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Show THE SIXTH HOYT LECTURE William F. Hoyt, MD William Fletcher Hoyt, MD, professor emeritus of Ophthalmology, Neurology, and Neurosurgery, University of California, San Francisco, was born and raised in Berkeley, California. He took his undergraduate education at the University of California, Berkeley and his medical education at the University of California, San Francisco (UCSF). After a year's study at the Wilmer Institute, Johns Hopkins University, under the mentorship of Frank B. Walsh, MD, he returned to UCSF in 1958 to found the neuro-ophthalmology service. During a 36-year academic career-all of it at UCSF-he authored 266 journal articles, co-authored (with Frank B. Walsh, MD) the biblical third edition of Clinical Neuro-Ophthalmology, and trained 71 neuro-ophthalmology fellows. In 1983, he received the title of Honorary Doctor of Medicine from the Karolinska Institute. He is widely acknowledged as one of the titans of twentieth century neuro-ophthalmology. In recognition of his contributions, the North American Neuro-Ophthalmology Society (NANOS), in conjunction with the American Academy of Ophthalmology, in 2001 initiated the Hoyt lecture to be delivered each year at the Annual Meeting of the American Academy of Ophthalmology. Romancing the Chiasm: Vision, Vocalization, and Virtuosity Joel S. Glaser, MD (J Neuro-Ophthalmol 2008;28:131-143) I would like to thank the North American Neuro- Ophthalmology Society (NANOS) committee for the invitation to speak in honor of William Hoyt, who has been for me, as for so many of us, an exacting teacher, a generous colleague, and a warm friend. While still a medical student, I was introduced to the optic chiasm during a Fight for Sight student fellowship at the University of California, San Francisco. Bill Hoyt assigned me the task of cutting out plastic templates of coronal sections of the optic chiasm, then pasting on the locations of crossed and uncrossed fiber pathways, and stacking the sections like slices of salami to form a three-dimensional model (Fig. 1). This labor was performed by hand, with a No. 15 Bard-Parker scalpel blade and normal clotting time. The previous Hoyt Lectures have featured timely topical reviews presented by skilled clinical scientists. I invite you instead on a journey, an adventure that includes a remarkable cast of historical figures-a tale of double-crossings and choosing sides, of black magic and alchemy, of misplaced anatomy and stunning intellectual insights, of why the motor system is crossed, and, especially, why the left brain is master of the right hand. And finally, to consider the synergy of vocalization with the virtuosic skill of the right hand. Considered the most mystical of the senses, the mechanism of vision has been for ages an intriguing philosophical question. In the ancient world, adolescent science was "natural philosophy," and in ancient Meso-potamia, the healing arts were the equivalent of magic practiced in religious temples (Table 1). The concept of the eye throughout the classic Greek period (400-300 before the common era, BCE) was characterized by a preoccupation with the flow of "humors" and the emission of "rays" originating from the eye (extramission). In 450 BCE, Empedocles declared that "...the eyes project rays that perceive objects and return" (1, p. 35). Even in the infancy of human intelligence, of course, it had been observed around campfires at night that animals' eyes glowed, suggesting that the sense of vision originated in the eye itself. This concept remained mostly unchallenged for a long number of centuries. Indeed, the majority of ancient physicians and philosophers believed in the idea of the proactive role of the eye, including Plato who, in the 4th century BCE, wrote that light emanated from the eye, seizing visual objects with its rays. More metaphorically, Theophrastus, a disciple of Aristotle, stated that the eye had "fire within," contradicting his teacher. Aristotle was among the first to reject the extramission theory of vision: "In general, it is unreasonable to suppose that seeing occurs by something issuing from the eye." Furthermore, if vision indeed originated within the eye, Aristotle reasoned "Why should the eye not be able to see in the dark?" Aristotle advocated the theory of intramission, by which the eye received rays rather than actively directing them outward (1, p. 41). Both Hippocrates and Aristotle considered that the eyes were attached to the brain by hollow tubes that permitted the "principle of vision" to flow away from and toward the brain. Humors would course from the brain down the hollow optic nerves into the eye, pass into space and apprehend the object of regard, return to the eye, be sensed by the lens, and conduct the image centrally where it J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 131 J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 Glaser Joel S. Glaser, MD was born in Brooklyn, New York, and was raised in Orlando, Florida. He obtained undergraduate and medical degrees at Duke University and ophthalmology training at the Bascom Palmer Eye Institute, University of Miami. After a year's fellowship in neuro-ophthalmology with William F. Hoyt, MD at the University of California-San Francisco, he returned to Bascom Palmer. In a 38-year career on the faculty there, he established himself as a world-renowned neuro-ophthalmologist, having trained many of the leaders in the field. He is the author of the respected single-volume textbook Neuro- Ophthalmology, now in its third edition. Joel S. Glaser, MD would be recognized. An overflow of humors, a cataract, would cloud the eye. Although Galen is credited with the initial description of the optic chiasm in the 1st century CE (or common era), our journey starts 2200 years before Hippocrates, during the third dynasty of the pharaoh Geozia (or Djoser, circa 2630- 2611 BCE), where we find an extraordinary genius, Imhotep (2), in many ways the spiritual father of the great physician Galen (and of Leonardo da Vinci). Imhotep was the right-hand man of the pharaoh, serving as grand vizier, banker-treasurer, architect and scribe, physician, and also chief priest of Ra at the Temple of Heliopolis. In this role, Imhotep acted as royal embalmer and practiced the art of mummification, becoming familiar with the anatomic contents of body cavities including the thoracic and abdominal viscera. Pulled out through the nose, the stuff of the brain was not likely to provide any neuroanatomic details. An ancient polymath arguably equal to a Leonardo, Imhotep designed and built the layered step pyramid in the burial complex of the pharaoh at Saqqara, the first functional building of which we are archeologically aware. Imhotep's architectural theories formed the basis for all later pyramid constructions. While the Druids had built Stonehenge (circa 2900 BCE), a Neolithic circle of quarried stones erected on Salisbury Plain, this structure was intended for seasonal calendar calculations, possibly a religious erection, but it definitely does not qualify as a functional building as does Imhotep's step pyramid. According to no less a personage than Sir William Osier, Imhotep was the original "Father of Medicine, the first figure of a physician to stand out clearly from the mists of antiquity" (3). Imhotep authored a lengthy medical treatise, the Edwin Smith Papyrus, remarkable for being devoid of magical thinking and containing anatomical observations and details of ailments and cures. Imhotep's career was so remarkable that a series of schools of healing were established in his name. Some centuries after his passing, Imhotep was deified, worshipped as the divine son of the principal Egyptian god Ptah, creator of the universe. At ancient Memphis, a cult center, Asklepion, was founded, and herein lies a major connection with Galen almost three millennia later. FIG. 1. Models of the optic chiasm constructed by Glaser, with representation of crossed and uncrossed visual fiber pathways. A. Anterior view. B. Posterior view. M, macular projection; IN, inferior nasal fiber pathway; SN, superior nasal fiber pathways. 132 © 2008 Lippincott Williams & Wilkins Sixth Hoyt Lecture J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 TABLE 1. Ancient world natural philosophy and science The evidence afforded by Egyptian and Greek texts supports the view that Imhotep's works and reputation were widely respected and admired by the Greek natural philosophers, including Pythagoras and Hippocrates. His prestige increasing with the passage of centuries, Imhotep's temples became, in ancient Greece, the centers of medical healing and teaching. Greek proto-scientists were intrigued by the possibilities of uncovering by careful observation and thoughtful experimentation the fundamental systems operative in nature, to find the "finger-prints" of the gods to provide evidence that confirmed an ordered universe. There is the improbable myth of Pythagoras, wondering at the spectrum of tones when hammers of different weights resounded on anvils. By experimenting with a monochord consisting of a single stretched gut string supported by a moveable bridge (the bridge effectively lengthens or shortens the vibrating segment, even as a musician's fingers press on strings to shorten the vibrating portion), Pythagoras discovered that the pitch of a note depends on the length of the string and that concordant intervals in a musical scale are produced by simple numerical ratios. With variable lengths of gut string, Pythagoras elaborated a series of whole number ratios (for example, 1:2, 2:3, and 3:4, constituting the "celestial harmonies of Pythagoras"). The essence of nature was mathematical, elegantly established by the disclosure of the presence of a whole number series of ear-pleasing harmonic ratios, which not incidentally comprised the first musical scale that ultimately became the seven-tone dominant scale of Western music. This discovery was a stunning break-through, a corner of science rounded. Harmonic ratios were found not just in music but embedded in the structure of an ordered cosmos; quality became quantity. Do not think that Pythagoras is a minor figure in science. With music, "the harmony of the spheres," the mathematization of human experience and true quantitative science began at the same point, and the contributions of Pythagoras were fundamental. Nor was he forgotten by Kepler and Newton. Pythagoras considered the earth a sphere and proposed a heliocentric system of planets. As eloquently expressed in Koestler's book The Sleepwalkers (4): "...harmony emerges from chaos. The maestro is Pythagoras of Samos, whose influence on the ideas, and thereby, on the destiny of the human race was probably greater than that of any single man before or after him." Recall that the step pyramid of Imhotep was based on a seven-layer structure, and that Plato's cosmology consisted of seven cosmic rings (synonymous with the seven Pythagorean spheres, and equivalent to the number of named notes in the musical octave, let alone the number of days of creation, the seven wandering stars-the planets-observed by the Babylonians, and the seven Gates to Paradise). Once it took root in Plato's philosophy (in Greek, "love of knowledge," a word invented by Pythagoras), the concept of the universe as a musically and numerically tuned system rapidly became the standard throughout the cultured Mediterranean world. Alexander's general and successor, Ptolemy the First, who like Alexander was a student of Aristotle, ruled Egypt and established the university and library at Alexandria (circa 320 BCE), where science flourished. At the illus-trious Alexandrian university, Euclid, the genius of optics and mathematics and best known as a geometrist, described spatial vision (the visual field) as a cone thousands of years before Traquair (5)! Also at Alexandria was Herophilus, who taught and practiced medicine and addressed the nature of nerves by human dissections, at times performed in public. In the Roman period we also recognize the name of Celsus (14 BCE-37 CE), whose medical encyclopedia De Medicina surveyed medicine, surgery, and dentistry. It was in this cultural and scientific milieu that young Galen would come to study. In ancient Asia Minor in the 2nd century CE, Pergamon (Bergama in modern Turkey) was a major center of learning especially dedicated to healing practices and the site of the second largest library of antiquity, the largest being in Alexandria. When papyrus imports from Egypt dried up, the Pergamenes substituted parchment (perga-menum), a local invention. The library accumulated an estimated quarter million volumes, but unfortunately the love-smitten Mark Antony made a gift of these to Cleopatra VII, the last Greek ruler in Egypt, and this Asiatic treasure along with the Alexandrian collection of Greek philosophy Mesopotamia-Sumer: Mathematics, Astronomy, Medicine Egypt Imhotep: Court physician, architect, priest Greek Science Pythagoras Empedocles Democritus Hippocrates Aristotle Ptolemy I (Soter) Euclid, Archimedes, Herophilus Cleopatra VII (Last Greek ruler) Roman Period Celsus Galen 3000 BCE 582-500 490-430 460-370 460-375 384-322 367-283 4th-3rd centuries 69-30 (circa 30 BCE-CE 200) 25 BCE-CE 50 130-200 CE 133 J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 Glaser and literature was eventually burned or scattered to Con-stantinople, Damascus, and Baghdad. Born in the sophisticated and intellectual city of Pergamon, Galen (130-201 CE) was home-schooled by his wealthy father Nicon, the king's architect, and so was well versed in mathematics, logic, astronomy, natural philosophy art, and architecture. At age 17, Galen became a student-attendant (therapeutes in Greek) in the healing temple at Pergamon. The word Asklepion, originally used for the school or cult of Imhotep at Memphis, had eventually been changed to Askelep, or Askelepius, and became the name of the mythologic Greek god of healing (5). Thus, Galen as a teenager was the true inheritor of the ancient art of medicine, training at the Temple of Pergamon dedicated to Askelepius, the Hellenized name of the "first physician," Imhotep. The works of Galen reached 22 volumes, dealing with philosophy anatomy, and medicine, including commentaries on Hippocratic texts. His writings on anatomy, although eventually proved to be scientifically stagnant, were pre-served as the core curriculum of medieval physicians. Galen's primary theory was that four body humors (blood, yellow bile, black bile, and phlegm) were each related to the elements of matter (fire-hot, air-dry, earth-cold, and water-wet) and that illness occurred when a humor became excessive or deficient. Galen also perpetuated the extra-mission theory of vision that supported his concept of sight as an optical pneuma (gas, vapor, breath, or animal spirit) that flowed from the brain to the eyes through hollow optic nerves. Based on the works of Rufus of Ephesus, one of the anatomists who dissected in Alexandria, Galen described the retina, cornea, iris, uvea, tear ducts, and eyelids, as well as two fluids, the vitreous and aqueous humors. According to Galen, "...a round lens in the middle of the eye...is the principal instrument of vision, a fact clearly proved by what physicians call cataracts, which lie between the crystalline humor and the cornea and interfere with vision until they are couched." Indeed, Galen himself performed cataract couching (6). Galen intuited that the retina and optic nerve were part of the brain, stating that "Its chief function, that for which it was sent down by the brain, is to perceive the alterations that occur in the crystalline lens and to communicate them to the brain" (1, p.45). Galen's direct observations of the optic nerves bear quoting (7): "...originating in different places, the optic nerves unite with each other but afterward diverge from each other again... for nature has not interchanged them...the shape of these nerves is very much like the letter chi. If anyone should dissect them rather carelessly, he would perhaps believe that they interchanged...but this is not true; for when they met within the cranium, they united their courses and then again separated, indicating clearly that they came together for no other reason than they might unite their courses..." [My italics]. This is an extraordinary conclusion because Galen was pragmatic, a diligent student of anatomy for 12 years, who published On the Usefulness of the Parts of the Body. Galen insisted that "...nature does nothing without a reason." There was an answer for all questions, but Galen contradicts himself with regard to his observation on the optic chiasm, concluding that the optic nerves "...came together for no other reason than they might unite their courses...and then again separated." Exceedingly successful as a physician, Galen at age 22 served the household of Emperor Marcus Aurelius and the stable of gladiators in Rome. As the team physician to the gladiators, he gained valuable practical experience in trauma and, shall we say, sports medicine. So great was Galen's influence that his anatomic dogma went practically un-challenged for 1400 years. As it turns out, Galen's observations tended to have Uttle to do with human anatomy, as he had dissected principally cats, dogs, Barbary apes, and especially the pig, which he declared "...the animal most similar to man." (For centuries human dissection was forbidden by the Church but also no doubt was considerably retarded by the absence of proper preservation or refrigeration). The most important physician of the Roman Empire, and arguably the most influential physician in medical history, Galen wrote entirely in Greek, and his medical writings preserved today are voluminous. Most were translated into Arabic in the 9th century in Baghdad, and through those translations Galen became the most important formative influence on medieval Islamic medicine. The Ummayad conquest of Spain and Sicily (661-750 CE) led to the revival of learning in medieval Western civilization, with a transfusion of Indian, Persian, Hebrew, and Greek knowledge, including astronomy, mathematics, philosophy, religion, and medicine. To al-Andalus (Spain), the Arabs brought linen paper from Samarkand and Baghdad, the abacus, algebra (al-jabr), chess, soft pillows (almuhada in Spanish) and the concept of the university based on older institutions in Fez and Cairo that offered a variety of academic degrees. During the centuries of the Christian reconquista (900-1400 CE), Arab and European scholars translated into Spanish and Latin the writings of Plato, Aristotle, Euclid, Galen, and other great works of antiquity, again stimulating a renaissance of Western intellectual life (8). With the waning of classical Greek and Roman civilization and an atrophy of accumulated knowledge, medieval Europe had been intellectually asleep for a thousand years. "Natural philosophy" passed into the hands and minds of Arab and Persian scholars, among whom vision and optics were the subjects of extraordinary interest. But human dissection was taboo, an almost insurmountable barrier to progress in anatomy and physiology. Galenic anatomy and physiology were universally accepted, but deviating opinions were expressed. Scholars such as 134 © 2008 Lippincott Williams & Wilkins Sixth Hoyt Lecture J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 Al-Rhazes (864-930 CE), who alone contributed more than 200 scientific treatises using neuroanatomical details for precise clinical localization, described (after Galen) seven pairs of cranial nerves, but refuted the Galenic doctrine that visual rays emanated from the eye (9). Ibn Sina (Avicenna, 980-1037 CE), author of the five volumes of The Canon of Medicine, also overturned the idea that the eye emits rays that bounce off viewed objects, stating that "...it is not the ray that leaves the eye and meets the object that gives rise to vision, but rather the form of the perceived object passes into the eye and is transmuted by the transparent body, the lens" (10). Al-Rhazes and Ibn Sina hinted at the possibility of total decussation of the optic nerves at the chiasm (11). In the Book of Optics (1021 CE) of Abu Ali Ibn Al Haytham (Alhacen, 965-1039 CE), a scientist and physician born in Basra, we find the oldest known pictorial representation of the chiasm (Fig. 2), actually redrawn after Greek concepts. Al Haytham hinted at the functional role of the chiasm, suggesting that only after the superimposition and fusion of the two monocular images here can a single visual experience occur at a higher center, the ultimum sensus (12, p. 83). With a rather simple experiment, Al Haytham contributed to the reversal of the ancient extramission concept that rays project from the eye to the objects of regard. Al Haytham looked briefly at the sun and noted that "...anyone who looks at a very strong source of light will experience both pain and damage to his eyesight..." and that the after-images persisted FIG. 2. Diagram of visual system acknowledging Galen, from Al Haytham's Book of Optics (1083 CE). Note hollow optic nerves merging in common cavity (asterisk) at chiasm (From Ref. 12, p. 84.). after closing one's eyes and looking away. He concluded that "...there is no vision unless something comes from the visual object to the eye..." (1, p. 78). Al Haytham argued that objects are seen because they reflect sunlight. He elaborated the laws of refraction, postulating point-to-point projection of "perpendicular lines" from objects to the surface of the eye. He rather amazingly considered the phenomenon of light to be streams of minute particles (10,13). Among those scholars who profited from the transfer to Europe of Islamic intellectual baggage was Albertus Magnus (Albert the Great; circa 1197-1280 CE), a Dominican friar and follower of the Aristotelian school of method. Albeit was familiar with the theories of both Galen and Al Haytham, as well as the medical works of such remarkable polymaths as Ibn Sina, Ibn Rushd (Averroes), and Moshe ben Maimon (Maimonides). In Paris, Albert contested scientific concepts with Roger Bacon, the mathematician and astronomer. Indeed it was Bacon who first recognized and discussed with Albert the visible color spectrum as discerned in a glass of water four centuries before Isaac Newton (1642-1727 CE) discovered that prisms could disassemble and reassemble white light. Thomas Aquinas was Albert's sometime student and Albeit is mentioned in Dante's La Divina Commedia. On the practice of medicine, Albert commented that it was "...a suitable occupation for manually adept members of the lower classes" (14). Albert described deformation and saccadic phosphenes, nystagmus in alcoholics and in sailors after long sea voyages. He commented on color theory and, as with Empedocles years before Traquair, stated that "...all vision takes place in the form of a pyramid." Albert may be credited with the initial clinical insight regarding the role of visual decussation, stating in De Sensu et Sensato that "...a soldier who was wounded in the left temple, lost vision of his right eye, which certainly happened because of the crossing of the nerves directed from the eyes to the front of the head..." (14). It was not physicians but Renaissance artists who took up the exercise of human dissection to refine the anatomical accuracy of their skills in painting, drawing, and sculpture. In the early 16th century, Leonardo da Vinci admonished his fellow artisans that "Those artists who are enamored of practice without science are like sailors... without rudder or compass...practice must always be founded on sound theory..." (15). Through human dissection, Leonardo produced the earliest existing anatomic representation of the chiasm (Fig. 3) in about 1504 CE. Given the wide breadth of his interests, Leonardo spent an inordinate amount of time dealing with the phenomenon of vision, the anatomy of the eye, and how images are formed. Leonardo did not alter the Galenic dictum that the optic nerves were hollow, but he did conclude that the lens was not the sensory organ and that the visual image was formed on the retina. By casual observations, he corroborated Al Haytham's earlier conclu-sion. In his notebook, Leonardo stated that: "If you look at 135 J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 Glaser U FIG. 3. Leonardo da Vinci's ana-tomic drawing of the chiasm, 1504. (From Ref. 6, p. 56). the sun or other luminous object and then shut your eyes, you will see it again in the same form within your eye for a long time: this is a sign that the images enter within it." Intrigued by the precision of conjugate eye movements, he asked, "whence the turning of the eyes when one draws the other after it?" and answered, as follows: "Saw a head in two between the eyebrows in order to find out by anatomy the cause of the equal movement of the eyes, and this virtually confirms that the cause is the intersection of the optic nerves" (15). Of course, here Leonardo is speaking of the chiasm itself! The extraordinary notebooks and pen and ink drawings of Leonardo could not be technically reproduced or disseminated, nor would he have permitted it. These treasures eventually came into the possession of Charles I of England and were not made available until they were finally published in the early 20th century. Although physicians occasionally took bold issue with visual humoralism, its legitimacy was not seriously challenged until 1543, when the 28 year-old Belgian Andreas Vesalius (Wesel) in Padua published De Humani Corporis Fabrica. Vesalius pointed out some 200 errors in Galen's description of anatomy, due primarily to its being based not on direct observation of the human body, but on fanciful and imaginative suppositions after animal dis-sections. According to Vesalius, "Each nerve of the first pair [optic] under the base of the brain where it rests on the sinus in which the gland which excretes the pituita from the brain is led forward somewhat obliquely, the right nerve extending toward the left and the left toward the right, and then both come together and are intermingled so that in no way can you separate the right from the left [my italics], so much so that it would be wholly fruitless to attempt to determine whether in this junction the right nerve remains on the right side or is led to the left side by an uninterrupted connection"(7, p. 163). Vesalius saw no tubes, but did not dispute the humor-tube theory propounded by the Greeks, so powerful was Galen's continuing influence. With Vesalius, however, true scientific methodology-the rejection of dogmatic techno-logic authority revered but not supported by reproducible critical observations and proofs-had been born. Of the personalities interested in the phenomenon of vision, the list reads like a "Who's Who of History." In the 17th century, Rene Descartes (1596-1650 CE), who entered college at age 8 and was learned in astronomy, geometry, and optics and practiced occasional vivisection, postulated a novel concept of the intrinsic organization of the visual system. Descartes hypothesized that the left retina projected to the left ventricle of the brain and the right retina to the right ventricle. Why the ventricles? Galen had said so! According to Descartes, the afferent images are then transmitted to the pineal gland and merge there "...the mind and body interact in the pineal..." (7, p. 163). Why the pineal gland? Finding it the only unpaired midline organ of the brain, Descartes concluded that this was the seat of the soul and of conscious appreciation and that it received impulses from double sensory organs such as the retinas (Fig. 4). Thus, it was Descartes who first suggested cerebral retinotopic representation, calling the pineal the neural center for fusion of visual images. 136 © 2008 Lippincott Williams & Wilkins Sixth Hoyt Lecture J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 FIG. 4. Illustration of the visual pathway from Descartes' Tractatus de Homine, 1686, indicating his theory of the binocular stereoscopic visual system through topographic (retinotopic) projection to the brain. Note right nasal fibers 5-6 and left temporal fibers 5-6 meeting at point c on pineal H, forming a "syn-dynamical" idea. There is no chias-mal decussation. (From Ref. 12, p. 103). The London surgeon Thomas Willis, Sedleian Pro-fessor of Natural Philosophy at Oxford University, was the first to number the cranial nerves in the current order in his celebrated Cerebri Anatome published in 1664. Willis sought every opportunity for "...opening heads...to estab-lish a more certain Pathologie of the Brain...." The illustrator of Willis's anatomical text was Sir Christopher Wren, the equally famous London architect who assisted in the rebuilding of London after the tragic fires of 1661. Wren had been a mathematician, astronomer, and anatomist before turning to architecture (16). Willis's experiments to elucidate cerebral arterial circulation owed their origin to Wren's technique of chirugia infusoria, the intravenous injection of various colored fluids such as "saffron, ink and milk" (17). Speculating that the fibers of the optic nerves are united and mixed at the chiasm, Willis stated that "The growing together of these optick nerves, and their again being separated, seems to be ordained for this end: that the visual images received from either eye might appear still the same and not doubled..." (18). Thus, a general surgeon, famous or otherwise, had declared that the chiasm served as a mechanism for the purpose of fusing the images of the two eyes and preventing double vision. Willis also stated that the optic nerves were not hollow, although humors of a sort still percolated and flowed along nerves. After 1400 years, the anatomical theories of Galen and the model of the hollow, humor-filled optic nerves of antiquity had finally been refuted. Wren was an acquaintance of the astronomer Edmond Haley, for whom the popular comet is named. These two founders of the Royal Academy of London questioned why the orbits of the planets were elliptical rather than strictly circular. They theorized that this phenomenon had to do with the effects of an "attraction" acting at a distance. It was to Newton, a brilliant mathematician at Cambridge, to whom they took this question. The young Lucasian Professor of Mathematics at Cambridge, a chair currently occupied by Stephen Hawkins, had declared that the attraction of bodies, or gravity, is inversely proportional to the square of the distance between them. With no firsthand working knowledge of anatomy, Newton published the earliest account of partial decussation of the optic nerve fibers (Fig. 5). Appended to the 1706 First Edition of Newton's book Opticks are a series of "Fifteen Queries." Rhetorically, Query 15 asks: "Are not the Species [images] of Objects seen with both Eyes united where the optick Nerves meet before they come into the Brain, the fibres on the right side of both Nerves uniting there, and after union, going thence into the Brain in the Nerve which is on the right side of the Head [that is, the right optic tract], and the fibres on the left side of both Nerves uniting in the same place, and after union going into the Brain in the Nerve [optic tract] which is on the left side of the Head, and these two Nerves [tracts] meeting in the Brain FIG. 5. Diagram of the hemidecussation concept of Newton, 1 705-1 706. Note right temporal point A joining left nasal point a in the chiasm at point p, continuing to theoretic cortex point a. (From Ref. 7, p. 648). 137 J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 Glaser in such a manner that their fibres make but one entire Species or Picture, half of which on the right side of the Sensorium come from the right side of both Eyes through the right side of both Optick Nerves to the place where the Nerves meet [chiasm], and from thence on the right side of the Head into the Brain, and the other half on the left side of the Sensorium comes in like manner from the left side of both Eyes. For the Optick Nerves of such animals as look the same way with both Eyes-as of men, dogs, sheep, oxen, etc.-meet before they come into the Brain, but the optick Nerves of such Animals as do not look the same way with both Eyes-as the fishes and the chameleon-do not meet, if I am rightly informed" (19). Evidently Newton was familiar with the recent publication of his friend William Briggs, entitled A New Theory of Vision, originally presented at the Royal Society of London in 1682. It stated that there is no decussation of visual fibers (20). Newton questioned Briggs' conclusion, and offered the following solution to the problem of formation of a single visual image: "...Perhaps by the mixing of the marrow of the nerves in their juncture [the chiasm] before they enter the brain, the fibers on the right side of each eye going to the right side of the head, those on the left side to the left" (7, p. 161). There are no further explanations of how Newton reached these conclusions There were no anatomic and, of course, no histologic attempts to prove his hypothesis. Is it possible that Newton had classic migraine with hemianopic visual aura and that his symptoms stimulated such speculations? In 1723 Abraham Vater and J. C. Heinicke described cases of transient "halved vision," at times provoked by "the abuse of sour and harsh new wine," which certainly sounds like a description of the hemianopic aura of classic migraine. They drew the conclusion that "...the optic nerves are not so much superficially joined, but rather in their coalescence their fibers decussate and unite, so that these same nerves after separating again, are divided in two equal segments corresponding to the cerebral hemispheres; and thus the right side of the tunica retina in either eye receives fibers from the right hemisphere, and the left side from the left...otherwise superficial conjunction of the optic nerves would have no special usefulness...without decussation of fibers in these nerves divided vision can in no way be explained" (7, p. 167). This report is the first documented clinical evidence of hemidecussion. In addition to his theory of chiasmal decussation, Newton famously propounded that a beam of light passing through a prism would be separated into its component colors-red, orange, yellow, green, blue, indigo, and violet. Here again is the number seven, which Newton knowingly and purposely matched to the proportions of the seven pitches of the Pythagorean musical scale. Of music and the laws of Nature, John Milton sang: Such sweet compulsion doth in music lie. To lull the daughters of Necessity, And keep unsteady Nature to her law, And the low world in measured motion draw After the heavenly tune, which none can hear... Milton "Arcades" (Poems, 1645) Newton dedicated as much time to the art and science of alchemy, searching for the elusive Philosopher's Stone with which to transmute base metals into gold. Alchemy was sometimes referred to as "black art," having arisen in ancient history when Egypt was known as Khem-the "black land." This proto-science was passed to Arab scholars who named it "Al-Khem." The forerunner of modern chemistry, alchemy, once stripped of mysticism, deserves a respectful place in the history and development of science. After all, it was practiced by Newton, admittedly an eccentric crank, but master physicist, mathematician, and premier figure of the scientific revolution of the 17th century. The "Chevalier" John Taylor (1703-1772 CE), a charlatan who traveled across Europe in a coach painted with images of eyes, deserves credit for contributing indirectly to the theory of chiasmal decussation. A man whose major talent was self-promotion, Taylor performed cataract couch-ing and probably accelerated the process by which both Georg Friedrich Handel and Johann Sebastian Bach became blind (21). Nonetheless, his intelligence is evident in the clear explanation, without reference to the work of his fellow Englishman Newton, of a theory to explain single vision that includes corresponding retinal points. Taylor wrote that "All the points of the left side or exterior [temporal] of the fundus of the left eye correspond with all the points of the left side or interior [nasal] of the right eye... each point in one eye with each point in the other which are respectively equidistant from the optic axis and at the same side of it..." (22). A full century after the paper of Vater and Heinicke, William Wollaston in 1824 communicated to the Royal Society his personal experience with hemianopic fortifica-tion spectra, proposing as an explanation the hemidecussa-tion of visual fibers (7, p. 168). His symptoms ironically and tragically were not caused by classic migraine; Wollaston died of a thalamic tumor. We may now indulge in some comparative chiasmol-ogy (Table 2). In general, vertebrates-even lower mamma-lians- show almost complete decussation of fibers at the chiasm. But even here there are aberrant uncrossed and even bipolar fibers of unknown function (23). In primates, and especially humans, the crossed-to-uncrossed ratio is, by modern consensus, approximately 1:1. The majority of axons that provide the uncrossed chiasmal pathway arise in the temporal retina. But also a primate feature is the inexact nasal-temporal spatial retinal segregation for crossed and uncrossed fibers. Different classes of retinal ganglion cells 138 © 2008 Lippincott Williams & Wilkins Sixth Hoyt Lecture J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 TABLE 2. Comparative Submammalian vertebrates Placentals Horses Cat/dog Man * There function (23). chiasmology: ratio of decussation Completely decussated* Mostly decussated 1/6 undecussated 1/4-1/3 undecussated 1/2 undecussated are aberrant uncrossed and bipolar axons of unknown have greater or less sharp divisions at the foveal vertical midline (24). Form follows function, and frontward-oriented mammalian eyes required fine coordination of movement for effective distant vision. Thus, as carnivorous hunters rather than herbivorous prey, many mammals developed over-lapping central visual fields and high degrees of stereopsis, coupled with precisely coordinated eye movements and fine control of yoked muscles for accurate conjugate lateral gaze (12, p. 309-23). At approximately the same evolutionary time, the median longitudinal fasciculus and associated nuclei developed and the optic tectum was slowly superseded by the blossoming of a large visual cortex (12, p. 309-23; 25, 26). Approximately a century after Newton, the anatomist Johannes Muller histologically demonstrated in 1826 that the lateral fibers in the chiasm do not cross. By the end of the 19th century, the work of Bernhard Gudden (1874) and Santiago Ramon y Cajal ascertained that both ipsilateral and contralateral optic fiber projections occur in most mamma-lian chiasms (12, p.156). Using the techniques of focal retinal photocoagulation and Nauta staining of degenerating axons, Hoyt and Luis (27) found that the macular projection was so diffuse that they declared the chiasm a "macular structure interspersed with, and surrounded by, extramacular axon projection," but provided strong evidence that un-crossed fibers remain mostly lateral in human and nonhuman primate optic nerve and chiasm. Now the questions arise: 1) Why is it necessary for visual axons to cross? 2) Who profits (survival value) from decussation? 3) How, if partial decussation is indeed the best plan, is it accomplished? and, 4) What is the reason the left brain is master of the right hand? Consider that the single eye resembles a simple camera, the camera obscura (literally, dark room) of earlier optical philosophy. The relationship of objects in space to the visual image on the retina is constant. The optics of the eye invert the image, both horizontally and vertically; that is, the biconvex lens acts as a cyclopean projection system and the image is inverted, but point-to-point order is preserved. The relative direction of objects and the spatial coordinates of the environment, whether for food or threat, are maintained. There is a panoramic retinal visual template (retinotopy) that is transmitted to a cortical visual template, retaining the precise geometric order of the visual environment, but no vertebrate has ever existed with a single cyclopean eye. Functionally (and teleologically) two eyes are better than one for the exploration of the environment and for panoramic defense. If there is no crossing of retinal fibers, at the cortical level there is visual confusion and panoramic chaos. With decussation, the physiologic dilemma is solved: there is no contradiction of spatial order (Fig. 6). Based on its universal occurrence, Stephen Polyak (12, p. 780-3) points out that the crossover of afferent visual sensations must be of fundamental importance in the organization of vision. With biologic purpose in mind, the Spanish histologist, physician, and Nobel laureate Ramon y Cajal (1898) derived a general theory of double decussation, such that the motor pathways to the opposite extremities also originate in the contralateral cerebral hemisphere (12, p. 156). This seemingly compheated organization is actually the most functional neurobiologic arrangement and fulfills an impor-tant principle of central nervous system structure termed neurobiotaxis by Kappers in 1921 (12, p. 783; 25). To be most useful for a motor executor (Umb movement, for example), an incoming visual message has to pass through the smallest number of neural relays via the shortest route; therefore, the proximity of sensory input to motor output. Related functions localize in adjacent structures. To summarize thus far, the uncrossed optic fiber pathways, along with the medial longitudinal fasciculus and expanded visual cortex, are evolutionary milestones pro-viding binocular fusion and stereopsis. This view may be a bit simplistic. After all, in birds and reptiles and in all animals below placentals, decussation is complete, yet spectacularly coordinated stereoscopy is evident in some species even with more than one macula per eye! Nonetheless, as a rule, the more overlapped the two visual fields, the more scrupulously eye fixation must be coordinated. But what are the mech-anisms that control axonal routing for decussation and non-decussation? The multiple routing factors that assure precise and proper traffic control are exceedingly complicated and vary considerably by species and onto-chronologic domains. A complete summary is beyond the scope of this report, for which reason the exemplary reviews by Jeffery (23) and Mann et al. (28) may be consulted. However, several key mechanisms should be mentioned here, if briefly. A deceptively simple time-related phylogenetic phenomenon bears some reiteration. In lower animals with laterally placed eyes, the chiasmal axons entirely cross to the contralateral brain. As ontogeny still recapitulates phy-togeny, in many vertebrates, including the human embryo, when the primitive optic stalks are initially directed lat-erally, at about 4-8 weeks, the first fibers from each developing retina meet 90 head-on at the chiasmal midline, 139 J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 Glaser FIG. 6. Ramon y Cajal's concept of the role of decussation in accurate retinotopic projection. Left Without decussation, the central template of arrow image L is discontinuous. Right With complete decussation, the central template C is reversed, but panoramic coordinates are ac-curately retained. Note cross-back of motor fibers M and sensory fibers S. (From S. Ramon y Cajal, Die Struktur des Chiasma opticum, 1899. Cited in ref 14, p 781). constituting the crossing system. When the eyes later swing to the frontal position at about 10 weeks, the temporal uncrossed retinal fibers sprout and remain principally in the lateral aspects of the chiasm. This straightforward time-step suggests a possible blueprint role for simple mechanical angulation. Moreover, the chiasmal neighborhood is already crowded with crossing fibers when late-comer uncrossed fibers arrive (23). There is also compelling evidence that each neural retinal anlage receives contributions from both sides of the primitive forebrain. Jacobson and Hirose (29) demon-strated in Xenopus that when cells originating from one cell of the two-cell blastomere stage of the frog embryo were labeled, either by injecting with horseradish peroxidase or by changing the ploidy, both methods showed that labeled cells were confined to the same side of the brain as the initially labeled blastomere, except for cells that moved from the opposite side into the ventral diencephalon and ventral part of the retina. Reciprocal movement of cells from each side of the prospective forebrain into the prospective retina on the opposite side starts before the neural tube closes and forms the basis of an incipient optic chiasm, which may provide the bridge for optic axons to grow from the retina to the opposite side of the brain. That is, with growth of visual axons there is re-direction back across to the originating sides. Perhaps some form of cellular memory leads the sprouting ganglion cell axons "back home," and this path-finding process probably takes the form of a number of remarkable "traffic-cop" molecules. In albinism, anatomic and electrophysiologic evidence has confirmed congenital misrouting of optic fibers, with most fibers from each eye crossing to the opposite lateral geniculate nucleus. Factors include disturbances in the timing of cellular development in the albino retina and the fact that fiber decussation also depends on the embryonic stage at which axons reach the chiasm (23). Furthermore, Ilia and Jeffery (30) showed that dopa, a precursor in melanin synthesis, is a major regulator of retinal cell differentiation and spatial organization and that dopa also influences the exit of cells from their growing cycles. In a number of mam-malian species, fiber growth in the developing retinofugal pathway is coincident with the presence of melanin in the retinal portion of the optic stalk. Transiently active melanin has been proposed to play a role in guidance of optic axons. It is furthermore suggested that stalk melanin accounts for differences in the size of the uncrossed retinal component in pigmented versus nonpigmented strains (31). In an elegant MRI study, Schmitz et al (32) showed that chiasms in albino subjects had narrower widths, smaller optic nerves and tracts, and wider angles between nerves and tracts compared with normal control chiasms. These radio-morphologic findings reflect atypical crossing of optic fibers, with reduced substance at the lateral aspects of the chiasm, the normal location of the non-decussating fiber paths. Again, in albino patients, functional MRI has dramatically demonstrated the relative absence of un-crossed retinal projections, the right retina projecting to the left visual cortex and the left retina to the right visual cortex (33). That melanin is one of the principal "traffic cops" seems incontrovertible. Deiner and Sretavan (34) have described the role of the protein molecule netrin-1 in retinal axonal guidance. 140 © 2008 Lippincott Williams & Wilkins Sixth Hoyt Lecture J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 Optic nerve formation involves the interaction between netrin-1 at the optic disk and receptors on retinal ganglion axons. Netrin deficiency causes path-finding defects. For example, retinal ganglion cell axons in netrin-1-deficient mice grow at unusual angular trajectories within the ventral hypothalamus, resulting in anomalous intrinsic hypotha-lamic axon projections and deficient gonad-releasing, antidiuretic, and oxytocin hormones. Mann et al (28) provided a current "navigation guide" that reviews in particular the key roles of netrin-1 (a chemoattractive cue secreted by glial cells at the optic disc) in determining that sprouting retinal ganglion cell axons are guided into the optic nerve head. They pointed out that ephrin-B helps direct crossed and uncrossed axon projections at the chiasmal midline. Other fundamental mechanisms of retinal-chiasmal axonal guidance include fiber-fiber interactions, fiber-glia relationships, patterns of retinal ganglion cell production, and axonal die-back (Table 3). For further details, the reader is referred to the excellent review on chiasmal architecture and development by Jeffery (23). The relationship of unique neural lateralization, highly skilled motor actions, and especially language, constitutes the quintessential cerebral functions that separates man from other primate species. And language evolution itself is an intriguing phenomenon, as is unilateral cortical localization almost exclusively to the left hemisphere. The overwhelming data indicate that cerebral lateralization is a ubiquitous trait that arose long before the hominid branch developed from our mammalian line of ancestry (35). Bilateral symmetry is the basic design of the musculoskeletal system, but asymmetry is the characteristic of the viscera of the abdominal and thoracic cavities. Then why is it surprising that the viscera of the cranial cavity-the brain-is not bilaterally symmetric? In the context of survival value, we may understand the environmental spatial significance of the bilateral representation of visual and auditory sensory input, but the production of speech and assimilation of communication skills, both spoken language or hand gestures, need not be bilaterally represented. Why waste valuable space? Even if language originated in a motor context, it is not deployed toward specific locations in TABLE 3. Optic chiasm development: general factors Species specificities Genetic components Chronologic domains, including "die-back" Ganglion cell location, density, pigment distribution Tissue environments: retina, glia of optic nerve and chiasm Inhibitory/ permissive adhesion molecules Membrane receptors, fiber-fiber and fiber-glial interaction Spatial angulation of embryonic optic stalk ambient space and needs no bisymmetric brain representa-tion. Although the substrate for oral communication may be genetically innate, a good case may be made that language is a refinement of hand gestures and, with the advent of an upright bipedal posture, the hands were freed for gestural communications during, for example, cooperative group hunting, food gathering, and weapon making. For an excellent exposition on linguistic development theories, see Frank Wilson's delightful book, The Hand. How Its Use Shapes the Brain, Language, and Human Culture (36). Language probably developed from gestures that were used for communication by humans living in social groups that provided for themselves by hunting and foraging. A better communication system was needed, which was the drive to develop and refine language. The increasing use of more and varied tools required that hands be better occupied than wasted on gesturing. Moreover, anatomic evidence supports the "gestural theory": the regions of cerebral cortex that are responsible for mouth and hand movements are intimately juxtaposed. Verbal language and sign language depend on related neural structures. The same left-hemisphere brain regions are active during sign language as during the use of vocal or written language (37). Patients who use sign language and have a left-hemisphere lesion show the same expressive disorders with their sign language as do vocal patients with their spoken language (38). It is not unreasonable to presume that, if prehistoric hunters gestured with the same (the right) hand, such hand signals would become standardized and therefore more easily understood and taught (39). Did the cortical mechanism for gesturing, tool use, and eventually proto-language settle by chance in the left hemisphere? More than 92% of humans are right-handed and, of these, 95% are left-brain dominant. About 70% of left-handers are also left-brain dominant for language skills (40). Nonhuman primate species arguably show no cross-population preference for either hand. Human preference for right-handedness is evident even in prehistoric Paleolithic eras. For example, analysis of the flaking patterns of primitive stone blades shows that the unformed target stone was held in the left hand while a second hammer stone in the right hand chipped off the perimeter to fashion a functioning sharp edge (41). Likewise, boring patterns from ancient awls and handles attached to axes and sickles designed for harvesting grains and grasses attest to forms that suited the right-hand grip (42) (Table 4). The dominance of the right hand is also historically evidenced by the trauma record. H. Australopithecus (1.5-2 MYA) ate baboons, whose clubbed skulls show left frontal or right occipital fractures, indicating that the weapons were wielded in the right hands of the hunters. And rare cases of apparent homicide show left-side skull fractures (42). Less 141 J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 Glaser TABLE 4. Right hand predominance established by microwear analysis Clockwise rotation of boring tools (500,000-100,000 BCE) Flaked tools, weapons (200,000-150,000 BCE) Striations of hide scrapers (35,000-8000 BCE) Bronze Age sickle handles, other tools (4000-3000 BCE) gruesome, cave art also presents ample evidence of ancient right handedness. Of 507 hand outlines on the walls of caves in France and Spain, about 80% are outlines of left hands produced by mouth-spraying of pigments though reeds held in the dexterous right hand (43). Kinsbourne (40) and others have established that language relates to right-sided motion; indeed both overt and covert verbal activity is accompanied by rightward shift of attention such as movement of the eyes and head to the right while pondering verbal problems. Rightward orient-ing serves no obvious adaptive purpose and probably is a manifestation of basic wiring of the human nervous system. But do the origins of language relate to lateral orienting behavior? According to Kinsbourne (40), when infants enter the babbling phase, an association between vocalization and orienting response is evident. The child points with the right hand while babbling. This phenomenon later becomes more evident when naming objects; the child points while naming and does not name without pointing. Infants at 12 months understand pointing by others, and themselves point at about 14 months. Anthropoid apes, including chimpanzees with whom we share 98% similar DNA, do not point. Kinsbourne adds that "...even in the most sophisticated speaker, verbal activity is not completely free of corollary somatic movement produced on an involuntary basis" (40). So the orator makes synergistic emphatic gestures typically with the right hand. Teachers of string musical instruments often enough encourage their students that the bow arm and hand (of course, the right) should be considered the artistically expressive voice of music-making, advising them to "sing with your bow arm." Many skilled musicians, including the great cellist Pablo Casals and the brilliant Canadian pianist Glenn Gould, could not suppress the involuntary synergy of vocalization while performing. Violinist virtuoso Yitzhak Perlman involuntarily moves his lips and mouth without actual vocalization while fiddling. The grunts and screams of tennis players are in another class entirely, probably being only a vocal accompaniment of explosive physical effort. Is it presently possible to explain why the function of language and right-handedness settled in the left cerebral hemisphere? Is this basic neural pattern the result of some potent sensory input, like vision from rightward spatial environment? Is the westward to eastward spinning of the globe or revolution about the sun a cosmic influence? In his book, The Throwing Madonna (44), Calvin theorizes that prehistoric mothers comforted their young by holding them with the left arm against the side of the chest where the mother's heart sounds best soothed the child, leaving the right hand free for food gathering and, when necessary, throwing a spear. Hence the natural selection for right-hand dominance. But chirality (handedness in Greek) occurs otherwise as a property common in several branches of science, referring to asymmetric chemical molecules, subatomic particles, crystalline solids, gastropod shells (mostly rightward coiling), and climbing vines, which may twine clockwise or counterclockwise, having nothing to do with survival value or location in the northern or southern hemispheres. Actually, floral chirality is directed by auxins, hormones that determine asymmetric elongation of growing cells. Most interestingly, from a study of ultrasound scans of 1000 human fetuses (45), an in utero preference for right thumb sucking was found to occur at 15 weeks' gestation. Followed to age 10-12 years, 60 of 75 right thumb sucking fetuses were right-handed, and 10 of 15 left thumb suckers were left-handed. The take-away: the hand favored even at 10 weeks' gestation probably will be the preferred hand for life. What possible influence could afferent sensory stimuli- visual, auditory, or verbal-have on this phenomenon for hand (and left cerebral hemisphere) selection? We assimilate language through hearing and seeing, the receptive neural centers of which are closely localized in proximity to the planum temporale of the left cerebral hemisphere, a cortical "learning center." In the same neighborhood is the motor speech area most frequently associated with the name of Paul Broca (46), whose 1865 rule may be expressed as follows: the hemisphere controlling speech is on the side opposite the preferred hand. In fact, 40 cases of left hemisphere damage with loss of speech and right-hand motor function were described in 1836 by Marc Dax, an obscure French country physician, but not published until 1867 (47). However, the common enough syndrome of loss of speech and right-hand skill was described in literature some 2500 years earlier. In 486 BCE, the Babylonian ruler Nebuchadnezzar invaded Judea and destroyed Jerusalem and the First Temple of Solomon, carrying into exile 10,000 citizens, where "by the rivers of Babylon" (the Tigris and Euphrates) they "sat and wept": If ever I forget you Jerusalem may my right hand lose its skill, and my tongue cleave to the roof of my mouth if I remember you not. -Psalm 137 And so our "romance" of the optic chiasm has taken us on a journey, with intriguing side trips, from ancient 142 © 2008 Lippincott Williams & Wilkins Sixth Hoyt Lecture J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 Egypt and the realm of "natural philosophy," through the age of flowing Greek humors, anatomic observations erroneous and accurate, architects and artists, histologic studies, Cajal's general theory of double decussations, the traffic police molecules that direct the mechanisms for optic axonal guidance, and the clarification of why the left brain is master of the right hand. I have touched on the anatomy and origins of language and why virruosic musicians move their lips. We have encountered a host of remarkable historical figures, many of whom were so much more than anatomists and some not even! I hope this fast trip in a time machine will please my honored teacher and good friend Bill Hoyt. REFERENCES 1. Park D. The Fire Within the Eye: A Historical Essay on the Nature and Meaning of Light. Princeton, NJ: Princeton University Press; 1997. 2. Hurry JB. Imhotep: The Vizier and Physician of King Zoser and Afterwards the Egyptian God of Medicine. New York: AMS Press; 1978. 3. Osier W. The Evolution of Modern Medicine. New York: Bibliobazaar; 2006:23. 4. Koestler A. The Sleepwalkers. A History of Man's Changing Vision of the Universe. New York: Macmillan; 1959:25. 5. Farnell LR. Greek Hero Cults and Ideas of Immortality. New York: Kessinger; 2004:chapter 10. 6. Scarborough J. Galen redivivus: an essay review. J Hist Med Allied Sci 1988;43:313-21. 7. 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