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Juhn Atsushi Wada was a Japanese–Canadian neurologist known for research on epilepsy and human brain asymmetry, including the development of the Wada test to assess cerebral hemispheric dominance of language function. He became a pioneer in the utilization of the kindling model of epilepsy, which permitted controlled studies of the development of epilepsy in the laboratory. Drs. Maryam Nouri and Laurent Sheybani interviewed Drs. Jerome (Pete) Engel Jr., Marilyn Jones-Gotman, and Solomon (Nico) Moshe about their memories and relationships with Dr. Wada and his impact on epilepsy research and clinical care.
Sharp Waves episodes are meant for informational purposes only, and not as clinical or medical advice.
Podcast Transcript
[00:00:00] Dr. Maryam Nabavi Nouri: I am Maryam Nouri. I'm a pediatric neurologist and an epileptologist. I work at Western University in London, Ontario.
[00:00:09] Dr. Laurent Sheybani: Hi everyone. Thank you again for participating in the podcast. So I am Laurent Sheybani. I've been trained in clinical neurology in Geneva. I also did my PhD in neuroscience in Geneva, and now I'm a postdoctoral research fellow at University College in London.
I'm working with Matthew Walker on epileptology. And yeah, I'm very pleased to have this meeting with all of you.
[00:00:32] Dr. Maryam Nabavi Nouri: Thank you all for joining us on this very, very special podcast session of sharp waves.
We're joined by very distinguished guests to discuss. The life and legacy of Professor Wada, who passed away in 2023. He leaves behind a wide legacy in neurosciences and epileptologist in particular, Dr. Wada was born in Tokyo in 1924 and was a prominent clinician scientist known for his groundbreaking contribution to epilepsy research.
He earned his MD from the Hokkaido Imperial University when he was 22, and he became an assistant professor of neurology and psychiatry in 1951. He eventually moved to Canada, where he settled at the University of British Columbia in 1956 until his retirement in 1994. We are honored to organize a podcast with three distinguished guests who know him and his work particularly well.
They will tell us about Professor Wada's career, medical achievements, and anecdotes about his life.
[00:01:38] Dr. Marilyn Jones-Gotman: My name is Marilyn Jones-Gotman, and I'm a neuropsychologist. I was at the Montreal Neurological Institute of McGill University for almost 50 years, first as a graduate student in 1970 and then as a researcher and clinician in epilepsy. I retired from the clinical work in 2009, but I continued with my research and academic activities.
[00:02:04] Dr. Jerome (Pete) Engel: I'm Pete Engel, officially Jerome Engel, Jr. I'm director of the Seizure Disorder Center at UCLA, and I've also been there for almost 50 years, still working.
[00:02:20] Dr. Solomon (Nico) Moshe: Hi, my name is Nico Moshe, officially called by Solomon, but nobody calls me Solomon. I've been at least 50 years at Albert Einstein College of Medicine, actually 50 years next year. I'm professor of neurology neuroscience and pediatrics and director of the Isabella Rapp Pediatric Neurology Program and the clinical neurophysiology program.
[00:02:45] Dr. Laurent Sheybani: Thank you very much. So to begin with, if we take the life of Professor Wada in chronological order, for example, we would be very interested in knowing how each of you got to know him.
Maybe we could start with you, Professor Jones Gotman. Would you like to tell us how you got to know him, or how you got to know his work and his career?
[00:03:08] Dr. Marilyn Jones-Gotman: Sure. I don't remember when I first met him, but I have felt, I felt such a strong connection with him through the test that many people call the Wada test, that it feels like I've always known him.
He had been a fellow at the Montreal Neurological Institute for one year from 1955 to 1956, which is when he left for Vancouver, but he was long gone when I arrived there in 1970, but the test was going strong and as a neuropsychologist, I was involved in administering it. And I'd like to point out here, that we don't call it the Wada test, and Dr. Wada didn't like that it be called that, but this didn't stop other people from calling it that. Some people even think that “Wada” is an acronym. Over the years, it has been referred to by a few descriptive names and acronyms, and most recently, I call it the Intracarotid Anesthetic Procedure, or IAP, and when I talk about that today, I'll call it IAP.
The answer to your question, although I don't know when or where I met Dr. Wada, I have enjoyed being a part of certain conferences in which he was celebrated. One was in Vancouver in 2007 at a special CLAE meeting in his honor. Another was in 2013 in Montreal, and he received a lifetime achievement award there at that time.
I've also been the happy recipient of one of his famous letters in which a pressed maple leaf was enclosed. Dr. Wada was known for sending letters with a maple leaf. Canada was his adopted country, and he loved it, and he was proud of it.
And what I can't imagine is all of the books that he must have had in his house with the maple leaves pressed between them, because it's as though he had an unlimited supply of maple leaves, but it's a really great excitement for me to have received one of those letters.
[00:05:19] Dr. Maryam Nabavi Nouri: Professor Engel, how did you get to know Professor Wada and how did you get to know him personally or through his work?
What was your sort of initial encounters with him?
[00:05:31] Dr. Pete Engel: Well, Juhn Wada obviously is best known for the Wada test but I think his major contributions were in basic research in kindling, which is an approach to developing seizures in animals that could be studied as the seizure development progressed.
And for many years, it was the major experimental model for the study of epilepsy, and because of him it was really a Canadian disease. He trained a lot of people and most of the major publications came out of workers across Canada.
I was studying… learning and memory was my interest. And I had been at the NIH and it helped develop a technique for doing chronic intracellular recording in cats to look at conditioning. And when I came back on the faculty at Einstein, this was in 1972, I got an NIH career development award, but it really didn't adequately support my research and I couldn't get a research grant because everybody thought that this was just too difficult.
Dominick Purpura, who was the head of the Kennedy Center where I worked, said, “You know, this is a macho thing with you. You just had to prove that you could do it. You did it. Now do something useful.” And I'll never forget that. I then went to the American Epilepsy Society meeting, which was in New York at the time, and I saw Juhn Wada coming out of the elevator.
And I started talking to him about kindling, and he had just started publishing kindling. And we had a really, very important discussion for my career on kindling and I realized that that's really what I should be doing. He was so open. I was nobody. I was, you know, just out of residency. And he was very happy to talk to me and tell me things and keep me under his wing.
So I went back and started kindling and got grants and it just really was an important change in my career that took off after that.
[00:08:00] Dr. Maryam Nabavi Nouri: Thank you, Professor Engel. Professor Moshe, can I ask you to share the same with us of your first encounters with Dr. Wada, please.
[00:08:12] Dr. Nico Moshe: What Pete did not tell you is that he went to UCLA in 1976 at the same time that I went to the Chair of Neurology and I suggested I was interested in studying epilepsy. And the Chair of Neurology said, “Oh, I would like somebody to do a kindling experiment. What do you know about kindling?” And I said, “Absolutely nothing.” But I learned. And what I found is at that time, Kindling 1, which was just called Kindling, was published. And that was edited by Juhn Wada. And I read it many, many times. And I discovered something interesting, which is that nobody was studying epilepsy in developing animals. There was a sentence in the discussion, the general discussion by Daley, saying one should wonder what's happening if you have a seizure, how kindling will occur in developing animals.
So that allowed me to go ahead and start with kindling. Through Pete and Bob Ackerman, we start developing the experiments. And then the next kindling meeting took place, and I was not invited because I was a nobody, and I just had published one paper, nobody knew about it.
And then suddenly, I got an invitation from Juhn to participate in Kindling 3. And that was a turning point in my life, because the kindling meetings in Vancouver were amazing. What will happen is that you go to the dorm, you stayed in a dorm. It was very, very Spartan. And you started the meeting at 9 o'clock on Thursday morning. And there will be one talk after another. He brought together everybody who was doing research in epilepsy in those meetings.
We had, I think, one more Kindling 4 meeting. And then after that Juhn stepped down a little bit. And Dr. Corcoran and I created Kindling 5, which was dedicated to Juhn, and Kindling 6. The investigators that Pete mentioned, are the names that we hear most of the time, especially one of them, who's named Ron Racine, and everybody talks about the Racine scale in developing of seizures, which is not what Ron described because he never gave it the name Racine scale. He just proposed five stages. And most of the time that the five stages that described now, nowadays had very little to do with Racine's classification, which had to do only with amygdala seizures and not for anything else. By the way, most of the work in kindling was done in the amygdala.
And nothing of this would have happened without Juhn, who presided over every session. And then he had the general discussion. And that was the fun, because you could take everything that happened and discuss it again and revisit it.
Oh, and talking to the leaves. Juhn did send the leaves to all of us. Sometimes they will be broken, but then there were no more letters sent because slow mail disappeared. So he started sending emails. He was an amazing artist among other things. He will send us designs that he created of the leaves, which represents the maple of Canada. And also sent us a message that it's universal, that the future is all yours for all the young scientists, that they should move forward to create new knowledge and the exploration of the brain, which was his main, main goal.
And if you think of the legacy of the people that he brought together, all the Canadian, American scientists, the Italians, the Mexicans and especially the Japanese, the French. Everybody was there in that meeting that we thought was the pinnacle of epilepsy research.
[00:12:34] Dr. Pete Engel: Juhn had become quite an artist. He did a sabbatical in Marseilles with Buddy MacKay and decided while he was there that he wanted to try watercolors. And he went out to the Calanques and saw the beautiful coastline and started doing watercolors, taught himself watercolors, and became quite accomplished to the point where he created notecards that he sent out to all his friends, and we all had bunches of notecards that he had done to use.
[00:13:15] Dr. Maryam Nabavi Nouri: And he learned the piano when he was 90.
[00:13:18] Dr. Nico Moshe: Very late, and I'm still jealous. He could play Beethoven, and my dream is to play a Beethoven sonata, which will never happen. But he did.
[00:13:28] Dr. Pete Engel: It's not too late, Nico. You're not 90 yet.
[00:13:33] Dr. Laurent Sheybani: Well, thank you for all these comments. We wanted to discuss a little bit more about his achievements during his career and we have already briefly addressed some of his achievement and it's probably difficult and also probably not always relevant to make a hierarchy, but we were interested in what you think is the most or one of the most important achievements in his scientific career.
Professor Jones-Gotman, would you like to comment on this?
[00:14:04] Dr. Marilyn Jones-Gotman: Sure. Well, among Dr. Wada's contributions to epilepsy and medicine and the one that I can speak to is his idea of how to know within individuals which hemisphere is dominant for speech. This idea came to him while he was in Japan. He was about 24 years old.
He was involved at that time in using bilateral convulsive treatment for psychiatric illnesses. In looking for a way to minimize the severe side effects of that treatment. He had explored the idea of lateralizing the shock. This exploration led him further to thinking about seizures. He hypothesized that one might prevent seizure lateralization by anesthetizing one hemisphere transiently through a carotid artery approach.
He had the opportunity to try this treatment when a young boy came to him in status epilepticus. He couldn't abort the seizure with chloral hydrate, and he stopped it with a left carotid sodium amytal injection. The boy became hemiplegic and mute, and then this followed by a period of dysphasia, and then those effects dissipated completely.
Wada followed up the observation of this boy with a study of 15 patients in whom he injected first the right hemisphere and then the left with sodium amytal through the carotid artery. He reported his findings in that famous article that he published in Japanese in 1949. His experience with the boy and his subsequent controlled study of the procedure that he'd used later became the basic element of the procedure that now, for many years, has been a critical part of the pre-surgical evaluation of patients who are candidates for epilepsy surgery. There have been some changes over the procedure in the years, but the basic procedure relies on Wada's notion of anesthetizing one hemisphere transiently.
The IAP is invasive because the anesthetizing agent is injected, and non-invasive methods have been developed using neuroimaging. But the IAP remains the gold standard, and it's used worldwide. As of 2015, when I did an international survey of 141 epilepsy centers about the IAP, I found that overall, worldwide, 78 percent of them were still using the IAP, either alone or in conjunction with fMRI.
This idea of the young Juhn Wada has had a huge and lasting impact on medicine and epilepsy.
[00:16:54] Dr. Nico Moshe: Can I add a little story that I think will increase the value of the IAP test, although I still like to call it Wada test. I think it was in the middle 1990s that Pete was the president of the American Clinical Neurophysiology Society, and I was the program chair and we arranged a meeting about the value of neuropsychological testing on assessing brain function. One speaker came up and he was discussing a new amazing technique and he said, or she said, I don't remember, “And you see, this is so much better than the stupid Wada test.”
So, I was sitting in the second row, and to my right was Juhn, and I looked at him. The face was motionless, nothing, nothing. I was getting red in the face, et cetera. The conference finished, the session finished. Juhn stood up, went to the speaker and said, “I'm Juhn Wada,” and the speaker melted and said, “I apologize. I apologize. I apologize.”
So for me, that was quintessential Juhn. “I am Juhn Wada.” That's it.
[00:18:18] Dr. Laurent Sheybani: That must have been a difficult moment.
[00:18:22] Dr. Nico Moshe: For whom?
[00:18:24] Dr. Laurent Sheybani: For the scientist.
[00:18:26] Dr. Nico Moshe: For the scientist, yes, but not for me. I learned something. I learned that you don't have to say anything more, if you are such an accomplished person, than to say, “I am Juhn Wada.”
[00:18:38] Dr. Maryam Nabavi Nouri: I wanted to actually come to you and Professor Engel and Professor Moshe about the kindling. I know you have told us quite a bit about it. And I through some readings have also learned about these symposiums that have been sort of recurring, so can you tell us a little bit more about them. I understand that you weren't all, you weren't invited from the first symposium, but you certainly became an integral part of it, and how long did they last. And, and it seems, you know, it seems to me that it was a place where a lot of live science happened. People from across the world came and gathered and discussed. It's a very unique concept to just, you know, gather all together and discuss such important topics. Were there papers that were coming out of this? Were they just hypotheses generating? I'd like to know – tell us a little bit more about the symposiums and the sentiment.
[00:19:34] Dr. Pete Engel: Well let me say something about kindling to begin with. I did my thesis with Frank Morrell at Stanford, my PhD thesis, in the mirror focus. Which was interesting at the time to epileptologists, where you could make an experimental epileptic focus in one hemisphere, and after a while, another one would develop on the other side, and you could study the development of epilepsy, called epileptogenesis, which was an important approach to understanding epilepsy.
Graham Goddard was a neuropsychologist in Halifax who was studying stimulation of the amygdala for behavioral studies and noticed that some of these animals developed epilepsy. And he had the presence of mind to give up his behavioral studies and study the epilepsy and discovered that if you stimulated the amygdala every day, eventually the animals would develop epileptic seizures.
And in fact, what he did was create the mirror focus under laboratory conditions where it could be studied in a much more experimentally rigid fashion. So that was the beginning of Canadian kindling, but Juhn Wada then took it up and within a very short period of time, Vancouver became the center of kindling and there were kindlers throughout Canada who were using this technique which rapidly became the most important experimental model of epileptogenesis throughout the world for multiple decades. And Juhn Wada was clearly the leader. And as the leader, well, Nico can follow it up from here.
[00:21:16] Dr. Nico Moshe: So, you asked what was the environment when we had the meetings. Lectures from 9 o'clock in the morning till about 6. Lunch was in the cafeteria of the university of British Columbia and we were in the dorm and for dinner we will go—we don't didn't have any cars. We did not have any phones. There was no Internet. So for dinner, we'll go and sit together and keep on talking, and that's where you get to know each other. And most of us who were there became tremendously interconnected. And we helped create the field and disseminate the information about kindling, which is still used widely today if you want to study animals and the development of the seizures.
One of the most amazing experiences that I had through Juhn is that he was interested in finding out how you can stop the epileptogenesis that was happening. And besides looking at intracortical connections, as Pete mentioned, there is the mirror phenomenon, the mirror focus that develops.
He was also extremely interested in the downstream, through the basal ganglia substantia nigra system, which now is part of what we do when we substantiate forms of thalamic or nigra or subthalamic nucleus stimulation for the control of seizures.
[00:22:50] Dr. Pete Engel: Juhn did a lot of important studies in kindling by making lesions and showing how kindling progressed through the brain, but also studied kindling in different animals, everything from frogs to monkeys. And one of the important demonstrations was he kindled rhesus monkeys and papio papio baboons. Papio papio baboons have a genetic form of epilepsy, and he showed that the period of time that it takes to kindle seizures in a papio papio was much faster than it was in the Rhesus monkey, showing that there was a genetic component that determined the development of epilepsy.
And as a result of these experiments, he was castigated by the animal rights people in Canada. He was hung in effigy I think. He had death threats for his work in monkeys.
[00:23:51] Dr. Laurent Sheybani: We speak a lot about his scientific contributions. I was curious how the clinic, how he was in in clinic and with patients, how was his teaching and the way that he coordinated clinical with research activities?
[00:24:07] Dr. Pete Engel: I never worked with him as a clinician, but I did visit his program on several occasions and he had developed the epilepsy program in Vancouver, including the epilepsy surgery program, and was very highly regarded there as a clinician and worldwide, so much highly regarded that he was chosen to be the president of the ILAE international congress that was held in Vancouver.
I don't remember the year, but he singlehandedly put together the congress, which is held every two years. And he actually had to mortgage his house in order to get enough money to put the program together.
[00:24:57] Dr. Nico Moshe: I don't know how well he dealt with patients. All I know is that the people that he trained, and many of them were, especially the Japanese doctors that they were coming to train with him, they went back to Japan, and they were considered amazing clinicians.
So, now you tell me how each one of them was an amazing clinician, unless they had an influence of a super amazing clinician who taught them how to approach patients.
[00:25:28] Dr. Pete Engel: Here's an anecdote about his program, his clinical and research program in Vancouver. I was on a site visit for his grant. In those days when you applied for a major grant, program, project grant they had site visits and they sent investigators out there to actually observe the program.
I was on the site visit. And I noted at the time that he was about 63 years old and this was a 5-year grant, that he would be over 65 when the grant was over. And was that okay, that he was going to be beyond retirement age? Little did I know that he was going to live to be 99 and be active almost his entire life.
[00:26:17] Dr. Laurent Sheybani: Professor Engel, you said that he was one of your mentors, is that right?
[00:26:22] Dr. Pete Engel: Yeah, early on he was the major influence in turning my career from trying to do impossible experiments to understand the fundamental neuronal mechanisms underlying learning and memory, which people are still struggling with, to studying epilepsy. I was doing epilepsy clinically but was resistant to do epilepsy research and he convinced me that this was the way to go. So this was a fundamental turning point in my career. And you know, I think we were close friends ever since.
[00:27:03] Dr. Nico Moshe: Between Kindling 4 and Kindling 5, there were at least 10 years. And when Corcoran and I decided to do Kindling 5, we told the people we're going to celebrate Juhn Wada and everybody showed up. And that's amazing.
It was not in Vancouver, but in Victoria Island. But everybody showed up and we are talking about people who were extremely established, Javits award winners, which is the highest prestigious award. Everybody came for Juhn and when Juhn got his life achievement award at the 2013 ILAE meeting it was an amazing experience. He came in dressed in a Japanese outfit. And he didn't have to say anything. All you have to say is, “I am Juhn Wada.”
[00:27:56] Dr. Pete Engel: (Dr.) Brenda Kosaka is a neuropsychologist who worked with Juhn. She came to UCLA and worked with us for a while and became very friendly not only with the faculty, but with the staff and my secretary continued that connection. So that she was sort of the glue between faculty and staff in the epilepsy program at UCLA and Juhn Wada, because she was so close to Juhn Wada. And the last time I saw Juhn was a few years ago. I had to give a talk in Vancouver and Brenda and Juhn and I went out to lunch.
So I remember very well the first time I met him. And I remember very well the last time I met him. He was already quite frail. And walking to the restaurant, he told me that he tripped over ants.
[00:28:52] Dr. Marilyn Jones-Gotman: As a neuropsychologist, I administered the IAP throughout my career. And the story of how he suggested this procedure is so powerful for me that I feel like I was there, although I wasn't.
It was during one of the MNI's (Montreal Neurological Institute) weekly seizure conferences when Wada was at the MNI, Wilder Penfield was the director, and the only neuropsychologist in the whole institute was Brenda Milner. She has told me this story so many times.
A patient was being discussed whose seizures arose from an early trauma in the left hemisphere. In that situation, there's a greater likelihood than normal of language developing atypically in the right hemisphere, or bilaterally. The patient was being considered for surgical treatment of his seizures, and in the discussion, Penfield reiterated his wish for a way to know before surgery.
Which hemisphere is dominant for speech? Wada, as a modest young fellow, was sitting quietly at the back of the room. I think he even raised his hand before speaking, but he did speak up timidly, and he said that he had an idea of how it might be possible to know which is the speaking hemisphere.
Penfield, I'm told, and I've actually, I think, seen this, used to whip off his glasses in tense or exciting moments, and he whipped them off at these words of Wada, and he glared at Wada, I'm sure, and he asked for more. Wada told the story of his experience in Japan with a carotid artery injection of sodium amytal.
This transient anesthetization of one hemisphere was exactly the solution that Penfield had been hoping for. So, that was a secondhand anecdote, but close to me. I wasn't present at the seizure conference, but then I'd like to mention something that occurred many years later.
This was in Vancouver in 2017 at a CLAE conference. It was the CLAE's 40th anniversary, and the Society celebrated their six founders at a dinner. June Wada was one of the founders, and I think, actually, he was the main mover in setting up the CLAE. In 2017, he was 93 years old. He got up at this dinner, and he spoke eloquently, and at length, about the founding and early days of the CLAE.
He spoke without notes. Without hesitation, and with his usual modesty, despite his lifetime of major accomplishments. Well, as you can all imagine, he had a standing ovation. I'm sure it wasn't his only one in his life either.
[00:31:47] Dr. Maryam Nabavi Nouri: Thank you Dr. Jones Gotman. I wanted to mention that he is, he was the founding president of the Canadian League Against Epilepsy, like you mentioned. From 1977 to 1979, he was one of the founding presidents and served between those two years. I think he also was the president of the American Clinical Neurophysiology Society, and of course, the president of American Epilepsy Society amongst many, many, other important roles that he carried.
Would you be able to share a few more of these anecdotes with us and with the listeners?
[00:32:23] Dr. Pete Engel: Well, I could just comment that I had the great honor to make a tour of Japan with Juhn Wada and Ron Racine, where we, I don't remember how many centers we went to but if you've ever been to Japan, you know that the guests of honor are feted sumptuously with great banquets and all kinds of amenities. And so it just was an incredible experience to travel through Japan with Juhn. And I was very surprised that Juhn gave his lectures in English. And I asked him why and he said, “Well, my Japanese just isn't that good anymore.” He was really a Canadian by then.
[00:33:08] Dr. Nico Moshe: He was the force, and everything he touched became gold, and the legacy is amazing. We are all very grateful that he was part of our lives, and I think we're better people for getting to know him and being his friend.
[00:33:27] Dr. Maryam Nabavi Nouri: As we're talking about all of this, of course, it's, incredibly touching. I can't even, I'm new in my role as a epileptologist with an interest in epilepsy surgery. And we're hearing about how kindling started and how we went about the lateralization of the dominant hemisphere. I can't even imagine a world in which these were had not even been established. These are such important contributions to the field that have been life changing day to day to day. So it's incredible to hear about it, how incredible to hear the whole way through of how he's created this legacy and also mobilized a lot of people in science.
[00:34:16] Dr. Pete Engel: But he was a role model just because of his humanity, because of who he was. I mean, he was the most humble person. There wasn't a boastful bone in his body. I never saw him angry. I never saw him say anything negative about anyone. It was amazing that somebody of his stature could go through life and continue to be so selfless and so humble.
[00:34:46] Dr. Nico Moshe: He was also a family man, and it was amazing to see him interacting with his wife and the family. It's also another way of being taught how to be a person and a successful investigator.
[00:35:02] Dr. Pete Engel: I think his unflappable personality was impossible to emulate. I wish I could say that I could follow in his footsteps of being so humble and unaggressive, but I didn't, and I don't know, I actually don't know anyone in our field who has been successful who has been as unaggressive and self-effacing as Juhn.
So it's rather amazing that he was as successful as he was when he didn't have the cutthroat aggressiveness that people think is necessary in academic medicine.
[00:35:47] Dr. Nico Moshe: You know that the American Epilepsy Society has an award for basic science and a clinician. It started in 1989 and Juhn Wada was the first chair of that. And I remember the way he handled the nominations with great care and respect for everybody who was nominated.
Which beyond teaching me how to be a better scientist, it also taught me, and I hope I followed it as much as I could, how to be able to work with people in a setting. Everything that he did is by example. His family ways, his research, his humanity, as Pete was mentioning, is something that we all admired and we tried to emulate.
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Founded in 1909, the International League Against Epilepsy (ILAE) is a global organization with more than 125 national chapters.
Through promoting research, education and training to improve the diagnosis, treatment and prevention of the disease, ILAE is working toward a world where no person’s life is limited by epilepsy.
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