The Brain and the World: A History of the Brain

Violent Beginnings

Remember when you were a child playing with your parent's books? You would pull them out of the shelf, stacking them like bricks into towers or castles or raising them like walls. You probably knew that these books were important, but you lacked the skills to understand why. You probably understood that their texts held some kind of wisdom, but that it was out of reach. You may have realized that it was incomprehensible to you now, but that you might later could learn to understand the content of these bricks.

That is the paradox of neuroscience. Trying to grasp the importance of what is right in front of you, knowing well enough that you cannot possibly hope to understand all of it. You simply lack the skills to see through the bricks and read the text.

Our understanding of the mind is limited by our own cognition itself. Our insight into psychology and neurology is too often limited by our lack of knowledge. Our understanding of the brain is halted by our own insufficient mental capacities.

This paradox of neuroscience is appropriately illustrated by the story of Edwin Smith. And by the unknown author of the papyrus that holds his name.
Violent Beginnings - History of the Brain I

Violent Beginnings - History of the Brain I

In 1862 in Luxor in Egypt, Edwin Smith purchased a papyrus from the antique dealer Mustapha Aga. Although an egyptologist, Smith's knowledge of the hieroglyphs on the papyrus was insufficient, and he was unable to read the text. Like so many other scientists, he could not penetrate or interpret the subject before him, simply because he lacked skills. Edwin Smiths was unable to realize the value of his purchase.
He kept the papyrus in his own possession until his death, at which point his daughter donated it to New York Historical Society where the task of translating the hieratics was given to James Henry Breasted. It was soon realized that the papyrus was a medical text describing the diagnostics and treatments of 48 traumatic injuries. Dated to 1600 BCE, it is speculated that the papyrus may have been a manual of military surgery. The text not only includes the first recorded mention of the brain, but holds also the first neurologic examinations and diagnostic findings.

In much the same way it is argued that war is the catalyst of civilizations, it must be admitted that the neurological sciences are based on deficits and injuries of the brain. The Edwin Smith Papyrus illustrates this discouragingly well; written as a military necessity, it is violence and traumatic injury that passes knowledge of the brain through more than three millennia to our present.

Case 6:

If thou examinest a man having a gaping wound in his head, penetrating to the bone, smashing his skull, (and) rending open the brain of his skull, thou shouldst palpate his wound. Shouldst thou find that smash which is in his skull [like] those corrugations which form in molten copper, (and) something therein throbbing (and) fluttering under thy fingers, like the weak place of an infant’s crown before it becomes whole [...] (and) he discharges blood from both his nostrils, (and) he suffers with stiffness in his neck, [thou shouldst say]: An ailment not to be treated.

In the commentary, Breasted cannot conceal his excitement of identifying the word:

as being “the earliest reference to the brain anywhere in human records.” The description is however rather disgusting, and the importance of this pulpish organ slips the author of the papyrus. Nevertheless, the text realizes that a trauma of this severity cannot be treated with any favorable outcome. It is an ailment "not to be treated," as so many battlefield surgeons have experienced since then.

The papyrus holds plenty of interesting details. In cases concerning head trauma, neck stiffness is often mentioned as “he suffers with stiffness in his neck, so that he is unable to look at his two shoulders and his breast.” This could easily be interpreted as the well known observation that head traumas with subarachnoid haemorrhage will cause neck stiffness in the patient. This finding is still a key diagnostic in clinical neurology today.

It also describes epileptic seizures following head trauma as a patient “shudders exceedingly”, realizing that this is “an ailment which I will contend. [...] thou shouldst not bind him, (but) moor (him) at his mooring stakes until the period of his injury passes by.”

And in case 20, like the child playing with books, the battlefield surgeon authoring the papyrus was on the brink of a very important realization. Describing a head trauma penetrating the temporal bone, it is noted that “if thou ask of him concerning his malady [...] he speak not to thee.” The description of speechlessness is exclusively limited to the traumas at the temple, and the conclusion that the temporal part of the brain holds the capacity for speech, seems imminent. However, this concept of cortical localization was missed by the author.
The Edwin Smith Papyrus reflects our current knowledge that the centre for speech is located in the temporal lobe of the human brain. But the idea that certain areas of the brain controls specific mental functions, slips the author. The concept of cortical localization would not emerge until the late 19th century. At that point it would be exactly the temporal lobe and the localization of speech that fascinated anatomist Paul Broca.

Pulp Appendix

The human brain is a yellowish greyish pulp overspread with small capillaries. You can hold it in one hand like a ball. It is not as soft as you would imagine, and not as light as you might think. You can cut it open, studying the fine structures of white and grey foldings in recognizable patterns. You can fry it with vinegar and garlic, and it will taste like vinegar and garlic.

What does it do?

Aristotle thought the function of the brain was to cool the blood. It is easy to see how this conclusion could be reached in an ancient world struggling with the interpretations of physiology. The pounding of the heart as an emotional response would easily prompt the idea that the heart was the seat of the soul. Blood was supposedly warmed in the heart, flowing through blood vessels to heat other organs. With the abundance of vessels in the skull and capillaries spreading out like a delta floodplain around the brain, it must have been an obvious assumption that blood could be cooled in this gooey mass, like hot water flowing over cold rocks.

Other physicians interpreted the anatomy differently. Based on the anatomical observations that the optic nerves connect the eyes with the brain, Alcmaeon of Croton recognized the brain as the organ of perception. Alcmaeon was also the first to identify the eustachian tubes linking the inner ear to the nasal cavity. These observations of pores, tunnels, chambers and canals of the skull must have led him to the obvious assumption that the brain is the centre of the senses.

In Alexandria, Herophilos and Erasistratus mapped the nerves leading from the brain to the muscles and discovered the difference between sensory and motor nerves. Herophilus in an apparently arbitrary insight located the soul to the fourth ventricle of the brain.

No text by Alcmaion or by Erasistratus exists in its entirety, but they are quoted by another important physician, the roman Galen. His teachings on human physiology and humorism would influence Western thinking for centuries. While working as a physician to the gladiators at Pergamon, like the Egyptian battle surgeon milleniums before him, Galen recognized that a blow to the head would cause the gladiator to pass out. He concluded that the brain must be the seat of consciousness.

The Rete Mirabili. In sheep.

Although an admirer of Aristotle, he opposed the idea of the brain as a cooling organ secondary to the emotions of the heart. And although schooled in the Aristotelian principle of recognizing only what could be experienced by the senses, Galen did publish a lot of unsubstantiated speculations. Fascinated by the rete mirabili, a complex of arteries and veins covering the brain at the basis of the skull, he wrote “[it] is not a simple network but (looks) as if you had taken several fishermen’s nets and superimposed them. [Y]ou could not compare this network to any man-made nets, nor has it been formed from any chance material. Nature appropriated the material for this wonderful network.” He excitedly concluded that vital spirits were produced in the heart, transported by the carotid arteries to the brain, and transformed to the highest spirits of man in the rete mirabili.

Galen could easily have been proven wrong though; had he dissected gladiators instead of sheep, he would have realized that the rete mirabili is found in only some mammals, but not in humans.

Other attempts were made. Leonardo da Vinci contributed to neuroanatomy with impressive drawings, beautiful and with an unmistakably Leonardian attention to detail. Using hot wax, he casted the ventricles of the brain, producing unprecedented anatomical insight. He’s idea that three ventricles held sensation, intellect and memory respectively, was however pure speculation and guesswork.

For centuries the comprehension of the human mind was based on anatomy alone. It would require the combination of anatomy and clinical findings to localize cognitive functions and substantiate our knowledge of the brain.

III

Disappointing Anatomy

Gijsbert Calkoen has gone down in history as a disappointed man. Immortalized by Rembrandt in 1656, the Dutch surgeon embodies the perplexity of the brain, and the frustrations felt by physicians through centuries.

But to understand his disappointment, we need first to explore an earlier painting by the same artist.

“Anatomy lesson of Doctor Nikolaes Tulp” is considered Rembrandt's breakthrough. At the age of 26, he was invited to depict a public dissection performed by the Amsterdam Guild of Surgeons. At this time, dissections of humans were considered a sin by the church. But a loophole was found by accepting the dissections of criminals - implying that criminals were inhuman. Annually, the public was invited to attend for a small fee, and on this occasion in 1632, the young and promising painter from Leiden was invited to preserve the moment. We know the name of every doctor in the picture, we know the name and the crime committed by the unfortunate corpse, and we guess that the book in the lower right corner is “De humani corporis fabrica” by Vesalius.

But all these details and facts are not what I like about this painting. What I like, is what most people like, and probably what the artist himself liked. What I like, is the fascination of anatomy. Look at how excited these doctors are about the tendons and muscles of the arm. As if they are looking upon the work of creation itself. And indeed, when examining the forearm you get a very palpable idea about how the human body works. You can pull a tendon and see the fingers move, and you can find the insertions of muscles onto the bone and make every joint work. For a 17th century doctor, this anatomy lesson would be a testimony of divinity.

We still admire the elegance of anatomy. Four hundred years later, this painting still fascinates as an example of how easily nature reveals itself. It is easy to marvel in the wonder of the human body while ignoring the inaccessible areas.

But the difficulties of anatomy and physiology were pointed out by Rembrandt just 24 years after the first painting. Now a mature artist, in “Anatomy lesson of Doctor Deijman” Rembrandt focuses on the most complex of organs; the brain.

Although partially destroyed by a fire in 1723, the painting is still beautiful, positioning the unfortunate criminel as a victim in an obvious tribute to Andrea Mategna’s painting “The Lamentation of Christ”. But instead of the mourning Mary, we find to the left the disappointed Gijsbert Calkoen. The Dutch surgeon has been given the appalling task of holding the skullcap of the executed criminal, but this doesn’t seem to bother him much. Instead he is distressed by the inaccessible anatomy of the brain. There’s nothing but a greyish yellow pulp of fat, some fluids and tiny blue vessels.

You almost feel sorry for him. Did he really think he could just open up the skull and see how the brain works, like he did with the arm? Maybe he thought there would be strings and gears and small light bulbs, that he could just pick it apart in some frankensteinian reversed engineering. Well, he was wrong. The brain does not reveal itself by inspection. It would be another two hundred years before we would even begin to peek at the underlying mechanics and functionality of the brain.

Map of Darkness

...with a certain eagerness [he] asked me whether I would let him measure my head. Rather surprised, I said Yes, when he produced a thing like calipers and got the dimensions back and front and every way, taking notes carefully.

In Joseph Conrad’s “Heart of Darkness” (1899) the narrator Charles Marlow has his head measured by a doctor. Claiming the measurement to be “in the interest of science”, this example of craniometry is central to the novel's exploration of the difference between "civilized people" and those described as "savages." The examination is performed prior to Marlows departure for Congo, suggesting that the characteristics of the adventurous narrator should be visibly measurable by the size of his skull.

The pseudoscience of phrenology suggested that specific personality traits could be identified by measuring bumps on the skull. Developed by Viennese physician Franz Joseph Gall (1758 - 1828), it rested on the idea that specific areas of the brain had specific functions. This was a novel concept, far from the perception of the brain as a fatty pulp, as exemplified in Rembrandt’s anatomy. The concept was met with opposition from established physiologists. Drawing on the claim by Descartes that the soul is immaterial and indivisible, it was considered impossible that the brain did not function as a united entity. That certain areas of the brain should be dedicated to specific tasks, was an appalling idea to conservative doctors.

Though the idea of cerebral localization later proved correct, the locations of the specific mental faculties in the phrenologic map of the brain were unsubstantiated. For instance, Gall localized “the love of children” at the back of the brain, and the ability for reasoning would be found at the frontal parts. Unsubstantiated was also the idea that mental qualities were determined by brain size and that the overlying skull fitted the brain like a glove. In phrenology, personality traits could be determined simply by measuring the area of the skull overlying the corresponding area of the brain. The bumps and dents in the cranium would serve as a map of the underlying personality. Gall was notoriously known for his collection of skulls.

Phrenology had its prime during the Victorian era when people would consult physicians and have their skull measured and mapped in the effort to learn about their own personality. It would later be applied to criminology, most infamously exemplified by Italian physician Cesare Lombrose who would postulate that criminals were “subhumans” identifiable by physical features of the skull and face. Phrenology would also provide a justification of European racism in its idea that certain physical features were suggesting an underlying character. In effect, the physiognomics of Europeans was interpreted as a more “civilized character” than lesser evolved “savages”. The racism inherent in phrenology is exemplified in Conrad’s work cited above and later also in the Quentin Tarantino movie “Django Unchained”.

Apparently Joseph Conrad’s doctor predicted the nonsense of phrenology. His measurements were futile, he admitted to Marlow, as “the changes take place inside, you know.”

And I hate to reduce Joseph Conrad’s “Heart of Darkness” to a piece about phrenology. All debates about racism set aside, this novel is a masterpiece of early existentialism, and I have loved it since introduced to the line “I have wrestled with death. It is the most unexciting contest you can imagine.” Thank you, Conrad.

As a young doctor for reasons now inexplicable to me, I one morning managed to show up early for work. And stranger still, so did a few other young doctors. So, unlikely as it was, there we were, sitting around the conference table at a small neurological department in Denmark, drinking coffee, chatting, waiting for the senior neurologists. At the middle of the table stood a ceramic phrenology head, and we found it easy to joke about the foolishness of phrenology. We joked about rich Viennese women going to the phrenologist to have their skull examined in an obvious sham driven by the Barnum effect. But a wiser colleague said, “Well, they were probably no different from people of all times; just very interested in knowing something about themselves.” We all silently agreed and drank our coffee.

It is easy to criticize phrenology. But phrenology did have one thing going for it; it did propose the idea that certain areas of the brain are dedicated to specific tasks. This concept of cerebral localization would push neurology towards our current understanding of the brain. Although unsuccesfully introduced by Gall, the paradigm shift was later convincingly proved by Paul Broca.

Unuttered Language

In 2007, Professor Paul de Saint-Maur was travelling through Paris with a peculiar piece of cargo. From its usual resting place at Musee Dupuytren to the Neuroradiology Department at Hôpital des Quinze-Vingts, the professor brought with him a brain. Probably the most important brain of the 19th century. Not the brain of Napoleon or Marx or Darwin, this brain had once rested in the skull of an epileptic craftsman. His name was Louis Victor Leborgne, but the scientific community of 1861 had come to know him as “Tan”.

In the first half of the 19th century, the paradigm of cerebral localization was heavily debated. The idea that specific areas of the brain served specific functions had been introduced by phrenologist Franz Joseph Gall, but because phrenology was an obvious sham, serious scientists struggled to reintroduce cerebral localization as a credible concept. The conservative view was that the mind was indivisible, and that the brain as a whole performed the faculties of perception, memory and intellect. The Tan case would shift the paradigm in favor of localization.

Louis Victor Leborgne had lost the ability to speak at the age of 21, probably due to epileptic seizures. He was hospitalized at Bicêtre Hospital in 1840 and would stay there for the remaining twenty-one years of his life. Though able to understand words spoken by others, he could utter only the one syllable “tan”, earning him that nickname throughout the hospital. In 1861, now a dying man, Leborgne was transferred to the department of physician Paul Broca.

At this point in his life, Broca was a highly respected physician, anatomist and anthropologist. He had been the vice president of Society Anatomique de Paris, he had founded the Société d’Anthropologie de Paris, and he had contributed extensively to the scientific community. Broca saw the speech impediment as an easily accessible test case for localization of language. In Broca’s own description of Tan, “[he] could no longer produce but a single syllable, which he usually repeated twice in succession; regardless of the question asked him, he always responded: tan, tan, combined with varied expressive gestures.”

When Tan died six days later, Broca performed the autopsy and identified a lesion in the left frontal lobe.

A few months later, Broca encountered another patient with a similar disorder. After suffering from a stroke, Lazare Lelong could utter five words; “oui” and “non” meaning yes and no, “toujours” meaning always, “Lelo” as a mispronunciation of his own name, and “tois” as a mispronunciation of “trois” meaning three and which he would substitute for any number. At autopsy, Broca found a lesion approximately in the same region as the first case, leading him to the conclusion that the left frontal lobe was indispensable to the ability to articulate language.

Broca presented the findings to the Société d’Anthropologie and to the Society Anatomique de Paris. The timing was right, and the respect for Paul Broca in the scientific community certainly aided the support for his conclusions. In the following years, Broca was presented with similar cases of aphasia and found in most of the cases a lesion at the same location in the left frontal lobe. This part of the brain is now termed Broca’s Area in a tribute to the man who not only localized language, but shifted the paradigm of neurology.

In the following decades, specific cognitive functions were localized to specific areas of the brain; Vision and the interpretation of sight was localized to the posterior parts of the brain, memory and the ability to learn was localized to the deep hippocampal structure, motor functions of the right part of the body was localized to the left hemisphere and vice versa.

High-resolution MRI of the preserved brain of
Leborgne. In Dronkers et al, 2007.

For more than a century, neurologists excelled in the art of localizing cerebral lesions based on clinical findings. It would take a new technological tool to support and extend these understandings. The tool was imaging, and this was what prompted Professor Saint-Maur to carry the brain of Leborgne through Paris. Broca had preserved the brains in alcohol, allowing posterity to examine them. His intention was fulfilled in 2007 when MRI scans were performed. The images revealed lesions extending deeper into the brains than originally reported, demonstrating areas of language function that had been inaccessible to Broca. The neuroscientists at the Neuroradiology Department at Hôpital des Quinze-Vingts acknowledged that Leborgne and Lelong “speak to us more eloquently now than they could over 140 years ago.”

Ode to Cajal

It looks like an impenetrable forest. Or maybe an enchanted underwater world. It is certainly beautiful, it is unmistakably a work of art.

Growing up in a small town in Spain, Santiago Ramón y Cajal (1852 - 1934) wanted to be an artist. He spent most of his childhood drawing, painting and taking photographs.

But his father had other ambitions. He was a doctor teaching anatomy at the university of Zaragoza, and he wanted his son to pursue a career as physician. Asking his son to help draw dissections for an anatomical atlas, he managed to arouse the interest of the young aspiring artist. In the words of Cajal himself: “My pencil, which was formerly the cause of so much bitterness, at last found grace in the eyes of my father [...] Gradually, my anatomical watercolors grew into a very large portfolio of which my father was quite proud.”

Cajal gave up his artistic talents for a while and enrolled at the medical school in Zaragoza.

After a few years practicing as a physician, Cajal turned to histology; the microscopic examinations of bodily tissues. Using a method developed by Camillo Golgi (1843 - 1926), Cajal improved the technique of staining brain cells to be viewed in the microscope. And applying his talents for painting, he would easily transfer his observations in the microscope into histological drawings. His illustrations would soon help answer some of the most important questions in neurobiology at that time.

A century earlier, Luigi Galvani (1737 - 1798) had established that nerves transmit information by electrical impulses. But how the information was passed from cell to cell was unknown. Further, the microscopic structure of the brain and nervous system was not yet recognized; it was unclear whether it was made of individual cells or by an extensive continuous network. Supporters of the reticular theory argued that the nervous system was formed by an undivided plexus of continuously interconnected cells - an argument reflecting the debate in functional neurology about cortical localization and the indivisibility of the brain.

Golgi had already described brain cells as composed of a cell body (soma) with a number of extensions protruding from it. Most protrusions were dendrites, but one long extension formed the axon and branched out to connect with other cells. It was also recognized that signals ran from the dendrites through the cell body and out the axon.

With the improved techniques of staining and imaging, Cajal was now able to identify discrete neurons in the brain. He realized that they were individual cells divided by gaps. Like trees in a forest, they could branch and interweave, but never fuse or unite.

Cajal presented his findings in Berlin in 1889. And although disapproved of by Golgi, the presentations gained the support of many others. German anatomist Wilhelm Waldeyer synthesized the ideas from cell theory with the observations made by Cajal and formulated the neuron doctrine. In fact, Waldeyer learned spanish just to fully appreciate the works of Cajal. He also coined the term neuron for the cells of the nervous system, including brain cells and nerves.

This up-to-date illustration of the neuron may be

correct in every detail; the cell body, the axon and

the synapsing with another neuron. But it lacks

the aesthetic simplicity of Cajal's.

Waldeyer’s neuron doctrine was a new paradigm. In short, it stated that the nervous system is composed of individual cells. Like every other cell in the body, the neuron is a single entity. And although connected in an intricate network, the neuron works independently.

This doctrine was proved with the introduction of electron microscopy in the 1950es. This technology confirmed the existence of individual neurons in the nervous system. It also demonstrated a gap between the axon on one neuron and the dendrite on another. This gap is called the synapse, and it transmits the signal from one neuron to another by releasing a chemical substance (a neurotransmitter) into the gap. When an electric impulse travels down the axon, the neurotransmitter is released into the synapse and is then picked up by receptors on the dendrite of the receiving neuron. The signaling between neurons via synapses is the mechanism of information transmission in the nervous system. The human central nervous system holds around 100 billion neurons, each connecting to other neurons with several thousand synapses. And the plasticity and ability to form new synapses from one neuron to the another is probably what enables the brain to learn and to remember.

Cajal never saw his observations confirmed by electron microscopy. But he dedicated his life to the histology of the brain, comparing the cerebral cortex to “a garden filled with innumerable trees, the pyramidal cells, which can multiply their branches thanks to intelligent cultivation, send their roots deeper, and produce more exquisite flowers and fruits every day.”

Cajal was a poet among scientists.

VII

Picture this

I once travelled to Florence by train. Arriving late in the afternoon, I went by bus to Piazzale Michelangelo as recommended by the guide book. By the winding roads on the map, it was clear that the plaza was situated at a slope above the city, but the two-dimensional drawing could not prepare me for the sight of Florence. Leaving the bus, I walked over the plaza to the railing, watching the sun set over the red rooftops, turning Ponte Vecchio into a yellow glow and the river Arno into a stream of small golden ripples. A burst of laughter from three american women made me look up from the amazing view.

“I would just give so much money for a picture of your face right now,” the american closest to me exclaimed. I must have looked absolutely amazed and overwhelmed.

Another traveller experienced a similar revelation, although of much more importance than the amusement of American tourists. In 1967 during a walk in the British countryside, Godfrey Hounsfield came up with the idea that would transform two-dimensional X ray images into three dimensional maps of the body. As an engineer, Hounsfield had initially worked with radar and later with transistor computers. He combined this knowledge, realizing that by taking several X-ray pictures in different angles, it would be possible to compute an image of density rather than a projected outline of tissue. The principle was not much different from solving a Japanese picture puzzle or nonogram, except that it would require X-rays in multiple angles and extensive data processing.

It was like inventing the knot; it seems incomprehensible without prior knowledge, but once you realize, how it is done, it is so obvious that you might ask yourself "why didn't I think of this?"

The first device for computed tomography (CT) was built on a lathe and rigged to a mainframe computer. Hounsfield’s team used the brains of pigs and bulls for the initial experiments, and it took days of scanning to collect sufficient data. The specimens would decay during the process, leaving gas bubbles as artefacts on the images. But the images were impressive nonetheless.

It would take another few years to convince radiologists of the feasibility of CT-scanning, but in October 1971 at Atkinson Morley’s Hospital in London, the first patient was scanned. The woman had clinical signs of a frontal lobe tumour, and the CT-scan revealed just that. The surgeon removing the tumor noted that “it looks exactly like the picture.”

The results were presented in April 1972 at the Congress of the British institute of Radiology, and attendees would later recall the amazement in the room. The images were immediately recognizable as a three dimensional representation of the brain, and the utility was obvious. It offered an insight into brain pathology in the living patient, and it produced evidence of clinical findings.

Today, the diagnostics and treatment of neurological diseases rely widely on imaging by CT-scans - and on the later developed Magnetic Resonance Imaging (MRI).

Imaging is just one example of a medical technology requiring not only physicians, but also engineers, physicists, mathematicians and several other professions. Neurology has been changed from a clinical practice to a field of modern technology.

Within the last two centuries, our understanding of the brain and the cognitive functions has changed from unfounded guesswork to the disciplin of neuroscience.

______________________

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