Picower Institute for Learning and Memory Inaugural Symposium: “The Future of the Brain," pt. 4

[MUSIC PLAYING]

PRESENTER: I want to welcome you all back to our final afternoon session. And as the title suggests, Expand Your Mind-- Getting a Grasp on Consciousness, the session should be mind boggling to coin a phrase. I mean, we've been talking about consciousness. We've been dancing around a little bit all morning and a little bit of the afternoon. I once asked half a dozen psychiatrists, psychologists what consciousness was. They all defined it in their own way. They said there really is no definition at this point. So we'll try to answer that question and get some different viewpoints on it.

And there are going to be short presentations. And at the end of each presentation, we'll have a little bit of a sort of a different kind of panel discussion and open the questions right to the audience. Our first speaker studies consciousness by altering it. Dr. Alexander Shulgin is a chemist and an author. He's also known as Dr. X.

The New York Times calls Dr. Shulgin a one-man, psycho-pharmacological research sector.

[LAUGHTER]

Timothy Leary called him one of the century's most important scientists. By Shulgin's own account, he has created nearly 200 psychedelic compounds-- among them stimulants, depressants, aphrodisiacs, and pathogens, convulsants, drugs that alter hearing, drugs that slow one's sense of time-- I'm reading from the New York Times article drugs that speed it up, drugs that trigger violent outbursts, drugs that deaden emotion-- in short, a veritable lexicon of tactile and emotional experience.

Many of these drugs, perhaps all of them, he has tested out on himself and his wife, with a few friends included at times. And in addition to inventing the drug Ecstasy, Dr. Shulgin is a consultant and very much in demand for by an eclectic group of clients that include NASA, Bristol Laboratories, NIH, University of California for his view on how to experience consciousness and what consciousness is. Please welcome Dr. Alexander Shulgin.

[APPLAUSE]

Don't tell him I used his name, Alexander.

SHULGIN: Well, it's a great pleasure to be here and a great honor to be here. I'm not a great lover of Micro-- is it MicroPoint?

AUDIENCE: PowerPoint.

SHULGIN: Magic-- PowerPoint. PowerPoint. Had I known that you were going to have a PowerPoint availability here, I probably would not have used it anyway, because every time I've tried using it, about 30% of the time, at least, it fails. It falls apart somehow. It never quite gets to where I want to go.

So I-- rather than put a lot of chemical structures, which would be boring to about 80% of the audience and fascinating to the other 20%, I suspect-- I'll just use my hands and wave my hands as it is appropriate.

[LAUGHTER]

I mean, molecules obviously are rings and chains and nitrogens. And there's no problem about that at all. My interest in the area-- actually this is a nice opportunity. I spent a couple of years of my life up river some, oh, 60 or so years ago-- more than that-- at Harvard, where I had the unfortunate pleasure of having a national scholarship, which got me in there free. And I found that everyone else had parents who had enough money to get them in there and paid their way. And I could find very little rapport with the masses of freshmen that were around me.

So I found it much more pleasurable to go in the Navy and spend three years in the Atlantic in the anti-submarine patrol, which actually gave me a very nice beginning on chemistry, in that one of the books I had with me was a book by Paul Carr, a Swiss chemist written about 1938 or 1940. And it was a complete over-- a statement-- complete statement of the subtleties and the complexities of organic chemistry.

And when you're spending three years in the Atlantic waiting for submarines, you have a lot of time spare.

[LAUGHTER]

And I not only read the book but substantially understood it. And it was a very, very great pleasure to get out of the Navy and back into the university at Berkeley, where I took organic chemistry as my major. And the greatest compliment I had was from a fellow by the name of [INAUDIBLE], who was a lecturer there at-- or professor at chemistry.

And he said, by the way-- he met him in the hall during the-- I guess, the second year of organic chemistry-- we're having a midterm this coming Tuesday. And you can take it if you want to--

[LAUGHS]

--which I thought was quite a compliment, because I was-- the average on the first midterm was something like 62 points out of 100. And I had 100%. And he--

[LAUGHS]

--didn't know exactly why. I mean, I can answer the questions without any problem, because they're all in Paul Carr's book. And I had memorized the book. That's, I think, honest. Anyway, that-- after that, I got into my AB in chemistry at Berkeley, a PhD in biochemistry at Berkeley, got involved in a little laboratory-- there were five of us-- called Bio-Rad Laboratory. It's now a multi-million dollar operation. Had I stayed with them, I would have been a very, very rich millionaire with ulcers at this point.

And I'm very glad I just-- I split the scene when there were still only five of us present, did a little radioactive synthesis in their name, did some postdoctorate work at Berkeley, went to Dow Chemical Company-- the Dow Chemical Company out with a branch of it there in Pittsburgh and near the Bay Area in California.

And it's there they really got initiated into what turned out to be a very important change in my life. I had my first experience with mescaline about 1960-- 1950-- 1960-- about 45 years ago-- 400 milligrams of the sulfate and had a good babysitter. And I had explored a great deal around various psychoactive drugs. This is supposed to be an erotic thing. That is supposed to be an amnesia thing. Each of these had their own little name. I had heard about mescaline, had never tried it.

And that one day, that eight or 10 hour experience, really changed my life for the next half century. I was totally fascinated with a drug that could get in there, allow you to see things you would not normally see, and yet, you knew to be valid. I have a reasonably limited knowledge of colors. Suddenly I saw colors that I had never really appreciated before. I could look at a flower and observe the beauty of a flower, could not open the flower, could not touch it. But I observed the beauty of a flower.

I had memories from childhood that I knew were valid. But I had not thought of them for years. It was a very, very delightful experience. But mainly what impressed me most thoroughly is that that experience was clearly not due-- the contents of that experience were not in that 400 milligrams of the drug. The drug-- what it did-- it catalyzed my mind. It got my mind back into that particular area. So I looked upon these materials as being catalytic, not productive. They do not do what occurs. They allow you to express what is in you that you had not had the ability to get to and express yourself without the help of a material.

So this really caught my fancy. And I said, if this little 400 milligrams of something could be an effective catalyst to reveal back to me what I had done, what I had seen, and such there is a great potential here for medical use-- and that caught me with my little knowledge of chemistry and my intense curiosity as what was going on upstairs in my head and that was revealed by this mescaline experience. I really went into a true new direction of chemistry.

And here is where I guess I kind of have two wave hands. Mescaline is a ring with three mythoxy groups out here. Don't worry what a methoxy group is. Someone near you will probably explain it later-- a carbon, carbon, and a nitrogen-- a very simple molecule.

And I said, you know, if this molecule can be this effective, what other kind of effects could be gotten by similar materials? So the first thing I did was stick a methyl group on down here-- so now I now have an amphetamine compound-- and took it very cautiously. We were talking a lot today already about experiments with mice and with rats and with various animals.

In my own case, the only animal I used was the human animal. I presume this is now a little awkward because of the various national and federal regulations that have come in. But I find that still the human animal is the only one that is really effective in evaluating and comparing these various psychedelic materials. And the work I do is still involved in that direction.

Here's a material that is identical with mescaline. I called it trimethoxyamphetamine-- TMA. And my golly, it was about twice as potent and totally different in its action. With the mescaline, I had this love and sensitivity to a flower that was on my coffee table, where I was living. And under the TMA experience, I got very curious about and tore it apart to see what was inside-- complete change of attitude towards something of precious beauty.

One was an absolutely [INAUDIBLE] sort of a reverence. And the other was one of dissective-- dissecting curiosity. And the activity was twice. So I went ahead and did that-- I put in ethyl, propyl, butyl, amyl-- put all kinds of different groups on that position. That's one of the beauties of things about having a little bit of fun with the art of chemistry is you can put things on and know where they're going and have ways of determining that their chemistry is going correctly. But the real charming thing and the really, to me, exciting thing was the fact that each thing that you came up with was a new material, had never been made before.

So you're looking at a white crystalline solid in a little beaker there. And you've never seen it before. No one in the world has seen this before. Far as you know, no one in the universe has seen this before. It's a new thing you've just made. And it's never seen you before.

So you, in essence, have no dialogue at all. How much do you start with? How much material do you use as a first experiment on a new chemical that's never been tried before by anyone? Well, obviously an amount that's small enough to not have any effect. But how small an amount is that?

And it's a very interesting additional nuance in this relationship that I developed over a period of time that you go with great caution, decide what is an amount that would have no effect, and take 1/1000 of that amount. It doesn't take much-- it takes time. But it doesn't take much more chemicals, because you use 1,000-- up to where you were, you'd use another milligram perhaps.

And so each of these materials had to be learned as an individual new meeting. And one of the outgrowths of that I discovered is that the beauty of your final results of finding out what the effects are-- you really can't be wrong, because you'll say, I found that this material caused a visual enhancement of that and a recall of memories of this and this and yonder. Anyone else who tries it who finds the same results will say, he is right. Anyone who tries it and doesn't get the results says, what did I do wrong? So in essence you come up with a winner--

[LAUGHTER]

--very nicely. Anyway, what I did-- put these on there. The methyl group was twice as active. I put a propyl with no activity at all-- the ethyl mescaline. And by that time, I had made materials up through the, oh, 9 or 10 carbon chains. So I didn't bother trying them. I went back, put stuff on the nitrogen-- your nitrogen atom-- no lost activity entirely, a couple of methyl groups out there-- you can go almost a gram and not get any effects.

Then you have the ring system. Now here you got really exciting-- you have these three mythoxy groups sticking out in the ring. If you can imagine a hexagon being held by a two carbon chain, you have the hexagon out here. You have 1, 2, 3, 4-- you have 5 positions, 3 of them were occupied methoxies. So here's your quiz of the day. How many ways can you put 3 methoxy groups on this 6 membered ring that are different compounds? And the answer is 6. You can have 3, 4, 5, 2, 4, 5, 2, 3 4, 2, 3, 5, 2, 3, 6, 2, 4, 6. If I had a slide, this would be obvious.

Anyway, so I synthesized the other five compounds. And by golly, the 2-4-5 was 10 times as active. 2-4-6 was also very active and very interesting. The other three were absolute duds-- nothing at all. So here suddenly I now know that you can get much more potency and complexity, more stimulation, more eye dilation, but also psychedelic effects with, say, 2-4-5.

So now you have a new material-- TMA-- I called it TMA-2. You have three methoxy groups out here at those positions. Try each of them into an ethoxy-- gives you three more compounds. And only the 4 position was sensitive. So suddenly you have a position out there that gives you more potency. So I put other groups doing it out that way and began realizing that this here structure-- these are all called phenethylamines, by the way. This structure is amenable to amplification complexity increasing if you substitute here but not there.

So that's where I go. We're talking earlier some talk about neurotransmitters. It occurs to me that that position with the methoxy group-- the methoxy group metabolize off easily. What about putting a group out there that won't metabolize often? Instead of methoxy, put a methyl group out there. So I made the compound 2,5-Dimethoxy-4-methylamphetamine.

And I said, it's either going to be much more active, because it can't come off and be metabolized easily-- and hence, or I'll have a more active compound-- or it will not be active at all. But it will go into the neurotransmitter site the psychedelics go into. And if there's anything to the argument that these are neurologically activating sites and may be activated by people who are with mental illness, you may have a therapy for mental illness. You can't lose.

So I made the compound, tried it. And it turned out to be quite a bit more potent yet. This is material called DOM, which that, of course, led to a whole new direction. If you have DOM out there, methyl-- what about ethyl? Active compound-- propyl? Active compound-- and if it's methyls and the propyls and so forth-- active-- put a bromine out there-- active compound. Put an iodine out there-- active compound.

So the thought occurred to me, if you have an alkyl group that's DOB and DOI. DOM is the one that got off into San Francisco into the name of STP and if any of you are young enough to know San Francisco in the '60s. But there was a STP. STP, I should say, was very active at that time.

And it was-- turned out that I found out that it was, indeed, DOM under another name, STP. They said Serenity, Tranquility, and Placidity was the name for it. And no one knew what placidity was. So it became Serenity, Tranquility, and Peace, which was a little bit more understood. To the police authorities who did not like this idea of this going around-- they didn't know what it was-- they called it Too Stupid to Puke, which was--

[LAUGHTER]

--their counterpart to the-- they used to hate Ashbury Clinic. And it was-- at this time, I was up the hill in the medical school. And this was going out there. And I had no idea what STP was-- one of my compounds. I talked at a media-- at a conference back in the east coast, here in the east coast, about a week or two earlier. And I talked about the material and gave it structure. And I suspect it was just synthesized from this seminar I gave.

[LAUGHTER]

Anyway, the bromo-- the--

[LAUGHS]

--it's a funny world. The bromo compound, iodo compound-- it occurred to me maybe it is because this alkyl group was active. And you have what's called a lipophilicity or hydrophobicness, where something likes something that's fatty. And maybe if I put something on there that was water loving like a nitro group, it would not be active when it goes into the neurotransmitter receptor site. [INAUDIBLE] nitro group-- active. Well, maybe it likes both-- it was putting his tail into this receptor site. Going to the right that's lipophilic and to the left is hydrophilic. What about putting a group on that is not philic at all? And they made fluorine.

So I put on-- I think it was a trifluoroethoxy analog. So I felt this would probably not be active at all-- also active. So it's just getting it-- the tail of the four position-- that molecule into the receptor site produced activity. So if that's an obvious step for it to go and make-- take off the methyl group, get away from the amphetamine chain. So I took the methyl group off. And that gave 2C-B, then 2CI-- a host of other materials in the same ilk that was just a beautifully rich collection of compounds-- many of them not as potent as the amphetamines but shorter lived and much more benign and much more friendly than the corresponding amphetamines.

So this is-- oh, another thing-- somewhere along the line, it occurred to me, if oxygen does a good job, put a sulfur on there. And you get now the 2C-T family-- 2C-T-2 up to about 2C-T-25 or so, of which about half of them are active. So this is kind of the handwaving world of synthetic chemistry.

I could go on for another 10, 15 minutes and get into thryptomenes and go through the same complexities. But do you have this as the active position? That is not as active. This is less active. Alkyl groups on thryptomenes are much enhancing in nature and complexity of action-- alkyl groups with the exception of MDMA and a couple of others. Naphthylamines destroys the activity of the phenethylamines. And so there are differences between these two families of compounds. But those differences are not negative. They are just informative.

Anyway, that's kind of the picture for I've been going for a while. I don't want to take too long here. What is, I think, a question that has often come up is how is this all going to work out? What are the goods and the bads of this entire area of psychedelic chemistry? Basically, the negatives are the terms many people from law writers to people in the street feel that this is an area of neurotoxicity, an area-- these materials cause neurological damage, cause people to lose control, commit crimes, and eventually collapse after 20 years of brain decomposition, which is, to a large measure, nonsense. However, I can't say it completely excludes. I've been into it for 45 years. And I'm having my usual expected amount of brain deterioration. But I don't think it's that serious yet. So I hope to have another decade or two of reasonable responses.

And you have the increasing urge to put laws against these things, because the psychology, the propaganda that they are negative, that they do damage is very real and very much believed by many people. Now I've been often asked, why use the word psychedelic? Itself is a pejorative term. I mean, there are empathogens, entheogens, hallucinogens, psychotomimetics-- other terms that are used widely in medicine that carry other messages but do not carry the intrinsic negativeness of the term psychedelic.

Well, my main argument for keeping continue to use the term is that people may not approve of what you're working in or what you're saying. But at least, they know what you're talking about.

[LAUGHS]

You stop nine people on Market Street-- 10 people. Nine people, you say, I work with empathogens when they ask you what you do. They have no idea what you're talking about. Nine people out of 10, when you tell that you're working with psychedelics would not-- maybe not approve. But at least they'd know what you're working with. So the idea of using a term that is in popular usage I consider to be quite positive.

Well, my clock is still going. The clock is supposed to go flashing three minutes from stopping. And the clock has stopped. So I don't know where I am. Let me-- let me wrap things up.

[LAUGHTER]

What are the positives? I consider the positives to be my main incentive for doing the work I've done for the last half century and continuing to do it now is I believe in this collection of materials you're going to develop tools that are going to answer many of the questions that have been brought up today, namely how can you find out how the brain works? You can use a rat. How does the mind work? What does the-- what kind of a probe can you make to look at the function of the mind?

To me, it's going to be a psychedelic material that has very little action in experimental animals to look into actions in man that are not seen in experimental animals. Maybe the idea of using these materials as eventual research tools, I consider to be extremely, extremely valuable.

I think what I'll do-- a point came up during lunch today. It brought up an interesting story that I think pretty well puts this into perspective about the need of tools for exploring research-- research tools for exploring this area of understanding the function of the mind. It was Eric this morning who was talking about animals being invested with the properties of schizophrenia.

And this was some years ago, back in the good old days before there were many inhibitory actions on human studies-- FDA approval, disapproval. You get clearance from the DEA, clearance from everything like that before you do any human experiments. Your board of your university has to see the research and approve of it. A lot of this experimental work was done back in the halcyon days when there were no such things as research approval boards.

I mean, in Berkeley we had the run of the place. We could fire up the cyclotron front and make an isotope and use it and try it. Their argument at Donner Labs-- that was the Donner, then went up on the hill in Lawrence Lab-- was stay if you want and do whatever you want. The tools are here. Here's the cyclotron. Here's your PET scanner. Do whatever you want. But just remember, when you leave, turn off the lights and lock the door. And we could work through the night there doing experiments, all kinds of beautiful things.

I remember one time and this is-- let me use this as sort of a windup. We had-- this was some maybe three or four decades ago. It was quite popular opinion that methionine was involved in schizophrenia, because some experiments had been done in which people who were schizophrenic were given methionine in rich dyads. And their symptoms became worse.

And yet, those people who were not diagnosed as schizophrenics with the methionine rich dyad had no changes at all. So we've talked about this-- pros and cons. And it was a neat experiment. What I did-- I took a-- I remember it was [INAUDIBLE] or some compound in that area. And I tucked on a fluorine-18, which makes it a positron emitter, which means you can go into a PET scanner and put this into a person and put the head of the person-- while the person is attached to the head still I mean. No--

[LAUGHTER]

--that didn't sound good. You had the person lie down on a little cot with the head going into a positron camera. And we've had a section of the brain just above the ear lobes that tells you where that chemical went. Being a positron emitter, it didn't have to have any reaction in the body. It just went where it went. And what we did-- this was work done with Tony some, oh, God, years-- a few decades ago.

I made this material. In fact, I made 10 batches over a period of time. The half life of fluorine is a little less than two hours. So you can't make a lot of it and keep it for a while. And he had good friends up at Mendocino Laboratory-- Mendocino Hospital. And he came back with five names of five schizophrenic patients, who were up at the hospital. And we had their names and the backgrounds of them. And in the Lawrence Lab, I managed to find five normal controls. That was a bit more tricky. But--

[LAUGHTER]

--we did. And 10 batches of this and we did 10 experiments. We put the material into these 10 people about a week apart and in each case, put them into the PET scanner. I remember one of the schizophrenics Tony had a lot of problems with, because he did not like radioactivity. And they said radioactivity is bad.

So we had down at Donner a great big sort of background counters, a big room with a big iodine crystal of 30-some odd inches in diameter and walls that were 3 inches thick lead overhead and the side. And Tony very nicely told him, if you go in here and spend a half an hour-- he'd give you a magazine, turn, and leave the light on-- if you go in here and spend a half an hour in here, your body will be so depleted of radiation that when we take you up on the hill and put you in the [INAUDIBLE], it will bring you back to normal. You'll be OK. He believed it.

[LAUGHTER]

Anyway, to wrap up with the result of the experiment, it was a fascinating thing. We ran 10 studies. And we had 10 photographs of the fluorine-18 disposition in the brain. And the 10 photographs were absolutely different from one another. There was no consistency through this group at all. And so we put them on the wall of the medical radiation thing up on the hill.

And across the back of the wall, every time someone come in from Washington to give a seminar or come in from somewhere of any importance, we say, by the way, here are 10 photographs of the fluorine-18 labeled material we gave. Five of these are schizophrenic patients. And five of them are normals. Which do you think are normals? Which do you think are schizophrenics? And we got absolutely random answers-- no pattern could be found at all.

Then about two months, three months later, one of the schizophrenic patients who liked Tony very much came down to visit and see how everything was going on-- very nice visit. And they were talking for a while. And he saw these 10 photographs on the wall. And he said, are those the 10 pictures you took of us? Tony said, Yeah.

And he looked at one and said, well, I reckon that's me. And he pointed to number seven or one of them over there. And he's absolutely right. He identified his own photograph from the PET scan of the distribution of that fluorine-18 thing. And Tony very mildly, casually said, oh, you know, you're right. Absolutely right-- how do you know? Oh, he said. That-- you see that little sort of star shaped shiny thing in the bottom right corner-- that little star shaped thing? Yeah, he said. I see it all the time.

[LAUGHTER]

So we have a long way to go before we really can understand how the mind works. But this is a start. Thank you very much.

[APPLAUSE]

PRESENTER: That's great. Have a seat. And then we'll call you back up here.

SHULGIN: [INAUDIBLE]

PRESENTER: That was terrific. We'll have a chance to question Dr. Shulgin and the other speakers when we sit down there in a little bit. You weren't the only one experimenting with psychedelic drugs in the '60s. I remember a friend of mine's father worked for the CIA was telling me about a few CIA agents who walked out of a window on LSD. And this was 10 years before it was uncovered in Congressional hearings.

Our next guest, Dr. Christopher Koch-- Christof Koch-- excuse me, says his aim in life is finding out how consciousness arises out of the brain. My long term goal, he says, is to discover and characterize the Neuronal Correlates of Consciousness-- the NCC. I collaborated for 16 years in this exciting endeavor with the late Dr. Francis Crick at Salk, a postdoc refugee from MIT.

Dr. Koch joined Cal Tech's newly started Computation and Neural Systems Option in 1986 as Professor of Computation and Neural Systems running K Lab as well as being executive officer of CNS. Here to tell us more about his views of consciousness is Dr. Christof Koch.

[APPLAUSE]

KOCH: Thank you. All right, so before we start, I have to make a conceptual distinction because different people use consciousness in very different ways. So first of all, particularly what clinicians are interested in their see different states of consciousness. Right now, nobody's asleep, at least yet, so that's one state of conscious. You're awake.

Then, of course, there's REM. There's different types of sleep, REM, and Slow Wave sleep. There's coma. There's Persistent Vegetative Syndrome. There's minimal conscious state.

There's stupor. There are all these other states. And so you can study people, folks, and you can kind of made a contrast between the awake state and the REM state.

So this sort of defines consciousness as such-- the ability of your brain to be conscious at all. So right now, we are conscious, but what most people who study this now are interested in is different states of consciousness. So while you're conscious, you can be conscious right now of my voice. I talk a little bit like my governor. And--

[LAUGHTER]

--or you can be conscious of blue or of something else. So this is the current content of consciousness. And the elements are called qualia. This is what philosophers refer to. So there's a qualia for sound. There's a qua-- you have a qualia for red, for blue, for being angry, for being you, for being late, living in the late, industrial post construction society, whatever.

Now, empirically, studying this aspect, I can show you is much, much easier because this, you can control very well in humans and in some animals. You can control the level of arousal, and then you can manipulate the content, particularly in the individual case. It's much more difficult to do this, for example, for self-consciousness. We don't have any good illusions. We don't have any good ways to manipulate self-consciousness.

For example, I can sort of, without taking drugs, which is a little bit uncontrolled, I can really switch my feeling of being Christof on and off in a time scale off of half a second. But I can do that perfectly well for visual consciousness.

And so here, the trouble is if you do a comparison between the wake and the REM or between the REM and Slow Wave or between Coleman and awake as people do, there are all sorts of different things that change at the same time. It's not only conscience. It's also tensions. It's memory. It's also motor behavior, so it's more difficult to control, experimentally.

What is it we can see for sure at this point in 2005 about the Neuronal Correlates of Consciousness? Well, first of all, we know it's a property of certain complex adaptive networks, not all networks. So you may know down here in your gut you have roughly on the order of 100 million neurons, and It's called enteric nervous system.

They're real neurons. They have synapses, a neurotransmitter. And for the most part, it's totally silent. You don't have conscious access to it, and if you do, usually it's bad what happens, right? The other systems like the immune system, we don't have any conscious access to the immune system, so it's not just any-- it's not just any cellular property. It's a property of particular neuronal networks using massive feedback.

Everybody believes without feedback, if you create, let's say a mouse that has no feedback connection, this mouse wouldn't be conscious. It's, of course, shaped by evolution by natural selection. Many species, certainly from a biological point of view, many species share aspects of conscience with humans. That's not to say that the consciousness of the mouse, of a monkey, of a dog is the same as us. It's certainly not true

But you can infer based on the very similar behavior, based on similar structure of the nervous system, and based on argument of evolutionary continuity, it is very likely that, let's say a dog or mouse or a monkey shares aspect like vision or like smelling that also a mouse. When the mouse, smells something, it's also feels like something to the mouse to smell something. We don't know right now the minimal. We have no idea about brain size, how brain size correlates with consciousness.

We all have the strong feeling that things like C. Elegans, like Drosophila, like a bee. Of course, they're bugs. They're not conscious, but we really don't know. And if you observe a bee can do in conditional experiment in one short learning, a bee has roughly a million neurons. It can do amazing feat of complex information positing and complex visual pattern recognition.

And you're not so sure anymore, non-reflective behavior. So I'm not really totally sure anymore that it doesn't feel like something to be a bee. The trouble is that right now we don't really have good acids to test that. As Eric emphasized this morning, and, of course, as we know now, 400 years of psychophysics and clinical research and physiology, much, if not most, of behavior occurs without consciousness, occurs either totally bypassing consciousness, or consciousness comes after the fact, like giving a talk like this.

Most of us when we talk, we have no idea what we're going to say. You hear these words coming out of my mouth. The only thing I know is sort of in the next two minutes, I want to make this point. I want to make that point, but it's not that I'm consciously Christof is sitting inside here, formulating a sentence, putting the verb and the noun together, translating it from English-- from German into English, and then sending it out to my larynx.

It all happens unconsciously. And we know this for sensory motor behaviors, for visual behaviors. There's lots of evidence for that. So this really gives rise to a contrastive strategy because you can now contrast at the level of brain architecture with the difference between those behaviors, so let's say in humans or in monkeys that give rise to conscious sensation versus those behaviors that do not give rise to conscious-- to conscious sensation.

The different brain areas, how that some brain areas, let's say down the brain in the catacombs of cortex, let's say in the basal ganglia in the parts of the midbrain. Are they never associate with consciousness? It used to be folks only believed in the 19th century, most thought that 20th century, that anything in cortex, if you have vigorous neural activity in cortex, that's always associate with consciousness.

We know that certainly, not two, for example, the experiments of Nico [INAUDIBLE] and the monkey, you can have neurons that fire very, very vigorously to a visual stimulus. However, if the animal does not perceive it because it's perceptual suppressed, the animal isn't-- it doesn't respond to it. The animal doesn't seem to be aware of it. Yet you have lots of neuron focus and visual cortex that fire to it. So that means just because you have some cortical neuron onset fire vigorously, it does not equate with the fact that those neurons, their representational content is made accessible to consciousness.

So what Francis Crick and I have advocated since many, many years-- and what people are doing now-- is look for the minimum neuronal mechanisms that are jointly sufficient for anyone conscious percept. Minimal, because we know the entire brain is sufficient. But we-- for example, in order for you to see this blue, do you need your cerebellum? Well, probably not.

Do you need your retina? Probably not, because you can close your eyes, and you can imagine the blue. Do you need your primal visual cortex? Well, that's much more controversial already. But-- all right, so this brings me to my next point.

[LAUGHTER]

Yes. When I talk to folks in the philosophy department, people ask me, well, how can you study consciousness without properly defining it? Of course, historically, as we all know, in science, progress almost always happens at the time when we don't have good definitions. And defining something too early is usually-- if you define it too prematurely, it can be a bad thing.

So here, this is what I mean by consciously. Well, what you should do now, fixate this course just look at this course here. Look at it very intent. Don't close your eyes. Don't move your eyes.

And then, what do you see? It's called Motion Induced Blindness. Okay, do some of you see this? So look at the course, and what you should see is that one or both of the yellow squares sometimes disappear. All right? You see this?

Okay, so here people-- so this sort of is an operational definition of conscience. When you're conscious of the yellow, you see it. You have sensations. You can see the yellow. It may remind of the yellow sun flower or van Gogh or yellow sun or whatever.

And when you don't see it, it's just not there. We're not conscious of it, but physically, the stimulus is all-the-time present, okay? So A, this sort of belies a common, naive, realistic notion that there's a simple one-to-one mapping between what's outside in the world, what's inside in the primacy of my head.

Because here, the yellow's present all the time, yet sometimes I see it, sometimes I don't. It also shows you in this less than ideal conditions, that we can manipulate now very well the relationship between the physical stimulus and the percept. In the lab, we can do it with a precision much less than a degree of visual angle, and we can do it with the precision of a fraction of a second that we can preci-- we can put something on your retina, but you don't see it unless we want you to see it.

So this is similar to a magician. You go to a magician like David Copperfield, and then he has this beautiful bikini-clad assistant, and she acts as an intentional distractor. Let me tell you, it works very efficient. And while you're looking at the scene in front of you, because you're distracted by her, you will not see things, although they are in front of your eyes.

And you can see he makes a sleight of hand. He makes things disappear. But if you go to the same show two or three times, you can perfectly, well see. So we can now do the same thing under laboratory conditions.

Now, you should continue to look here at the course because now-- next slide-- you should see an after image, right? You see the ghostly, bluish after image corresponding to the two yellow squares? All right, so we can-- so that's an after image. It's one of the oldest techniques in psychology, was invented sometime-- was discovered sometimes in the 17th century.

We can now ask a simple question, do you need to see the yellow square in order to get the after image? Okay, this sounds like a really stupid question, but just to show how we can now manipulate visual consciousness. Do you need to see the yellow square in order to afterwards see an after image, okay? And the way you can test this, you can compare all the times when you saw the yellow continuously, let's say, for two seconds.

Compare that with the-- and you measure these things of the after effect-- compare that with the after image you get when you didn't see the yellow, right? So I get subject to press a button whenever the yellow disappears, and then immediately afterwards, you check the strength of the after image. And it turns out, the after image is totally independent of whether you consciously saw the image or not. It doesn't matter. You still get the same after image.

What this tells us is that-- this is a phenomena, Motion Induced Blindness, has to occur somewhere early on in the system because usually in the retina, we think that after images arise, in this case, in the retina, and that the Neural Correlates of Consciousness of seeing yellow happens higher in cortex somewhere. And so what matters for the after image is just how long the image was physically present on the retina, but it doesn't matter whether you saw it or not.

So it allows you to infer something about the-- and that or both. This is what Bela Julesz called psychoanatomy, because it allows you to infer something about the location of the phenomena in the hierarchy without doing FMI and without doing single cell electrophysiology. You can also do-- and people have-- lots of people have done this. You can also do this to other after effects you can explore. This was done, in fact, here at Harvard.

Well, you have always so-called, the tilt effect, orientation-dependent after effect. This also doesn't depend on visual awareness. This affect do, so we had a-- you can do a very nice study show. There's something called face-specific aftereffect that for example, if you look at a morph of John Kerry and George W, and it's just morphed where half the time, you see George W. Bush and half the time, you see John Kerry, then I show you briefly-- I show you, let's say, for two or three seconds, I show you Bush. Then, if I now show you back the original image that's morphed, image much more likely to see John Kerry than Bush because you've adapted to Bush in something specific having to do with identity of the face.

Well, this, for example, does depend on consciousness if you don't see it because we suppress it. So we put these trace images on your retina, but we suppress them so you don't see them. You don't get the artifact anymore. So this is just a way just to show you one glimpse of what psychologists can now do to control-- dissociated physical stimuli from what you can actually perceive.

Okay, so in 10 years ago, Francis and I wrote us a nature paper where we based on the new anatomy of the macaque monkey for reasons I don't want to go into. We made two predictions. We said that a conscious perception, the particular visual perceptual requires activity in prefrontal cortex. At the time, people were profoundly skeptical of this because it was believed that essentially vision is just done in the back part of the brain.

And then, more relevant for today, is that the neural cortex are conscious are not in primitive visual cortex. In other words, that the visual input projects is from the eyes when the intermediate relay station to the back of your head here, the visual cortex. And that's the first stage called the primary visual cortex.

And we made a sense that our ideas, the support for ideas would be much greater if it was shown that invisible gratings produce activity in V1 neurons, in humans. Because then you can argue, well, you didn't see them consciously yet they still give rise to finding activity in neurons in primary visual cortex. So m that seems to imply that the neurons in V1 do not give rise to conscious visual-- to visual consciousness.

So there's a paper just came out in Nature Neuroscience. I'm just showing you to give you the idea that you can make progress in this very old-- consciousness is one of the oldest part of mankind. Aristotle has written already about it, 2,00 years ago. And we're not forever condemned to just philosophical speculation, but we can actually make progress.

So these people did the following as simple imaging study, and this is in a magnet. So they showed you this grate. Either you saw this grating. You fix it here, and you get this grating or into it this way. Or you fix it here, and you get a grating onto it that way.

And you get a-- in different parts of visual brain, you get a very strong response to either this grating or that grating. Okay, not very surprising. And in fact, what you can do, you can use a decoding algorithm. So this is the of one a subject. So you take his visual brain and flatten it out. I mean, you do it in a computer.

[LAUGHTER]

This is human, after all. And then, you can do what's called decoding. It's a standard technique in information processing. You essentially ask a little mathematical algorithm, which pattern give rise to this orientation? And which pattern gives rise to this orientation?

And then, I'm going to show this machine, this little algorithm I've cleaned up a new image, which the algorithm hasn't seen before and ask it to, based on this what you learned in the previous image is, can you tell me whether the subject saw this grating or this grating? And in this case, you can do it 82% correct, so far above chance. Chance would be one 1 out of 2.

So you can do it 82% correct in primary visual cortex. This is not at all surprising. This is what everybody expected. But now, you can do a really cute trick. You can hide this game using a masking technique.

You show the same stimulus very briefly, just like before, but now you hide it. You put stimuli before and afterwards. This is called visual masking. Essentially, you show an image, and immediately afterwards, you show another image.

So physically, the image is present exactly the same amount of time. It's the same signal energy you put into the signal as before, except subjectively and behaviorally, you didn't see the image anymore.