Part 2 of a 3 part interview, with Emeran Mayer, MD, PhD on the mind-gut connection. Dr Mayer talks about irritable bowel syndrome (IBS) as an example of a known brain-gut disorder, focusing on the research on dysbiosis—alteration of the gut microbe from healthy individuals—and what it means for the 15% of world population suffering from IBS. He answers the question: is it all in patients' heads? He also discusses the development of the gut microbiome in infants and the influence of prenatal events, breastfeeding, and antibiotics on gut content.

TRANSCRIPT
David Carreon: This is the fascinating idea that neural hacking, that the bacteria are hacking into our nervous system to get what they want. That's such a cool idea and I’m certainly excited to see what the science shows as this field develops. Would you talk a little bit about maybe an area where the communication relationship is more well established. You mentioned IBS a little bit earlier. Could you explain what is IBS and what is the gut microbiome have to do with it?

Emeran Mayer: IBS is the acronym for Irritable Bowel Syndrome, a very common disorder, about 15% of the world population are affected. It's a syndrome defined by symptoms because we don't really have a biomarker for it. It's a combination of chronic, recurrent abdominal pain and discomfort and altered bowel habits. It seems like a very loose definition, but it's pretty accurate, with a pretty high sensitivity and specificity, if you can rule out other causes for these symptoms.

David Carreon: I think just to pause and emphasize there's something that I don't think everybody is aware of, but 15% of population and you put an endoscope in, do a colonoscopy and there's nothing there, there's nothing that you can see or take tissue. It's not something that you can diagnose with objective, at least thus far, signs. That's a huge burden. I think the emphasizing the importance of figuring out what it is, what's going on, trying to better characterize this thing that's rather common and underdiagnosed.

Emeran Mayer: What has happened this area, because it's recognized as a brain-gut disorder, so when the microbiome science started, immediately people jumped on it, including ourselves. There's a series of studies that they all can be criticized based on small sample size, mixing males and females, not controlling for diet. Then, not unexpected, several labs found different abnormalities. These abnormalities are called dysbiosis; that means an alteration of the gut microbial composition from a healthy control population. Most of the studies have found evidence for dysbiosis even though the type of dysbiosis, what taxa are altered, if there's increased or decreased diversity and abundance has varied from study to study. The latest evolving concept is that there are several subtypes of IBS based on their microbial signature, as many want to call it. One that's indistinguishable from healthy controls and one that has significant dysbiosis. Interestingly, these two do not correlate with the typical clinical parameters that we use, like bowel habits, subtype, or pain versus discomfort. Seems to have a different function.

You may ask yourself, if half of the patients have a normal microbial composition, the others have an abnormal, but they have the same symptoms, do these microbes really have a causative role, or is this something that's a consequence of something else? My personal feeling about this is that, and that's often forgotten now in this fascination that the microbes can talk to us, that our brain can really effect the microbes, both their environment in which they live, meaning the transit rate through the intestine and the stomach, which is regionally regulated, slow versus fast transit, the secretion.

Many things are being secreted, which the brain sort of modulates, like the defensins from Paneth cells, there are many endocrine cells, serotonin cells in the gut, enterochromaffin cells, which are under autonomic control, so that we now know that serotonin, as well as norepinephrine, can, under stress for example, increase in the lumen of the gut. Since these microbes have receptor or analogs for those substances, can influence their behavior. What I think, and I've had sort of this bias for a long time and seen a lot of those patients, that this is something that really starts at the brain level, possibly, most likely early in life. Could be stress, hyper-responsiveness, or increased emotionality, which sends chronic signals to the gut and its microbes and changes their development. The first three years of life, the microbes, the community is actually shaped, so if during that time there's an imbalance of the autonomic influence on these microbes, they will assemble in a different way. That may happen in some patients and not in others. That's why I personally think you now find a subgroup of IBS patients that have a normal gut microbiota. There's other people that disagree with that, but I think, we'll see.

IBS has been an interesting research area, interesting in quotation marks. So many hypothesis, just during my career, have been proposed to explain it, and most of them have come and gone. Right now it's the microbiome. We'll see if this is the final answer.

Jessi Gold: I've heard people say that IBS is all in people's heads and it's all anxiety and there's nothing else besides anxiety and the idea that it's a separate disease entity is wrong.

Emeran Mayer: That's the thing. When people say it's all in the head, this got a bad name and a very bad impression for patients because what the physicians meant, it's not a neurobiological process, but it's a neuroticism. I still am, in my early parts of my career I sort of taped these talks of the leaders in the field that would say it's a disease of neurotic housewives, middle-aged neurotic housewives. I think now, when we know so much more about the brain and how intricately it is connected and wired with the gut and back to the brain, I think this has a different connotation. I would never use that term to a patient, "It's all in your heard," but surprisingly, if you explain to them with the concept of the brain-gut axis, they all agree, they'll all tell you, "Oh, yeah, I've always known that it's connected to my emotional state or to the stress." It's very few patients, if you give them the right model, that would not accept that.

David Carreon: One of the things you said just a few minutes ago was that the gut microbiome is established around the ages of zero to three, which, as a psychiatrist, is very interesting. We talk about how critically important the first few years of life are for the psychological development, but you're saying that those years are especially important for the microbiological development as well.

Emeran Mayer: Yeah. The microbiome has added another dimension to the importance of developmental diseases. We also know that it predates delivery as well, so prenatal influences. Very interesting studies that, for example, nutrition of the mother, the pregnant mother, stress of the pregnant mother have an influence on the development of the microbial composition and abundance and diversity, and there's even an animal experiment that shows some very intriguing mechanism that stress of pregnant mother changes the microbial composition of the vaginal microbiome and when the baby goes through the birth canal, one initial seeding of the infant's gut microbiome comes from the vagina. In these animal experiments, it's been shown that stressed mother, different vaginal microbiome, the gut microbiome of the newborn is different because of that different priming. Again, in animals, that was associated with a change in brain development in the first few months of life. If that happens also in humans, it just illustrates the importance of prenatal events on the development and the architecture of the gut microbiome of the infant.

After three months, it seems to be fairly stable. It's also very important concept. Regardless what you do later, if you become a vegetarian or become gluten-free or whatever, your microbes will change and the metabolites that they produce will change, but if you go back to the default diet, you'll go back to that same architecture that you had after three years. You don't change that basic ... You can modify it in a certain bandwidth, but you can not really reverse it. There's very few exceptions.

Treatment with antibiotics could do that and also there's this one infection, this C. difficile colitis, which can basically knock out most of your microbes and lead to this overgrowth of the C. difficile organism. Antibiotics, I should mention that they also now have gotten a very new meaning because an extensive amount of antibiotics given to babies, the mother during pregnancy, treatment of the vaginal area with antiseptics, prophylactic antibiotics to the mother to prevent sepsis, this is a huge field. The amount, I forgot the number, that infants by the age of three have received an antibiotic dose is just phenomenal. That clearly interferes with that establishment of the gut microbiome.

Jessi Gold: You're saying that before age three, there's stress, there's antibiotics, there's whatever else the mother went through, there's just natural stress to the infant, how does then from three on can you regain that, are you just now at a disadvantage as a kid because you have this altered microbiome for life?

Emeran Mayer: As I said before, it doesn't stay exactly the same, but I think the current thinking, and you always have to realize that we're just at the very beginning of this microbiome science. This is like, let's say the first decade of neuroscience 150 years ago. I think a lot of things we're talking about today will be thrown out. Yes, pretty much the basic structure, it's like the operating system is established. You don't change during life the operating system of your gut microbiome. You can add new software to modulate it, but the operating system stays the same.

David Carreon: Interesting. That's an interesting analogy. What is the heritability of it? Where do the microbes that are in my gut, where do they come from? You mentioned the birth canal is one source.

Emeran Mayer: Yeah, there are a lot of influences. I should have also mentioned breast feeding during the first three years of life. One very interesting mechanism of how they're programmed. One is clearly the genetic make-up of the infant's GI tract that attracts certain parts of the gut, different communities of microbes. The microbes are not, the microbiomes are not a homogeneous population from the stomach to the end of the colon. In each of those areas, we have to assume there's different communities that are attracted to these regions by genetic influences of the person.
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In addition, during programming, in the breast milk of the mother there are these so-called human milk oligosaccharides, or HMOs. These are large molecular substances that cannot be absorbed by the infant's GI tract, so they evolved to the evolution exclusively as food for the microbes of the infants. They play a major role in establishing this community early on. Does a large number of these HMOs that are contained in mother's milk, they're influenced by the genetics of the mother and they're also influenced by the diet of the mother. Two major genetic influences. One is through this early nutrition of the microbes comes exclusively from the mother, then the GI tract of the infant it comes only from genes of the father and mother. There are examples. Genetics don't dominate the population. They play an part. I think there is some mouse models, where  genetics play a much bigger role, but in humans, I think influences other than genetics have a major influence, including early nutrition.

The mind-gut connection: What is it and how did it evolve? That is the question posed for this short podcast (the first in a series of three on the topic) to gastroenterologist Emeran Mayer, MD, PhD, a pioneer of medical research into brain-gut interactions and author of The Mind-Gut Connection: How the Hidden Conversation Within Our Bodies Impacts Our Mood, Our Choices, and Our Overall Health. Here, Dr. Mayer talks about his interest in the mind’s relationship to the GI tract, some basics of what bacterial gut/brain communication is, and the evolutionary biology theories behind it. He even discusses the hypothesis that bacteria actually tells our bodies what to eat—like to crave sugary foods in obesity. Dr. Mayer's website is http://emeranmayer.com. Twitter: @emeranmayer.

TRANSCRIPT
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David Carreon: Hey everybody this is David Carreon.

Jessi Gold: And this is Jessi Gold.

David Carreon: And this is Psyched, a psychiatry podcast. Today we have Emeran Mayer on with us. He was born in a small town in Bavaria, where his family ran a confectionary business since 1873. After deciding against taking over the family business he finished medical school at Ludwig Maximilian’s University in Munich, completed his residency training at Vancouver General Hospital in Vancouver, before moving to Los Angeles. Dr. Mayer is a professor in the department of medicine, physiology and psychiatry at the David Geffen School of Medicine at UCLA, and Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience. And Co-director of the CURE: Digestive Diseases Research Center at UCLA. Dr. Mayer, thank you for joining us.

Emeran Mayer: It's a pleasure to be on the show.

David Carreon: So, you've done a fascinatingly broad set of work over your career, looking at your research interests from traditional healing, to hypnosis, to gut microbiology. How did you get such diverse research interests?

Emeran Mayer: Well, there was one common thread that goes through all of this from the very beginning and that is really I've always been interested in the interaction between the mind, the brain, and the body. And just have pursued this from really from college on, and so there's certainly a red line going, a straight line going through all of my visits to different topics in this area. I think right now ... so I was looking at the mind, brain, gut, micro environment interaction so that integrating all of these elements into one, and that's in some ways really been my interest from the very beginning.

David Carreon: Say more about that with the mind-gut connection. How do you conceive of the gut and how is there a connection?

Emeran Mayer: Well, I mean I've been interested in brain, gut interaction for the better part of my career. That topic was in some ways relegated to studying a disease called Irritable Bowl Syndrome, because that was sort of a classic entity where you had psychological commodity, GI symptoms, psychological interventions were beneficial. And then only about I would say seven years ago I developed this interest in including the gut microbes in this communication, so I think right now people are getting so excited about the microbes themselves. I mean there's always been this very intricate by directional communication between the brain and the gut. There's many interesting cells in the gut, but the microbes now play a role in using these various communication channels from the gut to the brain to be included in this dialogue.
Interestingly, and it was never been really great interest of people outside very narrow area of Neurogastroenterologists, until the microbiome arrived. Now, it's almost like everybody has become a gut microbiome expert of brain, gut microbiome expert. As you know there's many books written on this topic, the lay media loves it. And for me it's nice because at this stage in my career I get invited to all kinds of meetings outside of gastroenterology, including the APA meeting.

David Carreon: So, you said something that was rather astonishing I think to most people, that there's a dialogue between the microbes and the person, or the brain. Are there really like signals sent back and forth? How do you justify saying that this is communication?

Emeran Mayer: If you go back in evolution you'll find that microbes were obviously the dominant life form on planet Earth for billions of years, four and a half billion, a billion years, and then at some point there was a decision made by some algae in the ocean to settle inside the digestive system of a primitive marine animal, the Hydra. That animal itself was a floating digestive tube with a nerve net around it. Very similar actually to our GI tract, so our GI tract started ... like the earliest forms of life were GI tracts with an attached nervous system around it.
The microbes started living inside that system, and used their own communication signals that they had developed over four and a half billion years in the oceans to start communicating with the nerve cells of these floating digestive tubes. That actually explains a lot why the gut and the brain are so closely connected. And it also explains why the microbes have developed this ability, not just to communicate with the host but also to most likely exchange genes with this process lateral gene transfer, to the host. You can almost assume that the similarity of some neuro active substances that the microbes can produce, that we know today like GABA and tryptophan metabolites, where actually transferred then to the entire nervous system of these marine animals, and were really the origin of our own neurotransmitters ultimately. So, it's a very interesting story, which I think is quite convincing in terms of why that is happening.

David Carreon: Wait, so the thought is that there was the bacteria are sending their own genes into the host organism, and the host organism is incorporating those and then producing those things that the bacteria want?

Emeran Mayer: Yes. So, that's the assumption and that probably explains why the host has common language, it's common biological language, which goes from the microbes to various cells and receptors in the gut, including nerve cells. And also, since a lot of microbes live on plants, many plants have again, very homologous structures that sort of resemble some of our neurotransmitters. So, this clearly is a certain universality in terms of these signals, and the origin of all this is most likely the microbes that four and a half billion years to develop that language, had 400 times more genes than we humans have. And they have the ability, this ongoing evolution, I mean this is not a static system, so there's constant selection and that may be one of the advantages of having these microbes inside of us, because you can adapt to many things much better than our human system could adapt.

Jessi Gold: So, what you're saying is, there's things that the microbes signal for in us? Like, what kind of things would a microbe want our brain to be thinking, or doing, or can you explain that a little bit more?

Emeran Mayer: Yeah, so that's a very good question. I think right now it's more speculative, the answers, so somebody has suggested that the microbes may actually be able to hack into our reward system, and get us to do things, particularly to eat things that is beneficial for their own growth. And that is not been proven yet, I mean there's a recent study in fruit flies where it's been shown that microbes are able to change the behavior of these fruit flies. I mean obviously in humans and even in rodents we don't have this yet, but there's an interesting possibility for example in obesity where people develop this craving for high fat, high sugary foods. The normal composition of our microbes changes in a way that certain strains start dominating that then send signals to our brain, into the reward system, that makes us crave for these particular food items. Almost then it becomes like a parasitic relationship. It's no longer the symbiosis that exists normally, that everything is beneficial for both players. In this case the microbes then would take over in terms. It's really speculation. You know.

Jessi Gold: Yeah.

Emeran Mayer: But it's intriguing because we don't have the clear answer as what they would like to tell our nervous system, so I guess that's still really a mystery.

Here: Part 3 of a 3-part interview with Richard Bermudes, MD on transcranial magnetic stimulation (TMS). Dr. Bermudes is founder and medical director of TMS Health Solutions and founding member of the Clinical TMS Society. Part 1 can be found here: Transcranial Magnetic Stimulation: A Look Under the Hood. Part 2 can be found here: Transcranial Magnetic Stimulation: The Procedure.
Some say antidepressants work from the bottom up. and cognitive therapy and TMS, from the top down. In this final of three podcasts on TMS, Dr. Richard Bermudes highlights why magnetic stimulation might be an effective treatment for depression, particularly for symptoms that are resistant to pharmacotherapy.

He addresses these questions and more:
. What are the major cortical networks we are trying to change with TMS?
. Where will TMS fit into psychiatry in the next decade?
. What is psychiatry gettimg wrong right now?
Although TMS gives us a third pillar of treatment along with medications and psychotherapy, we don't always know what's going with each individual patient. We need some way to measure a biomarker to measure efficacy, whether we're doing psychotherapy, medication, or some sort of neuromodulation.
TRANSCRIPT:
Psyched! Episode 2 - Part 3 of 3
Bermudes: Although TMS has improved and give us this sort of third pillar of treatment to have along with medications and psychotherapy, in a way we still don't really know what's going on, with each individual patient, what's going on under the hood. We need some way to measure a biomarker. I think that will help us sort patients and monitor what's going on with our patients, whether we're doing psychotherapy, medication, or some sort of neuromodulation.
Jessi Gold: What sort of symptom differences would mean that you move like, two spaces to the right, or two spaces to the left?
Bermudes: There's a lot of debate about that. You know, I would just say the clinical trials really haven't ... There's sort of this initially FDA approved protocol, stimulation protocol, that targeted at the left front part of the head, or the left dorsolateral prefrontal cortex. There are other stimulation protocols that are emerging, but we don't really have a superior. They all seem to be about the same. Some of the doctors we ... If one's not working, we'll change to another stimulation protocol, because I think we want to do something. When the patient gets better, we assume it's because of that change.
It's much like working with anti-depressants. This person needs some activation, I'm going to add a little Wellbutrin.
Jessi Gold: Prozac didn't work, but we'll try Zoloft because they're so different.
Bermudes: Yeah, or they've only been on Prozac for three weeks. Yeah, they still need a little more active ... You know, they could use like a little more than a cup of coffee. You add that touch of Wellbutrin, and then they come back three weeks later like, "Oh, that's great." It's like, "See?" Somehow my measurement of their symptoms, in this change ... With head-to-head trials, we know that, yeah, they all sort of end up at the same place. That's where we're at with the stimulation protocols, unfortunately.
David Carreon: I know that we can't go into ultimate depth on the neuroscience of it, I mean in the same sort of cartoonish way that anti-depressants ... The story was that there's low serotonin, and so we need to increase the serotonin, but of course there's a lot of problems with that as a theory. We've made adjustments in anti-depressants, and the SSRIs do work, but maybe not by that initial cartoon version. What is, I guess, an equivalent TMS circuit cartoon? What are the major networks that you're trying to change?
Bermudes: Without getting too much into the details, the way I describe it to patients and colleagues is there's sort of this top down approach to some of our psychiatric treatments. There's cortical and sub-cortical loops, or circuits, and generally with depressed patients, they have a lack of cortical control, or sort of decreased top down functioning, if you will, between these areas of the brain. Generally, when you stimulate or modulate the dorsolateral prefrontal cortex, there's sort of this window into this cortical control circuit. What you see in time is increased blood flow, increased metabolism, and downward sort of top down control of maybe hyperactive or hyper-functioning circuits.
It kind of works in the opposite. Anti-depressants seem to, what they say, work from the bottom up. Where cognitive therapy and TMS seem to work from the top down. Where anti-depressants would sort of down regulate limbic systems, and then you'd get more cortical control that way. That's kind of how I try to keep it, sort of at these upper circuits and lower circuits. I got to point to my forehead and then…
Jessi Gold: I imagine it's not the easiest thing in the world to explain.
Bermudes: You know, I think when you keep it kind of, you kind of have these two ... There's obviously more than one network, but when you kind of keep it simple. I tend to be, I'm basically a general psychiatrist. I'm not a neuroscientist. I like to conceptualize things rather simply myself, and then sort of add to the model as I learn more and more about the neuroscience.
David Carreon: Where do you see TMS fitting into psychiatry, say in 10 or 20 years? What do you think this looks like when it's mature and developed?
Bermudes: I think that there's a few ways that our field can develop as a whole, and I think that TMS hopefully will be a part of that development. We talked about some sort of biomarker. I think there's a very big appetite with our field to find a biomarker that will help us sort patients into the right diagnostic categories. I think when we can get that, then hopefully that will help us get people to the right treatments quicker. There's really a big need for a biomarker to provide feedback into the treatments we're rendering. That's with TMS, [inaudible] therapy, as well as psychotherapy.
In terms of TMS specifically, I think one of the things that would be helpful is really finding other target, other, I call them cortical windows or windows into these networks. There are some emerging targets, depending on what's going on with the patient. We might want to move the coil over the supplementary motor area, for example. There's some indications that stimulating in that area of the brain helps people with a lot of obsessional symptoms. In terms of coil navigation, there's a lot of room for us to grow in terms of stimulation protocols, there's a whole variety that are being developed.
Targeting stimulation biomarkers, any of those three variables, that would change, I think the field, as well as TMS would improve.
Jessi Gold: TMS is just for depression, in your mind, or do you think that in 10 years, we'll be using TMS for other illnesses?
Bermudes: There's definitely a number of phase three trails that have been completed and are sort of going to the FDA in the next couple years. I think there will be an indication expansion. Both within psychiatric conditions as well as neurological conditions.
David Carreon: We're coming to the end of our time, and we like to ask our guests a few questions at the end about sort of, rapid fire. A question or two, a sentence or two, and then we'll cut you off after two sentences.
Bermudes: Yeah, sure.
David Carreon: We'll ask some of these questions. First off, what is something that psychiatry is getting wrong, or a major misconception in psychiatry right now?
Bermudes: Diagnosis.
Jessi Gold: Plain and simple, diagnosis.
David Carreon: There we go.
Jessi Gold: There we go.
David Carreon: I love it.
Jessi Gold: What's your favorite book?
Bermudes: Rapid fire, right?
David Carreon: We're doing it.
Jessi Gold: Yep, exactly. What's your favorite book?
Bermudes: What is it called, The Brain That Changes Itself.
David Carreon: Doidge.
Bermudes: Yep.
David Carreon: Fascinating book. Alright. Advice for a trainee?
Bermudes: Read.
Jessi Gold: Anything? Everything?
David Carreon: You're killing it. This is amazing. Most of our guests incapable of short answers.
Jessi Gold: Yeah, is it because you're a procedural person?
Bermudes: No, no. I really believe there's two things. Reading thirty minutes a day. It doesn't matter what you read. If you have a regular habit, you will change your brain. You will continually learn. It's about idea making. Reading, to me, is the way I keep up. It's not just about psychiatry, it's outside of that.
Jessi Gold: Would there be a person living or dead that you would consider a hero? It could also be a fictional character.
Bermudes: My father, actually. He was a teacher. He was an artist. He had his own construction company. He moved us to ten acres of land, without a well, without heat, electricity. Put a generator, single-wide trailer. It's a wonderful piece of property in northern California. He's passed, but just a really creative individual. He's someone who always told my brother and I that we could do anything.
David Carreon: Last, but not least. What's your favorite color?
Bermudes: Green.
David Carreon: Green. Thank you for joining us.
Jessi Gold: Thank you.
Bermudes: Thank you.

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Dr. Richard Bermudes (Part 2 of 3): Dr. Bermudes talks about the experience of TMS (including his own) as well as the future of neuromodulation as it transitions from research to practice. He is founder and medical director of TMS Health Solutions and founding member of the Clinical TMS Society. Part 1 can be found here: Transcranial Magnetic Stimulation: A Look Under the Hood.

Transcript:
David Carreon: Have you ever gone under the coil yourself?
Bermudes: Yes, I have. Several times. I think it's a procedure that is ... It's an interesting experience. Certainly I've sat through several treatments, in different systems, some of the coil types are different. I think it's a good thing to do. It's an interesting experience, and certainly, we all have our subjective sort of experience about what it felt like and what it did to our thinking, or mood, or whatnot.
David Carreon: No, I'm a big believer in that and especially done that myself within my own experience. It is really interesting, sort of the subjective effects and how it feels. What was your experience of, what does it feel like during the stimulation? What [crosstalk] the coil itself, when it goes off? What does it, what did you feel?
Bermudes: Yeah, you know, some of the descriptors that we use and that I would use, it's a tapping sensation. For me, underneath the coil, there's a lot of prickly, kind of pins and needles sort of sensation. I think at first, it's a bit like, oh, there is some sensitivity there. It's a sensation that seems to, at least my scalp, I was able to accommodate to pretty quickly. I was able to get up to a fairly high tolerance, even in the first couple of treatments that I did. There are times when we are on the sort of the trigeminal nerve, and there's sort of this optile [inaudible]. You can get some eye movement sometimes, some tearing. I experienced that as well during my couple sessions that I've sampled.
Jessi Gold: Is sampling just something that all people that do TMS do to themselves?
Bermudes: Yeah, I mean, I think experiencing that, sitting through actually complete treatment, I think is important. We actually have our doctors do it, unless there's of course, a medical contraindication. I think it's important the providers and the technicians ... We tend to have them do that.
Jessi Gold: Does it make you happier?
Bermudes: You know, for me, the way that my sort of subjective experience is ... I'm a big time trail runner, and I run basically every day about four to five miles. I get this sort of level of optimism after I run. Clarity of thinking, and I have a lot of ideas that I have during my runs. The four or five times that I've sat through a treatment, sort of randomly, they're not in a row, I have a similar sensation actually. Like I just went out for a nice four to five mile run, and sort of have this level of optimism about the day and clarity of thinking. That's been my experience. Not everybody has those sorts of immediate, sort of experiences with TMS. It can really vary.
David Carreon: I guess it depends on the day and the location. There's so many variables, and I think that the subjective effects of TMS are something that I think you need a lot more work. Because the standard story is, "No, you don't feel anything. It's just sort of the neuro-plastic effects over months," but I don't know. For some of my research subjects, and even myself and lab mates that have done it, there are some pretty significant subjective effects if you're at least either mindful enough or paying attention. It's pretty interesting. One of the times was this feeling of, for me it was more or less of a euphoria and more of a confidence, more of a mastery or control feeling.
Bermudes: Yeah, I would say it was that way for me as well. I tend to feel that way after I run. It's sometimes euphoric, but yeah, definitely a sense of here's what I'm going to do today and I can do it. Clarity of thinking.
Jessi Gold: Do you feel like if everybody felt like that, then they just wouldn't go for a run and would just put a magnet to their head?
David Carreon: What about recreational TMS?
Bermudes: I actually have thought about that. I'm kind of glad I get that, because it provides a lot of positive reinforcement for me to run. There are times when I start out in the day not wanting to, and I just sort of tap into that feeling. I'm getting this done, because I know I'm going to feel this way. Yeah, I'm glad there's not like a little device in my closet that I can kind of access, because I certainly know that I would slide on the exercise.
Jessi Gold: I think everybody would.
David Carreon: Any lab break-ins or clinic break-ins to TMS stimulation?
Bermudes: Not that I know of or will admit to.
David Carreon: This does raise the question of, I mean I know that with antidepressants, some of the probably more fringe opinions, but you know, everybody would be better if they were on an antidepressant. That antidepressants make anybody happier. Would you say something like that might be true of TMS, in a different world with different laws? What do you think it's doing to you or to me, to make us feel good, and is that a good idea?
Bermudes: I actually have some reservations about that, because I think that from a data point of view, we know that there are certain patients with clusters of symptoms. We can take patients with a certain score on the PHQ-9 or the [inaudible], and we know they have elevated depressive symptoms. We do a history, and we diagnose them with major depression. We know a certain part of them will have, basically network problems, so to speak. Broadly spoken, so there's sort of network disconnect. If we utilize TMS, we know that that network function improves, essentially. I'm trying to speak broadly, because without getting in to the specifics of the different networks that have been named and claimed, so to speak.
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I don't know that if we modulate sort of, healthy networks, that are in a homeostatic balance and functioning the way they "should be," that that is necessarily a safe thing to do. I think it's one thing to sit through one or two random treatments, and it's another thing to get stimulated four to five days a week. I wouldn't put myself through that sort of protocol unless there was really clear evidence that I needed a particular network modulated. There was a point when people talked about how, what would the world be like if everyone were on Prozac. I think we're past that. In fact, I've even read some editorials about, is there an increased level of treatment resistance that we haven't seen before? Could the prolific use of antidepressants maybe contribute to that? I don't know. I don't know enough about antidepressants to be able to speculate on that, but-
Jessi Gold: Like antibiotic resistance somehow?
Bermudes: Maybe, I don't know. I know that sort of, there is an editorial by [Inaudible] recently in brain stimulation, where there's pretty clear evidence that the chronic resistant depression that we're seeing today is definitely less responsive to medication than what they were seeing in the late 90's, for example.
David Carreon: That brings up, I think this is also something that is a new idea for me at least of recent years in psychiatry, of sort of ... There's some sort of a story of psychiatry where we have these diseases, and they're fixed. The prevalence is fixed, and they're just sort of, you drew the unlucky genetic hand. Things don't really change, and there's no real cultural influences. It's just sort of this fixed lump of a field. We come up with treatments and the diseases don't move. You're sort of describing psychiatry almost like the world of infectious disease, where sometimes new things come up and resistances develop.
It's just sort of this, much more dynamic process, that brain stimulation now is a possible way to treat something that is now no longer responsive to antidepressants. I guess that's a different world than the sort of fixed universe that people maybe described before.
Bermudes: Yeah. I think we're all very, I think psychiatry, I hope is moving sort of ... I don't know what the word is. Kind of trans-diagnostically beyond the DSM-5. There's some usefulness to the DSM-5 or DSM-4, but I've started to think more in terms of network connectivity. I think that's what TMS has taught me, is that some of these older models. The serotonin, the [inaudible] hypothesis. I'm a cognitive therapist, so there's sort of this cognitive model of the mind. Before that, there was the more psycho-dynamic, sort of models. Those were useful at the time because they drove treatment at that time.
I think TMS and other modalities that involve neuromodulation, DBS, DNS, TDCS. It's really about the network, and can you associate a network or a dysfunctional network with dysfunctional behavior, emotions, [inaudible], et cetera? Can we then develop stimulation protocols, patterns, frequencies, that can sort of bring those networks more into balance? I think it is dynamic. I don't know if there's a cure out there. The brain is incredibly dynamic. We're in a dynamic environment, and one environment for one person can produce sort of illness, where another person can have the same environmental stressor and only take something like abuse, or divorce, or bankruptcy.
These are big environmental stressors that a lot of us will encounter at some point during our lives. They don't all produce the same problem with the brain. I think it is very dynamic, if you will.
Jessi Gold: Then if someone comes into your office, is there a depression space in the brain that you're just putting a magnet, or how does that work?
Bermudes: Yeah, so I'm talking about this new, sort of way to think of the brain, but in a way, I don't have biomarkers to tell me what's going with each person who comes into our office. We're sort of stuck with this diagnostics symptom-based, we measure very carefully the symptoms, and then we make assumptions of where on the cortex the magnet needs to be. What sort of modulatory pulse sequence needs to be prescribed. Then what we do, is we have people go through treatment, but there's no biomarker feedback with that. We do more measurement with symptoms, and then we make assumptions about what's going on in the brain based on that.

Transcranial magnetic stimulation: an exciting FDA approved technology in psychiatry. But exactly what is TMS, and why should psychiatrists—and perhaps even the general—public be aware of it?

That's the key question the hosts of this short podcast (the first in a series of three on the topic) put to Richard Bermudes, MD, founder and medical director of TMS Health Solutions and founding member of the clinical TMS society, Inc. Here, Dr. Bermudes talks about some basics: what these devices look like, how they work, and about the patient experience.

​Transcript:
David Carreon: Welcome to Psyched, a podcast about psychiatry that covers everything from the foundational to the cutting edge, from the popular to the weird. Thanks for tuning in. This is David Carreon.
Jessi Gold: This is Jessi Gold.
David Carreon: This is Psyched. We have with us today, Dr. Richard Bermudes, the founder and medical director of TMS Health Solutions. He earned his medical degree from the University of California San Diego in 1997. He served as chief resident for the family medicine and psychiatry combined program at the University of Cincinnati, then completed a fellowship at the Beck Institute for Cognitive Therapy and Research in Philadelphia. He's the founding member of a clinical TMS society, and he chaired the first annual meeting in 2013. Now was elected president of the society in 2015. Dr. Bermudes, thank you for joining us.
Bermudes: Thank you.
David Carreon: I wanted to talk to you a little bit about TMS. This is something that is a new and exciting technology in psychiatry, and just wanted to give you the chance to talk about ... What is TMS, and why should psychiatrists and maybe even the general public be aware of it?
Bermudes: That's a great question, and actually, it's a question I think about a lot. Probably too much. In its simplest form, TMS is transcranial magnetic stimulation. It's an FDA approved treatment for adult patients who have not responded to one or more anti-depressants, medications. In its basic form, we're using high powered magnetic coil to generate energy across the cortex. We're using that to modulate populations of neurons, so to speak.
David Carreon: You're taking this device, and walk us through, what does the device look like? If you're a patient walking into the office, what happens to you?
Bermudes: Well, the devices are pretty ... Each device essentially has a few components, but there's generally a stimulator with a bank of capacitors. This basically is a way for energy to store up and be discharged quite quickly, in milliseconds. This current then goes through a coil. There are various shapes of coils, the most common being, there's kind of two shapes that are pretty common. I won't digress yet, but basically, this current gets discharged into a coil, and then perpendicular to that coil, a fairly high powered magnetic field abruptly is on and then off.
This happens, it's a fluctuating current, which produces a fluctuating field. It's because it's not static, because it's fluctuating in milliseconds that it actually affects [inaudible] channels essentially. The discovery of this in the 80's  by Mark George and others, that really kind of took our initial offering of, basically we've been waving magnets around the brain for quite a bit of time trying to change it. It's sort of this notion that it's a fluctuating current with a fluctuating magnetic field that makes it pretty powerful for the brain.
Patients would see, generally there's sort of a cart, or some sort of bank, or stimulator. Then there's some sort of arm that holds these coils. There's usually a user interface for the technician or physician to sort of navigate that coil around the person's head. There's generally some sort of medical looking chair to these systems as well.
Jessi Gold: I'd imagine patients don't get exposed to magnets in their brains very often. Probably the only thing they know from magnets would either be like, the little kid toys or maybe an MRI or something like that. Does that come up? Are people nervous about the idea of a magnet on their brain?
Bermudes: We get a lot of responses when we talk to patients about this procedure. I think it really depends on the patient, how they're conceptualizing their depression, or how they've been taught to think about their depression. Certainly, the experience of treatments and then, what treatments they're also being offered. For example, if I'm talking to a patient who's been on five, six, ten antidepressants and has suffered a lot of side effects, maybe have had an MRI in their life. The fact that it's a magnetic field, you know, they've had the MRI before, they know that's tolerable. Had side effects from the antidepressants, it's generally not a big deal to think about. Particularly for patients with moderate or moderately high or severe depression. They've been suffering for years.
It's not a first line of treatment. It's generally third, fourth, fifth line treatment. For the right patient population, it's actually pretty acceptable. Sometimes we have to clarify that it's not ECT. Patients will ask, "Are you going to shock my brain?" We're not generating a seizure. This is sub-seizure threshold. TMS actually introduced the idea that we could do neuro-modulation without generating a seizure and improve mood.
Jessi Gold: Since you brought up ECT, is there a reason why TMS doesn't get the reaction that ECT has? You know, right outside there were protestors. People tend to be pretty scared of ECT. The press has kind of destroyed it at one point and it's come back into fruition. They don't necessarily know it's better. Is there a reason TMS hasn't had that same reaction?
Bermudes:  I'm a big believer in ECT. I used to do ECT. It's a very powerful treatment, very effective treatment. We don't have to overcome the kind of stigma that I used to have with patients who were getting consultated for ECT. I think some of the reasons, you know, not having to go under general anesthesia. It's a treatment that is accessible for patients who aren't as severely ill as those who are getting ECT. It's an outpatient setting. There's been no cognitive side effects associated with this procedure. All the modern day stimulation protocols for ECT, the cognitive side effects are pretty mild to non-existent.
You know, you started battling that legacy with ECT. I think people have been able to differentiate the two treatments.
David Carreon: You say it's not shocking the brain, but come on, it's a pretty powerful magnet you're putting out. 1.5 Teslas for a lot of these guys. That's a pretty hefty stimulation, isn't it?
Bermudes: Yeah, so it's kind of an interesting dynamic when we're demonstrating this with patients, because on the one hand, I'm saying, "Yeah, it's a fairly benign procedure. The seizure is rare. It's a benign procedure. The seizure is rare. It's not what we're trying to induce. Here I'm going to place this over your meta-cortex, and I'm going to get your thumb to move." That's a pretty powerful demonstration of how we can do non-invasive neuro-modulation at this point in time. It is powerful, but it doesn't have that stigma.

Our discussion this month was with Dr. Paul Appelbaum. It ranged from the history of current settled ethical positions to hot issues in ethics and law in psychiatry today. We discuss the history of involuntary hospitalization, genetics, human freedom, and responsibility and how these issues impact practitioners, patients, the legal system, and the general view of psychiatry in the public.

Also, in the context of recent political events, we discuss the Goldwater Rule, which prohibits psychiatrists from commenting on the mental health of public figures and really try to understand its origins and purposes to the field of psychiatry.

About Paul Appelbaum
Paul S. Appelbaum, MD, is the Elizabeth K. Dollard Professor of Psychiatry, Medicine and Law, and Director, Division of Law, Ethics and Psychiatry at Columbia. Dr. Appelbaum went to Harvard Medical School and his residency at Massachusetts mental health center. Dr. Appelbaum is Past President of the American Psychiatric Association, the American Academy of Psychiatry and the Law, and the Massachusetts Psychiatric Society, and has twice served as Chair of the Council on Psychiatry and Law and of the Committee on Judicial Action for the American Psychiatric Association (APA). Dr. Appelbaum is currently Chair of the DSM Steering Committee for APA, and of the Standing Committee on Ethics of the World Psychiatric Association. Dr. Appelbaum performs forensic evaluations in civil and criminal cases, and treats patients with a broad variety of problems, including depression, anxiety, and adjustment problems. Twitter: @appelbap