Idea Transcript
700
CLINICAL NEURO-OPHTHALMOLOGY
ANATOMY AND PHYSIOLOGY OF NORMAL LACRIMAL FUNCTION ANATOMY OF TEAR SECRETION BY THE LACRIMAL GLANDS The lacrimal gland is situated in the superior lateral corner of the orbit, immediately behind the orbital rim within the lacrimal fossa of the frontal bone (Fig. 14.39). Inferiorly, it is in contact with the globe. Anteriorly, it is divided into an upper (orbital) and lower (palpebral) lobe by the lateral horn of the levator aponeurosis. The upper or superior lobe is bean-shaped, with its medial extremity lying on the levator and its lateral extremity lying on the lateral rectus muscle. The lower or inferior lobe, about half the size of the superior lobe, is situated underneath the levator aponeurosis and connects to the lateral superior conjunctival fornix by a series of excretory ducts. These ducts, about 12 in number, open into the conjunctival sac 4–5 mm above the upper border of the tarsus. The lacrimal gland is a typical tubuloalveolar exocrine gland composed of small lobules made up of many fine tubules. Each tubule is composed of a layer of cylindrical cells lining the lumen and a layer of flat basal cells lying on a basement membrane. The basal cells are myoepithelial and contractile. The cylindrical cells contain granular cytoplasmic inclusions that histochemically differentiate these
cells by their role in tear secretion. The collecting channels are initially intralobular, but later become extralobular, and finally empty into fine ducts. These ducts are lined with a double layer of epithelium. The ultrastructure of the human lacrimal gland has been described by several investigators (433–435). The fluid produced within the acini of the primary lacrimal gland and secreted by the gland contains water, electrolytes, and protein. The concentrations of these components are then modified by cells of the duct system (436). Parasympathetic and sympathetic nerves innervate the acinar cells, duct cells, and blood vessels of the gland. The parasympathetic nerves contain acetylcholine and VIP. Norepinephrine is contained in the sympathetic nerves, whereas the sensory nerves contain substance P and possibly calcitonin generelated peptide (CGRP). Aqueous tear secretion occurs not only from the primary lacrimal gland but also from the accessory lacrimal glands of Krause and Wolfring. These small glands are similar in structure to the main lacrimal gland but are much smaller. The glands of Krause are located in the upper fornix; the glands of Wolfring are situated further down on the eyelid, above the tarsus (Fig. 14.39). It has generally been accepted
Figure 14.39. Partial schematic representation of secretory tear system. Note locations of primary and accessory lacrimal glands. (Redrawn from Jones LT, Reeh MJ, Wirtschafter JD. Manual of Ophthalmic Anatomy. Rochester, MN, American Academy of Ophthalmology and Otolaryngology, 1970.)
ANATOMY AND PHYSIOLOGY OF THE AUTONOMIC NERVOUS SYSTEM
that the main lacrimal gland, having an efferent, parasympathetic innervation, functions primarily during reflex tear secretion, whereas the accessory lacrimal glands provide nonreflex, basal tear secretion (437–441) (see also Chapter 15). Afferent stimuli causing discharge of the brain stem lacrimal secretory neurons arise from peripheral sensory nerve endings, usually from the trigeminal nerve, but occasionally from the retina. There are two neural pathways by which impulses from the lacrimal nucleus eventually reach the lacrimal gland to induce tear secretion. The parasympathetic pathway is primarily responsible for the gross production of reflex and continuous tears, but the role of the sympathetic system remains controversial. PARASYMPATHETIC PATHWAY FOR LACRIMATION The cell bodies of the preganglionic neurons responsible for parasympathetic lacrimal secretion are located in the lacrimal nucleus within the tegmental portion of the pons in a small area dorsal to the superior salivary nucleus (442). After traversing the facial nucleus, the preganglionic axons join the sensory root of the seventh nerve (the nervus intermedius) that emerges from the lateral portion of the pons between the facial and auditory nerves (Figs. 14.40). The ner-
701
vus intermedius passes through the cistern of the pontine angle and then joins with the rest of the facial nerve, occupying an anterior superior position within the combined nerve as it courses laterally (443) (Fig. 14.41). The surgical anatomy of the nervus intermedius is important because it can be injured during the resection of vestibular schwannomas and other procedures in this area. Symptoms of such injuries include crocodile tears (the gustolacrimal reflex), reduced or absent tear production, and taste abnormalities. These symptoms reflect the sensory and parasympathetic components of the nervus intermedius (444). After joining the nervus intermedius, the facial nerve enters the internal auditory meatus within the petrous pyramid of the temporal bone (445–448). From here, the meatal segments of the facial nerve enter the labyrinthine segment of the facial canal, having pierced the meninges. After coursing above the vestibule of the inner ear and laterally 2.5–6 mm, the facial nerve trunk turns posteriorly at the geniculate ganglion (Fig. 14.42). The parasympathetic fibers destined for the lacrimal gland pass through the ganglion without synapsing and then separate anteriorly at the apex of the ganglion to become the greater superficial petrosal nerve (Figs. 14.42 and 14.43). The close relationship of the origin of the greater superficial petrosal nerve to the apex of the geniculate gan-
Figure 14.40. Relationships between nervus intermedius, facial nerve trunk, vestibulocochlear nerve trunk, and the superior cerebellar and anterior inferior cerebellar arteries. Nervus intermedius (VII N.I.) exits from the brain stem between the facial nerve trunk (VII) and the cochlear (VIII Co.) and superior vestibular (VIII S.V.) nerve trunks. Note relationships of the rostral (Ro. Tr.) and caudal (Ca. Tr.) trunks of the anterior inferior cerebellar artery (A.I.C.A) to the facial-vestibulocochlear nerve complex. V, trigeminal nerve; S.C.A., superior cerebellar artery; R.P.A., recurrent perforating artery; I.A.A., internal auditory artery; Mea. Seg., meatal segment. (From Martin RG, Grant JL, Peace D, et al. Microsurgical relationships of the anterior inferior cerebellar artery and the facial-vestibulocochlear nerve complex. Neurosurgery 1980;6:483–507.)
702
CLINICAL NEURO-OPHTHALMOLOGY
Figure 14.41. Location of the nervus intermedius within the facial nerve trunk just before it reaches the geniculate ganglion. The nervus intermedius (INT) occupies an anterior, superior position in the segment and makes up about 25% of the volume of the nerve at this point. Other branches of the facial nerve include F, frontal; OC, ocular; OR, oral; and ZY, zygomatic. (From Podvinec M, Pfaltz CR. Studies on the anatomy of the facial nerve. Acta Otolaryngol 1976;81⬊173–177.)
glion can be problematic, as this is the area where most of the facial sensory ganglion cell bodies are located. Thus, a geniculate ganglionectomy performed for facial neuralgia may include a section of the nervus intermedius to achieve a more complete deafferentation. Such a procedure may produce a severe decrease in tear secretion (449). The greater superficial petrosal nerve, containing the para-
sympathetic fibers for tear secretion, emerges from the temporal bone in the floor of the middle cranial fossa (Fig. 14.43). The nerve then passes beneath the dura of the middle fossa under the gasserian ganglion in Meckel’s cave. It enters the vidian canal at the anterior end of the foramen lacerum (Figs. 14.43 and 14.44), joining the deep petrosal nerve from the carotid sympathetic plexus to form the vidian nerve (450) (Fig. 14.44). The vidian nerve passes through the vidian canal directly to the sphenopalatine ganglion, where preganglionic lacrimal axons synapse with postganglionic secretomotor neurons (Figs. 14.8 and 14.44). The sphenopalatine ganglion is a small structure measuring about 3 mm along its longest diameter. It is situated deep in the upper part of the pterygopalatine fossa, close to the sphenopalatine foramen and immediately below the maxillary nerve that has exited via the foramen rotundum (Figs. 14.8 and 14.44). The pterygopalatine fossa is directly posterior to the maxillary sinus antrum, from which it can be entered surgically or invaded by tumor or infection. Secretory postganglionic neurons leave the sphenopalatine ganglion and immediately enter the adjacent maxillary division of the trigeminal nerve and travel into the inferior orbital fissure with its zygomatic branch (Figs. 14.8 and 14.44). These nerves run in the lateral wall of the orbit, reaching the lacrimal gland through an anastomosis between the zygomaticotemporal branch of this division and the lacrimal nerve, the latter being a branch of the ophthalmic divi-
Figure 14.42. Drawing showing the relationship of the nervus intermedius to the facial-vestibulocochlear nerve complex as it enters the cerebrospinal fluid-filled internal acoustic meatus, the location of the geniculate ganglion within the labyrinthine segment of the facial (fallopian) canal, and the location of the greater superficial petrosal nerve within its canal as it courses up the petrous pyramid toward the vidian canal. Inset shows the anatomic relationship of the nervus intermedius (1) and the geniculate ganglion (5) to the facial nerve (2–4) in more detail. 2, first part of facial nerve; 3, genu of facial nerve; 4, second part of facial nerve; 6, lesser superficial petrosal nerve; 7, greater superficial petrosal nerve.
ANATOMY AND PHYSIOLOGY OF THE AUTONOMIC NERVOUS SYSTEM
703
Figure 14.43. Emergence of the greater superficial petrosal nerve from the temporal bone in the floor of the middle fossa, viewed from above. The greater superficial petrosal nerve joins with sympathetic fibers (the deep petrosal nerve) to form the vidian nerve. Note anatomic relationships of the inferior orbital fissure, sphenopalatine ganglion in the pterygopalatine fossa, and the maxillary nerve (V2) behind the posterior wall of the orbit and maxillary antrum. V3, mandibular nerve.
sion of the trigeminal nerve. The fibers terminate in the gland between the cells and around the ducts. The autonomic fibers of the lacrimal gland surround the acini but do not penetrate into the glandular cells (451–453). The terminal axons of most of the autonomic fibers to the lacrimal gland contain vesicle-filled varicosities that contain a cholinergic substance and are thought to be parasympathetic in nature. These parasympathetic nerves to the lacrimal gland also produce VIP and induce lacrimation by stimulating a cyclic adenosine monophosphate (cAMP)-dependent signal transduction pathway. Some portions of the parasympathetic afferent pathway to the lacrimal gland can be evaluated by neuroimaging. In general, MR imaging is superior to computed tomographic (CT) scanning in imaging this pathway; however, CT scanning is more useful in imaging certain portions of the pathway. The lacrimal nucleus cannot be selectively imaged with any study. The nervus intermedius usually is too thin and too closely related to the main trunk of the facial nerve and the vestibulocochlear nerve complex to be imaged separately; however, the water-rich sleeve of cerebrospinal fluid in the internal auditory canal is easily demonstrated and provides an outline for the nerves it contains, including the
meatal segment of the facial nerve. The portion of the facial nerve within the cerebellopontine angle cistern and internal auditory canal is not normally enhanced after intravenous injection of gadolinium-DTPA (454); however, the intracanalicular portion of the facial nerve and the geniculate ganglion can be enhanced in pathologic settings because they have a fairly vascular perineurium. The facial canal can also be imaged by CT scanning (455), which is particularly helpful in the evaluation of fractures and other lesions of the tympanic and more distal portions of the facial canal (455). The portions of the parasympathetic pathway for lacrimation at and distal to the sphenopalatine ganglion may be imaged with CT scanning as a result of the natural contrast supplied by fat both within the pterygopalatine fossa and in the orbit and is complementary to MR imaging of these regions. SYMPATHETIC PATHWAY FOR LACRIMATION As discussed earlier in this chapter, preganglionic sympathetic fibers leave the lateral column of the spinal cord, travel along the cervical sympathetic chain, and synapse in the superior cervical ganglion. The postganglionic fibers join the carotid plexus, enter the base of the skull, and pass to
704
CLINICAL NEURO-OPHTHALMOLOGY
Figure 14.44. Vertical section through the axis of the petrous pyramid of the temporal bone showing the location of the geniculate ganglion and the course of the greater superficial petrosal nerve from the geniculate ganglion to the sphenopalatine ganglion. Some sympathetic fibers leave the internal carotid artery at the foramen lacerum to form the deep petrosal nerve. This nerve joins with the greater superficial petrosal nerve to form the vidian nerve. Also note the connections between the sphenopalatine ganglion and the maxillary nerve trunk (V2). V1, ophthalmic nerve; V3, mandibular nerve.
the lacrimal gland by multiple routes. One recognized route goes to the vidian nerve via the deep petrosal nerve (Fig. 14.44). These fibers pass through the sphenopalatine ganglion, join the zygomaticotemporal nerve, and then pass into the lacrimal gland with the parasympathetic motor fibers. Other sympathetic fibers reach the lacrimal gland via the carotid plexus, the ophthalmic division of the trigeminal nerve, and the lacrimal nerve. Still others may reach the gland via the cavernous sinus neural plexus, the ophthalmic artery, and the lacrimal artery. Sympathetic nerves play a role in normal continuous tear secretion in humans (456) and in many animals (457–459), but the mechanism by which they do so is unclear (436,460). In addition, some investigators believe that sympathetic fibers to the lacrimal gland serve more of a vasomotor than a secretory function, as they are sparse in lacrimal glands of human (451,453,461,462). SUPRANUCLEAR PATHWAYS MEDIATING TEAR SECRETION The cerebral structures and pathways supporting emotional tearing include cortical, limbic, and hypothalamic systems that discharge through descending hypothalamotegmental pathways to the parasympathetic lacrimal nuclei of the pons. Experimental study of these systems is limited by the fact that psychic tearing is a function unique to humans. Pfuhl (463) suggested that psychic lacrimation results from stimulation of the frontal cortical fields responsible for eye motion (the second frontal convolution). In cats, direct projections were demonstrated to the superior salivatory nucleus
from the amygdala, a region in the anterior temporal lobe that is involved in emotional regulation. It is noteworthy that these projections did not pass through hypothalamic synapses, suggesting that lacrimation can be directly affected by the cerebral cortex. Takeuchi et al. (464) and Botelho et al. (457) stated that psychogenic tears may be decreased or increased by lesions of the frontal cortex, basal ganglia, or hypothalamus. Mizukawa et al. (465) reported that stimulation of the ventromedial hypothalamic nucleus of the rabbit causes lacrimation. NORMAL TEAR FILM The term ‘‘tears’’ refers to fluid that exists as a precorneal film and in the conjunctival sac. The volume of tear fluid is about 5–10 L (466). Tears are produced by the lacrimal gland, the accessory lacrimal glands, and the goblet cells of the conjunctiva. Normal secretion of tears is about 1–2 ⬎L/min (466,467). Except for those tears that evaporate, the tear fluid drains through the lacrimal puncta and canaliculi to the lacrimal sac, which then communicates with the nasal cavity. Tears have a physically and chemically complex structure that interfaces between the ocular surface and the environment (468). The tear film is about 30–40 m thick and is composed of three layers: (a) a thick inner mucous layer containing mucins, electrolytes, water, immunoglobulin (Ig) A, and several enzymes; (b) a thinner aqueous middle layer that contains proteins, including several antibacterial enzymes; and (c) a very thin outer lipid layer. A detailed description of the composition of the tear film and the lacrimal
ANATOMY AND PHYSIOLOGY OF THE AUTONOMIC NERVOUS SYSTEM
secretory system can be found in the volume edited by Sullivan (469) and in Chapter 15 of this text. TYPES OF TEAR SECRETION Four different types of lacrimation can be identified in humans: (a) continuous tearing, produced constantly for protection and maintenance of a healthy corneal epithelium and a perfectly smooth and transparent corneal refractive surface; (b) reflex tearing, stimulated by exposure of the free nerve endings in the eye, nose, and face to light, cold, wind, foreign bodies, or irritating gases and liquids; (c) induced tearing, which often develops as an allergically or chemically mediated response to local irritants or by direct nonsynaptic parasympathomimetic action of some drugs on the cAMP-dependent signal transduction pathways in the secretory cells of the lacrimal glands (Fig. 14.45); and (d) psychogenic tearing or tears of emotion, which are unique to humans. Young infants cry without shedding tears during the first days of life, and infants born prematurely may not shed tears for weeks. This delayed capacity for psychogenic weeping suggests that the connections within the CNS that indirectly innervate the lacrimal system are not fully developed in most newborns (470).
705
REGULATION OF TEAR SECRETION Jones (439) hypothesized that tear secretion could be clinically separated into two types: basal secretion, which originated from the accessory lacrimal glands and occurred independent of stimulation, and reflex secretion, which originated from the main lacrimal gland and occurred only in response to neural stimulation. He believed that the tears that were produced after administration of topical anesthesia were caused by basal secretion. Regardless of the clinical advantages of this classification, this study may have led to the false impression that the role of the nervous system in the regulation of tear production is limited to parasympathetic neural stimulation of the main lacrimal gland. Proof that even basal tear production is neurologically regulated is that basal tearing is essentially eliminated in humans by the injection of lidocaine anesthetic into the sphenopalatine ganglion (471). Indeed, the formation of all three layers of the tear film is regulated, and much of this regulation is neurally controlled (470a), involving either classic innervation via synaptic connections or atypical, nonsynaptic modulation from the release of neurotransmitters into the biosphere of cells, such as
Figure 14.45. Schematic of the cAMP-dependent signal transduction pathway used to stimulate or inhibit main lacrimal gland electrolyte, water, and protein secretion. (From Dartt DA. Regulation of tear secretion. Adv Exp Med Biol 1994;350⬊1–9.)
706
CLINICAL NEURO-OPHTHALMOLOGY
the conjunctival goblet cells (436) (Fig. 14.46). For example, wounding of the corneal epithelium is followed by increased mucous secretion from conjunctival goblet cells. Secretion from goblet cells is also increased following the topical application of a number of neurotransmitters, including VIP, serotonin, epinephrine, dopamine, and phenylephrine. Thus, parasympathetic, serotoninergic, dopaminergic, and sympathetic nerves may all be involved in reflex secretion from conjunctival goblet cells (472). Although sympathetic and parasympathetic nerves are present in the meibomian glands within the upper and lower eyelids, these nerves probably do not regulate the production of the lipid layer of tears (473). This is because the oily
secretion of these glands is produced by holocrine secretion, in which entire cells, including their stored lipids, are released. Lipid layer secretion is believed regulated primarily hormonally, with modulatory neural influences possible. Facial nerve and orbicularis oculi muscle function may play a role in both meibomian gland excretion and the maintenance of the lipid layer of tears by maintaining normal pressure on the excretory ducts (473). The aqueous layer of the tear film most likely includes water derived not only from the main and accessory lacrimal glands but also from the corneal, and possibly the conjunctival, epithelium. Three classic neurologic pathways that stimulate secretion from the main lacrimal gland have been iden-
Figure 14.46. Schematic of the orbital glands and ocular epithelia that secrete the different layers of the tear film. (From Dartt DA. Physiology of tear production. In: Lemp MA, Marquardt R, eds. The Dry Eye: A Comprehensive Guide. Berlin: Springer-Verlag, 1992.)
ANATOMY AND PHYSIOLOGY OF THE AUTONOMIC NERVOUS SYSTEM
707
Figure 14.47. Schematic of 1,4,5 inositol triphosphate/Ca2Ⳮ/diacylglycerol-dependent signal transduction pathway used to stimulate main lacrimal gland electrolyte, water, and protein secretion. (From Dartt DA. Regulation of tear secretion. Adv Exp Med Biol 1994;350⬊1–9.)
tified: (a) the muscarinic cholinergic (Fig. 14.47); (b) the ␣1-adrenergic; and (c) the peptidergic (Fig. 14.45). Acetylcholine acts on the main lacrimal gland via a classic synaptic pathway in which it stimulates a muscarinic receptor and a G protein, leading to a rise of intracellular calcium concentration and the activation of Ca2Ⳮ/calmodulin protein kinases that phosphorylate specific proteins to activate ion channels in the apical and basilateral membranes. There follows electrolyte, water, and protein secretion and, thus, the production of the primary fluid (Fig 14.47). The pathway just described is known as the 1,4,5-inositol triphosphate/ Ca2Ⳮ/diacylglycerol-dependent signal transduction pathway and is unique to the main lacrimal gland. The pathway and the mechanism by which ␣1-adrenergic agonists stimulate lacrimal secretion are unknown. The main lacrimal gland has a neurally controlled cAMP-dependent signal transduction pathway that can either stimulate or inhibit water, electrolyte, and protein secretion. A number of neurotransmitters and neuropeptides, including -adrenergic agonists, VIP, dopamine, serotonin, and dibutyryl cAMP, all stimulate this cAMP-dependent signal transduction pathway
that phosphorylates protein kinases. The phosphorylated kinases, in turn, cause electrolyte and water secretion from the cytosol. Lacrimal secretion stimulated in this manner can be inhibited by the proenkephalin family of peptides acting through G proteins (Fig. 14.45). Tears do not originate solely from the main lacrimal gland. Structures to support neurally regulated secretion have also been identified in the accessory lacrimal glands located within the eyelids. Parasympathetic axons with large, dense core vesicles and sympathetic axons with small, dense core vesicles appear to stimulate the cAMP-dependent signal transduction pathway for secretion of water and electrolytes by the accessory lacrimal glands in a manner similar to that for the main lacrimal gland (474). These nerves use a number of hormones, neuromodulators, and -adrenergic agonists to accomplish this process (Fig. 14.45). Commonly employed pharmacologic therapies also affect tear secretion. For example, the diuretic hydrochlorothiazide depresses basal tear secretion (475). Even the corneal epithelium contributes cytosolic water by secretion into the aqueous layer of the tear film following stimulation by classic
708
CLINICAL NEURO-OPHTHALMOLOGY
neurotransmitters and neuropeptides, including -adrenergic agonists, dopamine, serotonin, and dibutyryl cAMP, similar to the membrane system in the lacrimal gland cells. REFLEXES ASSOCIATED WITH LACRIMATION Trigeminal-Lacrimal Reflexes Most reflex lacrimation originates from stimulation of the first division of the trigeminal nerve. The stimulus, if slight, may produce only ipsilateral lacrimation, but beyond a certain point it will affect both eyes (341). These stimuli include all painful diseases of the eye, corneal foreign bodies, and corneal irritants. Many nonocular sources of trigeminal stimulation produce lacrimation. These include tickling of the nasal mucous membrane, painful teeth, and painful sinus disease. Trigeminal-lacrimal reflexes may operate through brain stem connections between the descending spinal tract of the trigeminal nerve and the superior salivatory nucleus. Other Reflexes Associated with Lacrimation That bright light causes lacrimation is common knowledge, but the pathways that produce this reflex remain poorly understood. Strong gustatory stimuli may also cause lacrimation. Presumably, the gustatory-lacrimal reflex operates between the gustatory nuclei and the salivary nuclei (including the lacrimal nuclei) in the brain stem. Lacrimation can also be a part of the complicated synkineses of yawning, coughing, and vomiting. REFERENCES 1. Langley JN, Dickinson WL. On the local paralysis of the peripheral ganglia and on the connection of different classes of nerve fibres with them. Proc R Soc Lond (Biol) 1889;46:423–431. 2. Kaada BR. Somato motor, autonomic and electrocorticographic responses to electrical stimulation of rhinencephalic and other structures in primates, cat and dog. Study of responses from limbic, subcallosal, orbito insular, piriform and temporal cortex, hippocampus, fornix, and amygdala. Acta Physiol Scand 1951; 24 (Suppl 83):1–285. 3. Cannon WB, Rosenblueth A. The sensitization of a sympathetic ganglion by preganglionic denervation. Am J Physiol 1936;16:408–413. 4. MacDonald IA. The sympathetic nervous system and its influence on metabolic function. In: Bannister R, Mathias CJ. Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System. Oxford, Oxford Medical Publishers, 1992:197–211 . 5. Pick J. The Autonomic Nervous System. Philadelphia, JB Lippincott, 1970. 6. Burn JH. The Autonomic Nervous System, 5th ed. Oxford, Blackwell Scientific Publications, 1975. 7. Appenzeller O. The Autonomic Nervous System. An Introduction to Basic and Clinical Concepts, 2nd ed. New York, Elsevier, 1976. 8. Gabella G. Structure of the Autonomic Nervous System. New York, John Wiley & Sons, 1976. 9. Koizumi K, Suda I. Induced modulation in autonomic efferent neuron activity. Am J Physiol 1963;205:738. 10. Brodal A. Neurological Anatomy in Relation to Clinical Medicine, 3rd ed. Oxford, Oxford University Press, 1981. 11. Hockman CH. Essentials of Autonomic Function. Springfield, IL, Charles C Thomas, 1987. 12. Parent A. Carpenter’s Human Neuroanatomy, 9th ed. Baltimore, Williams & Wilkins, 1996. 13. Yates BJ, Miller AD. Vestibular Autonomic Regulation. Boca Raton, FL, CRC Publishing, 1996. 14. MacLean PD. Some psychiatric implications of physiological studies on frontotemporal portions of limbic system (visceral brain). Electroencephalogr Clin Neurophysiol 1952;4:407–418. 15. Papez JW. A proposed mechanism of emotion. Arch Neurol Psychiatry 1937; 38:725–743. 16. Adey WR, Tokizane T, eds. Structure and function of the limbic system. Prog Brain Res 1967;27:1–475.
17. Hockman CC. Limbic System Mechanics and Autonomic Function. Springfield, IL, Charles C Thomas, 1972. 18. DiCara LV, ed. Limbic and Autonomic Systems Research. New York, Plenum Press, 1974. 19. Isaacson RL. The Limbic System. New York, Plenum Press, 1974. 20. Hall E. The anatomy of the limbic system. In: Mogenson GJ, Calaresu FR, eds. Neural Integration of Physiological Mechanisms and Behavior. Toronto, University of Toronto Press, 1975:68–94. 21. MacLean PD. The Triune Brain in Evolution. New York, Plenum Press, 1989. 22. Dow R, Morruzzi G. Physiology and Pathology of the Cerebellum. Minneapolis, University of Minnesota Press, 1958. 23. Snider RS. Some cerebellar influences on autonomic function. In: Hockman CH, ed. Limbic System Mechanism and Autonomic Function. Springfield, IL, Charles C Thomas, 1972:87. 24. Gorski RA, Gordon JH, Shryne JE, et al. Evidence for a morphalogical sex difference within the medial preoptic area of the rat brain. Brain Res 1978;148: 333–346. 25. Braak H, Braak E. The hypothalamus of the human adult: chiasmatic region. Anat Embryol 1987;175:315–330. 26. Morton A. A quantitative analysis of the normal neuron population of the hypothalamic magnocellular nuclei in man and of their projections to the neurohypophysis. J Comp Neurol 1969;136:143–158. 27. Williams PL, Bannister R. Gray’s Anatomy, 38th British ed. London, Churchill Livingstone, 1995. 28. Ingram WR. Nuclear organization and chief connections of the primate hypothalamus. Proc Assoc Res Nerv Ment Dis 1940;20:195–244. 29. Cowan WM, Guillery RW, Powell TPS. The origin of the mammillary peduncle and the hypothalamic connexions from the midbrain. J Anat 1964;98:345–363. 30. Cross BA, Silver IA. Electrophysiological studies on the hypothalamus. Br Med Bull 1966;22:254–258. 31. Palkovits MC, Le´ra´nth C, Za´borszky L, et al. Electron microscopic evidence of direct neuronal connections from the lower brainstem to the median eminence. Brain Res 1977;136:339–344. 32. Saper CB, Loewy AD, Swanson LW, et al. Direct hypothalamo autonomic connections. Brain Res 1976;117:305–312. 33. Hancock MB. Cells of origin of hypothalamo spinal projections in the cat. Neurosci Lett 1976;3:179–184. 34. Hosoya Y, Matsushita M. Identification and distribution of the spinal and hypophyseal projection neurons in the paraventricular nucleus of the rat. A light and electron microscopic study with the horseradish peroxidase method. Exp Brain Res 1979;35:315–331. 35. Morton A. The time course of retrograde neuron loss in the hypothalamic magnocellular nuclei in man. Brain 1970;93:329–336. 36. Daniel PM, Prichard ML. Studies on the hypothalamus and the pituitary gland. Acta Endocrinol (Copenh) 1975;201 (Suppl 80):1–216. 37. Sherlock DA, Field PM, Raisman G. Retrograde transport of horseradish peroxidase in the magnocellular neurosecretory system of the rat. Brain Res 1975;88: 403–414. 38. Saper CB. Hypothalamus. In: Paxinos G, ed. The Human Nervous System. New York, Academic Press, 1990:389–713. 39. O’Steen WK, Vaughan GM. Radioactivity in the optic pathway and hypothalamus of the rat after intraocular injection of tritiated 5-hydroxytryptophan. Brain Res 1968;8:209–212. 40. Hendrickson AE, Wagoner N, Cowan WM. An autoradiographic and electron microscopic study of retino hypothalamic connections. Z Zellforsch Mikrosk Anat 1972;135:1–26. 41. Moore RY, Lenn NJ. A retinohypothalamic projection in the rat. J Comp Neurol 1972;146:1–14. 42. Moore RY. Retinohypothalamic projection in mammals. A comparative study. Brain Res 1973;49:403–409. 43. Sadun AA, Schaechter JD, Smith LEH. A retinohypothalamic pathway in man: light mediation of circadian rhythms. Brain Res 1984;302:371–377. 44. Moore RY. The organization of the human circadian timing system. Prog Brain Res 1992;93:99–115. 45. Zacharias L, Wurtman RJ. Blindness. Its relation to age of menarche. Science 1964;144:1154–1155. 46. Czeisler CA, Shanahan TL, Klerman EB, et al. Suppression of melatonin secretion in some blind patients by exposure to bright light. N Engl J Med 1995;332: 6–11. 47. Menaker M. Circadian photoreception. Science 2003;299:213–214. 48. Lucas RJ, Hattar S, Takao M, et al. Diminished pupillary light reflex at high irradiance in melanopsin-knockout mice. Science 2003;299:245–247. 49. Ruby NF, Brennan TJ, Xie X, et al. Role of melanopsin in circadian responses to light. Science 2002;298:2211–2213. 50. Hattar S, Liao HW, Takao M, et al. Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 2002;295: 1065–1070. 51. Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 2002;295:1070–1073. 52. Freedman MS, Lucas RJ, Soni B, et al. Regulation of mammalian circadian