Module 1-Special Senses | Case 1: Blurring of Vision - PDF

BICOL UNIVERSITY COLLEGE OF MEDICINE Health Sciences Building Daraga, Albay SMALL GROUP DISCUSSION MODULE 1-SPECIAL SENSES CASE 1:...

BICOL UNIVERSITY COLLEGE OF MEDICINE Health Sciences Building Daraga, Albay SMALL GROUP DISCUSSION MODULE 1-SPECIAL SENSES CASE 1: BLURRING OF VISION 1. The embryonic development of the eye OPTIC CUP AND LENS VESICLE The developing eye appears in the 22-day embryo as a pair of shallow grooves on the sides of the forebrain. With closure of the neural tube, these grooves form outpocketings of the forebrain, the optic vesicles. These vesicles subsequently come in contact with the surface ectoderm and induce changes in the ectoderm necessary for lens formation. Shortly thereafter, the optic vesicle begins to invaginate and forms the double-walled optic cup. The inner and outer layers of this cup are initially separated by a lumen, the intraretinal space, but soon this lumen disappears, and the two layers appose each other. Invagination is not restricted to the central portion of the cup but also involves a part of the inferior surface that forms the choroid fissure. Formation of this fissure allows the hyaloid artery to reach the inner chamber of the eye. During the seventh week, the lips of the choroid fissure fuse, and the mouth of the optic cup becomes a round opening, the future pupil. During these events, cells of the surface ectoderm, initially in contact with the optic vesicle, begin to elongate and form the lens placode. This placode subsequently invaginates and develops into the lens vesicle. During the fifth week, the lens vesicle loses contact with the surface ectoderm and lies in the mouth of the optic cup. RETINA, IRIS, AND CILIARY BODY The outer layer of the optic cup, which is characterized by small pigment granules, is known as the pigmented layer of the retina. Development of the inner (neural) layer of the optic cup is more complicated. The posterior four-fifths, the pars optica retinae, contains cells bordering the intraretinal space that differentiate into light-receptive elements, rods and cones. Adjacent to this photoreceptive layer is the mantle layer, which, as in the brain, gives rise to neurons and supporting cells, including the outer nuclear layer, inner nuclear layer, and ganglion cell. On the surface is a fibrous layer that contains axons of nerve cells of the deeper layers. Nerve fibers in this zone converge toward the optic stalk, which develops into the optic nerve. Hence, light impulses pass through most layers of the retina before they reach the rods and cones. The anterior fifth of the inner layer, the pars ceca retinae, remains one cell layer thick. It later divides into the pars iridica retinae, which forms the inner layer of the iris, and the pars ciliaris retinae, which participates information of the ciliary body. Meanwhile, the region between the optic cup and the overlying surface epithelium is filled with loose mesenchyme. The sphincter and dilator pupillae muscles form in this tissue. These muscles develop from the underlying ectoderm of the optic cup. In the adult, the iris is formed by the pigment-containing external layer, the unpigmented internal layer of the optic cup, and a layer of richly vascularized connective tissue that contains the pupillary muscles. The pars ciliaris retinae is easily recognized by its marked folding. Externally, it is covered by a layer of mesenchyme that forms the ciliary muscle; on the inside, it is connected to the lens by a network of elastic fibers, the suspensory ligament or zonula Contraction of the ciliary muscle changes tension in the ligament and controls curvature of the lens. LENS Shortly after formation of the lens vesicle, cells of the posterior wall begin to elongate anteriorly and form long fibers that gradually fill the lumen of the vesicle. By the end of the seventh week, these primary lens fibers reach the anterior wall of the lens vesicle. Growth of the lens is not finished at this stage, however, since new (secondary) lens fibers are continuously added to the central core. CHOROID, SCLERA, AND CORNEA At the end of the fifth week, the eye primordium is completely surrounded by loose mesenchyme. This tissue soon differentiates into an inner layer comparable with the pia mater of the brain and an outer layer comparable with the dura mater. The inner layer later forms a highly vascularized pigmented layer known as the choroid; the outer layer develops into the sclera and is continuous with the dura mater around the optic nerve. Differentiation of mesenchymal layers overlying the anterior aspect of the eye is different. The anterior chamber forms through vacuolization and splits the mesenchyme into an inner layer in front of the lens and iris, the iridopupillary membrane, and an outer layer continuous with the sclera, the substantia propria of the cornea. The anterior chamber itself is lined by flattened mesenchymal cells. Hence, the cornea is formed by (1) an epithelial layer derived from the surface ectoderm, (2) the substantia propria or stroma, which is continuous with the sclera, and (3) an epithelial layer, which borders the anterior chamber. The iridopupillary membrane in front of the lens disappears completely. The posterior chamber is the space between the iris anteriorly and the lens and ciliary body posteriorly. The anterior and posterior chambers communicate with each other through the pupil and are filled with fluid called the aqueous humor produced by the ciliary process of the ciliary body. The clear aqueous humor circulates from the posterior chamber into the anterior chamber providing nutrients for the avascular cornea and lens. From the anterior chamber, the fluid passes through the scleral venous sinus (canal of Schlemm) at the iridocorneal angle where it is resorbed into the bloodstream. Blockage of the flow of fluid at the canal of Schlemm is one cause of glaucoma. VITREOUS BODY Mesenchyme not only surrounds the eye primordium from the outside but also invades the inside of the optic cup by way of the choroid fissure. Here, it forms the hyaloid vessels, which during intrauterine life supply the lens and form the vascular layer on the inner surface of the retina. In addition, it forms a delicate network of fibers between the lens and retina. The interstitial spaces of this network later fill with a transparent gelatinous substance, forming the vitreous body. The hyaloid vessels in this region are obliterated and disappear during fetal life, leaving behind the hyaloid canal. OPTIC NERVE The optic cup is connected to the brain by the optic stalk, which has a groove, the choroid fissure, on its ventral surface. In this groove are the hyaloid vessels. The nerve fibers of the retina returning to the brain lie among cells of the inner wall of the stalk. During the seventh week, the choroid fissure closes, and a narrow tunnel forms inside the optic stalk. As a result of the continuously increasing number of nerve fibers, the inner wall of the stalk grows, and the inside and outside walls of the stalk fuse. Cells of the inner layer provide a network of neuroglia that support the optic nerve fibers. The optic stalk is thus transformed into the optic nerve. Its center contains a portion of the hyaloid artery, later called the central artery of the retina. On the outside, a continuation of the choroid and sclera, the pia arachnoid and dura layer of the nerve, respectively, surround the optic nerve. MOLECULAR REGULATION OF EYE DEVELOPMENT PAX6 is the key regulatory gene for eye development. It is a member of the PAX (paired box) family of transcription factors and contains two DNA-binding motifs that include a paired domain and a paired-type homeodomain. Initially, this transcription factor is expressed in a band in the anterior neural ridge of the neural plate before neurulation begins. At this stage, there is a single eye fi eld that later separates into two optic primordia. The signal for separation of this fi eld is sonic hedgehog (SHH) expressed in the prechordal plate. SHH expression upregulates PAX2 in the center of the eye fi eld and downregulates PAX6. Later, this pattern is maintained so that PAX2 is expressed in the optic stalks and PAX6 is expressed in the optic cup and overlying surface ectoderm that forms the lens. As development proceeds, it appears that PAX6 is not essential for optic cup formation. Instead, this process is regulated by interactive signals between the optic vesicle and surrounding mesenchyme and the overlying surface ectoderm in the lens- forming region. Thus, fibroblast growth factors (FGF) from the surface ectoderm promote differentiation of the neural (inner layer) retina, while transforming growth factor b(TGF-b), secreted by surrounding mesenchyme, directs formation of the pigmented (outer) retinal layer. Downstream from these gene products, the transcription factors MITF and CHX10 are  expressed and direct differentiation of the pigmented and neural layer, respectively. Thus, the lens ectoderm is essential for proper formation of the optic cup, such that without a lens placode, no cup invagination occurs. Differentiation of the lens depends on PAX6, although the gene is not responsible for inductive activity by the optic vesicle. Instead, PAX6 acts in the surface ectoderm to regulate lens development. This expression upregulates the transcription factor SOX2 and also maintains PAX6 expression in the prospective lens ectoderm. In turn, the optic vesicle secretes BMP-4, which also upregulates and maintains SOX2 expression as well as expression of LMAF , another transcription factor. Next, the expression of two homeobox genes, SIX3 and PROX1 , is regulated by PAX6. The combined expression of PAX6, SOX2 , and LMAF initiates expression of genes responsible for lens crystallin formation, including PROX1. SIX3 also acts as a regulator of crystallin production by inhibiting the crystallin gene. Finally, PAX6, acting through FOX3, regulates cell proliferation in the lens. 2. Coats of the eyeball The eyeball comprises three coats: outer (fibrous coat), middle (vascular coat) and inner (nervous coat). 1. Fibrous coat. It is a dense strong wall which protects the intraocular contents. Anterior 1/6th of this fibrous coat is transparent and is called cornea. Posterior 5/6th opaque part is called sclera. Cornea is set into sclera like a watch glass. Junction of the cornea and sclera is called limbus. Conjunctiva is firmly attached at the limbus. 2. Vascular coat (uveal tissue). It supplies nutrition to the various structures of the eyeball. It consists of three parts which from anterior to posterior are: iris, ciliary body and choroid. 3. Nervous coat (retina). It is concerned with visual functions. 3. The segments and chambers of the eyeball The eyeball can be divided into two segments: anterior and posterior. 1. Anterior segment. It includes crystalline lens (which is suspended from the ciliary body by zonules), and structures anterior to it, viz., iris, cornea and two aqueous humour-filled spaces : anterior and posterior chambers. Anterior chamber. It is bounded anteriorly by the back of cornea, and posteriorly by the iris and part of ciliary body. The anterior chamber is about 2.5 mm deep in the centre in normal adults. It is shallower in hypermetropes and deeper in myopes, but is almost equal in the two eyes of the same individual. It contains about 0.25 ml of the aqueous humour.  Posterior chamber. It is a triangular space containing 0.06 ml of aqueous humour. It is bounded anteriorly by the posterior surface of iris and part of ciliary body, posteriorly by the crystalline lens and its zonules, and laterally by the ciliary body. 2. Posterior segment. It includes the structures posterior to lens, viz., vitreous humour (a gel like material which fills the space behind the lens), retina, choroid and optic disc. 4. The function of the various parts of the eye. The outer white protective layer of the eyeball is the sclera through which no light can pass. It is modified anteriorly to form the transparent cornea, through which light rays enter the eye. The lateral margin of the cornea is contiguous with the conjunctiva, a clear mucous membrane that covers the sclera. Just inside the sclera is the choroid, a vascular layer that provides oxygen and nutrients to the structures in the eye. The retina, the neural tissue containing the photoreceptors, lines the posterior two-thirds of the choroid. The crystalline lens is a transparent structure held in place by a circular lens suspensory ligament (zonule). The zonule is attached to the ciliary body that contains circular muscle fibers and longitudinal muscle fibers that attach near the corneoscleral junction. The pigmented and opaque iris, the colored portion of the eye, is in front of the lens. The iris, ciliary body, and choroid are collectively called the uvea. The iris contains sphincter muscles that constrict (miosis) and radial muscles that dilate (mydriasis) the pupil that are under the control of parasympathetic and sympathetic nerves, respectively. Variations in the diameter of the pupil can produce up to a 16-fold change in the amount of light reaching the retina. The aqueous humor is a clear protein-free liquid that nourishes the cornea and iris; it is produced in the ciliary body by diffusion and active transport from plasma. It flows through the pupil and fills the anterior chamber of the eye. It is normally reabsorbed through a network of trabeculae into the canal of Schlemm, a venous channel at the junction between the iris and the cornea (filtration angle). Obstruction of this outlet leads to increased intraocular pressure (IOP), a critical risk factor for glaucoma The posterior chamber is a narrow aqueous-containing space between the iris, zonule, and the lens. The vitreous chamber is the space between the lens and the retina that is filled primarily with a clear gelatinous material called the vitreous (vitreous humor). The eye is well protected from injury by the bony walls of the orbit. The cornea is moistened and kept clear by tears that course from the lacrimal gland in the upper portion of each orbit across the surface of the eye to empty via the lacrimal duct into the nose. Blinking helps keep the cornea moist. 5. How light rays in the environment are brought to a focus on the retina and the role of accommodation and the pupil light reflex. Focusing Parallel light waves entering the eye must be bent in order to be focused to a common point, called a focal point. This is accomplished by the eye’s convex lens, which forms a real image. The distance from the lens to this point is its focal length, which is expressed in meters (Fig. 4.8). The muscles of the ciliary body can change the focal length by changing the curvature of the lens. When the muscles are fully relaxed, the lens is at its flattest, and the eye and the converging light rays are focused behind the retina. When the ciliary muscle is fully contracted, the lens is at its most curved state, and the eye is focused at its nearest point of vision. The ability to adjust the strength of the lens for close vision is called accommodation. With age, the lens loses its elasticity, and the point of vision moves farther away. This condition is called presbyopia, and supplemental refractive power, in the form of external lenses (reading glasses), is required for distinct near vision. Another age-related problem is the loss of transparency in the lens, a condition known as cataracts. Normally, the elastic fibers in the lens are completely transparent to visible light. These fibers occasionally become opaque, and light rays have difficulty passing through the opaque lens. Cataracts are treated by surgical removal of the defective lens. An artificial lens may be implanted in its place, or eyeglasses may be used to replace the refractive power of the lens. Accommodation reflex Accommodation is the process whereby the eye changes its optical power to maintain a clear vision on an object as its distance changes. Th is reflex action is in response to focusing on a near object and then looking at a distant object (and vice versa). When someone accommodates to a near object, two things happen. First, the eyes converge, which is accomplished by the ciliary muscles contracting, thus making the lenses more convex. This shortens the focal length so that the image lands on both retinas. Second, the pupil constricts in order to prevent divergent light rays from hitting the periphery of the retina and resulting in blurred vision. Pupillary constriction also improves the depth of vision. Both things happen automatically as part of the accommodation reflex. Accommodation is another visual reflex that diminishes with age universal occurrence. At about 60 years of age, most people will have noticed a decrease in their ability to focus on close objects. ACCOMMODATION When the ciliary muscle is relaxed, parallel light rays striking the optically normal (emmetropic) eye are brought to a focus on the retina. As long as this relaxation is maintained, rays from objects closer than 6 m from the observer are brought to a focus behind the retina, and consequently the objects appear blurred. The problem of bringing diverging rays from close objects to a focus on the retina can be solved by increasing the distance between the lens and the retina or by increasing the curvature or refractive power of the lens. The process by which the curvature of the lens is increased is called accommodation. At rest, the lens is held under tension by the lens ligaments. Because the lens substance is malleable and the lens capsule has considerable elasticity, the lens is pulled into a flattened shape. If the gaze is directed at a near object, the ciliary muscle contracts. This decreases the distance between the edges of the ciliary body and relaxes the lens ligaments, so that the lens springs into a more convex shape. The change is greatest in the anterior surface of the lens. In young individuals, the change in shape may add as many as 12 diopters to the refractive power of the eye. The relaxation of the lens ligaments produced by contraction of the ciliary muscle is due partly to the sphincter-like action of the circular muscle fibers in the ciliary body and partly to the contraction of longitudinal muscle fibers that attach anteriorly, near the corneoscleral junction. As these fibers contract, they pull the whole ciliary body forward and inward. This motion brings the edges of the ciliary body closer together. The nearest point to the eye at which an object can be brought into clear focus by accommodation is called the near point of vision. The near point recedes throughout life, slowly at first and then rapidly with advancing age, from approximately 9 cm at age 10 to approximately 83 cm at age 60. This recession is due principally to increasing hardness of the lens, with a resulting loss of accommodation due to the steady decrease in the degree to which the curvature of the lens can be increased. 6. The functional organization of the retina. RETINA The retina is organized into layers containing different types of cells and neural processes. The outer nuclear layer contains the photoreceptors (rods and cones). The inner nuclear layer contains the cell bodies of the excitatory and inhibitory interneurons including bipolar cells, horizontal cells, and amacrine cells. The ganglion cell layer contains various types of ganglion cells that are the only output neurons of the retina; their axons form the optic nerve. The outer plexiform layer is interposed between the outer and inner nuclear layers; the inner plexiform layer is interposed between the inner nuclear and ganglion cell layers. The rods and cones, which are next to the choroid, synapse with bipolar cells; the bipolar cells synapse with ganglion cells. There are various types of bipolar cells that differ in terms of morphology and function. Horizontal cells connect photoreceptor cells to other photoreceptor cells in the outer plexiform layer. Amacrine cells connect ganglion cells to one another in the inner plexiform layer via processes of varying length and patterns. Amacrine cells also connect with the terminals of bipolar cells. Retinal neurons are also connected via gap junctions. Because the receptor layer of the retina rests on the pigment epithelium next to the choroid, light rays must pass through the ganglion cell and bipolar cell layers to reach the rods and cones. The pigment epithelium absorbs light rays, preventing the reflection of rays back through the retina that would otherwise produce blurring of the visual images. 7. The sequence of events involved in phototransduction. Figure 10–10 summarizes the sequence of events in photoreceptors by which incident light leads to production of a signal in the next succeeding neural unit in the retina. In the dark, the retinal in rhodopsin is in the 11-cis configuration. The only action of light is to change the shape of the retinal, converting it to the all-trans isomer. This, in turn, alters the configuration of the opsin, and the opsin change activates its associated heterotrimeric G-protein (transducin) that has several subunits (Tα, Gβ1, and Gγ1). After 11-cis retinal is converted to the all-trans configuration, it separates from the opsin in a process called bleaching. This changes the color from the rosy red of rhodopsin to the pale yellow of opsin. The coupling of the light-induced reactions and the electrical response involves the activation of transducin, a G protein; the associated exchange of guanosine triphosphate for guanosine diphosphate activates a phosphodiesterase. This, in turn, catalyzes the breakdown of cyclic guanosine monophosphate (cGMP) to 5ʹ-GMP.When cellular cGMP levels are high (as in the dark), membrane sodium channels are kept open, and the cell is relatively depolarized. Under these conditions, there is a tonic release of neurotransmitter from the synaptic body of the rod cell. A decrease in the level of cGMP as a result of light-induced reactions causes the cell to close its sodium channels and hyperpolarize, thus reducing the release of neurotransmitter. 8. The electrical responses produced by bipolar cells, horizontal cells, amacrine cells, and ganglion cells. PROCESSING OF VISUAL INFORMATION IN THE RETINA A characteristic of the retinal bipolar and retinal ganglion cells (as well as the lateral geniculate neurons and the neurons in layer 4 of the visual cortex) is that they respond best to a small, circular stimulus and that, within their receptive field, an annulus of light around the center (surround illumination) antagonizes the response to the central spot. The center can be excitatory with an inhibitory surround (an on-center/off-surround cell) or inhibitory with an excitatory surround (an off-center/on-surround cell). The inhibition of the center response by the surround is probably due to inhibitory feedback from one photoreceptor to another mediated via horizontal cells. Thus, activation of nearby photoreceptors by addition of the annulus triggers horizontal cell hyperpolarization, which in turn inhibits the response of the centrally activated photoreceptors. The inhibition of the response to central illumination by an increase in surrounding illumination is an example of lateral inhibition— that form of inhibition in which activation of a neural unit is associated with inhibition of the activity of nearby units. It is a general phenomenon in mammalian sensory systems and helps sharpen the edges of a stimulus and improve discrimination. Neural network layer Bipolar cells, horizontal cells, and amacrine cells comprise the neural network layer of the eye. These cells together are responsible for considerable initial processing of visual information. Because the distances between neurons here are so small, most cellular communication involves the electrotonic spread of cell potentials, rather than propagated action potentials. Light stimulation of the photoreceptors produces hyperpolarization that is transmitted to the bipolar cells. Some of these cells respond with a depolarization that is excitatory to the ganglion cells, whereas other cells respond with a hyperpolarization that is inhibitory. The horizontal cells also receive input from rod and cone cells but spread information laterally, causing inhibition of the bipolar cells on which they synapse. Another important aspect of retinal processing is lateral inhibition. A strongly stimulated receptor cell can inhibit, via lateral inhibitory pathways, the response of neighboring cells that are less well illuminated. This has the effect of increasing the apparent contrast at the edge of an image. Amacrine cells also send information laterally but synapse on ganglion cells. Ganglion cell layer In the ganglion cell layer, the results of retinal processing are finally integrated by the retinal ganglion cells, whose axons form the optic nerve. Th ese cells are tonically active, sending action potentials into the optic nerve at an average rate of five per second, even when unstimulated. Input from other cells converging on the ganglion cells modifies this rate up or down.  Many kinds of information regarding color, brightness, contrast, and so on are passed along the optic nerve. The output of individual photoreceptor cells converges on the ganglion cells. In keeping with their role in visual acuity, relatively few cone cells converge on a ganglion cell, especially in the fovea, where the ratio is nearly 1:1. Rod cells, however, are highly convergent, with as many as 300 rods converging on a single ganglion cell. Although this mechanism reduces the sharpness of an image, it allows for a great increase in light sensitivity. 9. The neural pathways that transmit visual information from photoreceptors to the visual cortex. Visual pathways. Transection of the pathways at the locations indicated by the letters causes the visual field defects shown in the diagrams on the right. The fibers from the nasal half of each retina decussate in the optic chiasm, so that the fibers in the optic tracts are those from the temporal half of one retina and the nasal half of the other. A lesion that interrupts one optic nerve causes blindness in that eye (A). A lesion in one optic tract causes blindness in half of the visual field (C) and is called homonymous (same side of both visual fields) hemianopia (half-blindness). Lesions affecting the optic chiasm destroy fibers from both nasal hemiretinas and produce a heteronymous (opposite sides of the visual fields) hemianopia (B). Occipital lesions may spare the fibers from the macula (as in D) because of the separation in the brain of these fibers from the others subserving vision. Signals from the retina are modified and separated before reaching the thalamus and visual cortex. The retina, unlike a camera, does not simply send a picture to the brain. The retina spatially encodes (compresses) the image to fit the limited capacity of the optic nerve. Encoding is necessary because there are 100 times more photoreceptor cells than ganglion cells. The encoding is carried out by bipolar and ganglion cells. Once the image is spatially encoded, the signal is sent out the optical nerve (via the axons of the ganglion cells) through the optic chiasm to the lateral geniculate nucleus (LGN), which is in the thalamus.  Image crossover Information from the right and left visual fields transmitted to opposite sides of the brain represents another visual modification. The optic nerves, each carrying about 1 million fibers from each retina, enter the rear of the orbit and pass to the underside of the brain to the optic chiasma, where about half of the fibers from each eye “cross over” to the other side. Fibers from the temporal side of the retina do not cross the midline but travel in the optic tract on the same side of the brain. Fibers originating from the nasal side of the retina cross the optic chiasma and travel in the optic tract to the opposite side of the brain. The first stop in the brain where information is modified from the visual pathways is the LGN in the thalamus, where the divided output information is separated and relayed to fiber bundles known as optic radiations to different zones of the visual cortex in the occipital lobe of the brain. Mechanisms in the visual cortex detect and integrate visual information, such as shape, contrast, line, and intensity, into a coherent visual perception. Information from the optic nerves is also sent to the suprachiasmatic nucleus of the hypothalamus, where it participates in the regulation of circadian rhythms; to the pretectal nuclei, which are concerned with the control of visual fixation and pupillary reflexes; and to the superior colliculus, which coordinates simultaneous bilateral eye movements, such as tracking and convergence 10. The muscles involved in the four types of eye movements and the function of these movements. The eye is moved within the orbit by six ocular muscles that are innervated by the oculomotor, trochlear, and abducens nerves. Figure 10–19 below shows the movements produced by the six pairs of muscles. Because the oblique muscles pull medially, their actions vary with the position of the eye. When the eye is turned nasally, the inferior oblique elevates it and the superior oblique depresses it. When it is turned laterally, the superior rectus elevates it and the inferior rectus depresses it. Because much of the visual field is binocular, a very high order of coordination of the movements of the two eyes is necessary if visual images are to fall at all times on corresponding points in the two retinas and diplopia is to be avoided. There are four types of eye movements, each controlled by a different neural system but sharing the same final common path, the motor neurons that supply the external ocular muscles. Saccades, sudden jerky movements, occur as the gaze shifts from one object to another. They bring new objects of interest onto the fovea and reduce adaptation in the visual pathway that would occur if gaze were fixed on a single object for long periods. Smooth pursuit movements are tracking movements of the eyes as they follow moving objects. Vestibular movements, adjustments that occur in response to stimuli initiated in the semicircular canals, maintain visual fixation as the head moves. Convergence movements bring the visual axes toward each other as attention is focused on objects near the observer. Saccadic movements, pursuit movements, and vestibular movements depend on an intact visual cortex. Saccades are programmed in the frontal cortex and the superior colliculi and pursuit movements in the cerebellum. FIGURE 10–19 Diagram of eye muscle actions. The eye is adducted by the medial rectus and abducted by the lateral rectus. The adducted eye is elevated by the inferior oblique and depressed by the superior oblique; the abducted eye is elevated by the superior rectus and depressed by the inferior rectus. References: Langman's Medical Embryology Sadler, T. W. (2019). Langman's medical embryology (14th ed.). Wolters Kluwer. Gray's Anatomy: The Anatomical Basis of Clinical Practice Standring, S. (Ed.). (2020). Gray's anatomy: The anatomical basis of clinical practice (42nd ed.). Elsevier. Ganong’s Review of Medical Physiology Barrett, K. E., Barman, S. M., Boitano, S., & Brooks, H. L. (2019). Ganong’s review of medical physiology (26th ed.). McGraw-Hill Education. Comprehensive Ophthalmology Gupta, S. (2019). Comprehensive ophthalmology (6th ed.). Jaypee Brothers Medical Publishers. Kanski’s Clinical Ophthalmology: A Systematic Approach Bowling, B. (2022). Kanski’s clinical ophthalmology: A systematic approach (9th ed.). Elsevier. 1. Discuss the embryologic development of the ear and vestibular apparatus. EMBRYOLOGY OF THE EAR AND THE VESTIBULAR APPARATUS External Ear Development Unlike structures of the inner and middle ear, which develop from pharyngeal pouches, the ear canal originates from the dorsal portion of the first pharyngeal cleft. It is fully expanded by the end of the 18th week of development. The eardrum is made up of three layers (ectoderm, endoderm and connective tissue). The pinna originates as a fusion of six hillocks. The first three hillocks are derived from the lower part of the first pharyngeal arch and form the tragus, crus of the helix, and helix, respectively. The final three hillocks are derived from the upper part of the second pharyngeal arch and form the antihelix, antitragus, and earlobe. The outer ears develop in the lower neck. As the mandible forms they move towards their final position level with the eyes. The outer ear or external ear is derived from 6 surface hillocks (auricular hillocks), three on each of pharyngeal arch 1 and 2. The external auditory meatus is derived from the 1st pharyngeal cleft. Development of the human external auditory meatus (EAM) begins in the late embryo and continues through the fetal second trimester. The period the "metal plug" is present has been variously described. The best EAM developmental time course is described in two studies. External Auditory Meatus Timeline Period Week Description Funnel-shaped tube continues medially into mesenchymal tissue, forms a Embryo week 8 curved path. Fetus (first Ectodermal cells proliferate, fill the meatus lumen and form the "meatal week 9 trimester) plug". Meatal plug bottom extends in a disc-like fashion, so that in the horizontal plane the meatus is boot-shaped with a narrow neck and the sole of the Fetus (first week 10 meatal plug spreading widely to form the future tympanic membrane trimester) medially. At the same time, the plug in the proximal portion of the neck starts to be resorbed. Fetus (second Meatal plug disc-like, innermost surface in contact with the primordial week 13 trimester) malleus, contributes to formation of tympanic membrane. Meatal plug innermost portion splits, leaving a thin ectodermal cell layer of Fetus (second week 15 immature tympanic membrane. The neck of the boot forms the border trimester) between the primary and secondary meatus, and is the last part to split. Fetus (second The meatus is fully patent throughout entire length. Lumen is still narrow week 16.5 trimester) and curved. Epithelium cornification commences. Fetus (second week 18 The meatus is now fully expanded to its complete form. trimester) Abnormalities There are a range of external ear abnormalities relate to final structure, size and position. In some cases these abnormalities relate directly to pharyngeal arch development or may be part of a wider spectrum of abnormalities associated with a genetic or environmental (fetal alcohol syndrome) disorders. Some known abnormalities include: anotia, microtia, prominent ear, lop ear, cup ear, cryptotia and Stahl's ear. Other associated external ear abnormalities include the formation of the external auditory meatus (canal) and pre-auricular fistulae (pits) and appendages. Finally, a range of abnormalities can be found associated with the overlying skin of both the external ear and the ear canal. The external auditory meatus (canal) can also fail to canalise leading to a range of malformation including membranous and/or bony atresia and stenosis. There are also a range of pre-auricular fistulae (pits) and appendages that generally occur in a specific region beside the tragus and crus helicis. Middle Ear Development Tympanic Cavity and Auditory Tube Endoderm from 1st pharyngeal pouch gives rise to the Primitive Tympanic Cavity. This pouch found laterally to the primitive pharynx later expands laterally coming into close contact with the floor the 1st pharyngeal cleft. With further 1 development, the distal portion of this primitive cavity expands to form the tubotympanic recess. And the Proximal portion stays narrow to give rise to the auditory tube which allows the nasopharynx to communicate with the tympanic cavity. Ossicles As the Pharyngeal arches begin to form during the 4th week of embryonic development, it is visible to see the 1st and 2nd pharyngeal arches. The cartilage within these arches gives rise to the ossicles of the ear. The Malleus, Incus and Stapes. Ossicles appear during the 1st half of fetal life however in contrast to their position they remain embeded in this ectomesenchymal tissue until the 8th month. Once complete mesenchymal condesation has occured around the ossicles, the endodermal epithelium connects them in a mesentery like fashion to the wall of the cavity. This is the supporting ligaments of the ossicles develop later within these mesenteries. Tympanic cavity grows dorsally by vacuolization of surrounding tissue giving rise to the primitive tympanic antrum. Internal Ear Development Firstly, at approximately 22 days of development a thickening of the surface ectoderm on each side of the rhombencephalon can be seen. These are defined as the Otic Placode, with further development they invaginate forming otocysts. Moreover, each vesicle splits into a Ventral Component, gives rise to the saccule, cochlear duct and ductus reuniens The Primitive Dorsal Component gives rise to the utricle, endolymphatic duct and semicircular canals. Cochlea, Saccule and Organ of Corti On the 6th week of embryonic development, the saccule forms a tubular outgrowth at its lower border. This is the primitive Cochlear Duct. The surrounding mesenchyme is penetrated by this duct till the end of the 8th week of development. The ductus reuniens is the narrowing that forms of this duct connecting it to the Saccule. Later Mesenchymal condensation occurs surrounding the cochlear duct, this will differentiate into cartilage later forming the bony labyrinth. Moreover, During the 10th week within this cartilaginous shell vacuolization occurs that gives rise to the perilymphatic spaces these are the scala tympani and scala vestibule. Vestibular membrane also known as Reissner’s membrane is known to separate the scala vestibuli from the cochlear duct. And the Basilar membrane separates scala tympani and cochlear duct. Moreover, The Lateral wall of the cochlear duct remains is attached to the cartilage by the spiral ligament, today some authors believe that the cells within spiral ligament have neural crest cell origins. Utricle and Semicircular Canals Approximately during the 6th week, impulses generate within cristae and maculae triggered by changes in body and head position, these are carried to the brain via vestibular fibers of cranial nerve VIII. Moreover, the statoacoustic ganglion derived neural crest cells has also fully developed by this embryonic stage. This Ganglion subsequently divides into the cochlear and vestibular divisions that supply sensory cells in organ of Corti, saccule, utricle and semicircular canals. EMBRYONIC ORIGIN OVERVIEW External Ear ▪ Auricle - Pharyngeal Arches 1 and 2 (ectoderm, mesoderm) ▪ External Auditory Meatus - Pharyngeal Arch 1 groove or cleft (ectoderm) ▪ Tympanic Membrane - Pharyngeal Arch 1 membrane (ectoderm, mesoderm, endoderm) The external ear is derived from 6 surface hillocks, 3 on each of pharyngeal arch 1 and 2. The external auditory meatus is derived from the 1st pharyngeal cleft. The newborn external ear structure and position is an easily accessible diagnostic tool for potential abnormalities or further clinical screening. a. Pinna arises from fusion of six auricular hillocks. b. External auditory meatus is ectoderm of first pharyngeal cleft. TM ->Inner layer “endoderm”, Middle layer “mesoderm” and Outer layer “ectoderm”. Middle Ear ▪ Middle Ear Ossicles o malleus and incus - Pharyngeal Arch 1 cartilage Neural crest (ectoderm) o Stapes - Pharyngeal Arch 2 cartilage Neural crest (ectoderm) ▪ Middle Ear Muscles o Tensor tympani - Pharyngeal Arch 1 (mesoderm) o Stapedius - Pharyngeal Arch 2 (mesoderm) ▪ Middle ear cavity - Pharyngeal Arch 1 pouch (endoderm) The middle ear ossicles (bones) are derived from 1st and 2nd arch mesenchyme. 2  The space in which these bones sit is derived from the 1st pharyngeal pouch. a. Middle ear cavity and Eustachian tube -> from first pharyngeal pouch endoderm. b. Middle ear ossicles come from first (malleus and incus) and second (and stapes) pharyngeal arches mesoderm. Inner Ear ▪ Inner Ear Labyrinth o Cochlea - Otic vesicle - Otic placode (ectoderm) o Semicircular canals - Otic vesicle - Otic placode (ectoderm) o Saccule and utricle - Otic vesicle - Otic placode (ectoderm) ▪ Cranial Nerve VIII o Auditory component - Otic vesicle and neural crest (ectoderm) o Vestibular component - Otic vesicle and neural crest (ectoderm) The inner ear is derived from a pair of surface sensory placodes (otic placodes) in the head region. These placodes fold inwards forming a depression, then pinch off entirely from the surface forming a fluid-filled sac or vesicle (otic vesicle, otocyst). The vesicle sinks into the head mesenchyme some of which closely surrounds the otocyst forming the otic capsule. The otocyst finally lies close to the early developing hindbrain (rhombencephalon) and the developing vestibulocochlear-facial ganglion complex. a. Membranous labyrinth: derived from ectodermal invagination from otic placode. b. Bony labyrinth: from mesoderm 2. What are the major divisions of the ear? a. External Ear b. Middle Ear c. Inner Ear COMPONENTS OF THE EAR AND THE AUDITORY SYSTEM Each ear consists of 3 components: 2 air-filled spaces, the external ear and the middle ear; and the fluid-filled spaces of the inner ear (Figures III-5-8 and III-5-9). The external ear includes the pinna and the external auditory meatus, which extends to the tympanic membrane. Sound waves travel through the external auditory canal and cause the tympanic membrane (eardrum) to vibrate. Movement of the eardrum causes vibrations of the ossicles in the middle ear (i.e., the malleus, incus, and stapes). Vibrations of the ossicles are transferred through the oval window and into the inner ear. The middle ear lies in the temporal bone, where the chain of 3 ossicles connect the tympanic membrane to the oval window. These auditory ossicles amplify the vibrations received by the tympanic membrane and transmit them to the fluid 3 of the inner ear with minimal energy loss. The malleus is inserted in the tympanic membrane, and the stapes is inserted into the membrane of the oval window. Two small skeletal muscles, the tensor tympani and the stapedius, contract to prevent damage to the inner ear when the ear is exposed to loud sounds. The middle-ear cavity communicates with the nasopharynx via the eustachian tube, which allows air pressure to be equalized on both sides of the tympanic membrane. The inner ear consists of a labyrinth (osseous and membranous) of interconnected sacs (utricle and saccule) and channels (semicircular ducts and the cochlear duct) that contain patches of receptor or hair cells that respond to airborne vibrations or movements of the head. Both the cochlear duct and the sacs and channels of the vestibular labyrinth are filled with endolymph, which bathes the hairs of the hair cells. Endolymph is unique because it has the inorganic ionic composition of an intracellular fluid but it lies in an extracellular space. The intracellular ionic composition of endolymph is important for the function of hair cells. Perilymph, ionically like a typical extracellular fluid, lies outside the endolymph-filled labyrinth (Figure III-5-8). Clinical Correlate ▪ Middle-ear diseases (otitis media, otosclerosis) result in a conductive hearing loss because of a reduction in amplification provided by the ossicles. ▪ Lesions of the facial nerve in the brain stem or temporal bone (Bell palsy) may result in hyperacusis, an increased sensitivity to loud sounds. ▪ Presbycusis results from a loss of hair cells at the base of the cochlea. ▪ Sensorineural hearing loss: air conduction > bone conduction ▪ Conductive hearing loss: bone conduction > air conduction Auditory System Cochlear duct The cochlear duct is the auditory receptor of the inner ear. It contains hair cells, which respond to airborne vibrations transmitted by the ossicles to the oval window. The cochlear duct coils 2 and a quarter turns within the bony cochlea and contains hair cells situated on an elongated, highly flexible, basilar membrane. High-frequency sound waves cause maximum displacement of the basilar membrane and stimulation of hair cells at the base of the cochlea, whereas low-frequency sounds maximally stimulate hair cells at the apex of the cochlea. Spiral ganglion The spiral ganglion contains cell bodies whose peripheral axons innervate auditory hair cells of the organ of Corti. The central axons from these bipolar cells form the cochlear part of the eighth cranial nerve. All of the axons in the cochlear part of the eighth nerve enter the pontomedullary junction and synapse in the ventral and dorsal cochlear nuclei. Axons of cells in the ventral cochlear nuclei bilaterally innervate the superior olivary nuclei in the pons. The superior olivary nuclei are the first auditory nuclei to receive binaural input and use the binaural input to localize sound sources. The lateral lemniscus carries auditory input from the cochlear nuclei and the superior olivary nuclei to the inferior colliculus in the midbrain. Each lateral lemniscus carries information derived from both ears; however, input from the contralateral ear predominates (Figure III-5-9). 4 Inferior colliculus The inferior colliculus sends auditory information to the medial geniculate body (MGB) of the thalamus. From the MGB, the auditory radiation projects to the primary auditory cortex located on the posterior portion of the transverse temporal gyrus (Heschl’s gyrus; Brodmann areas 41 and 42). The adjacent auditory association area makes connections with other parts of the cortex, including Wernicke’s area, the cortical area for the comprehension of language. Clinical Correlate Lesions Causing Hearing Loss Lesions of the cochlear part of the eighth nerve or cochlear nuclei inside the brain stem at the pontomedullary junction result in a profound unilateral sensorineural hearing loss (A). All other lesions to auditory structures in the brain stem, thalamus, or cortex result in a bilateral suppression of hearing and a decreased ability to localize a sound source (B). If a patient presents with a significant hearing loss in one ear, the lesion is most likely in the middle ear, inner ear, eighth nerve, or cochlear nuclei, and not at higher levels of the auditory system. Hearing Loss ▪ Conductive: passage of sound waves through external or middle ear is interrupted. Causes: obstruction, otosclerosis, otitis media ▪ Sensorineural: damage to cochlea, CN VIII, or central auditory connections Auditory Tests ▪ Weber test: place tuning fork on vertex of skull. If unilateral conductive loss → vibration is louder in affected ear; if unilateral sensorineural loss → vibration is louder in normal ear. ▪ Rinne test: place tuning fork on mastoid process (bone conduction) until vibration is not heard, then place fork in front of ear (air conduction). If unilateral conductive loss → no air conduction after bone conduction is gone; if unilateral sensorineural loss → air conduction present after bone conduction is gone. 3. What composes the external ear? The auricle or pinna (L. pinna, wing) is an irregular, funnel- shaped plate of elastic cartilage, covered by tightly adherent skin, which directs sound waves into the ear. Sound waves enter the external acoustic meatus (L. passage), a canal lined with stratified squamous epithelium that extends from the auricle to the middle ear. Near its opening hair follicles, sebaceous glands, and modified apocrine sweat glands called ceruminous glands are found in the submucosa. Cerumen, the waxy material formed from secretions of the sebaceous and ceruminous glands, contains various proteins, saturated fatty acids, and sloughed keratinocytes and has protective, antimicrobial properties. The wall of the external auditory meatus is supported by elastic cartilage in its outer third, while the temporal bone encloses the inner part. Across the deep end of the external acoustic meatus lies a thin, somewhat transparent sheet called the tympanic membrane or eardrum. This membrane consists of fibroelastic connective tissue covered externally with epidermis and internally by the simple cuboidal epithelium of the mucosa that lines the middle ear cavity. Sound waves cause vibrations of the tympanic membrane, which transmit energy to the middle ear 4. What is the tympanic membrane? Describe it anatomically and its physiologic use. Tympanic Membrane: 5  Separates the tympanic cavity from the canal Gathers sound Provides sonic shielding of the round window membrane Directed obliquely downward and inward forming a 550 angle with meatal floor Approximately 9-10mm vertically and 8-9mm horizontally Fibrocartilaginous ring fixed in the tympanic sulcus 5. What are the boundaries of the tympanic cavity? Roof - Tegmen Floor - Jugular wall and styloid prominence Posteriorly - Mastoid, stapedius, pyramidal prominence Anteriorly - Carotid Wall, Eustachian tube, tensor tympani Medially - Labyrinthine wall Laterally - Tympanic membrane, scutum 6. What are the layers of the tympanic membrane? ▪ Lateral (Cutaneous) ▪ Intermediate/Lamina Propria (Fibrous) o Stratum Radiale o Stratum Circulare ▪ Medial (Mucous) 7. What are the functions of the Eustachian tube? The EUSTACHIAN TUBE connects the tympanic cavity with the nasopharynx, where the inlet of the tube forms a funnel-shaped orifice behind the choana. Functions of the Eustachian Tube: ▪ Ventilates the tympanic cavity and air cells. ▪ Equalizes pressure differences between the tympanic cavity and the atmosphere. ▪ Drains the middle ear spaces. ▪ Creates a barrier to ascending infection The Eustachian tube runs more horizontally in infants and small children than in adults. It is considerably shorter and broader and consists of softer cartilage. 8. What is the middle ear? The middle ear contains the air-filled tympanic cavity, an irregular space that lies within the temporal bone between the tympanic membrane and the bony surface of the internal ear. Anteriorly, this cavity communicates with the pharynx via the auditory tube (also called the Eustachian or pharyngotympanic tube) and posteriorly with the smaller, airfilled mastoid cavities of the temporal bone. The simple cuboidal epithelium lining the cavity rests on a thin lamina propria continuous with periosteum. Entering the auditory tube, this simple epithelium is gradually replaced by the ciliated pseudostratified columnar epithelium that lines the tube. Below the temporal bone this tube is usually collapsed; swallowing opens it briefly, which serves to balance the air pressure in the middle ear with atmospheric pressure. In the medial bony wall of the middle ear are two small, membrane-covered regions devoid of bone: the oval and round windows with the internal ear behind them. The tympanic membrane is connected to the oval window by a series of three small bones, the auditory ossicles, which transmit the mechanical vibrations of the tympanic membrane to the internal ear. The three ossicles are named for their shapes the malleus, incus, and stapes, the Latin words for “hammer,” “anvil,” and “stirrup,” respectively. The malleus is attached to the tympanic membrane and the stapes to the membrane across the oval window. The ossicles articulate at 6 synovial joints, which along with periosteum are completely covered with simple squamous epithelium. Two small skeletal muscles, the tensor tympani and stapedius, insert into the mal- leus and stapes, respectively, restricting ossicle movements and protecting the oval window and inner ear from potential damage caused by extremely loud sound. 9. What are the regions of the middle ear? 10. Describe the location of the inner ear. What are its components? The internal ear is located completely within the temporal bone, where an intricate set of interconnected spaces, the bony labyrinth, houses the smaller membranous labyrinth, a set of continuous fluid-filled, epithelium-lined tubes and chambers. The membranous labyrinth is derived from an ectodermal vesicle, the otic vesicle, which invaginates into subjacent mesenchyme during the fourth week of embryonic development, loses contact with the surface ectoderm, and becomes embedded in rudiments of the developing temporal bone. The embryonic otic vesicle, or otocyst, forms the membranous labyrinth with its major divisions: ▪ Two connected sacs called the utricle and the saccule, ▪ Three semicircular ducts continuous with the utricle, ▪ The cochlear duct, which provides for hearing and is continuous with the saccule. Mediating the functions of the inner ear, each of these structures contains in its epithelial lining large areas with columnar mechanoreceptor cells, called hair cells, in specialized sensory regions: ▪ Two maculae of the utricle and saccule, ▪ Three cristae ampullares in the enlarged ampullary regions of each semicircular duct, ▪ The long spiral organ of Corti in the cochlear duct. The entire membranous labyrinth is within the bony labyrinth, which includes the following regions: ▪ An irregular central cavity, the vestibule (L.vestibulum, area for entering) houses the saccule and the utricle. ▪ Behind this, three osseous semicircular canals enclose the semicircular ducts. On the other side of the vestibule, the cochlea (L.snail, screw) contains the cochlear duct. The cochlea is about 35mm long and makes 2 3⁄4 turns around a bony core called the modiolus (L. hub of wheel). The modiolus contains blood vessels and surrounds the cell bodies and processes of the acoustic branch of the eighth cranial nerve in the large spiral or cochlear ganglion. 11. Describe the functional anatomy of the cochlea. The cochlea is a system of coiled tubes, It consists of three tubes coiled side by side: (1) the scala vestibuli, (2) the scala media, and (3) the scala tympani. The scala vestibuli and scala media are separated from each other by Reissner’s membrane (also called the vestibular membrane), shown in Figure 52–3; the scala tympani and scala media are separated from each other by the basilar membrane. On the surface of the basilar membrane lies the organ of Corti, which contains a series of electromechanically sensitive cells, the hair cells. They are the receptive end organs that generate nerve impulses in response to sound vibrations. 7 12. What are the cochlear fluids? Differentiate Perilymph from Endolymph. The cochlear canals contain two types of fluid: perilymph and endolymph. Perilymph has a similar ionic composition as extracellular fluid found elsewhere in the body and fills the scalae tympani and vestibuli. Endolymph, found inside the cochlear duct (scala media), has a unique composition not found elsewhere in the body. COMPOSITION OF THE COCHLEAR FLUIDS A remarkable characteristic of the cochlea is the unique composition of endolymph. This liquid fills the scala media, and is extraordinarily rich in potassium (150mM), very poor in sodium (1mM) and almost completely lacking in calcium (2030 µM). Perilymph (in blue) fills the scala vestibuli (1) and scala tympani (2). Endolymph (in green) is limited to the scala media (= cochlear duct; 3), is very rich in potassium, secreted by the stria vascularis, and has a positive potential (+80mV) compared to perilymph. Note that only the surface of the organ of Corti is bathed in endolymph (notably the stereocilia of the hair cells), whilst the main body of hair cells and support cells are bathed in perilymph. Perilymph There are two types of perilymph: the perilymph of the scala vestibuli, and that of the scala tympani. Both have a composition similar to cerebro-spinal fluid (CSF): rich in sodium (140mM) and poor in potassium (5mM) and calcium (1.2mM). The perilymph in the scala vestibuli comes from blood plasma across a hemo-perilymphatic barrier, whereas that of the scala tympani originates from CSF. 8 Endolymph Endolymph is created from perilymph. The endocochlear potential is the sum of two potentials: a positive potential caused by active secretion of K+ by the stria vascularis (120mV) and a negative potential created by the passive diffusion of K+ ions from the hair cells (40mV), which can be visualized after an anoxia. Note that the ionic composition of endolymph develops prior to the endocochlear potential. In fact, in the mouse, endolymphatic ion concentrations are finalized during the first postnatal week. In comparison, the mouse endocochlear potential does not develop until the second postnatal week and doesn’t reach its final value until the third week after birth. Composition and properties of the two cochlear fluids Why endolymph? It appears that the cochlea has found a way of regulating potassium flow without expending any energy (ATP). Generally speaking, if an ion enters a cell in a passive way, it requires an active mechanism to leave it, and vice versa. Only the apical pole of the hair cells bathes in the potassium-rich endolymph, which has a positive potential of 80mV. K+ ions therefore enter these cells passively, as there is more potassium in the endolymph than in the hair cell and the latter have a resting potential of -60mV, which favors an influx of K+. These ions also leave the hair cells in a passive manner, due to the higher concentration of K+ ions inside the hair cell, compared to outside of the cell body bathed in perilymph. This all results in a significant saving of ATP by the hair cell. STRIA VASCULARIS The stria vascularis, a complex epithelial structure composed of various cell types, produces endolymph and releases it into the cochlea. The basal and marginal cells are true epithelial cells, whereas the intermediate cells are ‘melanocyte-like’. Intricate vasculature provides the oxygen and nutrients needed for the stria vascularis to function correctly. Structure of the stria vascularis (transmission electron microscopy) Highly vascular (C), the stria vascularis is composed of three cell types: Marginal cells (M), which line the endolymphatic canal and have an essential role in ion exchange Intermediate cells (I), which are rich in the pigment melatonin Basal cells (B). POTASSIUM CYCLE The potassium flow originating from the fibrocytes of the spiral ligament penetrates into the basal cells via a system of gap junctions composed of connexons, and hexamere 6 transmembrane proteins called connexins that form a hydrophilic canal of 2nm diameter. Connexins 26 and 30 (CX) are the most expressed connexins in the lateral wall of the cochlea and in the stria vascularis. Mutations in these two genes are the most common causes of prelingual human hearing loss. Potassium passes from basal cells (B) to intermediate cells (I) via the same network. It leaves the intermediate cells by the potassium channel Kir4.1 and rejoins the intrastrial space (in green). This passage of K+ ions across the intermediate 9 cells’ membrane gives rise to the endocochlear potential. Mutations in Kir4.1 in humans are known to cause EAST syndrome (Epilepsy, Ataxia, Sensorineural deafness and Tubulopathy). In order to generate a potential of 100mV, a weak concentration of potassium (around 1mM) is needed in the intrastrial space. This task is carried out by Na-K ATPase, which is expressed in the membrane of intermediate and marginal cells. Furthermore, the co-transporter NKCC1, expressed in the membrane of marginal cells, is also involved in this regulation by using the sodium gradient generated by the Na-K ATPase to cause the ingression of potassium into the marginal cell. The influx mechanism of potassium ions into the marginal cells is very efficient, using a single ATP molecule to cause the influx of 5 molecules of potassium (2 using Na-K APTase and 3 using the co-transporter NKCC1). Finally, chlorine ions, which enter the cell at the same time as sodium and potassium ions via the co-transporter NKCC1, are expelled by CIC-K chlorine channels associated with their regulating beta-subunit, barttin. Mutations in barttin expression are responsible for Bartter’s syndrome, causing both tubulopathy and hearing loss. Potassium is finally secreted into scala media via KCNQ1 potassium channels associated to their regulating subunit KCNE1. Mutations in these two genes give rise to Jervell and Lange-Nielsen syndrome, causing bilateral hearing loss and a long cardiac QT. In summary: Perilymph fills all regions of the bony labyrinth and has an ionic composition similar to that of cerebrospinal fluid and the extracellular fluid of other tissues, but it contains little protein. Perilymph emerges from the microvasculature of the periosteum and drains via a perilymphatic duct into the adjoining subarachnoid space. Perilymph suspends and supports the closed membranous labyrinth, protecting it from the hard wall of the bony labyrinth. Endolymph fills the membranous labyrinth and is characterized by a high-K+ (150 mM) and low-Na+ (16 mM) content, similar to that of intracellular fluid. Endolymph is produced in a specialized area in the wall of the cochlear duct and drains via a small endolymphatic duct into venous sinuses of the dura mater. 13. What is the basilar membrane and what is its importance in the resonance of the cochlea? The basilar membrane is a fibrous membrane that separates the scala media from the scala tympani. It contains 20,000 to 30,000 basilar fibers that project from the bony center of the cochlea, the modiolus, toward the outer wall. These fibers are stiff, elastic, reed-like structures that are fixed at their basal ends in the central bony structure of the cochlea (the modiolus) but are not fixed at their distal ends, except that the distal ends are embedded in the loose basilar membrane. Because the fibers are stiff and free at one end, they can vibrate like the reeds of a harmonica. The lengths of the basilar fibers increase progressively beginning at the oval window and going from the base of the cochlea to the apex, increasing from a length of about 0.04 millimeter near the oval and round windows to 0.5 millimeter at the tip of the cochlea (the “helicotrema”), a 12-fold increase in length. The diameters of the fibers, however, decrease from the oval window to the helicotrema, so that their overall stiffness decreases more than 100-fold. As a result, the stiff, short fibers near the oval window of the cochlea vibrate best at a very high frequency, while the long, limber fibers near the tip of the cochlea vibrate best at a low frequency. Thus, high-frequency resonance of the basilar membrane occurs near the base, where the sound waves enter the cochlea through the oval window. But low frequency resonance occurs near the helicotrema, mainly because of the less stiff fibers but also because of increased “loading” with extra masses of fluid that must vibrate along the cochlear tubules. 14. What is the function of the organ of Corti? The organ of Corti is the receptor organ that generates nerve impulses in response to vibration of the basilar membrane. Note that the organ of Corti lies on the surface of the basilar fibers and basilar membrane. The actual sensory receptors in the organ of Corti are two specialized types of nerve cells called hair cells—a single row of internal (or “inner”) hair cells, numbering about 3500 and measuring about 12 micrometers in diameter, and three or four rows of external (or “outer”) hair cells, numbering about 12,000 and having diameters of only about 8 micrometers. The bases and sides of the 10 hair cells synapse with a network of cochlea nerve endings. Between 90 and 95 per cent of these endings terminate on the inner hair cells, which emphasize their special importance for the detection of sound. The nerve fibers stimulated by the hair cells lead to the spiral ganglion of Corti, which lies in the modiolus (center) of the cochlea. The spiral ganglion neuronal cells send axons—a total of about 30,000—into the cochlear nerve and then into the central nervous system at the level of the upper medulla. The relation of the organ of Corti to the spiral ganglion and to the cochlear nerve Excitation of the Hair Cells Note in Figure 52–7 that minute hairs, or stereocilia, project upward from the hair cells and either touch or are embedded in the surface gel coating of the tectorial membrane, which lies above the stereocilia in the scala media. These hair cells are similar to the hair cells found in the macula and cristae ampullaris of the vestibular apparatus. Bending of the hairs in one direction depolarizes the hair cells and bending in the opposite direction hyperpolarizes them. This in turn excites the auditory nerve fibers synapsing with their bases. Figure 52–8 shows the mechanism by which vibration of the basilar membrane excites the hair endings. The outer ends of the hair cells are fixed tightly in a rigid structure composed of a flat plate, called the reticular lamina, supported by triangular rods of Corti, which are attached tightly to the basilar fibers. The basilar fibers, the rods of Corti, and the reticular lamina move as a rigid unit. Upward movement of the basilar fiber rocks the reticular lamina upward and inward toward the modiolus. Then, when the basilar membrane moves downward, the reticular lamina rocks downward and outward. The inward and outward motion causes the hairs on the hair cells to shear back and forth against the tectorial membrane. Thus, the hair cells are excited whenever the basilar membrane vibrates. Auditory Signals are transmitted mainly by the Inner Hair cells Even though there are three to four times as many outer hair cells as inner hair cells, about 90 per cent of the auditory nerve fibers are stimulated by the inner cells rather than by the outer cells. Yet, despite this, if the outer cells are damaged while the inner cells remain fully functional, a large amount of hearing loss occurs. Therefore, it has been proposed that the outer hair cells in some way control the sensitivity of the inner hair cells at different sound pitches, a phenomenon called “tuning” of the receptor system. In support of this concept, a large number of retro- grade nerve fibers pass from the brain stem to the vicinity of the outer hair cells. Stimulating these nerve fibers can actually cause shortening of the outer hair cells and possibly also change their degree of stiffness. These effects suggest a retrograde nervous mechanism for control of the ear’s sensitivity to different sound pitches, activated through the outer hair cells. 11 Hair Cell Receptor Potentials and Excitation of Auditory Nerve Fibers The stereocilia (the “hairs” protruding from the ends of the hair cells) are stiff structures because each has a rigid protein framework. Each hair cell has about 100 stereocilia on its apical border. These become progressively longer on the side of the hair cell away from the modiolus, and the tops of the shorter stereocilia are attached by thin filaments to the back sides of their adjacent longer stereocilia. Therefore, whenever the cilia are bent in the direction of the longer ones, the tips of the smaller stereocilia are tugged outward from the surface of the hair cell. This causes a mechanical transduction that opens 200 to 300 cation-conducting channels, allowing rapid movement of positively charged potassium ions from the surrounding scala media fluid into the stereocilia, which causes depolarization of the hair cell membrane. Thus, when the basilar fibers bend toward the scala vestibuli, the hair cells depolarize, and in the opposite direction they hyperpolarize, thereby generating an alternating hair cell receptor potential. This, in turn, stimulates the cochlear nerve endings that synapse with the bases of the hair cells. It is believed that a rapidly acting neurotransmitter is released by the hair cells at these synapses during depolarization. It is possible that the transmitter substance is glutamate, but this is not certain. 15. Trace the path of the sound waves through the ear. Hearing depends on a series of complex steps that change sound waves in the air into electrical signals. Our auditory nerve then carries these signals to the brain. 1. Sound waves enter the outer ear and travel through a narrow passageway called the ear canal, which leads to the eardrum. 2. The eardrum vibrates from the incoming sound waves and sends these vibrations to three tiny bones in the middle ear. These bones are called the malleus, incus, and stapes. 3. The bones in the middle ear amplify, or increase, the sound vibrations and send them to the cochlea, a snail-shaped structure filled with fluid, in the inner ear. An elastic partition runs from the beginning to the end of the cochlea, splitting it into an upper and lower part. This partition is called the basilar membrane because it serves as the base, or ground floor, on which key hearing structures sit. 4. Once the vibrations cause the fluid inside the cochlea to ripple, a traveling wave forms along the basilar membrane. Hairs cells—sensory cells sitting on top of the basilar membrane—ride the wave. Hair cells near the wide end of the snail-shaped cochlea detect higher-pitched sounds, such as an infant crying. Those closer to the center detect lower- pitched sounds, such as a large dog barking. 12  5. As the hair cells move up and down, microscopic hair-like projections (known as stereocilia) that perch on top of the hair cells bump against an overlying structure and bend. Bending causes pore-like channels, which are at the tips of the stereocilia, to open up. When that happens, chemicals rush into the cells, creating an electrical signal. 6. The auditory nerve carries this electrical signal to the brain, which turns it into a sound that we recognize and understand. 7. The remaining pressure waves are transferred to the scala tympani and exit the inner ear by way of the round window. 16. What is the “Place Principle”? The major method used by the nervous system to detect different sound frequencies is to determine the positions along the basilar membrane that are most stimulated. This is called the place principle for the determination of sound frequency. We can see that the distal end of the basilar membrane at the helicotrema is stimulated by all sound frequencies below 200 cycles per second. Therefore, it has been difficult to understand from the place principle how one can differentiate between low sound frequencies in the range from 200 down to 20. It is postulated that these low frequencies are discriminated mainly by the so-called volley or frequency principle. That is, low- frequency sounds, from 20 to 1500 to 2000 cycles per second, can cause volleys of nerve impulses synchronized at the same frequencies, and these volleys are transmitted by the cochlear nerve into the cochlear nuclei of the brain. It is further suggested that the cochlear nuclei can distinguish the different frequencies of the volleys. In fact, destruction of the entire apical half of the cochlea, which destroys the basilar membrane where all lower-frequency sounds are normally detected, does not totally eliminate discrimination of the lower-frequency sounds. 17. How does the auditory system determine the loudness? Loudness is determined by the auditory system in at least three ways: First, as the sound becomes louder, the amplitude of vibration of the basilar membrane and hair cells also increases, so that the hair cells excite the nerve endings at more rapid rates. Second, as the amplitude of vibration increases, it causes more and more of the hair cells on the fringes of the resonating portion of the basilar membrane to become stimulated, thus causing spatial summation of impulses—that is, transmission through many nerve fibers rather than through only a few. Third, the outer hair cells do not become stimulated significantly until vibration of the basilar membrane reaches high intensity, and stimulation of these cells presumably apprises the nervous system that the sound is loud. 18. What is the unit for sound intensity? Decibel Unit. Because of the extreme changes in sound intensities that the ear can detect and discriminate, sound intensities are usually expressed in terms of the logarithm of their actual intensities. A 10-fold increase in sound energy is called 1 bel, and 0.1 bel is called 1 decibel. One decibel represents an actual increase in sound energy of 1.26 times. Another reason for using the decibel system to express changes in loudness is that, in the usual sound intensity range for communication, the ears can barely distinguish an approximately 1-decibel change in sound intensity. 19. Discuss the auditory system, its structure, function, pathways and reflexes. Auditory System: Structure and Function The Vertebrate Hair Cell: Mechanoreceptor Mechanism, Tip Links, K+ and Ca2+ Channels The key structure in the vertebrate auditory and vestibular systems is the hair cell. The hair cell first appeared in fish as part of a long, thin array along the side of the body, sensing movements in the water. In higher vertebrates the internal fluid of the inner ear (not external fluid as in fish) bathes the hair cells, but these cells still sense movements in the surrounding fluid. Several specializations make human hair cells responsive to various forms of mechanical stimulation. Hair cells in the Organ of Corti in the cochlea of the ear respond to sound. Hair cells in the cristae ampullares in the semicircular ducts respond to angular acceleration (rotation of the head). Hair cells in the maculae of the saccule and the utricle respond to linear acceleration (gravity). (See the Vestibular System: Structure and Function). The fluid, termed endolymph, which surrounds the hair cells, is rich in potassium. This actively maintained ionic imbalance provides an energy store, which is used to trigger neural action potentials when the hair cells are moved. Tight junctions between hair cells and the nearby supporting cells form a barrier between endolymph and perilymph that maintains the ionic imbalance. The figure below illustrates the process of mechanical transduction at the tips of the hair cell cilia. Cilia emerge from the apical surface of hair cells. These cilia increase in length along a consistent axis. There are tiny thread-like connections from the tip of each cilium to a non-specific cation channel on the side of the taller neighboring cilium. The tip links function like a string connected to a hinged hatch. When the cilia are bent toward the tallest one, the channels are opened, much like a trap door. Opening these channels allows an influx of potassium, which in turns opens calcium channels that initiates the receptor potential. This mechanism transduces mechanical energy into neural impulses. An inward K+ 13 current depolarizes the cell and opens voltage-dependent calcium channels. This in turn causes neurotransmitter release at the basal end of the hair cell, eliciting an action potential in the dendrites of the VIIIth cranial nerve. Hair cells normally have a small influx of K+ at rest, so there is some baseline activity in the afferent neurons. Bending the cilia toward the tallest one opens the potassium channels and increases afferent activity. Bending the cilia in the opposite direction closes the channels and decreases afferent activity. Bending the cilia to the side has no effect on spontaneous neural activity. Sound: Intensity, Frequency, Outer and Middle Ear Mechanisms, Impedance Matching by Area and Lever Ratios The auditory system changes a wide range of weak mechanical signals into a complex series of electrical signals in the central nervous system. Sound is a series of pressure changes in the air. Sounds often vary in frequency and intensity over time. Humans can detect sounds that cause movements only slightly greater than those of Brownian movement. Obviously, if we heard that ceaseless (except at absolute zero) motion of air molecules we would have no silence. The pinna and external auditory meatus collect these waves, change them slightly, and direct them to the tympanic membrane. The resulting movements of the eardrum are transmitted through the three middle-ear ossicles (malleus, incus and stapes) to the fluid of the inner ear. The footplate of the stapes fits tightly into the oval window of the bony cochlea. The inner ear is filled with fluid. Since fluid is incompressible, as the stapes moves in and out there needs to be a compensatory movement in the opposite direction. Notice that the round window membrane, located beneath the oval window, moves in the opposite direction. Because the tympanic membrane has a larger area than the stapes footplate there is a hydraulic amplification of the sound pressure. Also, because the arm of the malleus to which the tympanic membrane is attached is longer than the arm of the incus to which the stapes is attached, there is a slight amplification of the sound pressure by a lever action. These two impedance matching mechanisms effectively transmit air-born sound into the fluid of the inner ear. If the middle-ear apparatus (ear drum and ossicles) were absent, then sound reaching the oval and round windows would be largely reflected. The Cochlea: three scalae, basilar membrane, movement of hair cells The cochlea is a long-coiled tube, with three channels divided by two thin membranes. The top tube is the scala vestibuli, which is connected to the oval window. The bottom tube is the scala tympani, which is connected to the round window. The middle tube is the scala media, which contains the Organ of Corti. The Organ of Corti sits on the basilar membrane, which forms the division between the scalae media and tympani. Figure 12.3 illustrates a cross section through the cochlea. The three scalae (vestibuli, media, tympani) are cut in several places as they spiral around a central core. The cochlea makes 2-1/2 turns in the human (hence the 5 cuts in midline cross section). The tightly coiled shape gives the cochlea its name, which means snail in Greek (as in conch shell). As explained in Tonotopic Organization, high frequency sounds stimulate the base of the cochlea, whereas low frequency sounds stimulate the apex. This feature is depicted in the animation of Figure 12.3 with neural impulses (having colors from red to blue representing low to high frequencies, respectively) emerging from different turns of the cochlea. The activity in Figure 12.3 would be generated by white noise that has all frequencies at equal amplitudes. The moving dots are meant to indicate afferent action potentials. Low frequencies are transduced at the apex of the cochlea and are represented by red dots. High frequencies are transduced at base of the cochlea and are represented by blue dots. A consequence of this arrangement is that low frequencies are found in the central core of the cochlear nerve, with high frequencies on the outside. Figure 12.4 illustrates one cross section of the cochlea. Sound waves cause the oval and round windows at the base of the cochlea to move in opposite directions (See Figure 12.2). This causes the basilar membrane to be displaced and starts a traveling wave that sweeps from the base toward the apex of the cochlea (See Figure 12.7). The traveling wave increases in amplitude as it moves and reaches a peak at a place that is directly related to the frequency of the sound. The illustration shows a section of the cochlea that is moving in response to sound. Figure 12.5 illustrates a higher magnification of the Organ of Corti. The traveling wave causes the basilar membrane and hence the Organ of Corti to move up and down. The organ of Corti has a central stiffening buttress formed by paired pillar cells. Hair cells protrude from the top of the Organ of Corti. A tectorial (roof) membrane is held in place by a hingelike mechanism on the side of the Organ of Corti and floats above the hair cells. As the basilar and tectorial membranes move 14 up and down with the traveling wave, the hinge mechanism causes the tectorial membrane to move laterally over the hair cells. This lateral shearing motion bends the cilia atop the hair cells, pulls on the fine tip links, and opens the trapdoor channels (See Figure 12.1). The influx of potassium and then calcium causes neurotransmitter release, which in turn causes an EPSP that initiates action potentials in the afferents of the VIIIth cranial nerve. Most of the afferent dendrites make synaptic contacts with the inner hair cells. Figure 12.6 looks down on the Organ of Corti. There are two types of hair cells, inner and outer. There is one row of inner hair cells and three rows of outer hair cells. Most of the afferent dendrites synapse on inner hair cells. Most of efferent axons synapse on the outer hair cells. The outer hair cells are active. They move in response to sound and amplify the traveling wave. The outer hair cells also produce sounds that can be detected in the external auditory meatus with sensitive microphones. These internally generated sounds, termed otoacoustic emissions, are now used to screen newborns for hearing loss. Figure 12.6 shows an immunofluorescent whole mount image of a neonatal mouse cochlea showing the three rows of outer hair cells and the single row of inner hair cells. The mature human cochlea would look approximately the same. Superimposed schematically-depicted neurons show the typical pattern of afferent connections. Ninety-five percent of the VIIIth nerve afferents synapse on inner hair cells. Each inner hair cell makes synaptic connections with many afferents. Each afferent connects to only one inner hair cell. About five percent of the afferents synapse on outer hair cells. These afferents travel a considerable distance along the basilar membrane away from their ganglion cells to synapse on multiple outer hair cells. Less than one percent (~0.5%) of the afferents synapse on multiple inner hair cells. Tonotopic Organization Physical characteristics of the basilar membrane cause different frequencies to reach maximum amplitudes at different positions. Much as on a piano, high frequencies are at one end and low frequencies at the other. High frequencies are transduced at the base of the cochlea whereas low frequencies are transduced at the apex. The cochlea codes the pitch of a sound by the place of maximal vibration. (Beware! It may initially seem backwards that low frequencies are not associated with the base.) Hearing loss at high frequencies is common. The average loss of hearing in American males is about a cycle per second per day (starting at about age 20, so a 50-year-old would likely have difficulty hearing over 10 kHz). The Range of Sounds to Which We Respond, Neural Tuning Curves Figure 12.8 shows the range of frequencies and intensities of sound to which the human auditory system responds. Our absolute threshold, the minimum level of sound that we can detect, is strongly dependent on frequency. At the level of pain, sound levels are about six orders of magnitude above the minimal audible threshold. Sound pressure level (SPL) is measured in decibels (dB). Decibels are a logarithmic scale, with each 6 dB increase indicating a doubling of intensity. The perceived loudness of a sound is related to its intensity. Sound frequencies are measured in Hertz (Hz), or cycles per second. Normally, we hear sounds as low as 20 Hz and as high as 20,000 Hz. The frequency of a sound is associated with its pitch. Hearing is best at about 3-4 kHz. Hearing sensitivity decreases at higher and lower frequencies, but more so at higher than lower frequencies. High-frequency hearing is typically lost as we age. 15  The neural code in the central auditory system is complex. Tonotopic organization is maintained throughout the auditory system. Tonotopic organization means that cells responsive to different frequencies are found in different places at each level of the central auditory system, and that there is a standard (logarithmic) relationship between this position and frequency. Each cell has a characteristic frequency (CF). The CF is the frequency to which the cell is maximally responsive. A cell will usually respond to other frequencies, but only at greater intensities. The neural tuning curve is a plot of the amplitude of sounds at various frequencies necessary to elicit a response from a central auditory neuron. The tuning curves for several different neurons are superimposed on the audibility curves in Figure 12.8. The depicted neurons have CFs that vary from low to high frequencies (and are shown with red to blue colors, respectively). If we recorded from all auditory neurons, we would basically fill the area within the audibility curves. When sounds are soft they will stimulate only those few neurons with that CF, and thus neural activity will be confined to one set of fibers or cells at one particular place. As sounds get louder, they stimulate other neurons, and the area of activity will increase. Auditory System: Pathways and Reflexes Connections in the Central Auditory System Cochlear Nucleus, Superior Olive, Lateral Lemniscus, Inferior Colliculus, Medical Geniculate, Superior Temporal Gyrus Connections in the central auditory system are complex, but a simple summary is that information proceeds from the Organ of Corti to spiral ganglion cells and the VIIIth nerve afferents in the ear, to the cochlear nuclei, many crossing in the trapezoid body to the superior olive in the brain stem. Then all ascending fibers stop in the inferior colliculus in the midbrain and the medial geniculate body in the thalamus, before reaching the cortex in the superior temporal gyrus. All auditory afferents synapse in the cochlear nuclei and in the thalamus. Beyond that simplification, second order fibers from the cochlear nuclei proceed rostrally in several different pathways. Afferents are generally distributed bilaterally so unilateral damage at any level does not usually result in deafness in either ear. 16  Figure 13.1 shows a fiber traveling somewhat directly from the cochlea to the cortex. (The red line). This is a fast-acting system. These fibers synapse in the dorsal cochlear nucleus and may function as a general warning (as when you might jump from a loud sound). These fibers decussate and ascend in the lateral lemniscus to the inferior colliculus. Figure 13.2 shows the more numerous connections that work their way rostrally through a more detailed pathway. This slow acting system involves much more processing and may provide more detailed information about the sound, such as its location. These fibers synapse in the ventral cochlear nucleus. Fibers from the ventral cochlear nucleus synapse in the ipsilateral and contralateral superior olivary nucleus. Some fibers from the ventral cochlear nucleus cross the midline in the trapezoid body. Thus, cells in the superior olive receive inputs from both ears and are the first place in the central auditory system where binaural processing (stereo hearing) is possible. The output of the superior olive travels in the lateral lemniscus. Some nuclei within the lateral lemniscus further process the sound. Most of these afferents synapse in the inferior colliculus. All afferents then synapse in the medial geniculate body of the thalamus. Thalamic afferents reach the superior temporal gyrus through the sub-lenticular portion of the internal capsule. Figure 13.3 shows the same detail processing system as in Figure 13.2, only now with the more realistic situation of input from both ears. The two different patterns of dashed lines combine to form a solid line above the superior olive, meant to indicate the combination of monaural inputs into bilateral and binaural activation. Primary auditory cortex, or Herschel’s gyrus in insular cortex, is tonotopically organized. Afferents from this longitudinal strip on the superior temporal gyrus diverge to a wide variety of other cortical processing areas, including Wernicke’s area in the parietal lobe where speech is processed. Auditory afferents are tonotopically organized from the ear to the cortex. This starts with high frequencies transduced at the base of the cochlea, and low frequencies transduced at the apex. Low frequency fibers then pass in the central core of the VIIth nerve surrounded by high frequency fibers (see Auditory System: Structure and Function). This segregation of high and low frequencies persists throughout the CNS. As seen in Figure 13.3, low frequencies are more lateral in primary auditory cortex. 17 In summary: The nerve fibers from the spiral ganglion of Corti enter the dorsal and ventral cochlear nuclei located in the upper part of the medulla. At this point, all the fibers synapse, and second-order neurons pass mainly to the opposite side of the brain stem to terminate in the superior olivary nucleus. A few second-order fibers also pass to the superior olivary nucleus on the same side. From the superior olivary nucleus, the auditory pathway passes upward through the lateral lemniscus. Some of the fibers terminate in the nucleus of the lateral lemniscus, but many bypass this nucleus and travel on to the inferior colliculus, where all or almost all the auditory fibers synapse. From there, the pathway passes to the medial geniculate nucleus, where all the fibers do synapse. Finally, the pathway proceeds by way of the auditory radiation to the auditory cortex, located mainly in the superior gyrus of the temporal lobe. Several important points should be noted: First, signals from both ears are transmitted through the pathways of both sides of the brain, with a preponderance of transmission in the contralateral pathway. In at least three places in the brain stem, crossing over occurs between the two pathways: (1) in the trapezoid body, (2) in the commissure between the two nuclei of the lateral lemnisci, and (3) in the commissure connecting the two inferior colliculi. Second, many collateral fibers from the auditory tracts pass directly into the reticular activating system of the brain stem. This system projects diffusely upward in the brain stem and downward into the spinal cord and activates the entire nervous system in response to loud sounds. Other collaterals go to the vermis of the cerebellum, which is also activated instantaneously in the event of a sudden noise. Third, a high degree of spatial orientation is maintained in the fiber tracts from the cochlea all the way to the cortex. In fact, there are three spatial patterns for termination of the different sound frequencies in the cochlear nuclei, two patterns in the inferior colliculi, one precise pattern for discrete sound frequencies in the auditory cortex, and at least five other less precise patterns in the auditory cortex and auditory association areas. 20. What are utricle and saccule? What are its roles? The interconnected, membranous utricle and the saccule are composed of a very thin connective tissue sheath lined with simple squamous epithelium and are bound to the periosteum of the bony labyrinth by strands of connect