ࡱ> e |bjbjJJ b(_b(_bU&6 6 6 6 6 $Z Z Z P T!|Z 6fz#z#(###}$}$}$6 6 6 6 6 6 6$7:-66 {&}$}${&{&-66 6 ##B6555{&6 #6 #65{&6555#7zO/55X6065J;1~J;5J;6 5}$Z$@5%4K%0}$}$}$-6-6q3}$}$}$6{&{&{&{&J;}$}$}$}$}$}$}$}$}$B : John C. Liebeskind History of Pain Collection Oral History Interview with Kenneth L. Casey Ms. Coll. no. 127.53 Conducted: 20-21 April 2000 Interviewer: Marcia L. Meldrum Duration: ca. 4.0 hours Pages: iv, 60 History & Special Collections for the Sciences UCLA Library Special Collections Los Angeles, California 90095-1798 2016 Biographical Sketch Kenneth Lyman Casey was born in Ogden, Utah in 1935. He received a B.A. in Biology from Whitman College in 1957, and M.D. in 1961 from the University of Washington School of Medicine in Seattle, Washington. Following his work in the Laboratory of Neurophysiology at NIH (1962-1964), Dr. Casey held a postdoctoral research position at McGill University working with Ron Melzack (1964-1966). In 1966 Dr. Casey joined the University of Michigan as Assistant Professor of Physiology. While teaching in Physiology, he performed his residency in Neurology and became Associate Professor of Neurology in 1975 and, in 1978, Professor of Physiology and Neurology. Since 1980 Professor Casey has been Chief of the Neurology Service at the Ann Arbor VA Medical Center. Dr. Casey has published numerous ground-breaking neurological and physiological research studies on pain. Included among the many distinguished positions Dr. Casey has held are President of the American Pain Society (APS) from 1984-1985, Founding Editor-in-Chief of Pain Forum, and Councillor for the International Society for the Study of Pain (IASP) from 1986-1990. Interview History Dr. Kenneth Casey was interviewed on April 20 and 21, 2000, at the VA Hospital in Ann Arbor, Michigan, by Marcia L. Meldrum. The interview lasted approximately four hours. The transcript was audit-edited by Cynthia Maya and reviewed by Dr. Casey prior to its accession by the History of Pain Collection. The tape and transcript are in the public domain, by agreement with the oral author. The original recordings, consisting of three (3) 90-minute audiotapes, are in the Library holdings and are available under the regulations governing the use of permanent noncurrent records. Records relating to the interview are located in the offices of History & Special Collections for the Sciences. Topical Outline (Scope and Content Note) The interview is arranged chronologically with topical digressions. In it he discusses his childhood, education and decision to study medicine; early research and interest in studying the brain at the University of Washington; debating whether to become a clinical neurologist or doing basic neurophysiological research; working with Paul MacLean at NIH for his military service; interest in pain research stemming from work of Wall and Melzack; gate control theory; working with Melzack at McGill; joining staff at Ann Arbor as a neurophysiologist; returning to clinical medicine in neurology in the early 1970s; animal models for the study of chronic pain; the Bat-Sheva seminar, John Bonica and Issaquah; the Pain Forum journal and experience as President of the American Pain Society; and medical training about pain. Throughout he discusses many of his significant research projects and experiments in diverse areas of the pain field. Access to the Interview This oral history interview, in its audio and transcript forms, is held by History & Special Collections for the Sciences, a division of UCLA Library Special Collections located in the Louise M. Darling Biomedical Library. Those wishing to use the printed transcript or the audiocassette version (which is available by appointment only) should contact: History & Special Collections for the Sciences, UCLA Library Special Collections, Louise M. Darling Biomedical Library, Los Angeles, California 90095-1798. Phone: (310) 825-6940. Terms and Conditions of Use By agreement with the oral author (interviewee), the contents of this interview are placed in the public domain and are made available for use by anyone who seeks to broaden the understanding of pain. However, users must fully and properly cite the source of quotations they excerpt from this interview (see Citation Information). Citation Information The preferred citation for excerpts from this interview is: Oral History Interview with Kenneth L. Casey, 20-21 April 2000 (Ms. Coll. no. 127.53), John C. Liebeskind History of Pain Collection, History & Special Collections for the Sciences, UCLA Library Special Collections. Editorial Note The interview transcript has been annotated -- with notes offset in [square brackets] -- to clarify and enhance the readers understanding of the concepts and events described, but as sparsely as possible, so as not to interrupt the flow of the oral authors thoughts. By and large, the transcript is a record of the oral authors ideas and recollections in his own words. Acknowledgments Support for the John C. Liebeskind History of Pain Collection and its Oral History Program came from the American Pain Society and the . . [PHOTO PORTRAIT NEEDED] Kenneth L. Casey, MD Neurologist KENNETH L. CASEY INTERVIEW TAPE ONE, SIDE ONE MARCIA MELDRUM: Good morning. KENNETH CASEY: Good morning. MELDRUM: Its April the twentieth in the year 2000, and were in Room 420 of the VA Hospital in Ann Arbor, Michigan, a really rainy day with buckets of water coming out of the sky, and were beginning our interview with Dr. Kenneth Casey, whos the Chief of Neurology here at the VA and a long-time researcher in many, many different interesting areas of the pain field. So Dr. Casey, Id like to begin the interview by asking you to think back to your childhood, when you were growing up, what your family was like. I dont even know where you grew up. Was it in Washington? CASEY: Well, I was born in 1935 in Ogden, Utah. But we didnt stay there very long. My father died in an accident before I was born, and my mother remarried, and by the time I was four or five years old, she had remarried, and my step-father worked for Federal Prison Industries. At that time, as the war was beginning, federal prisons were important sites for making clothing, skis, canning food, everything for the war effort. So they were big outfits. People didnt realize what was going on. I say that because it accounts for the itinerary of my childhood, which led from there very briefly to Bethesda for maybe a couple of years, and then from there to Steilacoom. My first really vivid memories are of growing up as a child in Steilacoom, Washington. Steilacoom is a town between Olympia, Washington, and Tacoma. Its right on Puget Sound. The reason we were there is because the federal prison, McNeil Island, was located on Puget Sound. My parents would go every day on a boat, a ferry boat, from Steilacoom out to the island, as they called it. I went to school in Steilacoom from the second through about almost the fifth grade, and it was a Huckleberry Finn type of existence. I played in the water and -- Fort Lewis was nearby, and a great sport was to go to the Fort Lewis dump as kids, where they threw away old helmets and leggings and ammunition belts, and things like that, and it was a great prize to get -- a helmet was the greatest thing you could get. Wed see the soldiers going through maneuvers in the town of Steilacoom. Anyway, all of this was going on. We made rafts and we would do all kinds of dangerous stupid things like going out on Puget Sound, just a couple of little kids. Anyway, it was a wonderful time. Then we moved from there to Atlanta, where theres also a federal prison, a completely different culture. And I had to survive as a Yankee. MELDRUM: In the South. CASEY: In the South, at that time. I adapted to all of that, but I had some unpleasant experiences in the South. And then we moved -- nothing serious, but I had a lot of fights. And the schools werent very good. MELDRUM: That was the fifties, right? CASEY: Yeah. Well, lets see. I was in the sixth grade through early high school in Atlanta. MELDRUM: Okay. That would have been the forties then. CASEY: I acquired a deep heavy Southern accent. MELDRUM: Did you really? CASEY: Oh, yes. I had to. [laughs] Unless I wanted to get into a fight every day. I didnt want to do that. Then we moved to Terre Haute, Indiana, where there is also a federal prison. And there, I worked on farms. We lived out in a rural community. I went to a high school called Honey Creek High School and graduated in a class of forty. Everybody was a member of the Future Farmers of America. MELDRUM: I grew up in Indiana. CASEY: I would work after school and during the summer plowing, running a tractor, putting up hay, castrating hogs, et cetera. Everything. For a while I worked at Pfizer Research Farm. Pfizer had a research farm outside of Terre Haute, and I worked on the research farm taking care of the animals, herding boars into where the sows were, and so on. [laughs] MELDRUM: Were they doing animal feed research? CASEY: Well, they were doing--I could tell they were doing vitamin research. I asked them what they were doing. And they were finding out how to grow bigger and better and healthier chickens and turkeys, and hogs, and so on. So I was really a farm -- I was then transformed into a farm kid. I had very little idea of going to college, except that three of us in the class, for reasons I dont really understand, but I think because it was a small school, teachers took a few of us they thought were interested in things and paid special attention to us. Anyway, I took four years of Latin, and I took some chemistry and physics, and I liked that. And I took -- what was it? -- _____ math up through solid geometry and a little bit of calculus, which at that time was very unusual. MELDRUM: That was a very rigorous program. CASEY: No. Actually, even -- despite all this, I didnt really have much of a notion about going to college. MELDRUM: What were you thinking of doing? CASEY: Well, I would have been perfectly happy to have been a farmer. [laughs] I mean, at that age and in that time, the future was the present. You didnt think much about it. You didnt worry about things. The things that ruled my life at that time were testosterone and corn. The testosterone was mine and the corn was somebody elses. But then a few of the teachers would say, Well, you should go to college. And my grandfather, that is, my biological fathers father, was an attorney in Walla Walla, Washington, and my biological father had gone to Whitman College, which is a small privately endowed liberal arts college in Walla Walla. Its a good school. So my grandfather said, You must go to Whitman College. He took an interest in me, and he paid part of my tuition, and I thought, Well, I dont have anything better to do, so I drove an old 36 Packard all the way from Terre Haute to Whitman College. Then that was an intellectual awakening for me. I went to Whitman from 1954 to 57 -- or 1953 to 57. And did well academically and was interested in everything -- literature, biology, economics, and had an awful time deciding what to do. Went through the business of sophomore anxiety of picking a major and that kind of thing. So a friend of mine said, Why dont you go to medical school? Doctors know a lot of things. [chuckles] So I thought, Why not? He said, If you dont like it, you can always quit. Yeah, thats true. So I said, Well, Ill do that. I applied to the University of Washington. And that was it. I only applied to one school, went in for an interview, and went through the University of Washington Medical School, which at that time was a very young school. Now well start getting into a little bit of the pain business, I think. Part of the requirements for going through -- part of the curriculum at the University of Washington at that time was to have students in physiology do a research project. I dont know whether they do that now still or not. Our class was seventy-five, a tractable number. So I was able to start a research project, and you had a choice of what to work on, and I thought that -- At that time, I was just learning that the brain was a rather interesting organ and that it was possible, at least in theory, to understand all of human behavior and everything else by analyzing the brain. I also learned that it was possible to record the activity of single neurons. This was still an early time. My mentor was Arnold Towe, and he was a very intelligent, thoughtful, quiet person, who encouraged me and I started recording single cells in the cerebellum. He gave me a problem about how the cerebellum controls motor output, in a general way, and specifically, how the cerebellum affected the motor cortex. Without going into detail about how we did that -- this was cat research. Anesthetize a cat, do the surgery, and it was a pretty complicated preparation when I come to think about it. Using chloralose anesthetic, which is no longer used, or very seldom used now. And recording a thing called the pyramidal tract reflex. As it turns out, you can stimulate the skin electrically, especially if an animal is anesthetized with this peculiar anesthetic, chloralose. You can stimulate the skin, and after a delay of several milliseconds, you can record the discharge of the fibers that are coming from the cortex and going all the way down to the brain stem and into the spinal cord, called the pyramidal tract. This was called the pyramidal tract reflex. Basically, what I did then was to open up the brain, put an electrode into the pyramidal tract, and stimulate the cerebellum and stimulate the skin. I would interact the stimuli in such a way as to demonstrate how stimulating the cerebellum affected the excitability of this pyramidal tract reflex. All these things took a long time. I spent nights working on these problems, and I also recorded from [them] as part of my MD thesis. At that time, you could do an MD thesis, which I decided to do. And you could record single cells in the thalamus, which is what I did at that time. So that was my research project. That was my first introduction to everything. The people who were in the Department of Physiology at that time are some of the great names in physiology, who came from Fultons laboratory at Yale -- Ted Roux and Harry Patton. Arnie Towe was a local person, but he was part of this team. So I then was privileged to hear their discussions of what they were doing and how they had an academic argument going with Vernon Mountcastle. MELDRUM: At Johns Hopkins. CASEY: At Hopkins. Thats right. And how Mountcastle was right or wrong, or what the conflict was. I could see that this was an interesting argument that was emerging. And these fellows, Patton and Towe and so on, would be quite vigorous. MELDRUM: Fierce. CASEY: Yeah, right. It really mattered. I could tell. MELDRUM: What was the argument about? CASEY: Well, there were several, and I forget them all. But one of them was whether or not the cortex was organized in columns. Arnie Towe had a very different approach to the analysis of cellular activity in the cortex, and that involved a statistical analysis and the probability of discharge of different cells and what kinds of inputs there were coming into these cells, and so on. That idea, which has some merit, I must say, but is messier than the very neat idea that the cortex is organized in columns, and it is modality specific, and some very nice crystalline organization, rather than this amorphous mush that -- MELDRUM: With everything going in every direction at once. CASEY: Right, yes. MELDRUM: Or potentially. CASEY: Thats right. I didnt get into that argument. I just stuck with my cerebellar area influence on pyramidal tract and let it go at that. Another person who had been there in Seattle was Vahe Amaasian, who is still active, and hes at NYU. So the ghost of Vahe Amassian was there, and I would hear about, well, Towe and Amassian did this, and they did that, and so on and so forth. So I could see that I was on the edge of doing important things. And it was fun! And it was challenging, and so on. In the meantime, I was still a medical student living at the Nu Sigma Nu House in Seattle. By this time, I had been engaged to a young woman that I had met at Whitman, but to make a long story short, this relationship fell apart after I moved up to Seattle, mostly of my own doing, I must admit. I met my wife on a blind date on Valentines Day [chuckles], and I could see right away that this was a good deal that I had here, so I proposed in two weeks and we were married in three months -- well, something like that -- and have been married ever since. MELDRUM: Yes. A true romance. Thats great. CASEY: Right. She would accompany me, both before we were married and after we were married, to the lab and do her studying while I was sitting there with this oscilloscope and neurons crackling in the background, and things like that. Ultimately, from that, I wrote an MD thesis, and Arnie Towe and I published a paper in the Journal of Physiology, so that was my first publication. I thought, Wow, this is really something. I can contribute that way. At the same time, while I was interested in the nervous system, there was Fred Plum. Fred Plum is a prominent neurologist, who himself has not done a lot of basic research but who has thought seriously about neurological problems and the basic mechanisms that are involved in clinical issues, or that neurologists see and face. He is a very compelling and interesting man, who exudes authority. [laughs] More, in fact, than I am used to, but I enjoyed interacting with Fred a lot. I took an elective in neurology in Seattle and traveled around, just Fred Plum and I -- fourth year medical student on an elective and Fred Plum, who subsequently then became chair of neurology at the New York Hospital, Cornell Medical Center. He knew of my basic research interest and told me that I should leave Seattle. And because I was interested in neurology -- MELDRUM: You should leave Seattle because of -- were there more research opportunities someplace else? CASEY: Well, no. He said that I should go to Cornell and go to the New York Hospital to learn clinical neurology from Harold Woolf. Harold Woolf, of course, was almost a mythical figure [chuckles] in neurology at that time and had a very strong interest in migraine headache and pain in general. He wrote the book at that time called Headache, which I have here in my library somewhere. So I thought -- Well, by that time we had one child. My wife was working as a dietician at -- She had a degree in administrative dietetics and was working. Well, we just packed up and drove our VW Beetle to New York City. MELDRUM: Let me ask you just two questions. CASEY: Sure. MELDRUM: Okay. So you had this interest in the brain, and you certainly had an interest in research. Were you thinking at this point of a medical career or a research career, or were you just sort of up in the air at that point? CASEY: Well, I was conflicted about that. First of all, when I entered medical school, I had no idea about going into research. I had this completely absurd and romantic idea, of which I told my young wife, of being a general practitioner in Alaska or Wyoming, where I imagined myself on the frontier taking care of all who came before me. [chuckles] And perhaps even flying in an open cockpit biplane, bush piloting into the woods, and so forth. Of course, with my background, I love the outdoors, and so on. So thats what I was going to be. I was going to be a GP and go out and do those things. After I started doing the research -- and Id always had very strong intellectual interests, and that took over. So I abandoned that idea. Then the issue was, Was I going to continue doing basic neurophysiological research, or was I going to become a neurologist, clinical neurologist? Or was there some way that these could be combined? So then, I went to Cornell, and I suppose that if Harold Woolf had lived, my life would have been quite different. But three months after I got to New York, Harold Woolf died at an early age, supposedly of cerebral hemorrhage or stroke. Im not entirely clear. He himself is said to have had very severe migraine, which puts you at risk for a stroke. At any rate, he died. So the Department of Neurology there then had no leadership really, temporary leadership, and at about that time, there was -- the doctors draft still existed. And I had -- MELDRUM: This was the early sixties. CASEY: Yeah, right. Vietnam was not salient then, but you still -- if you were a doctor, you would get drafted. You were still obliged to do this, because we just got out of Korea -- I mean, theres an interval there, of course, between Korea -- Korea ended in 54 or 55, and the doctors draft persisted -- the inertia of that program persisted. Then, it was clear that there were other conflicts going on in the world. They wanted doctors in the army and navy, and so on and so forth. In any case, at that time, a young man -- not woman -- but a young man had to decide how to handle this problem. You could either do nothing and take your chances and get drafted. If you got drafted, theyll send you wherever they please in any branch of the service that they wanted. Or you could join what was called the Berry Plan [Armed Forces Physicians Appointment and Residency Consideration Program], and the Berry Plan -- a congressman named [Frank] Berry, apparently -- and that was to sign up for four years. If you didnt do anything, you were in for two years. With the Berry Plan, you could make a choice about where you were going to go and do that for four years. And I thought of submarine medicine or the air force. [laughs] MELDRUM: You had really adventurous ideas. CASEY: Well, see, in Seattle, what I didnt tell you, while I was a medical student in Seattle, we were poor as could be, so I learned to dive in Puget Sound. I would go out on the weekends, early in the morning, and go out and free-dive. That means I would float on top of the water and hyperventilate until I became a little bit dizzy and then -- This is a very stupid thing to do -- and then Id just use my weight belt and would then go down and spear fish, and I would catch lingcod, and I would bring them up, and we ate lingcod. But I enjoyed diving, so I thought thats why submarine medicine would be a glamorous and wonderful thing to do. And the Air Force. Then somebody told me, Look, Ken, if you go into submarine medicine, youll be doing psychiatry because everybodys canned up in these things. And thats the main thing. If youre in the air force, youll be doing a combination of psychiatry and ear, nose, and throat. That didnt sound very interesting to me. Then he convinced me that I was not going to drive the submarine, and I wasnt going to fly the airplane either. [both laugh] MELDRUM: I dont want you to do any spear fishing CASEY: [chuckles] Yeah, I couldnt do much spear fishing. So I thought, Well -- He said, Well, you can go to NIH and join the Public Health Service. So I wrote to -- Ive forgotten exactly how I got the name, but I wrote to the Laboratory of Neurophysiology, and there was an opening in Paul MacLeans laboratory. He was looking for somebody, and I could join the Public Health Service, serve my country in what we then subsequently called the Yellow Beret, and thats what I did. I convinced them that, as a result of having published this one paper in the Journal of Physiology and that I could record single cells, and all that, that I was a tremendous asset to them, [chuckles] and so I went down there. MELDRUM: And this was in NINDS, right? CASEY: No. Well, yes, it was in NINDS. Well, at that time, it was NINDB, I think. Because that was before there was an eye institute, so it was National Institute of Neurological Diseases and Blindness. At that time, the Laboratory of Neurophysiology was run by Wade Marshall. Paul MacLean ran a section called the Section on Limbic Integration and Behavior. I thought that sounded pretty jazzy and interesting. He had a colony of squirrel monkeys. Paul MacLean was interested basically in sex and the brain. MELDRUM: Oh, really? CASEY: Yes. MELDRUM: I didnt know that. CASEY: Oh, yes. He was interested in the neurophysiology of penile erection. MELDRUM: Oh, really? [chuckles] CASEY: Thats correct. [chuckles] MELDRUM: Through the limbic system. CASEY: Through the limbic system. so he was interested in how the hippocampus and the temporal lobe received visual information, as well as other forms of information. Because he thought, Well, we have to have some kind of sensory input into the hippocampus to drive sexual behavior, that is, visually triggered sexual behavior. MELDRUM: Descending proper neural signals. CASEY: Thats right. So the other person who was there at that time, just before me, was Michel Cuenod, who is a very prominent neurophysiologist/neurochemist -- neurobiologist hed call himself -- at the Brain Research Institute in Zurich. He was, in fact, the director of the Brain Research Institute in Zurich. But at that time, he was just a young guy like myself. He and I worked together on recording single cells in the entorhinal cortex, which is the pathway into the hippocampus. And our job was to see how visual input, light input, got into the -- first of all, if it did. So there must be cells in the interrhinal cortex that responded to visual stimuli, and we were to demonstrate that, which we did with great effort [chuckles] by recording single cells. As part of this research on visual excitation of the limbic system, Paul MacLean had a program of recording of the erectile display of squirrel monkeys. He would show them mirrors, and this would get the squirrel monkeys very excited, and they would have erections. MELDRUM: [laughs] Looking at themselves! CASEY: Looking at themselves, yes. Well, it turned out that almost anything that excited the squirrel monkey caused it to have an erection. If you opened the door and yelled and screamed, [chuckles] they would have erections and urinate. So here were these streams of urine coming -- It was really a bizarre [laughs] -- He also had a program in which he -- a research program -- he had electrodes that stimulated the brain, and he was interested in the pathways in the brain stem, areas in the brain stem that triggered penile erection. He actually found these in the anatomical projection territory of the spinothalamic tract. He would stimulate with small amounts of current in various places, and -- the monkey would be awake, wide awake, sitting in a chair, and he would move the electrode down through the brain, and stereotaxically - he developed -- he built a very interesting platform device that sat on the squirrel monkeys head, and the holes were already drilled. All you had to do was put local anesthetic in where these holes in the platform were, and with a very quick drill, you drilled right through the monkeys skull and shoved this electrode down into -- basically into the brain stem and looked for those places which stimulation would result in an erection. One thing you could do, you could stimulate in the hippocampus and temporal lobe and so on and produce a seizure. And that then produced an erection. Then the monkey was -- he was grading the erections, so there were erections that were one-plus, two-plus, four-plus, and so on. If there was an ejaculation, that was a cause for celebration. MELDRUM: Poor monkeys. They must have been very frustrated. CASEY: Well, I dont know. One never knows what the monkeys felt. But as he was going down and stimulating, he found places where -- some of this is published in the Journal of Neurophysiology -- found places where the monkey would scratch. MELDRUM: Itch. CASEY: Itch. And places where the monkey obviously didnt like the stimulus. So he was in the spinothalamic tract. So here we had -- some of these areas were close to the areas that also resulted in erectile display, and so on and so forth. So here was sort of sex and pain together in the brain, and its all very important [laughs] but mysterious. Michel and I sort of watched this kind of research out of the corner of our eye, chuckling at it a little bit. Because we were recording single cells. We were doing real neurophysiology. Anyway, Paul then had a sabbatical, and he left me alone for a year, actually a year and a half, with this colony of squirrel monkeys and nothing -- and to my own devices. MELDRUM: No direction, yes. CASEY: Well, Paul was not completely non-directive. By that time, I was getting some ideas about what I wanted to do. First of all, I was at the same time reading about somatosensory research and keeping track of the somatosensory system and the limbic system. So here were these two entities, the somatosensory system and the limbic system, and I had been exposed to both of them. So, I was reading still about the somatosensory system, but at the same time I was thinking about what would be an interesting problem to do, and at about that time, I read a paper by Ron Melzack and Pat Wall, which Ron says nobody else but me ever read. MELDRUM: The one in Brain. CASEY: Thats right. Gosh, you know this. MELDRUM: Yeah, I do. CASEY: It was called, On the Nature of Cutaneous Sensory Mechanisms. I thought it was wonderful because it again took such a strong position against the prevailing theory at that time that everything was peripherally determined and that -- This article actually poked fun at the idea that there are separate nerve fibers for every little sensation, that, instead, this information, physiological information, was integrated somehow in the central nervous system and resulted in itch and pain and touch and the somatosensory experience. MELDRUM: Right. Complex sensations. CASEY: Exactly how that was done was not quite clear, but this paper, as I recall it, really said that there is not a single nerve fiber for every sensation. Its not all determined peripherally. So anyway, I thought that was a great paper because it was iconoclastic, and I was always a bit iconoclastic myself, and I thought, Well, this looks like an interesting idea. I remembered the arguments back in Seattle about how -- So I thought, Pain is an interesting thing because if you knew what was going on at the moments an organism experienced pain, if an organism could tell you that it experienced pain, then youd know that it was conscious. At least I thought that you would know that it was conscious. So that pain was a way to really tap into that problem, several problems. One is, because the animal makes a sudden behavior, you know that at that instant that theres been an experience, the animal experiences something. So if you knew what was going on in the brain at that time, you would understand the neurophysiology of at least that experience and perhaps most experiences. MELDRUM: So the connection between sensation and behavior. CASEY: Right. Oh, yes. And the other is that -- the problem of affect. I thought, Well, pain by itself -- I dont think I got this idea out of that article. In fact, I didnt get this idea out of the article that Ron and Pat wrote in Brain, nor which came out later, the gate control. That hadnt even been published. But I thought its also a way of -- since pain is intrinsically unpleasant, and by that I mean you dont have to think about it. A pin prick is something that motivates, even however briefly. Its an inherent property of the sensation itself, unlike other sensations. So I said, This is a way of looking at the neurophysiology of affect. MELDRUM: Was that much talked about at that time, the neurophysiology of affect? CASEY: No. Well, there was -- you could see the field was growing, but I -- No, there really wasnt. There really wasnt. MELDRUM: But it was something that interested you. CASEY: Yes, thats right. Thats right. Because I could see that if you worked at it, you could -- Its actually, when you think about it, a pretty silly idea that by going cell by cell you can figure out anything about the brain. But at any rate[laughs]thats what I thought could happen. And if you pick the right -- if your electrode is in the right place at the right time, you can figure all this out. At the same time at NIH at that time, Ed Evarts was there. He was recording pyramidal tract neurons in the monkey while they were moving. He had a very slick operation going, very systematic, thoughtful. I would talk to him, and he was interested in what I was doing, and of course I was very interested in what he was doing. He was far, far, far ahead. But I could see that you could record cellular activity in an awake animal that was behaving. MELDRUM: He was at NIMH. CASEY: NIMH, thats right. MELDRUM: He developed this microelectrode that you can insert without damaging the cells. Isnt that right? Maybe that was later. CASEY: Well, that would be for intracellular recording. No, he did all extracellular recording. He recorded from the motor cortex, and his question was -- and he stimulated the pyramidal tract -- actually, what Id done when I was a medical student. But he stimulated it so that he could fire impulses backward. And he could identify by recording in the cortex those cells that had axons projecting down the pyramidal tract. MELDRUM: Antidromic. CASEY: Antidromic activation. Thats right. And so, he could say, I have a pyramidal tract neuron, and here is what its doing when the monkey moves a bar to get a reward. That was it. So I thought that was pretty slick. I thought, I can do the same thing. I used Paul MacLeans platform and developed a -- I had them build me an apparatus at NIH. That was so wonderful that I could just tell someone, Build this. [laughter] And they built it. [laughs] So they built this thing that I could use to record from the thalamus. I decided, Well, the spinothalamic tract ends in the thalamus, Ill record in the thalamus. So then I spent that whole time recording from the thalamus in the awake unanesthetized squirrel monkey, because all these other studies done, by Mountcastle and everybody else, have been done on anesthetized animals, and that -- theres no way that you can figure this system out if you poison the brain with anesthetic. Youve destroyed the system that youre trying to record from. So in principle, the thing to do is to record in an awake animal. Then youd have the behavior. The animal would withdraw. So I did basically that. I could apply stimuli that the animal didnt pay much attention to, and then I could apply pinprick stimuli, and I could record from cells, and thats what I did. I published a paper in the Journal of Neurophysiology which still is cited. [laughter] In 1968 or something like that it was published. Nociceptive or noxious -- I forget what it is. MELDRUM: Nociceptive Mechanisms in the Thalamus of the Awake Squirrel Monkey. CASEY: Thats right. Nociceptive Mechanisms in the Thalamus of the Awake Squirrel Monkey. This paper was -- either that paper or the abstract that led to that paper -- was cited in the gate control paper. MELDRUM: Was it? CASEY: Yes. MELDRUM: Sorry I didnt pick that one up. CASEY: I dont have it here buried in my -- But if you read that paper, the argument is attacking again the so-called Specificity Theory. What I had demonstrated in that paper was that the responsiveness of cells was changed by the state of the animals END OF TAPE KENNETH L. CASEY INTERVIEW TAPE ONE, SIDE TWO KENNETH CASEY: So if the animal were asleep or awake or highly aroused, the responsiveness of the cell, of any individual cell, was greatly modified. This included those cells that responded differentially to noxious stimuli. There were no cells in this sample that I had, in both the medial thalamus or the lateral thalamus, that responded exclusively to noxious stimuli. So this was, in a sense, negative evidence. You cant prove that something doesnt exist. But it showed that the system, in principle, could operate by encoding pain, if you will, by frequency of discharge and that this discharge frequency could be greater or less depending upon the state of the brain. That was, at that time, an important thing to put into this gate control idea by saying, look, if things are not locked in, hardwired in this way, the code for pain, if you will, is modified. I mean, is modifiable. The code isnt modifiable, but the signal for pain, or the perception of pain, is modified in the brain, if you believe the discharge of these single cells is an indicator of pain. This supported -- and theres a thing in there that says, Yet Casey has shown that da, da, da, da. Well, at any rate, I didnt even know that at that time, that they had done this. Id demonstrated these cells and -- MARCIA MELDRUM: Let me -- This is from the article that I read. It said, Pain sensation is associated with distinctive changes in the activity of certain neurons rather than with the presence of activity in exclusively nociceptive elements. I thought that was so interesting, because youre essentially talking about plasticity, arent you? Youre talking about the potential of change in activity. CASEY: Yes, thats right. Thats true. Thats true. MELDRUM: And its like twenty years before people begin talking about plasticity as if it was a matter of course. CASEY: Yes, thats right. MELDRUM: So I thought that was really interesting. CASEY: Yeah, thats right. Thats true. Youre right about that. So I was obviously then into the pain business. Then I said, Well, Ive served my country and Ive published in the Journal of Neurophysiology and this is good stuff, and Im going to do more of it, and Ill just be a straight neurophysiologist, behavioral neurophysiologist. I thought I needed to know a little bit more about behavioral analysis, and so on, and besides, I could tell that Ron Melzack just wrote beautifully, and hed gone back to McGill. Hed been working with Pat [Wall] in the U.K., I guess, at MIT. I wrote to him and said, I want to come work with you. He was only about in his late thirties or mid-thirties, something like that. Mid-thirties. I went up there, and I got a special fellowship from NIH, and by that time, I had three children [laughs] and lived in Montreal. And that was a wonderful experience. So we were at McGill. I tried to do some other neurophysiological experiments there, and most of them didnt work, for one reason or another, technical problems. I couldnt record from awake animals again. So I tried to do some other things, looking at input into the brain stem, looking at the periaqueductal gray, and trying to tie the limbic system together with looking at somatosensory input into the limbic system, and those kinds of things. Actually, Ron, at that time, had a grant from ARPA, Advanced Research Projects Agency, which was the research arm of the CIA [laughs], and they were funding Ron to record temperature changes in the brain. Ron had the idea that now it was possible to record changes in temperature in thousandths of a degree and that the metabolism of nerve cells would be reflected in changes in temperature. It was possible to do this. And we did. We recorded -- and it was all totally his idea to do this. I thought it was kind of a funny idea. But he said -- He had the idea of memory and plasticity again, that pain and other kinds of interesting and important events would be reflected in long-term changes in the temperature of brain areas that he was interested in. So we set about doing that. MELDRUM: Was he thinking about blood flow? Or what was he thinking about? CASEY: Well, yes. There was a thing called a Gibbs probe, and so you were looking at blood flow. You were looking at changes in blood flow in very small areas of the brain. We actually published a paper, Ron and I, in Experimental Neurology showing that you could -- that there was a thermal map of the body surface in the thalamus. We had these very neat electrodes that were made for him by contract, with two electrodes on either side of a small thermister. The thermister was extremely sensitive and had these big amplifiers that would record temperature [the] same way as you record -- you know, these big things that record temperatures of rooms and things like that. We had these very big thermal recorders. We recorded electrical activity, multicellular activity at the same site where we were recording the temperature. You could show by taking all this multiple unit activity and running it through whats called a root mean square device, basically running it though a resister. You could record the root mean square of neural activity, sort of an integrated measure of total spike activity, at the same time you were recording the temperature at that site. You could see these cells going off and the temperature going up, and it was all very neat. But nothing ever came of it. [laughs] At that time, because I had come there from the laboratory of limbic integration and behavior, the section on limbic integration and behavior, and had just been thinking a lot about the limbic system, Ron said, Well, lets write a paper. He was invited to Tallahassee to a symposium on the cutaneous sensors. MELDRUM: Right. Organized by Dan Kenshalo. CASEY: By Dan Kenshalo, Senior. There were august presences there at this -- there was Ainsley Iggo and Zotterman, Yngve Zotterman, and Pat Wall, and Fred Kerr, and Wally -- I think Wally Nauta was there. Im not sure. No, I dont think he was there. Anyway, those are a few of the people who were there. And other somatosensory types of psychophysical types and people who were doing research on heptic recognition. MELDRUM: Im sorry. What was that? CASEY: Its like Braille and recognizing patterns, using the skin as a retina, sort of. They said, We should write a paper and expand the gate control theory. And I thought, Well, you know, why do you want to expand it? They said, Well, it doesnt tell us about -- it doesnt point to how affect and cognitive things come. I thought, Well, its pretty fancy. I was a little reticent to step into that territory. Ron said, No, weve got to do this. Tie the limbic system -- you just came from all this limbic system stuff down at NIH and doing all this work, and so on. And weve got this gate control idea, and Ive been working on pain most of my life. At that time, Ron had. So we need to put this together, you and I. So I said, Well, okay. Id been embedded in Wally Nauta and anatomy of the limbic system and the limbic midbrain and Paul MacLean stimulating the spinothalamic tract, getting these monkeys to scratch and itch, and all this other whole business. I figured out how the somatosensory system got into the limbic system. Or how it might. And how this could be the neurophysiological basis for the affective component of pain. There had to be another component of pain which told you where it was, and that had to be -- MELDRUM: Discriminative. CASEY: Discriminative, and it had to be in the lateral thalamus and in the cortex, and all of that. And these two things operated in parallel. So here I was, Ron and I would talk about this and say, Well, this is the way it works. Its like this. Its a parallel. So the buzz word now is a parallel distributed system. I had no idea that thats what it was [chuckles], but we could have used those terms, parallel distributed system. But thats what it was. MELDRUM: So this was pretty theoretical, right? CASEY: Yes, it was -- MELDRUM: Youre not looking at actual cell recordings. CASEY: No, no, no. We had cell recordings, and I could show that there were cells in the medial thalamus that behaved this way. Pain was getting in there, or nociceptive information was getting in there. It was sneaking into the limbic system. Other people had done studies showing you stimulate the periaqueductal gray and it hurt, and it was aversive. Jim [James] Olds had been in McGill, and that is where the pleasure center was discovered. There was Peter Milner there, and I could go in and talk to Peter Milner. Jim Olds had by that time moved to Michigan. I learned about how the pleasure centers and the positive reward and all this whole business had been developed there at McGill by Jim Olds, who was a social psychologist, came in and he and Peter Milner are very conservative engineering types. Anyway, they did this thing, opened up this whole business of affective coding, or affective mechanisms in the brain. So it all kind of fit together. And thats what we did. We wrote that and went down to Tallahassee. It was a firestorm. [laughs] I remember Fred Kerr, who didnt know what to do with us. It was sort of like Ron and I had dropped this bomb in everybodys lap, and they were -- hot potato or something. They didnt know what to do with it. I wasnt sure that I knew what to do with it either, but I remember being challenged occasionally by -- One time I was having lunch with Fred Kerr, who I had just met down there. He said -- and he was an anatomist and a neurosurgeon, and he said, How does output get from the periaqueductal gray into the thalamus and into the reticular formation? And I said, The substantia innominata of Weisketle[?], because I knew. I had looked at the old anatomical literature, which is still correct, that if you -- the projections from the periaqueductal gray just spray out like a flower and just go everywhere. This had been first -- I dont know first, but a prominent demonstration of this was done by a German neuroanatomist named Weisketle. The substantia radiata, thats what it was. The substantia radiata of Weisketle. Everybodys ignored that ever since then, but every time people put electrodes and start stimulating in the periaqueductal gray, including John Liebeskind, by the way, I think, Theres a lot going on there. Its not just something going down to the rete and all that business. I mean, that happens, obviously, but -- MELDRUM: But it really goes in many different _____. CASEY: Oh, yeah. And upstream. I was interested in the upstream portion of the periaqueductal gray. And still am, and theres plenty of research showing that thats a major projection. Wally Nauta called it the limbic midbrain. Connections with the hypothalamus, and so on and so forth. So when Fred Kerr said, How does it get there, and I said the substantia of Weisketle, that impressed him. He thought, Heres this punk kid [laughs] -- I was thirty-something, I think --young man whod read this business. Fred knew this. Ah, yes, he knew of Weisketle. Anyway -- Well, there it was, and I was in Montreal and working on actually a draft of this paper in the Journal of Neurophysiology. I was slow to publish, and I tend to be very -- basically, conservative, I guess, and compulsive about this. MELDRUM: Try to get all your ducks in order. CASEY: Well, yeah. But at any rate, I was still working on that manuscript. And I got a call from **James Runk**, who was a postdoctoral fellow in Seattle at the time I was a medical student. I could tell he was one of the brightest guys that ever walked the planet, and I still think so. James Runk was working with Woodbury, Don Woodbury, in Seattle. He had then come to Michigan where Horace Davenport was the chairman of physiology. On Queen Victoria Day, I was in the lab and he called me and said, We need a neurophysiologist down here in Ann Arbor. Where? [laughs] So I came down and presented my stuff on the thalamus, and **Matt Alfern** and Horace Davenport, and other people were there. Horace Davenport, I knew about because as a medical student, I had read and loved the ABCs of Acid-Based Chemistry. And these diagrams of the pH and so on. That is the way you could understand acid-based balance, what was going on, and so on and forth. So I knew Horace Davenport, but Id never met him, of course. Heres this tall imposing figure, about six-seven, lean guy. I talked to him and other people in the department and presented my stuff and went back up to Canada. Horace Davenport wrote me a little note on a strip of paper like this [laughs], which he had typed himself. He did all of his own typing, two fingers. He said, We have a job for you here at the University of Michigan. Please respond. [laughs] Well, he put down what the salary was, which I think was at that time something like fifteen thousand dollars a year. So I told my wife -- I went down a second time and told my wife, I think Id really like to go to Ann Arbor. So we came down and been here ever since. Its a wonderful, wonderful place to live, despite the rain and everything else. Very culturally rich. So weve been here in Ann Arbor ever since. So I started then in physiology, and after I got here, I thought -- I still wanted to -- I needed to know more about whats going on above the level of the spinal cord. It was, at that time, difficult, very difficult to -- no one had really recorded much from the spinal cord, the dorsal horn of the spinal cord, especially these supposedly small neurons in the substantia gelatinosa. And I thought, Thats a pretty tough job. I dont want to handle that. And theres the whole problem with pulsations and all this, and I could just see myself running into a horrible technical snarl. Furthermore, Pat Wall had published a paper in which he had recorded from the dorsal horn in the cat and had put stimulating electrodes in the thalamus and backfired them and found out that there were very, very few that really projected. He published it in, I think, Experimental Neurology, or something. So I thought, Wow. And people said, Well, you know, the cat doesnt have a spinothalamic tract, and I thought, Well, thats really nonsense. [laughs] Its just too tough to do this experiment. So I thought, Ill go where there are big cells. And besides, Bill Mehler -- I dont know whether hes still alive or not. MELDRUM: No, hes dead. CASEY: Anyway, Bill Mehler, who was a wonderful guy [chuckles], a very funny man, but very bright, he had been at Walter Reed when I was at NIH, and he had written his thesis on the spinothalamic tract in different species, opossum, and so on. Ive got his thesis here. It showed that the spinothalamic tract went right straight to the nucleus gigantocellularis of the medulla. Thats the first place it went. So I said -- so there have got to be cells there that respond to noxious stimuli. And Ill be able to see what kind of activity -- how they encode this. Ill be able at least to see if they respond differentially or specifically to noxious stimuli and how they do it. So I said, Well, Ive got to do this in an awake -- in an unanesthetized animal, going on my great principle that you cant anesthetize an animal and learn anything. [laughs] Which is wrong. So I decerebrated cats. MELDRUM: Yeah, but you can learn different things. CASEY: You can learn different things. Thats right. Thats right. MELDRUM: You cant learn everything from an anesthetized animal. CASEY: So I taught myself -- actually, I had done this before once or twice when I was in medical school, decerebrated a cat. I could see -- in fact, Harry Patton showed me how to decerebrate a cat. It was still a classical thing to do, decerebrate a cat in preparation -- Sherrington did this, you know, showed -- MELDRUM: You take out the cerebrum. CASEY: Yes. You cut off at the midbrain level, scoop all of that out and throw it away. Youre left with an animal that has -- the smartest thing hes got is a midbrain. He doesnt even really have that. The thing youve got in an intact pons and medulla, perfused by -- MELDRUM: So you have an active nervous system, but theres really no sensation or feeling as far as the cats concerned. CASEY: Right. Thats right. So you take a cat and put him in a box with ether, and then hes anesthetized, and you quickly take the cat out, put it in the stereotaxic device, open up the skull, chop out the brain, and hope for the best. Sometimes you can tie off the basal artery if you can. There are various ways of doing a decerebration. I tried anemic decerebrations to make it neater, and so on and so forth. But anyway, I used decerebrate cats without anesthesia -- MELDRUM: Okay. Let me ask you a question. Im sorry. Why cats? [chuckles} CASEY: The cat was the -- MELDRUM: I mean, why not monkeys, for example? CASEY: Right. Monkeys -- expensive. Cats -- cheap and conveniently sized. Most of the research in neurophysiology had been done on cats. That was true in Seattle. I mean, the cat was the research animal of choice. MELDRUM: I know. Im just trying to figure out why that was. Barry Sessle said it was because their heads were of uniform size. CASEY: That is another good reason. It is also true, there was an atlas for the cat brain. Atlases for the monkeys brain were not common and hardly existed. They werent stereotaxic. But there was the Jasper Atlas [Herbert H. Jasper and C. Ajmone-Marson, A Stereotaxic Atlas of the Diencephalon of the Cat (1954)] and one other one -- and a couple of other ones on the cat, and the cat -- youre absolutely right -- is of uniform size, and you can tell where you are. For this research, I actually didnt need an atlas. But cats -- I could get cats. So I then recorded -- got my microelectrodes out and found out that there were plenty -- a substantial number of cells in the nucleus gigantocellularis that responded to noxious stimuli, and they responded differentially, not absolutely exclusively, although you could tell that there were some that were pretty much only responding toward the high end of things. I could simulate and record peripherally. I could record that I was stimulating finely myelinated A delta afferent fibers. I could stimulate C fibers, and I could -- At that time, there was a tricky little thing you could do called anodal polarization. You could selectively, or reasonably selectively, block out the A fibers, the large diameter fibers, so you had a more or less of a pure A delta fiber volley. I showed that these cells responded -- some of them responded only to A delta fiber inputs. So here was -- and this was, as far as I can tell, the first demonstration of the supraspinal population of cells in an unanesthetized animal that responded and could encode pain, noxious stimuli. The problem was, they responded to stimuli on both sides of the body, and they had other peculiar properties. Youd stimulate one part of the body, and the cell would fire, and youd stimulate the other part of the body, and the cell would be inhibited. So there were complicated things going on. Nobody understood it. I didnt understand what it was. All I was interested in was saying, Well, look, this is the spinothalamic tract input and thats what this does. So there were a few papers there about that. And that got attention at that time, along with a little paper on anodal polarization and using that method to do this analysis. So that takes us up to something in the seventies. Theres another issue about the dorsal columns that came up at about this time, because I was not just interested in pain, I was interested in other aspects of somatic sensation also. Pat Wall had written a paper entitled, The Sensory and Motor Function of the Dorsal Columns. The whole idea was of that paper, which was a very sexy paper, in the rat, saying that if you cut the spinal cord and had only the dorsal columns left, that the animal could not use that information. He showed this with some behavioral experiments, stimulating with electrodes the right and left side of the body of the rat and looking whether or not it oriented toward one side or the other. This information going up the dorsal columns was, by itself, useless. What was happening was that this input was coming up and triggering a descending system that modulated or analyzed or did something interesting to ascending activity coming up other pathways, so that you had to have the dorsal column triggering things. Also, Ron Melzack had that idea, that the dorsal column was kind of a fast trigger. Triggered this descending activity, and that interacted with ascending activity. MELDRUM: From other pathways. CASEY: From the spinothalamic tract, actually. So I thought, Gee, thats kind of a neat thing, but there were things about the experiment that Pat had done that I was a little uncomfortable with, and I thought it would be an interesting experiment. I had a graduate student, **Peggy Corty**, at that time, who subsequently became head of CNS research in Kalamazoo at Upjohn. The question was, What happened if you made a lesion in the dorsal columns? And it turned out you had to destroy, again in cats, all of the dorsal columns, almost all of the dorsal columns, before you got a deficit. But you could demonstrate that there was a deficit. And this had not been done before. You could show that there was a discriminative deficit, and so on. No one was even really sure what the dorsal columns were doing, and thats still a serious question, but its a problem that has been abandoned now. Because there were some neurosurgeons, [A.W.] Cook and [E.J.] Browder, who had actually sectioned the dorsal columns in humans. These patients had a phantom from amputated fingers, and the phantom had unusual and strange positions. So the idea was that the dorsal columns mediated position sense, or kinesthetic sense, which I think in part they do. But they purposely cut them and found the deficits were really very modest. This idea was, the dorsal columns arent by themselves a sensory transmission system but works in company with other ascending pathways. I did a series of experiments with Gabe Frommer in Indiana, and we again took cats and we sectioned everything except the dorsal column and showed behaviorally and neurophysiologically -- mostly behaviorally -- that these animals could use dorsal column information in very explicit ways. They could learn discrimination, and they could maintain that task when learned. This struck at the heart of Pat Walls idea. There was another group in Canada that had done a similar experiment using electrical stimuli. Gabe and I used somatosensory stimuli. Then we also showed what happened after everything had been cut except the dorsal columns. We demonstrated plastic changes occurring in the cortex. But we didnt know what we were -- we said, Well, these things change. Jon Kaas subsequently took that and recognized it as being a very significant thing. But we saw this, and we said, Well, these are these big changes that are taking place, but we didnt call it plasticity. Those were the things I had done when I was in physiology. In the meantime, the Vietnam War came. I was very opposed to the war, and I was active then -- my wife and I were active in the Unitarian Church, opposition to the war, George Wallace was around. I thought, Things are really strange. I think that played into my decision to go actually into clinical -- back into clinical medicine, because I could see myself ten years down the road in a physiology laboratory, and I did not like the idea of that degree of isolation. I always enjoyed clinical medicine and the challenges it presented, so I said, Ill use my veterans benefits and maintain a part-time appointment in physiology and still teach physiology and teach medical students part-time and finish my residency. MELDRUM: So you were a resident in neurology at the same time you were a professor in physiology. CASEY: Thats correct. MELDRUM: I thought that was quite interesting. CASEY: An associate professor of physiology. MELDRUM: Associate professor. CASEY: And for that, I thank Horace Davenport, who could have said, This is nonsense. You cant do this. But he was very supportive and encouraged me in doing this. So I did it. And I dont know. That brings us -- well, not quite to the present. MELDRUM: No, no. Theres some other stuff. Youve continued working as a clinician. CASEY: Yes. MELDRUM: Are there particular things that youve learned from observing patients that you have then applied in your research? CASEY: Yes. Well, I became interested in pain due to neurologic disease, and Ive been exposed to all kinds of clinical phenomena -- not just related to pain but including that -- that have caused me to think about pain in different ways and to test hypotheses a little bit, one of which is -- one of the earlier questions I was asking is -- especially at the time that brain imaging -- just anatomical imaging -- when there became an opportunity in the late seventies, early eighties -- actually, just after Id finished my residency, CT scans became available. You could now, unlike when I was a resident and you had to do pneumoencephalography, and you had to put air into the nervous system to see whether there was a tumor, or what was going on. Now you could actually see the brain. Not very well at that time, but then of course subsequently the technology has gone -- so now you can see the anatomy of the brain in exquisite detail. That allowed me to begin looking at -- asking questions like, What lesions in the brain are associated with a loss of pain, and do you ever lose pain completely? The real thing about that was that I thought that probably you do -- you can, but its very rare. And if you do lose pain completely, youre likely to have a central pain syndrome. The brain doesnt like being without information about nociception, so the brain reorganizes in various ways, as we know now, and can reorganize in pathological ways to produce pain. But that was one sort of line of thinking that, again, technology drove, allowing me to start looking just at the patients that I was seeing, seeing where the lesion was, and studying them myself. And its still a legitimate line of activity. Its just that its very hard. Its going to take a long, long time. Ive subsequently read papers by Peter Nathan, looking at spinal cord lesions in humans and what sensory abnormalities are that develop. And there is still a great deal to learn about this. So I started collecting cases, which I hadnt published yet at all, of patients with lesions and what has happened to them. I became interested in, again, in affect, affective coding and discriminative coding. For example, people will come in with a large stroke, and you can go up to them at the bed and deliver a deep stimulus that would be noxious on the involved side, on the pathological side, and they would not recognize that it was there; however, they would grimace. They would grimace and make movement. Theyd move and squirm. Then I would say, Whats wrong? Then they would make up some excuse. Well, I dont know. Theyd be unable to identify what it was. I dont know. Something happened. I -- Then they would go off -- I lost something or I was worried about something, not related at all to -- Sometimes they would say, Something happened that I didnt like. I still make that observation. It happens to be an observation that I have not thought of a way yet -- other than telling people about it, and I cant quantify this, so I havent done research on it. And besides, it takes a long time to do this. How do you convince people that this -- [tape paused] MELDRUM: Im sorry. CASEY: So Im convinced that, on the basis of these observations, as well as others, that affective coding or affective experiences go on independent of discriminative experiences. In other words, the parallelism of the system is revealed in that way. Its always -- its much easier also to show that people -- Well, its easier to show that than it is to remove the affective component and leave the discriminative component intact. But that does happen. Its rare. With lesions that involve the mesial frontal cortex, there is a condition called akinetic mutism. The problem is that people with that disorder dont communicate. There are lesions that are produced purposely, surgically -- _____, and so on and so forth -- that attenuate the affective aspect of pain but also produce other -- Theres a loss of attentiveness, a loss of concern about other things. Its not specific to the somatosensory system. So thats the only way you can produce the uncoupling the other way. But I think that in principle the idea that Ron and I proposed thirty-four years ago is correct. In principle, it is correct. But I have not published anything of those observations. Ive talked about it in various symposia occasionally, and so on, but Ive never -- Ive got a whole lot of patients Ive put together, old CT scans, my own examinations, semi-quantitative, all observational stuff, and I frankly dont know quite what to do with it. I think maybe when I retire, Ill do something [chuckles] with this stuff. I dont know. But Ive got a whole bunch of patients that Ive studied this way, various lesions of the brain, various problems. I videotaped some of them. I have a -- Don Price and I got into a friendly collegial argument one time at the -- and staged an argument, or a debate, at the Society for Neuroscience several years ago. There, I was able to show one of these patients who has a lesion of the parietal lobe, right parietal lobe. Its a neglect syndrome. I could do with him -- the man was perfectly awake. The level of consciousness was high. He was perfectly fine. He would lie on the bed, and I could demonstrate with a calibrated pressure device how much I was stimulating him. On his neuronal side, if I told him to lie there with his eyes closed -- and Id say, Im going to push here, and you tell me when I -- Actually, I wouldnt even have to tell him what I was doing. Id say, Im going to stimulate you someplace, and you tell me what it is you feel and when it begins to feel painful. So Id go on to his right side and start pressing, and he would say -- Id get up to three kilograms, or something like that, and he would say its painful. And I would do that again several times consistently ____. Then without saying a word, Id say, Keep your eyes closed, and without saying a word, Id move over to the other side. Then I did the same thing on his left side, and I would be going up to five, six kilograms, and then he started to squirm and grimace. Then Id stop, and then -- END OF TAPE KENNETH L. CASEY INTERVIEW TAPE TWO, SIDE ONE MARCIA MELDRUM: Okay. You got familiar with -- KENNETH CASEY: The tail flick and found that there is a real flick and kind of a slow flick. MELDRUM: [laughs] I never have read this anywhere. Tell me. CASEY: The rat could move its tail in a variety of ways. I think in some experiments this has got to be a factor, that the tail might just kind of bend a little bit and move off of the point of stimulation, and at other times, the tail will vigorously flick. Its hard to know what to call as what. At any rate, we did find that if we stimulated the periaqueductal gray under the proper circumstances, et cetera, we could attenuate the tail flick. What we found was that as we were recording from nucleus gigantocellularis cells, we found a number of cells whose discharge began just before the tail flick. This was published in Somatosensory and Motor Research before Howard Fields published the paper on On cells. We actually probably saw Off cells but didnt go any further with that. I mean, we didnt recognize them as Off cells. We could only work with On cells because they responded to noxious stimuli, actually anywhere on the body most of the time, or large areas of the body. But as you heated the tail, they began to discharge just a jiffy or so before -- several hundred milliseconds -- before the flick. Then we -- well, we actually published a figure showing that with periaqueductal gray stimulation, you knocked out the response of what later then became an On cell, and the tail flick didnt occur, and so on. So we were thinking -- in fact, my own thinking was these cells could be, therefore, associated with analgesia in some way, so that was the hypothesis to prove. What I did not really think about was that they were part of a descending system that allowed the tail flick to occur, which I subsequently and only recently did -- Howard and Rami Bernstein published a paper showing that these On cells actually end in or send small terminals into the dorsal horn of the spinal cord and are not simply pre-motor cells, but in fact, they do, by all evidence, at least have a very strong probability of modifying sensory input. Then there are some other papers that theyve shown -- certainly they modify reflex responses. So thats what Tom did, and it was a neat experiment, and it was -- I think we published it directly in Somatosensory Motor Research, and it got very -- not much attention, I dont think. Then Howard and Allan [Basbaum] and somebody else published this paper on On cells and Off cells in Journal of Neuroscience, and -- Oh, well, thats -- yeah, we saw those. But I give full credit to Howard and all those other people for thinking about this problem and using it in a very creative and effective way. Since then, Tom has been instrumental in bringing computer monitoring and various technologies to the very difficult problem of recording single cells in the awake animal. So again, as I said earlier, my focus has always been on the idea that you really have to try to relate neuronal activity to behavior in an awake animal. I fully understand the utility of doing anesthetized preparations and making inferences about them, and so on and so forth, but I really wanted to do the other. So we had both rat and monkey experiments. We started doing monkey experiments, having monkeys pull a bar to receive a reward, and then as they were receiving the reward, we would give a stimulus, and if the stimulus was noxious, they were to release the bar and if it wasnt, they could continue to hold it out. We had a behavioral paradigm worked up to do that and to look at cells in the thalamus. In the process of doing all that, in the squirrel monkey, we found cells in the thalamus that responded differentially but not exclusively to noxious stimuli. It was somewhat of a repetition of the work that I had done before, except in the work that I had done before, in the one, nociceptive responses in the thalamus of the awake squirrel monkey, I didnt find any nociceptive cells in the ventral posterolateral thalamus, that is the classical somatosensory thalamus. The new thing was -- and we published this in Science in, I think, 83 -- was that we did find a significant percentage of cells, somewhere between ten and twenty percent, of the cells that we could show responded differentially -- not really exclusively but certainly differentially -- to noxious stimuli that produced a withdrawal response. And we went further. To elaborate that, we then went on to publish some other papers in the awake monkey showing again that behavioral state strongly influenced the response properties of cells in the ventral posterolateral nucleus of the thalamus and that if the animal -- we identified three states that we could quantify by wiring the animal up electronically, monitoring movements. We had quiet waking, awaking with movement, and drowsy. So the drowsy state, the animal was not moving, their eyes were partially closed, and there was alpha rhythm on the EEG, and so on. And we could now then just apply not noxious stimuli but innocuous stimuli and monitor the response of these cells as the animal went from one state to another. So this was -- because the technology had changed -- was much, much better. It was a much more compelling demonstration of the way in which a behavioral state -- actually, the behavioral state is defined by the responsiveness of these cells. See, its easy to say -- a lot of people, even my colleagues, will fall in the trap of saying, Attention causes this, or, The behavioral state causes this neurophysiological effect. In fact, the neurophysiological phenomenon that you are observing is a part of the behavioral state. You are defining the behavioral state from a neurophysiological perspective. Its not that some behavior is causing something to happen in the brain; its the other way around. MELDRUM: This is a question I was going to ask you a little earlier, and it probably is sort of speculative, okay? But in such a state -- I mean, youre talking about the cells in the thalamus. CASEY: Right. MELDRUM: But presumably -- I mean, there will be groups of other cells, for example, in the trigeminal nucleus. CASEY: Yes. MELDRUM: And in the reticular formation, which will be responding -- which will also have differential responses, depending on the animals state of alertness, or whatever. CASEY: Right. Yes. MELDRUM: So are we talking about centrally controlled phenomena whereby cells in the cortex are directing the activity of all these other cells? Or are we talking perhaps about interactive phenomena -- I know Im asking you to speculate -- where perhaps -- I dont know what you want to call it, but a kind of chain reaction sets off as the animal, for instance, begins to become more alert, perhaps triggered by an auditory stimulus, or something like that. Do you understand what I just said? CASEY: Yes. Ill put it this way. The brain -- well talk about a state of the brain. What does that mean? That means that there is or is not movement. There is or is not attention -- and we can talk about what that means in a minute -- to some aspect of the environment. The organism is alert, moving, directed toward some object or retreating from some object or about to get food or defend itself or do something of this kind. These are behavioral states. Actually, years and years ago, Warren McCulloch and somebody else tried to define all possible behavioral states. There were automatic behaviors, like walking, and consumatory behaviors, and so on and so forth. This is an area of psychology that I just only kind of know out of the corner of my eye a little bit. But if you work at it, I suppose you can define, roughly, several behavioral states. Well, these, I think, are simply, at the neurophysiological level, different probabilities of discharge of different neurons in different places, motor, sensory and cognitive, and so on and so forth. Then if you ask the question -- I think your question is sort of like this: What triggers the change in state? When we see changes in the probability of the discharge of sensory neurons or a motor neuron, or something like that, we are looking at a sample of the whole population of brain cells in a particular state. Now, to say what is it that causes the state to change from one to another is unanswerable in the present day and may be forever. MELDRUM: Oh, nothings unanswerable forever. [chuckles] CASEY: [laughs] But it is -- youd say, Well, theres probably some sensory event that causes this, an auditory stimulus or something of the sort. Lets say youre a monkey in the jungle and you hear a hiss, and theres something about that hiss that is very salient. And that primates brain is built from the ground -- genetically -- is built and evolved over eons, millions of years, to respond, to change state when that sound comes on. So I think in that case -- I mean, its almost impossible to turn it off, something like that. Pain is like that. MELDRUM: Yes. Pain is definitely like that, and we see this process whereby the body goes through [George] Bishop said the whole body can be disrupted by pain. You have nerves in different sets of nerve pathways -- and you talked about parallel pathways -- responding, and if the pain continues beginning to, in fact, alter the rate of response. And just -- okay. Ill put this line of questioning aside. [chuckles] It isnt fruitful. But it just seems -- are these sort of isolated phenomena? Were not assuming that, are we? Were assuming that there are connections between all of them and that they reinforce each other? Or perhaps not. CASEY: We still have a fairly primitive idea, I think, of how this all works. We still think in reflex terms, and I think theres a good reason for that. Its handy. A lot of things that happen are reflexive in some way and you can study them. But the brains just not a bundle of reflexes. And although the hiss of the snake activates the monkeys brain and not the brain of some other reptile who is going to interpret the hiss in a completely different way, and all that business. And similarly, pain is going to -- potential tissue damage is going to cause orientation, et cetera, and all those behavioral responses. The brain works independent of those things. If you are engaged in combat, or whatever, or food, or after something, then tissue damage doesnt mean much of anything at all. I dont know whether I -- my example is I was playing rugby and had my ear torn off. Well, part of it. It wasnt all torn off, but it was mostly torn off. [chuckles] I was totally unaware of this when I was doing that. So everybody has examples of things like that. I think the brain actively seeks -- its an active process. I think it does control sensory and motor function all the time. MELDRUM: Okay. I thought this paper was very interesting, so I wanted to ask you about it. This was actually on cats, not monkeys. This was about -- this turns out to be about humans. Forget that. [chuckles] It was about nocifensive behaviors and food related suppression of nocifensive behaviors in the cat. And I did bring this paper. Where is it? There. But you had a number of cats who were trained to eat, and thermal stimuli were delivered to them while they were eating, but over a period of time, the cats just started ignoring. Im sort of reciting this off the top of my head. I probably missed the point. CASEY: Well, we were going to try to record from the cats nervous system, not necessarily the spinal cord but from the brain, while the animal was engaged in some compelling behavior. Again its the whole idea of identifying a pain cell. What criteria would you use to say, This is a pain cell and not part of a nociceptive reflex that had nothing to do with pain, or part of a motor system, or something like that. Because if you record from an anterior horn cell, you will find that it responds to noxious stimuli. Its the output end of the reflex system. So we said, How can we do this? Well, cats are behaviorally difficult critters, and its hard to get them to do much of anything, but they like to eat, and you can train a cat to -- after you get the right kind of food, liquid smelly stuff, and you can get a delivery system. Actually, Gabe [Gabriel P.] Frommer from Indiana helped us with designing this. A light can come on and the cat sees that somethings about to happen, and so he puts his muzzle down into the dish, and when he does that, the food comes in and its very tasty and hes gobbling it up. So thats a nice behavioral state. He stays very quiet during that time. So how do you define a noxious stimulus? Well, I said, Well define a noxious stimulus as that kind of a stimulus that interrupts eating behavior. That is why we were doing that. We had shaved the thighs of the cat. The cat sat in a little cavity. They would actually climb up in there, sit down there, and wait for the food to be delivered. In the meantime, we kind of strapped them in and put thermodes on their legs, on their thighs. We could control the temperature of these thermodes very accurately. We then -- the first job was to identify the stimulus temperature which would interrupt eating behavior. That was the first experiment. That basically is what we did. We stimulated on one side or the other side at different temperatures and just computed the probability -- and I computed then using probability statistics, contract probability -- that a stimulus at a given temperature would interrupt this behavior. That was about it. Well, we then went on to show that those stimuli, in other experiments -- I cant remember whether it was that one or not -- but in related experiments, we showed that those stimuli would activate C-fibers. In that setting then, Ed Evarts came to visit. His daughter was at the University of Michigan Medical School. He came to visit, looked in the lab, and he saw -- heres a guy whod spent his time recording from awake monkeys, and he looked at that and said, My God. You should record from the spinal cord, because these cats were lying out there. Theyre four-legged critters, and theyre lying out there. You could just put an electrode right in the spinal cord. At that time, Linda Sorkin was a graduate student, so I said, This is it, Linda. Record from the dorsal horn of the cat, and you will identify cells that respond to these noxious stimuli and when the animal is eating. What we also showed in that paper was that if the cat had its muzzle in the food cup but there was no food, then if you gave a stimulus of, say -- I forget what it was -- forty-five degrees or something like that, he would pop up right away. Because if he popped up, he would interrupt the stimulus. But if food was actually being consumed, then you could stimulate it at up to fifty degrees or some other big time temperature, and the cat could care less. So we had in place -- its still a neat thing to do. If anybody wants to do it, theyre welcome to do it [chuckles] of a behavioral modification of the response to a noxious stimulus. If you had a pain cell someplace, its behavior should mimic the behavior of the cat. If it were not a pain cell, it would continue to respond slavishly to the stimulus intensity regardless of the animals behavior. So we set poor Linda Sorkin on this task of recording from the dorsal horn of the cat. And at that time, the only other person who was doing anything similar to that was Jerry Collins at Yale. MELDRUM: This was in the eighties? CASEY: Yes. No one else dared to do this kind of thing. All of these experiments that Ive been telling you about are highly [chuckles] labor intensive and do not result in hundreds and hundreds of publications like pharmacology papers where you give A and give B and -- [laughs] MELDRUM: Five papers out of one experiment. CASEY: Right. So its not great for building up a huge CV. At any rate -- but theyre good experiments, good things to do. So I set Linda on this. Well, Linda was doing this, and it was technically difficult, and by that time I was into clinical work too. Tom was monitoring her very carefully, and I was doing the best I could. I would come and say, Why arent there any of these dorsal horn cells firing? What Linda found was that the dorsal horn is -- the first thing to do was to identify -- if youre recording the dorsal horn, you may be recording afferent fibers, or you may be recording postsynaptic cells, so you had to determine whether you were recording an action potential that was presynaptic or postsynaptic. Thats the first problem. Out of all of that came her observation that not much is going on peripherally at all unless theres a stimulus. And that the dorsal horn tended to be quite silent unless a stimulus was going on. She was able to show for her thesis that there are cells in the dorsal horn, postsynaptic -- first of all, she was able to establish criteria that allowed her to identify presynaptic from postsynaptic activity in the dorsal horn of the awake cat. That by itself is a contribution. Then she was able to show with a few cells that there was modulation of the responsiveness of this cell when the animal was eating, was highly occupied. So that was an attention thing. But since then, Tom and I actually -- weve got a paper now coming out in Somatosensory Motor Research, if its not out already, on the monkey showing attention-related modulation of somatosensory cells in the ventral posterolateral thalamus. This is the first paper to show that that is occurring in that particular piece of tissue. MELDRUM: Okay. Now, just let me ask you, when you say modulation, what you mean is a change in the probability of firing, a change in the rate of firing, or how would you phrase it? CASEY: Well, theyre the same, actually. But it is actually a rate measure. That is, the likelihood that the cell is going to generate so many action potentials due to a stimulus of a given intensity is either up or down depending upon whether the animal is using the stimulus as a guide for behavior. So in this experiment that sort of derives from what Linda did -- that is the modulation idea, behaviorally related modulation -- we showed that the direct somatosensory pathway, that there is modulation taking place at that level and that if the animal is using a somatosensory cue to guide behavior, that is, what we did was stimulate the animal with a tactile stimulus, and as long as the stimulus was going on, the animal held out the bar and would be receiving a reward. And the animal was supposed to release the bar when the stimulus stopped. We could demonstrate that when the animal was attending to the stimulus that the response of the cell was greatly increased compared to when he was given a visual stimulus, which had nothing at all to do with guiding his behavior. Weve carried that on, and I think it will probably -- well, doing those monkey experiments, I think, is so time consuming and tough that were probably not going to do it anymore. At least I wont. But theres still a lot to be done. Then Tom was -- to get to your original question about Tom. Hes very excellent at setting up these behavioral devices, triggering this and recording that and quantifying the EEG response, and so forth. MELDRUM: Ive seen some stuff at NIH. I mean, you really have to design all the equipment specifically for the experiment. CASEY: Yes, right. MELDRUM: Its not like theres some -- you cant just [set a] computer up and say okay, were going to do X, Y, and Z. CASEY: No. Thats right. MELDRUM: Everything has to be essentially custom built, thats what Im trying to say. CASEY: Thats right. Yep, thats right. MELDRUM: Very labor intensive. CASEY: Yes. Well, so when functional imaging came on, why it made a big difference. MELDRUM: Okay. I want to talk about functional imaging a little bit more, but first I have a question. You seemed to change your point of view. Its about animal models. At one point, you published, I guess, an editorial in which you suggested that maybe -- this was in 1986 -- that it was probably not appropriate to use animal models to study chronic pain. Then a few years later in another editorial that you wrote with Ron Dubner, I think you had really changed that point of view, and I wondered if you wanted to talk about that. CASEY: Yes. Okay. Yes, I know. I remember. That rankled a number of people. In the first -- well, lets not talk about the editorial, lets talk about the issue. The issue is, Why do you use an animal model? What is the animal model modeling? The idea was that chronic pain is a clinical problem, and so we need an animal model of chronic pain. And so, if youre going to do that, the animal model must be one of chronic pain but must reflect in some way, or be relevant to, human diseases that are chronic. At the time that I wrote that editorial, it seemed to me that there were a number of experiments that were being done related to inflammation and the peripheral apparatus that responds to inflammatory processes -- and these are acute inflammatory processes that occur in the body or the viscera, or whatever. If youre interested in that problem, although it may, down the road, lead to chronic pain, it is not a chronic pain problem, in fact. Inflammatory pain, by and large, is easily treatable and is not much of a clinical problem. Most inflammatory pain goes away with healing. In any case, [it] does not -- in fact, rarely does a tissue injury result in any kind of indelible change in the nervous system that causes a neurological change. In other words, if you break your leg -- although we know now that there are reorganizational changes that take place in the central nervous system as a result of amputation, and so on and so on and so on. We know all that now. These reorganizational changes that take place, most of them, are not clinically significant. If you break your leg, or even if you cut off your leg, the likelihood that youre going to have phantom limb pain is way less than fifty percent. In fact, its probably more like five or ten percent. Most of the vets that I see coming around in wheelchairs like this, if you ask them if they have a phantom, they say, yes theyve got a phantom, but we dont have a whole line of people with amputated legs and arms coming into the clinic saying I cant stand this phantom pain. Its not a common problem. MELDRUM: And maybe over-exaggerated because people who write about it -- I mean, those are the cases they see. You dont see the cases that dont have it. CASEY: Thats right. Thats right. I mean, its an interesting problem. Dont get me wrong. People who have it, its a tough thing. But inflammation of a limb from formalin or whatever the devil it is does not produce chronic pain. Every day, everybodys getting banged and has inflammation or gout or something like that, and it all goes away, and its not a problem. So you dont need to have an awake animal to study the peripheral apparatus that is involved with any inflammatory response. At the time, what I was seeing was that these animal models, inflammatory models and so on, and chronic pain models of various kinds were being used unnecessarily to ask questions that could be done with an anesthetized preparation. So here I was in a sense saying -- I had spent most of my career saying you [have] got to record from awake animals, but I was addressing a central problem and using stimuli that were brief and actually using acute pain stimuli to dissect out the physiology of the neuronal pain pathways, and so on, in awake animals. I never used a chronic animal like that. So given the climate at the time, which was people tearing up laboratories in England and Willie Dong getting trashed in Seattle and all kinds of things, very, very serious animal rights business. Here we are, the Pain Society, studying pain. My note was intended to be cautionary. It said, Look, if youre going to use a chronic pain model, then it had better be very relevant to the clinical chronic pain problem, and most of these are not. Well, so, people were very upset with this. [laughs] Because I was being critical of using animal models of chronic pain in ways that I felt were inappropriate and that made them vulnerable to criticism from animal rights people. So then, this -- Caseys written this paper. Hes against research on chronic pain, and so on and so forth. [chuckles] The way I had written it was -- I tend to write very tightly. I wanted to make every sentence have a meaning. So it was hard for people -- I think harder than necessary to read. Actually, as I read it, its not too bad. MELDRUM: I thought it was pretty clear. CASEY: And Ron [Melzack] -- I forget why Ron -- was he editor, I think, or co-editor then with Pain? MELDRUM: Well, he was a co-editor of Pain. CASEY: Yeah, maybe at that time. So anyway, we got together and wrote this paper, which didnt really change my position but simply said, Look, there are -- I think we identified different patients. Ron actually doesnt do clinical work at all, but I do. At any rate, I agreed with him that there are patients where theres a clear organic cause for the pain, and there are patients where there is no apparent organic cause for the pain at all, and that we dont have an animal model for the second group of patients and should not even try to develop one. I forget what the rest of that editorial actually was all about. Id have to -- It was simply saying, I think, that -- MELDRUM: That there might be a model where there was an organic cause? I mean, werent you talking about the possibility of peripheral input causing persistent pain? CASEY: No. Actually, Ron is still doing research on persistent pain. But most pain, even if it goes on for a while, does not -- MELDRUM: Doesnt create this -- CASEY: Lets see here. This is chronic or recurrent sources of nociceptive input. Then source of nociceptive input in the second group -- [reading] source of nociceptive input is poorly understood, but organic cause may be inferred because of characteristic clinical presentation. That would be like migraine. Thats what I had in mind. You cant see the pain causing migraine headache, but its been, over centuries, so well described and treatable now. Thats what I had in mind. [reading] Evidence obtained through history or physical examination. And ran into individuals behaviors that resemble those of these other two but without any evidence for a source of chronic or abnormal nociceptive input. Okay. These are the patients that we see from time to time in the clinic. My own approach to those folks is to do no harm. If I do not have a clear cause for their pain, I am not going to treat something I dont understand. Im not going to put them through a series of expensive and potentially dangerous or invasive diagnostic studies, et cetera. Follow them along, see if something else turns up, and approach this very conservatively. MELDRUM: So theres no clear organic cause for the pain, and the clinical presentation is not one which causes you to recognize a potential syndrome thats easily definable. CASEY: Thats right. So if someone comes in and says, for example, I have terrible back pain and it radiates into my foot, that suggests root radiculopathy; however, then if I go on and I find that their strength is normal, their reflexes are normal, and they have no sensory loss, we treat that conservatively. I dont send them off and call in the neurosurgeons and say weve got a blah, blah, blah. Rest and conservative management with mild analgesics, and so on and so forth. And that will go away. Most of that goes away. If they start to get weak or reflexes dropped or theres definite sensory loss, then theres evidence of root damage in that case, and then we go a little further and we get imaging studies, and that leads maybe to surgery and maybe not. At least we know that something else is going on that deserves attention. Someone comes in -- we have a lot of people who come in with back pain that doesnt do anything like that, no evidence of neurologic disease. Presumably this is due to -- based on history or something like that -- pain in muscles and joints and so on, and we reassure the patient and give them a program of physical therapy and tell them whats going on. Usually weight loss is an important part of all this, et cetera. But we are not going to send them off for a laminectomy or something of that kind, which is probably one of the most overdone operations in the world. MELDRUM: Really? CASEY: Oh, yeah. Twenty-first century medicine can do really horrible things to you. MELDRUM: That is a characteristic, I think, of twentieth-century medicine. CASEY: Thats right. MELDRUM: Were continuing. CASEY: [laughs] Well, thats right. Well, its very wonderful. Wonderful things can be done, but they have to be done judiciously. So when -- back to this thing here. Thats these individuals with no evidence on any basis for organic disease of the nervous system. Now I will continue to read this. Here is an important statement, that we understand and further define what we mean by these three categories and give examples. The second group where theres no clear organic cause would be like headache, migraine, pain of musculoskeletal origin, and so on and so forth. Some of these may be refractory to treatment. Why that is, the case is not known. But the important statement is that both of these first two groups where theres clearly a cause or where by history or other evidence there is very likely to be a cause that the chronic pain often resolves spontaneously or can be successfully treated. Thus, chronic nociceptive input alone does not necessarily produce an irreversible pathologic change in the central nervous system that sustains the pain long beyond the time that the nociceptive source is eliminated. And that, I think, I stand by still. All of the plasticity notwithstanding, that is still true. If you start examining people with arthritis or this or that or the other thing, that have had pain for a long time, there may be changes in their nervous system, if you look for them, but theyre not the cause of disability. They do not have a disabled nervous system. MELDRUM: Right. And their nervous system is essentially still functioning normally. CASEY: Yes. So to say that chronic nociceptive input leads inexorably to some horrendous neurological problem down the road is simply not true, and it was not true then, and it is not true now. [chuckles] Okay. So let me go on with this third group of -- Then, given that, those caveats, then the question of when do you develop an animal model of chronic pain. Then wed say there are models of inflammation and then there are -- Im paraphrasing all of this now -- and then there are also models of neuropathic pain where there is damage to the nervous system. So without reading this any further, I can now go on. I think thats true. The animal models of inflammatory pain, which we have used, are -- END OF TAPE KENNETH L. CASEY INTERVIEW TAPE TWO, SIDE TWO MARCIA MELDRUM: This is the second side of tape two of our interview with Ken Casey. So he thinks hes got a what? KENNETH CASEY: Well, he thinks -- he says something -- hes worried about something. I forget exactly what he said, but he had a -- there was something bad that happened, he was uncomfortable, he was worried about something. It may have been visceral. He said, I may have a stomachache, or something like this, but clearly had not the faintest idea that I had just pushed five kilo or more on his periosteum. I could repeat that again and again. If I called attention to it and said, Open your eyes now, then his threshold was elevated, but he could identify where it was. So my argument then was that, Here it is. This man has an affective experience in the absence of any discriminative function. At least under those circumstances where he doesnt have visual cues, and because he has a perietal cortical lesion. In any case, whatever you may think about the parietal cortex and what it does -- and I think it happens to be a pretty important part of the brain -- we have uncoupled discriminative and affective processing. I probably should do something about that. I may not. I dont know. MELDRUM: Well, its interesting. Rick Gracely has this differential descriptor scale where he asks people to give him a reading on the sensory intensity on the one hand and on the affective and unpleasantness on the other, and he says that people are able very easily to do this, discriminate one from the other. Thats mostly been used experimentally. CASEY: Thats right, and these are not patients. MELDRUM: No. These are subjects. CASEY: And theyre trained. I dont doubt Rick Gracelys results, but at the bedside, its a little difficult to apply. I think this is a robust demonstration of this. Its just that the demonstration of it is -- I dont know -- its like growing flowers or something. Its there. It speaks for itself. And theres not a good medium. Or maybe there is a good medium for it now. I could take this old tape and show that and show some other -- I could probably make a good story out of this. But theyd have to believe me. It couldnt be reproduced. It would have to be another neurologist, or somebody like that, who does the same kind of thing. But I just might do it. As Im talking to you, I think, gee, I really could do this. [chuckles] Instead, what happened was functional imaging of the brain. MELDRUM: And of course, thats very, very sexy. People really like to look at that. CASEY: Right. MELDRUM: Well, its fascinating. CASEY: Yes. Thats right. So I think that Im going to do that now for the rest of my career. There are a lot of simple straightforward questions to ask. I think the tendency is to use this to -- and it gets criticized, I think -- the methodology gets criticized justifiably as being sort of a slick way of looking at all kinds of funny things and not really leading to an understanding of how the brain is functioning, and so on. The thing about pain is that -- or sensory system -- is that it allows you to introduce a stimulus in a quantitative way and to, fortunately, the blood flow change and synaptically -- I once used the term synaptically induced blood flow, regional blood flow -- changes occur -- are correlated with stimulus intensity and, in fact, with perceived intensity. Coghill and Mike Iadarola and others have shown that. Weve done experiments. They scooped us. But wed done a more elaborate analysis of that, Satoshi Minoshima and I. So you can ask questions like, If such and such an area of the brain is gone or you interfere with this discriminative capacity in some way, what areas are affected? Im starting to study patients now with pain abnormalities, and in particular, Im interested in neuropathic pain and then, more particularly, in pain due to central nervous system disease. People will have stroke, will have spinal cord disease from multiple sclerosis or spinal cord injury, usually multiple sclerosis is what I see. They will have continuous pain. How does that happen? Well, without being more elaborate about it, I think that by having a specific hypothesis about a few specific areas, now that we know what to predict, we can begin to dissect out what role each of these areas is playing as part of the pain system. And were already -- Cathy [M. Catherine] Bushnell and her group and [Pierre] Rainville and so on are already looking at some aspects of affective coding using this method. I think as we study patients, well learn more and more. Were just publishing a paper now in Journal of Neurophysiology on how opiates act in the brain using this method, and it raises the issue, again, of activating descending systems in the brain, in the cortex, that may play a role in producing analgesia. So I think it opens up a whole area of research that -- MELDRUM: Well, it seems to me -- this is probably very simplistic, but what brain scan[ning] enables us to do is to actually see how complex noxious -- I mean, noxious stimulation, or pain, doesnt set off just one pathway, it sets off a whole series of synaptic interactions, and by sorting those out, youve gotten a sense of how complex this process really is. Isnt that true? CASEY: It is true, but we dont need to -- we know its complex. [laughs] We dont need to impress ourselves anymore with how complex it is, I dont think. The imaging brings that home, I agree. But as I wrote recently somewhere, we knew from single unit studies that nociceptive information was distributed all over the place, in various kinds of places. All you could do then was say, Well, maybe it does this and maybe it does that, maybe it does this. MELDRUM: So this gives you a better ability to do differential studies? CASEY: Thats right. Thats right. It gives you that opportunity. What we have now here is an animal model of how to, basically. I said to myself, The human studies are very good because they drive -- you can ask specific hypotheses about certain areas and test certain things out, and if youre not just kind of using this gee whiz approach, lets do this and see what happens, but instead ask some questions quantitatively as best you can about certain areas, how they might interact, well learn something. But from humans. Humans can tell you whats happening. Thats really the beauty of it. You can see -- they tell you whats happening, and most of them are honest about it, so you can learn something about whats going on in the brain. But you cant tell that much about the organization, about the physiology without an animal model. Because with an animal model, you can start tampering with the brain. You can give drugs you cant give to humans, and you can destroy parts of the brain. So I have a very simple thing, which weve never done. Nobodys ever done it. But lets say you have three areas of the brain that are activated by a noxious stimulus. There are more than that, but well just pick three that we can predict. I think were good enough now so that we can pretty well -- I can pretty well predict, Id say with eighty percent accuracy or ninety percent maybe even. If you threw up a PET scan, I can say thats pain. There are conditions that would mimic that but not very many. So lets just pick three areas that we can predict will be active. If you make a lesion in one of them, you cannot predict how it will affect the other two, at the moment. So you dont know whether these areas are activated in parallel or in series, for the simplest question like that. That would be very interesting. So Im just now working on a paper to submit to the Journal of Neurophysiology. Im looking at the brain areas that are activated early in a sequence of noxious stimuli, and those that are activated late, after youve been stimulating for several seconds, big difference. These things have a temporal as well as a spatial -- I mean, that doesnt surprise anybody, but Im just saying, in this paper, we can begin to analyze this. With PET scanning, the quantitative aspects of it are better developed than they are in FMR, and you can see the whole brain, and you can study patients that have metal in them and Pacemakers, which you cant do with FMR. _____ a background of activities -- of databases that will allow us to look at some of these matters. You cant make lesions in the human brain, except those that nature makes, so we now have a rat model developed -- Tom [Tomas J.] Morrow and Pam [Pamela E.] Paulson and the people in the labs across in that building right there -- where we can look at synaptically induced blood flow changes in the rat. There are these nice animal models and various ways of testing rat behavior that a lot of people know about and accept. The formalin test that actually Ron developed, Ron Melzack, John OKeefe. And the chronic constriction injury of the sciatic nerve model, Gary Bennett, and all of this business. We can see what happens in the brain when you do these things. Well, it turns out the brain changes a hell of a lot when you start fiddling around with the nervous system. I think those things are likely to be important in the perception of pain. We have another modality that were also using in humans in conjunction with that, and thats a laser stimulator, a laser -- its an infrared laser. It applies a pulse of infrared stimulation to a small area of the skin, and it activates selectively heat sensitive nociceptive afferent fibers. And you can record this potential in the brain. Ive got a young man here now, Jrgen Lorenz from Hamburg. Were working together, and he is an expert in this particular area, worked with Burkhart Bromm in Hamburg. We now have the ability using some fancy analytical processes, neuroscan, to locate the generator of these pain potentials, if you will, in the brain, and we can do that with fast unmyelinated nociceptors, the A-delta fibers. And thats been done by others also. We can do that. We can now then see how those change, if they do, in patients. More what were working on now is the ability to record in the awake human on-site brain potentials generated by C-fiber activation and do whats called a current equivalent dipole localization. We can look at it and ask the question, Where is the generator, or where are the generators of this C-fiber potential? And what happens to it, normally and during attention, et cetera, in neuropathic pain syndromes, and so on and so forth. That then leads to -- the final question related to that is, Why do we have these two sets of nociceptors anyway? And I have some ideas about that. MELDRUM: Would you like to share those? CASEY: Okay. [laughs] MELDRUM: Id really like to know those. This is something that really fascinates me. CASEY: I dont think its a new idea really, but Ive thought about writing about this, and part of it is really difficult to prove. I think its very simple. The A-delta -- well call it the A-delta system -- fast nociceptors, mechanical stimuli, some thermal stimuli -- travel about fifteen meters per second, gets to the brain up here at about two hundred and fifty milliseconds, or thereabouts, fast enough so that you can recognize it and do something about it, fast enough to excite local brain stem and spinal cord reflexes. So its an escape system. Its there for protection. When a noxious stimulus arrives, this system is fast enough so you do something about it. C-fibers, I think, have practically nothing at all do to with that kind of thing. It takes one second for a C-fiber activity, if activated synchronously. The best you can do is get it to the brain in a second. Those are the fastest C-fibers. If theyre conducting at one meter per second and your arms a meter long, its a second before it gets to the spinal cord. A system like thats totally useless for escape or warning. These fibers are active with inflammatory processes and are slowly discharged. Probably an important part of informing -- and Pat Wall has used this term -- informing the nervous system about the state of tissue. We can talk about that a little bit. I think it is an immobilization system. They just remind you that you have an injury and that you should not use that body part, that you should immobilize yourself or perhaps go off somewhere and get out of the action for a while. MELDRUM: Yes, and you see this in animals. CASEY: Right. Thats basically the theory -- and Jrgen Lorenz and I have now done, with Satoshi Minoshima and others, a PET scan where we have put capsaicin on the skin. Were just writing this abstract up now for Sciatic Nerve Science. Put capsaicin on the skin and it activates C-fibers, mostly, almost exclusively. The latest paper in Science tells us that capsaicin activates at least half the C-fibers but less than ten percent of the A-delta fibers. It would certainly sensitize the C-fibers, and then if you apply a heat lamp slowly to the skin, it produces a burning sensation, and you can apply a stimulus that normally is warm, forty-three degrees, to this surface capsaicin area. This is not a capsaicin thats injected into the skin like most -- its just on top of the skin. Then on top of that you apply this warm sensation, and its painful. It is as painful as say -- forty-three degrees, which is normally painless, on this sensitized skin is as painful as forty-seven degrees on normal skin. So we did this scan, basically asking the question, Is there a difference between the pattern, or the activity in the brain, that is activated by this predominately, if not exclusively, C-fiber stimuli, compared to the normal pain pattern that weve seen in our other studies. Huge difference. MELDRUM: Not surprising, but thats very interesting. CASEY: And a lot of limbic structures. So I think that the C-fiber system in the brain is activating certainly autonomic and other behaviorally-related structures that dont have much to do with escape and that are influenced by morphine. Whereas, the escape system, the A-delta system, is pretty resistant to morphine, as it should be if its going to serve over evolutionary time. MELDRUM: Yes, were really talking about evolutionarily developed systems. CASEY: Absolutely. So before I start writing about this, unless somebody else does it before me, Ive got to get a good read on when does this differentiation take place? Probably mammalian. But that gets me back to Paul MacLean and the reptilian and old mammalian brains, all of that. Except Ill be interested in who has C-fibers. MELDRUM: Yeah, thats quite interesting. Theres not been too much work done on that? Not that I know of. CASEY: People are interested in genes. MELDRUM: Yes, endlessly. And people are mostly interested in mammalian genes. CASEY: Right. MELDRUM: And fruit flies occasionally. CASEY: Right. Those things have immediate commercial value. Nothing I have ever done, except function as a practicing neurologist, has any commercial value whatsoever. [chuckles] So I have an inexpensive hobby. MELDRUM: Okay. Well, theres a lot of stuff I want to ask you about, but maybe for the end of -- as were running out this tape, lets go back a little bit because there was one event that we sort of skipped over. In 1973 you went to a seminar in Israel. CASEY: Yes. MELDRUM: This was a Bat-Sheva seminar [Bat-Sheva Seminar on Pain Mechanisms and Therapy]. Im very interested in this event because it seems to me its really important in terms of the developing history of the pain field. So maybe you can -- how did you happen to go? Do you remember [John] Bonica was there, Melzack, Noordenbos, a whole lot of people. Do you remember anything in particular about that seminar? CASEY: Well, that was quite an experience to go to Israel. I think that from the point of view of science and conceptual things, it didnt mean that much to me then. I didnt see -- I mean, the meeting at Tallahassee was really something else. And actually, the other time was when I presented my data at the World Congress of Physiology in Washington, D.C. I presented this data that Id collected on cells in nucleus gigantocellularis that responded to noxious stimuli. At that meeting, Yngve Zotterman got up and cheered and hugged me. [laughs] It was really strange. He got up -- he leaped onto the platform and shook my hand because Id found a pot full of nociceptive cells. At that time, it was kind of a big deal. But at Israel, there were interesting people there, and Pat had connections in Israel, one of which was romantic, actually. And it was a fun place to go and interesting from all kinds of points of view. But Im not aware -- at least, my own impression is that it was not a mover and shaker kind of meeting. MELDRUM: It was Pat Wall getting some friends together to talk to people in Israel. CASEY: Thats it. Thats pretty much it. And John Bonica was there. But I can talk about John Bonica. MELDRUM: Well, tell me about John Bonica. CASEY: When I was a medical student, there was no Department of Anesthesiology at the University of Washington. So I was in the gross anatomy lab, four of us at a table. And here comes this guy, short guy built like a little truck with cauliflower ears and an accent like the south side of Brooklyn or someplace. We all wondered, Who is this guy? He would come over to our table and poke his finger down into the abdomen, or something, and say, Whats this? Or he would ask us a question like, If you put a needle in here and went through here, what would you hit? None of these questions we could answer. We were terrified of this guy. But he was a very nice guy. You could tell he was very smart and basically a kind person, but mentally tough. That was John Bonica. There were all these tales about him being a wrestler, and so on and so forth. And he was being courted to come up and be chair of anesthesiology. Well, that was it. I didnt hear about John Bonica then until years later when in 73 the meeting that was a mover and shaker meeting was in the Issaquah nunnery. MELDRUM: Okay. Stop, stop, stop. Dont go any further. Okay. In the letter in which John -- okay. Issaquah was in May of 73, and of course, yes, this was the formative meeting. Prior to the meeting, John Bonica sent around a letter to a number of people saying that he had been talking to people about the idea of forming an international multidisciplinary association for the study of pain. I dont remember exactly how he phrased it, but thats what he said in that letter. It was to a select few. It wasnt everybody that went to the meeting. But I know John Liebeskind got one, and I presume you did too. In the second paragraph, he said, Recently I had the opportunity to talk to Melzack, Wall, Casey, Noordenbos. Now, the only time I know that he had the opportunity to talk to all those people at one time was at the Bat-Sheva meeting. CASEY: I see. Youre probably right. Youre probably right. I dont remember him -- I mean, I remember he was there, certainly. Of course youre right, the society hadnt been formed then. [excitedly] Oh, here is what I remember. Here is something. Here is something about that meeting. John Bonica -- in the early seventies, Id done some of this work, and he became aware of me and remembered that I was an old medical student, all that business. Then he said -- he wanted me to write a chapter in his book, in the revised edition of his famous Management of Pain book, which was in 1954, or something like that. So I worked like hell and I wrote the chapter, and I sent it to him. And I waited, and I waited, and nothing happened. And John got very upset. I would write occasionally to John, and he was very embarrassed about this. He was also doing all kinds of other things other than this book. He was spreading himself a little thin. And here I was. I had written my -- been a good boy and Id written my chapter and nothing was happening. In my hotel room in Jerusalem, John Bonica comes in -- its a surreal thing, domed room and a minaret right outside my window and this guy wailing, strange, wonderful place. John Bonica comes in, sits on my bed and goes over the chapter and tries to explain to me why the book isnt being written, and so on and so forth. That was early on. Then I had several other conversations with him, but I do not recall him asking me specifically, Should we form this society? He probably asked Ron that and Pat Wall, and they all said yes, and so on. I dont think Ed Perl was at that meeting. Ed Perl would never be at that meeting, no. MELDRUM: No. I dont know. I dont think so. Noordenbos was there though. CASEY: Oh, Noordenbos was there for sure. Ed Perl, however, was at the Issaquah meeting. MELDRUM: Okay, so tell me about the Issaquah meeting. CASEY: We came to this meeting, and we were trapped. It was an abandoned -- or almost abandoned -- nunnery. Off in the distance occasionally you could see a nun scurrying across the field or something. We stayed in these spartan rooms [laughs] and had these meetings, lots of meetings about this and that, organized -- David Bowsher was there. So we had all kinds of meetings. Ed Perl and Pat Wall had some kind of disagreement and -- at any rate, what I remember about that meeting that really was so personally meaningful to me was that Jean-Marie Besson -- and I just read a paper of his -- had also recorded from the nucleus gigantocellularis. He got up and presented a paper which said, We agree with Casey. [laughs] MELDRUM: Oh, thats wonderful! CASEY: And I thought, This is the most wonderful thing, to have somebody else come up and say yes, this is right, this is right. Hed done some other things that elaborated on it, and so on. Another thing I remember about that meeting was that Ron Melzack showed a movie of trepanation, so here this guy was on the big screen, his head was shaven, and an incision was made, and blood started pouring down his face, and in the back of the room, something when thwump. Some guy -- I dont know who it was -- in the back of the audience fainted. [laughs] Another thing I remember about that meeting was Bill [William H.] Sweet. Bill Sweet was on a crusade against another guy who was on a crusade about psychosurgery. So there were some neurosurgical papers there about surgery for pain, and so on, and Bill Sweet had been doing prefrontal leucotomies. There was this other fellow who was going around -- I forget his name now -- who was making a big deal about how bad this was, how bad any surgery on the brain was because we were all going to make lesions in peoples brains and control them, and so on and so forth. And of course, this was a Vietnam kind of era. So Bill Sweet got up and just laid into this guy, who wasnt there, by the way, and called him -- oh, whatd he say? [chuckles] He said, This man is nothing but a malinformed buccaneer! [laughs] And I thought that was wonderful. Then of course, I remember all the Italian people that were there, and Procacci and Pagni was there, and I thought this is a pretty big deal and interesting. And so we formed the society. MELDRUM: Yeah, Bonica was great at that. CASEY: Yes, he got everybody _____, organized everybody. And that was it. I didnt go to the first meeting in Florence, but Ive been to every IASP [] meeting since then and now has a life of its own. When John Bonica died, I remember having a conversation with John Liebeskind, and I thought -- Bonica had been such a powerful influence in this whole thing that I fear for the survival of IASP and for the American Pain Society. Then there was Wolff -- Bert Wolff -- on the eastern coast and John Bonica on the West Coast, and the Western Pain Society, and so were going to form the American Pain Society, and so theres a turf battle. I remember John Bonica -- I was here doing my clinical stuff and just being a neurologist. John Bonica gets on the phone and says, Ken, youve got to go to Chicago tonight! Because Bert Wolff is taking over the American Pain Society. And stuff like this. I said to myself, Well, John, you know. [laughs] At times like that, I think to myself, Twenty-five years from now, whos going to really care? [chuckles] So I didnt go. But other people went. John Loeser went and they had their battles and stuff. So we had the formation of the American Pain Society, and I was worried about the future of that society absent John Bonica. But I think that both of these now have a life of their own. Pain is sufficiently interesting now. There are so many people in it. I feel like Ive been standing at the bottom of a pit, and I didnt know it. Then as I look up, I see that its much bigger than I thought. [both laugh] MELDRUM: Yeah, it was pretty humongus. I mean, this last meeting in Vienna was -- good Lord! CASEY: But thats true of neuroscience in general. Its now -- I remember when there wasnt a Society for Neuroscience. We all went to Atlantic City and you did your little thing by yourselves. I didnt mind that, actually. MELDRUM: No? CASEY: No. I still like small groups. MELDRUM: Well, small groups are much more fertile in a way. CASEY: Yeah. MELDRUM: In big groups, you sort of have to stake out your territory and defend it. CASEY: I think its sort of the nature of my work. I dont have a big lab. Molecular biologists have big labs with people doing various kinds of plots and things going on, and Ive never been attracted to that very much. MELDRUM: Well, its a different kind of style. CASEY: Yes. MELDRUM: Okay. Its just about noon. CASEY: Does that answer your -- MELDRUM: Answers my -- Well, it doesnt exactly answer my Bat-Sheva question. Nobody remembers what happened at that meeting, and something, Im sure, happened. [both laugh] END OF SESSION; TURN OFF TAPE RESUMING INTERVIEW ON APRIL 21, 2001 MARCIA MELDRUM: Okay. We concluded this tape at noon on the twentieth. And were now going to resume the tape. Its the twenty-first. Its about 9:45. Okay. So good morning again, Dr. Casey. KENNETH CASEY: Good morning. MELDRUM: Its now about ten oclock on a still gray but not quite so rainy morning. Id like to talk a little bit more about some of the experimental work that youve been doing. Youve done a lot of your work with Dr. [Thomas J.] Morrow? CASEY: Yes. MELDRUM: And hes been a long-time collaborator? CASEY: Yes. MELDRUM: What does each of you bring to that? Obviously, its been a successful collaboration. CASEY: Tom was a graduate student when I was, I guess, an assistant professor or associate professor -- I cant remember which -- and he wrote really a terrific comprehensive exam. I thought, This guy is really pretty smart. At that time, however, he was in physiology but he was involved with a professor of fisheries, of all things, who was -- his name escapes me just at the moment -- who subsequently moved to Hawaii. Tom was interested in the lateral line organ and sensory functions in the fish and was headed toward a career in fish physiology. Then this guy said, Im going to move to Hawaii and wanted Tom to come with him. Well, Tom didnt want to go to Hawaii, and his wife didnt want to -- they didnt want to leave the area. So he began looking for something else and became attracted to the sensory system that I was working in, somatosensory system and in pain, so we started doing this. Early on, Tom had just asked my permission to have a fish tank in my laboratory because he hadnt decided yet. While this move was taking place with the other professor in fisheries, Tom had a little experiment going on and needed a place for it. So for a while I had a fish tank in my lab. I had not idea what to do with it. So finally, I told Tom, We cant do fish here. I gave him a problem, which was to, at that time, look at the periaquaductal gray. It was just after Mayer and Liebeskind, et al., and [Huda] Akil and so on had done this experiment stimulating the periaqueductal gray and found localized analgesia in the leg of it. Actually, Im not aware that that has since been duplicated, that is, that particular aspect of it that analgesia is localized in one part of the body, which is an important conservation. As I talk about it, I reflect on that and wonder if that has been a repeatable finding. If not, then it raises questions. Its not really that much of a challenge, but it gives a different picture of the neurophysiology of this system. In fact, it was very surprising to me that given the large projectionary on the anatomy and what little we knew about the physiology of periaqueductal gray at the time that it should have a localized effect. It should have a very generalized effect, both rostrally and caudally, which I think, in fact, it certainly does. So I told Tom, Look, we have these cells in nucleus gigantocellularis that I found some years ago that responded to noxious stimuli, and so, if these cells have something to do with pain -- although they receive nociceptive information -- if they have something to do with pain and if reducing their discharge, especially with analgesia, then stimulation of the periaqueductal gray that produces analgesia should reduce the response of these cells. The idea then was to behaviorally produce analgesia a la [David] Mayer and Liebeskind and Akil, and so on. Actually, Reynolds was the first one who did this in Canada. So, to produce this analgesia, and the prediction would be that the nociceptively responding cells in nucleus gigantocellularis should be reduced when analgesia was produced but not when analgesia was not produced. There should be a correlation. So really, stimulating the periaqueductal gray was a means of producing a behavior, or a behavioral state, which we would then make predictions about with regard to the responsiveness of cells in the gigantocellularis reticular formation. It turned out that, in fact, that worked. In the process, we found, as others have, that stimulating the periaqueductal gray is a very bizarre thing to be doing to almost anything. These animals would have -- startled, they would give behavioral evidence, some of them of being in pain, which was consistent with what had been found by **Mashold** and others who actually had done this in humans. So it made me somewhat skeptical still about the business of you just put this in the periaqueductal gray and turn on the current and youve got analgesia. It was all too mysterious and simple for me to buy, completely. Something about it just didnt quite fit. We did this experiment anyway. That worked. In the process, what Tom did -- what Tom brings to this team is technological expertise. There is almost nothing about biologically appropriate electronics and computer monitoring, and so on, that Tom knows -- theres nothing he doesnt know thats worthwhile. [laughs] Hes extremely clever and knows all this and actually brought me kicking and screaming into the computer world, which actually for both of us was a long process because the technology kept changing, and we kept trying to keep up with it and rebuilding and doing things, and I think we wasted a lot of time. I think it would have been better to wait and have somebody else do this. Anyway, we were doing _____ logic and building a lot of our own stuff, and that was okay, but it took a lot of time. What Tom brought to this particular experiment was the monitoring of the temperature of the -- what we did to determine that the rat was analgesic was use tail flick. So we put a thermocouple on the rats tail and then began to heat it up. He built a little tail flick device and heated up the tail and determined the temperature of the tail at which the flick would occur, and when we stimulated the periaqueductal gray -- END OF TAPE KENNETH L. CASEY INTERVIEW TAPE THREE, SIDE ONE MARCIA MELDRUM: Okay. Were starting tape number three of this interview with Ken Casey. Theyre models of subacute pain. KENNETH CASEY: Right. The formalin test, which we have used in the rat, lasts for an hour and is a useful model for studying acute pain. There may be some of my colleagues who believe that this leads to some permanent chronic change in the nervous system, but I dont think theres any evidence for that. Were talking about, really, pain that lasts for an hour. I think most people call that acute pain. Its a prolonged but -- and things can happen in the dorsal horn and everywhere else during this late phase, and so on, but its an hour. MELDRUM: And then it goes away. CASEY: And then it goes away, without any treatment. The animal then recovers. You can study an animal like that and learn about analgesics and neurotransmitters and behavioral things that modify the pain, and so on and so on. Its a very useful model. The rat recovers. Hes okay. Thats okay. I think thats all right. Were not studying chronic pain here. MELDRUM: No. But its ethically justifiable and its scientifically useful. CASEY: And its scientifically useful, right. Thats okay. I think we say that in that paper. Others use _____. I think Ron [Melzack] uses that as a -- and carrageenan. Well, thats a little different. Theres more permanent tissue damage there maybe. But also, the animals recover and it goes away. I think in all of those cases, if youre looking at whats happening in the dorsal horn, the spinal cord, youre not studying the disease of chronic pain. Now, Ron uses the term and others use the term persistent pain. Im not quite sure what he means by that, but I think as long as the inflammation is going on, the pain is there. Is there a good reason to stop the pain before the inflammation goes away? Well, maybe. That might help some folks. Thats okay. But again, its not studying chronic pain. Ron Dubner and everybody else, Clifford Woolf, all those people who are studying those kinds of things are studying subacute, or really acute pain. And I will say here, no matter what they say [laughs], this is what they are studying in inflammatory pain. Now then, the other thing that we talk about in this paper is neuropathic pain. Thats a different matter. As a neurologist, people I see, patients in the clinic -- they have nerve damage. Most people who have nerve damage do not have pain but a significant minority do have persistent pain. I actually dont know that theres good data about this. If there is, I probably should know it. I mean, how many people with -- its hard data to get, people with nerve injury. People with diabetes, they have chronic pain, and theres good evidence that this nerve damage is producing several things. One is abnormal discharges of regenerating C-fibers peripherally. It changes the biochemistry and the physiology of dorsal horn cells. They start firing **pl___** action potentials and have tetrodotoxin resistant sodium channels, et cetera. So theres something pathologically wrong with the nervous system, which is persistent. In the case of diabetic neuropathy or nerve injury neuropathy, its anybodys call right now whether the problem is treatable entirely by attacking the peripheral nervous system or the central nervous system or both. Im willing to buy the idea that some of these very long-term neuropathological changes could, over time, alter the central sensitivity of these cells and cause the pain to persist and make it more refractory and difficult to treat. There are cases of nerve injury, again, most people dont have this problem following nerve injury, but its very common to have allodynia or abnormalities of sensation that reflect central changes, and so on and so forth. So here, I think, at least part of the central nervous system can be involved in having this pain persist. But again, this is neuropathic pain, and thats why we now still -- we do study using the [Gary J.] Bennett model. And theres the [Jin Mo] Chung model, and so on and so forth. But this is neuropathic pain. Now then, these animals -- so it is a significant clinical problem, and we do need to know more about it. Again, its still a minority of the patient population, but its there, and something ought to be done about it. The animal model in that case, which is the Bennett model or the Chung, or whatever, and theres another one, Schweitzer or somebody or other. But at any rate, doing those things to the peripheral nervous system is appropriate. Those animals, weve studied them out to twelve weeks, and they get better. Ours started getting better at eight weeks. We study their spontaneous behavior and their response to stimuli. The rats continue to eat and they look okay. Are they disabled? Yes. Are they in pain? Yeah, some. Are they suffering? Well, I dont know whether rats suffer very much, but they maintain their weight and they respond to handling without being obviously distressed, and so on. And they get by pretty well. Given the fact that its a clinical problem, and the rats arent really suffering in a sense. Theyre not depressed, theyre continuing to eat, engage in other normal activities, and I dont feel bad about that. I think its appropriate. Thats what I was getting at with the original thing. Here is an animal model -- wasnt developed then, when I wrote that editorial, or I dont think it was. MELDRUM: No. It was just before. CASEY: Just before. So heres an animal model thats appropriate for a clinical entity, that exists. Then there is an area that Im also aware of that also affects a significant minority of patients where we know that the problem is central, and that is central pain. Injury to the spinal cord. I see patients with multiple sclerosis, and its a minority. Latest data from Jrgen Boivie and his colleagues in Linkping in Sweden is that thirty percent of patients with multiple sclerosis have pain due to their disease. My own experience isnt in accord with that necessarily. Its more like ten percent, or something like that. I think that there are ten percent, or thereabouts, of patients with stroke who have pain as a result of stroke, and most of the time, its not terribly disabling, but it is quite bothersome to them, and if they dont understand what it is thats going on, its frightening. Here theyve had a stroke, and then three months later they start having pain in the paralyzed arm, and they wonder, What the devil is this? They think something else is happening. And you tell them, Yes, yes. This is central pain and try to explain to them whats happening. Well, I think that is -- thats a clinical problem. We dont have an animal model for it, really. The group in Galveston has an animal model. We havent used it. Im not convinced about it yet that we need it. Zsuzsanna Wiesenfeld-Hallin in the Karolinska Institute with her colleagues _____ have developed an ischemic model of spinal cord injury that results in a temporary but very persistent -- several days or months in some animals -- allodynia. So its an ischemic injury of the cord that produces pain. Theres a significant clinical problem here. If you look at people who have spinal cord injuries -- quadriplegics. If you talk to people here, Jim Leonard will tell you that at least half of the people who are quadriplegic from spinal cord injuries have pain below the level of the injury. If you listen to Christopher Reeves, who goes around very -- his problems pain. Of course, he cant walk and all that, but if he -- and his pain isnt -- hes not writhing on the table. (He could writhe.) Hes not complaining bitterly of pain all the time, but its there. Its a chronic, nagging thing that is with him all the time, and I think it affects the quality of his life, and I think that affects the quality of life of these other people who have stroke and who have pain and who have spinal cord injury, multiple sclerosis who have pain, and so on and so forth. Well, we dont have an animal model for it, so I study now, thanks to functional imaging, Im looking at patients -- beginning -- if I can ever get funded to do this -- beginning to look at patients with different lesions. MELDRUM: Is it possible that functional imaging, although it probably wont ever -- wouldnt necessarily obviate the need for animal models, but it does really reduce -- I mean, it allows us to examine in humans things we could never before examine except in animals. CASEY: Thats true. MELDRUM: At least not in any ethical procedures that we knew of. [chuckles] CASEY: Thats true. Thats true. Well, I think it does -- yes, it eliminates the need for at least some animal models, I suppose. We have an animal model of PET in the sense that we are looking at synaptically induced blood flow -- I think I mentioned this already -- in the rat. Were using that in conjunction with the Bennett chronic constriction injury model. So weve got a neuropathic pain. We followed these animals -- I think this is one that were preparing this paper, but we can show that after this twelve-week period while the animals are still recovering, their brains are abnormal. I think that says that there are these reorganizational changes that take place. Their brains may be abnormal because they may have recruited -- I mean, one speculation is that theyve recruited over time all these descending inhibitory mechanisms and that thats what were seeing. Thats a possibility, that their descending inhibitory systems have been called into action, and that is why theyre better. They may be getting better because their brain is different. I cant prove that now. This is speculation. But it is for sure that when these animals are better, theyre walking around, they look just fine. And you test them or do our imaging paradigm on them, theyre brains arent normal. Theyre definitely abnormal. Now whether theyll all gradually come back to normal again or not, I dont know. But I think its an adaptive process in the metasystem. I think that what happens with people with stroke or with other injuries is that this adaptation takes place, or there are adaptive processes that take place that are abnormal, that are maladaptive, and that -- why that happens is a biochemical genetic question thats going to be answered by somebody, not me, but somebody whos doing the proteins and looking at the details of the neurochemistry of this system. But what we have to do, what I can do maybe, is identify the conditions under which that happens. Basically identify the phenotype, to put it in modern terms. And having identified the phenotype, say, This is what occurs, this is the maladaptive reorganization, here is the time and here is the place where you have to look to find the abnormality. Otherwise, youre looking for a needle in a haystack. MELDRUM: Thats real interesting. Okay. CASEY: So I havent changed my mind about this. I think that animal models have to be clinically relevant. I think that there was an enthusiastic idea among basic scientists and others that anything -- you could do anything and say it was all related to chronic pain. And its not. MELDRUM: Okay. I think thats very clear now. Thank you. Thats very helpful. Okay. I want to look at one of the PET studies as well, the one I mistakenly looked at earlier, where you were studying -- this was a study of humans -- warmth, heat, and deep cold? CASEY: Yes. MELDRUM: Its a fairly recent experiment, I think, where you subjected them to a variety of stimuli. There are two basic questions I want to ask you first. One is, you use a stimulus intensity reading of zero to ten, where seven is barely painful and ten is then barely tolerable. This is something youve used in several of your experiments. So essentially, youre asking the subject to give you stimulus intensities from zero to six, which is simply recognizing increasing intensity without recognizing any degree of pain at all. Im just wondering if theres a particular purpose behind this. I mean, you could just use something like four, where zero is no sensation, one is detecting the sensation, two is barely painful, and then moving on to there. CASEY: Right. MELDRUM: So thats one thing. And then, the second thing is perhaps even more trivial, which is that you test right-handed people by stimulating their left arm, and I think thats interesting. So maybe you want to comment about that. Anyway, thats what I wanted to talk about. CASEY: Okay. The first question -- pain tolerance. Most people dont like fifty degrees centigrade on the hairless surface of their forearm for very long. Thats pretty close to tolerance for a lot of people. Forty-five degrees is arguably pain threshold. Thats five degrees. But below forty-five degrees you have probably ten degrees where people can recognize differences in temperature. So if you say the skin is probably somewhere around thirty-three, thirty-five degrees, well, people can recognize thirty-six, and they can recognize thirty-six from thirty-seven, thirty-seven from thirty-eight, thirty-eight from thirty-nine, so the range of discriminable innocuous stimuli is ten degrees, and the range of discriminable noxious stimuli is five degrees, before you hit ceiling. Thats why I developed this asymmetrical scale. I was criticized for that. But it works, so informally Ive had -- MELDRUM: It works. How does it work? CASEY: Well, people will -- actually, if you then go back -- thats the answer to your question. Thats my rationale for having an asymmetrical scale. But why do we use it for cold? Well, we wanted to use the same -- we developed the scale for heat stimuli, so we have used it for other stimuli as well. Subsequently, having been criticized for this, at the suggestion actually of Don Price, I think who criticized this, we went back and did an experiment that he suggested. Have people use zero to ten. Because first of all, rather than use a scale zero to ten in which zero is no pain, we had to use a scale in which zero was no heat and no warm sensation. If you look at a lot of the pain literature, zero to ten, they go from no pain to pain and forget about all of the other stimuli below the pain range. Well, if youre doing a study to identify pain in humans and youre looking at the brain, youve got to include -- MELDRUM: Exactly. Because youre going to have the brain firing as the sensation occurs, even though what theyre -- thats just an indication of sensory discrimination. CASEY: Thats right. Hence, the purpose of this study -- looking at warmth. Anyway, at Prices suggestion -- we havent published this, but we will. Its coming out from Mike Geisser, whos working with us on the program project. You take a group of people and say, Okay, the scale is now zero where there is no sensation of heat, and ten, its intolerable. Give us a rating of the intensity of this and tell us when it is that pain takes place. In other words, this is four. Was it painful? No. This is five. Was it painful? Well, no, its pretty warm. And six -- well, it turns out that its six and a half. [laughs] So ha ha ha. I think its six and a half. Maybe its six. I dont know. But its asymmetrical. MELDRUM: Its asymmetrical. Presumably, there are other levels above barely tolerable where you could become intolerable. CASEY: Oh, yeah. In fact, we had a German student who came in. We were testing him, and there was something wrong with the stimulator. Well, we burned him. While he was being burned, he said, Gee, this is pretty intolerable. [laughs] He thought this was the way it was supposed to be. [both laugh] MELDRUM: Uh-oh, mistake. Okay. So why do we apply the stimulant to the non-dominant arm, that is, the left arm? CASEY: Very simple reason. The PET scanner is in a room in which the left arm is more accessible than the right arm. MELDRUM: [laughs] Thats a good reason. CASEY: By the way, on that issue, the dominance problem has not been adequately addressed with this methodology. MELDRUM: I was wondering about that. CASEY: _____ dominance, and it needs to be addressed. Its an important issue, with pain was well as with other things. MELDRUM: Okay. So talk a little bit about the study because it seems to be very interesting. The patient was given various warmth stimuli, and then the left hand was immersed in cold water, experiencing deep cold pain. And this showed a different type of response pattern. CASEY: Well, the question was, Are there groups of structures in the brain that respond to pain no matter how you give it? So there really are two papers like that. Theres this one on warmth, cold, and heat, and theres another one with Peter Svensson on cutaneous pain and deep muscle pain. So on that issue, the final answer is this, that if you take the different subtraction images that you get with these different pain stimuli and subtract them from one another statistically, you wind up with nothing. That means that the activity that is generated by each stimulation is activating the same structures. Now, its activating them with different intensities to different degrees, and there is almost certainly something else going on within each of these structures that tells you that its muscle or that its cold, or something like this. There are differences, but the overlap is great enough so that if you subtract cold pain from heat pain, you wind up with nothing. The overlap is very great. That was what we were trying to get at. So how do you -- youd say, Maybe with cold pain theres a whole group of other brain areas that light up. Nobody knew that, and thats why we did this experiment. The other reason is, for warm, we wanted to say, Is there a limit? Will we be able to image those structures that respond simply to warm? And we got very little activity. Its clearly intensity dependent. You would probably get better activation of some of these somatosensory structures in the warm case if you gave them a task so that they had to attend very carefully to differences within the warm range. You could probably do it. But my guess is that the synaptic activity that is necessary to do that is pretty small. You could do an experiment probably where they detect movement of the hair, but I think youd have to be very specific, bring your statistical threshold down, focus in on specific areas of the brain in order to be able to see the somatically(?) induced blood flow that was caused by a very fine tactile stimulus. At any rate, we showed that pain is quite different than warmth but that cold pain and warm pain and heat pain and, later on, cutaneous pain and muscle pain are activating the same basic structure. Then I think with that and with the other studies that other people have done, were -- as I said earlier -- were close to being able to throw up a PET scan and say, Yeah, that looks like pain and be right about it ninety percent of the time, maybe. MELDRUM: So conceivably, if a person presents with no organic cause for pain, with no apparent clinical syndrome thats recognizable, but they say, I have really bad back pain, or whatever it is, and it wont go away, you can do a PET scan and say yes, these nerve centers are definitely active. Could you do that? CASEY: [sighs] MELDRUM: And what would that tell you? CASEY: Right. That question gets asked all the time. Can we read the mind? Thats basically -- I call [it the] Reading the Mind question. [chuckles] I think that, in theory, it is possible to do that. I think, though, that youd have to demonstrate that you could do that by predicting in a blind fashion from the scan to the complaint. Youd have to line up a hundred scans and be able to pick out the eighty scans that were pain-free, and then those eighty individuals, each of them would say, Youre right. I have no pain. The other twenty would say, Yes, I have pain. Youd have to be able to do that. Were not there yet. Then, even if you could do that, you would still most likely be presented with the uncertainty when somebody said, Yes, I do have pain. At some point, theres going to be a conflict. Somebody is going to say, No, I know that you can predict accurately 100 percent of the time when somebody has pain because youre looking at their brain in such and such a way -- this is fifty years or a hundred years from now -- but I dont care. Its not good enough. I have pain. Or, I do not have pain. Nothing you can do with that. I think that the practical issue about that is, Is there something that you should do? If you had somebody whose scan said there was no pain, and the person said, Yes, I am in pain all the time, and there was no organic cause, et cetera, youre in the same situation that were in in clinic every day when someone complains of pain and theres no obvious organic cause. You cant say, Well chase it down somehow. Were going to put you into this, that, and do this study and the other, and so on. Youre not going to do it. Youll do no harm. MELDRUM: I understand that part. I guess I was thinking more that this would be a verification that there was actually such a thing as neural activity, and therefore these people were not, in fact, making this up. CASEY: Right. Well now, that comes to -- MELDRUM: Of course, it could be their imagination. [chuckles] CASEY: That comes to a study, which I hope to be funded for on this round, and that is fibromyalgia, something I do not see. I do not see patients with fibromyalgia. Theyre seen by rheumatologists. But the issue comes up, Do these people have a central nervous system abnormality? Well, theres a smattering bit of evidence that, in fact, they do. They have sleep disturbance, theres -- then there are some -- theyve got too much substance P or not enough in their cerebral spinal fluid. Jrgen Lorenz, whos with me, showed, using laser evoked potentials, that they had enhanced laser evoked potentials compared to normal subjects, but that other -- auditory evoked potentials and other evoked potential studies show that these people are normal in that respect, so they have some kind of abnormality of nociceptive processing by that evidence, and so on and so forth. Theres other bits of evidence that these -- mostly women, rarely men -- my colleague here at Michigan, Leslie Crawford, has evidence, and others have evidence that theres something wrong with their pituitary access, hypothalamic pituitary access. Cortisol, et cetera. All that endocrine stuff gets pretty fancy. Somethings wrong. So theres enough there, and people are interested in it enough, and I think its interesting enough from the imaging point of view to say, Look, we know now from our own studies, from [George] Coghill and [William] Derbyshire and others, that you can generate a stimulus response function of regional cerebral blood flow that correlates parametrically with the individuals perceived intensity of the stimulus. So if thats true, then these people should show a left shift of the stimulus response curve in regional blood flow and in their perceived intensity of heat pain. And that is what we will do if we get -- So my colleagues say, Look, thats fine if you show that. What if you dont show it? [laughs] Then I would have to say, Yes, thats true. But then all we can say is that this technology does not tap into whatever it is thats going on with these people. There is no evidence, however. Doesnt prove -- I mean, lack of evidence is not evidence of lack. But theres no evidence that they have an abnormality of nociceptive processing. So the best technology we have to look internally at nociceptive processing in the human brain is this. So we will do it. MELDRUM: I hope you do get funding for that. I think it should be quite interesting. CASEY: Well, I got a one ninety-five, or something like that, last time, so -- and they said, Youve got to do the psychophysics first. Well, its already been done by other people, but okay, Ill do it and well send it in, and hopefully, itll get funded before I meet my maker. [chuckles] MELDRUM: I know. It gets tougher and tougher, doesnt it? CASEY: Well, the imaging studies are -- there are a lot of goofy imaging studies done, and that gives it a bad name. But of course, when I was doing single cell recording, there were a lot of goofy single cell recordings being done too. MELDRUM: Yeah. Technological toys -- CASEY: Right. Can be misused. MELDRUM: I think there really is a problem. There are just more applications floating in all the time than the study sections can deal with sometimes. CASEY: Oh, yes. MELDRUM: The whole thing has grown geometrically and then beyond geometrically at this point. CASEY: Yes. I look at the study section; theyre all Ph.D.s. Maybe one M.D. in there somewhere. Nobody with just an M.D. like me. [laughs] And I say, [whispers] Why dont you get somebody on there? Actually, when I took this job in 1980, I was asked to be on Study Section B, and I turned them down. I said, No, Im moving, and Ive got too much to do. Im told that -- and they havent asked me since, except for special study sections, and so on. And Im told that they have a tough time getting clinical people on these study sections, scientifically qualified clinical people. I mean, there are just not that many. But theyre doing the best they can and make reasonable judgments, and its tough, I guess. MELDRUM: Okay. Well, I have a couple more sort of organizational type questions to ask you about, but did you want to -- is there any other aspect of your work that youd like to comment on? CASEY: Well, no. Youve covered it very well. Youve pushed all the right buttons. I was very interested that you dug out this editorial on chronic pain. Thats interesting. MELDRUM: Its a subject of interest to me. CASEY: Has anybody else ever mentioned that as an issue, or has that issue come up in your interviews? MELDRUM: What? Animal models or -- CASEY: Right, animal models and the appropriate use of animal models, and so on and so forth. MELDRUM: Not specifically mentioned it. Sometimes I ask them about it. Obviously, when I interviewed Gary Bennett, we did a lot of talking about animal models. But Im sort of interested in the multi-facets of this question, which is, What can we use animals to model? And what is it to say -- what do we mean when we say the animal is in pain, because animals dont necessarily think -- I mean, to an animal, chronic pain is not going to be the same as to a human no matter what we do. CASEY: Thats true. Thats true. Well, I dont know if my position on that now is clarified or not. But I think theres an appropriate use, but I think that a lot of my colleagues in the pain field think that theyre studying some kind of a terrible chronic pain problem, and theyre not. [chuckles] MELDRUM: Exactly. Its not difficult to create a problem in an animal which looks like pain. CASEY: Yes. MELDRUM: So its a kind of a historical question, which I have some interest in. Anyway. Okay. I just wanted to ask you a couple more questions about your organizational work. You were the founding editor-in-chief of Pain Forum. CASEY: Yes. MELDRUM: I liked Pain Forum. CASEY: A lot of people did. MELDRUM: So I was just sort of wondering how that came about that you decided to start this -- or took over the journal, or whatever. CASEY: John Liebeskind called me. MELDRUM: Oh, really? He didnt tell me that. CASEY: He called me. I think he was president or had just been president, or something like that, and other people had said, the American Pain Society is big now. Weve got to have a journal. So when he called me, and I thought -- Bob Addison had asked me earlier, Please be editor of the Pain Journal. Youve done basic research, and you do clinical work. I said, Theres not enough good stuff out there. I didnt want to be the editor of a journal with ridiculous papers. So I said, Theres just not enough original stuff out there. I dont want to do it. So John called me and said, Weve got to have a journal. You decide what kind of journal you want it to be. I thought about it then, gave it some more thought. I thought, What is really needed is a journal where some of these issues that are unsettled and conflicting, where there are really conflicting opinions about things, and so on, where you can thrash that out, because you cant do it in the discussion section of Pain or anyplace else for that matter. You can sort of tangentially refer to so-and-so in a very nice polite way. I thought, We need something where you can -- not the gloves off entirely but take the gloves off a little bit. Instead of using sixteen-ounce gloves, you use eight-ounce gloves. [chuckles] And come head-to-head with these issues. And in the process of doing that, somebody can read the argument -- theres two arguments -- and say, I kind of see where this field is now. Even if they arent involved in it, they could, just by reading the two commentaries, or even one commentary, they could say, Oh, I see. They could update themselves very efficiently. Theyd know where the problems are in that particular area. So thats what I said, thats what we ought to do. Make it scholarly so people have to have citations, and the argument has to be reasonable, and yet they cant make personal attacks and call each other names, and things like this. Which I did have trouble with. One of our most august personages in this field. But anyway, so you set those rules out. And youre right. People liked that. The problem was, the National Library of Medicine didnt like it. MELDRUM: Yes, and they wont index it. CASEY: Would not index it. So I walked in with my eyes wide closed [chuckles] into this business of indexing a journal. The process is unclear. It is opaque. It is mysterious. The criteria are -- those criteria which are clear do not appear to be followed. It is a very unreasonable process, at least so far as a journal like Pain Forum is concerned. For example, one of our colleagues in the American Pain Society was a member of a group that was supposed to judge journals that had been submitted for indexing. So now we had somebody who was inside, at least we thought was inside. He said that hed received a list of two hundred and fifty journals and was asked some simple question like, Do you read this journal, and do you think it should be indexed or not indexed? Do you get this journal? And so, the group that got this, other than himself, would be people who would never have gotten Pain Forum. So when they said, Do you read this journal? they would check no. Should it be indexed? They would either say undecided or no. Because they couldnt say yes. And that was it. That was how it was judged. That was my best insight into the critical nature of the review of this thing. My guess is that this group is probably underfunded, understaffed. They had all kinds of journals coming in. They had no way of judging them themselves. They throw this questionnaire out. They dont have a very good way of evaluating the question itself, and so on and so on. And so they are using very simple, crude criteria, and thats all. This journal was too far out for them to accept. MELDRUM: Well, I find it frustrating. CASEY: Well, I was really frustrated. MELDRUM: Youre not the only person, because its not just the people who read the journal and the people who write for the journal and want their work to be indexed, its those of us who are trying to find out things -- trying to research questions and trying to find ways into understanding problems. Say youre coming from another field and you dont have any -- END OF TAPE KENNETH L. CASEY INTERVIEW TAPE THREE, SIDE TWO KENNETH CASEY: Well, the Pain Forum is dead. It will be accessible through the Journal of Pain and through -- the American Pain Society, I am told, will have a website so you can go back -- I see Pain Forum referenced. Just the other day I was looking at an article, and somebody said published in Pain Forum, so if somebody wonders where that is, theyll find out that it was the official journal of the American Pain Society. If theyre really interested, theyll get on the American Pain Society web and theyll have access to the article. Otherwise, its not going to be published. We now have the Journal of Pain. We have the first issue, and Jerry Gebharts the editor and Im associate editor. Bud Craig wrote a very nice article in that journal, and there are some original articles there. Now I think -- Pain Forum started in 1990 or 1991. The first issue, I think, was in 1991. So now its ten years later. Theres more stuff. So I think it could work. MARCIA MELDRUM: And this journal will look more like a real journal. CASEY: Thats right. That component of Pain Forum is going to be retained in the Journal of Pain, but there will be the addition of original articles, and so on. So hopefully that will get it indexed. I hope so. But anyway, that was -- I failed. [laughs] I failed, but it wasnt my fault. [chuckles] Well, in a sense it was because -- MELDRUM: I dont think you did fail. CASEY: Well, it depends on how you define -- MELDRUM: The journal, in a sense, was not a success. CASEY: Well, in a sense it was a success. Everybody told me. Theyd come up and say, Gee, I really like this journal. Its a lot of fun to read, and so on and so forth. But it never got indexed. MELDRUM: Okay. Interesting commentary. Okay. You were president of APS in, lets see, 84, 85? CASEY: Yes. MELDRUM: Do you want to comment on your experience as president? CASEY: I dont think I was a very good president. I think I wasnt a very good president because I didnt want the society to be a big thing, that is, commercialized. I visualized the American Pain Society as a group of serious scholars doing research, and so on and so forth, and I wasnt very -- to the extent that it had a political impact, it would be because it was that, it was a resource of solid clinical and basic information about pain and was not interested in promoting anything, or that kind of thing. But there were others in the society who had different ideas, and they wanted the society, for example, to be a credentialing society, and they wanted to have the Pain Society promote pain clinics in various ways. That is, if they had a clinic that was a pain clinic, then they wanted to be sanctified by the American Pain Society. Then, if youre going to do that, then you have to have criteria. That leads to specialization in pain, clinically. So now we have a pain specialist, and I didnt want to see that. So I wanted to strip down -- I couldnt do it (chuckles), but I wanted to strip down the society, eliminate certain committees, and get rid of all this other stuff and have a pure American Pain Society. Didnt work. (laughs) I was a bad president. Probably most people didnt recognize that I was a bad president, but I was a bad president, from that point of view, I think. I ran the committees, and so on. I did have the unfortunate experience of having the management, society management, at that time, was inadequate, improper. In fact, the person who was assisting me was disturbed. She could not keep track of this, that, or the other thing. Appointments were being missed and people were not being contacted. There were an abundance of communication problems. MELDRUM: This was the first group that the society hired. CASEY: Yes, right. We first hired an individual. Then we hired a little company. And that didnt work. There were all kinds of communication problems, and I thought things were being done and they werent being done, so somebody would call me, and so on. Thats why I think what most people saw. When I say I was a bad president, thats just in my heart I was probably a bad president. I probably wasnt as bad as Im making it out to be. MELDRUM: Its difficult with a society which has -- it has had a lot of conflicting agendas. CASEY: It is also -- most people dont know how I feel about pain clinically, as a clinician and as a teacher. I think that every doctor should know a lot about pain. Every doctor. I dont believe that it should -- I will say this here that I am stridently unenthusiastic about pain clinics and pain as a specialty. I have doubts about it. I think that there is a place for someone who knows more about pain than anybody else. Whether that is a specialty or not, I dont know. I suppose anesthesiologists ought to be pretty good at that, with nerve blocks and those kinds of things. But every doctor should know how to take a history of a patient with pain and, on the basis of that history, focus the examination, and on the basis of that information, determine what the cause of the pain is and treat it. If he finds out the cause of the pain cannot be removed, the pain should be treated vigorously with all of the pharmacologic _____ that is available, and that doctor should know a reasonable amount about how these drugs act and when to start them and when to stop them and do all this other business. I dont think that that is a specialty. I think that the problem is carrying pain to the family practitioner and to the specialists. Pain is still under-treated. A very good close friend of mine had a terrible experience with a broken ankle and was told, We wont give you a narcotic because its likely to be addictive. This guys says, Ive got this terrible, terrible pain. He was told, You probably have a low pain threshold. I said, This is the twenty-first century. This is where we are. And this is the problem. I give one hour of lecture to medical students about pain. And Ill bet thats true at UCLA. Ill bet its true everywhere. The American Pain Society and all the IASP and everything else, were talking to ourselves and we think that -- Howard Fields put out a thing on core curriculum for pain. Ill bet it goes nowhere. Its not his fault. Its just because it is such a big -- medical education itself, the whole issue of how do you educate doctors is a big deal now. Nobody wants to pay for it, for one thing. So in the middle of all of that, you have this business of teaching doctors about pain. So, what do I do about it? Well, every day I go to clinic. I hear -- ninety percent of the patients who come to see a neurologist complain about pain. Well, I think thats true probably of at least eighty to ninety percent of people who go to anybody. MELDRUM: Right. Thats probably the most common complaint. Thats what drives you to the doctor. CASEY: Thats right. MELDRUM: You can tolerate almost anything else, unless youre dying. CASEY: Right, thats right. Yes. So thats where I think the effort should be. Not in generating yet another specialty about pain. John Bonica would throw me to the floor in a hammer lock if he heard me say this, but I have said it in so many ways at various times. So I think that the American Pain Society ought to work very hard at making sure that weve got a scientific base there, that it doesnt become some kind of advocacy organization for pain clinics. It will probably do that. It probably does it. But we cant lose the other. But the economic forces that drive it to this advocacy position -- and you see this all the time. Weve got to talk to Congress. Weve got to just -- because CARF, the Committee on Accreditation of Rehabilitation Facilities. Theyre worried about the CARF criteria and all this business. Oh, no. MELDRUM: Well, some people see those structural things as -- structure is what actually is going to bring about change. TJC [The Joint Commission] regulations, or the change in TJC regulations requiring pain assessment. CASEY: Well, that is a good thing. That is a good thing. But that is a good thing to the extent that it is general. We actually have in this hospital -- I pass around the American Pain Society pain guide. But we have at the VA here a pain clinic. I dont have much to do with it, nor the pain clinic at the University of Michigan, largely because I have other irons in the fire. Im trying to do the best I can otherwise. But I think that my efforts should be directed toward -- such as they are -- directed toward the pain education of neurologists and the medical students that I see and not in taking care of patients who are dumped into the pain clinic. The trouble with pain clinics in general is that they do not make a diagnosis, and they dont do a very good job in general, in my opinion, in making a diagnosis and then treating accordingly. MELDRUM: Well, so often, by the time they come into the pain clinic, theyve had some diagnoses -- the patients have been treated on the basis of that diagnosis, and that hasnt worked, and then they go someplace else. CASEY: Yes. I havent gone in and made surveys and probed deeply and deeply into how pain clinics -- how good they are or not good. Thats a separate career. I just do what I can do. MELDRUM: Well, is there anything else we should talk about? CASEY: Boy, that covers it all. (laughs) MELDRUM: I think it does. Okay. So, its noon on the twenty-first. Thank you very much. Its been a most interesting interview. CASEY: Its been a pleasure. 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"SystemyMy--@Times New Roman--- O2 v-0 John C. Liebeskind History of Pain Collection              2 vy0   @Times New Roman---  2 0     2 0     2 0   @Times New Roman--- ,2 0 Oral History Interview       2 40    2 y0 with   2 0    #2 80 Kenneth L. Casey    2 80   ---  2 U0     2 q`0     2 `0   @ Arial--- &2 -0 Ms. Coll. no. 127.     2 0 53   2 0   ---  2 `0     2 `0     2 `0    2   0 Conducted:     2 0 2   2 0 0   2 0 - 2  0 21 April 2000     2 %0    2 5 0 Interviewer:       %2 5w0 Marcia L. Meldrum        2 540     2 Q*0 Duration: ca.      2 Q0 4.0    2 Q0   2 Q0 hours    2 Q0    2 m[0 Pages:    2 m0 i  2 m0 v  2 m0 ,  2 m0 60   2 m0     2 `0     2 `0     2 `0     2 `0   @Times New Roman---  2 0    82 0 History & Special Collections         2 0 for   2 0   2  0 the Sciences     2 X0    ;2 &  0 UCLA Library Special Collections            2 &'0    .2 >0 Los Angeles, California        2 >0   2 >0 90095   2 >0 -  2 >0 1  2 >0 798   2 >40     2 V0     2 n0    2 0 2016   2 0   @Times New Roman--- --  00//.. ՜.+,D՜.+,@ hp  UCLAZ +HOWARD FIELDS INTERVIEW.John C. Liebeskind History of Pain CollectionOral History InterviewwithKenneth L. CaseyConducted: 20-21 April 2000/History & Special Collections for the Sciences!UCLA Library Special CollectionsBiographical SketchInterview History)Topical Outline (Scope and Content Note)Access to the InterviewTerms and Conditions of UseCitation InformationEditorial NoteQThe interview transcript has been annotated -- with notes offset in [square bracAcknowledgmentsQSupport for the John C. Liebeskind History of Pain Collection and its Oral Histo[PHOTO PORTRAIT NEEDED]Kenneth L. Casey, MD NeurologistKENNETH L. CASEY INTERVIEWTAPE ONE, SIDE ONEKENNETH L. CASEY INTERVIEWTAPE ONE, SIDE TWO'END OF TAPE KENNETH L. CASEY INTERVIEWTAPE TWO, SIDE ONE'END OF TAPE KENNETH L. CASEY INTERVIEWTAPE TWO, SIDE TWO Title Headings*HX|_AdHocReviewCycleID_NewReviewCycle_EmailSubject _AuthorEmail_AuthorEmailDisplayName_ReviewingToolsShownOnceU?HCasey transcript (UCLA John C. Liebeskind History of Pain Collection)rjohnson@library.ucla.eduJohnson, Russell  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~Root Entry F0}7z1TableJ;WordDocumentbSummaryInformation(DocumentSummaryInformation8CompObjr  F Microsoft Word 97-2003 Document MSWordDocWord.Document.89q