“It is in the brain that the poppy is red, that the apple is odorous, that the skylark sings.”
—Oscar Wilde (1854–1900)

We moderns take it for granted that consciousness is intimately tied up with the brain. But this assumption did not always hold. For much of recorded history, the heart was considered the seat of reason, emotion, valor and mind. Indeed, the first step in mummification in ancient Egypt was to scoop out the brain through the nostrils and discard it, whereas the heart, the liver and other internal organs were carefully extracted and preserved. The pharaoh would then have access to everything he needed in his afterlife. Everything except for his brain!

Several millennia later Aristotle, one of the greatest of all biologists, taxonomists, embryologists and the first evolutionist, had this to say: “And of course, the brain is not responsible for any of the sensations at all. The correct view [is] that the seat and source of sensation is the region of the heart.” He argued consistently that the primary function of the wet and cold brain is to cool the warm blood coming from the heart. Another set of historical texts is no more insightful on this question. The Old and the New Testaments are filled with references to the heart but entirely devoid of any mentions of the brain.

Debate about what the brain does grew ever more intense over ensuing millennia. The modern embodiment of these arguments seeks to identify the precise areas within the three-pound cranial mass where consciousness arises. What follows is an attempt to size up the past and present of this transmillennial journey.

The field has scored successes in delineating a brain region that keeps the neural engine humming. Switched on, you are awake and conscious. In another setting, your body is asleep, yet you still have experiences—you dream. In a third position, you are deeply asleep, effectively off-line. What is more, I and others have labored on discovering critical brain regions that imbue us with specific forms of conscious experience: perceptions of the orange hues of a sunset, pangs of hunger or the stabbing pain of a toothache. Those are in the neocortex, the brain's outer surface, which generates the particular content of experience as it plays out from one moment to the next.

From Heart to Head

By and large, classical Greece and Rome were in thrall to cardio-centric thinking. The brain proper looked too mushy, coarse and cold to host the sublime soul. Yet some clinicians and anatomists had already deduced that the brain was intimately tied to sensation and movement. Two remarkable examples are the fourth-century B.C. work by Hippocrates—On the Sacred Disease—that combines a rejection of superstition in treating brain disorders with an accurate clinical description of epilepsy. Later, in second-century A.D. Rome, the renowned Greek physician Galen became, in essence, the first experimental neuroscientist by testing the hypothesis that the brain controls all muscles by means of the nerves. Famously, Galen argued that the vital spirit that animates humans flows up from the liver to the heart and into the head. There, inside the ventricles—the brain's interconnected fluid-filled cavities—the vital spirit becomes purified and gives rise to thought, sensation and movement.

The quest for the seat of consciousness began in all the wrong places. Embalming procedures in ancient Egypt (1) discarded the brain because it was thought that the heart, liver and other organs hosted the soul. Hippocrates and Galen, physicians from antiquity depicted in a 13th-century fresco (2), realized that the brain controlled our thoughts and actions. During the Renaissance, Andreas Vesalius, credited as the father of modern anatomy, captured details of the brain's surface (3), a prelude to René Descartes's speculation that the pineal gland (onion-shaped structure, 4) is where consciousness resides. Credit: DEA, C. Sappa Getty Images (1); DEA, A. Dagli Orti Getty Images (2); World History Archive Alamy (3); Interfoto Alamy (4)

For more than 12 centuries afterward, the world plunged back into dogma, mumbo jumbo, exorcism and mysticism until the beginning of the European Enlightenment. The publication of Cerebri anatome in 1664 by English doctor Thomas Willis heralded the beginning of today's neuro-centric age. It featured meticulous drawings (by the young Christopher Wren, England's most acclaimed architect) of the brain's convolutions that transcended previous renditions, which greatly resembled a tangle of intestines.

Neuroscience has always retained a creative tension between holists, who argue that mental activity and other brain functions cannot be tied to a specific region in the brain, and locationists, who claim that specific loci, hot spots in the language of brain imagers, are responsible for carrying out specific functions. Locationism rose to dominance after 1861, when French neurologist Paul Broca presented the landmark case of a patient unable to speak except for a single word. The patient's brain exhibited widespread damage to the left inferior frontal gyrus, part of the neocortex that crowns the top part of the brain. An analysis of a second patient reinforced Broca's conclusion that this small region was responsible for productive speech (touch the bottom of your left temple to get an idea of where it is). The identification of this region, which has been named Broca's area, also fortified the view of the neocortex as the jewel in the crown of the central nervous system, the region most closely associated with higher-order cognitive functions, including consciousness.

In those early days during the Second Empire in France, doctors depended on keen observations of symptoms and on dissection of the brains of patients who had died to reliably infer the site of a lesion and connect it to its likely function. Today neurologists can make these connections by directly peering inside the heads of their living patients using x-ray computed tomography, magnetic resonance imaging and other powerful imaging techniques.

Damage to the brain comes in many forms: strokes, hemorrhages, tumors, viruses, bullets and blows. Examining such destruction, when limited in size, can illuminate the link between the brain's complex structure and what happens when a particular region shuts down. Interpreted carefully, such clinical studies have by far been the most fecund source of knowledge concerning the relation between the physical brain and the conscious mind.

The Brain's Light Switch

Some areas of the brain are more instrumental than others in generating a conscious state. The brain stem at the top of the spinal cord is one of them. If the brain stem is damaged or compressed, consciousness will flee the victim. Indeed, even a small injury to parts of it can lead to a profound and sustained loss of consciousness. The patient can go into stupor and can only be partially aroused after vigorous and prolonged stimulation. Worse, the patient can lapse into a coma, an enduring, sleeplike state of immobility with closed eyes, from which arousal may prove to be difficult.

A Guided Tour Scientists fall into two camps when discussing the brain. Holists argue that consciousness is generated by the entire three-pound mass made up of 170 billion cells, of which half are nerve cells. Locationists support the idea that specific neural circuits are responsible for specific functions, including consciousness. On closer inspection, neuroanatomists have realized that one confined area, the brain stem, ensures that we do not lapse into a coma or suffer from a sleeping sickness. Meanwhile rear areas on the surface of the brain are needed to generate mental imagery and other specific conscious experiences, such as recognizing your grandmother. Credit: © iStock.com

During and after World War I, a remarkable wave of “sleepy sickness,” or encephalitis lethargica, swept the world. The condition helped to point to the brain stem as a mediator of sleep and wakefulness. This form of encephalitis induced in many of its victims a state of almost permanent and statuelike sleep, from which they would awaken only for a few hours at a time. It was the astute observation by Austrian neurologist Baron Constantin von Economo of victims of this epidemic that led to the hypothesis that a brain center in the hypothalamus actively promotes sleep, whereas another in the upper brain stem produces wakefulness.

A more precise localization came from classical experiments by Italian Giuseppe Moruzzi and American Horace Magoun in the late 1940s, demonstrating that a brain stem region known as the midbrain reticular formation modulates the level of wakefulness (“reticular” here refers to the mesh or netlike appearance of this part of the brain).

In more recent years this notion of a monolithic system that activates consciousness has given way to a recognition that 40 or more nuclei are housed within the brain stem, all of which exhibit a specific neurochemical identity. These conglomerations of neurons are profoundly different in structure from the layered organization of the cortex. Cells in different nuclei manufacture, store and release different neurotransmitters or neuromodulators at their synaptic terminals—acetylcholine, serotonin, noradrenaline, GABA, histamine and orexin. Many of these brain stem nuclei monitor and modulate our conscious state, including wake-to-sleep transitions. Collectively they transmit signals that control internal bodily processes, such as breathing, thermal regulation, muscle tone, heart rate, and so on and process signals relating to the working condition of the body's organs.

Brain stem neurons promote consciousness by suffusing the cortex with a cocktail of these neurochemicals to keep cortical neurons in an aroused state. These substances alone are incapable of producing an experience. Rather they form the background—a neural palette—on which any conscious experience occurs, and this chemical mix acts as a “switch.” But if the cortex is severely damaged, it cannot receive the signals that maintain the light of conscious experience. Patients who have brain stem function that has been relatively spared but who have widespread cortical destruction typically remain in a vegetative state, permanently unresponsive but with eyes open, experiencing or feeling nothing.

Where Consciousness Resides

At this point, the story gets personal. In the late 1980s, as a freshly baked assistant professor at the California Institute of Technology, I started having regular conversations with Francis Crick about the mind-body problem. Crick was the physical chemist who, together with James Watson, discovered in 1953 the double-helical structure of DNA, the molecule of heredity. In 1976, at age 60, when Crick's interests shifted from molecular biology to neuroscience, he left Cambridge, England, in the Old World to establish his new home in La Jolla, Calif. Despite an age difference of 40 years, Crick and I struck up an easy friendship and a collaboration that would last for 16 years and result in two dozen scientific papers, essays and two books. All of them focused on the anatomy and physiology of the mammalian brain and its connection to consciousness.

The brain stem (left, highlighted in yellow) serves as an engine of consciousness. When injured, it may extinguish all conscious activity. The modern search for key brain loci that imbue us with consciousness began with Francis Crick, the author's mentor (right), decades after he had co-discovered the structure of DNA. Credit: Getty Images (left); Daniel Mordzinski Getty Images (right)

When we began this labor of love in the late 1980s, writing about consciousness was viewed as a fringy subject, a sign of a scientist's cognitive decline. Retired Nobel laureates did it, as did philosophers and mystics, but not hard-core scientists. When the topic arose, graduate students, always finely attuned to the mores and attitudes of their elders, rolled their eyes and smiled indulgently. Betraying an interest in consciousness was ill advised for a young professor, particularly one who had not yet attained the holy state of tenure.

Those attitudes have since changed. Together with a handful of colleagues, Crick and I gave birth to a science of consciousness. Its physical basis in the brain is now investigated worldwide, and questions concerning what makes any system, biological or man-made, exhibit a conscious state are hotly debated. Consciousness is no longer the unspoken taboo.

Our goal from the outset was to identify the mechanisms in the brain that, at a minimum, are needed to create a specific conscious experience: seeing the setting sun, recognizing your grandmother or feeling that god-awful toothache. We called these the “neuronal correlates of consciousness,” or NCC. The definition of an NCC was by no means clear. Must, for instance, some nerve cells vibrate at a particular magical frequency? And if that is true, what is it about the biophysics of particular bits and pieces of highly excitable brain matter vibrating at a specific frequency that is able to produce the glorious surround sound and Technicolor that constitute the sounds and sights of life? Are these special consciousness neurons all located in a particular part of the brain, as René Descartes famously postulated back in the middle of the 17th century for the pineal gland, probably the first hypothesized neuronal correlate of consciousness?

It is important to stress the “minimal” in defining the NCC. Without that qualifier, all of the brain could be considered a correlate: after all, the brain does generate consciousness, day in and day out. But Crick and I wanted to find the specific synapses, neurons and circuits that generate—that, in fact, cause—an equally specific conscious experience. Being careful scientists, we used the more cautious “correlates” in place of the more definitive “causes” of consciousness.

Based on our knowledge of the highly sophisticated nature of cortical nerve cells and their response to stimuli in the external world, we set our sights on the cortex, the gray matter on the brain'souter surface. The cortex is a laminated sheet of nervous tissue about the size of a large pizza. Two of these sheets are crammed into the skull, side by side, making up the left and right cortical hemispheres. The cortex is subdivided into the neocortex—a defining hallmark of mammals—and the evolutionarily older archicortex. All available evidence points toward certain key regions within the 11 ounces of highly structured neocortical tissue as the location of content-specific NCCs.

Lesions to the rear section of the neocortex—for instance, from a stroke or some other damage—demonstrate what happens when activity in the back of the brain shuts down. A patient so afflicted cannot recognize a set of keys on a chain dangling in front of her. She looks at them and sees texture and lines and colors but not keys. Yet if she grasps them or if they are jingled, she immediately knows what they are. Poetically termed Seelenblindheit in German (literally, “blindness of the soul”), this condition was rechristened agnosia by Sigmund Freud, a term that persists. The late neurologist Oliver Sacks brilliantly wrote about patients with agnosia and how their loss shaped the way they experienced the world.

Consider A.R., who suffered a blockage to the cerebral artery that damaged a small region on one side of his occipital cortex. The stroke briefly blinded him. He eventually recovered sight but permanently lost color vision in the upper left quadrant of his field of view, corresponding to the site of a pea-sized lesion in his right occipital visual cortex. A.R.'s low-level vision—detection of brightness, lines, and so on—and his motion and depth perception were normal. The only other deficit was a difficulty distinguishing —he could not read text—but this problem was confined again, to the upper left quadrant.

Functional MRI and EEG are some of the most common ways to look for neural correlates of consciousness in healthy volunteers. These techniques can identify a bevy of brain areas related to face recognition in volunteers within regions of the ventral temporal cortex, called the fusiform gyri (bottom area toward the back of the head). Found bilaterally, the regions are referred to as the fusiform face area and respond more strongly to pictures of faces, compared with scrambled faces or other objects and scenes.

Epileptic patients have played an outsized role in consciousness research. This is especially true of those who had electrodes implanted to control their seizures. A study of 10 such patients conducted in 2014 at Stanford University used the electrical signals recorded by implanted electrodes to confirm that both the left and the right fusiform gyri responded selectively to faces, compared with pictures of body parts, cars or houses. These electrodes could also directly excite the underlying cortical tissue using electrical pulses. Stimulating the right fusiform gyrus led to reports of perceiving faces. In one study, a patient who looked at his neurologist remarked: “You just turned into someone else. Your face metamorphosed. Your nose got saggy and went to the left. You almost looked like somebody I'd seen before but somebody different. That was a trip” [see graphic below].

When the left fusiform gyrus was stimulated, patients either did not make such reports, or they were restricted to simple, nonface imagery, such as twinkling and flashing lights or traveling blue and white balls.

This study underscores the truth behind the oft-repeated mantra that correlation is not causation. Just because the left fusiform gyrus is selectively activated by a sight, sound or action does not imply that the area is essential for vision, hearing or movement. These patients also teach us that electrically stimulating the right ventral temporal cortex can give rise to imagined faces. Indeed, this region is the best candidate we have for a content-specific NCC like “seeing” a face. Its activity correlates closely and systematically with facial perception. Stimulation of it induces or alters the perception of faces, and, crucially, people become face-blind when this region is destroyed.

Now You See Me, Now You Don't Electrical stimulation of the right fusiform gyrus, seen from below, in four epileptic patients undergoing surgery caused distorted perception of faces. The red dots represent electrodes that produced distorted views, whereas the blue ones did not do so in one patient. Source: “Electrical Stimulation of the Left and Right Human Fusiform Gyrus Causes Different Effects in Conscious Face Perception,” by Vinitha Rangarajan et al., in Journal of Neuroscience, Vol. 34, No. 38; September 17, 2014; De Agostini Picture Library Getty Images (brain)

Sometimes not finding something where you expected it can be as important and revealing as finding it. This observation applies to the cerebellum, tucked below the cortex at the back of the brain, and even pertains to parts of the cortex.

If the cerebellum is damaged, both animals and people have difficulty making precise movements, and the movements they do make lose precision and become erratic, jerky and uncoordinated. Yet patients with cerebellar lesions do not complain of being unable to see, hear or feel. Nor do they experience transient or permanent loss of consciousness. Their subjective experience of the world appears intact and normal. Consider the rare, and extreme, case of a 24-year-old woman born without a cerebellum.

Although she has mild mental impairment and moderate motor deficits and talks with a slight tremor, she can speak clearly about her daily experiences, her likes and dislikes, and her life with a young daughter. This is surprising given that her brain scans [see 2 below] show she has only a fluid-filled cavern where her cerebellum should be.

This absence is remarkable because the cerebellum contains Purkinje cells, whose fan-shaped structures are among the most beautiful and complex of all neurons. And astonishingly another cell type in the cerebellum—the granule neuron—outnumbers cortical ones by a factor of four. Despite this intricate physiology, neural activity in the cerebellum does not give rise to consciousness.

Tools in the hunt for consciousness include EEG (1) and MRI brain scans (2). These scans show a woman with an empty space where her cerebellum should be. AJ Photo Getty Images (1); from “A New Case of Complete Primary Cerebellar Agenesis: Clinical and Imaging Finidngs in a Living Patient,” by Feng Yu et al., in Brain. Published Online August 22, 2014 (2)

Even more intriguing than the cerebellum are the frontal lobes of the neocortex. Traditionally they are thought to be the key hallmark of our species, having expanded more in Homo sapiens than in all other higher primates. Functional MRI has also shown them to be involved in tasks that involve planning, short-term memory, language, reasoning and self-monitoring. Yet more than a century of reports describing electrical brain stimulation carried out during neurosurgery while the patient is awake suggest that it is difficult to directly elicit sensory experiences from stimulation of frontal sites.

Indeed, it is common surgical knowledge that removing much of the front of the cortex causes no apparent major deficit! This surprising realization stems from insight gained from hundreds of neurosurgeries for tumors, epileptic seizures and other neurological conditions during the first half of the 20th century, when neurosurgeons routinely excised large swathes of frontal or prefrontal cortex on both sides. What is remarkable is how unremarkable these patients appear from their clinical description.

The most dramatic example is Mr. A, a patient of neurosurgeon Walter Dandy in 1930. Because of Mr. A.'s massive tumor, the surgeon had to amputate the patient's frontal poles, the protruding sections at the front of the brain. The patient survived this bilateral frontal lobectomy for 19 years and continued to speak. A note in his file observed that “one of the salient traits of Mr. A's case was his ability to pass as an ordinary person under casual circumstance.” When he toured the Neurological Institute in the company of distinguished neurologists, “no one noticed anything unusual.” Mr. A. did exhibit some of the behaviors associated with frontal lobe removal, such as childlike behavior, lack of inhibition and a need to tell jokes. Neither he nor other patients who submitted to similar surgeries were robbed of conscious behaviors. Their capacity to see, hear or experience the world remained intact, despite the drastic surgical intervention.

That the anterior cortex may not be necessary for sensory consciousness does not imply that it does not contribute directly to any given aspect of consciousness. After all, being self-conscious (reflecting on what one perceives) is different from perceiving something, yet both are subjective experiences. Perhaps reflection, effort, and so on are generated by the anterior cortex, although no firm evidence exists yet. The prefrontal cortex might then be involved in unconscious planning, strategizing, forming memories and focusing attention.

The Hot Zone

Since the modern quest for the NCCs at the end of the 20th century, progress has been rapid compared with previous millennia. First, conceptual work has clarified the importance of investigating the neural correlates of both specific conscious contents and consciousness as a whole. Second, some parts of the brain have been identified as contributing little to conscious experience. The areas of the brain that make us conscious appear to be centered on a more restricted hot zone in the posterior part of the neocortex, with some possible additional contributions from some anterior regions.

These findings raise the question of why the seats of consciousness are so circumscribed. Is there something so different in the wiring or behavior of neurons in the back of the cortex from those in the front? Future investigations will be needed in the decades—maybe centuries—ahead to further illuminate the types of neural activity that underlie the infinite varieties of human experience.