Clinical Anatomy 27:54–60 (2014)
ORIGINAL COMMUNICATION
Olfaction: Anatomy, Physiology, and Disease RIDDHI M. PATEL
AND
JAYANT M. PINTO*
Department of Surgery, Section of Otolaryngology-Head and Neck Surgery, The University of Chicago, Chicago, Illinois
The olfactory system is an essential part of human physiology, with a rich evolutionary history. Although humans are less dependent on chemosensory input than are other mammals (Niimura 2009, Hum. Genomics 4:107–118), olfactory function still plays a critical role in health and behavior. The detection of hazards in the environment, generating feelings of pleasure, promoting adequate nutrition, influencing sexuality, and maintenance of mood are described roles of the olfactory system, while other novel functions are being elucidated. A growing body of evidence has implicated a role for olfaction in such diverse physiologic processes as kin recognition and mating (Jacob et al. 2002a, Nat. Genet. 30:175–179; Horth 2007, Genomics 90:159–175; Havlicek and Roberts 2009, Psychoneuroendocrinology 34:497–512), pheromone detection (Jacob et al. 2002b, Horm. Behav. 42:274–283; Wyart et al. 2007, J. Neurosci. 27:1261–1265), mother–infant bonding (Doucet et al. 2009, PLoS One 4:e7579), food preferences (Mennella et al. 2001, Pediatrics 107:E88), central € ssen 2009, B-ENT 5:129–132), and even nervous system physiology (Welge-Lu longevity (Murphy 2009, JAMA 288:2307–2312). The olfactory system, although phylogenetically ancient, has historically received less attention than other special senses, perhaps due to challenges related to its study in humans. In this article, we review the anatomic pathways of olfaction, from peripheral nasal airflow leading to odorant detection, to epithelial recognition of these odorants and related signal transduction, and finally to central processing. Olfactory dysfunction, which can be defined as conductive, sensorineural, or central (typically related to neurodegenerative disorders), is a clinically significant problem, with a high burden on quality of life that is likely to grow in prevalence due to demographic shifts and increased environmental exposures. Clin. Anat. 27:54–60, 2014. VC 2013 Wiley Periodicals, Inc. Key words: olfactory; sensorineural; neurodegenerative
INTRODUCTION The sense of smell has been often overlooked in comparison with other sensory modalities. This may be due to the challenges to studying odorous stimuli and measuring responses, or due to adoption of evolutionary models, which posit that olfaction has regressed in humans. Such a hypothesis poses that as humans began to walk upright and distanced themselves from the odor-rich floor, the biologic need for sense of smell decreased, and so did the relative size of human olfactory structures and number of olfactory receptor (OR) genes (Rouquier et al., 1998; Gilad et al., 2003; Shephard, 2004), perhaps in parallel to rises in the roles of other senses (vision, hearing).
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2013 Wiley Periodicals, Inc.
Grant sponsor: McHugh Otolaryngology Research Fund; Grant sponsor: National Institute on Aging at The University of Chicago; Grant numbers: K23 AG036762; AG12857. *Correspondence to: Jayant M. Pinto, Section of Otolaryngology-Head and Neck Surgery, The University of Chicago Medicine and Biological Sciences, 5841 South Maryland Avenue, MC 1035, Chicago, Illinois 60637. E-mail: [email protected] Received 1 October 2013; Accepted 2 October 2013 Published online 22 November 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ca.22338
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Fig. 1. Schematic of neuroanatomic connections of the olfactory system. Shown is a sagittal cross-section of the lateral nasal wall. Olfactory neurons are depicted in blue, and their axons form filia of the olfactory nerve,
which crosses the cribiform plate, synapse in the olfactory bulb, and continue to the various portions of the central nervous system. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
However, in comparative studies of olfactory detection, human detection thresholds are actually more sensitive than those in rodents and primates (Laska and Seibt, 2002), and that humans can readily discriminate between two different odors that differ by a single molecular component (Laska and Tuebner, 1999). Human olfactory perception is clearly highly sensitive and specific, and advances in our ability to study this modality have highlighted this impressive physiologic performance. Clinically, the importance of olfaction in human lives and behavior is readily apparent. As opposed to the animal kingdom, where odors have powerful impacts due to their association with predators, food, and sexual gratification (Gottfried, 2006), evidence exists that odors can also modulate human behavior. Infants can recognize their own mothers’ odors that is useful for suckling (MacFarlane, 1975; Russell, 1976); Doucet et al. 2009, perfumes may alter social interactions (Baron, 1988); male and female odors may influence reproductive physiology and mating patterns (Ober et al., 1997; Wyart et al. 2007; Jacob et al., 2002aJacob 2002b; Havlicek and Roberts 2009; Horth 2007); and odor signals are important in food preferences, even over visual cues (Beauchamp and Maller, 1977; Menella 2001). Our sense of smell is also integrative, in which multiple odorants are synthesized together simultaneously. Also, it remains plastic and contextual, being strongly modulated by visual, perceptual, and cognitive factors and a large component of relies on learned experience (Zellner and Kautz, 1990; Niimura 2009; Dalton, 1996; Dalton et al., 2000; Distel and Hudson, 2001).
cavity (Fig. 1 and Fig. 2). The paired nasal passages are divided in the midline by the nasal septum. Each lateral nasal wall is formed by up to four bony outgrowths or turbinates (generally inferior, middle, superior, and in some cases supreme). The nasal valve lies anteriorly at the vestibule of the nose and is formed by the lower border of the upper lateral cartilage, the septum, and the anterior portion of the inferior turbinate; this crosssectional area is the point of highest resistance of the respiratory tract. Airflow patterns in the nose are affected by anatomic and physiologic factors that may modify these structures. Alteration of the normal laminar airflow through the nose results in turbulence, which not only affects the other functions of the nose (humidification and warming of air before its arrival in the lower airway by the turbinates (Ingelstedt, 1956)) but also may impair the direction of air superiorly toward the olfactory epithelium (Zhao, 2004). The detection of odorants on a physical basis starts with a sniff, resulting in turbulent airflow that carries odorants to the olfactory epithelium superiorly in the nose. The odorants then diffuse into the mucus and are transported to the OR by chaperones called odorant-binding proteins, which are thought to speed up the transport of the odorants to their receptors on the surface and also to help remove them to clear the signal. Binding of the odorant to the specific OR(s) then induces signaling. A second method of perception of odorants comes posteriorly through the nose via retronasal olfaction, where odorants arise through the nasopharynx, ascend through the choanae of the nose posteriorly, and rise to the olfactory epithelium via this route. Retronasal olfaction is thought to play a key role in the sensation of flavor during consumption of food and liquids (Carmichael et al., 1994).
ANATOMY OF OLFACTION Peripheral Pathway The structure of the nose is designed, in part, to direct inspired air toward the olfactory epithelium, located in superiorly and posteriorly within the nasal
Central Pathway—Cranial Nerves Chemosensation in the nose is mediated by both the olfactory nerve (cranial nerve I) and trigeminal
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Fig. 2. CT scan shown in bone windows (a, coronal and b, axial) of a normal patient, demonstrating the olfactory cleft, which is at along the cribiform plate at the superiormost portion of the nose, both medial to and along the superior turbinate.
nerve (cranial nerve V) (Pinto, 2011). The olfactory neuroepithelium is characterized by the presence of olfactory neurons whose axons project across the cribriform plate at the roof of the nasal cavity, where they synapse with neurons in the central olfactory nervous system. Classically, the distribution of olfactory epithelium has been thought to be along the cribriform plate at the superior-most portion of the nose, medial to the superior turbinate and along this turbinate itself. However, more recent studies have revealed a more extensive distribution that extends farther down the nose as far as the anterolateral mid-
Fig. 3. Sagittal T1 weighted magnetic resonance imaging image of a normal patient, demonstrating the primary olfactory cortex in the orbitofrontal region.
dle turbinate and also inferiorly from the cribriform plate down the posterior and middle nasal septum (Kern, 2000). The location of the olfactory epithelium is variable among people and is thought to change with time, due to conversion to or ingrowth of respiratory epithelium with comcomitant loss of olfactory neurons. This process occurs with age and also, potentially, from environmental insult (toxins, volatile chemicals, tobacco smoke, and industrial or occupational or airborne pollutants) or pathophysiologic processes such as infection or inflammation (Baroody et al., 1999). In addition to its function in olfaction, the other major chemosensory component of the nose is the trigeminal system. Trigeminal chemosensory nerve endings in the nose are in the airway’s first defense against noxious stimuli. Branches of the trigeminal nerve (cranial nerve V), specifically the ophthalmic and maxillary nerve, innervate the mucosa of the nose and sinuses and mediate irritant responses. These afferent axons synapse in the trigeminal nucleus, which relays signals to the ventral posterior medial nucleus of the thalamus and then cortical areas that process facial irritation and pain. Nociceptive neurons of the trigeminal nerve are activated by chemicals classified as irritants, including air pollutants, ammonia, ethanol and other alcohols, acetic acid, carbon dioxide, menthol, capsaicin, and others. Many substances also elicit olfactory signals in addition to trigeminal responses, although the threshold concentrations for trigeminal chemoreception seem to be much higher than those for olfaction. Responses to trigeminal chemosensory stimuli include pain, irritation, sneezing, salivation, vasodilation with resultant nasal obstruction, tearing, nasal secretion, sweating, a decreased respiratory rate, and bronchoconstriction.
Anatomy, Physiology, and Disease Many of these responses are simulated by neuropeptides released from stimulated nerve endings. If irritants reach the lower airways, analogous responses in the lower airway can trigger sensory activity with resultant bronchoconstriction, bronchospasm, mucus secretion, and neurogenic inflammation.
Central Pathway—Olfactory Epithelium and Central Connections Approximately 10 to 20 million olfactory neurons within the olfactory epithelium are located among a variety of supportive cells. This pseudostratified columnar epithelium includes basal cells that have been shown (in animals, but not conclusively in humans) to function as stem cells that can give rise to all components of the epithelium, Bowman’s glands, microvillar cells, and sustentacular cells, which are thought to support olfactory neuron function. Bowman’s acini are exocrine and produce substances that are essential for olfaction. Key components of olfactory mucus are chaperone proteins called odorantbinding proteins that act to facilitate odorant–receptor interaction. The precise function of the other cell types aiding in neuronal function via other, less well-defined mechanisms are not well known, although perhaps this occurs through providing an appropriate local environment for optimal signal transduction (Pinto, 2011). Indeed, it is possible to obtain putative stem cells from humans through endoscopic biopsies for growth and differentiation in culture, with potential therapeutic effects (Winstead et al., 2005). The regenerative power of the olfactory neuron perhaps represents an evolutionary response to the continual physical challenge of this cranial nerve’s unique direct exposure to the environment and allows for a reparative function on damage. In addition, ensheathing shells that support these olfactory axons may have therapeutic uses (Chiu et al., 2009), potentially in nerve injury or neurodegeneration models. Olfactory neurons are bipolar cells that project a single dendrite with a thickened ending (the olfactory knob) that extends to the epithelial surface and contains nonmotile, sensory cilia where odor molecules bind to their receptor, and an axon that transmits signals to the brain. Axons from these olfactory neurons form nerve bundles (fila olfactoria) that cross the cribriform plate to synapse with other neurons in the glomeruli of the olfactory bulb. The crossing of the olfactory nerve across the skull base through about 20 foramina in the bone makes this region particularly sensitive to traumatic injury, especially through frontal or occipital trauma, a frequent etiology of olfactory loss (Collet et al., 2009). In addition, this also provides a potential route of access to the central nervous system for toxins and pathogens. A complex process of signal transduction and coding of complex signals occurs in the olfactory bulb before information is processed and sent to other areas of the central nervous system (Rawson, 2006; Ma, 2007). Subsequent connections as defined by human functional magnetic resonance imaging studies
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to the “‘primary olfactory region” (piriform cortex, olfactory nucleus and tubercle, amygdala, and entorhinal cortex) and secondary olfactory areas (hippocampus, hypothalamus, thalamus, orbitofrontal cortex, and the cerebellum) may account for the role of olfaction in mood and emotion, pleasure sensation, memory, and many other processes of the central nervous system (Sobel et al., 2003; Katata et al., 2009) Figure 3. More specifically, axons of the mitral and tuft cells of each olfactory bulb coalesce to form the olfactory tract, one on each side. This tract lies in the olfactory sulcus of the basal forebrain and conveys information to the primary olfactory cortex, only ipsilaterally. As the tract courses posteriorly, collateral branches peel off and synapse upon the anterior olfactory nucleus, and then divide into the lateral, intermediate, and medial olfactory stria (although the lateral olfactory tract is the only significant one in human brain) (Gottfried, 2006). The targets of the lateral olfactory tract is the piriform cortex, amygdala, and rostral entorhinal cortex. Additional targets, including the olfactory tubercule and basal forebrain, are found in animal models but it is not known if those exist in human (Carmichael et al., 1994; Shipley and Ennis, 1996). Higher order projections converge on the oribital prefrontal cortex, agranular insula, amygdala subnuclei, thalamus, hypothalamus, basal ganglia, and hippocampus (Gottfried, 2006). The piriform cortex is the major recipient of inputs from the olfactory bulb and is the largest of the central olfactory areas Figure 3. The amygdala receives the terminal ends of many bulb projections, specifically within the discrete amygdala subnuclei. Neurophysiologic recordings in animals and humans (Cain and Bindra, 1972; Tanabe et al., 1975; Hughes and Andy, 1979; Hundry et al., 2001) suggest that amygdala in particular is highly responsive to odor stimulation. Finally, the orbitofrontal cortex represents the main neocortical projection of the olfactory cortex, where direct afferent inputs arrive from all primary olfactory areas and feedback projections travel back to these areas. Interestingly, there is no thalamic intermediary to odor-evoked signals to central brain areas, which is unique among sensory modalities (Gottfried, 2006). Other unique characteristics of the anatomical pathway of olfaction include its true ipsilateral nature and the abundant “limbic” overlap, which may explain the profound ability of odor to affect emotional processing (Gottfried, 2006).
Molecular Basis for Chemosensation in the Nose In 1991, Linda Buck and Richard Axel discovered both the family of transmembrane proteins that were believed to be the odor receptors and some of the genes that encode them, a seminal breakthrough in our understanding of the olfactory system culminating in a Nobel Prize awarded in 2004. The superfamily of OR genes, the largest in the genome, includes approximately 900 genes (although about half are
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nonfunctional) from 18 gene families that reside across the genome, emphasizing their ancient nature, and comprises nearly 3% of the approximately 30,000 genes of the human genome, highlighting their critical role in mammalian physiology and evolution (Miller, 2004). Perhaps most interesting are more recent discoveries of expression of subsets of these genes in nonolfactory tissues including sperm and gut, implicating functions for these genes outside their traditional role in olfaction. In mice, each olfactory neuron expresses only one OR gene (a process regulated by mechanisms that are unclear), and precise spatial patterns of expression of certain classes of ORs and chemosensory receptors (see below) exist in animals and probably in humans. Odorants or mixtures of odorants bind a pattern of ORs, resulting in activation of the G proteins. This results in cyclic AMP–mediated opening of cyclic nucleotide–gated ion channels as well as calcium and sodium ion influx, depolarizing the OR neuron and beginning an action potential that carries the information to the brain. Odorants are thought to bind a number of ORs of varying affinities, resulting in complex signals that the brain is able to interpret through a complex system that is now under active investigation. Because most odors in the environment are mixtures of many components, the complexity of studying the precise signaling responses is enormous and such research relies entirely on animal model systems. In addition, the methods used by the olfactory system to distinguish among odors are not clear. Specific anosmias, the inability to detect particular odors, may reflect a lack of particular OR genes or downstream signaling pathways, rendering the subject unable to smell specific scents (Olender et al., 2008). In other situations, an opposite effect may manifest as hyperosmia, or increased sensitivity, to certain odors (Whissell-Buechy and Amoore, 1973). Adding further complexity to odor detection are the discoveries of additional chemoreceptor genes. For example, trace amine–associated receptors (TAARs) have been found in mice to respond to biogenic amines and mouse urine, potentially modulating species-specific olfactory signals (Menashe et al., 2007). There are six TAAR genes in humans, but there are few data to show how they might function in chemosensation in our species. Another family of genes involved in chemosensation in animals are the vomeronasal type 1 receptors, a multigene family (Dulac and Axel, 1995; Liberles and Buck, 2006) that is expressed in an accessory olfactory region in the nose called the vomeronasal organ, which is thought to be vestigial in humans (Young et al., 2010). These genes are thought to have degenerated through evolution; for example, there are only five of these genes that retain an intact open reading frame in the human genome (Witt and Hummel, 2006). Finally, formyl peptide receptors are candidate chemosensory receptors that might be involved in the detection of normal bacterial flora or mitochondrial proteins in lower animals (Rodriguez and Mombaerts, 2002). Overall, the combinatorial diversity of signals allows for the detection and discrimination of perhaps an unlimited diversity of odorants. Models of olfactory
information processing from insects and lower animals are providing insights for application to human physiology (Liberles et al., 2009).
Variability in Olfactory Function The etiology of the wide variability in olfactory performance is one of the most fundamental questions in olfactory biology. This may reflect different expression patterns of sets of OR genes, central processing effects, or genetic variability in the OR genes themselves, as has been shown in a proof-of-principle study (Cassenaer and Laurent, 2007). Studies have implicated genetic variation as a factor in the individual variation in human olfaction. Surveys of more recently identified forms of genetic variation in the human genome have demonstrated the evolutionary importance of olfaction. For example, a high percentage (68%) of the regions containing segmental copy number variations, which are associated with developmental disorders and susceptibility to diseases, overlap with genes involved in sensation, including olfaction (Wong et al., 2007). Similarly, common deletion variants were found to be present in genes involved in olfaction (McCarroll et al., 2006). Two examples show the ability to tie genetic variation with specific variation in human olfactory function. Keller et al. (2007) demonstrated the first link between the function of a human odorant receptor both in vitro and in odor perception, highlighting a mechanistic basis of variation in olfactory ability between individuals. Similarly, Menashe et al. (2007) identified variation in an OR gene and related it to sensitivity to a specific odor, that of isovaleric acid. Finally, two linkage studies for olfactory phenotypes have been performed (Doty et al., 1996), including our study in which the largest linkage signal for hyposmia (P < 0.0013) was on chromosome 4q, suggesting a role for genetic variation in olfactory performance in humans (Pinto et al., 2008).
CLINICAL ASPECTS OF OLFACTORY DISEASE Approximately 14 million Americans are estimated to have chronic olfactory impairment (Murphy et al., 2002) and more than 200,000 physician visits each year are due to this sensory loss (Panel on Communicative Disorders, 1979; National Institute on Deafness and Other Communication Disorders (NIDCD), 2004). Olfactory impairments can be classified into three broad categories of etiology: conductive losses from obstruction of the nasal passages, sensorineural causes from damage to the olfactory neuroepithelium, or central dysfunction related to central nervous system disease. These categories are not mutually exclusive. Olfactory disease can also be described on the basis of perceptual symptoms: difficulty with odor identification (dysosmia); sensation of an odor different that the typical for that substance (parosmia); and perception of an odor when none is present (phantosmia). The causes of olfactory decline are varied: most predominant is aging in the general population
Anatomy, Physiology, and Disease (Rawson, 2006), followed by upper respiratory tract infections, head trauma, and sinonasal disease (Murphy et al., 2003). There are a number of pathophysiologic changes that cause this olfactory dysfunction. For example, inflammatory diseases such as rhinitis or sinusitis commonly cause conductive olfactory loss due to both physical obstruction (edema impeding nasal airflow and odorant movement) and direct effects of inflammation on olfactory neuroepithelium. Trauma to the nose such as skull base fractures, surgical alterations of anatomy, or congenital disorders such as choanal stenosis or nasal cysts can affect airflow and therefore olfaction. Sensorineural causes are due to alterations on an epithelial level, which can happen in inflammatory or autoimmune disease, infection, or congenital syndromes such as Kallmann’s syndrome or agenesis of the olfactory bulb. Finally, olfactory decline has been associated with several € ssen (2009), neurodegenerative diseases, Welge-Lu including Alzheimer’s disease and Parkinson’s disease. Other physiologic or pathophysiologic conditions that alter olfactory dysfunction include endocrine changes including pregnancy, diabetes, Addison’s disease, vitamin deficiency (primarily vitamins A and B and thiamine) (Martin et al., 2009), as well as renal and liver disease. Chemicals such as benzene, menthol, sulfur dioxide, carbon disulfide, heavy metals, and dust have also been associated with olfactory loss. Medications such as steroids, cancer chemotherapy, antibiotics (aminoglycosides, macrolides, tetracycline), antithyroid medication, opiates, sympathomimetics, antacids, and L-dopa can all affect olfaction. The workup of olfactory dysfunction begins with a careful history recording the onset of symptoms, rate of decline, and associated factors. Inflammation accounts for the most easily treatable cause, and therefore, determining associated nasal symptoms is very useful. Central nervous system disease can be investigated if there are any pertinent neurologic symptoms or history. The physical examination focuses on a thorough nasal and neurologic examinations. Objective testing allows the characterization of the nature and degree of olfactory loss, establishes the validity of disease, and allows monitoring. The most commonly used technique clinically is an odor identification test, which assesses how well patients can identify specific odors in a forced choice format (The University of Pennsylvania Smell Identification Test, a 40-item scratch-and-sniff smell test) (Doty et al., 1984). Imaging with sinus computed tomography scan or magnetic resonance imaging are not useful as screening measures but are indicated if the history or physical exam findings warrant it. Treatment is usually limited to anti-inflammatories as indicated and counseling regarding lifestyle safety measures (inability to recognize toxic smells including gas leaks, smoke detectors, etc.). Prognosis is dependent on the mechanism of loss, with medical and surgical therapies having the best outcomes for conductive disease. Patients may recover from traumatic and postviral loss, with return of some smell function at 1 year being a positive prognostic sign (Pinto, 2011). Currently, there is no treatment available for sensorineural loss and neurologic etiologies.
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Unfortunately, options for treatment are limited for the majority of patients with olfactory dysfunction. Thus, this area is rich for advancement of both basic and clinical knowledge that will help human health.
CONCLUSION Olfaction is a critical physiologic process of the nasal airway, mediated primarily by the olfactory nerve. Peripheral and central components of the olfactory systems, as described above, modulate the perception and function of this vital chemical sense. Olfaction remains a critical part of human behavior and emotional experience, and clinical implications of olfactory loss is continuing to emerge as its prevalence increases and effects on quality of life are becoming more apparent.
ACKNOWLEDGMENTS The authors declare no conflicts of interest.
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Murphy C, Doty R, Duncan H. 2003. Clinical disorders of olfaction. In: Doty R, editor. Handbook of Olfaction and Gestation. New York: Marcel Dekker. Murphy C. Symposium overview: Chemical senses and longevity. 2009. Ann N Y Acad Sci 1170:680–681. National Institute on Deafness and Other Communication Disorders (NIDCD). 2004. URL: http://www.nidcd.nih.gov/health/statistics/smell.asp.2004 [accessed November 2010]. Niimura Y. 2009. Evolutionary dynamics of olfactory receptor genes in chordates: Interaction between environments and genomic contents. Hum Genomics 4:107–118. Ober C, Weitkamp LR, Cox N, Dytch H, Kostyu D, Elias S. 1997. HLA and mate choice in humans. Am J Hum Genet 61:497–504. Olender T, Lancet D, Nebert DW. 2008. Update on the olfactory receptor (OR) gene superfamily. Hum Genomics 3:87–97. Panel on Communicative Disorders (U.S.). 1979. Report of the Panel on Communicative Disorders to the National Advisory Neurological and Communicative Disorders and Stroke Council. Bethesda: U.S. DHEW, Public Health Service, NIH. 351 p. Pinto JM, Thanaviratananich S, Hayes MG, Naclerio RM, Ober C. 2008. A genome-wide screen for hyposmia susceptibility Loci. Chem Senses 33:319–329. Pinto JM. 2011. Olfaction. Proc Am Thorac Soc 8:46–52. Rawson NE. 2006. Olfactory loss in aging. Sci Aging Knowledge Environ 2006:6. Rodriguez I, Mombaerts P. 2002. Novel human vomeronasal receptor-like genes reveal species-specific families. Curr Biol 12: R409–R411. Rouquier S, Friedman C, Delettre C, van den Engh G, Blancher A, Crouau-Roy B, Trask BJ, Giorgi D. 1998. A gene recently activated in human defines a new olfactory receptor family in mammals. Hum Mol Genet 7:1337–1345. Russell MJ. 1976. Human olfactory communication. Nature 260: 520–522. Shephard GM. 2004. The human sense of smell: Are we better than we think? PLoS Biol 2:E146. Shipley MT, Ennis M. 1996. Functional organization of olfactory system. J Neurobiol 30:123–176. Sobel N, Johnson BN, Mainland J. 2003. Functional neuroimaging of human olfaction. In: Doty RL, editor. Handbook of Olfaction and Gustation. New York: Marcel Dekker. p 251–274. Tanabe T, Iino M, Takagi SF. 1975. Discrimination of odors in olfactory bulb, pyriform-amygdaloid areas, and orbitofrontal cortex of the money. J Neurophysiol 38:1284–1296. € ssen A. 2009. Ageing, neurodegeneration, and olfactory Welge-Lu and gustatory loss. B-ENT 5:129–132. Whissell-Buechy D, Amoore JE. 1973. Odour-blindness to musk: Simple recessive inheritance. Nature 242:271–273. Winstead W, Marshall CT, Lu CL, Klueber KM, Roisen FJ. 2005. Endoscopic biopsy of human olfactory epithelium as a source of progenitor cells. Am J Rhinol 19:83–90. Witt M, Hummel T. 2006. Vomeronasal versus olfactory epithelium: Is there a cellular basis for human vomeronasal perception? Int Rev Cytol 248:209–259. Wong KK, deLeeuw RJ, Dosanjh NS, Kimm LR, Cheng Z, Horsman DE, MacAulay C, Ng RT, Brown. CJ, Eichler EE, Lam WL. 2007. A comprehensive analysis of common copy-number variations in the human genome. Am J Hum Genet 80:91–104. Wyart C, Webster WW, Chen JH, Wilson SR, McClary A, Khan RM, Sobel N. 2007. Smelling a single component of male sweat alters levels of cortisol in women. J Neurosci 27:1261–1265. Young JM, Massa HF, Hsu L, Trask BJ. 2010. Extreme variability among mammalian V1R gene families. Genome Res 20:10–18. Zellner DA, Kautz MA. 1990. Color affects perceived odor intensity. J Exp Psychol Hum Percept Perform 16:391–397. Zhao K, Scherer PW, Hajiloo SA, Dalton P. 2004. Effect of anatomy on human nasal air flow and odorant transport patterns: Implications for olfaction. Chem Senses 29:365–379.
ORIGINAL COMMUNICATION
Olfaction: Anatomy, Physiology, and Disease RIDDHI M. PATEL
AND
JAYANT M. PINTO*
Department of Surgery, Section of Otolaryngology-Head and Neck Surgery, The University of Chicago, Chicago, Illinois
The olfactory system is an essential part of human physiology, with a rich evolutionary history. Although humans are less dependent on chemosensory input than are other mammals (Niimura 2009, Hum. Genomics 4:107–118), olfactory function still plays a critical role in health and behavior. The detection of hazards in the environment, generating feelings of pleasure, promoting adequate nutrition, influencing sexuality, and maintenance of mood are described roles of the olfactory system, while other novel functions are being elucidated. A growing body of evidence has implicated a role for olfaction in such diverse physiologic processes as kin recognition and mating (Jacob et al. 2002a, Nat. Genet. 30:175–179; Horth 2007, Genomics 90:159–175; Havlicek and Roberts 2009, Psychoneuroendocrinology 34:497–512), pheromone detection (Jacob et al. 2002b, Horm. Behav. 42:274–283; Wyart et al. 2007, J. Neurosci. 27:1261–1265), mother–infant bonding (Doucet et al. 2009, PLoS One 4:e7579), food preferences (Mennella et al. 2001, Pediatrics 107:E88), central € ssen 2009, B-ENT 5:129–132), and even nervous system physiology (Welge-Lu longevity (Murphy 2009, JAMA 288:2307–2312). The olfactory system, although phylogenetically ancient, has historically received less attention than other special senses, perhaps due to challenges related to its study in humans. In this article, we review the anatomic pathways of olfaction, from peripheral nasal airflow leading to odorant detection, to epithelial recognition of these odorants and related signal transduction, and finally to central processing. Olfactory dysfunction, which can be defined as conductive, sensorineural, or central (typically related to neurodegenerative disorders), is a clinically significant problem, with a high burden on quality of life that is likely to grow in prevalence due to demographic shifts and increased environmental exposures. Clin. Anat. 27:54–60, 2014. VC 2013 Wiley Periodicals, Inc. Key words: olfactory; sensorineural; neurodegenerative
INTRODUCTION The sense of smell has been often overlooked in comparison with other sensory modalities. This may be due to the challenges to studying odorous stimuli and measuring responses, or due to adoption of evolutionary models, which posit that olfaction has regressed in humans. Such a hypothesis poses that as humans began to walk upright and distanced themselves from the odor-rich floor, the biologic need for sense of smell decreased, and so did the relative size of human olfactory structures and number of olfactory receptor (OR) genes (Rouquier et al., 1998; Gilad et al., 2003; Shephard, 2004), perhaps in parallel to rises in the roles of other senses (vision, hearing).
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2013 Wiley Periodicals, Inc.
Grant sponsor: McHugh Otolaryngology Research Fund; Grant sponsor: National Institute on Aging at The University of Chicago; Grant numbers: K23 AG036762; AG12857. *Correspondence to: Jayant M. Pinto, Section of Otolaryngology-Head and Neck Surgery, The University of Chicago Medicine and Biological Sciences, 5841 South Maryland Avenue, MC 1035, Chicago, Illinois 60637. E-mail: [email protected] Received 1 October 2013; Accepted 2 October 2013 Published online 22 November 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ca.22338
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Fig. 1. Schematic of neuroanatomic connections of the olfactory system. Shown is a sagittal cross-section of the lateral nasal wall. Olfactory neurons are depicted in blue, and their axons form filia of the olfactory nerve,
which crosses the cribiform plate, synapse in the olfactory bulb, and continue to the various portions of the central nervous system. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
However, in comparative studies of olfactory detection, human detection thresholds are actually more sensitive than those in rodents and primates (Laska and Seibt, 2002), and that humans can readily discriminate between two different odors that differ by a single molecular component (Laska and Tuebner, 1999). Human olfactory perception is clearly highly sensitive and specific, and advances in our ability to study this modality have highlighted this impressive physiologic performance. Clinically, the importance of olfaction in human lives and behavior is readily apparent. As opposed to the animal kingdom, where odors have powerful impacts due to their association with predators, food, and sexual gratification (Gottfried, 2006), evidence exists that odors can also modulate human behavior. Infants can recognize their own mothers’ odors that is useful for suckling (MacFarlane, 1975; Russell, 1976); Doucet et al. 2009, perfumes may alter social interactions (Baron, 1988); male and female odors may influence reproductive physiology and mating patterns (Ober et al., 1997; Wyart et al. 2007; Jacob et al., 2002aJacob 2002b; Havlicek and Roberts 2009; Horth 2007); and odor signals are important in food preferences, even over visual cues (Beauchamp and Maller, 1977; Menella 2001). Our sense of smell is also integrative, in which multiple odorants are synthesized together simultaneously. Also, it remains plastic and contextual, being strongly modulated by visual, perceptual, and cognitive factors and a large component of relies on learned experience (Zellner and Kautz, 1990; Niimura 2009; Dalton, 1996; Dalton et al., 2000; Distel and Hudson, 2001).
cavity (Fig. 1 and Fig. 2). The paired nasal passages are divided in the midline by the nasal septum. Each lateral nasal wall is formed by up to four bony outgrowths or turbinates (generally inferior, middle, superior, and in some cases supreme). The nasal valve lies anteriorly at the vestibule of the nose and is formed by the lower border of the upper lateral cartilage, the septum, and the anterior portion of the inferior turbinate; this crosssectional area is the point of highest resistance of the respiratory tract. Airflow patterns in the nose are affected by anatomic and physiologic factors that may modify these structures. Alteration of the normal laminar airflow through the nose results in turbulence, which not only affects the other functions of the nose (humidification and warming of air before its arrival in the lower airway by the turbinates (Ingelstedt, 1956)) but also may impair the direction of air superiorly toward the olfactory epithelium (Zhao, 2004). The detection of odorants on a physical basis starts with a sniff, resulting in turbulent airflow that carries odorants to the olfactory epithelium superiorly in the nose. The odorants then diffuse into the mucus and are transported to the OR by chaperones called odorant-binding proteins, which are thought to speed up the transport of the odorants to their receptors on the surface and also to help remove them to clear the signal. Binding of the odorant to the specific OR(s) then induces signaling. A second method of perception of odorants comes posteriorly through the nose via retronasal olfaction, where odorants arise through the nasopharynx, ascend through the choanae of the nose posteriorly, and rise to the olfactory epithelium via this route. Retronasal olfaction is thought to play a key role in the sensation of flavor during consumption of food and liquids (Carmichael et al., 1994).
ANATOMY OF OLFACTION Peripheral Pathway The structure of the nose is designed, in part, to direct inspired air toward the olfactory epithelium, located in superiorly and posteriorly within the nasal
Central Pathway—Cranial Nerves Chemosensation in the nose is mediated by both the olfactory nerve (cranial nerve I) and trigeminal
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Fig. 2. CT scan shown in bone windows (a, coronal and b, axial) of a normal patient, demonstrating the olfactory cleft, which is at along the cribiform plate at the superiormost portion of the nose, both medial to and along the superior turbinate.
nerve (cranial nerve V) (Pinto, 2011). The olfactory neuroepithelium is characterized by the presence of olfactory neurons whose axons project across the cribriform plate at the roof of the nasal cavity, where they synapse with neurons in the central olfactory nervous system. Classically, the distribution of olfactory epithelium has been thought to be along the cribriform plate at the superior-most portion of the nose, medial to the superior turbinate and along this turbinate itself. However, more recent studies have revealed a more extensive distribution that extends farther down the nose as far as the anterolateral mid-
Fig. 3. Sagittal T1 weighted magnetic resonance imaging image of a normal patient, demonstrating the primary olfactory cortex in the orbitofrontal region.
dle turbinate and also inferiorly from the cribriform plate down the posterior and middle nasal septum (Kern, 2000). The location of the olfactory epithelium is variable among people and is thought to change with time, due to conversion to or ingrowth of respiratory epithelium with comcomitant loss of olfactory neurons. This process occurs with age and also, potentially, from environmental insult (toxins, volatile chemicals, tobacco smoke, and industrial or occupational or airborne pollutants) or pathophysiologic processes such as infection or inflammation (Baroody et al., 1999). In addition to its function in olfaction, the other major chemosensory component of the nose is the trigeminal system. Trigeminal chemosensory nerve endings in the nose are in the airway’s first defense against noxious stimuli. Branches of the trigeminal nerve (cranial nerve V), specifically the ophthalmic and maxillary nerve, innervate the mucosa of the nose and sinuses and mediate irritant responses. These afferent axons synapse in the trigeminal nucleus, which relays signals to the ventral posterior medial nucleus of the thalamus and then cortical areas that process facial irritation and pain. Nociceptive neurons of the trigeminal nerve are activated by chemicals classified as irritants, including air pollutants, ammonia, ethanol and other alcohols, acetic acid, carbon dioxide, menthol, capsaicin, and others. Many substances also elicit olfactory signals in addition to trigeminal responses, although the threshold concentrations for trigeminal chemoreception seem to be much higher than those for olfaction. Responses to trigeminal chemosensory stimuli include pain, irritation, sneezing, salivation, vasodilation with resultant nasal obstruction, tearing, nasal secretion, sweating, a decreased respiratory rate, and bronchoconstriction.
Anatomy, Physiology, and Disease Many of these responses are simulated by neuropeptides released from stimulated nerve endings. If irritants reach the lower airways, analogous responses in the lower airway can trigger sensory activity with resultant bronchoconstriction, bronchospasm, mucus secretion, and neurogenic inflammation.
Central Pathway—Olfactory Epithelium and Central Connections Approximately 10 to 20 million olfactory neurons within the olfactory epithelium are located among a variety of supportive cells. This pseudostratified columnar epithelium includes basal cells that have been shown (in animals, but not conclusively in humans) to function as stem cells that can give rise to all components of the epithelium, Bowman’s glands, microvillar cells, and sustentacular cells, which are thought to support olfactory neuron function. Bowman’s acini are exocrine and produce substances that are essential for olfaction. Key components of olfactory mucus are chaperone proteins called odorantbinding proteins that act to facilitate odorant–receptor interaction. The precise function of the other cell types aiding in neuronal function via other, less well-defined mechanisms are not well known, although perhaps this occurs through providing an appropriate local environment for optimal signal transduction (Pinto, 2011). Indeed, it is possible to obtain putative stem cells from humans through endoscopic biopsies for growth and differentiation in culture, with potential therapeutic effects (Winstead et al., 2005). The regenerative power of the olfactory neuron perhaps represents an evolutionary response to the continual physical challenge of this cranial nerve’s unique direct exposure to the environment and allows for a reparative function on damage. In addition, ensheathing shells that support these olfactory axons may have therapeutic uses (Chiu et al., 2009), potentially in nerve injury or neurodegeneration models. Olfactory neurons are bipolar cells that project a single dendrite with a thickened ending (the olfactory knob) that extends to the epithelial surface and contains nonmotile, sensory cilia where odor molecules bind to their receptor, and an axon that transmits signals to the brain. Axons from these olfactory neurons form nerve bundles (fila olfactoria) that cross the cribriform plate to synapse with other neurons in the glomeruli of the olfactory bulb. The crossing of the olfactory nerve across the skull base through about 20 foramina in the bone makes this region particularly sensitive to traumatic injury, especially through frontal or occipital trauma, a frequent etiology of olfactory loss (Collet et al., 2009). In addition, this also provides a potential route of access to the central nervous system for toxins and pathogens. A complex process of signal transduction and coding of complex signals occurs in the olfactory bulb before information is processed and sent to other areas of the central nervous system (Rawson, 2006; Ma, 2007). Subsequent connections as defined by human functional magnetic resonance imaging studies
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to the “‘primary olfactory region” (piriform cortex, olfactory nucleus and tubercle, amygdala, and entorhinal cortex) and secondary olfactory areas (hippocampus, hypothalamus, thalamus, orbitofrontal cortex, and the cerebellum) may account for the role of olfaction in mood and emotion, pleasure sensation, memory, and many other processes of the central nervous system (Sobel et al., 2003; Katata et al., 2009) Figure 3. More specifically, axons of the mitral and tuft cells of each olfactory bulb coalesce to form the olfactory tract, one on each side. This tract lies in the olfactory sulcus of the basal forebrain and conveys information to the primary olfactory cortex, only ipsilaterally. As the tract courses posteriorly, collateral branches peel off and synapse upon the anterior olfactory nucleus, and then divide into the lateral, intermediate, and medial olfactory stria (although the lateral olfactory tract is the only significant one in human brain) (Gottfried, 2006). The targets of the lateral olfactory tract is the piriform cortex, amygdala, and rostral entorhinal cortex. Additional targets, including the olfactory tubercule and basal forebrain, are found in animal models but it is not known if those exist in human (Carmichael et al., 1994; Shipley and Ennis, 1996). Higher order projections converge on the oribital prefrontal cortex, agranular insula, amygdala subnuclei, thalamus, hypothalamus, basal ganglia, and hippocampus (Gottfried, 2006). The piriform cortex is the major recipient of inputs from the olfactory bulb and is the largest of the central olfactory areas Figure 3. The amygdala receives the terminal ends of many bulb projections, specifically within the discrete amygdala subnuclei. Neurophysiologic recordings in animals and humans (Cain and Bindra, 1972; Tanabe et al., 1975; Hughes and Andy, 1979; Hundry et al., 2001) suggest that amygdala in particular is highly responsive to odor stimulation. Finally, the orbitofrontal cortex represents the main neocortical projection of the olfactory cortex, where direct afferent inputs arrive from all primary olfactory areas and feedback projections travel back to these areas. Interestingly, there is no thalamic intermediary to odor-evoked signals to central brain areas, which is unique among sensory modalities (Gottfried, 2006). Other unique characteristics of the anatomical pathway of olfaction include its true ipsilateral nature and the abundant “limbic” overlap, which may explain the profound ability of odor to affect emotional processing (Gottfried, 2006).
Molecular Basis for Chemosensation in the Nose In 1991, Linda Buck and Richard Axel discovered both the family of transmembrane proteins that were believed to be the odor receptors and some of the genes that encode them, a seminal breakthrough in our understanding of the olfactory system culminating in a Nobel Prize awarded in 2004. The superfamily of OR genes, the largest in the genome, includes approximately 900 genes (although about half are
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nonfunctional) from 18 gene families that reside across the genome, emphasizing their ancient nature, and comprises nearly 3% of the approximately 30,000 genes of the human genome, highlighting their critical role in mammalian physiology and evolution (Miller, 2004). Perhaps most interesting are more recent discoveries of expression of subsets of these genes in nonolfactory tissues including sperm and gut, implicating functions for these genes outside their traditional role in olfaction. In mice, each olfactory neuron expresses only one OR gene (a process regulated by mechanisms that are unclear), and precise spatial patterns of expression of certain classes of ORs and chemosensory receptors (see below) exist in animals and probably in humans. Odorants or mixtures of odorants bind a pattern of ORs, resulting in activation of the G proteins. This results in cyclic AMP–mediated opening of cyclic nucleotide–gated ion channels as well as calcium and sodium ion influx, depolarizing the OR neuron and beginning an action potential that carries the information to the brain. Odorants are thought to bind a number of ORs of varying affinities, resulting in complex signals that the brain is able to interpret through a complex system that is now under active investigation. Because most odors in the environment are mixtures of many components, the complexity of studying the precise signaling responses is enormous and such research relies entirely on animal model systems. In addition, the methods used by the olfactory system to distinguish among odors are not clear. Specific anosmias, the inability to detect particular odors, may reflect a lack of particular OR genes or downstream signaling pathways, rendering the subject unable to smell specific scents (Olender et al., 2008). In other situations, an opposite effect may manifest as hyperosmia, or increased sensitivity, to certain odors (Whissell-Buechy and Amoore, 1973). Adding further complexity to odor detection are the discoveries of additional chemoreceptor genes. For example, trace amine–associated receptors (TAARs) have been found in mice to respond to biogenic amines and mouse urine, potentially modulating species-specific olfactory signals (Menashe et al., 2007). There are six TAAR genes in humans, but there are few data to show how they might function in chemosensation in our species. Another family of genes involved in chemosensation in animals are the vomeronasal type 1 receptors, a multigene family (Dulac and Axel, 1995; Liberles and Buck, 2006) that is expressed in an accessory olfactory region in the nose called the vomeronasal organ, which is thought to be vestigial in humans (Young et al., 2010). These genes are thought to have degenerated through evolution; for example, there are only five of these genes that retain an intact open reading frame in the human genome (Witt and Hummel, 2006). Finally, formyl peptide receptors are candidate chemosensory receptors that might be involved in the detection of normal bacterial flora or mitochondrial proteins in lower animals (Rodriguez and Mombaerts, 2002). Overall, the combinatorial diversity of signals allows for the detection and discrimination of perhaps an unlimited diversity of odorants. Models of olfactory
information processing from insects and lower animals are providing insights for application to human physiology (Liberles et al., 2009).
Variability in Olfactory Function The etiology of the wide variability in olfactory performance is one of the most fundamental questions in olfactory biology. This may reflect different expression patterns of sets of OR genes, central processing effects, or genetic variability in the OR genes themselves, as has been shown in a proof-of-principle study (Cassenaer and Laurent, 2007). Studies have implicated genetic variation as a factor in the individual variation in human olfaction. Surveys of more recently identified forms of genetic variation in the human genome have demonstrated the evolutionary importance of olfaction. For example, a high percentage (68%) of the regions containing segmental copy number variations, which are associated with developmental disorders and susceptibility to diseases, overlap with genes involved in sensation, including olfaction (Wong et al., 2007). Similarly, common deletion variants were found to be present in genes involved in olfaction (McCarroll et al., 2006). Two examples show the ability to tie genetic variation with specific variation in human olfactory function. Keller et al. (2007) demonstrated the first link between the function of a human odorant receptor both in vitro and in odor perception, highlighting a mechanistic basis of variation in olfactory ability between individuals. Similarly, Menashe et al. (2007) identified variation in an OR gene and related it to sensitivity to a specific odor, that of isovaleric acid. Finally, two linkage studies for olfactory phenotypes have been performed (Doty et al., 1996), including our study in which the largest linkage signal for hyposmia (P < 0.0013) was on chromosome 4q, suggesting a role for genetic variation in olfactory performance in humans (Pinto et al., 2008).
CLINICAL ASPECTS OF OLFACTORY DISEASE Approximately 14 million Americans are estimated to have chronic olfactory impairment (Murphy et al., 2002) and more than 200,000 physician visits each year are due to this sensory loss (Panel on Communicative Disorders, 1979; National Institute on Deafness and Other Communication Disorders (NIDCD), 2004). Olfactory impairments can be classified into three broad categories of etiology: conductive losses from obstruction of the nasal passages, sensorineural causes from damage to the olfactory neuroepithelium, or central dysfunction related to central nervous system disease. These categories are not mutually exclusive. Olfactory disease can also be described on the basis of perceptual symptoms: difficulty with odor identification (dysosmia); sensation of an odor different that the typical for that substance (parosmia); and perception of an odor when none is present (phantosmia). The causes of olfactory decline are varied: most predominant is aging in the general population
Anatomy, Physiology, and Disease (Rawson, 2006), followed by upper respiratory tract infections, head trauma, and sinonasal disease (Murphy et al., 2003). There are a number of pathophysiologic changes that cause this olfactory dysfunction. For example, inflammatory diseases such as rhinitis or sinusitis commonly cause conductive olfactory loss due to both physical obstruction (edema impeding nasal airflow and odorant movement) and direct effects of inflammation on olfactory neuroepithelium. Trauma to the nose such as skull base fractures, surgical alterations of anatomy, or congenital disorders such as choanal stenosis or nasal cysts can affect airflow and therefore olfaction. Sensorineural causes are due to alterations on an epithelial level, which can happen in inflammatory or autoimmune disease, infection, or congenital syndromes such as Kallmann’s syndrome or agenesis of the olfactory bulb. Finally, olfactory decline has been associated with several € ssen (2009), neurodegenerative diseases, Welge-Lu including Alzheimer’s disease and Parkinson’s disease. Other physiologic or pathophysiologic conditions that alter olfactory dysfunction include endocrine changes including pregnancy, diabetes, Addison’s disease, vitamin deficiency (primarily vitamins A and B and thiamine) (Martin et al., 2009), as well as renal and liver disease. Chemicals such as benzene, menthol, sulfur dioxide, carbon disulfide, heavy metals, and dust have also been associated with olfactory loss. Medications such as steroids, cancer chemotherapy, antibiotics (aminoglycosides, macrolides, tetracycline), antithyroid medication, opiates, sympathomimetics, antacids, and L-dopa can all affect olfaction. The workup of olfactory dysfunction begins with a careful history recording the onset of symptoms, rate of decline, and associated factors. Inflammation accounts for the most easily treatable cause, and therefore, determining associated nasal symptoms is very useful. Central nervous system disease can be investigated if there are any pertinent neurologic symptoms or history. The physical examination focuses on a thorough nasal and neurologic examinations. Objective testing allows the characterization of the nature and degree of olfactory loss, establishes the validity of disease, and allows monitoring. The most commonly used technique clinically is an odor identification test, which assesses how well patients can identify specific odors in a forced choice format (The University of Pennsylvania Smell Identification Test, a 40-item scratch-and-sniff smell test) (Doty et al., 1984). Imaging with sinus computed tomography scan or magnetic resonance imaging are not useful as screening measures but are indicated if the history or physical exam findings warrant it. Treatment is usually limited to anti-inflammatories as indicated and counseling regarding lifestyle safety measures (inability to recognize toxic smells including gas leaks, smoke detectors, etc.). Prognosis is dependent on the mechanism of loss, with medical and surgical therapies having the best outcomes for conductive disease. Patients may recover from traumatic and postviral loss, with return of some smell function at 1 year being a positive prognostic sign (Pinto, 2011). Currently, there is no treatment available for sensorineural loss and neurologic etiologies.
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Unfortunately, options for treatment are limited for the majority of patients with olfactory dysfunction. Thus, this area is rich for advancement of both basic and clinical knowledge that will help human health.
CONCLUSION Olfaction is a critical physiologic process of the nasal airway, mediated primarily by the olfactory nerve. Peripheral and central components of the olfactory systems, as described above, modulate the perception and function of this vital chemical sense. Olfaction remains a critical part of human behavior and emotional experience, and clinical implications of olfactory loss is continuing to emerge as its prevalence increases and effects on quality of life are becoming more apparent.
ACKNOWLEDGMENTS The authors declare no conflicts of interest.
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