KMK Ocular Physiology Textbook

Eyelids

- eyelid closure is a result of CONTRACTION OF THE ORBICULARIS OCULI MUSCLES, *NOT* relaxation of the levator muscle - there are 3 main types of eyelid closure: blinking, winking, and spasm - because winking is a form of voluntary blinking, we will divide the following discussion into blinking and spasm BLINKING - there are 3 main types of blinking: spontaneous, reflex, and voluntary blinking 1. Spontaneous Blinking - the most common type of blinking; it results from contraction of the palpebral portion of the orbicularis oculi in the absence of an external stimulus and occurs at an average rate of 12-15 blinks/min - spontaneous blinking helps maintain the optics and comfort of the eye by STABILIZING the tear film; during a spontaneous blink, new tears are secreted and spread across the ocular surface while old tears are pushed medially towards the nasolacrimal drainage system **a decreased rate in spontaneous blinking results in decreased tear secretion and an increase in tear evaporation, resulting in DRY EYE SYNDROME and secondary EPIPHORA - a decreased blink rate commonly occurs when reading, watching TV, or after LASIK surgery due to a decrease in corneal sensitivity 2. Reflex Blinking - a blink caused by SENSORY stimulus, including: (a) auditory: loud noises sensed by CN VIII can elicit a blink reflex (b) touch or irritation: mediated by CN V - cotton swab testing evaluates the health of V1 by determining its ability to initiate reflex blinking in response to an irritating stimulus (c) dazzle: bright light detected by CN II stimulates a reflex blink (d) menace: CN II detects an unexpected object threatening the eye and initiates a blink reflex - the efferent loop of reflex blinking in response to auditory, touch/irritation, and menacing stimuli begins in the FRONTAL LOBE (i.e., involves cortical input); the dazzle reflex is the only reflex blink that does NOT involve the cortex - remember that the efferent loop involves stimulation of the orbicularis oculi via CN VII - unlike reflex blinking, spontaneous blinking occurs in the absence of an external stimulus; the palpebral portion of the orbicularis is responsible for both spontaneous and reflex blinking 3. Voluntary Blinking - the amplitude and duration of voluntary blinking is varied and more prolonged compared to spontaneous and reflex blinking *Winking: a form of voluntary blinking that requires simultaneous contraction of the ORBITAL and PALPEBRAL PORTIONS of the orbicularis oculi SPASM - includes the condition BENIGN ESSENTIAL BLEPHAROSPASM *characterized by bilateral, involuntary, sustained twitching and/or closing of the eyelids *results from spasms of the orbicularis oculi, procerus, and corrugator masculature **TIGHT OR FORCED EYELID CLOSURE requires contraction of the ORBITAL PORTION of the orbicularis oculi; BELL'S PHENOMENON, a normal defense reflex present in about 75% of the population, occurs after forced lid closure and is characterized by an upwards and outwards rotation of the globe ROLE OF THE EYELIDS IN TEAR PROCESSES 1. Production - Meibomian glands: sebaceous glands located within the upper and lower tarsal plates of the eyelids that are responsible for secreting the ANTERIOR LIPID LAYER of the tears; BLINKING stimulates lipid release via HOLOCRINE SECRETION - Accessory lacrimal glands: tubuloacinar exocrine glands that contribute to the aqueous layer of the tears (a) Glands of Krause are more numerous and are located in the fornices (b) Glands of Wolfring are less numerous and are found in the tarsal conjunctiva 2. Distribution - the upper eyelid closes laterally to medially during a blink, spreading the MUCIN LAYER of the tears evenly across the corneal epithelium and bulbar conjunctiva to aid in proper tear film formation 3. Drainage - the lacrimal pump theory, popularized by Jones and Wobig, summarizes how eyelid closure affects tear drainage *when the eyes is OPEN, tears passively drain into the puncta via CAPILLARY ATTRACTION *when the eyelids close during a blink, the MUSCLE OF HORNER contracts, causing the canaliculi to shorten as they move medially towards the lacrimal sac; this action helps to "pump" the tears into the lacrimal sac; remember that the muscle of Horner is part of the palpebral portion of the orbicularis oculi and surrounds the canaliculus *as the eyelids close, the orbicularis oculi also contracts, stretching the temporal wall of the lacrimal sac away from the nose; this action creates a negative pressure that helps to draw tears into the lacrimal sac - newer theories suggest that contraction of the orbicularis oculi causes lacrimal sac COMPRESSION (NOT dilation), forcing tears into the nasolacrimal duct **BLINKING occurs from the lateral to medial canthus and helps to move tears towards the puncta; blinking also lowers the pressure in the canaliculi, creating a pressure difference between the atmosphere and the lacrimal sac that promotes tear drainage 4. Protective Function of the Eyelids - CILIA (eyelashes): responsible for screening and sensing the environment and inducing blink reflexes when necessary; there are approximately 150 eyelashes in the upper eye.lid and 75 in the lower eyelid - GLANDS OF THE EYELIDS: secretions from the glands of the eyelids not only help promote the tear film, but also help to move debris away from the cornea in concert with spontaneous blinking

Uvea

- function and aging changes of the components of the uvea 1. Functions of the Iris - Regulates pupil size to control the amount of light entering the eye and to reduce spherical, coma, and chromatic aberrations *pupil size helps to optimize retinal image quality by regulating the amount of light that reaches the retina; for example, the pupil size is larger under dim illumination to increase the amount of light reaching the retina *smaller pupils reduce spherical and chromatic aberrations and increase the depth of field 2. Aging changes of the iris - increase in pigment deposition on the anterior structures of the eye from the posterior pigmented iris epithelium - the pupil becomes more resistant to dilation due to aging changes in the iris sphincter and dilator muscles 3. Functions of the Ciliary Body - contains the ciliary muscle for accommodation - produces and secretes aqueous humor - contains the ciliary stroma that contributes to aqueous humor drainage via the uveoscleral meshwork 4. Aging Changes of the CB - aqueous humor formation decreases with age - ciliary muscle contraction DOES NOT decrease with age; loss of accommodation with age (presbyopia) is secondary to changes in the lens 5. Functions of the Choroid - provides nutrients to the outer layers of the retina and contains pigment that absorbs excess light that passes through the RPE - contains the suprachoroidal space that serves as a passageway for nerves and arteries from their posterior insertion sites to the anterior segment of the eye - contains a high protein content relative to the retina, establishing a protein gradient that promotes the absorption of excess H2O from the retina into the choroid 6. Aging Changes of the Choroid - age-related changes in the choroid: (1) Bruch's membrane increases in thickness with age; drusen accumulates on Bruch's membrane with age (2) the choriocapillaris decreases in thickness with age (3) the overall choroidal thickness decreases with age

Retina

1. Composition of the Disc Outer Segment - the outer segment contains stacks of discs that enclose photopigments (rhodopsin and iodopsins); in rods, rhodopsin is embedded within the disc membranes; in conds, iodopsins are stored in ivaginations of the plasma membrane (NOT within discs); see ocular anatomy for more detail 2. Formation of Disc Outer Segments - photopigments are produced in the photoreceptor inner segment and then travel through the cilium to the outer segment; the discs and plasma membranes that enclose the photopigments are produced in the outer segment 3. Composition of Visual Pigments - the three cone photopigments (cyanolabe, erythrolabe, and chlorolabe) are used for PHOTOPIC VISION AND COLOR VISION; rhodopsin is the photopigment found in rods that is used for SCOTOPIC VISION; cone and rod visual pigments contain the same basic structure: (1) Opsin: membrane apoprotein (allows for varied absorption spectrum) (2) Chromophore: 11-cis retinal (Vitamin A derivative) **vitamin A gains access to the RPE via diffusion through the large fenestrations in the choriopcapillaris; vitamin A is an alcohol retinol that is oxidized in the RPE to form 11-cis retinal 4. Formation of Visual Pigments - light absorption in the outer segment damages the photoreceptors and renders them in need of constant replacement - rod outer segments are shed in the MORNING via phagocytosis by the RPE - cone outer segments are shed and renewed in the EVENING 5. Stages of the Visual Cycle - the transformation of retinoids due to light exposure and their subsequent movement between the retina and RPE is called the visual cycle (1) light absorption by a photoreceptor results in the transformation of 11-cis retinal to ALL-TRANS RETINAL (2) all-trans retinal moves from the disc lumen into the cytoplasm where it is reduced to all-trans retinol (3) all-trans retinol is transported to the RPE cells where it is converted to 11-cis retinol; 11-cis retinol is then oxidized to 11-cis retinal (4) 11-cis retinal is shuttled back to the photoreceptors for incorporation into the photopigments in the disc outer segments **Stargardt's disease is most often due to a mutation in the ABCA4 transmembrane protein that is responsible for moving *all-trans retinal* within the photoreceptor discs, leading to degeneration of the photoreceptors and RPE 6. Photoreceptor Electrophysiology - process of PHOTOTRANSDUCTION (1) photoreceptors maintain a slight negative electrical charge of about *-50 mV* in the dark; Na+/K+ ATPase pumps on the inner segment plasma membrane use ATP to pump Na+ out of the inner segment while moving K+ inside the inner segment while moving K+ inside the inner segment (2) Na+ then re-enters the inner segment through Na+ channels located in the outer segment (3) this flow of cations into and out of the cell under dark conditions is referred to as the DARK CURRENT **the membrane potential of a photoreceptor in the dark (-50 mV) is more positive than normal cells (around -70 mV) due to the dark current; thus, photoreceptors are DEPOLARIZED and constantly release glutamate to bipolar cells (they are constantly turned "on"); *cGMP* keeps Na+ channels open to promote depolarization (4) the absorption of light by rhodopsin triggers PHOTOTRANSDUCTION, a biochemical cascade that converts absorbed light into an electrical signal; during this process, the dissociation of rhodopsin triggers the activation of the G protein TRANSDUCIN, leading to a cascade that ultimately results in a decrease in concentration of cGMP (5) decreased cGMP levels results in the closure of the SODIUM CHANNELS, resulting in an increase in the negative charge of the cell membrane to *-65 mV*; this hyperpolarization of the cell membrane results in a DECREASE in the release of glutamate to bipolar cells **the closure of sodium channels is a key event during PHOTOTRANDUCTION and effectively "shuts off" the photoreceptors by decreasing their release of glutamate **note that photoreceptors do not produce action potentials but rather produce GRADED POTENTIALS 7. Retinal neurotransmitters (1) Glutamate: an excitatory neurotransmitter released by all rods, cones, bipolar cells, and most ganglion cells in the vertebrate retina (2) GABA and Glycine: inhibitory neurotransmitters that are released by horizontal cells and most amacrine cells 8. Function of Retinal Cells (Receptor Fields) (1) Bipolar cells have center-surround receptive fields (i.e., spatial antagonism) - Cone cells have hyperpolarize or depolarize the center of bipolar cells; thus there are two types of cone bipolar cells that are classified by their response to LIGHT; ON-center depolarizing or OFF-center hyperpolarizing bipolar cells *ON-center bipolar cells are INHIBITED by glutamate and are thus hyperpolarized in the dark; when LIGHT IS PRESENT, less glutamate is released, resulting in DEPOLARIZATION of the ON-center bipolar cells *OFF-center bipolar cells are EXCITED by glutamate and are thus depolarized in the dark; when LIGHT IS PRESENT, less glutamate is released, resulting in hyperpolarization of the OFF-center bipolar cell - Rod bipolar cells always DEPOLARIZE in response to LIGHT **regardless of their response, bipolar cells respond to glutamate with GRADED POTENTIALS (2) Horizontal cells receive input from a large number of photoreceptors; they DO NOT have center/surround receptive fields - horizontal cells respond with graded potentials and HYPERPOLARIZE in response to light - horizontal cells impact the SURROUND RESPONSES of bipolar cells by providing inhibitory feedback to photoreceptor cells (which then impacts the bipolar cell), or by directly synapsing with the bipolar cell (feed-forward synapse) - horizontal cells provide LATERAL INHIBITION, which helps to fine-tune the neural signal sent from neighboring photoreceptors *remember photoreceptors, horizontal cells, and OFF-center cone bipolar cells are unique because they HYPERPOLARIZE in response to light (3) Amacrine cells have center/surround receptive fields; they respond with ACTION POTENTIALS and always DEPOLARIZE in response to light - amacrine cells fine-tune the signal between bipolar and ganglion cells (similar to horizontal cells at the level of the photoreceptors) (4) Ganglion cells have center/surround receptive fields and respond to bipolar cells with ACTION POTENTIALS; they are classified into two types of based on their responses to light: ON-center/OFF-surround or OFF-center/ON-surround ganglion cells - ON-center/OFF-surround ganglion cells synapse with ON-center bipolar cells and DEPOLARIZE in response to light - OFF-center/ON-surround ganglion cells synapse with OFF-center bipolar cells and HYPERPOLARIZE in response to light - remember that MIDGET GANGLION CELLS are small ganglion cells that have a single dendrite that synapses with one midget bipolar cell, which synapses with a single cone in the fovea, allowing for a resolution of very fine details TO SUMMARIZE: 1. Action potentials - all or nothing response 2. Graded potentials - response is influenced by the number of photons absorbed (not an all or nothing response) 3. Amacrine and ganglion cells respond with action potentials; all other retinal cells respond with graded potentials 9. Aging Changes of the Retina (a) retinal nerve fibers within the optic nerve disease, resulting in an increase in the diameter of the vertical cup (b) ILM thickens with age, causing the foveal reflex to become dimmer (c) rod density decreases with age, although note that scotopic function DOES NOT decline (d) the total number of RPE cells decreases significantly with age; lipofuscin within RPE cells and drusen increases with age (e) atrophy increases throughout the retina, including around the optic disc (peripapillary atrophy), throughout the posterior pole (as seen by a decrease in pigmentation in the RPE/choroid), and in the periphery (e.g., pavingstone degeneration)

Lens

1. Function of the Lens - provides one-third of the total dioptric power of the eye and allows for accommodation to near objects; the following changes occur during accommodation: (1) parasympathetic stimulation causes contraction of the ciliary muscle, resulting in a decrease in the tension in the lens zonules (2) the anterior pole of the lens moves forward and the anterior curvature increases (3) the posterior pole of the lens moves back slightly and the posterior curvature increases (4) the lens thickness (anterior-posterior dimension) increases and the anterior chamber depth decreases (5) the lens diameter decreases (6) the lens power increases **note that accommodation causes a temporary decrease in IOP because ciliary muscle contraction pulls the scleral spur posteriorly and opens up the pores of the TM; accommodation may also result in a temporary increase in IOP due to a decrease in the depth of the anterior chamber because the anterior pole of the lens moves forward, the anterior lens curvature increases, and the lens thickness increases; in patients with narrow angles, these changes may induce "pupillary block" and result in significantly elevated IOP, which are important adverse effects of MIOTIC DRUGS such as pilocarpine 2. Metabolism of the Lens - although the lens is avascular, it has the largest concentration of proteins of any structure in the body and thus requires glucose and oxygen from the aqueous in order to maintain the following functions: (1) production of new lens fibers and protein synethesis (2) maintenance of the Na+/K+ ATPase pump that helps to establish a balance between H2O and ions within the lens to maintain lens transparency; the Na+/K+ ATPase pump on the epithelial cells constantly move Na+ into the aqueous humor (and K+ into the lens); H2) ultimately follows Na+ into the aqueous, contributing to lens dehydration and transparency - the following are noteworthy facts regarding lens metabolism: (1) over 70% of the glucose required by the lens is produced through anaerobic glycolysis; aerobic metabolism (via the Kreb's cycle and the electron transport chain) is limited to the lens epithelium (2) the first step in both aerobic and anaerobic respiration involves the conversion of glucose to glucose 6-phosphate via the enzyme HEXOKINASE; if hexokinase is not available, glucose is converted to sorbitol via the enzyme aldose reductase (3) excess SORBITOL can accumulate in the lens, creating an osmotic gradient that favors the movement of H2O into the lens, ultimately causing lens swelling, lens fiber damage, and cataract formation **excessive levels of glucose in diabetes leads to the accumulation of sorbitol within the lens, ultimately leading to early cataract development and an acute shift in the refractive error secondary to lens swelling 3. Regulation of Lens Proteins - effects of glutathione and ascorbic acid on lens clarity (1) Glutathione: the primary protector against oxidative damage in the lens - acts as the reducing agent and detoxifies hydrogen peroxide - is transported into the lens from the aqueous, but can also be synthesized from lens epithelial cells and superficial fiber cells - deep fiber cells and nuclear cells produce minimal glutathione and thus rely on diffusion of glutathione from the superficial fibers and lens epithelial cells **glutathione diffusion diminishes with age and is a factor in the formation of cataracts (2) Ascorbic acid (Vitamin C): helps to protect the lens from oxidative damage; ascorbic acid is found in a much higher concentration in the lens compared to the aqueous humor 4. Theories of Lens Transparency - the following factors help to maintain lens transparency (1) Active Na+/K+ ATPase pumps located on the lens epithelial cell membranes maintain electrolyte balance by pumping Na+ into the aqueous humor and K+ into the lens (2) The lens is avascular (dependent on nutrients that diffuse from the aqueous humor), which minimizes light scattering (3) Lens fiber cells lack membrane-bound organelles to minimize light scattering (4) Lens fiber cells are packed very close together and are uniformly spaced (5) The cytoplasm of the lens fibers are crowded with crystallins that minimizes light scattering by destructive interference (6) Multiple transport processes are present to carefully monitor and limit the concentration of Ca2+ inside the lens in order to prevent cataract formation 5. Mitotic Activity of Lens Epithelium - the embryonic nucleus is formed from primary lens fibers of the posterior lens epithelium during embryological development; all remaining growth of the lens is due to the production of secondary lens fibers by the anterior lens epithelium - mitosis of fiber cells occurs in the *germinative zone of the anterior lens epithelium*; after mitosis, lens fiber cells gradually migrate through the transition zone and into the equator, where fiber elongation occurs; during this process, lens fibers lose their membrane-bound organelles and acquire crystallins - the anterior lens epithelium has the greatest metabolic demand of all lens components and thus contains a significant amount of mitochondria to produce energy for mitosis; remember that aerobic respiration is limited to the anterior lens epithelium! - aqueous humor travels over the anterior surface of the lens and provides nutrients (including glucose and O2) to the anterior lens epithelium for mitosis **remember that the ANTERIOR LENS EPITHELIUM is responsible for transporting nutrients from the aqueous humor into the lens; Na+/K+ ATPase pumps located on the epithelium cell membranes are responsible for maintaining the appropriate ion balance to control lens dehydration 6. Aging Changes in the Composition of the Lens - age-related changes in the lens: (1) Decrease in crystallin (soluble lens proteins) and an increase in insoluble lens proteins due to increased cross-linking between lens fiber cells; cross-linking results in the formation of lens protein aggregates that alter the amount of H2O within the lens - ALPHA CRYSTALLINS decrease dramatically with age; by age 45, there are NO alpha crystallins in the lens nucleus - remember that alpha crystallins function as MOLECULAR CHAPERONES by preventing the degradation of other crystallins; a reduction in alpha crystallins results in an increase in degradation of lens fiber cells and ultimately contributes to cataract formation (2) Lens thickness increases 0.02 mm per year; the lens diameter is relatively stable after the teenage years (3) the anterior lens capsule thickness (produced by the anterior lens epithelium) increases with age; the posterior lens capsule thickness is relatively stable with age **remember that the lens capsule is thickest at the anterior mid-peripheral portion of the lens (pre-equatorial region) and is thinnest at the posterior pole; it is the thickest BM in the entire body and is comprised of type IV collagen (4) the radius of curvature of the anterior and posterior lens decreases with age (i.e., becomes more convex); (theoretically, a more convex lens should result in the patient becoming more myopic due to age; researchers have suggested that the gradient refractive index of the lens also changes with age in a way that prevents the eye from becoming more myopic) (5) the center of the lens moves anteriorly, causing a decrease in the anterior chamber depth with age (6) amino acid concentration decreases with age; remember that the lens usually contains a higher concentration of amino acids for protein synthesis compared to the aqueous humor (7) glutathione activity decreases; Na+, Ca2+, and H2O concentrations in the lens increase: *an increase in intracellular Ca2+, a decrease in glutathione, and a decrease in crystallins are factors that significantly contribute to cataract formation with aging (8) nuclear fibers begin to lose their nucleus and organelles; they also accumulate a yellow-brown pigment that contributes to the formation of a nuclear sclerotic cataract; nuclear sclerosis begins in the embryonic nucleus and expands to include the fetal and adult nuclei; it is the most common cataract due to aging **remember that the embryonic nucleus (center of the lens) has the highest refractive index (1.41) because it has the highest concentration of crystallins in the lens; aslo recall that the T sutures seen during slit lamp biomiscroscopy demarcate the boundaries of the fetal nucleus

Vitreous

1. Functions - functions of the vitreous: 1. provides a transparent, unhindered medium for the passage of light; also acts as a UV filter by decreasing the transmission of light at 300-350 nm in order to protect the retina 2. provides structure to the eye and likely cushions the globe (especially the retina and lens) by absorbing vibrations and other external forces during eye movements and trauma 3. serves as a storage area for lens and nutrients for the retina and lens, including O2, H2O, Na+, K+, Cl-, phosphate, glucose, and proteins **the gel-like consistency of the vitreous decreases the bioavailability of topical drugs entering the posterior segment 2. Composition - remember that the vitreous is approximately 4 mL in volume, making it about 80% of the total volume of the eye - the vitreous weighs approximately 4 grams and is composed of approximately 99% H2O combined with Type 2 collagen fibrils and hyaluronic acid (GAG) molecules that create a gel-like consistency - HYALURONIC ACID is a non-sulfated GAG in the vitreous that provides support to collagen fibers, helps maintain proper collagen fibril spacing, and maintains the viscosity of the vitreous - Vitamin C concentration is higher in the vitreous compared to the blood plasma; amino acids are found in a lower concentration in the vitreous compared to the blood plasma **Vitamin C (aka ascorbate) concentration in the vitreous is as high as 40x greater than in the blood plasma; vit C buffers O2 as it travels from the retinal vessels towards the lens, which helps to reduce oxidative stress and minimize tissue damage; it also protects the retina from other metabolic and light-induced free radicals SUMMARY OF PHYSICAL CHARACTERISTICS OF THE VITREOUS 1. Visible Light: vitreous transmits >90% 2. UV Light: transmission drops at 300-350 nm 3. IR Light: transmission drops off at 800 nm 4. Volume: 3.9 mL (80% of the globe) 5. Water content: 99% 6. n (index): 1.3345-1.3348 (similar to aqueous) Remember the following values: - wavelengths below 300nm are absorbed by the cornea - wavelengths between 300 and 400 nm are absorbed by the lens - wavelengths above 400 nm are transmitted to the retina **the lens absorbs the majority of UV-A and UV-B light, which protects the retina from UV damage 3. Metabolism - metabolic functions of the vitreous (1) minimal metabolic activity occurs in the vitreous; instead, the vitreous acts as a METABOLIC BUFFER AND STORAGE AREA for the retina and lens (2) as an example, glucose and glycogen stored in the vitreous can be used for supplement metabolic activities in the retina during anoxic conditions 4. Aging Changes in Composition - the gel structure of the vitreous becomes more liquefied with age; the following is a summary of the aging changes that result in vitreous liquefaction (1) with increased age, the liquid portion of the vitreous increases as H2O starts to collect into pockets in a process known as liquefaction (2) these water pockets cause the vitreous gel to break down, resulting in the aggregation of collagen fibrils (i.e., condensation) into FLOATERS **the process of liquefaction and condensation are collectively referred to as VITREOUS SYNERESIS; oxidative damage is thought to induce structure changes in hyaluronic acid, causing changes in the hyaluronic acid-collagen network that promote vitreous syneresis **vitreous syneresis is the most common cause of a posterior vitreous detachment (PVD); risk factors for PVDDs include age, myopia, diabetes, intraocular surgery, intraocular inflammation, and trauma - remember that collagen concentration is highest at the vitreous base and lowest in the center of the vitreous; loss of structure is thus most likely to occur within the center of the vitreous - the concentration of HA remains stable from approximately 20-50; after age 50, HA concentration increases

Aqueous

1. Functions of Aqueous - maintains the pressure and shape of the eye and provide a transparent, colorless refractive index to enhance the overall optics of the globe - provides nutrition for the avascular cornea, lens, anterior vitreous, and TM - serves as a collection bin for metabolic waste products of surrounding tissues and clears out inflammatory products and blood from the globe 2. Volume, Osmolarity, Viscosity - Volume: 250 uL that is completely replaced around every 2 hours; recall that 2.5 uL of aqueous is produced and 2.5 uL of aqueous is drained every minute in healthy eyes - Osmolarity: slightly hyperosmotic to plasma - Viscosity: 1.025-1.040 relative to water 3. Formation of Aqueous - recall that aqueous humor is produced and secreted by the non-pigmented ciliary epithelium of the ciliary processes; aqueous production involves the processes of diffusion, ultrafiltration, and active secretion (1) Diffusion - involves the passive movement of ion size and solubility; small lipid soluble substances are able to easily diffuse out of the fenestrated capillaries of the ciliary body vasculature into the ciliary stroma; diffusion plays a minimal role in aqueous humor production (2) Ultrafiltration - involves the passive flow of blood plasma from the capillaries into the ciliary stroma and is caused by an increase in hydrostatic pressure (pressure from the heart) compared to pressure within the surrounding tissue **although substances can leave the blood through diffusion and ultrafiltration, most substances must be actively secreted across the non-pigmented ciliary epithelium in order to produce aqueous humor; ACTIVE SECRETION of ions across the ciliary processes into the posterior chamber creates a gradient where the aqueous is hypertonic to the blood by approximately 5 mOsm (3) Active Secretion - involves the active transport of large, water-soluble, charged substances across the non-pigmented epithelial cell membranes against an electrochemical gradient; requires ATP - active secretion accounts for 80-90% of total aqueous humor formation; providing further evidence that alterations in blood pressure have little effect on aqueous humor formation - the pigmented ciliary epithelium and non-pigmented ciliary epithelium have several ion transport mechanisms that are essential for aqueous formation; a detailed overview can be found in Remington's text; the following is an over-simplified summary of key parts of active secretion: (1) Na+/K+ ATPase pump: located within the NPCE cell; it utilizes ATP to pump Na+ out of the NPCE cell into the posterior chamber (with water following); this pump helps to maintain a gradient that constantly moves Na+ from the ciliary stroma into the PCE (2) Carbonic anhydrase: catalyzes the following reaction in the PE cells that yields bicarbonate: CO2 + H2O → H2CO3 → H+ + HCO3- - bicarbonate ions are believed to increase aqueous production by increasing Cl- and Na+ flux into the posterior chamber **active transport facilitates the movement of sodium, chloride, and bicarbonate ions to create a gradient for water movement and aqueous humor production; agents that disrupt this process include oral cardiac glycosides (alter the Na+/K+ ATPase pump) and carbonic anhydrase inhibitors 4. Factors Influencing Rate of Flow - each of the follow impede aqueous outflow and may lead to glaucoma (1) Covering the TM - Diabetes: proliferative DR may lead to neovascularization and accompanying fibrous tissue in the angle, causing obstruction of the TM and acute angle closure secondary to PAS formation; CRVO, OIS, and retinal detachments may also lead to neovascularization of the angle - Uveitis: inflammatory cells may impede outflow by clogging the TM; posterior and peripheral anterior synechiae can cause angle closure - Hyphema: blunt trauma can lead to bleeding of the iris and/or ciliary body, causing blood to accumulate in the anterior chamber and impede aqueous outflow through the angle (2) Injury to the TM - Fuch's heterochromic iritis: results in chronic inflammation that can permanently damage the TM - Glaucomatocyclitic crisis: acute inflammation of the TM (i.e., trabeculitis) that leads to an acute and dramatic rise in IOP - Angle recession glaucoma: trauma to the iris can cause separation of the iris from the iris root, resulting in angle recession and damage to the TM; angle recession is seen as a very wide ciliary band on gonioscopy (3) Occlusions of the TM - Pseudoexfoliative glaucoma: aging epithelial cells of the iris basement membrane lens capsule release pigment and pseudoexfoliative material, respectively, that accumulates within the angle and damages the TM - Pigment dispersion glaucoma: pigment is released from the posterior layer of the iris (usually as a result of posterior bowing of the iris against the lens zonules) and accumulates within the angle, causing damage to the TM ------- 6. Composition - summary of aqueous humor composition - the aqueous humor has less protein but more amino acids than plasma; the concentration of protein in the aqueous is <1% that of plasma, which limits light scattering - the aqueous humor has high amounts of ascorbate (vitamin C); the concentration of vitamin C in the aqueous is 20x higher than in plasma - the aqueous humor has more lactate than plasma, primarily as a result of anaerobic glycolysis in the lens and cornea - the aqueous humor has less bicarbonate ions than plasma and is slightly more acidic (pH = 7.2) 7. Blood Aqueous Barrier - aqueous formation begins with ~20% of the substances trickling through the capillary walls of the MACI, then through ciliary stroma, and finally across both ciliary epithelial layers before being transmitted through the tight junctions of the NPCE into the posterior chamber via active secretion - remember, the ciliary stroma capillaries are fenestrated and allow substances to diffuse out of the vessels; the tight junctions of the NPCE that line the posterior chamber help to regulate the substances that ultimately form aqueous humor - the blood aqueous barrier consists of tight junctions located in 3 places: the iris vessels, the endothelium of Schlemm's canal, and the NPCE **uveitis is secondary to a breakdown in the blood aqueous barrier

Tears

1. Functions of Tears (1) Optical: the primary role of the tear film is to create a smooth optical surface for clear vision; remember, the largest change in refractive index occurs between the air/tear film interface (2) Nutritional: the primary source of O2 for the corneal epithelium is from diffusion of atmospheric O2 through the tear film (3) Mechanical: the tear film collects debris and moves it away from the cornea during a blink; it also helps to remove metabolic waste products from corneal epithelial cells (4) Antibacterial: the aqueous layer of the tears (secreted by the main and accessory lacrimal glands) contains lysozyme, lactoferrin, IgA, and other proteins of the immune system (5) Corneal transparency: the tear film has a specific osmolarity (308 mOsmol) and pH (7.5) that is maintained by the secretory glands and the corneal epithelial cells, thus helping to prevent corneal edema 2. Production and Composition of Tears - although widespread research has been conducted, there has been a lack of consensus regarding the total thickness of the tear film, with studies reporting a range of results from 7 um to 45 um; despite continued variability in results, newer research performed with non-invasive techniques suggests the total tear film thickness in approximately 3 um (a) Anterior Lipid Layer - the anterior lipid layer is composed of free fatty acids, cholesterol, and waxy esters - it is secreted by the meibomian glands - the main purpose of the anterior lipid layer is to SLOW THE EVAPORATION OF THE AQUEOUS LAYER of the tears; it also helps to maintain optical clarity - although BLINKING is the primary method for releasing lipids from the glands, parasympathetic innervation from nerves surrounding the glands may also increase lipid secretion (b) Aqueous Layer - the aqueous layer of the tears serves the following functions (1) Provides protection through antibacterial proteins (2) Provides nutrition by supply glucose to the cornea epithelium (VERY MINOR, more from aqueous humor!) (3) Adds thickness to the tear film - the aqueous layer contains the following components: (a) water (the main component of tears) (b) electrolytes: Na+, K+, and Cl- (c) antimicrobial components: IgA, lactoferrin, lysozyme, beta-lysin, and interferon; lysozyme cleaves peptidoglycan bonds in bacterial cell walls; lacteroferrin chelates Fe2+, an essential nutrient for bacterial cell growth and metabolism; beta-lysin destroys bacterial cytoplasmic membranes and acts in concert with lysozyme (d) lipocalins: decrease the surface tension of the tears to enhance spreadability and act as a carrier for all-trans retinol; also block Fe2+ binding receptors on the surface of bacteria (e) Vitamin A: present within tears in the form of *all-trans retinol*; necessary for the development of goblet cells of the conunctiva (f) enzyme cofactors (Fe2+, Mg2+, Cu2+, Ca2+): help maintain the membrane permeability of corneal epithelial cells (g) HCO3-: acts as a buffer for tears (h) solutes: GLUCOSE, urea, lactate, citrate, ascorbate, and amino acids (i) additional proteins including albumin, growth factors interleukins, and VEGF -the composition of the aqueous layer of the tears changes with increasing age, contact lens wear, and under closed eye conditions *increasing the age is associated with a decrease in the levels of lysozyme and lactoferrin proteins within the tears, as well as an overall decrease in the aqueous secretion *contact lens wear causes an increase in electrolyte and protein concentration due to increased evaporation of the tears *the aqueous layer of the tears under closed eye conditions has a higher concentration of *IgA* and serum albumin compared to open eye conditions; lysozyme and lactoferrin levels and essentially the same - the MAIN LACRIMAL GLAND and the ACCESSORY LACRIMAL GLANDS of Krause and Wolfing secrete the aqueous layer of the tears * the main lacrimal gland is innervated by parasympathetic fibers from *CN VII*, sympathetic fibers, and sensory nerves of VI *the ACCESSORY LACRIMAL GLANDS are thought to be innervated by PARASYMPATHETIC NERVES; however, neural control of the accessory lacrimal gland secretions is not well understood and conclusive research is unavailable -although conventional theory states that the main lacrimal gland is responsible for reflex and emotional tearing and the accessory lacrimal glands are responsible for maintenance (i.e., basal) tearing, a more recent theory holds that both the main AND accessory lacrimal glands are responsible for basal tearing **the sensory nerves (V1) of the cornea and involved in a reflex arc that causes LACRIMATION (through parasympathetic stimulation of the lacrimal gland via CN VII), MIOSIS, and a PROTECTIVE BLINK; the dazzle blink reflex can also stimulate lacrimal gland secretion (c) Mucous Layer - CONSISTS OF AN OUTER MUCIN LAYER that interacts with the glycocalyx of corneal epithelium and helps to spread the tears across the corneal surface, as well as trap debris, bacteria, and sloughed corneal epithelial cells **remember that mucin molecules are unique in that they are capable of mixing with lipid AND water; this property allows the mucous layer to mix with the aqueous layer of the tears and spread it evenly over the hydrophobic corneal epithelial surface - the mucous layer is produced by the GOBLET CELLS of the conjunctiva and the squamous cells of the cornea and conjunctiva *goblet cells are predominately found in the INFERONASAL FORNIX and the BULBAR CONJUNCTIVA (most concentrated temporally) *goblet cells require VITAMIN A for development, which is found in the aqueous layer of the tears as all-trans retinol; vitamin A deficiency results in keratinization of the conjunctiva and cornea **VITAMIN A deficiency can result in BITOT'S SPOTS (foamy build-up of keratin) on the conjunctiva - sensory nerves in the corneal and conjunctival epithelium stimulate sympathetic and PARASYMPATHETIC nerve endings surrounding goblet cells; parasympathetic stimulation causes an increase in mucous secretion **MUCOUS FISHING SYNDROME occurs as a result of patients "fishing" for and removing excess mucous in the conjunctiva; this results in damage to the conjunctival epithelium and a subsequent increase in mucous production, creating an unfortunate cycle that exacerbates symptoms; DRY EYE SYNDROME is the most common cause of mucous fishing syndrome **although traditionally the tear film is viewed as three separate layers, new research suggests that the aqueous and mucin layers are intermixed, with a greater mucin concentration towards the corneal surface of the tears 3. Tear Film Distribution, Structure, and Stability - recall that the eyelids play an important role in spreading the mucous layer evenly over the corneal epithelium; the mucin layer interacts with GLYCOCALYX of the corneal epithelium, allowing the tear film to be evenly spread across the corneal and conjunctival epithelium **the stability of the tears can be examined clinically by analyzing the tear break up time (TBUT); fluorescein is instilled in the eye and spreads evenly throughout the tears; over time, the aqueous layer evaporates as a result of an insufficient LIPID LAYER, resulting in a break up of the tears; blinking promotes secretion of the anterior lipid layer and restores the tear film; a TBUT less than 10 seconds is considered abnormal 4. Elimination of Tears - approximately *25%* of secreted tear volume is continuously lost via evaporation; the remaining 75% of the tear volume drains through the nasolacrimal system or into the systemic circulation via absorption into the conjunctival and/or nasolacrimal vasculature **the total tear volume on the ocular surface is approximately 7-9 uL; the maximum amount of fluid the eye can hold within the tear film and the fornices is 20-30 uL; normal tear production is approximately 1 uL/min and the average eye drop contains 50 uL; drop instillation or tear production greater than 1 uL/min results in tear overflow onto the cheeks (i.e., epiphora) 5. Physico-chemical Properties of Tears - the normal tear film on a healthy ocular surface has an osmolarity of approximately *308 mOsm/L* and is ISOTONIC to the HEALTHY CORNEAL SURFACE; tear film osmolarity can vary depending on the blink rate, humidity, contact lens wear, and ocular pathology - Na+ and Cl- ions within the aqueous portion of the tears are the main contributors to tear osmolarity; Ca2+ and K+ are also important components of the aqueous portion of the tears: (a) Calcium is essential for hemidesmosomes formation in the basement membrane of the corneal epithelium; excess calcium can deposit on contact lenses, forming "jelly bumps" that may decrease visual acuity (b) Potassium helps to maintain the health of the corneal epithelium and has a 4x greater concentration in the tears compared to blood plasma **Dry eye syndrome causes an increase in tear osmolarity; hypotonic eye drops (osmolarity 150 mOsm/L) are often utilized in treatment 6. pH Buffering and Temperature - the bicarbonate ion (HCO3) within the aqueous layer of the tears are an excellent buffer and can tolerate ophthalmic solutions with a pH ranging from 3.5-10.5; the average pH of the tears is 7.45 - the pH of the tears during sleep decreases (becomes more acidic) due to byproducts of anaerobic respiration **most ophthalmic topic solutions are weak bases; because the pH of the tears is 7.45, most ophthalmic drugs are present in the non-ionized form within the tear film, promoting drug absorption across the hydrophobic corneal epithelium and endothelium

Circulation

1. Hemodynamic Patterns - blood flow and pressure differences in the eye play a pivotal role in maintaining normal ocular function; current research is focused on this area because disruptions in normal blood flow have been found to be related to several of the core ocular disease processes, including diabetes, macular degeneration, and glaucoma; the following equation demonstrates the components that influence blood flow through the vessels: F = [P arteries (entering a tissue) - P veins (leaving the tissue)] / [R (resistance) where F = flow, P = pressure, and R= resistance - Mean arterial pressure of the arteries entering the eye is around 65 mmHg; the pressure in the episcleral veins leaving the eye is around 15 mmHg - Perfusion pressure indicates how easily blood can pass through a given tissue and is the difference between the pressure of blood flow entering and leaving the eye; perfusion pressure in the eye is ~50 mmHg - Ocular perfusion pressure (OPP) = diastolic blood pressure - IOP; glaucoma patients with low OPPs are 1.5x more likely to develop progressive optic neuropathy secondary to ischemia *if IOP decreases, OPP increases; conversely if IOP increases, OPP decreases *if diastolic BP decreases, OPP decreases - AUTOREGULATION is the process by which blood vessels alter their diameter (in the absence of neural control) in order to increase or decrease RESISTANCE to blood flow; PERICYTES are most likely responsible for autoregulation within the blood supply of the retina and the optic nerve *remember that a smaller blood vessel diameter offers more resistance, resulting in a decrease in blood flow; retinal arteries are smaller than choroidal arteries thus offer more RESISTANCE **autoregulation allows blood flow to be maintained at a constant rate despite moderate variations in the mean arterial pressure and intraocular pressure - Transmural pressure describes the pressure across the blood vessel wall and is determined by subtracting the pressure outside the vessel from the pressure inside the vessel - Critical closing pressure is the pressure at which the blood vessel collapses and blood flow stop **elevated IOP in ACUTE ANGLE-CLOSURE causes a reduction in blood flow through the central retinal artery, leading to a decrease in the perfusion pressure of the retinal tissue; the retinal vessels detect this change in transmural pressure and increase their vessel diameter through autoregulation to improve perfusion; however if IOP remains acutely elevated long enough, the CRA will reach its critical closing pressure, resulting in a CRAO; remember that the immediate threat to vision in a acute angle closure is CRAO! 2. Autonomic Nerve System Control A. Sympathetic Innervation - sympathetic fibers are prevalent throughout the uveal tract but they DO NOT innervate the central retinal artery past the lamina cribosa and therefore do not influence retinal blood flow - sympathetic innervation causes VASOCONSTRICTION of uveal blood vessels; it is important in maintaining adequate blood flow through the uvea during sudden increase in blood pressure; a sudden spike in BP increases the force of blood flow through the small vessels of the uvea; the sympathetic system responds by causing constriction of the blood vessels, resulting in a compensatory reduction in blood flow B. Parasympathetic Innervation - parasympathetic fibers from the oculomotor and facial nerves are also prevalent throughout the uveal tract; parasympathetic innervation is most prominent in the anterior uvea and has a minimal influence on choroidal and retina blood flow - parasympathetic innervation causes VASODILATION of the uveal blood vessels in response to sudden decrease in blood pressure **unlike the choroid, retinal vasculature is NOT under autonomic control 3. Unique Environment in the Eye - the following unique characteristics of the eye allow for appropriate structure and function: (1) IOP must be greater than the episcleral venous pressure so aqueous humor can drain from the anterior chamber, through the corneoscleral meshwork, and into the venous system (2) IOP must be greater than the intracranial pressure in order to maintain an axoplasmic (i.e., pressure) gradient that flows from the optic nerve towards the brain **papilledema results from a reversal in the axoplasmic gradient between the eye and the brain due to an increase in intracranial pressure; this reversal causes cerebrospinal fluid to spill from the subarachnoid space onto the optic disc margins and the surrounding RNFL (3) IOP must be lower than the pressure in the retina and uveal arteries, allowing nutrients to be delivered from the choriocapillaris to the RPE cells (4) protein content must be highest in the choroidal vasculature so excess water is pulled from the retina, across the RPE, and into the choroid, which promotes the adherence between the RPE and the neurosensory retina 4. Uveal Blood Flow (1) Choroid: the majority of blood flow in the ocular vessels occurs in the choriocapillaris (approximately 60%) - huge fenestrations within the choroidal vessels allow nutrients to easily diffuse out of the vessels and into the RE and the outer 5 layers of the retina **remember that the primary responsibility of the choroid is to provide the outer retina with nutrients such as oxygen, glucose, and vitamin A (non-exhaustive list) (2) Ciliary Body: contains the AMCI that is formed by anastomoses between the anterior ciliary arteries and the long posterior ciliary arteries - MACI → ACAs + LPCAs - remember that the ciliary body and choroidal capillaries are fenestrated (3) Iris: contains the minor arterial circle of the iris that is formed by anastomoses of the iris radial vessels; blood flows from the major circle → minor circle → pupillary margin, and then back again - remember the iris and retinal capillaries are non-fenestrated and contribute to the blood-aqueous and blood-retinal barriers, respectively 5. Retinal Blood Flow - the retina has a dual blood supply - the inner 2/3 of the retina is supplied by the CRA, while the outer 1/3 is nourished by the choroid - remember that the outer plexiform layer is a watershed area that is supplied by both the CRA and the choroid *the CRA artery forms two networks of capillaries within the inner retinal layers; the superficial capillary network is located in the RNFL, and the deep capillary network is located in the INL *the retinal capillary networks become very dense around the fovea, but remember that the center of the fovea is AVASCULAR! the central fovea obtains its blood supply from the underlying choriocapillaris *the extreme anterior edges of the peripheral retina (approximately 1.0 mm from the ora serrata) are also avascular (A) Blood Retinal Barrier - because blood is toxic to the retina, it is essential that blood perfusing through the retinal vessels and choriocapillaris is kept isolated from the retinal tissue; the blood retinal barrier is formed by TIGHT JUNCTIONS in two locations: (1) between endothelial cells lining the retinal vessels (2) between RPE cells **Diabetic retinopathy results from damage to the blood retinal barrier; increased blood glucose levels damage pericytes and basement membranes of the retinal capillaries, allowing blood and plasma to leak into the surrounding retinal tissue; the most important risk factor for the development of retinopathy in a patient with insulin-dependent diabetes is the DURATION OF DIABETES

Visual Pathway

1. Lateral Geniculate Nucleus (LGN) - the LGN is located on the dorsolateral aspect of the thalamus; the following is noteworthy information regarding the LGN: (1) the main purpose of the LGN is to process visual information from the retina before relaying only the most relevant information tot he visual cortex; thus, the LGN helps to regulate the strength of the visual signal sent to the primary visual cortex (2) the axons of the retinal ganglion cells terminate in the LGN and are thought to be the "drivers" for LGN output (3) the LGN also receives input from the superior colliculus and feedback from the visual cortex regarding the visual signal; these inputs are believed to be "modulators" of LGN output (4) axons that leave the LGN are called the OPTIC RADIATIONS **the LGN is not just a simple relay station, but rather a center for processing input from multiple sources to allow filtration of only the most relevant information to V1 (5) there is an LGN located on the left and right sides of the thalamus; remember that each LGN contains 6 layers: (a) Magnocellular layers: layers 1 and 2 on the ventral side (i.e., bottom) of the LGN (b) Parvocellular layers: layers 3, 4, 5, and 6 on the dorsal side (i.e., top) of the LGN (c) Koniocellular layers: located between each of the 6 layers throughout the LGN (6) each layer receives input from ONLY ONE EYE; the type of input is dependent on the location of the object in the visual field; this organization allows fibers from each eye that carry information from the same parts of the visual field to lie adjacent to one another in the LGN (i.e., retinotopic mapping) - as an example, when an object is located in the right hemifield of each eye, the layers of the LGN on the LEFT SIDE of the brain will respond in the following manner: - Layers 1, 4, and 6 receive fibers from the contralateral (right eye) nasal retina - Layers 2, 3, and 5 receive fibers from the ipsilateral (left eye) temporal retina (7) traveling medial → lateral in the LGN corresponds to moving from the superior peripheral -> inferior peripheral visual field (8) macular fibers project to a large central DORSAL wedge that makes up approximately 2/3 of the LGN (9) traveling from dorsal → ventral LGN corresponds to the SAME spot in the visual field, but the eye providing input differs with each layer (10) optic radiations leave the posterior aspect of the LGN **BINOCULAR VISUAL PROCESSING does NOT occur at the LGN level - the LGN neurons are still MONOCULAR; the visual cortex (*V1*) is the first location along the visual pathway to combine monocular input for binocular processing RECEPTIVE FIELDS OF THE LGN - magno and parvo cells of the LGN have -CENTER-SURROUND receptive fields, similar to the bipolar and ganglion cells of the retina; magno and parvo cells differ in their response to illumination, color, contrast, and motion - PARVO CELLS are most sensitive to red-green, fine details (high spatial frequencies), and slow motion (low temporal frequencies) and have a slower speed of transmission of visual signals - MAGNO CELLS are monochromatic and are most sensitive to fast movements (high temporal frequencies) and large details (low spatial frequencies); they have a higher speed of transmission of visual signals due to larger axons compared to the parvo cells - KONIO CELLS respond to blue-yellow contrast 2. Visual Cortex (V1) - also called the striate cortex, Brodmann Area 17, or V1 - the primary visual cortex begins on the outer surface of the occipital lobe and extends anteriorly along the medial surface of the lobe to the parieto-occipital sulcus ; it contains six layers (similar to the LGN), with each layer containing two maps (one for each eye) of the opposite visual hemifield (unlike the LGN); remember the following points regarding V1: (a) the activity of V1 cells depends on the input from the LGN via the optic radiations (the "drivers" of V1 activity); V1 also increases input from several cortical areas (b) V1 is the first location in the visual pathway that combines monocular input for BINOCULAR PROCESSING and evaluation of binocular disparity (c) V1 is the first location in the visual pathway that begins evaluating visual input based on the size, orientation, and direction of movement of the stimulus; ti also discriminates the shape of texture of objects (d) LAYER 4 receives the primary visual input from the LG; remember that cells are organized into OCULAR DOMINANCE COLUMNS that respond to visual input from one eye only; ocular dominance columns are further organized into hypercolumns, which combine a set of ocular dominance columns (one from each other) with all orientation columns (contain cells that respond to specific stimulus orientations); - Layer 4 contains the following cell types: - NON-ORIENTED CELLS: have center-surround receptive fields that do not respond to the orientation of the stimulus; they receive input from the LGN - SIMPLE CELLS: have elongated center-surround receptive field that respond to ORIENTATION of the stimulus; the stimulus must be the correct width, orientation, and located in the correct position within the receptive field in order for a simple cell to respond; simple cells also respond to edges, colors, and depth; P CELLS (of the parvocellular system) are simple cells that are organized into blobs within V1; blobs respond to color; interblobs respond to size and orientation - COMPLEX CELLS: respond to objects MOVING IN A CERTAIN DIRECTION WITH A CERTAIN ORIENTATION; they do not respond to the position of the object in space (the complex cell will respond as long as the object is located somewhere in its receptive field); M CELLS (of the magnocellular system) are complex cells - END-STOPPED CELLS: respond to LINES WITH A SPECIFIC LENGTH (e) Layers 2 and 3 are processing layers and send axons to other cortical layers (f) Layers 5 and 6 send axons to subcortical areas (e.g., superior colliculus), thalamus, midbrain, pons); remember that LAYER 6 provides DIRECT FEEDBACK TO THE LGN, allowing V1 to regulate its own input **V1 examines basic stimulus features before relaying information to more complex processing centers known as the EXTRASTRIATE CORTEX (V2-V5) for further processing V2-V5: located on the lateral aspect of the occipital cortex; these areas are responsible for complex processing of visual information; visual input ultimately travels to two locations within the extrastriate cortex *INFEROTEMPORAL (IT) CORTEX: allows for identification of the object ("what"); involves object recognition, visual attention, and object constancy *MIDDLE TEMPORAL (MT) CORTEX: allows for identification of the spatial relationship of the object to its surroundings ("where"); involves direction, velocity, motion integration, and figure-ground segregation Superior Colliculus (SC): receives information from V1 and from fibers that exit the posterior optic tract prior to reaching the LGN; the SC controls saccades, visual orientation, and foveation; it does NOT analyze visual input for perception Frontal Eye Fields: receives information only from V1; the frontal eye fields are located in the frontal lobe and have two primary functions: (1) pupillary response to near objects (2) activates during initiation of voluntary and reflex eye movements **voluntary saccades are initiated by input from the frontal eye fields and the superior colliculus 3. Receptive Field Properties - we now summarize receptive field properties of cells of the visual cortex; remember that the "average" visual scene that elicits a response in a cell is its RECEPTIVE FIELD; cortical neurons have more complex receptive fields than lower level cells (retinal ganglion cells and LGN cells), and are thus tuned to respond to edges and specific orientations of stimuli; the following cells are found in the visual cortex: (1) SIMPLE CELLS have elongated center-surround receptive fields that respond to the orientation of stimuli and can detect complex structures including bars and edges; their receptive fields are likely a product of the combined input of multiple circular center-surround RFs of LGN cells (2) COMPLEX CELLS process higher levels of perceptual detail and respond to the motion and orientation of visual stimuli; their receptive fields do NOT have a center-surround orientation and are a product of combined in put from many simple cortical cells (3) END-STOPPED (HYPERCOMPLEX) CELLS process combined input from multiple complex cells; they can respond to line stimuli of a specific length in addition to orientation **in summary, the visual system processes images in a HIERARCHICAL fashion, with neurons responding to more basic stimuli feeding information to higher order neurons that respond to increasingly complex images **visual input from the fovea makes up a large percentage of the visual cortex; this phenomenon, known as CORTICAL MAGNIFICATION OF THE FOVEA, allows us to identify small central objects and fine details more easily 4. Gross Electrical Potentials (1) Electrooculogram (EOG) - the EOG measures the difference in electrical charge between the front and back of the eye - the EOG analyzes the health of the RPE by examining differences in electrical potentials that are generated as patients perform eye movements under dark adapted and light adapted conditions - electrodes are attached near the inner and outer canthus of the eye; the patient is instructed to make a series of right and left movements and the electrical potential is recorded over a period of about 30 minutes - the electrical potential is lowest after about 8 minutes of dark adaptation (dark trough), and is highest after about 10 minutes of light adaptation (light rise) - the ratio of light peak/dark trough is the ARDEN RATIO and provides an indication of the health of the RPE *ARDEN RATIO = light rise / dark trough **an Arden ratio greater than *1.8* is considered normal; 1.65-1.8 is considered subnormal, and less than 1.65 is considered very abnormal - the EOG is not clinically useful in differentiating between diseases that affect the RPE but it may be helpful in diagnosing Best's disease, Stargardt's disease, advanced drusen, and patterned RPE anomalies (2) Electroretinogram (ERG) - the ERG records graded potentials produced within the retina in response to light *the ERG represents the activity of the OUTER RETINAL LAYERS (photoreceptor cells and bipolar cells); it does not include the ganglion cell layer *prior to performing an ERG, the patient is maximally dilated and dark adapted for about 45 minutes; the retina is then flooded with various rates, wavelengths, and intensities of light stimuli *the patient is tested under dark-adapted and light-adapted conditions, allowing for the isolation of cone and rod function for analysis **rod function is isolated by using a blue flash with a slow flicker in a dim background **cone function is isolated by using a red flash with a fast flicker in a bright background *the ERG response is composed of 3 waves: (1) A-wave: a negative wave that represents photoreeptor activity (2) B-wave: a positive wave that represents activity of bipolar and Muller cells (3) C-wave: a positive wave that represents RPE cells; the C-wave is rarely evaluated clinically; an EOG is the test of choice to analyze RPE function **an electronegative ERG is characterized by loss of b-wave *Remember that the overall proportion of rods to cones within the retina is 13:1; thus rods, contribute approximately 75% and cones contribute approximately 25% to the amplitude of b-wave under dark adapted conditions **pattern ERGs target the ganglion cells by using a complex stimulus rather than a simple flash of light - multifocal ERGs record responses at multiple locations within the retina, allowing for localization of retinal disease - serial ERGs can be used to track intraocular foreign bodies that cannot be removed **Retinitis Pigmentosa (RP) is characterized by vessel attentuation, bone spicule pigmentation, and waxy optic disc pallor; in early cases of RP, only the scotopic (rod) ERG is abnormal; in late stages of RP, the ERG is completely extinguished due to poor function of the rods and cones (3) Visual Evoked Potentials (VEP) - The VEP analyzes the electrical response (latency) of brain activity to a visual stimulus - wires are placed on the area of the scalp overlying the primary visual cortex within the occipital lobe; the patient sits in front of a screen that displays an alternating checkboard pattern - the abrupt pattern differences of the alternating checkerboard produce responses in the visual cortex within 100 milliseconds in adults - a normal VEP graph contains a large positive wave that peaks at 90-110 msec after the initial stimulus presentation; waves that peak after 110 msec are abnormal - the VEP can detect an anomaly between the fovea and V1, but it cannot localize the defect! **VEK can be helpful in the diagnosis and evaluations of conditions including optic neuritis, optic nerve tumors, retinal disorders, and demyelinating diseases (e.g., multiple sclerosis)

Pupillary Pathways

1. Light Response - afferent pupillary fibers travel with the ganglion cell fibers until the posterior 1/3 of the optic tract, when the pupillary fibers exit and travel within the brachium of the superior colliculus to synapse at the PRETECTAL NUCLEUS in the midbrain - the fibers then project from the pretectal nucleus to the ipsilatearl and contralateral Edinger Westphal (EW) nuclei, forming the tectotegmental tract **damage to the tectotegmental tract can lead to an Argyll-Robertson pupil, which is characterized by light-near response dissociation; Argyll-Robertson pupil is associated with neurosyphilis - pre-ganglionic parasympathetic fibers leave each EW nucleus and travel to the ciliary ganglion within the orbit - post-ganglionic parasympathetic fibers project from the ciliary ganglion to the iris-sphincter and the ciliary muscles **EFFERENT parasympathetic fibers responsible for miosis and accommodation begin in the EW nucleus; remember that ANISOCORIA is ALWAYS a result of an efferent pathology 2. Near Response - the NEAR REFLEX TRIAD of convergence, accommodation, and pupillary constriction occurs when fixation is shifted from a far to a near object - in this case, pupillary constriction is mediated by supranuclear input from the FRONTAL EYE FIELDS instead of the pretectal nucleus - the FEF activates the EW nucleus, which projects fibers to the ciliary ganglion and then on to the sphincter muscle and ciliary muscle, similar to the light response pathway **the light and near pupillary responses both utilize the EW nuclei and the ciliary ganglion as the efferent pathway for pupillary constriction 3. Relationships Between Pupillary Pathways and the CNS - the sympathetic nervous system actively inhibits the EW nuclei through supranuclear control *when uninhibited, EW neurons continuously fire action potentials to the sphincter muscle for miosis *sympathetic stimulation (e.g., during waking hours) results in supranuclear inhibition, causing a decrease in EW activity and normal pupil size *during sleep or anesthesia, supranuclear input is reduced, causing an increase in EW activity with resulting MIOTIC pupils

Neurophysiology

1. Major Neural Pathways - we introduce several major neural pathways, paying particular attention to the points of midline crossover 2. Pyramidal Motor Pathway - the pyramidal motor pathway (PMP) begins in the motor cortex (located in the precentral gyrus) and plays a large role in COMPLICATED VOLUNTARY MOVEMENTS (a) pyramidal motor cell axons come together, forming the iNTERNAL CAPSULE in the forebrain; these fibers then travel through the cerebral peduncles, pons, and medulla and form the medulla pyramids - note that ffibers that innervate cranial nerves break away from this path at certain regions of the middle pons and middle medulla; this "break way" tract is called CORTICOBULBAR TRACT (b) the major pathway continues until it reaches the PYRAMIDAL DECUSSATION in the caudal medulla, where most (85-90%) of the fibers cross to the opposite side of the spinal column and become the LATERAL CORTICOSPINAL TRACT, which controls the distal musculature (c) the remaining fibers make up the ANTERIOR CORTICOSPINAL TRACT and eventually decussate at the level of the spinal cord; these fibers control the proximal musculature **a lesion ABOVE THE MEDULLA will lead to problems with motor control on the CONTRALATERAL SIDE 3. Reticulospinal Pathway - the reticulospinal tracts are also involved in the control of COMPLEX VOLUNTARY MOVEMENTS, as well as the integration of sensory information to direct motor control; these pathways offer an alternative to the pyramidal motor pathway for muscle control - fibers originate from the reticular formation (diffuse collection of neurons) within the pons and the medulla; they descend ipsilaterally and eventually synapse with neurons at all levels of the spinal cord 4. Tectospinal Pathway - although the exact functions of the tectospinal tract are unknown, it is thought to play a role in reflexive head movements in response to visual stimuli - fibers originate in the superior colliculus; they immediately cross the midline and then descend through the pons and medulla, traveling anterior to the medial longitudinal fasciculus (MLF) - fibers eventually synapse at the cervical level of the spinal cord 5. Auditory and Vestibular Pathways - the cochlear and vestibular nerves combine to form the vestibulocochlear nerve (CN VIII), which carries information to the primary auditory cortex, the cerebellum, and the spinal cord for hearing and balance (A) COCHLEAR NERVE: composed of fibers that originate from the SPIRAL GANGLION of the cochlea; these fibers travel through the organ of Corti before exiting via the internal meatus and ending at their cell bodies located in the cochlear nuclei of the medulla - the second order neuron axons ascend on both sides (i.e., crossed and uncrossed fibers) of the trapezoid body to the SUPERIOR OLIVARY COMPLEX within the brainstem; this is the first location of bilateral auditory input - fibers from the superior olivary complex (third order neurons) form the LEMNISCUS PATHWAY and eventually synapse in the INFERIOR COLLICULUS of the midbrain and the medial geniculate body in the thalamus (fourth order neurons) before traveling to the primary auditory cortex (B) VESETIBULAR NERVE: composed of axons originating from the vestibular ganglia at the distal end of the internal auditory meatus; these fibers join the cochlear nerve of CN VIII and carry sensory information from the semicircular canals and otolith organs of the ear; most of the fibers synapse with 4 vestibular nuclei in the medulla and pons; the remaining fibers directly project to the cerebellum via the inferior cerebellar peduncle to control movements necessary for balance (1) primary ascending fibers from the superior and lateral vestibular nuclei carry sensory information to the thalamus, which then sends fibers to the primary vestibular cortex (exact location in the cerebrum is unknown) (2) ascending fibers from the superior and medial vestibular nuclei travel through the MEDIAL LONGITUDINAL FASCICULUS to the nuclei of CN 3, 4, and 6 and help to coordinate head and eye movements (3) ascending fibers from the inferior and medial vestibular nuclei travel to the CEREBELLUM to help coordinate balance (4) descending fiibers from the lateral vestibular nuclei form the LATERAL VESTIBULOSPINAL PATHWAY that travels along the ipsilateral spinal cord and helps control movements that allow us to walk upright (5) descending fibers from the medial vesetibular nuclei form the MEDIAL VESTIBULOSPINAL PATHWAY that travels along either side to the thoracic segments of the spinal cord; this pathway helps to integrate head movements with eye movements 6. Spinothalamic Pathway - The spinothalamic pathway carries PAIN AND TEMPERATURE from the BODY; note that this overall pathway is sometimes called the ANTEROLATERAL SYSTEM - Nerve endings in the periphery synapse at the SUBSTANTIA GELATINOSA within the dorsal horn of the spinal cord; fibers that leave the substantia gelatinosa cross the midline and become the LATERAL SPINOTHALAMIC PATHWAY - The fibers remain contralateral until they terminate in the VENTRAL POSTERIOR THALAMUS 7. Trigeminothalamic Pathway - the trigeminothalamic pathway (TGP) carries PAIN AND TEMPERATURE INFORMATION FROM THE FACE; the pathway originates in the trigeminal ganglion cells, as well as facial pain and temperature receptors that extend into the brainstem at the level of the pons - these axons descend into the medulla (forming a tract known as the SPINAL TRACT OF CRANIAL NERVE V), where they synapse onto second order neurons in one of two sub-regions of the trigeminal complex of spinal cord - axons from the neurons within the trigeminal complex then cross the spinal column in the medulla and ascend contralaterally until they terminate in the thalamus ** a lesion to the trigeminothalamic pathway above the crossover point will result in a loss of pain or temperature information from the contralateral side of the face 8. Medial Lemniscus Pathway - the medial lemniscus pathway carries information about TOUCH, PRESSURE, AND VIBRATION - peripheral information from mechanoreceptors in the upper body travels along the CUNEATE TRACT (located more laterally), while information from the lower body travels along the GRACILIS TRACT (located more medially) - these tracts enter at the cervical and lumbar regions of the spinal cord, respectively, and ascend to the cuneatus and gracilis nuclei in the caudal medulla, respectively - axons from the secondary neurons in this region cross the midline at the level of the medulla and become the INTERNAL ARCUATE FIBERS; these fibers continue to travel contralaterally until terminating in the VPL **a lesion in the medial lemniscus pathway BELOW THE CROSSOVER POINT affects the IPSILATERAL SIDE, while a lesion ABOVE THE CROSSOVER POINT affects the CONTRALATERAL SIDE 9. Autonomic Pathways - remember that the autonomic nervous system (ANS) is composed of neurons within the central and peripheral nervous systems that control input to the VISCERAL ORGANS, SECRETORY GLANDS, AND SMOOTH MUSCLE of the cardiovascular, digestive, excretory, and thermoregulatory systems of the body; input from the ANS is NOT voluntary and helps to maintain homeostasis * the ANS is composed of a sequence of two neurons between the CNS and the target tissue; the first (pre-ganglionic) neuron is located within the brainstem or spinal cord; the second (POST-GANGLIONIC) neuron is located in the autonomic ganglia in the periphery (outside the CNS) - the autonomic nervous system is separated into two divisions: the sympathetic nervous system and the parasympathetic nervous system (1) Sympathetic Nervous System: responsible for the "fight or flight" response; it increases heart rate and blood pressure, dilates the bronchioles, causes vasodilation within skeletal muscles, increases blood glucose levels, and decreases GI motility and blood flow - pre-ganglionic neurons are located in the thoracic and lumbar sections of the spinal cord in the lateral horn of the grey patter; their axons ascend the spinal cord to enter the sympathetic chain of ganglia located along the vertebral column - fibers that cary information to the head and thorax regions synapse within the ganglia of the sympathetic chain; post-ganglionic fibers then continue to travel up the spinal cord to their target tissue - fibers carrying information to the pelvic and abdominal viscera pass through the sympathetic chain WITHOUT synapsing; they travel to the autonomic plexi that surround the large branches of the abdominal aorta, where they eventually synapse; post-ganglionic fibers then travel a short distance from the autonomic ganglia to the target tissue - autonomic ganglia include the celiac, superior mesenteric, and inferior mesenteric ganglia - pre-ganglionic sympathetic fibers release ACETYLCHOLINE; post-ganglionic sympathetic fibers release NOREPINEPHRINE **the adrenal gland is the ONLY gland that is innervated directly by PRE-GANGLIONIC sympathetic fibers (2) Parasympathetic Nervous System: responsible for the "rest and digest" response; it decreases heart rate, constricts the bronchioles, increases salivary and lacrimal gland secretions, increases GI motility, and causes PUPIL CONSTRICTION AND ACCOMMODATION - pre-ganglionic neurons are located within the cranial nerve nuclei of the brainstem, or in the 2nd-4th sacral segments of the spinal cord; the brainstem parasympathetic fibers innervate structures of the head, thorax, and abdomen; the sacral spinal cord parasympathetic fibers innervate pelvic viscera - post-ganglionic neurons are located within ganglia that are very close or adjacent to their target tissue - pre- AND post-ganglionic parasympathetic fibers release ACETYLCHOLINE 10. Significance of CT, MRI, PET scans (1) Computed Tomography (CT): scan of choice for analyzing BONE AND CALCIFICATION and for EMERGENT SITUATIONS (CT scan is faster than an MRI) - uses ionizing radiations to create ~3mm thick cross-sectional images of tissue in order to compare the calcium density of neighboring tissues - as tissues undergo apoptosis, calcium enters cells and increases the density of the tissue; this denser tissue appears whiter on CT scans **CT scans are often utilized in the diagnosis and management of ORBITAL FRACTURES (2) Positron Emission Tomography (PET): scan that is used to analyze the METABOLIC ACTIVITY OF TISSUES by comparing glucose uptake of neighboring tissues - PET scans are often used in conjunction with CT scans to monitor metastasis in cancer (3) Magnetic Resonance Imaging (MRI): scan of choice for analyzing detailed pathology in SOFT TISSUE - the MRI machine used a strong, static magnetic field of radiofrequency energy to excite free protons (located mainly in water) to a higher energy state - as the protons relax back to their baseline level, they give off energy that is detected by antennae inside the MRI unit - the MRI unit then performs a series of complex mathematical computations to produce a detailed spacial map of the tissues in question - as a general rule, diseased tissue has higher water content than healthy tissue and will thus have more free protons **MRI contraindications include severe claustrophobia and magnetically activated implanted devices (e.g., pacemakers, defibrillators, cochlear implants)

Intraocular Pressure

1. Methods of Measurement (1) Goldmann Applanation Tonometry - the probe is designed with a precise size (diameter of 3.06 mm) and weight in order to minimize potential error from tear film surface tension and corneal elasticity; the probe is used to gently flatten (i.e., applanate) the cornea to to obtain a measurement of IOP in mmHg - GAT is based on the IMBERT-FICK LAW, which states that the pressure inside an infinitely thin, dry sphere covered by a thin membrane is equal to the force necessary to just flatten that sphere; it assume that the force from the surface tension of the tear film cancels the opposing elasticity of the cornea - GAT's method assumes that all corneas have the same average thickness of approximately 520 um; this assumption causes us to overestimate IOP in thicker corneas and to underestimate IOP in thinner corneas **current studies have shown an average corneal thickness of approximately 555 um (2) Noncontact Tonometry - a form of indentation tonometry that utilizes an airstream of known force to flatten a circular area of the cornea; the NCT machine contains a photocell that reaches its optimal output when air returns from the corneal surface - the amount of time between the initiation of the airstream and the peak response of the photocell is converted to mmHg - IOP measurements are variable and less predictable compared to Goldmann applanation tonometry (3) PASCAL Tonometry - also known as dynamic contour tonometry; the tonometry tip is contoured and resembles the shape of the cornea when pressure on both sides of the probe is equal - the contoured tip helps to minimize the effect of the unique characteristics of the patient's cornea (e.g., corneal thickness) on the IOP measurement 2. Normative Values - Average IOP and variations *Average IOP: 15.5 mmHg *Two SDs: 21 mmHg / 97.5% *Three SDs: 22 mmHg / 99.9% - the statistical curve on these measurements is skewed to the right, meaning that more people have an IOP > 22 mmHg than the above numbers indicate - Diurnal Variation * IOP varies throughout the course of the day; studies have shown that IOP is highest during nocturnal hours (12:00-6:00 AM) with the peak IOP commonly occurring between 3:30-5:30 AM * 24 hour variations of 2-5 mmHg in IOP are common in the normal population * glaucoma patients can have pressure differences of 10 mmHg or more throughout the course of the day 3. Factors Controlling Aqueous Production - Agents that decrease aqueous production include: 1) beta blockers 2) alpha-2 agonists 3) carbonic anhydrase inhibitors 4) cardiac glycosides 5) hyperosmotic agents 6) significant decline in blood pressure (although minimal effects) 7) uveitis (the inflamed, sick ciliary bocky produces less aqueous) 4. Factors Controlling Aqueous Outflow - in order to maintain the pressure gradient between the posterior and anterior chambers that is necessary for aqueous flow, the amount of aqueous that enters the posterior chamber must be equal to the amount of aqueous that leaves the anterior chamber; this is further complicated by the resistance to outflow inherent in the conventional cornealscleral outflow pathway; recall that aqueous leaves the AC through two different routes: (1) Corneoscleral outflow - drains 2.25 uL/min (80% of aqueous outflow) - aqueous flows from the AC across the TM into Schlemm's canal; the episcleral veins drain aqueous from Schlemm's canal - the rate of drainage in this pathway is PRESSURE DEPENDENT; in general, as IOP increases, aqueous drainage increases; however, if IOP is acutely elevated, Schlemm's canal may collapse on itself, preventing entry of aqueous humor into the venous system (2) Uveoscleral outflow - drains only 0.25 uL/min (20% of aqueous outflow) - aqueous drains through the ciliary stroma into the surrounding vessels of the venous system - the rate of aqueous outflow is INDEPENDENT of IOP SUMMARY EQUATION FOR AQUEOUS OUTFLOW - the following equation, described in Adler's Text and with the variables manipulated and renamed by this author, can be used to summarize the key points regarding aqueous outflow F out = Corneoscleral (IOP - EVP) + Uveoscleral *F out = aqueous outflow * EVP = episceral venous pressure - recall that the aqueous produced in the healthy eye must be equal to the amount of aqueous that is drained from the eye - the total amount of aqueous drainage is a combination of outflow through the corneoscleral meshwork (pressure dependent) and the uveoscleral meshwork (pressure independent) - the total amount of aqueous outflow is about 2.5 uL/min; the total volume of aqueous humor is 250 uL; thus, the total volume of aqueous humor fluid is replaced every *100 minutes* **as can be seen from the above equation, AN INCREASE IN EPISCLERAL VENOUS PRESSURE WILL INCREASE IOP; wearing a necktie can compress the external jugular vein, which leads to an increase in EVP and a reflex increase in IOP; an acute rise in EVP will result in a 1:1 ratio of increased IOP (e.g., increase in EVP by 5 mmHg will cause an increase in IOP by 5 mmHg); Sturge-Weber syndrome and arteriovenous fistulas are two conditions that can increase EVP 5. Factors Influencing IOP - body position - IOP is highest in the supine (lying on back) position - corneal thickness - thicker corneas cause artificially high readings, while thinner corneas cause artificially low readings - blood pressure - no consistent effect on IOP - prolonged exercise - can decrease IOP - blinking/squeezing the eyes/straining - can increase IOP - caffeine - can occasionally cause a transient rise in IOP

Cornea

1. Permeability Characteristics of Corneal Layers - Corneal epithelium: contains zonula occludens junctions (tight junctions) that force molecules to travel THROUGH the cells rather than passing between cells; the epithelium is highly lipophilic (aka hydrophobic), limiting the absorption of hydrophilic, ionized molecules - Corneal stroma: highly hydrophilic; hydrophilic, ionized substances can easily pass through the corneal stroma - Endothelium: contains macula occludens junctions; the ednothelium is highly lipophilic (similar to epithelium) and allows only lipophilic, non-ionized substances to pass through 2. Theories of Corneal Transparency - the following facts regarding light transmission through the cornea are noteworthy: (1) recall that the UV spectrum can be divided into UV-C (100-280 nm), UV-B (280-315 nm), and UV-A (315-400 nm) light waves; the energy per photon increases as the wavelength decreases (2) the corneal epithelium and Bowman's layer protect the inner layeres of the eye by absorbing shorter wavelengths of UV light (UV-C and UV-B below 300nm) (3) the cornea transmits light with a wavelength of 300 nm (UV) to 2,500 nm (infrared) - the visible wavelengths of light (400 to 700 nm) are transmitted through the cornea with a high degree of precision; more than 99% of light above a wavelength of 400 nm is transmitted through the cornea **the corneal epithelium is most sensitive to radiation in the UV-C range (particularly 260-280 nm); snow-blindness, welder's keratitis, and tanning sun lamps can cause ultraviolet keratitis - the following factors contribute to minimal light scattering, allowing for optimal corneal transparency (1) corneal crystallins are located in the cytoplasm of epithelial and endothelial cells and help to maintain corneal transparency by limiting light scattering, similar to crystallins in the lens (2) ascorbate (vitamin C) and glutathione are located within the epithelial cells and help to protect the cornea from UV rays and free radical scavengers (3) the corneal stroma contains approximately 200-250 layers of 30 nm lamellae composed of collagen fibrils (type 1) (n = 1.55) that lie within a network of GAGs (n = 1.345); collagen fibrils have a UNIFORM SIZE and are PRECISELY SPACED less than one half the wavelength of visible light from one another - Proteoglycans (PGs) are present within the ground substance that fills the space between the corneal cells and collagen fibrils and lamellae; the glycoaminoglycan side chains of PGs help to maintain appropriate collagen spacing by forming negatively charged bonds with water molecules - Precise spacing of the collagen fibrils increase destructive interference, thereby minimizing light scattering and increasing corneal transparency (4) the avascular nature of the cornea minimizes light scattering and contributes to its transparency (5) the high water content of the cornea helps maintain the regular spacing between collagen fibrils; remember that the sclera has a lower concentration of GAGs (75% less) compared to the cornea, and is thus dehydrated (65% H2)) and less transparent compared to the corneal stroma (78% H2) **Proteoglycans are composed of a core protein with one or more covalently linked glycosaminoglycan (GAG) side chains; sulfonation of the GAG side chains in the corneal stroma allows proteoglycans to bind to water, creating a hydrophilic environment that helps to maintain the precise spacing of collagen fibrils; the major proteoglycan in the corneal stroma is keratin sulfate 3. Factors Influencing Corneal Thickness/Hydration - the most important factors that influence corneal thickness (hydration) and maintain corneal deturgescence include epithelial pump mechanisms, endothelial pump mechanisms, and aquaporins **CORNEAL DETURGESCENCE is the state of relative dehydration maintained by the normal cornea that is necessary for transparency; 75-80% stromal water content is optimal; deturgescence relies on the endothelial (main contributor) and epithelial transport mechanisms (A) Epithelial pump mechanisms - the BASAL MEMBRANE on the posterior surface of the corneal epithelial cells (surface closest to the stroma) contains two transport mechanisms: Na+/K+ ATPase pump and the Na+/K+/Cl- cotransporter *Na+ passively enters the epithelial cell from the tear film covering the anterior surface of the cell; the Na+/K+ ATPase pump actively moves Na+ from the epithelial cell into the corneal stroma, creating a higher Na+ concentration in the stroma compared to the epithelium *The Na+/K+/Cl- cotransporter utilizes the Na+ concentration gradient to passively move Na+, K+, and 2Cl- from the stroma into the epithelial cells; Cl- and K+ each have their own channels that allow for passive diffusion back into the tears and towards the aqueous humor, respectively *movement of K+ into the aqueous humor will stimulate Cl- to move into the tears; water will follow Cl-, contributing to the dehydration of the cornea; the K+ channel has been shown to respond to pH changes within the cornea; for example, a hypoxic cornea (e.g., after prolonged contact lens wear) will have higher acidity (lower pH) and increased thickness due to corneal swelling; the K+ channel responds by moving more K+ into the aqueous causing more Cl- and H2O to move into the tear film to restore normal corneal thickness (B) Endothelial Pump Mechanisms - there are multiple mechanisms (most are poorly understood) that are believed to play a role in the transport of ions and water across the endothelium; the most thoroughly understood mechanism is the Na+/K+ ATPase pump (1) Na+ enters the endothelial cell from the corneal stroma via ion exchangers; the Na+/K+ ATPase pump, located on the basolateral membrane of the endothelial cell, pumps Na+ out of the endothelial cell into the aqueous humor, establishing a higher Na+ concentration in the aqueous humor compared to the corneal endothelium (2) the Na+/H+ pump utilizes the Na+ concentration gradient to move H+ ions out of the endothelial cells into the aqueous in exchange for the transfer of Na+ ions back into the endothelial cells; movement of H+ ions into the aqueous humor results in a decrease in extracellular pH, causing Co2 to diffuse into the endothelial cell (3) CO2 is combined with H2O to form H2CO3, which then dissociates into H+ and HCO3- (bicarbonate) ions (4) bicarbonate and Cl- move out of the endothelial cell and into the aqueous humor; H2O will then follow, contributing to the dehydration of the cornea **Cl- excretion and Na+ absorption are the major factors for water transport across the corneal epithelium and endothelium (C) Aquaporins - proteins embedded within the apical and basal membranes of corneal epithelial and endothelial cells that regulate bi-directional water transport 2. Oxygen Requirements of Corneal Layers - the entire cornea receives oxygen primarily from the atmosphere; the aqueous humor, limbal vasculature, and palpebral conjunctival capillaries provide a minor contribution of O2 to the cornea under open-eyed conditions - the total amount of pressure in the atmosphere is 760 mmHg; since 1/5 of the atmosphere is oxygen, the partial pressure of oxygen in the air is 155 mmHg - because the cornea receives O2 from the atmosphere under open eye conditions, the partial pressure (PP) of O2 within the tears is 155 mmHg; this PPO2 is high enough to provide O2 to the entire cornea, although as previously mentioned, the aqueous humor and limbal capillaries provide additional support - during closed eye conditions, the PPO2 is approximately 55 mmHg; O2 supply varies depending on the layer of the cornea: (1) the superior palpebral conjunctiva (primary contributor) and the limbal vasculature supply the epithelium and the anterior stroma (2) the aqueous humor supplies the posterior stroma and endothelium **MILD CORNEAL EDEMA occurs after awakening in all healthy individuals; in fact, the cornea is always thickest in the morning! mild corneal edema is due to a build-up of lactate from anaerobic respiration and the limited supply of O2 when the eye is closed **the critical PPO2 for the cornea is *10-20 mmgHg*; a contact lens that is worn while sleeping must maintain a partial pressure of O2 above the critical value; remember that minus lenses are thinner in the center and thus are likely more capable of transporting O2 compared to plus lenses 3. Oxygen Diffusion During Contact Lens Wear - the following formula is useful in looking at how O2 flow to the cornea is affected during CL wear: J/A = Dk/t (P1 - P2) *J/A = how much oxygen flows over a certain area *Dk refers to the oxygen permeability of a material; the higher the Dk, the more readily oxygen will diffuse through a specific area of a material *Transmissibility (Dk/t) is a measure of how much oxygen will diffuse through a contact lens of a given thickness; it is determined by dividing the Dk by the thickness of the lens (t) **Transmissibility is a given as a number X 10^-9 (cm/sec) (ml O2/mL mmHg); the initial number is quoted with the units and power of 10 assumed; for example, the Dk of Acuvue Oasys is 103, and the Dk/t is 147 - proper control of pH within the cornea (pH = 7-7.3) is essential for maintaining corneal transparency; decreased levels of O2 (hypoxia) can lead to an accumulation of H+ ions produced in glycolysis, resulting in increased acidity of the corneal cells - decreased corneal pH causes a change in K+ channels, resulting in a massive efflux of K+ from the keratocytes with subsequent collagen damage and scar formation 4. Nutrient Characteristics of Corneal Layers - glucose is produced for the cornea via anaerobic glycolysis (85%), aerobic glycolysis, and the hexos monophosphate shunt *glucose concentration is low in the tears but is high in the aqueous humor; as a result, the aqueous humor is the primary contributor of glucose to all corneal layerse *the aqueous humor also serves as the primary source of amino acids and vitamins for all layers of the cornea **corneal epithelial cells are unique because they can store large amounts of glycogen for basal cell mitosis and epithelial wound healing; the endothelium also requires large stores of energy in order to maintain the function of the Na+/K+ ATPase pumps that contribute to corneal transparency 5. Corneal Regeneration (A) Maintenance Epithelial Regeneration - the entire corneal epithelium replaces itself every 7-14 days - recall the following noteworthy facts about epithelial regeneration: (1) Basal cells are the only mitotic cells in the epithelium; they are derived from differentiating limbal stem cells from the Palisades of Vogt (2) Basal cells differentiate into wing cells and then squamous cells before reaching the corneal surface; old superficial corneal cells are shed as this process occurs (B) Traumatic Epithelial Regeneration (1) First step: basal cell mitosis is inhibited (2) Second step: after epithelial or stromal injury occurs, fibronectin is released and serves as a scaffolding for epithelial cells to migrate over the wound in response to the release of cytokines and growth factors; hemidesmosomes are then created to allow for proper adhesion between the migrated epithelial cells and the basement membrane (3) Third step: basal cell mitosis resumes at a rapid rate; this will occur once the wound is closed with a single layer of cells and cell-to-cell junctions are created - if the basement membrane remains intact, corneal regeneration occurs quickly; if the BM is damaged (most commonly a result of sharp cutting objects such as fingernails or paper cuts), corneal regeneration occurs more slowly - complete healing of the BM (with creating of intact hemidesmosomes) takes approximately 8 weeks **matrix metalloproteinases can degrade hemidesmosome formation; because corticosteroids and tetracyclines have been shown to decrease the activity of metalloproteinases, they are often included in the treatment regimen for RCEs **corneal abrasions result from trauma; RCEs occur in eyes with poor adhesion between the corneal epithelium and basement membrane from previous abrasions or corneal dystrophies (#1 EBMD) - Summary of all corneal layers *epithelium and Descemet's membrane CAN regenerate *Bowman's layer and the ednothelium CANNOT regenerate *stroma will replace itself if damaged, but with a very different textured tissue; the new collagen is larger and less organized, resulting in a scar **BOWman's "bows out" (will not regenerate) if damaged; Descemet's "D-3" will regenerate via the endothelium; remember that Descemet's membrane is always growing and triples in thickness (5 um to 15 um) from young to adulthood 6. Physiological Characteristics of Corneal Nerves - recall that there are NO NERVES in Descemet's membrane or the endothelium; corneal nerves enter at the level of mid-stroma and travel through Bowman's layer to the corneal epithelium - corneal nerves respond to several different types of sensory stimuli including mechanical, thermal, and chemical factors (e.g., low pH) - the corneal nerves can detect foreign agents and elicit the BLINK REFLEX, protecting the epithelium from potential invasion - the majority of sensory nerves are considered nociceptors, which have a low threshold and mediate pain - the corneal nerves serve a TROPHIC FUNCTION: sensory innervation is essential for epithelial cell maintenance and regeneration - reduced corneal sensitivity is typical after LASIK and with aging **NEUROTROPHIC KERATITIS is characterized by CN V damage and decreased corneal sensitivity and can be diagnosed with the cotton swab test; HERPES SIMPLEX AND ZOSTER, stroke, and DM are common causes of neurotrophic keratitis 7. Aging changes of the cornea - the vertical meridian flattens, resulting in an increase in ATR astigmatism - light scattering increases - corneal sensitivity decreases - the basement membrane thickens - the degree of corneal arcus in the peripheral stroma increases - Descemet's membrane thickens, causing an increase in the number of Hassal-Henle's bodies in the corneal periphery - the endothelial cell density decreases as the endothelium becomes thinner with age

EOMs

1. Vestibular Control Mechanisms (A) MIDDLE EAR - separated from the external ear by the tympanic membrane; sound waves are amplified 10-20X by the TYMPANIC MEMBRANE (EAR DRUM) before being converted into mechanical vibrations and sent into the inner ear; the middle ear contains the following (1) Tympanic Cavity: the space internal to the tympanic membrane (aka "middle ear") (2) Auditory Ossicles: the small ear bones, including the malleus, incus and stapes; these bones are located in a series between the tympanic membrane and the oval window; the malleus is first in the series and is attached to the tympanic membrane, followed by the incus, and then the stapes, which is attached to the oval window; the auditory ossicles amplify and transmit vibrations received by the tympanic membrane (3) Stapedius and Tensor tympani muscles: these muscles dampen the amount of vibrations placed on the auditory ossicles; the stapedius muscle is innervated by a branch of CN VII just before it exits the skull via the stylomastoid foramen; the tensor tympani muscle is innervated by a branch from the mandibular division (V3) of CN V **the chorda tympani nerve of CN VII (carrying taste sensations from the anterior 2/3 of the tongue) and the tympanic nerve plexus (branching from CN IX) travel within, but do not innervate, the middle ear cavity (B) INNER EAR - converts mechanical vibrations into neural signals - vestibulocochlear organs help to maintain balance, receive sound, and contribute to ocular reflex actions - the BONY LABYRINTH consists of three parts that are innervated by CN VIII: (1) Cochlea: shell-shaped portion of the inner ear; contains the organ of Corti that contains hair cells that control hearing (2) Vestibule: contains the utricle and saccule that help maintain balance; these organs detect static linear acceleration (movement of the head or body from side to side) and cause reflex eye movements (LINEAR VOR) that are equal and opposite to the motion of the head; the utricle detects horizontal linear movement; the saccule detects vertical linear movement; the vestibule area is continuous with the cochlear duct for hearing (3) Semi-circular canals: communicate with the vestibule and contain ampullae that detect angular acceleration (rotational movements of the body or head) and cause reflex eye movements known as the ANGULAR VOR **in summary, the TYMPANIC MEMBRANE separates the external and middle ear; the OVAL WINDOW separates the middle and inner ear; the tympanic membrane is much larger, allowing amplification of sound; the malleus, incus, and stapes bones lie between the tympanic membrane and the oval window 2. Supranuclear Control of Eye Movements - most voluntary eye movements are a combination of saccades and pursuits (A) Saccades - rapid eye movements that maintain fixation (aka foveation) on the object of regard - horizontal saccades are controlled by the CONTRALATERAL FRONT EYE FIELD in the frontal lobe and the superior colliculus; for example, the right frontal lobe controls saccades towards the left (B) Pursuits - smooth tracking movements that maintain foveation on slow-moving objects - controlled by the IPSILATERAL PARIETAL LOBE; for example, the right pursuit is driven by the right parietal lobe, and the left pursuit is driven by the left parietal lobe (C) Vergence - control of vergences is presumably located at the level of the brainstem - divergence and convergence (i.e., motor fusion) eye movements are likely driven by RETINAL DISPARITY and help to maintain sensory fusion and stereopsis