Physiology of olfaction

olfaction -- smell. From cummings Otorhinolaryngeology

1. Physiology of Olfaction Dr . Jinu V Iype 1 st year Post Graduate Department of ENT

2. Reference from Cummings Otorhinolaryngeology book

3. INTRODUCTION Sense of smell has been recently heavily studied because of it’s importance to human being’s survival . It helps to track food , can alert us to danger like gas leak, fire, rotten food. It is also linked to brain that process emotion and memory .

4. Olfaction or Olfactory perception - the sense of smell mediated by a group of specialised sensory cells in nasal cavity. Odour -the property of a substance which gives it a particular smell.

5. Anatomy of Olfactory Stimulation Nasal Passageways

6. Olfactory nerve (cranial nerve I) stimulation, which is necessary for identification of most odorants, depends on the odorant molecules’ reaching the olfactory mucosa at the top of the nasal cavity.

7. Although molecules can reach the olfactory cleft by diffusion, essentially olfaction requires some type of nasal airflow. During eating, there is a retro nasal flow of odorant molecules that stimulate the olfactory receptors at the top of the nose and contribute greatly to the flavor of the food.

8. Swallowing and Deglutition Retronasal Airflow Production of flavour from swallowed food Adds Smell to Taste

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

10. Sniffing is an almost universally performed maneuver when a person is presented with an olfactory stimulus. It increase the number of olfactory molecules in the olfactory cleft by means of a transient change in the airflow pattern of the nose. A sniff also may allow the trigeminal nerve to alert the central olfactory neurons that an odorant is coming.

11. For molecules to reach the olfactory area, they must pass through the tall but narrow nasal passageways. The epithelium lining the walls of these passageways is wet, has variable thickness.

12. 2. Olfactory Mucus After the odorant molecules reach the olfactory region, they must interact with the mucus overlying the receptor cells. The 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)

13. To reach the olfactory receptors, the odorant molecules must be soluble in the mucus. Changes in the thickness or composition of the mucus can influence the diffusion time required for odorant molecules to reach the receptor sites

14. Once in the olfactory mucus-epithelial system, the rate at which the odorant is cleared also is important. Studies shows that 79% of a radioactively labeled odorant ( butanol ) remained trapped in the mucus 30 minutes after inspiratory exposure, whereas radioactively labeled octane cleared rapidly.

15. 3. Olfactory Epithelium Located 7 cm inside the nasal cavity, the olfactory sensory neurons are protected in a 1-mm-wide crevice of the postero superior nose. At the epithelial surface, these bipolar neurons are exposed to the outside world through their dendrites and cilia.

16. A number of research groups have shown that there is mixing of olfactory and respiratory epithelial tissues in adult. The number of these clumps of respiratory epithelium, which are found in the olfactory area, increases with age, suggesting that a loss of primary olfactory neurons at least partially explains the decreased olfactory ability associated with aging.

17. Low magnification of the surface of the nasal cavity taken from a transition region. Patches of respiratory (R) epithelium (dark areas) can be seen within the olfactory (O) region

18. Low-power three-dimensional scanning view of the olfactory epithelium and lamina propria . The olfactory epithelium (E) overlies a thick connective tissue lamina propria that contains olfactory axon fascicles (A x) and blood vessels (V) (×248). The human olfactory epithelium covers an area of roughly 1 cm 2  on each side. The epithelium is pseudostratified columnar , and it rests on a vascular lamina propria with no submucosa

19. This portion of mucosa can be readily identified from the rest of the nasal mucosa by its unique yellowish color. 

20. Embryologically Olfactory receptors derive from neuroblasts . These neuroblasts differentiates to form olfactory placodes . The central part of each placode invagiantes giving rise to olfactory sac. Olfactory sac opens anteriorly

21. Olfactory organ is the only part of the body in which the cell bodies of neurons lie at the surface, directly in contact with the external environment.

22. four main cell types ciliated olfactory receptors 2. microvillar cells 3. supporting ( sustentacular ) cells 4.basal cells

23. The olfactory receptor neuron Bipolar Club-shaped peripheral “knob” that bears the cilia. Extends odourant receptor-containing cilia into mucus. olfactory nerve 15 to 20 foramina in the cribriform plate to synapse in the bulb

24. High-power magnification of an olfactory knob with long cilia gradually tapering as they extend over the epithelial surface. At the base of individual cilia, a necklace-like structure (arrow) can be seen on the surface of the olfactory knob 

25. Allison et al estimate the rabbit to have approximately 50 million olfactory axons, whereas Jafek estimates humans to have only 6 million bilaterally.

26. The olfactory ensheathing cells are unique in that they share characteristics that are common with Schwann cells and central glial cells . Because olfactory neurons - ability to regenerate and make functional synapses with the olfactory bulb. possible therapeutic potential for repair of peripheral neuronal injury. potential agents for reversing spinal cord injuries and demyelinating diseases.

27. The microvillar cell one tenth as often as the ciliated olfactory neurons. flask-shaped , is located near the epithelial surface, and has an apical membrane containing microvilli that project into the mucus overlying the epithelium  The deep end of the cell tapers to a thin, axon-like cytoplasmic projection that proceeds into the lamina propria .

28. Low-power magnification of fractured olfactory epithelium illustrating the axon-like processes (arrows) from microvillar cells (M), which extend basally between supporting cells

29. SUPPORTING CELLS / SUSTENTACULAR CELLS Tall cells have an apical membrane that joins tightly with the surface of the receptor cells and the microvillar cells. Do not generate action potentials, nor are they electrically coupled to each other

30. Play a role in ion and water regulation  and, along with Bowman’s gland duct cells, contain xenobiotic enzymes such as cytochrome P-450 that likely contribute to odorant metabolism.

31. Cross-sectional view of the olfactory epithelium showing the columnar supporting cells (S) that extend the full length of the epithelium. An olfactory neuron (O) with its dendrite and basal cell (B) can be seen among supporting cells

32. BASAL CELLS Sit along the basal lamina. Two groups of replicating cells Horizontal basal cells Globose basal cells are just above positioned between the basal lamina the horizontal basal cells & immature neurons.

33. The globose basal cells seem to be responsible for the continuous replacement of olfactory receptor neurons

34. During severe insult →repopulate the nonneuronal components of the epithelium .  The replication cycle is between 3 and 7 weeks.  When the new receptor cell forms, it also projects its axon to the olfactory bulb, where it synapses with second-order neurons, thereby ensuring continual olfactory function and continual olfactory neuron replacement.

35. Vomeronasal Organ Many mammals have an identifiable pit or groove in the anteroinferior part of the nasal septum that contains chemosensitive cells.  In most of these animals, a nerve can be identified connecting these cells to the central nervous system, to an accessory olfactory bulb.

36. 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. Electrical activity elicited by certain compounds directly delivered to the vomeronasal area has been shown to cause changes in blood pressure, heart rate, and hormonal levels.

37. It is believed to detect external chemical signals called pheromones. These signals, which are not detected consciously as odors by the olfactory system, mediate human autonomic, psychological, and endocrine responses.

38. Olfactory Bulb Located directly over the cribriform plate. first relay station in the olfactory pathway where the primary olfactory neurons synapse with secondary neurons.

39. Neural components are arranged in six concentric layers: the olfactory nerve glomerular External plexiform mitral cell internal plexiform granule cell

40. The receptor cell axons of the olfactory nerve layer →the glomeruli → synapse with the dendrites of the mitral and tufted cells within the spherical glomeruli .

41. These second order cells, in turn, send collaterals that synapse within the periglomerular and external plexiform layers, resulting in “reverberating” circuits in which negative and positive feedback occur. mitral cells modulate their own output by activating granule cells (which are inhibitory to them).

42. The mitral and tufted cell axons project ipsilaterally to the primary olfactory cortex via the olfactory tract

43. Olfactory tract enters brain 2 pathways Lateral Olfactory stria Medial Olfactory stria

44. MEDIAL OLFACTORY AREA consists of a group of nuclei located in the mid basal portions of the brain immediately Contain septal nuclei- feed into the hypothalamus and other primitive portions of the brain’s limbic system

45. Composed of prepyriform pyriform cortex cortical portion of amygdaloid nuclei. signal pathways- almost all portions of limbic system , especially hippocampus- important for learning like or dislike for food stuffs.

46. An important feature of the lateral olfactory area is that many signal pathways from this area also feed directly into an older part of the cerebral cortex called the paleocortex in the anteromedial portion of the temporal lobe. This is the only area of the entire cerebral cortex where sensory signals pass directly to the cortex without passing first through the thalamus.

47. The mitral and tufted cell axons project ipsilaterally to the primary olfactory cortex via the olfactory tract without an intervening thalamic synapse

48. Primary olfactory cortex is comprised of the Anterior Olfactory Nucleus - Pyriform Cortex- Olfactory tubercle - Entorhinal area - Amygdaloid Cortex - Corticomedial nuclear group of amygdala .

49.  Anterior Olfactory Nucleus Coordination of inputs from contalateral olfactory cortex Transfer of Olfactory memories from one side to other Pyriform Cortex Olfactory discrimination Amygdala Emotional response to olfactory stimuli Entorhinal Cortex Olfactory Memories

50. Olfactory pathway First order neuron : olfactory Epithelium to glomerulus Second order neuron :It is formed of the cells of the olfactory bulb (mitral cells & Tufted cell) Passes centrally as the olfactory tract . Third order neuron : Pyriform Cortex(Area 28) contain primary olfactory cortex, which contain 3 rd order neuron

51. Very Old Olfactory System More primitive responses to olfaction s alivation , primitive emotional drives to s mell Less Old Olfactory System Learned control of food intake Aversion to food that have caused nausea & vomiting Newer System Odour discrimintation & analysis of odour

52. Olfactory Transduction and Coding Once the odorant molecule is dissolved in the olfactory mucus

53. Soluble binding proteins, like odorant-binding protein -> enhance the access of odorants to the olfactory receptors. Same odorant-binding protein molecules act to remove odorant molecules from the region of the receptor cell after transduction.

54. The actual transformation of odorant chemical information into an electrical action potential occurs as a result of specific interactions between odorant molecules and receptor proteins on the surface of olfactory cilia . With the binding of the receptor to an odorant, adenylate cyclase is activated by G protein–coupled receptors  and converts adenosine triphosphate ( ATP ) into cyclic adenosine monophosphate ( cAMP ).

55. The cAMP then binds to a Na, Ca ion channel to allow influx of these ions. As more channels open, the cell depolarizes, and an action potential is produced

56. Once the peripheral olfactory receptor cells are depolarized, there begins a convergence of electrical information toward the olfactory bulb → glomeruli and mitral / tufted cells of the olfactory bulb → Olfactory cortex

57. Molecular structure – M oncrieff 1967 Electrochemical Reactions Stereospatial patterns Molecular Properties Olfactory mucus morphology

58. MOLECULAR STRUCTURE By M oncrieff 1967 Suggested that molecular structure is important. No stereospecific olfactory receptors have been demonstrated.

59.  Odour mol + Receptor  Photochemical reaction  SIGNAL TRANSDUCTION Receptors containing carotenoids By Briggs and Duncan,1962

60. By Mozell , 1970 Certain receptors could have a stereospatial, lock and key form, and receptor cells fire when the surface membrane is altered.

61.  L O CK KEY Confirmational change in receptor+mol complex SIGNAL T RANS DUC T I O N

62. By Laffort et al ,1974 Molecular properties depends on -molecular volume at boiling point -proton affinity and donation, -local polarization within the molecule .

63. Holley and Doving,1977 Nature of smell - Pattern of stimulus within mucosal configuration of receptor cells This theory is based on specific receptor sites & on their position within olfactory mucosa

64. Vibration Theory Olfactory Pigment Theory Enzyme Theory Penetrating and Puncturing theory

65.  Randerbrock 1968 Olfactory perceptors are peptide chains vibrating in an alpha helix. Odourant molecules forms a band with peptide chain modulating the vibration-transmitted to nerves . Pigment Theory Rosenberg 1968 odourant molecule + olfactory pigment- increased electrical conductivity

66. By Davies Odourant molecules penetrate membrane of olfactory receptor cell- diffuse-leaving a hole . Leakage of Sodium & pottasium occurs- nerve impulse

67. OLFACTORY DYSFUNCTION

68. Anosmia Hyposmia Hyperosmia Phantosmia Olfactory Agnosia Cacosmia / Parosmia / Troposmia Presbyosmia Osmophobia

69. TYPES OF OLFACTORY DYSFUNCTION Anosmia- absence of smell Hyposmiamicrosmia- diminished olfactory sensitivity Dysosmia- distorted sense of smell Phantosmia - perception of an odorant when none is present l / Olfactory hallucination. Agnosia- inability to classify, contrast, or identify odor sensations verbally, even though the ability to distinguish between odorants may be normal Hyperosmia- Abnormally acute smell function ( Rare condition )

70. CLASSIFICATION & ETIOLOGY TRANSPORT OLFACTORY LOSS Olfactory dysfunctions can be caused by conditions that interfere with the access of the odorant to the olfactory neuro-epithelium due to either swollen nasal mucous membrane, structural changes and/or mucus secretion. Causes- Allergy rhinitis, Bacterial rhinitis and sinusitis, Congenital abnormality like encephalocele, Deviated Nasal Septum, Nasal neoplasms, Nasal polyps, Nasal surgery, Old age, Viral infections.

71. SENSORY OLFACTORY LOSS Olfactory dysfunctions can be caused by conditions that damage to the neuroepithelium. Causes- Drugs that affect cell turn over and inhalations of toxic chemicals, viral infections, neoplasms, radiation therapy.

72. NEURAL OLFACTORY LOSS Olfactory dysfunctions can also be caused by conditions that damage the central olfactory pathways. Causes- AIDS, Alzheimer’s disease, Alcoholism, Chemical Toxins, Cigarette smoke, Diabetes Mellitus, Depression, Drugs, Huntington’s chorea, Hypothyroidism, Kallmann syndrome, Korsakoff psychosis, Malnutrition, Neoplasm, Neurosurgery, Parkinson disease, Trauma, Vitamin B12 def., Zinc deficiency

73. APPROACH TO OLFACTORY DYSFUNCTION DETAILED MEDICAL HISTORY Onset, course, nature of impairment, their previous illness and the n medications taken . PHYSICAL EXAMINATION Thorough ENT, head and neck examinations including nasal endoscopy. A neurological examination emphasizing the cranial nerves, cerebellar and sensorimotor function is essential . Psychological examination like general mood and check for signs of depression should be done.

74. LABORATORY FINDINGS Biopsy of olfactory neuroepithelium can be done in rare cases IMAGING Coronal CT scan and MRI Brain are useful.

75. sudden olfactory loss suggests the possibility of head trauma, infection, ischemia, or a psychogenic condition. Gradual loss the development of degenerative processes, progressive obstructive lesions or tumors within the olfactory receptor region or more central neural structures. Intermittent loss can be indicative of an intranasal inflammatory process.

76. A family history of smell dysfunction may suggest a genetic basis Kallmann’s syndrome : Delayed puberty in associationwith anosmia (with or without midline craniofacial abnormalities, deafness, and renal anomalies

77. Quantitative Olfactory Testing (1)verify the validity of the patient’s complaint, (2)characterize the exact nature and degree of the problem, (3) accurately monitor changes in function over time (4) detect malingering, (5)obtain an objective basis for determining compensation for disability.

78. UNIVERSITY OF PENNSYLVANIA SMELL IDENTIFICATION TEST (UPSIT) Most commonly used & most superior and reliable test. Self-administered in 10-15 minutes Scored in < 1 minute by non-med person Available in various languages 40 “scratch & sniff “ patches Pt. chooses from 4 answers & must choose 1 Can detect malingering Dysfunction classified as Normosmia , anosmia , mild, moderate or severe microsmia , or probable malingering

79. UPSIT

80. To assess olfaction unilaterally, the naris contralateral to the tested side should be occluded without distorting the nasal valve region. This can be easily accomplished by sealing the contralateral naris using a piece of MicrofoamTM . The patient is instructed to sniff the stimulus normally and to exhale through the mouth. Such occlusion not only prevents air from entering the olfactory cleft from the contralateral naris

81. Olfactory event-related potentials (OERPs) synchronized brain electroencephalographic (EEG) activity induced by repeated pulsatile presentations of an odorant is isolated from overall EEG activity Used as :- sensitive and useful in detecting malingering

82. ELECTRO-OLFACTOGRAM (EOG) Detected via an electrode placed on the surface of the olfactory neuroepithelium

83. DIFFERENTIAL DIAGNOSIS At present, no psychophysical methods to differentiate sensory from neural hearing loss . History of olfactory loss gives an important clues to the cause . Leading causes of olfactory dysfunctions are head trauma and viral infections . Head trauma are more common cause of anosmia in children and young adults whereas viral infections are more common cause in older adults .

84. Congenital anosmia occurs in Kallmann syndrome and also in albinism. Meningioma of inferior frontal region is the most common neoplastic cause of anosmia . Dysomia is associated with depression.

85. TREATMENT Transport olfactory loss The following treatments are effective in restoring sense of smell : Allergy management Antibiotic therapy Topical and systemic glucocorticoid therapy Operations for nasal obstruction.

86. Sensorineural Olfactory loss . No treatment with demonstrated efficacy for Sensorineural Olfactory loss. Fortunately, spontaneous recovery occurs . Some clinicians advocate zinc and vitamin therapy esp Vitamin A.