Wilder Penfield, Neural Cartographer

The patient lies on the operating table, with the right side of his body raised slightly. The anaesthetist sterilizes his scalp and injects it with Nupercaine to produce analgesia - the patient will remain fully conscious throughout the procedure. Behind the surgical drapes, three large incisions are made in his scalp. A large flap of bone is then cut from his skull, and turned downward to expose the surface of his brain. The ultraviolet lights which illuminate the operating theatre and keep the air sterile are positioned in such a way that they do not shine directly upon the cortex.

Using an atomizer, the surgeon sprays a small amount of Ringer's solution onto the brain substance, to keep it moist. He then manoeuvres an electrode attached to a special holder which is clamped to the margin of the opening in the skull, so that it comes into direct contact with the brain. He adjusts a dial on the stimulator to 0.5 volts, and a current with a frequency of 60 cycles per second is applied to the patient's cortex. After asking the patient if he feels anything, and getting a negative response, the surgeon reaches for the stimulator again. He turns the voltage dial up a notch so that it reads 1 volt, and applies another current. This time, the patient reports a tingling sensation in his face and, when asked to indicate exactly where, raises an arm and points to his left cheek and temple.

The surgeon dictates these results, via a microphone, to a secretary in the viewing stand. He then places a small numbered ticket on the part of the brain he has just stimulated, and manipulates the electrode again, bringing it to bear on another point several millimetres away from the last. Upon application of current, the patient reports a sensation on the inner surface of his left forearm, and there is a slight movement of his left thumb. He knows that his face, arm and thumb have not been touched; although aware that his thumb moved, he knows fully that he did not will the action, and realizes that he can reach across with his right hand to prevent the movements.

The patient is an 18-year-old male with a small tumour in his right frontal lobe. It is an unusual type of hemangioma that may have been present since early on in the patient's life, located immediately adjacent to the primary motor cortex, one of the regions of the brain which controls voluntary movement. It therefore causes waves of abnormal electrical activity to sweep across the motor cortex, leading to epileptic seizures which begin with a sensation in the left side of the body and are followed by rapid, jerking movements of the left arm and left leg. The patient's epilepsy is intractable - his symptoms were not alleviated by phenytoin, the most widely used anticonvulsant at the time - and so, as a last resort, it has been decided that his tumour should be surgically removed.

The surgeon, Wilder Penfield, faces a major challenge. Because the motor cortex controls the muscles in the throat and tongue which are needed for articulation, as well as those involved in limb movements, he must remove the tumour without damaging these parts of the cortex, in order to avoid paralysing the patient, or leaving him with a speech deficit. Using a technique he had developed more than 20 years earlier, Penfield identifies these crucial areas by electrically stimulating the tissue surrounding the tumour with his electrode. This elicits a movement in that part of the patient's body controlled by that specific region of cortex. By carrying out multiple stimulations and meticulously recording the patient's response to each one, Penfield can identify the abnormal tissue causing the patient's seizures and delineate those areas surrounding the tumour which he must avoid damaging.

Penfield was one of the greatest neurosurgeons of the twentieth century, whose pioneering work revolutionized the discipline. His technique for treating intractable epilepsy, which was developed with his colleague Herbert Jasper, came to be known as the Montreal Procedure; it was ground-breaking because it applied of the principles of neurophysiology to the practice of neurosurgery. In using this technique to carry out presurgical evaluations of his patients, Penfield amassed a large body of data, which together constituted the first detailed large scale functional map of the human cerebral cortex. Penfield not only revolutionized neurosurgery, but also left a long-lasting influence on related fields such as neurology and neuropsychology. But less well known is that he was also a talented researcher whose experiments resolved a debate about the cellular structure of the brain.

The Montreal Procedure was based upon the earlier work of a number of great clinicians and investigators. One of these was John Hughlings Jackson (1835-1911), the father of English neurology. Prior to Jackson's work on epilepsy, seizures were thought to originate in the medulla oblongata, the lower part of brain stem which is attached to the spinal cord. In the 1860s, while at the National Hospital for the Paralysed and Epileptic (now the National Hospital for Neurology and Neurosurgery) in London's Queen Square, Jackson observed and described numerous patients with epilepsy. Some of these had sustained blunt head injuries, which, as Jackson noted, usually resulted in first seizures, and then paralysis, in the opposite side of the body. Based on these clinical observations, Jackson concluded that seizures were the result of abnormal electrical discharges in the cerebral cortex.

Jackson also observed that patients with an external injury lying over the posterior region of the frontal lobe usually experienced speech difficulties, either during or in between their seizures. These observations were consistent with those of the French physician Paul Broca (1824-1880), who had been working with stroke patients and examining their brains after they died. Aphasia, or an inability to speak, is a common symptom of stroke, and Broca noted that his patients consistently presented with damage in the same discrete region of the left frontal lobe. He therefore concluded that the faculty of speech is located in that part of the left hemisphere, which subsequently came to be known as Broca's area.

In 1870 the German physiologists Gustav Theodor Fritz (1838-1927) and Julius Eduard Hitzig (1838-1907) performed the first direct electrical stimulations of the mammalian cerebral cortex. Using electrodes, they stimulated the front half of the brains of lightly anaesthetized dogs, and found that this produced movements of the leg on the opposite side of the body. Stimulation of the posterior half, however, did not elicit any movements. Several years later, this work was extended by the Scottish experimental neurologist David Ferrier, who obtained similar results in both dogs and monkeys. Ferrier also noticed that lesioning the frontal cortices of his animals led to a loss of the movements elicited by electrical stimulation.

These early studies, together with case studies of brain-damaged patients such as Phineas Gage, strongly suggested that the cortex of man and animals was divided into functionally distinct areas and, as Ferrier said at a meeting of the Royal Society, paved the way for "a scientific phrenology". When Penfield began his career as a surgeon, the ground work had thus already been laid, but the human cerebral cortex was still largely uncharted territory. Using the technique he and Jasper developed, Penfield made the "scientific phrenology" to which Ferrier had alluded a reality. Today, he is best known for the functional mapping of the human cortex, but he also made a significant contribution to the then emerging field of neurocytology. Before drafting his map of the human cortex, Penfield surveyed the brain's microgeography, and fully characterised, for the first time, a type of cell called the oligodendrocyte.

Although Penfield studied under Harvey Cushing, the father of modern neurosurgery, it was the eminent British physiologist Sir Charles Sherrington who inspired him to become a surgeon. In 1914, as an undergraduate medical student at Princeton, Penfield secured a Rhodes Scholarship, and enrolled in Sherrington's mammalian physiology course at Merton College, Oxford University. This 3 year course consisted of a series of what Sherrington called "exercises", involving various procedures, such as the dissection of the peripheral nerves and spinal cord of animals. Penfield thus learned how to handle living tissues with the greatest of care, and how to dissect them with fine surgical instruments while preserving the vital functions of the experimental animals. 

Upon completing this course, Penfield finished the clinical part of his medical training at Johns Hopkins University, and, after graduating in 1918, was interned at Peter Bent Brigham Hospital in Boston, where he did his apprenticeship with Cushing. He had been interested in epilepsy since his undergraduate years, during which he had read Jackson's work. After finishing his internship, Penfield took a position at the New York Presbyterian Hospital, and it was here that he first operated on epileptic patients.

Penfield believed that a class of non-neural cells called microglia were involved in the formation of the scars which develop in damaged brain tissue. These scars form at the site of an injury and are part of the healing process, but they are also the origin of the abnormal electrical activity underlying epileptic seizures. In the early 1920s, he was therefore looking for a method to stain scarred brain tissue, in order to gain a better understanding of the origins of epilepsy. His work reached a dead end, however, because he could not find a way to stain the non-neuronal cells. At Oxford, Penfield had experienced some problems staining neurons, and he remembered that Sherrington had told him not to give up until he had tried the methods developed by the outstanding Spanish neuroanatomist Santiago Ramon y Cajal.

In the late nineteenth and early twentieth century, Cajal had used a modified version of a staining technique developed by Camillo Golgi to carry out a comprehensive and systematic study of the cellular architecture of the nervous system in a wide variety of species. It was largely because of his work that the Neuron Doctrine, which states that the nervous system consists of cells instead of a continuous network of tissue, came to be accepted in the 1890s. As well as describing the structure of neurons and astrocytes in great detail, Cajal also identified a mysterious and poorly understood "third element" of the nervous system, which apparently consisted of 2 types of non-neuronal cell that were different from astrocytes. Later, his student Pio Del Rio-Hortega developed a technique for staining one of these, the microglial cells, and published detailed drawings of their structures. However, his method did not stain the other type well, so they remained improperly characterized. They were, Penfield wrote, "no more than ghosts".

The cells that Penfield was most interested in were amongst this third element, so he decided that he needed to travel to Spain to work with Cajal and Rio-Hortega, to "study the brain of man, and then move on to the effects of disease on the brain".  In January 1924, Penfield approached Allen Whipple, chief of surgery at the Presbytarian Hospital, to try to obtain funds. Whipple was supportive, and contacted Mrs Percy Rockefeller, on whose daughter he had recently operated free of charge. He managed to secure a grant from her, and funds were also obtained from several other benefactors. Some time later, Penfield set sail to Spain with his wife and two children. He was so enthusiastic that he and his family embarked on their journey before receiving any confirmation - it was only when they were half-way across the Atlantic that Rio-Hortega replied, in a telegram containing a single word: "venga" ("come").

Penfield spent 5 months working with Cajal and Rio-Hortega at the Laboratorio de Histopatologia in Madrid, and the collaboration proved to be a successful one. Penfield learned Rio-Hortega's "ammoniacal silver carbonate" method for staining the non-neuronal cells, then modified and improved it, thus developing the first reliable stain for oligodendrocytes. Using his new technique on brain tissue from rabbits, Penfield was able to provide a detailed description of the cells. He published his results, complete with beautiful diagrams of the cells, in a seminal 1924 paper in the journal Brain:

Before Penfield's visit to Spain, whether oligodendrocytes constituted a distinct type of cell in the central nervous system was still a matter of debate. Unable to stain them properly himself, Cajal argued that they were not, and that the "third element" of the nervous system consisted solely of microglia. Penfield's research showed that oligodendrocytes were indeed distinct from other types of glial cells, and that they could be distinguished from astrocytes because they lacked "sucker feet" (structures which today are called vascular endfeet). It also clearly showed that there was a difference in how astrocytes and the other types of glial cells are related to the blood vessels in the brain: whereas both oligodendrocytes and microglia contact blood vessels with their cell bodies, astrocytes do so only with their endfeet.

Penfield and Rio-Hortega also investigated how the non-neuronal cells in the brain are involved in pathological processes, and gained considerable insight into scar formation following injury. The reason that Penfield had travelled to Spain was to elucidate this process. The observations he and Rio-Hortega made of these processes were published 3 years later. Their description of how scar tissue forms in the brain is very similar to that of modern neuropathologists:

Upon his return to New York, Penfield resumed his work at the Presbytarian Hospital. Several years later, in 1927, he decided to compile "a textbook on the general principles of neuropathology without describing specific diseases", with his colleague William Cone. Modestly, Penfield believed that others could write parts of the book better than he, and so wrote to a number of researchers asking them to contribute. By then, Penfield had made a very good reputation and was widely respected. All but one of his requests for contributions to the book were accepted. It was Cajal who refused the request to write a chapter, "saying he had advancing arteriosclerosis," Penfield explains, "the histologist's way of describing old age". Even so, Cytology and Cellular Pathology of the Nervous System was eventually  published in 1932; it was dedicated to Cajal, and instantly became both successful and influential.

Uncertain about his future in New York, Penfield had moved to Montreal in 1928, where he hoped to establish a neurosurgical unit with William Cone. Later that year, Penfield's sister Ruth developed a tumour, and he was called upon to surgically remove it. Ironically, her tumour was an oligodendroglioma, consisting of the very same cell type that Penfield had characterized while in Spain. On December 11th, 1928, Penfield performed a rather radical procedure to remove it, but he was unsuccessful - he did not remove it entirely, and it grew back some time later. In November of 1930, Cushing attempted a second operation, but she died the following year.

Shortly afterwards, Penfield visited the German neurologist and neurosurgeon Otfried Foerster, who showed him a method for excising scars from the brains of epileptics, involving the electrical stimulation of the cortex while the patient was under local anaesthesia. In 1930, the two of them published the first cortical map, albeit an incomplete one, based on the observations they made during over 100 operations. They also examined under the microscope the damaged tissues they removed from these patients, and so gained further understanding of the scar formation process:

Subsequently, Penfield received a $1,232,000 donation from the Rockefeller Foundation, and used it to establish the Montreal Neurological Institute (MNI) at McGill University. The Institute opened in 1934, with Penfield as its first director; he remained in that position until 1960. Under his direction, the MNI quickly became a centre of excellence for both the practice and teaching of neurosurgery. Just like its founder, the Institute was a pioneering place: Clarence Greene, the first Afro-American board-certified neurosurgeon in North America, trained there under Penfield between the years of 1947-1949, at which time the United States was still racially segregated.

With his expertise in neurocytology and neurophysiology, Penfield now considered himself as "a neurologist in action", and he set about working on a way to improve surgical treatments for patients with epilepsy. In his new position as director of the MNI, he was not constrained in his work, and so began to develop Foerster's method in the hope of improving the outcome of his operations. Perhaps he was compelled to do so because of his sister's death; more likely, given his long-held interest in epilepsy, he would have done this regardless.

Penfield used platinum electrodes with glass handles, sterilized by autoclaving before the operation, and attached by means of insulating wires to an instrument called a thyratron stimulator, with which the amplitude and frequency of the current were controlled. A local anaesthetic would be administered to the patient's scalp, and a craniotomy performed to expose the surface of the brain. First, small electrical stimuli, insufficient to elicit a response, would be applied to the cortex. The current would then be gradually increased until the patient gave a positive response. Usually, the first thing Penfield did was to outline the central sulcus, a deep chasm which separates the undulating folds of the frontal and parietal lobes. This served as a prominent landmark which enabled him to get his bearings as he navigated his way around this most complex of organs. 

The primary motor cortex, or precentral gyrus, is a strip of tissue lying immediately anterior to (in front of) the central fissure in the frontal lobe, and extending into its banks; it contains cells which send axons down through the spinal cord, where they form synaptic connections with the motor neurons which project out to the limb muscles. Immediately posterior to (behind) the central sulcus, in the parietal lobe, lies another strip of tissue called the primary somatosensory cortex, or postcentral gyrus, which receives tactile stimuli from the entire body. Flanked by these regions, the central sulcus could be found easily. A stimulus of sufficient amplitude, applied to the motor cortex, would elicit in the patient a movement of a specific muscle or muscles in the opposite side of the body. If applied on the other side of the central sulcus, the same stimulus would instead elicit the sensation of being touched, again in a specific part of the opposite side of the body.

In this way Penfield carried out, over the course of many years, a meticulous survey of the surface of the brain. For the patient lying on his operating table, the sensation elicited by electrical stimulation of a region of somatosensory cortex is indistinguishable from the one that occurs when the part of the body represented by that region is actually touched. In the latter situation, the pressure of a touch activates the nerve endings of the sensory nerves, which convey the information into the spinal cord and from there up to the brain. The sensation is only "felt" once the information reaches the cells in the somatosensory cortex. If those cells are instead activated by electrical stimulation, exactly the same sensation is felt. Because the patient is local anaesthesia, she would be fully conscious, and so able to report accurately where in her body she felt a sensation. Some of the verbal responses given by patients while Penfield pinpointed the central sulcus included: "I feel a numbness in my finger", "My right thumb is tickling", "I felt as though I could not speak" and "My tongue seemed to be paralyzed".

By recording the responses of his many patients, Penfield refined the cortical map produced earlier with Foerster. Each operation made possible the delineation of a previously unrecognized landmark on the map. When trying to remove tissue from a part of the brain he had not operated on before, Penfield would first stimulate the surrounding tissues and so begin to understand,  from the patient's responses, what their function might be. Every time a stimulus from the electrode elicited a response in the patient, he would place a small square piece of paper, numbered or lettered, on the exact point on the brain's surface. He also gave a running description of the details of the operation, so that they could be recorded by a stenographer and, after each stimulation, used a sterile paper and pencil to record the exact location on a sketch of the patient's brain (above).

One of the many significant discoveries Penfield was that the postcentral gyrus contains a somatotopic representation of the body. The body is faithfully mapped, in an orderly manner, onto the somatosensory cortex, so that inputs from adjacent parts of the body are encoded in adjacent parts of the strip. In almost every patient who presented with a tumour or scar tissue there, stimulation of a point located behind the ear invariably elicited a tingling sensation in the tongue. Stimulating the area slightly higher up evoked a tactile sensation in the lips. Application of a current further up always produced a sensation somewhere in the hand. Further up still, in positions successively closer to the brain's midline, the electrode would elicit sensations in the wrist, elbows, shoulder, trunk, hip and knee. Stimulation of the tissue lying on the medial surface, within the longitudinal fissure which separates the two hemispheres, produced sensations in the ankle and toes.  

Here is the case of a boy suffering from focal epileptic seizures which are characterized by a sudden sensation on the right side of his body and movements of the right hand. The first 14 responses were obtained by stimulation of the postcentral gyrus from above down and the remainder (beginning with the point labelled G) from the precentral gyrus, also from above down:

14. Tingling from the knee down to the right foot.

13. Numbness all down the right leg, excluding the foot.

12. Numbness over the wrist, lower border, right side.

11. Numbness in the right shoulder.

3. Numb feeling in hand and forearm up to just above the forearm.

10. Tingling feeling in the fifth or little finger.

9. Tingling in first three fingers.

4. Felt like a shock and numbness in all four fingers but not in the thumb.

8. Felt sensation of movement in the thumb.

7. Same as 8.

5. Numbness in the right side of the tongue.

6. Tingling feeling in the right side of the tongue, more at the lip.

15. Tingling in the tongue, associated with up and down vibratory movements.

16. Numbness, back of tongue, midline.

5. Numbness in the right side of the tongue.

(G) Flexion of knee.

18. Slight twitching of arm and hand like a shock, and felt as if he wanted to   move them.

2. Shrugged shoulders upwards; did not feel like an attack.

(H) Clonic movement of the right arm, shoulders, forearm, no movement in trunk.

(A) Extreme flexion of wrist, elbow and hand.

(D) Closure of hand and flexion of his wrist, like an attack.

17. Felt as if he were going to have an attack, flexion of arms and forearms, extension of wrist.

(E) . Slight closure of hand; stimulation followed local flushing of brain; this was repeated with the strength at 24. Flushing was followed by pallor for a few seconds.

(B) Patient states that he could not help closing his right eye but he actually closed both.

(C) Made a little noise; vocalization. This was repeated twice. Patient says he could not help it. It was associated with movement of the upper and lower lips, equal on the two sides.

Although the exact size of somatosensory cortical region devoted to each body part differed in size among patients, the sequence of sensations elicited by repeated stimulations that began behind the ear and moved successively closer to the midline was always exactly the same. The region of somatosensory cortex devoted to each part of the body was not found to be related to the size of that body part, but rather to its sensitivity. Thus the lips, tongue and hands are disproportionately represented in the somatosensory cortex, with the vast majority of the strip of tissue being devoted to them. Less sensitive regions of the body, such as the trunk, are represented by much smaller regions. 

Similarly, stimulations of the primary motor cortex elicited an invariant sequence of movements in Penfield's patients. A large area to the side of the motor cortex produced either movements of the jaw, lips or tongue when stimulated; sometimes stimulation would elicit salivation. The movements were similar to those produced during chewing or swallowing and sometimes made it difficult for the patient to speak. Stimulation further up almost always led to flexion of one of the digits; yet further upwards, to movements of the whole hand, wrist, elbow, and so on. In the motor cortex, the lips, tongue and hands are again disproportionately represented, because these parts of the bodies contain a large number of muscles. Penfield illustrated all these findings in the sensory and motor homunculi (singular homunculus, or "little man"), the well known visual depictions which show the areas of motor and somatosensory cortex devoted to each part of the body, and their proportions relative to one another.

We now know that the somatosensory system reorganizes itself following injuries such as stroke, and are beginning to understand the cellular and molecular mechanisms by which it does so. This reorganization occurs because the brain remains "plastic" throughout life, and in some cases leads to considerable recovery of function. Something similar takes place following amputation, and is widely believed to underly phantom limb syndrome, in which amputees experience sensations, including painful ones, from their missing limb. At the time, such processes were thought to be impossible - that the adult human brain is not plastic was one of the central dogmas of brain research, which persisted until relatively recently. Penfield, however, may have unknowingly observed functional reorganization of the cortex more than 70 years ago; he seems to be alluding to it in this passage: