In the field of medical science, the eponym Willis refers to several anatomical structures, including the cerebral arterial circle (Arráez et al., 2015). In 2014, the 350th anniversary of the publication in London of the famous work by Thomas Willis, titled Cerebri Anatome, was commemorated. This text was deeply influenced by the political and cultural context of Baroque Europe, particularly 17th-century England. According to Arráez et al. (2015), this work, a product of what is now known as translational research, marked the beginning of modern neurology and laid the foundation for future investigations in the fields of clinical and comparative anatomy of the nervous system.
Biography
Shortly after the death of William Shakespeare and Queen Elizabeth, during a period when England still enjoyed the artistic and cultural flourishing of the Elizabethan era, Thomas Willis was born on January 27, 1621, in Great Bedwyn, Wiltshire, about 70 miles northwest of London (Arráez et al., 2015). His father, who had served several nobles, settled as a farmer in a village near Oxford. He attended Edward Sylvester's school and was admitted to the University of Oxford on March 3, 1637. Initially, he studied at Christ Church College under Dr. Thomas Isles' guidance and later moved to All Saints College. According to Arráez et al. (2015), he earned a Bachelor of Arts degree on June 12, 1639, and a Master of Arts degree on June 18, 1642, the same year his father died defending the king during the siege of Oxford.
Originally inclined towards an ecclesiastical career, he learned Latin, the language of both religious authority and political power (Arráez et al., 2015). Although he did not enjoy the rigidity of theology, his mastery of Latin proved extremely beneficial in his later medical writings. During this time, he worked as a servant for Dr. Thomas Isles and Mrs. Isles, who were the canon of Christ Church College and an unofficial physician, respectively. His interest in medicine arose while assisting Mrs. Isles in preparing medical remedies, which introduced him to the growing field of alchemy. In 1642, he began his medical studies. In November of that year, King Charles I took residence at Christ Church College in Oxford, accompanied by the royal physician William Harvey. According to Arráez et al. (2015), Willis had the opportunity to learn about the main advances in medicine thanks to the lectures given by Dr. Harvey.
As a royalist, Thomas Willis joined the auxiliary regiment of the Earl of Dover in the fight against the Parliamentarians (Arráez et al., 2015). On December 8, 1646, his loyalty was rewarded with a medical degree after only six months of study, allowing him to begin his medical practice before Oxford was taken by Parliamentary forces (Arráez et al., 2015). After obtaining his license, according to Campohermoso et al. (2019), Willis faced difficulties in starting his practice, not due to a lack of knowledge but because of his lack of resources to dress appropriately and his stammer, which made him appear less competent than he truly was.
Despite the ban on Anglican worship during the Protectorate, he began holding religious assemblies in his home (Arráez et al., 2015). Meanwhile, at the University of Oxford, traditional teaching was replaced by new trends that turned Oxford into the center of scientific knowledge, encouraged by Puritan thought and inspired by Francis Bacon's work. In response to Puritan influence, some members of London's Invisible College founded the Oxford Experimental Philosophy Club, which Willis joined in 1649. In this club, according to Arráez et al. (2015), he interacted with figures such as Robert Boyle, the father of chemistry; William Petty, philosopher, physician, entrepreneur, and economist; Christopher Wren, professor of astronomy at Oxford and architect; Thomas Sydenham, known as the English Hippocrates; Robert Hooke, physicist and microscopist; and Thomas Millington, physician and professor of natural philosophy at Oxford.
This group frequently met to discuss scientific topics and conduct experiments, promoting independent translational research in Oxford (Arráez et al., 2015). Aristotle’s natural philosophy was replaced by Pierre Gassendi’s atomism, whose ideas influenced Willis’s work, along with the iatrochemical concepts of Walter Charleton and Théodore Turquet de Mayerne. It was common for physicians to consult one another about their patients, and Willis did so with many clinicians. In fact, the Library of St. John's College, Oxford, preserves letters exchanged between Willis and Richard Higges, which are valuable for studying Willis's reasoning, which differed greatly from that of his contemporaries. According to Arráez et al. (2015), in a letter to Higges dated March 24, 1665, he provides details on treating a patient’s feet and preparing medication, demonstrating how he used his knowledge to help patients.
On December 14, 1650, Willis and Petty had an unusual experience when they revived a corpse (Arráez et al., 2015). Anne Greene, accused of murdering her baby, was hanged and declared dead before being placed in a coffin (Molnar, 2004). Upon opening the coffin, a strange noise was heard, prompting the start of resuscitation. Anne fully recovered, married, and had three more children (Molnar, 2004). This event significantly impacted his professional career (Arráez et al., 2015). On April 7, 1657, he married Mary Fell, sister of John Fell (Campohermoso et al., 2019). In 1660, following the Restoration, Oxford was purged of Puritan elements (Arráez et al., 2015). That same year, he became a doctor of medicine and Sedleian Professor of Natural Philosophy at Oxford. Arráez et al. (2015) mentions that although this position required lectures on Aristotelian tradition, his education from members of the Invisible College contrasted with the restored scholastic tradition.
Thanks to the support of his friend Gilbert Sheldon, Bishop of London, Willis was able to present his students with his theories and personal observations (Arráez et al., 2015). Among his students were John Locke, physician and philosopher, and Richard Lower, whose notes from Willis’s lectures formed the basis of Willis’s Oxford Lectures. Lower became a notable anatomist while assisting Willis in neurological studies and later conducted blood transfusion experiments presented to the Royal Society (Arráez et al., 2015). According to Campohermoso et al. (2019), in 1662, King Charles II founded the Royal Society of London, and a year later, Thomas Willis was elected a member, being admitted on October 24, 1667.
In 1664, he was elected honorary fellow of the Royal College of Physicians of London (Arráez et al., 2015). In 1665, Sheldon proposed he return to London, a major center for scientists at that time. By the end of 1666, he moved to St. Martin's Lane and quickly achieved success, becoming “the most famous physician in Europe,” according to a commemorative plaque in the chapel of St. Martin in Fenny Stratford. In 1674, he bought 3,000 acres of land near Bletchley from the Duke of Buckingham. He finally died on November 11, 1675, from tuberculosis and pneumonia. According to Arráez et al. (2015), his remains rest next to those of his wife in the north transept of Westminster Abbey.
Work and Publications
His writings were dismissed by his contemporaries (Arráez et al., 2015). However, his work has been well documented by Hughes and Isler and in Munk’s roll. Willis's scientific output consists of seven works, organized into three stages. This reflects his interest in studying the soul from an iatrochemical perspective. During the Reformation, which promoted the use of local languages, most of his contemporaries published their works in English. In contrast, Willis chose to write in Latin, as he considered this language to be more refined and elegant. Additionally, Latin supported traditional medical education, backed by the University, the Monarchy, and the Church. Nevertheless, Willis's "Plain and Easie Method" was originally published in English, as it was a posthumous edition of a work written in 1666. According to Arráez et al. (2015), the collected editions of Willis’s works, which appeared in the 50 years following his death (nine in Latin and two in English), demonstrate his extensive influence.
Willis's main contribution to medicine lies in his research on the morphology of the nervous system, including embryology, comparative anatomy, and pathological anatomy, as a foundation for understanding neurological pathology (Fresquet, 2005). In 1664, "Cerebri Anatome" was published, while René Descartes published "Traité de l’homme" (Arráez et al., 2015). Arráez et al. (2015) mentioned that both authors shared the goal of understanding the structure and function of the nervous system in their effort to comprehend the relationship between the soul and the body, although their approaches were quite different.
Unlike René Descartes, Willis's ambitions were more modest (Arráez et al., 2015). He did not speculate on the relationship between the soul and the body; instead, he prioritized observing the structure as it was, without altering it to fit any theory. Willis sought to understand the normal functions of the nervous system in order to address neurological pathologies. In line with Arráez et al. (2015), for Thomas Willis, a defect or lack of nervous fluids could affect the vital spirit, an idea reflected in his work "De Anima Brutorum," where he studied the "animal" or "sensitive" soul of the human being.
Although this work might seem theoretical and speculative, it made significant contributions to the comparative anatomy of the nervous system, basing his theories on animal research (Arráez et al., 2015). He held that the "animal soul" was the most subtle and fiery part of the blood and that all sensations, movements, and impulses depended on the "animal spirits." In contrast to the material nature of the "sensitive soul," the "rational soul" was immaterial and immortal; it housed the faculties of wisdom and reason and was therefore exclusive to humans. In this context, he suggested that neuropsychiatric diseases arose when both the "sensitive and rational souls" were altered. Finally, Arráez et al. (2015) indicated that Willis provided one of the earliest systematic descriptions of neuropsychiatric diseases, such as headache, sleep disorders, coma, apoplexy, vertigo, paralysis, mania, delirium, and melancholy.
"Cerebri Anatome"
The Body-Brain-Soul Relationship as a Starting Point for Willis' Work
He began his research on the understanding of the "rational soul" and its interaction with the brain due to the need for material for his lectures (Arráez et al., 2015). In the Dedication addressed to Sheldon, he made it clear that "natural philosophy" and "Christian theology" should not be considered rivals. He also stated that anatomy could reveal the hidden places of the mind and explore the living, breathing Chapel of Deity. He concluded his dedication by asserting that after studying the brain, even the most stubborn atheist might recognize the existence of God, or else reject both religion and reason. In the Preface, his religiosity, combined with his scientific methods, led him to view the brain as a harmonious and interconnected system designed by God. Later, according to Arráez et al. (2015), when writing about the brain, he used a metaphor to express his views on the role of the king and the church, a common technique in the lectures and philosophical works of the Restoration era.
He also argued that by studying anatomy, he could demonstrate the structural similarities between humans and animals, despite the differences in their higher functions (Arráez et al., 2015). This implied that humans possessed an "immortal soul" in addition to the one "shared with animals." For this reason, the work "Cerebri Anatome" is a comparative anatomy that includes numerous references and drawings comparing humans to horses and sheep. Willis realized that the functions of the nervous system were far more complex to understand than those of other organs. Consequently, he replaced Nemesius's doctrine and deduced that the ventricles contained cerebrospinal fluid, which collected the waste products from the effluvia. Likewise, according to Arráez et al. (2015), he recognized the cortex as the substrate of cognition and claimed that gyrencephaly was related to a progressive increase in cognitive complexity.
In his functional scheme, he placed the origin of voluntary movements in the cerebral cortex, while involuntary movements came from the cerebellum; memory was located in the white matter; the gyri controlled memory, will, and imagination; and the striatum played a crucial role in sensation and movement (Arráez et al., 2015). Willis was an advocate of the "animal spirits," which were extracted from a cerebral distillation of blood and descended through the nerves to the organic territories to cause sensations and movements. According to Arráez et al. (2015), the nervous fluids carried by the "spiritus" were not inside the nerve fibers, as was believed at the time, but in their interstitial space.
He also hypothesized about sensation and movement, involving the nerve tubules discovered in the brain by Malpighi and the membranous fibers of Baglivi (Arráez et al., 2015). Additionally, he considered the chemical process to be crucial: the substance had to reach the muscles through the nerves to bind with the "animal spirits" extracted from the blood. According to Arráez et al. (2015), this reaction triggered muscle contraction.
Willis' New Technical Approaches to Study
The first chapter, which is also the most extensive of his work, addresses new approaches and technologies in the field of organ preservation and the injection of colored solidifying substances (Arráez et al., 2015). In this context, he explicitly details his scientific methodology. Regarding the dissection method, he observed that previous anatomists analyzed the brain through in situ dissection, meaning that after opening the skull, they removed successive sections of the brain. This procedure allowed for a thorough study of the ventricles but complicated precise observation of the delicate structure of the brainstem. Instead, Willis opted to extract the entire brain intact, allowing him to examine a less distorted organ. According to Arráez et al. (2015), while writing "Cerebri Anatome," Willis had a large collection of anatomical plates and atlases that served as the basis for his original research.
Although Willis acknowledged Galen of Pergamum (129 AD – 210 AD) and Hippocrates (460 – 377 BC) as the founders of medicine, he believed that classical anatomists not only lacked detailed anatomical knowledge but were also influenced by an incorrect belief system of pagan origin (Arráez et al., 2015). This lack of faith prevented the ancients from recognizing the true beauty of humanity, which Willis considered God's final work. Additionally, Willis was a pioneer in brain preservation techniques for later study. According to Arráez et al. (2015), to delay the rapid decomposition of the brain, Thomas Willis preserved it in pure alcohol, a method previously suggested by Boyle.
Illustrations and Engravings
One of his most notable achievements in his work was his ability to accurately illustrate the findings obtained during dissection (Arráez et al., 2015). Leonardo da Vinci encouraged the anatomist to abandon the idea that the structure of the human body could be fully understood through words. Beginning with the publication of "Historia de la Composición del Cuerpo Humano" by Valverde de Amusco in 1556, anatomical texts gradually began to include visual legends and higher-quality illustrations, engraved on copper plates. In fact, according to Arráez et al. (2015), the 23 figures contained in "Cerebri Anatome" were unprecedented in the history of anatomy.
New Anatomical Descriptions
In his work, he described in detail several brain structures, including the striatum, internal capsule, cerebellar peduncles, anterior commissure, claustrum, inferior olivary nucleus, pyramids, thalamus, terminal stria, and certain nerves (Arráez et al., 2015). He also noted that brain tissue is insensitive to painful stimuli, in contrast to the meninges, which are sensitive. Finally, according to Arráez et al. (2015), Willis provided details about the autonomic nervous system and proposed a classification that included nine cranial nerves.
The Sympathetic Nerves and the Vagus Nerve
The division between the sympathetic nerves and the vagus nerve is often attributed to Charles Estienne (Arráez et al., 2015). However, Eustachius and Willis were the only anatomists of the time to provide clear examples of this separation. They also asserted that the sympathetic subdivision of the autonomic nervous system had an intracranial origin. Consequently, some authors suggest that Willis knew of Eustachius's unpublished plates, while others believe that different lines of thought led to similar conclusions. The book "Cerebri Anatome" includes two clear and precise illustrations of this separation, which resemble those of Eustachius. Although Willis's images lacked the artistic refinement of Eustachius's, they stood out for their ability to show the topographical relationships between visceral organs. According to Arráez et al. (2015), Willis also posited that the vagus nerve had greater relevance for lower animals compared to the sympathetic nerves.
One of his most important principles suggested that the brain influenced the cerebellum through the quadrigeminal plate and the superior cerebellar peduncles (Arráez et al., 2015). For this reason, the cerebellum coordinated the vagus and "intercostal" nerves, both involuntary. This influence commonly manifested in hysteria, causing difficulty breathing, chest pain, abdominal distension, as well as episodes of crying and laughing. Thus, Willis anticipated contemporary ideas about the physiology of emotions. Willis's description of the intercostal nerves has been scarcely addressed by medical historians. However, these nerves play a fundamental role in his neurology. According to Arráez et al. (2015), Willis believed that through these nerves, which connect the brain with the heart and lower viscera, the brain regulated the passions and instincts of the lower body.
The Accessory Nerve
Willis was the first anatomist to describe and illustrate the accessory nerve as an independent nerve (Arráez et al., 2015). During his studies, he observed that in fish and poultry, the accessory nerve supplied the fins and wings, unlike in humans and other mammals, where this nerve is related to the neck muscles. According to Arráez et al. (2015), the temporary connection between the accessory nerve and the vagus nerve caught Thomas Willis's attention, leading him to speculate on how the brain responds to fear and other emotions that influence the muscles of the neck and arms.
The Cranial Nerves
Willis made important contributions to the naming and numbering of the cranial nerves (Arráez et al., 2015). From Galen until the 16th century, these nerves were referred to as "cerebral nerves." According to Arráez et al. (2015), Willis fixed the origin of these nerves inside the skull, stating that the nerve pair is born within the skull.
Willis's popularity helped consolidate a new classification composed of nine cranial nerves (Arráez et al., 2015). In accordance with Arráez et al. (2015), his classification of cranial nerves was a marked improvement over its predecessors, as it included nine cranial nerves, most of which are recognized today.
In Willis’s scheme, the seventh nerve comprised the facial and vestibulocochlear nerves; the eighth nerve included the glossopharyngeal and vagus nerves, along with the cranial root of the accessory nerve; and the fourth nerve consisted of the hypoglossal nerve and the spinal root of the accessory nerve (Arráez et al., 2015). This classification remained in use for the next 114 years until 1778 when Sömmering introduced the current classification of 12 cranial nerves. In fact, according to Arráez et al. (2015), Willis's work was so popular in England that some English publications continued to use his classification until the end of the 19th century.
The Cerebral Arterial Circle
In his work "Cerebri Anatome," the first complete illustration of the arterial anastomosis is presented, depicted as a closed circle at the base of the brain (Arráez et al., 2015). However, it should be noted that Willis never claimed to be the discoverer of this arterial circle. His immediate successors in this field did not mention him, or anyone else, as responsible for the discovery of the arterial circle, although most commented, either appreciatively or critically, on his work, particularly regarding the description of the cerebral arteries. Despite this, Willis was the first to understand the functional and pathological importance of this arterial circle. As an academic physician and pioneer in translational research, he conducted experimental surgeries to demonstrate cerebral compensation mechanisms, also identifying the blood-brain barrier. According to Arráez et al. (2015), Willis suggested that only the smallest particles, necessary for rapid nervous function, could pass from the blood to the brain.
Legacy
His name has endured primarily for his description of the Circle of Willis, an arterial structure at the base of the brain (Molnar, 2004). The idea of the circle arose during the autopsy of a man who died of stomach cancer when Willis was able to demonstrate its functionality by tracing the path of a post-mortem ink injection. His achievements are remarkable, especially considering that he made his observations by dissecting unfixed brains, some of which must have been in severely deteriorated conditions. During these studies, according to Molnar (2004), he redefined the cranial nerves, surpassing the classification established by Galen.
In this regard, he accurately identified the first through sixth cranial nerves as they are known today (Molnar, 2004). Although he described the seventh nerve as the auditory nerve, with two branches, he identified the eighth as the vagus nerve, recognizing its branches extending to the heart. Along with Richard Lower, they demonstrated the functions of the vagus nerve through experiments on dogs. He also discovered the spinal accessory nerve, and his illustrations depicted the glossopharyngeal and hypoglossal nerves, though with different terminology than what is used today, and he highlighted the importance of the medulla oblongata in regulating the functions of the heart, lungs, and intestines. According to his observations, as referenced by Molnar (2004), nerve impulses were transmitted from the brain, and "animal spirits" were reflected in the periphery from the striated body.
It is surprising that his theories on the transmission of nerve impulses anticipated the discovery of electrical currents (Molnar, 2004). Additionally, he proposed that higher cognitive functions originated in the convolutions of the cerebral cortex, an innovative idea for his time. At that time, the dominant view was Galen’s, who believed that the fluid-filled cavities in the brain contained a substance known as "animal spirits," which was considered the final product of a perfect distillation. It was believed that three cells were involved in cognitive functions: the first, the sensus communis, received sensory signals; these signals were mixed and passed to the middle ventricle, where reason, thought, and judgment were processed. Finally, memory was formed in the third ventricle. According to Molnar (2004), this paradigm was challenged when da Vinci discovered that most sensory nerves led to the third ventricle, suggesting that the sensus communis resided there.
On the other hand, Willis was a pioneer in the study of disorders such as sleep, sleepwalking, insomnia, narcosis, and lethargy, linking lethargy to obstructive hydrocephalus, brain tumors, and strokes (Molnar, 2004). Additionally, as noted by Molnar (2004), by performing dissections on his own patients, he sought to correlate psychiatric symptoms, such as mania, melancholy, and hysteria, with specific brain pathologies.
References
Arráez, L., Navia, P., Fuentes, T., & Bueno, J. L. (2015). Thomas Willis, a pioneer in translational research in anatomy (on the 350th anniversary of Cerebri anatome). Wiley Online Library. Recuperado 13 de enero de 2022, de https://onlinelibrary.wiley.com/doi/full/10.1111/joa.12273
Campohermoso, O. F., Solíz, R. E., Campohermoso, O., Flores, R. I., & Huallpara, V. (2019). Tomas Willis, neuroanatomista y padre de la neurología. Scielo. Recuperado 12 de enero de 2022, de http://www.scielo.org.bo/scielo.php?pid=S1652-67762019000200013&script=sci_arttext
Fresquet, J. L. (2005). Thomas Willis (62-675). Historia de la Medicina. Recuperado 12 de enero de 2022, de https://www.historiadelamedicina.org/pdfs/willis.pdf
Molnár, Z. (2004). Thomas Willis (1621–1675), the founder of clinical neuroscience. Research Gate. Recuperado 12 de enero de 2022, de https://www.researchgate.net/publication/8666149_Thomas_Willis_1621-1675_the_founder_of_clinical_neuroscience
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