scales are provided either as a ruler in the image (mm) or as a longitudinal
bar (1 mm). Microfil introduced into the subarachnoid space was observed around the olfactory bulb (a), in the
perineurial spaces of the olfactory nerves (b, c), and in the lymphatics of the nasal septum (d), ethmoid labyrinth
(e), and superior turbinate (f). Some lymphatic vessels ruptured and Microfil was noted in the interstitium of the
submucosa of the nasal septum (d). In (e), Microfil is observed in the subarachnoid space and the perineurial space of
olfactory nerves. The perineurial Microfil is continuous with that in lymphatic vessels (arrows). Intact lymphatic
vessels containing Microfil are outlined with arrows (d-f). Key to abbreviations: b – brain; fs – frontal sinus; cp –
cribriform plate; et – ethmoid turbinates; ob – olfactory bulbs; on – olfactory nerves; ns – nasal septum; sas –
subarachnoid space. Reproduced with permission from Johnston, Zakharov et al. (2005). (A black and white version
of this figure will appear in some formats. For the color version, please refer to the plate section.)

general, there is a high rate of blood flow within the human nasal respiratory epithelium
(~42 ml/100 g/minute), as measured by Laser-Doppler flowmetry, but the blood flow
rate in the human olfactory epithelium is unknown.
Lymphatic Drainage. It is not widely appreciated that the nasal cavity is a major route for
lymphatic drainage of cerebrospinal fluid (CSF). It is clear from observations in mice
(Weller et al., 2009) and humans (Johnston et al., 2005) that CSF drains along olfactory
perineural lymphatics from the subarachnoid space through the cribriform plate into the
nasal cavity, terminating in cervical lymph nodes (Figure 1.5). As explained in Chapter 7,
pathogens could use this drainage pathway in reverse direction to access the CSF and
brain.

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Anatomy and Physiology of Olfaction

7

Figure 1.6 Electron photomicrograph of transition zone between the human olfactory epithelium (bottom) and
the respiratory epithelium (top). Note the long olfactory receptor cell cilia compared to the cilia in the respiratory
epithelium. Arrows signify two examples of olfactory receptor cell dendrites with cilia that have been cut off. Bar = 5
μm. From Menco & Morrison (2003), with permission. Copyright © 2003, Richard L. Doty.

Olfactory Receptor Cells (ORCs). In humans, the 6–10 million ORCs, collectively termed the
first cranial nerve (CN I), are found at different stages of maturity in the olfactory epithelium.
These bipolar cells are the first-order neurons of the system, and their central axons project
directly from the nasal cavity to the olfactory bulb without an intervening synapse, making them
a major conduit for CNS pathogens (Doty, 2008). When mature, each ORC projects up to 30
cilia into the mucus, which form knob-like dendritric extensions (Figure 1.6). These cells are
unique in several ways. For example, they serve as sensory transducers, whereas in most other
sensory systems the transducing cell is not a neuron, but it is synaptically connected to an
effector sensory neuron. When damaged, ORCs, like the other cell types within the olfactory
neuroepithelium, can be replenished from neuronal progenitor cells and basal stem cells located
near the basement membrane (Loo et al., 1996).
Many other types of cells are located within this unique epithelium. Glial-like supporting
(sustentacular) cells separate the ORCs from one another and may play some role in
paracrine modulation of olfactory receptor cell activity. Another cell linked to paracrine
activity is the ubiquitous microvillar cell, which is involved in modulation of ORCs via
secretion of acetylcholine into the mucosa (Schiffman & Gatlin, 1993). A small number of

such cells appear to project to the olfactory bulbs (Rowley et al., 1989). Most of the mucus
that bathes the olfactory epithelium is derived from Bowman glands, whose ducts permeate
the olfactory epithelium (Figure 1.7).
It is important to recognize that many odorants and chemicals are actively metabolized
by the olfactory mucosa, being deactivated, detoxified, or, in rare cases, transformed into
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Smell and Taste Disorders

Figure 1.7 Low-power cross-section of the human olfactory neuroepithelium depicting the four major types of
cells: bipolar receptor cells (arrows point to cilia at dendritic knob; c, cell body), microvillar cells (m), sustentacular
cells (s), and basal cells (b). Key to abbreviations: bg – Bowman’s gland; lp – lamina propria; n – collection of axons
within an ensheathing cell; d – duct of Bowman’s gland; bs – basal cell undergoing mitosis. Electron
photomicrograph courtesy of Dr. David Moran, Longmont, Colorado.

toxic metabolites. The sustentacular cells, acinar and duct cells of Bowman glands, are
enriched with xenobiotic-metabolizing enzymes. More than ten different P450 enzymes
have been identified in the olfactory mucosa of mammals, including members of the
CYP1A, 2A, 2B, 2C, 2E, 2G, 2J, 3A, and 4B subfamilies. Many P450s are preferentially
expressed in the olfactory region, such as CYP2G1.
The ORN are among the few cells of ectodermal origin capable of regeneration. Others
include cells within the subgranular zone of the hippocampal dentate gyrus, the
sub-ventricular zone (SVZ) in the wall of the lateral ventricle, the organ of Corti, and the
granule and periglomerular cells of the olfactory bulb (Maier et al., 2014). The latter cells
arise from neuroblasts formed within the SVZ that migrate to the bulb along the rostral
migratory stream. Approximately 95 percent of these neuroblasts become granule cells,

whereas the remainder become GABAergic and dopaminergic periglomerular cells.
The olfactory receptor proteins are found on the cilia that, in many cases, lie along the
surface of the mucus covering the epithelium. Unlike the cilia of the respiratory epithelium,
these long cilia lack contractile (dynein) arms and, thus, intrinsic motility.

Olfactory Transduction
The primary second messenger for mammalian odor transduction is cAMP, whose essential
function is to amplify the incoming signal from odorant receptors and ultimately facilitate
release of glutamate, the primary neurotransmitter of the olfactory receptor cells. Opening
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Anatomy and Physiology of Olfaction

9

Odorant
receptor

Olfactory
neuron

Odorant

GTP

G off
β
γ

GDP

Adenylate
cyclase III

Cilia
ATP cAMP
Na+
Ca2+
Cell
body

Na+

Na+Ca2+
Cyclic-nucleotidegated channel

Axon
Projects to olfactory bulb
Figure 1.8 Simplified diagram of the mouse cAMP-related olfactory signal transduction cascade. Odorant binding
to the olfactory receptor activates Golf. Activated Golf then dissociates from Gβγ and activates adenylate cyclase III,
leading to an increase in the intracellular cAMP concentration, which in turn opens the cyclic-nucleotide-gated
channels. The consequent influx of Na+ and Ca2+ ions generates an action potential, which travels into the olfactory
bulb. Reproduced with permission from Ebrahimi & Chess (1998).

of a cyclic nucleotide-gated channel causes movement of Na+ and Ca2+ into the cell
(Figure 1.8). As Ca2+ enters the cytoplasm of the cilium through this channel, a secondary
depolarizing receptor current is activated that mediates an outward Cl− movement in the
receptor neuron. Due to the high Cl− concentration within this neuron, an elevated

reversal potential for Cl− is induced. This increases the outward movement of Cl− across
the membrane and the induction of depolarization. Both N-methyl d-aspartate (NMDA)
and non-NMDA receptors are subsequently activated by glutamate on the dendrites of the
second-order neurons. Although the second messenger, inositol 1,4,5-trisphosphate
(IP3), has been implicated in both invertebrate and vertebrate olfactory transduction, it
appears to play a lesser role than cAMP-mediated receptor processes in mammalian
olfactory signal transduction (Benbernou et al., 2011). Implementing calcium imaging,
only about 5 percent of all mammalian olfactory cells utilize IP3 as a second messenger
(Elsaesser et al., 2005).
Olfactory Receptor Gene Superfamily. In a 1991 landmark study that led to the 2004 Nobel
Prize for Physiology or Medicine, Linda Buck and Richard Axel identified the first 18
members of the olfactory receptor gene superfamily using a degenerate polymerase chain
reaction strategy (Buck & Axel, 1991). This superfamily comprises 18 gene families and 300

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10

Smell and Taste Disorders

6
2
6
11
10
3
14 N
7

7
G
16
15

1

4

16
5

8 15
P 4 11

15 8

II
R 7

17 N

I

3

25
3

25

D
14

21
24
13
2

15

2

D

11
4
*
* 15
*
* 8

24
13

* 12

Y
11 22

*
7
*
5
16
14
3 *
10*
*
20
*
17 6 13

III
23 19 26
* * * * 15
16
* 22
* 11
13
7
4
W
18
25
17 6

Figure 1.9 Left: Presumed odorant-binding pockets of an odor receptor protein. Overhead view of the seven
transmembrane-spanning barrels of an odor receptor protein modeled against the rhodopsin G-protein coupled
receptor (GPCR). Residues that are conserved among all GPCRs are shown in open circles. Colored squares and circles

represent positions of conserved and variable residues, respectively, in OR proteins. Residues that align with ligand
contact residues in other GPCRs are colored green and residues that do not align with such residues are colored red.
The residues in each helix are numbered separately, according to the predicted transmembrane boundaries.
Hypervariable residues (putative odorant-binding residues) are indicated by asterisks. Area II denotes a hypervariable
pocket that corresponds to the ligand-binding pocket in other GPCRs. Reproduced from Pilpel & Lancet (1999).
Right: Predicted structure for mouse olfactory receptor (OR) S25. Model depicts the putative binding pocket for the
hexanol ligand (purple) to the receptor protein (side view). Each transmembrane and inter-transmembrane loop
is labeled. The membrane is represented in yellow. This computed model of the S25 odorant receptor protein atoms
successfully predicts the relative affinities to a panel of odorants, including hexanol, which is predicted to interact
with residues in transmembranes 3, 5, and 6. Reproduced with permission from Floriano et al. (2000). (A black
and white version of this figure will appear in some formats. For the colour version, please refer to the plate
section.)

subfamilies (Olender et al., 2008). The receptors, like other G-protein-coupled receptors,
have seven transmembrane domains with a stereotyped topology (Figure 1.9). The internal
transmembrane domains, which are hypervariable in evolution, are believed to interact with
odorants in a manner analogous to the α2 adrenergic receptor-ligand interaction (Buck &
Axel, 1991).
Olfactory receptors generally fall into two classes: Class I and Class II receptors (Freitag
et al., 1998). The preferred odorant agonists of Class I receptors, which include receptors found
mainly in fish, are generally water-soluble odorants, whereas this is not the case with Class II
receptors. Amphibians and mammals express both Class I and Class II receptors.
Although humans have ~950 genes that express olfactory receptor proteins, less than 400
are functional. The remainder are pseudogenes which probably have no function – although
this is not yet certain. A given olfactory receptor neuron expresses only one receptor type,
resulting in ~380 different receptor elements embedded within the 6–10 million receptor cells.
However, a single odorous chemical commonly binds to a subset of receptors that may
overlap with additional subsets activated by other odorants. Receptor genes are found in
about 100 loci spread over all chromosomes except for chromosome 20 and the Y chromosome (Olender et al., 2008) (Figure 1.10). Six chromosomes (1, 6, 9, 11, 14, 19) contain

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Anatomy and Physiology of Olfaction

11

Figure 1.10 Chromosome locations of human OR genes. There were 630 OR genes that localized to 51 different
chromosomal loci distributed over 21 human chromosomes. OR loci containing one or more intact OR genes are
indicated in red; loci containing only pseudogenes are indicated in green. The cytogenetic position of each locus is
shown on the left, and its distance in megabases from the tip of the small arm of the chromosome is shown on
the right (chromosome-Mb). The number of OR genes at each locus is indicated in parentheses, and the number of
OR genes on each chromosome is indicated below. Most human homologs of rodent ORs for n-aliphatic odorants
are found at a single locus, chromosome 11p15. Reproduced with permission from Malnic et al. (2004). Since this
map was published OR genes have been found on chromosome 8. (A black and white version of this figure will
appear in some formats. For the color version, please refer to the plate section.)

nearly three-quarters of the receptor genes, whereas a single gene is found on chromosome 22.
Chromosome 11 contains 51 percent of the receptor genes and harbors the two largest
receptor gene clusters found in the mammalian genome (Olender et al., 2008).
Interestingly, the olfactory subgenome spans ~30 Mb, a length that represents about 1 percent
of total human genomic DNA.
The molecular phenotype of the olfactory sensory neurons is one of the most diverse
in the nervous system, given the large number of different receptors, second-messenger
pathways, and cell-surface antigens (Shepherd et al., 2004). At one time it was believed
that all of ORN replenished themselves every 30 to 40 days, but it is now known this is
incorrect (Mackay-Sim et al., 2015). Thus, long-lived receptor cells are present within
the epithelium and regulatory mechanisms influence the timing and extent of receptor
cell neurogenesis from the basal cell population (Hinds et al., 1984). Unfortunately,

regeneration after toxic, viral, or other insults is rarely complete and, as a result, the
olfactory epithelium becomes replaced and stippled by islands of respiratory-like
epithelium.
Several investigators have overcome the extreme difficulty in establishing the specific
ligands for olfactory receptor cells, a process termed deorphanizing the receptors
(Peterlin et al., 2014). This process has been challenging, since more than one ligand
can bind to a given receptor and the expressed proteins remain embedded in the plasma
membrane (Lai et al., 2014). One of the more recent examples of deorphanizing
olfactory receptors comes from a study by Saito et al. (2009). They deorphanized 52
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Smell and Taste Disorders

10

11m

11

14

47/12

OB

AOG

OT

AON
Tu

LOG

OS

MOG

12

G

PO

38
OpT

L
34
G
PIR-FR

AM

EA

MB
CP

28

PIR-TP

Figure 1.11 Base of human brain showing the ventral forebrain and medial temporal lobes. The blue oval area
represents the monkey olfactory region, whereas the pink oval represents the probable site of the human olfactory region
as identified by functional imaging studies. Modified from: Gottfried J.A., Small D.M., & Zald D.H. (2006), Chapter 6, Plate 9.
Key: numbers refer to the approximate position of Brodmann areas as follows: 10 – fronto-polar area; 11/11 m –
orbitofrontal/gyrus rectus region; 28 – posterior entorhinal cortex; 34 – anterior entorhinal cortex; 38 – temporal pole;
47/12 – ventrolateral frontal area. Other abbreviations: AM – amygdala; AOG/POG/LOG/MOG – anterior, posterior, lateral,
medial orbital gyri; AON – anterior olfactory nucleus; CP – cerebral peduncle; EA – entorhinal area; G – gyrus ambiens;
L – limen insulae; MB – mamillary body; PIR-FR – frontal piriform cortex; PIR-TR – temporal piriform cortex; OpT – optic
tract; OS – olfactory sulcus; OT – olfactory tracg with deionized water. A total of 96 forced-choice
trials (4 tastants × 4 lingual regions × 6 repetitions) was presented. The maximum score a
subject can attain across all segments of the tongue for a given tastant was 24.
Using this technique, gustation was evaluated in six patients with taste impairment
associated with Terbinafine (Lamisil®), a widely prescribed oral antifungal agent. They
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30% Sucrose
Other Liquids

NUMBER OF PERSONS PREFERING

Measurement of Gustation

157

20
10

10
20

20

30

40

50

60

70

80

90

BLOOD GLUCOSE LEVEL (mg/100 ml)
Figure 4.11 Number of subjects preferring a 30% sucrose solution in relationship to blood glucose levels. From
Mayer-Gross & Walker (1946).

(a)

MEAN (±SEM) TRIALS CORRECT

25

SUCROSE
.03

NACL

(b)
25

20

20

15

15

10

10

5

5

0
(c)
25

T

C

CITRIC ACID

0
(d)
25

.04

T
CAFFEINE

.000

.004

20

20

15

15

10

10

5

5

0

T

C

C

0

T

C

STUDY GROUP
Figure 4.12 Influence of Terbinafine (Lamisil®) on taste identification test scores for stimuli representing the four
major taste qualities. The agents were presented to the left and right anterior and posterior regions of the tongue
using micropipettes. The test scores represent the summation of scores across all four lingual regions. T = Terbinafine
patients; C = Controls (see text for details). From Doty & Haxel (2005).
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Smell and Taste Disorders

were compared to six age-, sex-, and race-matched controls (Doty & Haxel, 2005). Despite
the small samples, the mean taste scores were significantly lower in the Terbinafine group
than in the controls for all stimuli, particularly for citric acid (sour) and caffeine (bitter)
(Figure 4.12). In the case of NaCl, the Terbinafine-related deficit was largely confined to
the posterior sectors of the tongue.

Normative Data for Regional Taste Testing
Like whole-mouth testing, few normative data are available for assessing regional taste dysfunction relative to healthy controls. An exception is a study by Pingel et al. (2010): no right-left side
differences were apparent in their control sample, in keeping with other normative data. They
used four concentrations of sucrose (0.03, 0.1, 0.4, 2.0 g/mL), citric acid (0.01, 0.05, 0.1, 0.15 g/
mL), NaCl (0.025, 0.075, 0.15, 0.36 g/mL), and quinine HCl (0.0002, 0.0005, 0.001, 0.01 g/mL).
Stimuli were administered using an 18 cm long, 0.4 cm diameter “glass probe”. As noted by
these investigators,
A drop (approximately 20 μL) of liquid sweet, sour or salty tastant was applied on both sides of
the anterior third of the extended tongue (sweet on the tongue tip; sour and salty on the tongue
edge). The bitter tastants were presented on both sides of the posterior third of the extended
tongue. The tastants were applied in a pseudo-randomized order starting with the lowest
concentration, ending with the highest quinine hydrochloride solution and alternating the side
of stimulation. In a multiple-alternative procedure, taste stimuli were presented at intervals of
about 30 s. After presentation of the stimulus and with their tongue still extended, subjects were
asked to pick one of the five descriptors (“sweet”, “sour”, “bitter”, or “water/no taste”).

The test score was the sum of correct responses on each side of the tongue (total possible =
16). Given that no left-right side differences were found, the normative data are presented in
Table 4.5 for both sides combined. The scores when each side of the tongue is tested can be
halved. It is apparent from this table that scores at or below ~23 infer gustatory dysfunction
regardless of age. The lack of a sex difference and the very weak effect of age is apparent. It
might have been preferable to have subdivided the >55 age category, since the most severe

taste deficits occur after the age of 60.
It is unfortunate that there are few published normative data available for threshold or
suprathreshold testing. For routine clinical work borrowed controls may suffice, but for
most research purposes it is recommended that investigators obtain control data from the
local population to avoid confounding from, e.g., social, ethnic, linguistic, and occupational influences.

Electrogustometry
Basic Considerations
As mentioned earlier in this chapter, electrical, rather than chemical, stimulation of the taste
system has numerous practical advantages. The duration and extent of electrical stimulus
can be controlled without difficulty, rinsing between stimulus presentations is not necessary, areas of the palate can be tested easily, and mixing and storage of tastants is not
required. The device is portable, making it amenable to bedside and other out-of-laboratory
applications.

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Measurement of Gustation

159

Table 4.5. Normative data (percentiles) for a taste study in men (top) and women (bottom) that combine
responses to sweet-, sour-, bitter-, and salty-tasting agents presented to the anterior tongue using glass probes.
Note minimal influences of both age and sex on the test scores. Modified from Pingel et al. (2010).

MEN
AGE GROUP (Years)
5–15

16–35

36–55

>55

95th Percentile

32

32

32

32

90th Percentile

32

32

32

32

75th Percentile

32

32

32

32

50th Percentile

32

30

30

30

25th Percentile

30

28

26

28

10th Percentile

27

24

24

24

5th Percentile

25

24

22

23

Mean (SD)

30.7 (2.1)

29.7 (2.9)

28.6 (3.6)

29.1 (3.3)

N:

31

99

177

139

WOMEN
AGE GROUP (Years)
5–15

16–35

36–55

>55

95th Percentile

32

32

32

32

90th Percentile

32

32

32

32

75th Percentile

32

32

32

32

50th Percentile

30

32

30

30

25th Percentile

29

30

27

28

10th Percentile

28

28

24

24

5th Percentile

24

26

22

23

Mean (SD)

30.3 (2.0)

30.7 (2.1)

28.7 (2.8)

29.9 (2.8)

N:

20

121

193

164

In the most common electrogustometry paradigm, low microampere currents, usually of
half-second duration, are applied to selected regions of the tongue via a stainless steel
electrode, typically the anode. The cathode is attached elsewhere, e.g., the nape of the neck
or on the hand. The electrogustometer (EGM) takes into account resistance differences
among people, i.e., it is a constant current generator, thus eliminating any issues associated
with different resistances due to body size, composition, or distance between the anode and
cathode. Nevertheless, the physiologic basis for the production of electrical sensations
remains controversial and electrogustometry rarely produces classic taste sensations
(Murphy et al., 1995). In fact, sweet responses are never observed, in accord with observations
of rat studies that anodal current does not activate sucrose sensitive fibers (Ninomiya &
Funakoshi, 1981). Nonetheless, functional imaging studies demonstrate that electrical
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Smell and Taste Disorders

Figure 4.13 The Rion TR06 Electrogustometer. This is a popular commercially available model. Discrete stimulus
pulses can be presented at durations varying from 0.5 to 2 sec duration and currents adjustable from −6 dB (4µA) to
34 dB (400µA) in 21 steps. From left to right: earth strip which is placed around the neck; gustometer with stimulating
electrode below. Also supplied is a foot pedal and remote stimulator switch (not shown).

stimulation of the tongue activates essentially the same taste-related brain regions as chemical stimulation (Barry et al., 2001), as explained later in this chapter.

Electrogustometric Threshold Testing
Several psychophysical procedures that employ low electrical currents have been used
to activate taste afferents on the tongue or palate. The more prevalent methods are
staircase procedures. The Rion TR06 (Figure 4.13) is popular partly because it can
deliver the lowest current discernable by most healthy people (−4 µA). This is of particular
relevance when examining tongue regions such as the tongue tip that are densely
packed with papillae. Despite this, “basement” or “floor” effects are often seen in
threshold experiments, particularly when forced-choice procedures are involved
(Loucks & Doty, 2004). Clinically this is not a major problem, since basement effects
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Measurement of Gustation

161

signify normal function, but it does reduce the ability to establish a participant’s

specific threshold values over regions densely populated with papillae. This might
become an issue when subtle effects of medication and other interventions, such as
surgery, need to be assessed.
Although chemical thresholds decrease monotonically, i.e., in the same orderly direction, as stimuli increase up to 1.5 sec (Bagla et al., 1997), thresholds based upon electrical
stimulation are different. For example, one study found that, as expected, electrical thresholds were lower for stimuli of 1.0 sec duration compared to 0.5 sec, but remarkably,
thresholds for longer stimuli, lasting 1.5 sec, were equivalent to those of 0.5 sec duration
(Loucks & Doty, 2004). Thus, electrical threshold values behaved in a U-shaped curve and
were raised if the stimulus duration exceeded one second, unlike chemical thresholds that
continue to decline (i.e., show better sensitivity) with increasing stimulus duration. A source
of confusion in the literature is the fact that not all studies employ the same stimulus
durations, with values ranging from 0.25 sec to 2.0 sec. It is also important to recognize that
EGM thresholds obtained on tongue regions where papillae are less dense are lower and
more reliable for larger (125 mm2) than smaller (25 mm2) electrodes, presumably reflecting
the number of taste afferents that are activated (Nicolaescu et al., 2005). This becomes
important because electrode sizes vary among studies [e.g., 12.5 and 50 mm2 electrodes by
Miller et al. (2002) and Loucks & Doty (2004), 20 mm2 electrodes by Krarup (1958) and
Lobb et al. (2000), 60 mm2 electrodes by Grant et al. (1987), and 234 mm2 electrodes by
Coates (1974)], making difficult any comparisons across laboratories. Although EGM
thresholds correlate well with regional taste tests, often they do not correlate well with
whole-mouth taste tests. This would be expected, since they stimulate only small lingual
sectors that need not be representative of the taste bud distribution of the entire tongue.

Normative Data for Electrogustometric Thresholds
Like chemical taste testing, reports of “normal” electrical thresholds differ markedly from
one study to the next and normative data are rare. Reflecting other taste measures, EGM
thresholds are influenced by age and, in some studies, gender, although large individual
differences mask such effects frequently. A major issue is how to determine the cut-off for
abnormality. In this section, abnormality is defined as thresholds that fall around or below
the fifth percentile, as in Tables 4.3 and 4.5.
The distribution of EGM thresholds obtained in 460 subjects aged 15 to 94 years is

presented in Figure 4.14 (Nakazato et al., 2002). Two lingual regions on each side of the
tongue were evaluated (Figure 4.15), namely an area on the anterolateral tongue 2 cm from
the midline and a region on the foliate papillae. Palatal regions innervated by the greater
(superficial) petrosal nerve (CN VII) located 1 cm posterior to the uvula and 1 cm to the left
and right of the midline were also assessed (not shown).
In a recent study, EGM thresholds were determined for 74 men and 82 women, all nonsmokers, aged 10 to 80 years (Pavlidis et al., 2012). They examined six regions of the
tongue and palate as shown in Figure 4.16. Stimulus duration was 1 second and a nonforced-choice staircase threshold test was employed. Subjects were instructed to be certain
they experienced a metallic rather than electrical sensation, under their assumption that
the former was induced by the gustatory system and the latter by the trigeminal system.
The right side was tested first. On the basis of learning or other testing order effects, it
would be predicted that test performance might be higher on the left than on the right, but
the opposite was found. Most thresholds were lower on the right than on the left side at all
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Smell and Taste Disorders

Chorda Tympani Nerve
60
50
40
30

Normal Abnormal

20
10

0

.8 1.2 1.9 3.1 5.0 8.0 13 20.5 33 53 84 130 210 330 520
Glossopharngeal Nerve

80
FREQUENCY

70
60
50
40
30

Normal Abnormal

20
10
0

.8 1.2 1.9 3.1 5.0 8.0 13 20.5 33 53 84 130 210 330 520
Greater Petrossal Nerve

45
40
35
30

Normal Abnormal

25
20
15
10
5
0

.8 1.2 1.9 3.1 5.0 8.0 13 20.5 33 53 84 130 210 330 520
THRESHOLD (Microamps)

Figure 4.14 Frequency distribution of EGM thresholds obtained from three regions using an ascending singleseries non-forced-choice threshold measure. Cut-off for abnormality is at ~5th percentile in each case. Note
similarities in the distributions between the chorda tympani (CN VII) and glossopharyngeal (CN IX) responses, and
the higher thresholds for the greater petrosal nerve (CN VII). Modified from Nakazato et al. (2002).

the target sites for both sexes. Since counterbalancing of test order was not done, it is not
known if this was a true effect or due to some confound, such as adaptation or subject
fatigue.
The average test results are presented for each tongue region, sex, and age group in
Table 4.5. Pavlidis et al. (2012) reported that thresholds of the subjects older than 65
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