physiology of smell

PHYSIOLOGY OF SMELL

Smell is a result of input from the olfactory, trigeminal, glossopharyngeal, and vagus nerves.

The olfactory epithelium is a pseudostratified columnar neuroepithelium located in the superior cleft between the middle and superior turbinates and the septum. It rests on a vascular lamina propria with no submucosa.

4 types of cells:

1. Ciliated olfactory receptors

2. Microvillar cells - The microvillar cell occurs about one tenth as often as the ciliated olfactory neurons.21,22 The cell body is flask-shaped, is located near the epithelial surface, and has an apical membrane containing microvilli that project into the mucus overlying the epithelium

3. Supporting (sustentacular) cells - These tall cells have an apical membrane that joins tightly with the surface of the receptor cells and the microvillar cells

4. Basal cells - Deep to all of these cells, the basal cells sit along the basal lamina. The basal cells are divided into two groups of replicating cells. The horizontal basal cells are just above the basal lamina, and the globose basal cells are positioned between the horizontal basal cells and immature neurons. The globose basal cells seem to be responsible for the continuous replacement of olfactory receptor neurons; however, during severe insult, they may repopulate the nonneuronal components of the epithelium as well

The olfactory bulb lies at the base of the frontal cortex in the anterior fossa - where the primary olfactory neurons synapse with secondary neurons. These synapses and their postsynaptic partners form dense aggregates of neuropil called glomeruli.

Biopsy studies of the nasal mucosa in the small pit often seen along the anteroinferior nasal septum (Jacobson’s organ) show olfactory-like histology but no central connection.

The most common reasons for olfactory loss

· include chronic rhinosinusitis and polyps

· upper respiratory infections

· head trauma and aging: Patchy replacement of olfactory mucosa with respiratory epithelium appears to be common with aging.

Testing methods

At physiologic airflow rates, approximately 50% of the total airflow passes through the middle meatus, with approximately 35% flowing through the inferior meatus. About 15% flows through the olfactory region.

Olfactory ability is best when this epithelium is moderately congested, wet, and red, such as during an upper respiratory infection. Olfactory ability seems to improve with narrowed nasal chambers, but nasal cycle do not have any effect on olfactory ability. Respiratory molecules land on/are absorbed into mucus overlying the respiratory epithelium. This mucus apparently comes from both Bowman’s glands deep in the lamina propria (only of serous type in humans) and the adjacent respiratory mucosa (goblet cells). Changes in the thickness or composition of the mucus can influence the diffusion time required for odorant molecules to reach the receptor sites. Adrenergic, cholinergic, and peptidergic agents have caused these changes in the mucus overlying the olfactory receptors through their effects on the secretory activities of the mucosal glands. Moreover, these same agents have influenced the sensitivity of the olfactory receptor cells themselves. Olfactory receptor neuron is bipolar and has a club-shaped peripheral “knob” that bears the cilia - no dynein arms on these cilia. Motility is NOT important for olfaction!

Odorants reach the nasal olfactory receptors from the front through the nostrils (orthonasal stimulation) and from the back through the posterior choanae (retronasal stimulation).

Anna See ENT R1 2013-2014

PHYSIOLOGY OF SMELLOlfactory epithelium

The human olfactory epithelium covers an area of roughly 1 cm2 on each side.

Located 7 cm inside the nasal cavity, the olfactory sensory neurons which are bipolar, are protected in a 1-mm-wide crevice of the posterosuperior nose. At the epithelial surface, these bipolar neurons are exposed to the outside world through their dendrites and cilia. Proximally, axons of these same neurons synapse at the base of the brain (olfactory bulb).

Olfactory Connections in the Brain. Olfactory map exists.

The more central olfactory connections include the

olfactory tubercle the prepiriform cortex, part of the amygdaloid nuclei, and the nucleus of the terminal stria,

with further projections to a number of structures, including the hypothalamus. With increasing complexity of olfactory processing tasks, areas outside those used for passive perception (amygdala, piriform cortex, orbitofrontal cortex, and thalamus) are recruited with each combined set of regions specific for the task at hand.

Although these structures receive olfactory input, they also serve other functions, such as

food intake temperature regulation sleeping cycles vision memory hearing taste

These connections may explain the strong memories and emotional context of various odors. It also is possible that these structures influence the olfactory process by efferent connections.

The organization of like olfactory receptors projecting into the olfactory bulb with the formation of an olfactory map (described later) appears to also occur to some degree in higher cortical areas. In mice, single


PHYSIOLOGY OF SMELLodorants activate distinct patterns in the anterior piriform cortex.. These findings suggest an organization of axonal projection and stimulation in response to odorant stimulation within the cortex.

Free nerve endings of three cranial nerves—trigeminal (the most important), glossopharyngeal, and vagus—provide added chemoreceptivity in the mucosa of the respiratory tract. CNV is sensitive to the burn of ammonia and the bite of hot pepper. In the nose, virtually all odorants stimulate olfactory and trigeminal nerves, even when no apparent pungency can be perceived.

Olfactory Transduction and Coding

The nose has

narrow passageways lined by wet mucus and swept by alternating air currents

Odor presentation factors in constraints of sorption, solubility, and chemical reactivity.

2 additional hypotheses:

1. Soluble binding proteins, like odorant-binding protein, have been described. These proteins enhance the access of odorants to the olfactory receptors, thus increasing their concentration in the environment of the receptor cell by as much as 1000 to 10,000 times more than their concentration in the ambient air.

2. Chemical-sensing system that can produce degradative enzymes that transform stimulants into inactive products, and vice versa.

Molecular pathways of odour presentation:

Processes involved: Beyond receptor cell membrane depolarization initiate the action potential

cyclic adenosine monophosphate (cAMP) and inositol phosphate (IP3) are the primary signaling pathways that can mediate olfactory transduction,

the olfactory receptors are members of G protein–coupled receptors (Golf), with the binding of the receptor to an odorant, ATP is converted into cAMP. The cAMP then binds to a Na, Ca ion channel to allow influx of these ions depolarization

Inability to perceive particular odorants (specific anosmia) has been associated with loss of specific odor receptor genes, yielding clinical evidence for receptor specificity of odorants.

there tends to be more evidence for a right hemisphere dominance in olfactory functioning.

Testing methods

The two aspects of olfaction most commonly tested are threshold and identification ability. Of these, identification is more closely related to everyday olfactory functioning.

Or divided into interactive – needs intact cognition vs non-interactive

Threshold - The measurement of the detection threshold attempts to quantify the most dilute concentration of a particular odorant that an individual can detect.

Pyridine and n-butyl alcohol (1-butanol) are two of the most widely used test chemicals because of their water solubility, easy identifiability, and history of successful use, phenylethyl alcohol, which has a roselike smell, may be a better choice, because it has less trigeminal reactivity

The odorants are presented from lowest to highest concentration until the subject correctly identifies four odorants at a given concentration. This order of presentation avoids the adaptation (i.e., the loss of sensitivity from mere stimulation) that might occur if strong concentrations were to be used first.166 In the test situation,


PHYSIOLOGY OF SMELLthe subject is presented with two bottles, one containing the odorant and the other a blank. The subject is asked to choose the bottle that contains the odorant (two-alternative, forced-choice procedure).

Identification

Subject to smell a number of odorants and name them correctly. The test is a suprathreshold test; identification tests presume normal cognitive ability

Cain and associates have developed an identification test of 8 common household items (e.g., baby powder, coffee, Ivory soap) are presented to the subject in screw-top jars. The subject is graded on how many of the odorants he or she can identify correctly.

Doty uses scratch-and-sniff booklets containing 40 microencapsulated odorants. The test can be self-administered and the subject is asked to choose the correct answer from a list of four possible answers, a chance performance would be 25% correct. Obviously, anyone scoring much less than this should be considered for malingering. The portability of the booklets, the freshness of the stimulus, and the fun of taking the test contribute to its popularity.

Alcohol pad test: A simple olfactory screening test has been described that is available to all clinicians and is based on the ability to detect the odor of an opened alcohol pad. The patient is told to close the eyes, and the open pad is slowly brought closer to the nose. The patient notifies the test giver when an odor is detected, and the measured distance between the alcohol pad and the nose correlates with the extent of olfactory impairment.174 The test has been able to differentiate hyposmic and anosmic patients and can be modified for unilateral testing.

The use of the principle that taste is intimately related to smell to detect olfactory malingerers: Westerman has developed a simple test for such an evaluation, whereby the odorant is placed on the tongue and the subject is asked to describe the flavor of the material. This test also may be used to identify malingerers, because few individuals know that flavor is largely mediated through the sense of olfaction. When asked, therefore, to identify the taste of the coffee placed on the tongue, the blindfolded olfactory malingerer, who should report a bitter taste, identifies its taste as coffee but disclaims any ability to identify the coffee odor when it is held in front of the nose.

Electrophysiogic testing: Electrophysiologic testing of olfactory ability in humans has been developed and is available in laboratories. Accurate delivery of the odorant molecules to the nose in warmed and humidified air is mandatory in all of these objective studies.186,187 The most peripheral of these tests, the electro-olfactogram (EOG), is obtained by placement of an electrode directly on the olfactory epithelium.188 When an odorant stimulates the receptor cells, a slow negative shift in voltage is seen

2) Measurement of brain evoked potentials: A second objective testing method, used with success in other sensory systems such as hearing and vision, is measurement of brain-evoked potentials. In this test, the summated percutaneous brain electrical activity is averaged after multiple timed exposures to an odorant. Using this test in their research center, Kobal and Hummel192 have succeeded in determining when the olfactory stimulation arrives at the receptors and have shown differences between pure olfactory stimulation and trigeminal stimulation. Maximal amplitudes of potentials evoked by substances that partly or exclusively excite the trigeminal nerve (high concentrations of carbon dioxide, menthol, acetaldehyde) were found at the vertex and are defined as chemosomatosensory-evoked potentials. Substances that exclusively, or to a great extent, excite the olfactory nerve (hydrogen sulfide, vanillin) caused maximal responses in the parietal area and are defined as olfactory-evoked potentials. This method would correlate best with subjective testing of odor perception.

Another type of induced brain wave activity is the endogenous component, called the contingent negative variation (CNV). The brain waves are called “endogenous” because their presence depends on subjective response strategies rather than stimulus characteristics. The method would correlate best with subjective


PHYSIOLOGY OF SMELLtesting of odor discrimination. When the olfactory-evoked potentials and contingent negative variation are measured simultaneously, objective assessments of clinical status can be made. When both are absent, anosmia is present. When just contingent negative variation is present, there likely is an olfactory distortion. Finally, in hyposmia, when the odorant presented is just above the discrimination threshold, the amplitude of the contingent negative variation is enhanced, and the olfactory-evoked potential is undetectable. This technique is clearly a useful clinical tool, although it is not generally available.

Factors Affecting Olfactory Testing

Age

no consistent results in testing children younger than 10 years, by the age of 14 years, the children’s performance was equal to that of adults. consider use of pictures to represent the odorants instead of words, reliable results could be obtained

from children as young as age - abbreviated odorant identification task

Using a technique not often used in testing adults, Richman and colleagues201 have developed a match-to-sample odorant discrimination task that has been useful in testing children as young as age 5 years. To date, this approach seems the most reliable way to test young children.

GenderGirls > boysMenstrual cycle influences womens’ olfaction threshold levels, which are best at ovulation and poorest during menstruation. Adaptation and HabituationThe perception of a strong odor noticeable on entering a barn will disappear after a time.

Olfactory cross-adaptation is the ability of one chemical to decrease the subject’s responsiveness and sensitivity to another chemical. It has been proposed that the greater the cross-adapting effect on one odorant by another, the more likely they are to share common sensory channels.210-214 The manner and degree to which the odorants cause the receptors to adapt may not result from a simple mechanism, because even if two different odorants are matched in subjective intensity, their cross-adapting effects may be asymmetric.214,215 For example, pentanol seems to have a strong cross-adapting effect on propanol, whereas propanol has only a small cross-adapting effect on pentanol.216Clinical Olfactory ProblemsDecreased and Distorted Olfactory AbilityLife for the person with anosmia has a very “flat” quality to it. Patients say that they select food by texture, color, and custom. Some state, for example, that they must identify sour milk from its lumpy character. Others do not use perfumes for fear of overapplication..

In contrast to this lack of sensory input, there are individuals who have a distorted perception of odorants (parosmia) or the constant perception of an odor (usually foul in character) (phantosmia). Obstructive Nasal and Sinus Disease

Total nasal obstruction, such as caused by nasal polyps (Fig. 41-10), bony deformities, tumours extreme mucosal swelling (Fig. 41-11), or simply finger occlusion of the nostrils produces anosmia. area through which air flows to get to the olfactory cleft, is thought to be medial and anterior to the

lower part of the middle turbinate.221,222 This area may function as a regulator of airflow to the olfactory cleft, and changes in its anatomy clearly affect olfactory ability.

Obstruction of the olfactory cleft with edema and polyps has been thought to be the mechanism of olfactory dysfunction in patients with chronic rhinosinusitis. This conclusion may be only partly accurate. Kern234 analyzed olfactory mucosa biopsy specimens from patients with chronic rhinosinusitis and found inflammatory changes within olfactory epithelium in a large number of subjects who performed poorly on odorant identification testing. This finding suggests that an inflam-


PHYSIOLOGY OF SMELLmation-driven, primary neuron dysfunction may be contributing to olfactory disability with or without a concurrent obstructive process. In fact, evidence exists for active apoptosis of olfactory receptor neurons in patients with chronic rhinosinusitis,235 which may explain the finding of smell loss unresponsive to oral steroids in patients with a long history of sinus disease.

Another form of obstructive olfactory loss can be seen in patients with a long-standing deficit, lack of trauma or sinonasal disease, and absence of a previous upper respiratory infection. Enlargement or medialization of the middle turbinate, of the superior turbinate, or of both, can be seen on nasal endoscopy and CT.

Olfactory Loss after Upper Respiratory Infection

Transient – mucosal edema Permanent - Biopsy specimens of the olfactory cleft in these patients show either decreased numbers

of olfactory receptors or a complete absence of them.242-244 MRI measurements of olfactory bulb volume in these patients reveals a decrease in size that correlates with severity of loss as well as duration of the hyposmia.245

Head TraumaIncidence of olfactory loss is between 5% and 10% Frontal blows most frequently cause olfactory loss; however, total anosmia is five times more likely with an occipital blow.Pathophysiology: shearing of the olfactory nerves as they exit the top of the cribriform plate257 or to contusion of the olfactory bulbs or other central processing areas. (1) the olfactory nerves were damaged at the time of the trauma, perhaps at the cribriform plate; (2) the normal response of the olfactory nerves is to regenerate, but the axons cannot form functional synapses because of either scar formation at the cribriform plate or irreversible damage to the olfactory bulbs; and (3) without this connection with the bulb, the cells will not produce olfactory knobs or cilia.

AgingOlfactory identification ability has been shown to drop sharply in the sixth and seventh decades of life such that more than one half of those aged 65 to 80 years show major olfactory declines.263 Loss of olfactory bulb volume with aging.AD/PD/DS


PHYSIOLOGY OF SMELL Alzheimer’s disease is characterized by the presence of neurofibrillary tangles and neuritic plaques in most of the central olfactory pathways.276-279 These tangles and plaques are presumed to account for the clinical deficits of the disease.

Congenital DysfunctionThe usual history of the person with a total congenital loss of the sense of smell is that he or she is otherwise healthy and began to learn at about age 8 that friends, parents, and siblings could perceive something he or she could not. In most of these people the other chemosensory functions are intact, so that pungency, irritating odors, and tastes can be detected normally.295 Types Many more people have an isolated loss of sensitivity to a particular chemical or group of chemicals (also known as specific anosmia), for example, musks, trimethylamine (a fishlike odor), hydrogen cyanide (almond-like), butyl mercaptan (an additive to natural gas), and isovaleric acid (a locker-room odor). Perhaps the best-known type of congenital anosmia is associated with hypogonadotropic hypogonadism and is known as Kallmann’s syndrome.298,299 This disorder affects approximately 1 in 8000 males and 1 in 40,000 females, mostly in a sporadic manner. Mutations in the X chromosome–located KAL1 gene involved in the migration of gonadotropin-releasing hormone neurons during development are being discovered.300 At least some patients with Kallmann’s syndrome have been shown to have agenesis of the olfactory bulbs and stalks and incomplete development of the hypothalamus.301-303

Kallman’s renal abnormalities cryptorchidism, deafness midline facial deformities diabêtes

Toxic Exposure Formalin Dental work Industrial Gas

NeoplasmsBoth intranasal and intracranial tumors can affect the sense of smell. The intranasal tumors most commonly seen are

inverting papillomas adenomas squamous cell carcinomas esthesioneuroblastomas PNS masses

Intracranial meningiomas pituitary tumors gliomas temporal lobe tumors have been estimated to cause an olfactory disturbance

Human Immunodeficiency Virus InfectionPatients infected with human immunodeficiency virus (HIV) have been found on testing to have decreased olfactory ability.

EpilepsyOlfactory auras are sometimes associated with epilepsy. Pathophysiology - temporal lobe?


PHYSIOLOGY OF SMELL

Psychiatric DisordersPatients with depression, schizophrenia, and hallucinations may have olfactory complaints. Chemicals that are thought to cause the symptoms of depression affect the neural connections between the limbic system and the hypothalamus.

MedicationsAlthough medications seem to affect the taste system more than the olfactory system, many can cause olfactory dysfunction (Table 41-2).

Hypothyroidism/Zinc deficiencyWhy?? 1. Respiratory and sinus infections

Respiratory and sinus infections cause swelling and prevent odor molecules from reaching the olfactory receptors.

2. Nasal polyps

3. Enlarged adenoids

Enlarged adenoids represent inflamed lymphoid tissue in the back of the nose.

4. Hormonal changes

5. Medications

Antibodies, antihistamines, and blood pressure medications may impact the olfactory system.

6. Injury to the nose

7. Exposure to some pesticides and solvents

8. Normal aging


PHYSIOLOGY OF SMELL

SurgeryThese losses could be caused by neural damage at the time of the surgery or the narrowing of the nasal airways by anatomic changes or scar tissue.338 In patients who undergo a total laryngectomy, inspired air has been rerouted away from the nasal cavity. Much of the cranial and skull base surgery in the region of the olfactory bulbs has been associated with a total and permanent loss of olfactory ability. However, techniques have been developed for preservation of the olfactory tract.344-346 Diagnostic Assessment

Smell Identification Test


PHYSIOLOGY OF SMELLManagementNasal: Medical therapy, including intranasal steroids, antibiotics, and allergic therapy, is the mainstay of management. Oral steroids have been particularly useful in shrinking thickened nasal mucosa; surgical therapy. Tumors are managed according to usual oncologic principles. Often the nasal disease is associated with (or perhaps caused by) adjacent ethmoid sinus disease. Functional ethmoidectomy, often conducted with the use of an endoscope, can improve the health of these sinuses and, in turn, allow the olfactory cleft to open. Phantosmia by removing olfactory epithelium from the underside of the cribriform plate. The advantage to this procedure seems to be that the olfactory ability is not irreversibly destroyed in some people. This is difficult surgery that entails repair of CSF leakage.


PHYSIOLOGY OF SMELL


physiology of smell

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