In our interview with Carol Tamminga, MD, we discuss biological psychiatry and the evolution of the field of psychiatry to now include a greater understanding of the neurobiologic underpinnings of disease through brain imaging, genetics, and circuits. We talk about the "battle" between biologic and psychologic and whether this should exist.
Dr. Tamminga also discusses her groundbreaking research on schizophrenia and how trying to find biological confirmation for DSM diagnoses led her to finding "clusters" or "biotypes" instead. She details how she hopes her research will inform treatment in the future, as well as measurement of treatment response. She adds information about early intervention approaches for schizophrenia treatment and the role of cannabis in schizophrenia development.
Dr. Tamminga is Lou and Ellen McGinley Distinguished Chair and the McKenzie Chair in Psychiatry at the University of Texas Southwestern Medical School and the Chief of the Translational Neuroscience Division in Schizophrenia at University of Texas Southwestern Medical Center, Dallas, TX.
Links referenced in this podcast:
A dimensional approach to the psychosis spectrum between bipolar disorder and schizophrenia: the Schizo-Bipolar Scale
Identification of Distinct Psychosis Biotypes Using Brain-Based Biomarkers
Brain Structure Biomarkers in the Psychosis Biotypes: Findings From the Bipolar-Schizophrenia Network for Intermediate Phenotypes
Associations between adolescent cannabis use and brain structure in psychosis
David Carreon: Hey, everybody. My name is David Carreon.
Jessi Gold: And this Jessi Gold.
David Carreon: And are sitting with Carol Tamminga, the Lou and Ellen McGinley Distinguished Chair and McKenzie Chair in Psychiatry at UT Southwestern. She's the chair of UT Southwestern's department of psychiatry, and Chief Translational Neuroscience Division in schizophrenia.
David Carreon: Thank you for joining us.
Carol Tamminga: Well thanks a lot for inviting me I appreciate being here.
David Carreon: For those psychiatrists that are not terribly familiar with biological psychiatry, what is biological psychiatry?
Carol Tamminga: Biological psychiatry I guess would be that group of people who are interested in the biology of the brain that underlies psychiatric conditions. This is a very, very old society that's gone up and down, and their attention on different kinds of biology over the years. And now the biologic basis, the biologic understanding of the brain and its normal function has grown so much over the last 25 years, that is a very exciting time in biological psychiatry.
David Carreon: Yeah I think that's something that's interesting to me too about like biology 50 years ago mean molecules, and, you know, and serotonin or dopamine. Now what is for somebody who went to residency 20 years ago or 30 years ago, what is biological focusing on these days?
Carol Tamminga: Yeah biology is such a general term, and it's like the physiology of internal medicine or something like that. I don't think we have a better word to use right now, because we don't understand what the specific biologic ... perhaps pathophysiology would be a better word. We do not understand the pathophysiologies for our diseases, but as soon as we do then we'll be able to make that term, biology, more specific. And we'll be able to say that it's self-firing or it's circuit biology or something like that.
David Carreon: So is it that society's been around for a long time...
Carol Tamminga: It's a fairly long society. As you might imagine 50 years ago the biology that they talked about was fairly crude, and it was a little bit more than a black box when this started, but now there's so much in that black box, it's really fabulous.
Carol Tamminga: Brain imaging has opened up the world of biology. Human postmortem brain analysis have opened all of it up. Of course genetics and then the transcriptome analysis have opened up what we know about different regions in the brain, and their connection to function. It's an exciting time in biology.
David Carreon: I should say so.
Jessi Gold: I would assume that would make it an exciting time to be a psychiatrist too.
Carol Tamminga: It is. When I started out being a psychiatrist, and I would tell people about diseases, psycheat- what I call psychiatric diseases, I would really draw the brain in a black box, because we knew such a little bit about it.
Carol Tamminga: Then we knew a few things about things like dopamine, and serotonin, and got to know a little bit more about the synapse, and what was the structure of the synapse, and how cells communicated with each other. And then we thought it was really all about cells, and how one cell converted with another. But these days there's a real emphasis on circuits, and how different regions of the brain are connected with each other, and how they're connected with each other not only by neuronal connections, but by the characteristics, by the dynamic characteristics of the connections. The terminology that they use these days, I'm gonna have to practice a little bit offline on the connection that they- on the language that they use, it's very interesting, very interesting.
Jessi Gold: I'd imagine the language for all of this changes pretty rapidly.
Carol Tamminga: It does. Yes, yes.
Carol Tamminga: You know, the brain is the last undiscovered organ in the body. We know a lot about the heart, we know a lot about the pancreas. They're accessible to us, the brain has never been accessible, and it's much more complicated than any other organ. So it's taken a little while for us to get the brain ... for us to understand how even a normal brain works.
Carol Tamminga: And then we don't know the pathophysiology for any of our diseases, so we don't even how to segment psychiatric syndromes into understandable units.
David Carreon: Now that's something that I think I'd like to talk more about, because the average person thinks about something like major depressive disorder or schizophrenia as a thing, as an entity, as some thing existing in reality, like diabetes exists in reality. What's your perspective on psychiatric nosology or how these diagnosis work?
Carol Tamminga: So I used to think schizophrenia was an entity too, and I used to call myself a "schizophrenia scientist", I don't anymore. We did an experiment a few years ago where we took ... we decided to study the dimension of psychosis. So we took a number of different diagnosis and we did deep phenotyping on all the diagnosis. So we took people with schizophrenia, people with schizoaffective disorder, people with psychotic bipolar disorder. If we could've found enough people with psychotic depression we would've taken those too, but we didn't find enough.
Carol Tamminga: Then we did, we had, this was a study across five sites in the United States, so we had an opportunity to recruit quite a number of people. About a thousand probands, and about 500 normal people when we did deep phenotyping project.
Carol Tamminga: So we looked at brain based behavior very carefully, we looked at brain imaging, we looked at EEG brainwave analysis, we looked at eye tracking analysis, we looked at cognition. We looked at signs and symptoms of course. And our intent was to find some number of tests that psychiatrists could use when a patient walked in their office. A psychiatric patient walks in psychiatrist office, and a psychiatrist sits down and talks to them for an hour. You know, they walk into a neurologist office, the neurologist says, "What are your complaints?". And they'll talk to them for 10 minutes, and send them off for three tests, and then they'll come back two weeks later and they'll get a diagnosis.
Carol Tamminga: We kind of wanted a system like that, and we hadn't started out to ... not, we started out hypothesizing that we would find biomarkers associated with diagnosis, and we didn't find one. We had about 50 or 60 different phenotypes, and we didn't find one that clearly fell in a diagnostic way on any of these different psychotic diagnosis. So we were pretty disappointed, and we spent a little time being quite depressed, because it really meant that we didn't know anything. We didn't even know how to take psychotic disorders, and cluster them.
Carol Tamminga: So we finally got over that part of it, because we needed to get our grant renewed. So we just simply stripped the diagnosis off all the probands together into a single group of psychosis people, and we took the brain biomarkers. We took the EG, we took the cognition, we took the brain imaging, and we u- we didn't take any signs and symptoms, we took just took the brain measures, and we took them together, and we reclustered the people. And we came out with three groups of three total experiment groups. These are, we're not up to diagnosis or anything like that. These are just are experimental groups. But the experimental groups had very interesting biological characteristics, and so we decided to study them more, and now we're into a second phase.
Carol Tamminga: These are clusters of individuals, all with psychosis, as the diagnosis are spread through all the cluster, so why bother with that? The only reason we now have to really confirm that this makes sense for selecting treatments, or biologic sense so that we would have genes that perhaps, genes or epigenetic phenomena that categorize the groups. So we're now in the process of doing that.
Jessi Gold: Would you say that the initial failed experiment kind of forced you to rethink kind of what you had put on the diagnosis? Like being able to kind of shake up your thinking, and to clustering things, instead of just assuming that things fell into these nice diagnosis, that DSM created. Having the failed experiment sort of forced you away from that?
Carol Tamminga: Totally, totally. We never would've thought of it otherwise. Because we didn't start out making the hypothesis that we didn't know anything, in terms of how to cluster our patients in a group. If people have lesions, so, in Alzheimer's disease patients have plaques and tangles. It's at least a place to start, you may not know the complete path of physiology, but at least you have the lesion. Parkinson's disease, you know, if you have the VTA, the dopamine cell degeneration a lot, it's very simplistic, but at least it's a place to start. We don't have that in psychiatry for psychiatric diagnosis.
Carol Tamminga: So I think that the way that we did it for a long time is just by pure phenomenology. That we looked at people, we looked at their symptoms, we looked at their course of illness, and we assumed that that was meaningful way to ... divide people up. But it's turned out to not be a good thing to do, it's a little bit like dropsy in 1910. Dropsy is morbid obesity- excuse me, morbid edema. And dropsy is really a group of illnesses that determined my cardiac pulmonary renal disorder. So that's how I kind of think of psychosis. So now it's really back to the drawing board.
David Carreon: Now this is really astonishing. I mean if we think, I mean, there are some people that I've talk to who just start out skeptical. There are some people that I've talked to, that never since they were a young psychiatrist believed in DSM or the diagnostic categories, but it sounds like you're saying you were somebody who really believed at the beginning of your career that schizophrenia was a thing, and then over the course of your research you changed your mind.
Carol Tamminga: That's it. That's it.
Carol Tamminga: I don't know that I ever believed that schizophrenia, and schizoaffective disorder were very different from each other. That's seemed like a little wishful thinking, but I certainly understood, I always believed that schizophrenia was an illness. And now I really think that psychosis is a category like congestive heart failure, and that we'll over the course of the next, I don't know how many years find individuals.
Carol Tamminga: The three groups we've found we've named BSNIP biotypes. They're very different from each other, and they're very interesting, and I think that if each of these three different group hadn't been so interesting, from a biologic perspective, we would never have gotten caught on them.
Carol Tamminga: This BSNIP biotype one is a group of people that have very low cognition, they have very low brain EEG, and they have the highest gray matter reduction of the three groups.
Carol Tamminga: The group in the middle, which we call them biotype two, was a group with only modestly low cognition. And instead of low EEG, they had high EEG. So they had, instead of hyporeactive brains, they had hyperreactive brains. Both at rest, and in evoked potential paradigmes.
Carol Tamminga: And then biotype three was the most amazing of all the groups, because of all the biotypes that we used to measure, they were hardly abnormal at all. But their psychosis was just as bad as all the other people's psychosis. So it was ... it's a group of people who are kind of a negative control with the same clinical presentation.
Jessi Gold: What do you think that actually means?
Carol Tamminga: We were wondering. And we were sitting around a table thinking, so this is all of the 5 PI's, and all of the friends and stuff. So we were thinking.
David Carreon: Paint this picture, where was this table?
Carol Tamminga: We get together once a year. And we get together once a week by telephone and talk about a lot of practical things. And once a year we get together and sit around in a library. It was a kind of old fashioned not very updated room, where we're sitting on chairs that are falling apart, you know. We have a lot of coffee around the table, and there's a little bit of fruit in bowls in the middle.
Carol Tamminga: So we're talking about what clearly the people who are very, very low cognition, very low EEG people look like. What we had all probably imagined psychosis or schizophrenia was gonna look like. We were surprised in the second group by modestly low cognition, and very high, we didn't expect people to have very high EEG. It wasn't synchronous EEG , so we didn't imagine that the EEG was productive in some way. That those were people who were smarter in s- they weren't smarter, but they had high EEG anyway.
Carol Tamminga: Then we were puzzling about what was happened to this third group, and one of the guy's all of a sudden said, "I know those are the potheads". So there was one of the five sites, it just happened to be mine, that taken a careful enough marijuana history, because one of the people at our sites is interested in marijuana. And this was in fact, the statistics aren't very strong because it was just one of the five different sites, so it was not nearly a thousand people. But in fact they were, there was a good, a very high percentage of early cannabis use. And there was a 90% of that third group had at least some adolescent cannabis use, not even early adolescent cannabis use. So now in our second iteration of going back and looking at these things we have a very careful, especially early cannabis, early psychosis screening.
Jessi Gold: When you look at that, and then you see all these people coming and saying like cannabis no problems, and cannabis is-
Carol Tamminga: Oh boy I really worry. It looks to me, and most of our studies. It looks like the worst time for cannabis is somewhere between 9 and 15 years of age. And that ... still a vulnerable time for cannabis is somewhere up to 20. But if you smoke cannabis after 20 it doesn't look like much bad happens. So it's clearly a vulnerable window for cannabis. It may be a vulnerable window for other things too we don't know, but we're studying it.
David Carreon: With this, I mean this transition from the DSM to ... I guess this is some people would categorize what you're doing, and maybe explicitly as being under the research domain criteria. Is that true?
Carol Tamminga: Well we got started before Doctor Enzo had suggested the RDoC, so we call ourselves "pre-Doc". But I think the RDoC principles must've been emerging all at the same time. They must have been emerging at the same time as we had developed measure where we could really distinguish, brain measures where we could distinguish one person's brain activity from another.
Carol Tamminga: We now have, we took fibroblast from at least some of these people. And we transformed them to iPS cells, and now we're growing them to matur-
David Carreon: What's a iPS cell?
Carol Tamminga: Pardon?
David Carreon: What's an iPS cell?
Carol Tamminga: It's stem cell. So we took fibroblast and transformed them to stem cells, and then we took stem cells and transformed them to neurons. So now we get a chance to see whether between biotype one, two, and three, we can find cellular fingerprint of what we're, of some kind of pathology. I mean it would be very nice to have some kind of pathophysiology for all of this.
Carol Tamminga: Still, I don't think, I don't think at all that these three different categories, we're still in the process of figuring out how many categories there outta be, and figuring out- these are still hypothetical categories I should say it that way. We don't think that those three categories are even gonna be diagnosis, we think that each of those three categories have buried in them perhaps a hundred different diagnosis, maybe. It would just be a guess without any, based on no knowledge.
David Carreon: And I guess, what is the average practicing psychiatrist to do with this information? I mean we see people every day who have a you know, they come in and it's a you know, 34 year old patient with schizophrenia. What does that, what am I supposed to take that as if I'm in the emergency room or if I'm in clinic? What does that mean?
Carol Tamminga: So psychiatry doesn't have tools that are specific and selective enough to bother with the kind of data I just talked about. So what we would like to do with these data is find out what the pathophysiology is, and find out what the target for drug development is, and then find you new drugs, find psychiatrists new drugs to use in the emergency room. So that when somebody walks in, and they, the doctor can do more than say, "You have cancer". I mean if you walk in we would like to say, "You've got this kind of cancer, and these are what the cells look like, and your cells are responsive to the following medication".
Carol Tamminga: So really it's almost premature to learn about what I'm saying, because we can't do anything about it anyways. Well we could tell teenagers never to use marijuana, but this is for sure good advice, I know that. What we would hope to do one day is to work backwards to pathophysiology, and then use pathophysiology to move forward to provide new treatments.
Jessi Gold: To make our treatments a little bit less like a dartboard that you just shoot at depending on side effects?
Carol Tamminga: Exactly. Sometimes it's not, it's most of the time it's much less precise than exactly what you're talking about. In ... I work at the state of Texas, and there's clearly not enough psychiatrists there. When psychiatrists see patients they treat the serially, and one person will give them an antidepressant, one person will give them a mood stabilizer, another person will give them antipsychotic. And no doctor really takes away what other people have hade before.
Carol Tamminga: So you see these people on, in fact in this particular study where we had probands, we psychotic probands, we had a wide range of diagnosis. So people always say, "Well you must've found that people in different diagnostic categories were treated with different drugs?".
Carol Tamminga: And the sad part about it is the answer to that question is, "No". We found almost all the patients treated with almost all of the drugs that we have. So how wrong is that?
Jessi Gold: Something's wrong.
Carol Tamminga: But it's unclear how to tell somebody how to do it in a better way.
Jessi Gold: Do you feel like that's because we also don't know how to really measure response?
Carol Tamminga: You're exactly right. And response comes ... not right away. I mean we work with symptoms ... where it may take a while for the drug you have the person to work, but you don't know how long it's going to take, and you don't how long to wait. Most people wait maybe two weeks or something, before making a change.
Carol Tamminga: The kind of symptoms that psychiatrists look at are, that first of all, are poorly treated and generally treated by the drugs that we have. So that's clears. And then they ... we don't know what the relationship is between the background of the illness with the drugs that we use. We're pretty lucky to have the drugs that we use. We could have nothing, because we don't know pathophysiology. I'm not gonna say we don't know anything, but we don't know pathophysiology.
Carol Tamminga: The drugs that we have were just accidentally discovered, and then very well exploited from their discovery, but we need to know a lot more to get more precise drugs.
David Carreon: And I think, I'm interested also, I think there is almost this feeling in psychiatry sometimes that it's a battle between the biological psychiatrists, and the people who care something about psychology. And that these, you know, people are dismissing each other, there's these two camps and battle lines are drawn. But would you say your perspective on this ... ought there be a battle?
Carol Tamminga: No, no, no. Not a battle at all. In fact all behavior is based on brain behavior, so even psychological phenomenon, even though we look at them as psychological phenomemon are totally based in brain behavior. And I'm not psychologically oriented as a psychiatrist, but I would think that there's a huge area of looking at the relationship between brain changes and psychoanalysis that could really be looked at. Because psychoanalysis can't be anything other than changes in brain regional plasticity. And they would be very, very easy to study. Every time I interact with my psychoanalyst colleagues I try to talk them into doing brain imaging, and other kinds of tests.
Jessi Gold: When you were in training, did you know that you weren't like psychotherapeutic minded, and you wanted to be more focused on biology, like the whole time?
Carol Tamminga: I did. I'm sorry to say. I studied Freud when I was a resident, I think all residents really do. And I asked biologically oriented questions of Freud to my teacher, and I quickly learned that that was not the proper student attitude. This was a long time ago. So I stopped asking questions. But I, you know, I, even Freud himself said all of these big behaviors are gonna be explained by brain activity in the future. So Freud himself when he was was explaining in using psychological phenomenon to explain to his students, he was very biologically oriented himself.
Jessi Gold: And I know that, maybe, even if you're not so much like a therapeutically minded you are really early intervention minded, when it comes to early psychosis.
Carol Tamminga: Yes.
Jessi Gold: What does that look like? Can you explain that a little bit more?
Carol Tamminga: Well this is another kind of phenomenon that I've only come to realize recently. You know when you talk about cancer care, early detection is what it's all about. You don't let the cancer develop and loo at where the metastasis go, and how fast they grow, before you decide treat it. That's what we do in our field. Somebody gets a little bit psychotic, and you wait for it to develop a little further. You see if the psychosis is paired with affect changes. Whether the affect changes started before or after. Then you let it go a little bit more, and see what their social function is. If their social function deteriorates fast, deteriorates slowly.
Carol Tamminga: And finally we do most of our testing for new drugs, and a lot of our research, we do in people who are 30 to 40 years old, and have had their illness for 15 years. And I think that the realization that we really need to get to all of this very early, and we need to get to people who are psychotic early to stop their psychosis, and particularly stop the psychosocial deterioration early. And then they'll stay better for longer. We're still in the process of testing whether they really stay better for long, and we'll have tweak our treatments so that they help the people stay better for longer. But I have no doubt that we're on the right track.
David Carreon: You know, and that's something that also I, at some point in my career that I've heard lectures about schizophrenia that are rather fatalistic. It's this, you know, it's a biological illness, which has a 1% chance, and it just if you happen to have the unlucky gene at birth then you're just kind of up a creek, and so no point in early detection because it is what it is, and there's no turning, you know, changing it.
David Carreon: Is that a true view of schizophrenia?
Carol Tamminga: So I think that's wrong. I don't think that there would be a lot of psychiatrists who would be so ... fatalistic, would see it as such a single path forward. I don't think that we can take every person with a diagnosis of psychosis or schizophrenia and turn their illness around and cure them. We can't take everybody with cancer and cure them. We can't take everybody with heart disease, and give them, even do a transplant and get them cured. But we can do our best in tryin to predict which people to do the complex early treatments with.
David Carreon: And what is that, for those who may never have heard of the early intervention, what does that involved? And I guess how, just very superficially or overview wise, how could that change somebody's course? Somebody on track to another or would get what we call schizophrenia? How would that change
Carol Tamminga: So a lot of people, these studies started in Europe and most European countries. Probably in the 1990s, and there were several studies that studied at them, giving intensive interpersonal psychosocial, and constant antipsychotic treatment to people with early schizophrenia. These studies happened in Europe.
Carol Tamminga: There were a couple of scientists in the U.S., Lisa Dickson being one of them, who kept and eye on those studies, and who was very interested in early treatment. And she was very interested in treating early everything that was, all of the psychological and medical burdens of people with early psychosis. So she paid attention to drug abuse in early schizophrenia. She paid attention to not only just the psychosis, but of course she treated the psychosis too, but she cared about families, and family patient interactions, and things like that.
Carol Tamminga: She's the one that was the inspiration RAISE Study which then got completed around the country. Which was a two year early intervention study. Where people who with psychosis got, they were watched very carefully over two years. They had ... very intensive treatments, both psychological treatments, and the pharmacologic treatments, and family treatments, and CBT, and cognitive remediation for two years. And at the end of the two years, the people were better
Carol Tamminga: Why they're better is unclear. It could be, it has to be that they watched very carefully by a group of people who were treating them, and therefore they stayed on their medication more. That must be a possibility. And another possibility there's just nothing that's worse for psychosis than drug abuse. So that drug abuse was given some attention, and people were treated for their drug abuse. Whether or not the cognitive remediation turned things around cognitively in the brain is a big question.
David Carreon: Okay well we are coming to the end of our time. I wanna as-
Carol Tamminga: Well it's been nice talking with you guys.
Jessi Gold: You too. Thank you for making time.
David Carreon: We have some rapid fire questions to close it out.
Carol Tamminga: Okay.
Jessi Gold: What's your favorite book?
Carol Tamminga: One of my favorite books is Elyn Saks' book "The Center Cannot Hold". And Elyn Saks is a lawyer, very accomplished person, brilliant, brilliant person. And she has what she always thought was schizophrenia for her whole life, and she was, she had a rather typical schizophrenic course. She was able to partition her psychosis to a part of her life, so she still had, she could still go through law school and come out in the top of her class, and she can get her job at University of Souther California. And you guys may know her, do you?
Carol Tamminga: And then she always said she was never gonna telly anybody she had schizophrenia, because she'd never get a good job. So she came to California, got a job at the university in the law school at U.S.E. And she went from assistant professor to associate professor, she finally got to be full professor with tenure, and then she wrote her book.
Jessi Gold: Oh that's awesome.
Jessi Gold: Is one of the reasons you like it because she is so high functioning, and tells a different story of schizophrenia?
Carol Tamminga: She talks about her, in one of her books, "The Center Cannot Hold", she talks about the nature of her symptoms. And she's so bright, she can explain it so that you and I can understand it. And she can tell you what her experiences are. And people who are a little less bright, can't quite say it very clearly, and their own symptoms interfere with their articulation of it, but she's really brilliant.
Jessi Gold: Our next quick question is, what would be your best advice to psychiatry trainee?
Carol Tamminga: Oh learn about the brain. Oh without doubt, absolutely.
David Carreon: What is your favorite psychiatry word?
Carol Tamminga: Biotype.
David Carreon: And last but not least, who is your favorite hero, either from history or fiction?
Carol Tamminga: My favorite hero from history or from ... I mean it could be a good writer or something like that?
David Carreon: It could be.
Jessi Gold: Or like a role model or anything that you remember someone, like looking up to someone.
David Carreon: Spider-Man, I mean.
Jessi Gold: Wonder Woman.
Carol Tamminga: Wonder Woman, no. I'd have to think about that for a while too. I think I maybe have ... I probably have to many people to be able to think of a single person. I'll thin about that.
David Carreon: You could do top five also.
Jessi Gold: But I would a better, maybe a easier rephrase of the first question might be, what's the most common question you get about psychiatry that, you like repeatedly have to answer, that you wish you didn't have to answer?
Carol Tamminga: Well some people don't think that psychiatry, and psychiatric syndromes have neural basis to them. And a lot of neurologist simply think that as soon as we explain the biology of our illnesses, they'll become neurological illnesses. I just drop my jaw at that. No. These are psychiatric illnesses, they're psychiatric syndromes. We will explain their biology, we're already on our way to explaining them.
Carol Tamminga: And so I don't ... actually what's happening in Texas, and it may be happening in other places too, is that the public is getting quite interested in psychiatric phenomenon. They see them in their own children ... their children's involvement with drug abuse. They suicides where there shouldn't be suicides. And they're really becoming in tune now. And the public's interest, the public itself wants to know what the neurobiology of our illnesses are, so we need to get on this stat.
Jessi Gold: Yeah we're lucky to have people like you fighting the good fight.
Carol Tamminga: Thank you.
Carol Tamminga: And like you, you guys will do it tomorrow.
Jessi Gold: Hope so.
David Carreon: Thank you for joining us.
Jessi Gold: Thank you so much.