Cliff Mead: Good afternoon everybody and thank you for coming on this lovely sunny Thursday afternoon. This is a official welcome to the 2006 Pauling legacy award lecture sponsored by the Oregon State University libraries my name is Cliff Mead and I am the Head of Special Collections at the OSU Libraries home of the Ava Helen and Linus Pauling Papers. Before we begin I should particularly like to thank Karyle Butcher the university librarian for continuing to offer financial support for this biannual endeavor.

The Pauling Legacy Award was established in the year 2001 in honor of Linus Pauling and dedicated to the recognition of outstanding achievement by an individual or organization in a subject of interest to Linus Pauling. Previous reward recipients have been Daisaku Ikeda President of Soka Gakkai, Nobel laureate Sir Joseph Rotblat Professor Emeritus at the University of London, and Mathew Meselson Director of the Meselson Lab at Harvard University. This year's recipient is Dr. John D. Roberts, Institute Professor of Chemistry Emeritus, California Institute of Technology.

Dr. Roberts is considered by many to be the intellectual founder of modern physical organic chemistry and the many offspring of that field. He is a brilliant researcher, whose style of research permeated chemistry. He is a charismatic and inspirational teacher in fact he is probably one of the great teachers of this generation of chemists and biochemists. He is a scientist who is especially good at taking ideas from one field and transferring them to another, in this case physical chemistry to organic chemistry. He is also a voice for integrity in science.

According to professor George Whitesides the head of the department of chemistry and biology at Harvard University Professor Roberts is the person who taught organic chemists how to use physical chemistry, molecular orbital theory, nuclear magnetic resonance spectroscopy, isotopic labeling, etc. to define and think about molecules. These contributions to chemistry are so fundamental that they are now part of the foundation of the field. He is also the person most responsible for the idea of reaction mechanism in American chemistry, that is, chemists should understand how a reaction occurs and not just what reactants and products are. Although it is not commonly acknowledged, Roberts has been influential in the field of mechanistic biochemistry and was one of the first to use and develop techniques now taken for granted such as isotopic labeling, detailed studies of complex organic reaction mechanisms, development of nitrogen 15 and in particular for spectroscopy techniques, use of quantum mechanics to understand organic structure and reaction, and defining methods for establishing structures of reactive intermediates. Professor Roberts' work in NMR spectroscopy for organic chemistry was years ahead of its time and has been especially influential he being the first person to use many of these new techniques especially nitrogen 15 spectroscopy for biological systems.

This work lead the way for the more sophisticated methods that are currently used. Professor Roberts is considered one of the all time great teachers of American chemistry. He wrote books for graduate students on NMR spectroscopy and molecular orbital theory that were very influential introducing these influential techniques, these unfamiliar techniques. His textbook written with Margerie Casserial for undergraduates in first year organic chemistry was innovative on its emphasis on molecular orbital theory and spectroscopy and is used as a model for modern organic textbooks. Professor Whitesides believes that Roberts has had more diverse and more far reaching influence on chemistry through his teaching than almost anyone now alive.

He is an active of the national academy of science and Jack Roberts has always been on the side of integrity, always without compromise, honest, a beacon for uncompromising standards in science. I give you Dr. John D. Roberts in the 2006 Pauling legacy award lecture: Useful Knowledge about Magnetic Resonance Imaging. Professor Roberts. [5:17]

John D. Roberts: Good afternoon. Can we turn the lights down just a little bit so we can see better on the screen? It's a great honor for me to receive the Pauling Legacy Award. I have many many memories of Linus Pauling, a scientist, a humanist, a faculty colleague, chairman of chemistry and chemical engineering at Cal. Tech. and a most inspiring individual. I could spend an hour talking about Linus in addition to telling you if you haven't seen it, the marvelous collection of Pauling papers and memorabilia here at [Oregon] State, you should go. Clifford Mead and his staff have done unbelievable wonders with organizing and displaying the real Pauling legacy. But I have to be fairly brief about Pauling, because I expect that he may need to be convinced as to whether the collections committee made a reasonable or a not so reasonable choice this time around.

Now when I was young, a long time ago, when chemists got together and talked about chemists, which we liked to do, they'd find topics of conversation that were almost invariably Robert B. Woodward a young genius of organic chemistry at Harvard, later to get a Nobel prize, and a bit older Linus Pauling, who later got two Nobel prizes. There were plenty of things to discuss and both were already legends, but I had never seen Pauling in many of those early conversations. And so just 59 years ago I had my first exposure to him while I was an instructor at MIT. And he was to receive the Theodore Richard's medal from the Northeast section of the American Chemical Society. Our younger group could hardly wait for our first glimpse of the great man. When he came in I was surprised, I had no idea what he was like and he was much taller than I expected and as a wonderful showman he carried a large brown paper bag that caused all of us to wonder what was next.

After the introduction, which I don't remember a word of, he gave his introduction, which for many years I could almost reproduce verbatim. The theme was unsolved problems and at first he showed his general curiosity and how he used it to understand unsolved problems posed by advertisers. I'll just give you two examples, one was Canada Dry and the slogan "pinpoint carbonation, which makes your drink livelier and more bubblier longer" Linus said this violated the principle of conservation of carbon dioxide, how could you have more bubbles and yet last longer. He wrote to Canada Dry research department, but did not get a satisfactory answer. Then there was Air Wick, Air Wick is a popular solution used in the old days to destroy odors in your house. Linus' attention was particularly drawn by the use of what they called activated chlorophyll, because Linus had worked with chlorophyll and he was interested, that was supposed to catalyze this process. No answer from their research department. So he looked up their patent and that involved 100 pounds of chlorophyll mixed with 1000 gallons strong formaldehyde solution Linus concluded that the chlorophyll didn't do any activation but the formaldehyde deactivated your nose. What about the paper bag? After telling us about the then unsolved problems of ozone and some other molecules Linus pulled out of the bag a black box with steel needles sticking out of the corners and faces. To illustrate the unsolved problem of tantalum complexes he pulled out oranges and apples out of the bag and stuck them on the corners of this needle or in the face. Now needless to say the audience was enthralled and Linus became even more of a hero to me, but then I never dreamed we would become colleagues. Well I could tell you more about Linus, but I'm going to give you a talk, which is purely a exercise in education. [11:18]

If NMR or MRI specialists are present in the audience perhaps they should... Talk about nuclear magnetic resonance here and I pushed in nuclear magnetic resonance because I left MRI in the official title because I thought that it might get more people in to this and find it interesting, but I'm going to stick you with NMR in the process, so what is it, is there a simple explanation for how it works? NMR is what runs MRI. So this is an NMR spectrum and it's pretty complicated, but it can be calculated with a very few simple parameters with the peaks' positions and their intensities.

So the M in NMR stands for magnetic and we're going to be talking about atomic nuclei that have magnetic properties and of these we're going to consider particularly hydrogen (protons) because they are very abundant. There are this many hydrogen nuclei approximately in your body most of them in the form of water. And they're also the next to strongest nuclear magnets that we know of, very helpful. And so where does nuclear magnetism come from? Well every atomic nucleus has a positive charge and many but not all of them act as though they are spinning, and so if they're spinning they generate a magnetic field. And that's where the nuclear magnetism comes from. Magnetism also results from when electrons circulate in a wire coil and form an electromagnet, so that's a very common example of the same thing although you might think they're very very different.

So we can think of a nuclear magnet that's being an electron's nucleus, surrounded in electrons hold it in place and the nucleus is spinning around. Now this is not quite the way physicists think about it, we're simplifying virtually everything, but we here at least some ideas to show you how MRI works. So really NMR is understood by quantum mechanics and it's not easy quantum mechanics by any means, but fortunately these things can be described in classical terms. [14:14]

And so what I'm going to do is kind of outrageous. I'm going to compare a spinning nuclear magnet to a compass and a compass has a north and south just like a nuclear magnet has lines of force that connect the north and south. So to that extent they're going to be about the same. So I'm going to talk about a compass now at equilibrium in the magnetic field of the earth and I'm going to give it a tap and it's going to relax back to equilibrium. If you've held a compass in your hand you've surely seen that happen. Well that's what physicists call relaxation and we're going to talk a lot about relaxation later on because that's a part of MRI that's extremely important. So we know from magnetism that north and south poles attract one another and north north and south south both against repel each other and we can see these in the conventional diagrams where they show the lines of force by using iron fillings and you see the repulsion that's occurring here and the attraction that's going on over there. So we're going to use that fact in what's called the Oersted principle to manipulate a compass needle.

To do this we're going to have to generate magnetic fields by passing electric current through coils of wire near the compass needle. So we're going to use a rig like this, in which we start with this arrangement of coils battery and a double pole switch so we can make the current go one way or the other. And then we put a magnet in the middle of that and we're going to now see what happens when we turn on the power. So when the power's on the lines should be red and they'll be grey when the power's off. So it goes one way and that causes the needle to respond because the north pole goes towards the south pole of the electromagnets and then if we swing it the other direction by changing the position of the switch the current's going the other way it's attracted in the other direction.

Alright so what we want to do is get this swinging and we do it by alternately turning the coils one direction or the other and it's just like you have a swing and you push on it and pull on it and push on it and pull on it and you get things swinging. So we've got this compass needle so it's swung out as far as we need to have it go and now we're going to talk about its relaxation to go back into the magnetic field of the earth. And so it settles down that same way, it starts off far over and then it goes back and forth and finally winds up at equilibrium. So that's the equilibrium process here, but that doesn't help us very much with NMR or MRI, let's see what we can do about that.

We need to know what's going on and we're going to use the Oersted principle, which is vital to this activation, we've already used that, so now we're going to use Faraday's principle, which is vital to the detection of NMR signals. Now Michael Faraday discovered in 1831 that you could produce an electric current by moving a magnet inside a coil of wire, and this is a basis of electric generators and all types of modern things. He was asked by the queen one time when he met here what good was going to come of this and he said "Madame, at some time you're going to be able to tax it." And so now you move the magnet in and the voltage generated to the right and the faster you move it in the more coils you cut through the larger the voltage and then you push it out the other way and it starts going back and finally when you get it back outside the current goes off.

Alright so how does this work with a compass needle that's not in equilibrium with the earth's gravitational field? Well we start with the needle over on one side and we let it relax. And so here it is over on this side and we have it connected now to a chart which measures the voltage and the red line will dim a little bit as the times when it's swollen in current as it goes back and forth and what we see are points taken as we go along like this as the compass needle is swinging back and forth and when it goes through zero at some point goes to the top and stops and comes back on later on.

So we get a decaying curve, it's a rough curve and if we had more points it would be much smoother up here, but it's still the right idea. And this is an idea which is very prevalent in NMR. This is what happens in NMR when you do the same thing with the nuclear magnets and you record their coming back, relaxing back to their equilibrium state. [20:14]

So our procedure up till now with either the compass needle or with NMR is to have those in their equilibrium in the magnetic field and then we supply this push pull magnetic field to get them, compass needle or the magnetic nuclei, oscillating and then we shut off the magnetic inductor and we follow the decay sensing the voltage as we go along by using the coiled wire so NMR and our compass needle are very much the same, we'll pick up some differences a little further along.

So we have here a decay curve, which is of signal versus time. Now there's another way of playing this game and that's to apply a strong magnetic pulse and then follow the relaxation, which we call a FID, and the FID (free induction decay) is observed as the NMR signal decays away. Well now the power of NMR in chemistry arises from the fact that even hydrogen nuclei put in different parts of a chemical molecule have different frequencies. And so they oscillate and interfere with each other in the FID because they're different frequencies. If they were all one frequency then we'd have the smooth curve that we'd had before, but when you have different frequencies you have interference patterns and so you get something like this and that is not very useful because we can't see the peaks that we saw in the initial NMR spectra and you have to use what's called a Fourier Transform.

Fourier Transforms are interesting, developed in about 1810. Fourier was a Frenchman and his colleagues didn't like his development at all and the reason they didn't like it was because it's so hard to calculate you had to take thousands of sines and cosines and that's not an easy process with the mathematics at the time when they didn't have computers. So now we can do that very very rapidly and we can confer this FID which has all of the frequencies in it which is a function of time, into something then which is a function of frequency.

Well this was the first hydrogen NMR spectrum of an organic compound which really showed something and that is a ethyl alcohol and it's a very familiar compound to all of you but this was enormously influential, because it turned out that as I said before, when you put the nuclei in different places in the molecule they normally have different frequencies. And so here we have three main frequencies and the structure of ethyl alcohol as HOCH₂CH₃ and we have here one hydrogen you can see the peak corresponds to one, this one's two, and this one's three and so there's an absolutely unique analytical system here that you can hardly do with any other form of spectroscopy, in which you can measure directly the amount of hydrogen that's in one group or another group or still another group. And that prompted people to get into NMR pretty fast.

And this is ethyl alcohol in a more modern spectrometer, still isn't the ultimate, but you have the FIDs shown here and then you have the Fourier Transform of it. Now you see something new that the people earlier in 1951 did not see because they didn't have enough resolution to get four peaks in the middle and three peaks on the end and those tell you an enormous amount about the structure of the molecule and we call ... splitting. I'm not going to go into detail about that because it's not important for MRI. [24:45]

So we've got NMR sort of covered in a way here. It's wonderful because it's nondestructive so samples can be recovered and used over again. It works for gases, liquids, and solids. It can be used to establish a structure of very large molecules to a limit but very large proteins, in fact, in solution you don't have to run a crystalline structure you can do them in solution and see how they move around. And it can be used to measure very very fast reactions and analyze complex mixtures. And you can run it in all kinds of solvents, which you can't do with many other forms of analysis. You can run it in sulfuric acid or you can run it in hydrocarbons like acetylene.

Though this is an old NMR spectrometer it was the first one we had in 1955, that was many years ago, it doesn't look much like our compass, but the parts are there. And this was the magnet, which weighed two tons, water cooled, and the oscillator and receiver coils are in the center of the magnet gap along with the sample and the sample is that little tiny glass tube that you can barely see in there, about that thick, still the same size today as the standard that uses normally about 1mL sample.

So now let's go to MRI and see how it's related to NMR. This is an early MRI, which was done in color, unfortunately radiologists don't like things in color, they like them in greys and black and white, and they're probably right, but this makes a nice colorful display of your head anyway and you can see the eyes very clearly and lenses of the eyes and so on. This is a fun that and I have a big reproduction of it in my office.

So now if we're going to do MRI we want to see how it compares with NMR. We've got to have a magnet and I put in a horseshoe magnet, which is really not correct, but it's good enough for what we want to do, you know there's a magnet there and a magnetic field. And then we need something which is a magnetic oscillator like we had before from which we had those coils and we moved the compass needle back and forth and we're going to move the nuclei back and forth now. And we have to have something which is sensitive to the variations in the magnetic field which you get when the thing is moving back and forth during the process of relaxation. And finally we have to have somebody in the middle to use as a sample preferably with a lot of hydrogens and magnetic nuclei.

Okay, in just twenty-five years MRIs have become an absolutely pervasive vitality for investigating human anatomy it is always regarded as being much too expensive and now most hospitals and so on have two or three of them. And so it's a variation of NMR, then why isn't it called NMRI? Well that was because general electric, who was manufacturing the early MRI machines, they wanted that N letter out of there. They were afraid that the public would associate it with nuclear medicine and radioactivity. Now there's a new idea we need here, how can MRI map anatomy? How can it locate positions of different things in the body like your eyes or something like that? Well our approach to the mapping problems, first to try to explain what we're trying to do, and how we do it in a very very simple kind of way. But you have to understand that we're not going to really solve the human problem very easily because the human problem is 3 dimensional and we're going to get something that's going to be represented on a flat surface like a film or a picture or whatever.

Now one way you'll find out about the way in which things are constructed like a cucumber, we slice it up with a knife and look at the various sections and draw conclusions from that. And MRI and CAT scans provide those representations without the aid of a knife fortunately. So what we're going to do is to use two dimensions instead of three and we're actually going to start out with almost a one dimensional spot. And so we're going to start with a head, which has just two dimensions and a brain which is made up of three tubes of water. [29:49]

Okay so we're going to have these three tubes of water, I had them originally with the diagram of a head behind it, but it doesn't matter, and we want to be able to find the distance of each one of those from the magnet. Now use the magnet's surface let's say as our zero point and we want to measure those things separately from that and so that's going to look like it's going to be quite a job. We're not going to be able to use a ruler by any means. You can't use a ruler inside somebody's head and yet the basic idea about this is very very simple, now look carefully. Now first of all you have to know, and we haven't mentioned this before, that the frequencies of nuclear oscillations that we see can vary very precisely on the strength of the magnetic field. The key equation is very simple it's simpler even than πr2 that the frequency is equal to B which is the strength of the magnetic field times a constant, now that's not very complicated. So we need to know that, so that's the key to this whole business. And so now we can make a plot of how the frequency some nucleus will depend on the magnetic field and we plot the linear plot, it goes straight up and as you expect the value of the constant determines the slope of the line but basically it's going to be a linear plot of frequency versus magnetic field.

Well what can I do with that? Well I could make a magnetic field change with distance from the magnet then the NMR frequency of the sample of D₁ should be different from the frequencies of D₂ and D₃. In other words, magnetic field falls off say as a function of distance then each one of those is going to have a different frequency, very simple. So let's start and generate a magnetic field that decreases with distance and goes like this. This is a B field, that's how the magnetic field and this is how it decreases as a function of distance. Now I've done this by a straight line, but it doesn't have to be a straight line, it can have loops and anything else as long as you know what the variation is like. You have to know what the variation is like to play this game. We'll assume it's a linear line, it just makes it simpler. Alright so now we put the frequency as function of magnetic field with the distance graph on the same slide and now we locate, we know the magnetic field and so we know a distance if we know the magnetic field. And so we can go forth from there backwards and now we can go use this value here of the magnetic field and, I keep forgetting that you're looking at something that I'm not looking at, and see how it goes, but anyway you can see how it goes from right to left on the B graph and then we can take the number that we get there and put it over on the magnetic field strength and then we can go upward to the frequency and now we know what the frequency is.

Alright, so now we can turn all of that around because frequency is what we measure and we can start off with the frequency and go backwards and wind up to get the distance. And so that gives us a very simple way of measuring the distance. And the extraordinary thing about this development is that, and I'm ashamed to say because I was one of those involved, it took 15 years before that was recognized that this was a way of measuring distance. I could be a millionaire if I'd thought of that, but that's not much fun.

Alright so now we know where that tube is so we'll start a map of the head of the person that's in this simple minded thing and we'll put a point there that belongs to D1. And then we play the same game for the other things we know where there frequencies are we can get from them the distances. And that gives us a map of a three dimensional thing, which we're thinking of in just one dimension now and we have to go a little farther later on to find out how we get the other dimensions. [35:08]

Now this is the first example of somebody doing this intentionally. I'm sure that I did it many a time unintentionally and I was mad at the magnet because it was giving me different frequencies for the same thing as I moved it around the field. Well Paul Lauterbur who got a Nobel prize in 2003 for this development. He took three tubes of water just like I did back there and showed that they could get different factor of something through the tubes of water by using a known variation of the magnetic field. Brilliant guy.

Well now we come to the real problem. What do we do when we have to plot out something for lets say the whole ball of wax here, what we really need is we use a two dimensional thing which corresponds to a slice. So I think about this in terms of many tubes of water. There are 45 tubes in here and each one of them has a different color more or less. Anyways so that's what we need to do, well how do we do it? Well we need to locate what we're doing and how do we start? Let's say we're going to start by locating one signal from just one tube near the center of the rectangle of the tubes, well how do we do that? Well first we do what we did before. We put a gradient field on and now remember these tubes, each one with water in them, and each one has the same frequency in the same magnetic field and so what we're seeing here is something in which we apply a field in the direction in which if giving each one of those the same frequency. So all of the ones in that row are going to have the same frequency and show up on our screen well that's not quite what we want.

So we do this and we get this composite like this that has all of them in the row and not the one we particularly want. So to get a signal from that one separate from the others that are in that same row we have to run our gradient field in a different direction. So we run it the other way, in other words we now get all of the ones that are crosswise and so they all come in as one just like the first one goes the other way. So now if we applied two gradients at the same time then we are able to get from this, one gradient gives you direction one way and the other gradient gives you the direction other way. So just changes in the magnetic field that are giving you the information you need to spot that one point in the center. And so we can operate from there and we can do the one next to it in the same way and we can do the one next to that and so on. And so finally after a lot of messing around we can get them all and we've got an array in two dimensions. Very very simple, all that's involved is variations in the magnetic field when we have frequencies that are compatible with the nuclear magnets.

Well, this is not actually the best way to do it. You have to find one spot by using gradients and now in three dimensions, if you're going to get the three dimensions you're going to have to have a gradient in one more direction and this however was used by the way we've done it here by Damadian in 1977. And this is the first MRI image of a human body and it was Dr. Damadian who was kind enough to send me a copy of his first body scan. And two of my kids were going into medical school at the time and I asked them what they thought of it and they sniffed, but I think they now have come to the point where they realized that it's actually pretty good. This is the, over here on the lower right, you see a gentleman who produced the scan and he had to sit there for four hours while they kept moving the magnetic field around to get the picture that's on the left, but it is a real first and that's a very important contribution to medicine. [40:39]

So now what we do is use a more efficient process and that's really to do a slice. We can do a slice one time by having a gradient in a particular direction, getting all of those nuclei activated in one plane. And then going through with other gradients and sorting them out so that you get a particular point. That's technologically a fairly difficult process, but the theory of it is really quite easy. So we have this difference between point by point and the slice activation.

Now let's look at some images. I'm ashamed to say for any radiologists that are here that these are very very old images, but that's not the point. The point is to illustrate to you what we're trying to get out of it. And we see here different ways that you can look at the human head by very simply changing the direction of the gradient and the so called transactional form we're activating along this way through your head and the coronal thing we're activating this way and then the sagittal thing we're activating this way. It's very very straight forward and it's easy to do because you don't have to change the position of the patient at all. All that you have to do is change the position of the magnetic field. And when we get down to more details we can see things like this is a special picture of an eye that I've always liked and that I included shows the very closely what the eye is like and what nerves come out of it and so on, it's a very nice picture and done very early.

Now this is the first imager that I was exposed to in 1982. It was the first imager in southern California and the doctor who was in charge of that would have to be one of my students, a Cal. Tech. student, who happened to be one I taught organic chemistry to. He's an interesting man because he got a Ph. D. in chemical engineering at Princeton and then he went to medical school and he came with a real knowledge of physics which is very important and unfortunately most of the doctors were not so well off in that regard.

This is the way you probably have gotten, I don't know how many, how many people in this audience have ever been in an MRI image, raise your hand. I'm getting nearly everybody, that's pretty good. And this is the more common thing from general electric that its older model, but it's the same thing. You go in and then they turn all of these gradients on. This is one and I don't think it's so popular anymore, but some people get very claustrophobic inside an MRI magnet and this is one way to solve that problem, but it's hard to get a large enough magnetic field that way.

Now we've solved one problem, but we haven't really solved all of them by any means. And one problem is that we haven't done, why do we see different amounts of black and white, which correspond to blood and fat, bone, muscle, and all of those things. We've seen how we can get the distance, but we haven't seen how we can get our different colors for those. And here I'm going back to the compass needles and their behavior in the magnetic field. So this is what you would have expected from what we were doing before, that we would have a compass needle and we would have the magnetic inductors and so on. But that's not enough, what we've got to have is something that we can compare to another place in the body, in other words we're going to have fat on the head here and watery stuff in the middle, we've got to have a comparison between those. That's what the contrast is all about. [45:09]

So we'll illustrate this with four needles, which is not enough compared to the ones that are in your body, but it's enough to illustrate the principle of things and that's what I'm trying to do. Okay so now we've got these four needles, compass needles, and we're going to activate those in the usual way sending them into oscillation and we do pull and we do push and then we do pull and finally we've done enough in principle so that we know what we've got, we've got those needles moved over out of the normal direction of the magnetic field. So now relaxation starts. In this process it generates an FID and so what we want to do now is watch whether these needles swing together as they're relaxing or they swing at different rates. And so we see these like this, they swing together and we call this "phase coherence", in other words the needles are cohering with, acting together and that is a very important kind of relaxation. So the coherence signal decay is going to give a nice smooth FID that's going to last for quite a while and that's one what that this thing's going to happen. But then there's a different kind of decay, in which the needles do not decay together, they get out of coherence and so we start them off with relaxation and we see that they start to swing back and forth and they're going to loose phase coherence like this one and the second one up is in different position than the others. If they're decaying at different rates, that causes the overall decay to become faster and so this means then that if we four needles say in our liver and another four needles in our muscle that they're not going to decay at the same rate.

Alright so if we take this back to physics what we see then is something that's, coherent decay we're going to call T1 and the noncoherent decay or less coherent decay T2. And T1 is going to be longer than T2 because there are no interferences in it. And so this is going to be the basis of how we tell them apart. How can we do this? Well, what we have to do is to look at these FIDs that come from those decays and the ones in the picture up here on the left, the upper one, when we do a Fourier Transform we get a sharp line and when they have a faster decay that we have lower down, then it's going to give a broad line. And this is a marvelous demonstration of the Heisenberg uncertainty principle. If you can't observe something long enough to tell how sharp the line is or it starts to get fuzzy on you that gives you the broad line and if you can observe it for a longer time then you can get a sharp line out of it. It's a simple statement of the uncertainty principle and maybe you can use it someday.

So we get three ways now to measure the blackness or the lightness of the image at any particular location when we have a signal from that, either it's going to be a sharp signal or it's going to be a broad signal. Well one thing we can do is to look at the area under the curve and that's a measure of the number of hydrogen nuclei that are there. Unfortunately most of us are made up of a lot of water and the water is going to be pretty much the same where we are and this isn't a great way to find out, but it's a possible way. We can look at the height of the peak, which measures T2 decay, we can measure the rate of T1 decay. Any of those will give us something because T1 isn't going to be the same for all parts of the body and T2 isn't going to be the same for all the parts of the body. So this is what we're going to be doing and it turns out that T2 is uniquely useful and if we look at the body and we look at the rates of decay as a function of how much the molecules and nuclei move around, it turns out that if they move fast like on the left hand side you see that up there the signal decay times are longer, they're more like that. T1 and T2 go along together for a while until things start to get gooey. The motion starts to slow down. And so then T2 continues on downward as T1 goes back up and then this has a little bit of a problem because we have two different values depending on if we're on the right side or the left side. But biological material is more or less right in the middle of where the dip is and that makes things a little difficult because it's harder to separate out everything that you want to separate. [51:26]

Well now supposedly we just look at T₂ signal decay and the height of the line and we can assign that different colors. This is very short, we call that bone would be an example and water in bone isn't going to move around very much, muscle is going to be a bit more viscous, and blood is going to be something else again. Now we can assign things that are decaying fast, make those black, and we can make the muscle grey and we can make the blood white. Now remember, blood, white.

Okay so here's a T₂ weighted image of a head. This is the same head weighted by T₁. And if you want to really impress your NMR, MRI operator tell him you want a T₂ image, he'll be confounded. Now why do we want a T₂ image? Well you can see these aren't the same, they're the same individual, and the reason, the real reason, is the blotches in here are a sign of MS and that means they're more watery, they can move faster. And so this is a wonderful diagnosis for that purpose. And here's an example of one head in 25 milliseconds, 25 thousandths of a second, to the next one to the right is 50 milliseconds down below is 75 and then 100 here. And you notice how things are changing and that depends on the T2 of the material. Now up here on the top of the left one you see fat. Well fat doesn't move very much and so it's not surprising that it decays away pretty fast. Now other things that are more watery tend to stay bright longer and this gives us some valuable information

Now here we have a full body scan that's possible to do, and this individual is a good example of fat. Alright, now what's really important for many diagnostic techniques is that Damadian established that cancer tissue has more water in it and a longer T₁ and T₂ values than normal tissue. So what can we do with that? Well here's an example of someone who has a liver tumor. Now this is the first one in the upper left. That one is very shortly after the pulse and the decay hasn't really had much effect yet, everything's about the same. But as the decay goes on the tumor which is this big site thing over here begins to be whiter because it has a longer T₂. And then as you go further down and over to the right the other things have pretty much decayed away and Damadian was right, the tumor does have a slower rate of decay than the other things that are around. So it's a very nice diagnostic tool. [54:55]

Here's another one, which I have to explain in a little more detail. This is a midsection; you can see the remnant of an arm over here on the left like a lamb chop, which is not surprising. And so what do we have here, well this is a aorta and this is an enlargement and see here on the right, upper right, that there is some plaque in that aorta, which could be, I'm not a, I don't know how dangerous it gets and you have to do something about it, but anyway you can see that plaque is there. Now if you move down just one inch then you find that there's less plaque than there is further up. So you can locate the plaque as it is up and down the aorta. Well I said that blood is gonna be white, but you notice back here that the blood is black and so why is that? Well it's very simple. What I'm going to so is active my patient right across here and when I activate them I'm going to activate the blood that's in the aorta that's shown by the pulsed blood in the aorta and then in a very short time the blood's going to move away. The activated blood is moved away and then unactivated blood is going to take its place and that blood's going to be black. So that's why things that look black after blood, after time. But we can change that by following the activated blood.

One case, on the left, we're seeing the blood go up into the brain in the other case, on the right, we're seeing blood coming down through the legs. And when you look at people who have been in an automobile accident, their legs, you find that they're going to be very messed up when you run the spectrum like this one. Now the heart is an interesting example; it's something that moves all the time which is not so good for MRI or the older type particularly because we're taking the spectra pictures over maybe 5 minutes or so. And so there's a lot of motion going on and that's going to blur the thing, but the heart though beats pretty regularly so you can arrange it so that the pulse comes every time in the same part of the heart beat. And so when you do that you can get coherent pictures and they have wonderful ideas about what the heart's doing and movies and all kinds of things. And here we have one person that looks pretty normal over here on the right looks a little different because there's a malformation of the heart and the blood doesn't clear as well as it should. An ordinary heart you time it right, that blood should move out, but it doesn't in this case so you find out something about the heart circulation with the MRI.

Now originally radiologist and orthopedic surgeons were skeptical about using MRI for bones and joints, but it turned out to be really important. And we have a knee joint over on the left, it's not a great one, but it's pretty good. And we have the back, a fairly normal one on number B. And then we have my own back on C and you can see it's a mess and I keep hoping someone will find out what to do with it. But anyway it's a very wonderful modality because you can take a picture straight down this way and you can't do that easily with x-rays, you just have to start at your head and go all the way down. And so it's a really marvelous modality in which you can take in every direction by simply taking and changing the magnetic field gradients.

Now a very big step forward in all this is a Echo-Planar Imaging developed by a man named Mansfield in England. And he had been pushing this for a really long time and he finally got is so he can make images in a fraction of a second. They're not as good of resolution as the best, but nowadays it's coming to very very good resolution over a very short time with the improvement of electronics and improvements of magnets and everything else. And so these are single shot images of an abdomen about 0.046 seconds about 1 inch apart. And you can see that they're different and they're very important because your intestines and so on and motion of the liver makes early MRI images of the abdomen not so reliable and well that is now possible using echo-planar and other kinds of imaging. The reproductions here are terrible, but they're actually much better pictures than this. [1:00:26]

And so here's a spectrum that looks very strange. We've got a big white area that's down here. You might say, uh-oh that's a brain tumor. Well it isn't, it has something to do with how the brain works, which is very very popular today. And this is one of the first examples is to take a subject, cover one eye and put light in the other eye and see what happens in the brain. And it turns out that the brain has activity that wants to use oxygen, needs to use oxygen, in order to activate the nerves and everything. And so what's happening in this process is that the brain actually puts in more oxygen than it really needs to because it doesn't really know how long you're going to want to experience this sensation.

And it turns out that changes relaxation time, oxygen helps to facilitate relaxation. And that gives an image in which now we're having more rapid relaxation than we'd have otherwise and it's turned out that mapped out this particular way. This is just going like wildfire all over the country. People are trying to find out how different emotions, how different motions, and how different sensations effect the parts of the brain and are doing wonderful work mapping out where these things occur in the brain and comparing the individuals that do it.

So I want to acknowledge my debt to William Bradley who was a Ph.D. in chem. engineering from Princeton who I worked with some. I actually tried to start a little research in MRI, but I kept running into problems, in which somebody would say you're using our magnets and we've got somebody outside on a gurney and we've got to do an MRI right now. And so that didn't fit with research very well. And then he was there and went to Long Beach, and now he's the chairman in the department of radiology at the UCSC and he provided almost all of the MRI scans that were used in this talk. So here's somebody who's a early electronic experimenter, that's me. And that's the end, thank you very much.

Yeah, I've got a microphone if I can understand what they're saying. It's a big crowd in a big room so we have to do something. Yeah.

Audience Member: Dr. Roberts, when the blood is activated, in the MRI the blood goes through and you said it becomes dark.

John Roberts: No the dark blood moves in.

Audience Member: How long with the blood actually stay activated?

John Roberts: Well it depends on T₂ for one thing, if the blood has got something in it like oxygen then it will tend to have a shorter T₂. So let's say if you take blood and put it outside in an NMR spectrometer without the physiological parts of about it takes about two seconds for the water to relax.

Audience Member: Can you get it so detailed that it's looking at the platelets in terms of how much for something like leukemia?

John Roberts: It makes a difference, but I don't know how important those differences are. Now as I said Damadian made a big difference for cancerous tissue. Now if you're trying to look at something like MS you see that already that there's a difference there. So a lot depends on how sensitively you set the thing up that's one thing, but I would expect that almost all things that you can see in the brain, problems you can see, strokes or malformations or whatever, all of those are going to somewhat different T₂'s. [1:05:05]

Now let me say one more thing and then I'll get down. As I said before when I've given this lecture the first question is always "why is this so noisy?" And the explanation is very simple and sometimes even MRI technicians don't even know the answer, which really surprised me. It's that basically these coils are very analogous to a loud speaker. And so when you pulse with a gradient in order to change the magnetic field, what you're doing is basically putting sound energy into the framework because the coils are fastened to the framework. And so you're getting that kind of thing and as you use different gradients you hear different sounds. Sometimes it sounds like a chirping sometimes it sounds like it's going to blow you out of there. And all of this is just a really loud speaker kind of thing going on, that is the result of putting in a gradient.

Audience Member: I was wondering, what would happen if you go into the MRI machine with a metallic object like a watch....With a metallic object. Like if you have metal on you.

John Roberts: Well there are all sorts of problems with pace makers and things that you have in your head, plates from surgery and so on. So you'd for example, a pace maker, they'll ask you if you have a pace maker and you've got one they'll tell you that no you can't come in here because they use a magnetic field that changes the rate of a pace maker. So when you get in a big magnet it shuts the thing off. And that's not so good, but it doesn't seem to turn out to be very important about the fillings in your teeth, although in Russia they had a lot of steel fillings and those really distorted the mouth. So there's all kinds of things like that, details of operation. Okay, I hope I answered your question.

Audience Member: What are some of the general field strengths achieved inside the MRI machine where a body is placed into? How much you have to change the gradient? What is the field strength inside the area where a person goes into?

John Roberts: When you want to get some line along there? I'm not quite sure exactly what you want. This is for, I'm not sure about the strengths of the gradients or what? Well that will depend on how much magnification you want and it will also depend on what the magnetic field is, how much of a gradient you have to have and how much resolution you want to get. Now you can use MRI, it's used by biologists on a micro scale. You can actually look at individual cells and take slices of those. But if you want to do that you've got to have a very steep gradient in order to get differences in frequency and so that determines really what's going on. What kind of resolution you want and what kind of a system you have, okay?

Audience Member: I have another question, I was concerned with blood. Now blood contains hemoglobin, which contains iron, which is paramagnetic. And so how does that, and when you have a magnetic field something is going to happen. So what happens to the hemoglobin in the blood when there's a magnetic field around it?

John Roberts: Well actually not so much as you'd expect. We've done some experiments on the, you might say, the packing of blood. There's a technical term for it, when you condense blood down to almost where there's just a single mass of stuff to very dilute blood. And it doesn't really seem to make that much of a difference the reason is that, the action is mostly in the water because of motion and inside the hemoglobin the stuff is giving the signals, it's just decaying so fast you can't see it okay?

Thank you. I think we've worn them out.