The archetypal Renaissance man, Leonardo da Vinci draws wide admiration for his unequaled range of intellectual passions. The creator of the Mona Lisa and other artistic masterpieces in the second half of the 1400s and early 1500s was also an accomplished musician, entertainer, scientist and engineer whose inventions included ball bearings, instruments to measure the specific gravity of solids, and fantastic war machines (although he abhorred the "most bestial insanity" of battle).

Less well known--largely because hundreds of his pages of notes and detailed anatomical drawings went unpublished until the late 19th and early 20th centuries--are his remarkable and penetrating findings in neuroscience. In an era more comfortable accepting notions handed down from medieval science and ancient Greece and Rome, he pioneered the practice of sketching anatomical features based on his own direct observations. He also strove to establish a physical basis by which the brain interprets sensory stimuli and through which the mind functions. And he developed a coherent theory of how the senses operate, in particular how the eye sees--mechanistic explanations of such phenomena that reflect the thinking typical of his primary career, engineering.

Leonardo never went to university and only began studying Latin in his 40s. As he wrote, my works are the issue of pure and simple experience, which is the one true mistress. As a keen student of nature, Leonardo stands apart from most of his contemporary anatomists, who tended to regurgitate the dogma of earlier Greek and Roman authorities--from the school of Hippocrates to the teachings of Galen. Yet he was not entirely unfettered by his era's reliance on the past. The views common in his day also shaped--and sometimes confounded--his efforts to understand the structure and functions of the brain.

Foundation of Life
Leonardo was born on April 15, 1452, near Vinci, some 20 miles from Florence. As a teenager he joined the workshop of Andrea del Verrocchio in Florence, and at age 20 he was admitted to the Company of Painters. Artists in Renaissance Florence were encouraged to perform, or at least observe, dissections. Leonardo's paintings such as the St. Jerome, composed around 1480, indicate that he had gained knowledge of human musculature. But little evidence suggests that he performed autopsies or displayed a deeper interest in anatomy until later in the 1480s, when he moved to Milan. There his relentless curiosity would lead him to a striking series of discoveries in the fields of neuroanatomy and neurophysiology.

Leonardo's earliest surviving anatomical drawings are related to the nervous system and date from circa 1487, when he pithed a frog (pierced its spinal column). He may have been the first person to perform this experiment. He wrote: The frog instantly dies when its spinal medulla [medulla oblongata] is perforated. And previously it lived without head, without heart or any interior organs, or intestines or skin. Here therefore, it appears, lies the foundation of movement and life. Leonardo loved animals: he was a vegetarian, was known to buy birds at the market to set them free, and was an avid enthusiast of horses. Perhaps for this reason none of the rest of his many hundreds of experiments recorded vivisection.

On the same sheet with the frog, he sketched the spinal cord and added the words generative power, reflecting the belief, which had originated 1,900 years earlier with the famed Greek physician Hippocrates, that sperm derive from the spinal cord. Next to the spinal cord, Leonardo drew a tube, with a caption that said that the sense of touch was the cause of motion and the passage for animal powers (transito della virtu anjmalia).

Leonardo might have been exposed to the ideas of animal spirits through the writings of Galen of Pergamum (roughly around A.D. 130 to 200), the greatest physician of the ancient Roman era. After Galen's death, progress in anatomy stalled for eight centuries, until the rise of Islam. Galen described a concept first developed by a physician from the famous medical center at Alexandria, Erasistratus of Ceos (who flourished circa 300 B.C.). Erasistratus believed that air breathed in is converted to vital spirit, which is conveyed to the brain's ventricles, where it becomes animal spirit. This animal spirit filled the hollow nerves and enabled them to control the movement of muscles. (Today we understand that nerve cells are not hollow and that they propagate an electrical signal to the nerve terminal, where chemical neurotransmitters are released across the synapse, a small gap between the neuron and muscle cell. These chemical transmitters induce a muscle cell to contract.)

Turning to Leonardo's early drawings of the brain, we find a remarkable page dated to approximately 1487 [see illustration on page 85] showing a cross section of an onion and several drawings of the human head with schematic views of the eye. Beside the images, he wrote: "If you will cut an onion through the middle, you will be able to see and enumerate all the coats or rinds which circularly clothe the center of this onion. Similarly, if you will cut through the middle of the head of a man you will first cut the hairs, then the scalp, then the muscular flesh and pericranium, then the cranium; and inside, the dura mater, the pia mater and the brain; then again the pia mater and dura mater and the rete mirabile and then the bone, their foundation." This text was derived from Ibn Sn (also called Avicenna, who lived from A.D. 980 to 1037), a Persian philosopher and physician who grew to prominence comparable to Galen's, largely through his encyclopedic Qanun fi-al-tibb (Canon of Medicine). The Qanun formed one of Leonardo's principal sources.

Leonardo's depiction of the skull includes the frontal sinus, shown as a protrusion just above the eye, which is one of his original discoveries. The optic nerve projects from the eye toward the center of the brain, encountering the first in a row of three oval ventricles--they look quite different from the actual appearance of these cavities filled with cerebrospinal fluid. Leonardo's ventricles also appear in a view from above, which shows the optic and auditory nerves entering the anterior ventricle.

What inspired Leonardo to draw the brain's ventricles this way? Galen had localized cerebral functions, including sensory and motor output, to brain regions near the ventricles. Galen's interpreters subsequently introduced the doctrine of three ventricle cells, ascribing various brain functions to them. An anterior cell was thought to serve as the common meeting place for all the senses, and hence it was called sensus communis in Latin. (Our phrase "common sense" derives from this term.) Most authors placed fantasy and imagination in the sensus communis as well. The middle ventricle housed cogitava, ratio or estimativa--what we call rational thinking. Ibn Sn's Qanun explained that the sensus communis in the anterior ventricle receives sensory information, the imagination holds the sensory perceptions after they have subsided, and the cogitative faculty in the middle ventricle can manipulate images stored in the imagination--creating the idea of a flying man or an emerald mountain, for example. Most authors agreed that the posterior ventricle was the seat of memory.

In many dozens of medieval and Renaissance manuscripts, we find diagrams in which the sensus communis is depicted in the anterior ventricle, such as Leonardo indicates in the illustration on page 85. But Leonardo modified his views in a dramatic contrast to the prevailing dogma, transferring the sensus communis to the middle ventricle and now labeling the anterior ventricle "imprensiva." The word "imprensiva" is difficult to translate, and no anatomist before or after Leonardo has used this term. It refers to a site for the processing of sensory impressions, in particular visual input. Thus, he continued to show the optic nerve terminating in the anterior ventricle. The olfactory and auditory nerves entered the middle ventricle, which was labeled senso comune or sometimes comocio (thought) or volonto (will).

Leonardo's unique labeling of the ventricles reflects the tremendous importance he accorded to the sense of vision, which he described as the window to the soul and the most important basis of all experience. To him, the role of the artist was to depict nature--"the painter's mind must of necessity enter into nature's mind in order to act as an interpreter between nature and art"--and this role primarily involves vision. Unlike any other artist or anatomist, Leonardo equated artistic perception with an anatomical framework for seeing, and it is extraordinary that he places emphasis on the visual system above other senses as acting through the imprensiva. He believed that once information passed to the senso comune it was judged, and he thought of this function as an inner eye or occhio tenebroso ("the eye in shadows"--that is, the eye without external light).

Between 1487 and 1493 Leonardo went on to create a number of marvelous drawings of the skull. These beautiful, lifelike images are among his most inspired anatomical works. In one [see illustration below], we see a skull divided down the middle, allowing a view of multiple depths. On the left side is the maxillary antrum, a cavity in the facial area, which Leonardo was the first to identify. The accompanying text concerns the location of the senso comune relative to the face, as well as a discussion of the number of teeth. (Leonardo corrected Aristotle, who had suggested that men have more teeth than women.)

Another anatomical tour de force [see illustration on opposite page] provides the first accurate depiction of the meningeal arteries; the blood supply to the brain was significant to Leonardo as the source of "vital spirit" to the ventricles. This diagram also shows the cranial nerves leading to the geometric center of the brain, where Leonardo located the senso comune. The nerves do not in reality converge in this way, so Leonardo's arrangement followed what he thought should be, rather than what he had actually observed.

Locus of the Soul
To Leonardo, the judging of information by the soul also took place in the senso comune. "The soul seems to reside in the judgment, and the judgment would seem to be seated in that part where all the senses meet; and this is called the senso comune," he wrote circa 1489. "All our knowledge has its origin in our [sense] perceptions," he concluded. Visual objects, smells and sounds converge on the senso comune, while "perforated cords" convey sensory information from the skin.

Leonardo invoked a military metaphor to explain how motor output is also controlled by the senso comune and the soul. As he put it, "The nerves with their muscles obey the tendons as soldiers obey the officers, and the tendons obey the senso comune as the officers obey the general. Thus, the joint of the bones obeys the nerve, and the nerve the muscle, and the muscle the tendon, and the tendon the senso comune. And the senso comune is the seat of the soul, and memory is its ammunition, and the imprensiva is its standard of reference because the sense waits on the soul and not the soul on the sense. And where the sense that ministers to the soul is not at the service of the soul, all the functions of that sense are also wanting in that man's life, as is seen in those born mute and blind." Leonardo's interest in the soul often turned to such questions of disease. He wrote: "How nerves sometimes operate by themselves without any command from other functioning parts of the soul. This is clearly apparent, for you will see paralytics and those who are shivering and benumbed by cold move their trembling parts such as head or hands without the permission of the soul; which soul with all its forces cannot prevent these parts from trembling. This same thing happens with epilepsy and with severed parts such as the tails of lizards."

Because Leonardo based his theories of the mind on physical laws, he sometimes was led in unexpected directions. For instance, he argued at length that ghosts cannot exist: "There can be no voice where there is no motion or percussion of the air; there can be no percussion of the air where there is no instrument; there can be no instrument without a body; and this being so, a spirit can have neither voice nor form nor strength."

After 1493, Leonardo set his anatomical studies aside for about 15 years. He stayed in Milan through the 1490s, working as an entertainer in the court of Ludovico Sforza, engaging in artistic projects such as the Last Supper, performing civil and military engineering, and writing his treatise on mechanics called the Elements of Machines. In 1505 he continued his earlier studies of the flight of birds and the possibilities of human-powered airplanes and gliders. His focus on mathematics sharpened as he tried to apply the science of perspective to his painting. His efforts were shaped by an obsessive desire to understand what he called the four powers of nature: movement, weight, force and percussion.

Leonardo's belief in the body as a mechanical instrument subject to these four powers led him to impressive innovations when he returned to the topic of anatomy. Consider his studies of the heart. He was the first to realize that the organ has four chambers, not two, and he discovered the atria (what he called the two "upper ventricles"). He correctly surmised that the atria contract to propel blood. During an autopsy, he even identified an atrial septal defect, a hole in the septum separating the two atria. He made a three-dimensional glass cast of the aorta to study its function and performed detailed investigations (including glass models) of the tricuspid, pulmonary, mitral and aortic valves. He discovered the moderator band, a muscle spanning the right ventricle.

And so when Leonardo again took up his explorations of the structure and function of the brain, around 1508 to 1509, his approach was built on a sounder background than his initial studies had been. He invented a brilliant technique: after drilling a hole in the base of the brain of a dead ox, he used a syringe to inject hot wax into the ventricles. When the wax set, he cut away the brain tissue and thus made a reasonably accurate cast of the ventricles. This is the first known use of a solidifying medium to measure the size and shape of any internal body structure, and it provides an example of how Leonardo used his training as an artist--in this case, as a sculptor--to develop a new scientific approach.

Leonardo proceeded to make an impressive drawing of a human head, this time depicting the ventricles in more realistic shapes based on what he had observed in the ox [see illustration on opposite page]. Equally astute was his positioning of the cranial nerves. We can identify seven pairs, including the olfactory nerves, which had never before been described as cranial nerves, and the optic nerves. He was the first to diagram in a naturalistic way how the nerves cross over at the optic chiasm. All these cranial nerves no longer entered the ventricles, as they had in the traditional illustrations, but instead traversed the surrounding brain tissue. Leonardo had progressed as an anatomist to the point that he drew what he saw, even when it contradicted the enormous weight of authority.

Leonardo performed his experiments on the brain in a broader context of his studies on the nature of sensory stimuli and the function of the eye. He maintained a largely traditional theory of how the eye detects images of things we see. Light, he believed, is a "power" that carries visual rays from an object to the eye in the form of "pyramids" that meet the eye at the top of the pyramid. Waves of "percussion" pass through the pupil and lens down the optic nerve to the imprensiva and then to the senso comune, where they enter consciousness. Having read the literature regarding optics and then performed his own experiments, Leonardo struggled to the conclusion that we see objects because the eye receives light. This view was in opposition to those espoused by Plato, Euclid, Galen and others, who held that visual power emanated from the eye, although it was supported by some, including the great Arab philosopher and physicist Alhazen.

Despite such challenges, Leonardo made enormous strides in one lifetime. If he could travel forward in time to visit our society, he would surely marvel at our further progress in understanding the brain's physical functions through the use of observation and experimentation. At the same time, he might be surprised to learn how many of the questions he posed still remain incompletely addressed by modern neuroscience: How is it that we read or remember? Why do some people have mental retardation or epilepsy? Why do we dream or even sleep? What is the soul? Thanks in part to the foundations laid by Leonardo and others, perhaps we will have answers within the next five centuries.