When you look at the structure of the brain it's made up of neurons. Of course, everybody knows that these days. There are 100 billion of these nerve cells. Each of these cells makes about 1,000 to 10,000 contacts with other neurons. From this information people have calculated that the number of possible brain states, of permutations and combinations of brain activity, exceeds the number of elementary particles in the universe.

The question is how do you go about studying this organ? There are various ways of doing it. These days brain imaging is very popular. You make the person perform some task, engage in conversation or think about love, for that matter, or something like that, or imagine the color red. What part of the brain lights up? That gives you some confidence in saying that that region of the brain is involved in mediating that function. I'm sort of simplifying it, but something along those lines. Then there is recording from single cells where you put an electrode through the brain, eavesdrop on the activity of individual neurons, find out what the neuron is responsive to in the external world. There are dozens of such approaches, and our approach is behavioral neurology combined with brain imaging.

Behavioral neurology has a long history going back about 150 years, a venerable tradition going back to Charcot. Even Freud was a behavioral neurologist. We usually think of him as a psychologist, but he was also a neurologist. In fact, he began his career as a neurologist, comparable in stature with Charcot, Hughling Jackson, Kurt Goldstein. What they did was to look at patients with sustained injury to a very small region of the brain—and this is what we do as well in our lab. What you get is not a blunting of all your mental capacities or across the board reduction of your mental ability. What you get often is a highly selective loss of one specific function, other functions being preserved relatively intact. This gives you some confidence in saying that that region of the brain is specialized in dealing with that function.

It doesn't have to be a lesion; it can be a genetic change. One of the phenomena that we've studied, for example, is synesthesia, the merging of the senses (which I'll talk about in a minute) where's there has been a genetic glitch. It runs in families in whom some gene or genes cause people to hear colors and taste sounds. They've got their senses muddled up. We've been studying this phenomenon.

In general, we look at is curious phenomenon, syndromes that have been known for ages, maybe 100 years, 50 years, that people have brushed under the carpet because they're regarded as anomalies, to use Thomas Kuhn's phrase. What do you make of somebody who says, "I see five as red, six as blue, seven as green, F sharp as indigo." It doesn't make any sense and when you see this in science, the tendency among most scientists, most of my colleagues at any rate, is to brush it under the carpet and pretend it doesn't exist, deny it. What we do is to go and rescue these phenomena from oblivion, studying them intensively in the laboratory. Nine out of ten times it's a wild goose chase, but every now and then you hit the jackpot and you discover something really interesting and important. This is what happened with synesthesia. Another example, which maybe I'll begin with, is one most people have heard of, our work on phantom limbs and mirrors, which I'll touch on in a minute.

One of the peculiar syndromes, which we have studied recently, is called apotemnophilia. It's in fact so uncommon that many neurologists and many psychiatrists have not heard of it. It's in a sense a converse of phantom limbs. In a phantom limb patient an arm is amputated but the patient continues to vividly feel the presence of that arm. We call it a phantom limb. In apotemnophilia you are dealing with a perfectly healthy, normal individual, not mentally disturbed in any way, not psychotic, not emotionally disturbed, often holding a job, and has a family.

We saw a patient recently who was a prominent dean of an engineering school and soon after he retired he came out and said he wants his left arm amputated above the elbow. Here's a perfectly normal guy who has been living a normal life in society interacting with people. He's never told anybody that he harbored this secret desire—intense desire—to have his arm amputated ever since early childhood, and he never came out and told people about it for fear that they might think he was crazy. He came to see us recently and we tried to figure out what was going on in his brain. And by the way, this disorder is not rare. There are websites devoted to it. About one-third of them go on to actually get it amputated. Not in this country because it's not legal, but they go to Mexico or somewhere else and get it amputated.

So here is something staring you in the face, an extraordinary syndrome, utterly mysterious, where a person wants his normal limb removed. Why does this happen? There are all kinds of crazy theories about it including Freudian theories. One theory asserts, for example, that it's an attention seeking behavior. This chap wants attention so he asks you to remove his arm. It doesn't make any sense. Why does he not want his nose removed or ear removed or something less drastic? Why an arm? It seems a little bit too drastic for seeking attention.

The second thing that struck us is the guy would often take a felt pen and draw a very precise irregular line around his arm or leg and say, "I want it removed exactly that way. I don't want you removing too little of it or too much of it. It would feel wrong. I want you to amputate it exactly on that line." And you could test him after a year it is the same wiggly line which he couldn't have memorized, and this suggests already that this is something physiological, and not something psychological that he is making up.

Another theory that is even more absurd (found in some papers, and again, it's also a Freudian theory) is that the guy wants a big stump because it resembles a giant penis. Sort of wish fulfillment. This again is ridiculous, complete nonsense, of course. The question is why does it actually happen? What we were struck by was that there are certain syndromes where the patient has a right hemisphere stroke, in the right parietal cortex. The patient then starts denying that the left arm belongs to him. He says, "Doctor, this arm," he'll often point to it with his right arm and say, "this arm belongs to my mother." Here's a person who is perfectly coherent, intelligent, can discuss politics with you, can discuss mathematics with you, play chess with you, asserting that his left arm doesn't belong to him.

This is different from apotemnophilia. In apotemnophilia the patient says, "This arm is mine, but I don't want it. I want it removed." But there are similarities, there's an overlap, so we suggested that maybe there's something wrong with his body image in the right hemisphere, which alienates the left arm, or the right arm, for that matter, from the rest of the person's body and the sense of alienation leads to the person saying, "I don't want it. Have it removed."

More specifically, messages from the arm and the skin throughout the body, in fact, go to the parietal lobe to a structure, the postcentral gyrus. There's a big furrow or cleft right down the middle of the brain called the central sulcus. Just behind that sulcus there is a vertical, narrow strip of cortex where there's is a complete map of your body's surface. Every point of your body's surface is represented in a specific point on the cortex and there's a complete map called the Penfield Map. That's where touch sensations, and behind it, joint sensations and muscle sensations, are all represented in this somatosensory map.

The first thing we—Paul McGeoch, Dave Brang and I—did was an MEG recording. MEG is a functional brain imaging technique—to map out the body of these people. Normal people have a complete point by point map on the surface of this strip of cortex. We said, well, maybe this guy has a hole in that region corresponding to the arm he wants removed because it feels alien. But what we found is there are no holes. It’s a completely normal map so we were disappointed. Then what we found was there's another region behind it called the superior parietal lobule. This region actually constructs your body image. When I close my eyes I have a vivid sense of my different body parts. Some parts are more vivid than others and this comes mainly from joint and muscle sense, partly from my vestibular sense—saying that I'm standing erect, that my head is not tilted—and partly when I open my eyes I confirm it with vision. So there's a convergence of signals from vision, touch, proprioception, vestibular sense, vision —all of that—helping you construct a vivid internal picture of your own body called the body image. That gets partial input from the map I was telling you about, namely the touch map, the map for joints and muscle sense. It also gets input from hearing. It gets input from vestibular sense. It gets input from vision. All of it is converging to create a body image. That map, we found, does not have the representation of the arm that the patient wants to get rid of (you don’t see this in every patient; in some the malfunction may be in the zones that the body image map subsequently projects to).

So our hypothesis was the signals arrive in S1 (touch) and S2 (joint and muscle sense). All the sensory signals arrive here and they're all normal and they're received in the brain, but when the signal gets sent to the body image center in the superior parietal lobule in the right hemisphere there is no place in the brain to receive that signal and, therefore, this creates a tremendous clash and discrepancy, and the brain abhors discrepancies. The discrepancy signal is then sent to the amygdala, the limbic structures produces an aversion to the arm, and the patient says, "I want the arm removed. It feels intrusive." Words like, "intrusive," over –present” and so I want it removed.

Here's a bizarre psychological syndrome: the person wants his arm removed. Discard the Freudian idea that he wants a big, giant stump or wishful that he wants attention and things like that, and you come up with a precise circuit diagram of what's going on.

We tested this because it is not enough to come up with a theory. How do we test it? It turns out if I poke anybody with needle that pain sensation goes to the sensory pain region in the brain, probably in the thalamus and cortex, and then it goes to the amygdala. The amygdala alerts you to the pain and you say, "Ow." Right? And then it goes down to the anterior cingulate that feels the agony of the pain. There's a cascade of events. There's a sensation of pain and then the agony of pain, and then messages go down the autonomic nervous system and make you start sweating, preparing for action, fleeing, fighting, or whatever the required action is. So if you poke somebody with a needle, this whole cascade of events is set in motion. You can measure the skin resistance, which measures the sweating, you start sweating when poked.

Now, when I poked him with a little pencil above the line where he wanted his arm to be amputated nothing happened. Just a little gentle pencil prick. It's not a painful stimulus. Not much happened. There's no galvanic skin response, there's no arousal. But if you touch him below the line where he wants the amputation, there's a huge, big galvanic skin response. You can actually measure the aversion physiologically, not just rely on the subject to report. There's no way you can fake the galvanic skin response. It's the basis of all lie detector tests.

Then, of course, we went straight to the brain and we said let's map it out. And as I said we found S1 was normal, if you go to S2 that's normal. If you go to the superior parietal lobule where the body image is constructed, to some extent the inferior parietal lobule, right parietal, let's say, where the body image is, there is no arm representation in that center. That's what we found. If you touch the arm there's no activity there. If you touch above the line of amputation or touch the normal arm the activity is completely normal. So that region of the brain is abnormal, but we also speculate that the regions of the brain in the frontal lobes and insula/amygdala to which that SPL/IPL projects, there could be an interruption of signals. In either event there's a physiological reason why this happens. This is giving you insight into how the normal brain constructs a body image.

At this point I should add a note of caution that unlike our work on phantoms and synesthesia which has been confirmed on dozens of subjects—both by us and others—this work on apotemnophilia is very preliminary; we need more subjects. And that’s not a legal disclaimer—it’s the truth. Lets wait and see. Then the question is can you treat the guy? And we're working on that. We don't know how. In case of phantom limb there are ways of treating phantom pain.

We don't deliberately go after these odd phenomena. Somebody phones me and says, "I have this curious phenomenon, Dr. Ramachandran. Can you solve the problem?" Ninety percent of the time we can't, but every now and then we discover something amazing as I said.

So what we do is, we look at the patient and the first question is why does this patient have this syndrome? Why this peculiar behavior? What's going on in the brain? Can you explain it? First of all show that he's not crazy. Show that it's a real, authentic syndrome. There are bogus syndromes and I will talk about that if you like. They're not real. But given that it's a genuine syndrome and you prove that it's authentic, which is often very difficult to do, then having done that you say "what are the precise brain mechanisms that give rise to these curious symptoms?" So the first two questions are: is it real and if so what causes it.The third question is who cares? What does it matter? Each of these three questions needs to be answered if you want to make progress, if you want to draw people's attention to the phenomenon that you're studying.

So lets take synesthesia. First thing we did was to show that these people are not crazy. They're really seeing colors when they see numbers. They're not just making it up. The second thing we did was to ask what are the brain mechanisms, what's going on in the brain? Ed Hubbard, Boynton and I have shown that when they see non-colored numbers the color area in the brain lights up. So what? Why should I care? We've shown this quirky phenomenon has broad implications for understanding creativity and metaphor. Well, we haven't actually shown it, but speculated on that possibility. So in each case what we do is we rescue this phenomenon, this anomaly, from being brushed under the carpet, find out what the mechanism is in the brain, and talk about its deeper implications for all of us, for normal behavior.

Now, we seek odd syndromes to try and explain the symptoms in neural terms and hopefully shed light on aspects of human nature, which have remained ineffable for the longest time. But sometimes you come across a syndrome where you cannot quite know for sure if this is a legit syndrome or not, even though you can find it in the bible of clinical psychologists called DSM, Diagnostic and Statistical Manual, which is the official book for clinicians. If they can label you, give your syndrome a name, they can charge you, charge an insurance company, so there has been a tendency to multiply syndromes.

There's one called, by the way, Chronic Underachievement Syndrome, which in my day used to be called stupidity. It actually has a name and it's officially recognized. Then there is a syndrome called De Clerambault Syndrome. De Clerambault Syndrome refers to, believe it or not, a young woman developing an obsession with a much older, famous, eminent, rich guy and develops the delusion that that guy is madly in love with her but is in denial about it. This is actually found in a textbook of psychiatry, and I think it's complete nonsense. Ironically, there's no name for the converse of the syndrome where an aging male develops a delusion that this young hottie is madly in love with him, but is in denial about it. Surely, it's much more common and yet it doesn't have a name. Right?

You have to have a nose for anomalies, nose for the right kinds of syndromes to pursue. I'll give you examples and I think two will suffice. Let's return to synesthesia which I have been excited about studying for the last three or four years. It's not really a neurological syndrome, but it is an anomaly of sorts. Francis Galton described it in the Nineteenth Century, the great Victorian polymath who was a first cousin of Charles Darwin. Galton noticed that some people in the population who were otherwise quite normal, except they had one quirk: and that is every time they saw a number, the number would evoke a specific color. So five would be tinged red, six would green, seven would be indigo, eight would be blue, and nine would be orange, or something like that. Also, sometimes in the same subjects or in other people, each tone would evoke a color. So F sharp would be blue, C sharp would be green, so on and so forth.

Galton also noticed that this runs in families and may have a genetic basis and published this, I think it was in Nature, in the Nineteenth Century. Since then there have been dozens and dozens of case reports of people experiencing this, but it was regarded as a curiosity mainly and also is thought to be very rare, estimates ranging from one in a thousand to one in 10,000.

I became very intrigued by this phenomenon and I said, "Why would somebody see five as red?" Now, as I said, it's been known for a long time, for over 100 years, and people ignored it because it didn't fit the big framework of science. What do you make of someone who says F sharp is blue and C sharp is green? It doesn't make any sense. Or five is green or five is red? And I tend to get intrigued by these phenomena. I said, "Well, what's going on in their brain?" The first thing we wanted to show was that this was a legitimate phenomenon, that these people are not making it up.

There are several theories of synesthesia. One theory is that they are crazy. Maybe, but let's set that aside for a minute. One of the things we learn in medicine is when a patient is trying to tell you something when you think he's crazy, it often means that you're not smart enough to figure it out. Sometimes he's crazy, but usually it means you're not smart enough to figure it out, so look carefully, talk to the patient.

In the case of synesthesia, another odd aspect of it is that it's much more common amongst artists, poets, novelists, and other creative people. In fact, seven or eight times more common. This is controversial, but the strong evidence is that this is true. Now why would that be the case? I mean, one of my students has shown this to be the case, Ed Hubbard; why would this happen? There are several little mini-mysteries here about synesthesia. Why would it run in families? Why would they say numbers are colors or tones are colors for that matter? Why would it be more common in artists, poets, and novelists? So on and so forth. So it's a medical mystery worthy of Sherlock Holmes, waiting to be solved.

The first thing we want to show is these people are not crazy. By the way, another common theory is that they are on drugs like LSD –– acid junkies or pot heads. Sure enough it's more common among people who are high on acid, but that makes it even more intriguing. Why would some drugs produce this merging of the senses, this peculiar phenomenon of numbers evoking colors?

Another theory is they're being metaphorical as when you and I say, "It is the east and Juliet is the sun." Or we just say, "This is a loud tie." The tie isn't loud. It doesn't make any sound. Why do you say it's a loud tie? Or cheese. Cheddar cheese is sharp. Now sharp is a tactile adjective, a sharp nail or something. Why do you use a tactile adjective to describe a taste, a gustatory sensation? You say well, it's a metaphor. That's circular. Why do you want to use a tactile metaphor for a taste sensation?

Explaining synesthesia as just a metaphor doesn't explain anything because it's trying to explain one mystery with another mystery and that doesn't work in science. Another example of a metaphor would be, "It is the east and Juliet is the sun." You don't say, "Juliet is the sun." Does that mean she's a glowing ball of fire? No, you don't say that. You say, "She is warm like the sun. She is radiant like the sun." "Is nurturing like the sun" is a celestial body like the sun (a pun rather than a metaphor) "is the center of my solar system" and so on. The brain forms the right links. Synesthesia, by the way, is a completely arbitrary link between five and red. It's not a metaphor in that sense, so I was uncomfortable with the idea, but I thought there might be something to it. But we'll come back to that later as we go along. About a decade ago, by the way, I proposed there may be unconscious synesthetic propensities in all of us, which has now been amply confirmed in many studies including a recent one from Oxford.

Another theory is they're remembering childhood memories. Maybe they played with refrigerator magnets and five was red, and six was blue, and seven was green and for some reason they're stuck with these memories. Well, this again begs the question of why you and I have played with magnets, but we don't have synesthesia presumably. Most of us don't. We found, by the way, the phenomenon of synesthesia is quite common. You see it in one in 50 people. It's not one in a thousand or one in 10,000. People often don't come out and say that they do because they're worried you might think they're crazy

So the childhood memories thing doesn't work because, as I said, why would it run in families? Another reason for not believing it, you would have to say the same magnets were being passed from generation to generation and it doesn't make any sense. Metaphor? Maybe they are being metaphorical in some sense. Maybe it's related to metaphors. They're crazy? That's not a real argument. They're on drugs — no, that doesn't work either.

The first thing we wanted to show is they're not crazy. They aren't making this up. We generated a computerized display made up of fives, lots of scattered fives on the screen, and among those fives were scattered some twos. When you look at a two and a five, a five is a mirror of a two in a sense, in terms of its shape. So you have a bunch of outline drawings of fives. Scattered among them are some twos forming a shape. The twos cluster to form a triangle or a square or a circle like your Ishihara color test in traffic, when you're going through a traffic school eye exam for color vision. It's similar to that.

A normal person looking at it, the non-synesthete looking at this, says, "Oh, fives? You mean there are twos in here embedded? Let me see. Oh, there's a two there. There's a two. Okay. Oh, there's a two there. There's another one there." They take 20 or 30 seconds to find the hidden shape. A synesthete who sees five as red and two as green instantly sees a green circle or a green square or a hidden green shape pop out from the background. He's much faster in detecting the circle or the square than you and I are. If he's crazy how come he's better at it than us? Secondly, if you ask him what he sees he says, "I see a green triangle. I see a green square." Phenomenologically, perceptually, he literally sees the green square or the triangle or the rectangle. What this suggests is that it's a sensory experience not a memory association at least in some synesthetes. Jamie Ward has recently replicated our findings.

It turns out there is a heterogeneity of synesthetes, there are some synesthetes that we will call lower synesthetes, in whom the color is actually perceptually evoked and the numbers seem tinged with color—red, green, blue, yellow, chartreuse or indigo. But there are also more conceptual synesthetes where it does seem to be more like a memory association. We were focusing on the perceptual synesthetes, sensory synesthetes because they are easier to study scientifically.

First, we've shown they're not crazy, it's a real phenomenon. (Remember, I had three steps. First, to show it's real. Second, what are the brain mechanisms? Third, what are the broader implications? Why should I care?) We've solved the first problem which is it's a genuine phenomenon.

The second question is what causes it? Well, Ed Hubbard and I were looking at brain atlases and we were struck by the fact that there's a structure called the fusiform gyrus in the brain buried inside the folds of the temporal lobes. This structure, the fusiform gyrus it turns out, is where the color area of the brain is, V4, which was discovered by Semir Zeki. Right next to it, almost touching it, is the number area of the brain. It represents the visual representations of numbers. The two areas are almost touching each other. We said what's the likelihood that the most common type of synesthesia is the number-color synesthesia, and the number region and color region are adjacent to each other in the brain. This seems unlikely to be a coincidence. Then we said maybe there's an accidental cross-wiring between these two regions of the brain.

How do you prove that? We did brain imaging. You take a normal person and do and FMR, functional magnetic resonance imaging, or MEG, and show them numbers. Only the number area in the fusiform gyrus will light up. Show colored numbers to a normal person, V4, the color area, and the number area will both light up. If you show a synesthete a black and white number, both the number area and color area light up, thereby directly proving that there's a cross-activation going on.

Now, I should add that three out of four groups has shown it to be the case. There's one group who claims they don't see the activation. There's always uncertainty in brain imaging - inherently there is some noise -so it has not entirely been nailed down, but I think it's very likely that we are on the right track. Romke Rowlte in Amsterdam has studied this and she has also shown that there is an actual increase in white matter, actual fibers connecting V4 (color) and the number area within the fusiform gyrus, so that's about as good as it gets.

Now why would this happen? Why do these people have this cross-wiring? That's the next question. A clue first comes from observations made by Francis Galton and has been confirmed since then: it runs in families, it may have a genetic basis. So we said if you take the infant brain, a fetal brain, there's a tremendous redundancy of connections. Everything is connected to everything. It's a crude approximation, but it's almost true. Then what happens is there are pruning genes which prune away the excess connections between adjacent brain regions (or even separated brain regions that were densely connected). This creates a characteristic modularity of the adult brain. Now, if something goes wrong with the pruning gene, if pruning fails to occur in adjacent brain regions, like the color and number area remain connected even in the adult, and if the gene is selectively expressed in the fusiform gyrus through transcription factors, for example, if it's expressed in the fusiform gyrus then you're get a number/color synesthete. Every time your guy sees a number, because of the cross- wiring, the color neurons are going to be activated. Every time he sees a number he sees a color.

In our early papers we noted that such cross-activation could also be based on transmitters that cause disinhibition; probably both things are going on. Voila, you explain number/color synesthesia. You started with a gene. The gene has not been cloned yet, but people are trying. You explain what's going on in the brain, why these people have these quirky visual experiences of seeing colored numbers.

The last question—why should I care? The answer comes from the observation, the claim that synesthesia is seven or eight times more common amongst artists, poets, and novelists. Artists like Kandinsky,for example. Why would this be the case? What do artists, poets, and novelists have in common? They're all very good at metaphor and analogy. Seeing hidden links that most of us lesser mortals have difficulty in seeing. So when Shakespeare said, "It is the east and Juliet is the sun," as I have said before, you don't say, "Juliet is the sun," does that mean she's a glowing ball of fire? You make the right links, you say she's celestial like the sun. You make any number of links. She's the center of my solar system like the sun is the center of the solar system. She's radiant like the sun. She's warm like the sun. She's nurturing like the sun. Shakespeare was very good at picking these metaphors, which have multiple layers of metaphors and resonance.

What has this got to do with synesthesia? What's going on in a metaphor? You're linking seemingly unrelated concepts and ideas, right? If the same synesthesia gene, instead of being expressed selectively in the fusiform gyrus and producing this quirky phenomenon of number/color synesthesia, if it were to be expressed throughout the cortex, throughout the brain, it's going to create a higher propensity, higher opportunity to link seemingly unrelated ideas and concepts in far flung brain regions. If we think of ideas and concepts as also located in specific brain regions, occupying specific brain regions, and if you have these long-range connections then it permits greater opportunity for linking seemingly unrelated concepts. Hence, the basis of creativity and metaphors. Hence, the eight times higher incidence of synesthesia among artists, poets, and novelists.

In other words, what I'm getting at is, an evolutionary biologist could ask the question what use is this gene? It's seen in one in 50 people. It's fairly common, not rare. Why is it conserved in evolution? If there's a gene in evolution that's useless—it's completely useless to see five as red and six as green—it would have been eliminated from the gene pool eons ago, 10,000 years, 20,000 years ago. Clearly, this gene has been around and has been conserved. Now why? Why is this gene still around if it's completely useless?

Well, one possibility is it confers some outliers in the population with the ability to link seemingly unrelated ideas making them artistic, more creative. But when I give these talks people often ask me why, if it's that good that that gene makes you artistic, creative, and metaphorical, why doesn't everybody have it? Well, it's a silly question because evolution takes time and given another 20,000, 100,000, 50,000 years everybody will have this gene and we'll all be creative. But that's not the right answer. It may be a partial answer, but the real answer, I think, is that you don’t want everyone being creative; we need engineers!

You can see what we've done here, as with apotemnophilia, but even more so with synesthesia. It started with this peculiar phenomenon where people see number as color or tones as color. Then from that we said what is it, is it real? We showed that it was a real phenomenon using a number of perceptual psychological tests that can't be faked. From that we went to the brain anatomy doing brain imaging and showed what parts of the brain are involved. Then from that we were able to say there's a genetic basis. So from gene to neuroanatomy to perceptual phenomenology. Finally, all the way to metaphor, Shakespeare, and poetry. All from starting with this peculiar quirk called synesthesia. This is what we do with every one of our syndromes. Sometimes we're partially successful. Sometimes we're fully successful in doing this.

Given our lab is well know for studying these odd quirks of human behavior and explaining what's going on in the brain, and showing there are broader implications for understanding human nature, human consciousness—these things that everybody is curious about—when people have something quirky they come and phone me up. Or if a physician stumbles on a new case which he finds he can't explain, he or she will often phone me. Nine out of ten times I can't do anything about it, but every now and then I find out what's going on in the brain and discover it's something very intriguing and possibly important.

In the case of synesthesia, it was regarded mainly as a curiosity and an anomaly. People were just brushing it under the carpet saying, "What do you make of somebody who says five is red? They're just making it up or they're crazy. That's why it's more common among artists because we all know artists are a bit crazy anyway and they all want to draw attention to themselves." There are all kinds of silly theories floating around. In fact, some synesthetes were diagnosed as psychotic and diagnosed as having schizophrenia. They were told they were hallucinating colors. They were prescribed psychotropic drugs for the schizophrenia. Then they came to realize that they had this perfectly normal phenomenon, not normal, but not pathological either, phenomenon called synesthesia.

I think it's fair to say that we, and Jamie Ward and Julia Simner and a couple of other groups, came and revived interest in this field, brought it into the mainstream. So now there are about 20 or 30 books on synesthesia. Not 20 or 30, maybe a dozen books on synesthesia. On just this is one topic. When I started this nearly ten years ago, nobody was interested in this topic. There was one book by a clinician, a neurologist named Cytowick , but he was a prophet talking in the wilderness. Nobody paid any attention. He didn't really do any definitive perceptual experiments on it. He just said, "Here's a phenomenon worthy of studying." We were the first to actually start doing experiments on the phenomenon—to show that it's authentic, show that it's perceptual, and then pin it down to brain anatomy.

The reason I was attracted to it was because I'm curious about neurological syndromes given my background in clinical neurology, among other things. I began with being intrigued by phantom limbs. Patients would come into the clinic with an arm missing or a leg missing and continue to vividly feel the presence of that missing arm or leg. And again, it has been known for about 100 years and people thought of it as a curiosity, as a case study to be reported during grand rounds: 'Here is a patient with phantom limb.' Nobody knew what to make of it and certainly there was no interest in mainstream neuroscience in phantom limbs.

What we found is quite intriguing: two or three things. One discovery goes back about 15 years. Let's say I'm the guy with the phantom limb, I've lost my left arm and you're the physician. You come and touch the left side of my face. I start feeling the stroking sensation in my phantom thumb! Even though you're stroking my face I feel it in my phantom. If you touch this region, it's my index finger, that's my pinky. There's a complete map of the missing hand on the face. Now, why would this be? Here again is the medical mystery.

I started thinking about and drew inspiration from animal studies that have shown if you cut the nerves going from the arms to the spinal cord what happens is a complete reorganization of the sensory map in the brain. What happens in this patient is when you remove the arm?

You remember earlier when I spoke in the context of apotemnophilia I said there's a complete map of the body surface on the surface of the brain, the post central gyrus. There's a vertical furrow on the side of the brain. Behind that is the map. This map is systematic and point to point for the most part, but it turns out that the face area on the brain is right next to the hand area of the brain. It's a quirk and nobody knows why. The map is continuous and systematic, but oddly enough, the hand area is right next to the face area.

In an adult if you remove the arm, the hand area of the brain is now devoid of sensory input. It's hungry for new sensory input and it's not getting any sensory input. The sensory input from the face skin which normally only goes to the adjacent face area in the brain now invades the vacated territory corresponding to the missing hand and activates the hand cells in the brain. That, of course, misinforms higher centers in the brain that the hand is being stimulated. The patient then experiences the sensations as arising from the missing phantom limb. When you touch the face skin the message not only goes to the face area, but also activates the hand area in the brain. So you're getting cross-wiring between the hand area and the face area of the brain.

We did a ten minute experiment to show this, and it challenged the doctrine in neurology that neural connections of the brain are laid down in the fetus and in early infancy and once they've been laid down by the genome there's nothing you can do to change these connections in the adult brain. That's why if you have a lesion in the adult brain, say following a stroke, there's such little recovery of function and why neurological syndromes are so difficult to treat, notoriously difficult to treat.

It was believed there was no plasticity in the brain connections. We showed in our experiment that, in fact, there's a tremendous scope for rewiring. So much so that over a two centimeter distance in brain tissue in the cortex the face input has now invaded the hand territory of the brain. Then we did brain imaging and showed that this invasion had actually occurred, but we already knew this from the psychological experiment. So I guess my mind is primed to think about cross connections in the brain.

Now that's an example of cross connections caused by amputation depriving sensory input. In synesthesia, just like the face and the hand area, the color and the number area are right next to each other. I started thinking, well, maybe this is cross-wiring again. But in this case the cross- wiring is not due to deafferentation by removing the sensory input, but due to genes, given that it runs in families.

Typically what happens is somebody phones me. It's usually a neurologist or psychiatrist. They say, "Here's a strange case of a patient with apotemnophilia or Capgras Syndrome or some such syndrome. Can you take a look at the patient and tell us what you think?" The patient shows up in the laboratory or in my office and tells me what the problem is. I start thinking about it. You don't tell the patient ahead of time what your theory is because you don't want to cue them. Then you do various experiments on the patient and test your hypothesis about what's going on in the brain in terms of known anatomy and physiology of the brain, not some sort of mumbo jumbo psychological theory. Then you go and test the theory using brain imaging or doing simple psychological experiments.

Sometimes we're able to devise treatment for the patients. For example, in phantom limbs, two-thirds of the patients with phantom limbs experience excruciating pain. There's no known treatment. I should re-state that: There are 20 known treatments, none of them work. So we started investigating it to develop a treatment for it. But sometimes even just explaining to the patient he's not crazy, telling him, "You've got a phantom limb. The reason for this is something is going on in the brain," is a tremendous relief for him. Somebody has apotemnophilia and wants his arm removed. Telling him, "You're not crazy, it's not Freudian, it's a specific anatomical reason why you're experiencing this." Then you go to the next step and say you have this hypothesis about what's going on. You've tested it, you know what's going on in his brain. But can you actually help the patient?

In the case of phantom limbs we've done experiments to show that we can; but let me give you another example. There's a curious disorder that I've not talked about in the past. Candy McCabe in England is studying it, and we are also studying it, and it's called RSD, or reflex sympathetic dystrophy. It's another one of these disorders that is not rare. I'd say one out of 20 stroke patients has it. You also see it in patients who don't have stroke but have a trivial injuries of the finger, like a metacarpal bone fracture that causes an injury with intense, excruciating pain.

It turns out there are two kinds of pain. We think of pain as one thing subjectively, but evolutionarily there are two kinds: there is acute pain and there's chronic pain. Acute pain occurs when you touch a flame or a hot kettle and you say, "Ouch," and you withdraw your hand. Chronic pain is when there's gangrene or a fracture, typically a fracture and there's excruciating pain caused by the fracture and your hand becomes immobilized – you don’t withdraw it. What's the evolution? Even though they feel the same perceptually, evolutionarily they're very, very different.

The function of acute pain is to mobilize the hand and remove it from the source of tissue injury to protect the hand. Chronic pain is the exact opposite. When there's an injury to a metacarpal bone, your hand freezes up and gets "paralyzed" temporarily. It's excruciatingly painful. Any attempt to move it is painful so you don't move the arm. In the case of acute pain you mobilize the arm rapidly. In the case of chronic pain you immobilize it. Why? Because moving it would cause further tissue injury. So it's a protective reflex—immobilization. And then, of course, as the injury heals you start moving your hand again and the pain goes away. That's a normal cause of events.

But in a certain proportion of patients, stroke patients and in a certain proportion of patients with a tiny, little fracture, even a little hairline fracture, or ruptured ligament, the pain persists with a vengeance. Even after the injury is healed, even as the fracture is healed, the pain persists for weeks, months, years, sometimes for life, for decades. Not only does the pain persist, the hand gets swollen and paralyzed, the pain spreads over the entire hand. This from just an injury to one little bone and it involves the entire hand, the entire forearm. There's swelling of the hand, swelling of the arm, warmth, inflammation—all of that takes place on the arm. Again, you're stuck with it and there's no known treatment that works.

We started thinking about this and why should this be? Well, as I said, it's a reflex in mobilization and it's painful. Anytime you attempt to move the hand it causes excruciating pain so the patient gives up and says, "I'm not going to move my hand." Sometimes what happens is you get stuck with this, and this we call "learned pain." Any attempt to move it, the signal that gets sent to the hand to move it, becomes associated with excruciating pain in your brain, so putting it crudely you get a form of learned pain, a learned association between a motor command and the sensation of pain. The brain just gives up and the hand gets paralyzed. Any attempt to move it becomes excruciatingly painful.

How do you break the cycle? We said, "Let's use a mirror." So we put a mirror in the center of the table. This is similar to a mirror treatment for phantom pain and for stroke we discovered over a decade ago. You put a mirror in the center of the table and the patient puts his painful dystrophic, swollen, immobilized, paralyzed arm on the left side of the mirror. The shiny side of the mirror is on the right side and the patient puts his right hand on the right side of the mirror, positions it so it mimics the posture and location of the hidden dystrophic painful left hand. He looks inside the mirror and sees the reflection of the normal hand. Suddenly his hand looks normal, no longer swollen. That's obvious because he's looking at the reflection of the normal hand and it looks like you resurrected his normal hand in the mirror, and it's optically superimposed in the position of dystrophic swollen hand.

Now you ask him to send signals to both hands as if he were moving them, clenching and unclenching or rotating while he's looking in the mirror. Now he's going to get the impression— you don’t initially ask him to actually move the left hand because if he moved it would be painful, he only moves his right hand —and he imagines his left hand moving. What then happens is the patient gets the visual image that his left hand, which is immobilized and paralyzed, is again obeying the brains command, it looks like it's moving and is not painful. This way you unlearn the learned pain and the learned paralysis. The astonishing thing is that the hand actually does start moving for the first time in his life, first time in decades, first time in years. It works better if you do it very soon after the dystrophy sets in, a few weeks or months afterwards. The hand starts moving again and the pain subsides, and in a remarkable example of mind/body interaction, the swelling also subsides, often in a matter of hours.

This chronic pain disorder is considered intractable, incurable. It has been known for decades. I think it was discovered over 100 years ago, for which people have done dorsal rhizotomy, cut the nerves going to the spinal cord, cut the spinal cord to treat it. They do a sympathetic ganglionectomy that does work to some limited extent. You can treat it equally effectively, if not more effectively, with just a two-dollar mirror. The patient looks inside and moves his normal hand. We suggested this therapy some years ago, but it was actually Candy McCabe who first properly described it. We suggested the idea, but she discovered it independently,

There have been clinical trials on this from a group in Germany, I believe, on 50 patients. The discovery was originally made on a handful of patients. Since then their have been double blind, placebo controlled crossover trials, which is the best type of clinical trial you can do, and people have found dramatic recovery from this pain in a matter of a few weeks of mirror treatment. Then the pain stays gone for a period of at least six months and then you may need a refill after that. Imagine the amount of pain and agony and invasive surgery this has saved. Sometimes you come up with an off-the-wall half—plausible hypothesis and there can actually be a clinical use for it. One example is RSD, or reflex sympathetic dystrophy ( now called Complex Regional Pain Syndrome.)

We've talked about synesthesia, we've talked apotemnophilia, and we've talked about reflex sympathetic dystrophy. There are other syndromes like this that we've studied. Another syndrome called Capgras Syndrome where a patient has been in a coma for a week or two and comes out of the coma. He's a little bit slowed down. He has mild dysarthria, problems talking, otherwise mentally, perfectly lucid and normal and can hold a fluent conversation, can play chess with you, can do arithmetic. Everything seems fine except a little bit of slurring of speech. This chap looks at people and can recognize them, no problem. He's not psychotic, not mentally disturbed. The conversation is normal except for the little bit of slurring.

He looks at his mother and says, "Doctor, this woman, you know, she looks just like Mother, but she's not. She's a stranger, some other woman who looks like my mother, but in fact, is not my mother. She's an imposter." Sometimes it develops a paranoid touch. He says, "Why is this woman following me all the time? She's not my mother. She's pretending to be my mother."

Why does this happen? The Freudian explanation again—(By the way, I don't mean to do too much Freud bashing. I know it's fashionable in New York, but I think that he had deep insight into the human condition, especially the role of the unconscious, which we are increasingly realizing is largely true, and Eric Kandel has written about this. But anyway, it's fun to do.) So some Freudians had a theory about Capgras Syndrome that when this chap was a young baby, when he was an infant, he had a strong sexual attraction to his mother, Freud called it the Oedipus Complex. As he grew up the cortex developed and started inhibiting these latent sexual urges towards his mother and therefore, as an adult, he's no longer sexually turned on by his mother. But then a blow to the skull damages the cortex and these flaming sexual urges come to the surface of consciousness and suddenly and inexplicably he finds himself sexually aroused by his mother. He says, "My god, this is my mom. How can I be sexually turned on? This must be some other strange woman."

This is, of course, a very ingenious idea, as indeed a lot of Freudian ideas are. It doesn't work because I've seen patients, at least one patient, who had the same delusion about his pet dog, pet poodle. Saying, "Doctor, this is not Fi-fi. It's some other dog pretending to be Fi-fi." Now if you try to apply the Freudian analysis to this you've got to start talking about the latent bestiality in all humans and some rubbish like that. So it doesn't work. This got me thinking that there's something going on that's probably neurological in the brain.

I'm mainly an experimental scientist and we go with the flow. It's like charting the source of the Nile. You don't know when the next surprising twist and turn is going to be. It's a great adventure. A grand love affair with nature with all these twists and turns and unpredictable events. That's how we do experiments, but all of it is headed towards the goal of understanding human nature, but understanding it piecemeal. For example, you can't ask, "What is consciousness?" Some people do, but it's too nebulous an idea. In fact, philosophers have criticized this approach. But I think it's okay to ask question like Francis Crick did.

Well, what is consciousness? Philosophers like Colin McGinn and others have argued that this is utterly mysterious. The human brain can never comprehend itself and certainly not comprehend mysterious phenomenon like consciousness. Somebody like Crick would vehemently disagree. And I would agree with Crick.

Crick and Koch, for example, have argued that there is a structure called the claustrum that is a thin layer of tissue underlying the insular cortex of the brain. What's exciting about this layer of tissue, what caught Crick's eye and Koch's eye, was that it doesn't have any known function unlike other regions of the brain. There are many regions that we don't know the function of, but the claustrum is especially mysterious. It's not a tiny, little structure. It's a medium sized structure, and it's homogenous in its cell constituents. It also doesn't have the layered structure as with the rest of the cortex.

The astonishing thing that Crick noticed was it's connected to almost every part of the brain including every part of the cortex. It seems reciprocal. It sends connections to the somatic sensory cortex and receives connections back from the somatic sensory cortex. It sends signals to the amygdala, back from the amygdala, to the anterior cigulate, back from the anterior cigulate. In fact, it's very hard to find any region of the brain that is not connected to the claustrum. John Smythies, in our lab, and I have now picked up the gauntlet where he left it.

Crick, for example, has been rewarded in the past for analogies, for big metaphorical leaps. I don't think he actually says this, but if you look at the double helix and the complementarity of the helix, the two sides of the helix, we're struck by the analogy between this and the complementarity between parent and offspring. There's a huge leap of faith there. He says why do dogs give birth to dogs and not to pigs? Any child will ask this question, you and I won't. But Crick asks that question—why do dogs give birth to dogs and not to pigs? There's a complementarity between offspring and parent. Might it be the case that the complementarity of the two strands of the helix actually dictates complementarity of offspring and parents? This was the big leap. Then, of course, he figured out the genetic code and modern biology was born. He's primed to think in terms of linking seemingly unrelated phenomenon, of linking structure and function.

Then he approaches the claustrum and he says, What's the most fundamental thing about consciousness? So axiomatic, in fact, that you take it for granted? That is the fact that you are one person; unity of many attributes of human consciousness. The continuity. The time travel—the ability to go to and from in time—looking into the future, visit nostalgic memories from the past, string them together in approximately the right sequence. Laughter is uniquely human and we can't imagine laughing without being conscious, many attributes of human conscious experience. Self-awareness is another attribute. Putting it crudely consciousness is aware of itself.

Now, the central attribute of human conscious experience, so fundamental, in fact, that we take it for granted, don't pause to think about it, is the sense of unity. You've got a diversity of sensory experiences. You see things, you listen to things. This harks back to what I was saying about synesthesia. You taste things. You have hundreds of memories throughout a lifetime. Yet you think of yourself as a unified person. Yet all of these happen to you. You, John, or me, Rama. It all happened to me and I'm one person. Despite this diversity of sensory experiences, this bewildering sensory cognitive blitz of memories and sensory impressions I experience unity. How does that come about?

Another way to formulate this question is that there are different brain regions actively processing different aspects of information including memories and yet you experience yourself as a unity. Many philosophers will argue this is a pseudo problem, not a true problem. In fact, Crick adopts the opposite view; he and Koch debunk the idea that it's a pseudo problem. He says the most axiomatic thing about consciousness is its unity. And guess what the claustrum is doing? It's getting sensory inputs, even inputs from the motor cortex. It's getting inputs from every region of the brain in one little gathering place and sending messages back. It's ideally suited for performing this unifying role.

There's an analogy here between what the structure of the claustrum is and what the phenomenology of consciousness is. Maybe this is not just a superficial analogy. Maybe it's deep. Maybe the clue to consciousness lies in looking at the structure of the claustrum, a detailed study of its microanatomy and its connections to the rest of the brain.

Questions of that nature, trying to explain functions like consciousness, like self-awareness, like qualia, in terms of brain structures, is something that Crick pursued, and I think its something that I'd like to pursue as well, and we have been trying. We all share his agenda—though obviously not his stature.