On this episode of Psychiatric News Special Report, Editor in Chief Dr. Adrian Preda sits down with Dr. Joshua Brown, a leading expert in neuromodulation and Medical Director of the TMS Service at McLean Hospital, to explore how transcranial magnetic stimulation is reshaping the treatment of depression and other psychiatric disorders. Dr. Brown shares the clinical stories that drew him to TMS, explains how this “electric brain” approach drives synaptic plasticity, and walks through what actually happens at the level of NMDA and AMPA receptors. The conversation covers how TMS compares with medications and ECT, why it should not be viewed as a last resort, and how emerging strategies like accelerated protocols and pharmacologic augmentation could boost response and remission. Looking ahead, they discuss new indications, evolving training pathways, and why TMS is moving from niche tool to foundational treatment option in modern psychiatry.

Read the full Special Report on TMS here: https://www.psychiatryonline.org/doi/10.1176/appi.pn.2025.11.11.4

PsychNews Special Report is a production of Psychiatric News, a media platform dedicated to serving as the primary and most trusted source of information for APA members, other psychiatrists and physicians, health professionals, and the public about developments in the field of psychiatry and mental health that impact clinical care and professional practice. Learn more at psychiatryonline.org/journal/pn.

Transcript

Dr. Adrian Preda (00:12) Welcome to the Psychiatric News Special Report podcast, a monthly podcast from Psychiatric News produced for the APA Medical Minds channel. I'm Dr. Adrian Preda, Editor-in-Chief of Psychiatric News and Professor of Clinical Psychiatry and Human Behavior at University of California Irvine School of Medicine. Each month, we sit down with the author of our special report to discuss key issues at the intersection of mental health, psychiatric clinical care, research, and advocacy. Today we are diving into something that is genuinely reshaping the practice of psychiatry, transcranial magnetic stimulation, TMS. Our guest is Dr. Joshua Brown, Assistant Professor of Psychiatry at Harvard Medical School and Medical Director of the TMS Service at McLean Hospital, one of the leading TMS centers in the country. He's the author of the special report, 12 Notes About TMS, published in this month issue of Psychiatric News. Josh, welcome. It's a pleasure having you.

Dr. Joshua Brown (01:12) You're here. Thank you, Adrian. It's a pleasure to be here and great to see you again.

Dr. Adrian Preda (01:17) Good seeing you. I would ⁓ love to start at the beginning. ⁓ When we encounter a clinician deeply committed to a treatment modality, it's very often because of a story, either a patient, a mentor, or something that shifted how you thought about psychiatry and the brain. What's the story?

Dr. Joshua Brown (01:37) that's a good question. you should prepare me for these questions in advance. ⁓ I would say I have answers from two directions. ⁓ I have a clinical answer that comes to mind, which is, ⁓ and also a scientific answer that comes to mind. So, ⁓ from the clinical standpoint, ⁓ I remember clearly as a resident, training at MUIC, ⁓ seeing a patient that described that they had been depressed for 20 years, like as long as they can remember. And they were at the tail end of their TMS course and they were at or near remission. And, you know, at that time I was thinking, wow, like this is ⁓ such a powerful tool. It's, it's a pleasure and a privilege to be able to have something like that to help patients with. And obviously that's why we do what we do so that we can, you know, use the education that we have, use the knowledge that we have to be able to help, help those folks. so. That was one of the things that kind of cemented in my mind that that was what I wanted to do clinically. From a research standpoint, ⁓ this is a story that goes back quite a bit further. ⁓ And you told me to try to keep my answer shorter, so I'll try to be brief. But my interest in understanding the brain actually goes back to undergraduate. ⁓ I was in psychology. I was planning on heading a different direction. an understanding of, I remember there was a lecture on the physiology of vision and it was sort of this understanding of physically how things worked down to a molecular level. And it was one of those key moments that turned the course. knew it was a pivotal moment at that time and it sort of guided the decision since then to do a combined, uh, MD, PhD and to do neurology and psychiatry. And as I was in, uh, my PhD and studying mechanisms of synaptic plasticity, which is using a lot of electrophysiology. ⁓ The intention was always to move that to human level research and an obvious translation of that is brain stimulation. My first exposure in med school at the Medical College of Wisconsin was to deep brain stimulation. We didn't have TMS at the time. And so that was kind of the leading thing that I was thinking, but I was sort of aware of some of these other forms and TMS included. And, and, that was part of what drew me to, uh, uh, go to MUSC, train with Mark George, um, who's a pioneer and, and, uh, considered by many as a father of TMS for depression. So, um, but they have, you know, uh, kind of a broad brain stimulation focus there. And there was a, uh, another pivotal moment where I, clinically recognize that TMS was probably more in line with the things that I was hoping to do from a research and clinical standpoint ⁓ during residency. So I'd say that would be the quick way to put that.

Dr. Adrian Preda (04:40) So you are a clinician and a scientist, and as it turns out, TMS is actually really an exciting modality with regards to what we learn about the brain using TMS and we'll discuss neuroplasticity. But it's also a pretty amazing and transformative clinical intervention at this point, right? Yeah. So in your article, you actually make the point that in psychiatry, we know our medications and we are getting good results across diagnosis, right? We know our psychotherapy and and he has been around for a while, but somehow is still underutilized. And that's despite the fact that when used for approved indications, including depression, we are looking at really pretty significant numbers with regards to remission ⁓ and response. So what's going on there? Why the delay into into getting it up into the clinical landscape?

Dr. Joshua Brown (05:38) Yeah, it's something that we talk about a lot and think about a lot. I'm involved heavily in the clinical TMS society also. And that's one of the main missions is to try to get training and education out there to at whatever level. I think that we see the emergence of TMS almost more of like a grassroots kind of a thing. So somebody has to know about it. It has to be, you know, whether it's a patient that goes to their psychiatrist and it's like, Hey, I heard about this thing. Can you give me a recommendation or referral? ⁓ A lot of times it actually comes, I found from like psychologists or therapists that have maybe had another patient that did it, responded well. And so they start recommending it to some other patients. And a surprising number of people come in for a consultation referred by their therapist, ⁓ even more I would say than psychiatrists. I think that there's a tendency when we go through training and we kind of... It'll, almost get a little bit fixed in, in what we know at that time. I feel the same tendency myself with, medications that, that we typically would prescribe, ⁓ you know, where I train and then, you know, new medications will come out and it's just not as much on the radar. I don't know as much about it. Haven't had as much familiarity with it. And so even if I maybe have heard of it, I'm, I'm, you know, less likely to, you know, to push that or to, use it when I have other tools that I'm more familiar with, even if they're. maybe not the ideal tool for that patient. So I think that part of it is the limitation in training. there's not very many, if you think about when it started, so as FDA cleared in 2008, and that's, I'd say when it really hit the clinical scene, didn't start getting approved by insurances until like 2013. That was probably the earliest. And so ⁓ you had private clinics, which usually were not affiliated with residencies. And so you think, Unless you were doing, unless it was an institution that was involved in those pivotal studies early on, there would have been no exposure to TMS. And so I don't think people have started getting consistent exposure in that until probably 2015 and after. So really on the last 10 years, which means, you know, only in the last five years have people been coming out of residency with this. And that's still a fairly small proportion. But one of the things that I think will help is ⁓ as a field we are trying, led by Sean Siddiqui, we're trying to create a ⁓ subspecialty and it's in process of brain stimulation and TMS is a major part of that. I think that as that becomes solidified and ⁓ finalized, I think that we'll start to see more recognition of this general approach and to be taken up clinically. And I think that more of the uh, training opportunities that a lot of people are looking for. And those of us that are at centers that have a lot of TMS or brain stimulation, a lot of people, uh, at the training level will reach out wanting to get exposure. So you see a ton of interest from, from the early stages. Uh, and it's, it's, it's a, it's kind of a, well, I just, I'd say it's in demand, um, at that point, but it's a lot of the people that have that trained before this really kind of came in vogue. Um, you know, they didn't really get that, um, that exposure. so that's why I think it's not as much on many people's minds.

Dr. Adrian Preda (09:04) So ⁓ it might be a combination of factors, Lack of training opportunities, then lack of exposure, which results in lack of familiarity. I mean, we all tend to do what we are familiar with. And if ⁓ the training is really going to be focused on pharmacotherapy and psychotherapy, that's really going to be what people will probably go to most of the time. Could be also the perception, I wonder, that TMS, transcranial manic distillation, is some electricity that we are kind of, know, subjecting the brain to. And that kind of maybe brings up associations with ECT. And I wonder, do you, when you interact with people, is maybe part of this, perception that TMS might be an invasive treatment? But let's put that to rest. Is it or is it not?

Dr. Joshua Brown (09:56) Yeah, no, it's not. ⁓ So it's not invasive and that's one of the kind of the hallmarks of it. It's actually very safe and very well tolerated and I think that that's almost maybe like it's a double-edged sword because then you also have some people that maybe take it further than it's then the evidence actually supports and that's something that we're also trying to temper. So, you know, there's some people for example that advertise it for autism or for various things and that's It's not at that level of evidence at this point. so because it's safe, think some people, some providers will feel like, there's no harm in doing this. Anecdotally, they see that it benefits certain people and there can be a place for that when there's nothing else to offer and when it's appropriately discussed with the pros and cons. But to your question specifically about, it like ECT or how much is it like ECT? It's a question that a lot of people ask, patients especially, and what I would say is TMS, a lot of times we describe it to patients sort of like, why I was about to say like going to the dentist, but my wife hates going to the dentist, so I won't put it like that. You sit in a chair and you get anywhere between ⁓ three and a 20 minute treatment. ⁓ Patients come in, they can drive themselves in, they can drive themselves home. They can do it in the middle of a workday etc. Like there's no impairment of consciousness or anything. Whereas ECT, ⁓ know ECT we also you know, it's a very valuable tool for us, but it is a different scenario. You have to have someone else drive you in. ⁓ You have you're there for a couple of hours, you know before getting ready for the treatment and then ⁓ a period of time recovering after the treatment and then someone to drive you home. And so, know in all it's you know, four hour up to a four hour deal. which I know that you have experience with and as a clinician. So ⁓ it's quite different in that way. And you didn't ask, but it comes to my mind, a lot of people wonder like, would I know to refer someone for TMS versus ECT? A lot of places that have comprehensive centers ⁓ and they're seeing people in treatment resistant clinics like treatment resistant depression. And, you know, they'll basically make the determination that's kind of this, the environment in which I trained as well. I, I typically think of, of ECT for people that are assuming they haven't tried either yet. ⁓ ECT for people that are more severe, ⁓ like they're, you know, they're not functioning in their jobs. They're already taking off time off work. ⁓ cause that is one of the, one of the, ⁓ downsides of ECT is that you need to take. you know, four to six weeks off of work ⁓ or school to be able to do it. TMS, you don't need to do that. So people that are somewhat functional, it's a, you know, in my mind, clear indicator for TMS. If there's things like, ⁓ you know, if there's features like psychosis, if there's features like catatonia, these are, you know, really clearly ECT oriented. And so I would just go right to that. And But so essentially, you know severity can be looked at as a kind of a guide in my mind for Which direction to go?

Dr. Adrian Preda (13:12) And you made the point and I think it's worth emphasizing that there is no need for general anesthesia, right? And really there are no cognitive deficits. People kind of, you know, come, it's almost like an appointment. They come in for their appointment that they get their TMS session. They don't need to wait four hours after the TMS is completed to make sure that they are not drowsy or sedated. TMS is completed. They go back to their car. They go back to work or, you know, ⁓ whatever it is that they need to do for the rest of the day. So that's a significant, significant difference. And then the other part is that maybe there is this impression because we are talking about severe depression and that's when people think, well, know, ECT, TMS, they are similar. Well, in that respect, the very ⁓ intense spectrum of severity, ECT is recommended. But at the same time, for treatment resistant depression, for people who have multiple treatment failures, medication failures, TMS, ⁓ really the data shows that there are pretty impressive results, right? 50 to 60 % of treatment-resume patients improve and there is up to 50 % reported rates of remission, isn't it?

Dr. Joshua Brown (14:20) Yeah, yeah, that's right. And I think that that's one of the things that stands out and most of the time I give talks, I sort of focus on that feature where, you know, medications are great for two thirds of patients, but you have that remaining third of treatment resistant depression and adding more meds is a very low chance of improvement at that point. ⁓ You know, we don't have an exact number, but a low single digit percentage relative to that, as you said. 50 to 60 % of people are having a meaningful response, about half of those people remit. That's a really promising outcome for those that otherwise wouldn't have much of a chance without brain stimulation. There's also two recent studies from 2024 that actually did the head-to-head comparison after people had not responded to two medications, then they randomized them to... TMS or to ⁓ a change in medication. One of the studies had a third arm where they ⁓ simply augmented with Abilify. And in both cases, TMS was clearly superior in producing response and remission in those people. ⁓ that's a nice head-to-head feature. And that's actually kind of shifted. ⁓ For a while with insurance companies, they've required four medications. ⁓ from at least two different classes to approve coverage of their TMS and insurance coverage is a pretty big deal because it can be expensive out of pocket. Now two medications, ⁓ are the most common requirement and most, most insurance companies have shifted towards that. know, on the note of insurance, depression is almost universally covered, ⁓ in all parts of the country and, ⁓ and, and in many parts of the world for that matter. For OCD, it's only about half of insurance companies are approving. So, you we have a split here in Massachusetts ourselves in terms of some that are covering it, some that are not. You know, the evidence is growing and it was, as I already pointed out, it was like a five-year plus period for depression. And I think that, you know, we're seeing a little bit more rapid development, you know, with OCD, but OCD is also not as common ⁓ as depression. as far as the number of people. And so it takes longer to collect the naturalistic data that would be helpful in sort of proving to insurance companies that this is efficacious. This is a thing that is worth covering. So that's part of the overall mission that we're working on. In addition to all the other disorders that are being investigated, mean, PTSD and addiction, these are disorders that I would expect will be have a growing amount of evidence and I expect that there'll be FDA cleared at some point in the not too distant future.

Dr. Adrian Preda (17:25) And you know, so what I hear you saying at the same time is that, know, with this expanding of indications, it's a little bit of an uphill battle. And part of it might be, you know, we live in a sort of pharmacotherapy driven culture, I would say, when it comes to treatments in psychiatry. And part of that is that the way we think about the brain is that there is this soup of neurotransmitters and receptors, which then, of course, you know, what can we do when there is dysfunction? Well, we fix the chemical abnormalities. That's a very different way of thinking about psychopathology and pathophysiology when it comes to what's happening in the brain than from a TMS perspective. ⁓ In fact, in your paper, you talk about this concept of the electric brain, which might not be very, very familiar to many people out there. Can you explain what you meant with that?

Dr. Joshua Brown (18:21) Yeah, happy having to explain that. mean, it, it'll harken you back to the first year of medical school as you ⁓ think about and understand that electricity is really how the brain ⁓ communicates with itself. So it's, it's mediated by ions like sodium, potassium, you know, we know, we remember these pumps in it. And we have these action potentials that very quickly move down the length of an axon and that leads to And these are all electrically mediated. so electrical stimulation could directly activate that. And we see that with deep brain stimulation and, you know, ECT, TDCS and so forth, you know, various electrical forms of stimulation with, and TMS leverages that actually by an old physics principle ⁓ from Michael Faraday called Faraday's Law. It's from the early 1800s and 1830. ⁓ this principle essentially is that magnetic waves and with you know, if you have a fair magnetic wire and you induce, you know pulses of magnetic of magnetic energy you induce an electrical current in that and similarly pulses through electric current can induce a magnetic wave and so you actually have that process the coil is You know copper whiling wiring coil It creates magnetic waves that pass into the brain And then the neurons act sort of like fibers that receive, that are activated by these magnetic waves, ⁓ activating these channels and then action potentials move down cause, then it moves to that sort of chemical part. Cause you know, it's truly the brain is an electrochemical organ. So we have both at play and then you have these synaptic, ⁓ connections between neurons. And, ⁓ and, that's, you know, that's where we get activation of circuits and. ⁓ circuits comprise brain networks. so that's how we can activate these. And ⁓ the idea with TMS at a very basic level, and when we think of how it works is doing this a bunch of times, sort of like a whole bunch of repetitions at the gym or something, working out a muscle, you activate this a lot and we invoke the ⁓ of ⁓ the principle that neurons that ⁓ fire together, wire together. ⁓ And so this was coined by Carla Schatz and attributed to Donald Hebben, this heavy in plasticity. So that's kind of the idea with TMS is that we're ⁓ repeatedly activating these connections. You could almost think of it as similar to repeatedly trying to remember something. And if you do it enough times, it's like, it gets pretty ingrained in there, you know, like something like your phone number, you have to say it so many times and use that a lot. And so it becomes very simple and easy to pull up. And animal and animal models, actually can either through learning processes, like learning and memory tasks or through electrical stimulation, you can induce the same process, ⁓ the same biochemical processes and doing one actually has the same effect as doing the other. And that's kind of what we see with brain stimulation therapies is we're a little, you know, ⁓ I think sometimes of therapy is like very fine-tuned micro circuit changes because we're actually inducing learning and memory in those cases and doing TMS is kind of like hitting, you know, it's a little bit of a sledgehammer relative to the, you know, the kind of things that we do with therapy, but it's the same principle where we're inducing these same, we suppose biochemical changes.

Dr. Adrian Preda (22:01) Let me try to unpack a ⁓ bit because I think there are a couple of important concepts that are worth clarifying. So first, through TMS, it seems like we get the chance to change what's happening with regards to the brain plasticity, right? And that's really important. And by the way, right, it's interesting. ⁓ I did my residency training when I graduated, which was at the end of the last century. So, you know, we've been taught that the brain is actually not neuroplastic. There is no neuronal regeneration, right? What you are born with, that's what you're going to die with. And then over time, we learned that actually we could see neuronal regeneration in certain parts of the brain with different interventions, including some antidepressants. And there is a lot to be said about synaptic plasticity, right? meaning that we could in fact improving what's happening at the level of synapses. And in your paper you discuss actually very nicely, you sort of introduced this idea of ⁓ long-term potentiation, LTP and long-term depression, right? And how things actually can be changed at the synoptic level through TMS, right? You know, just getting a little bit, not into too much detail, but just sort of a 12,000 feet view of the molecular mechanisms that are at play here. You are talking about the AMPA receptors and the NMDA receptors. What's happening in the synapse with the AMAs?

Dr. Joshua Brown (23:45) Yeah. So, you you kind of brought up a couple levels of plasticity and maybe from that 12,000 foot view, ⁓ just kind of a brief contextualization of that is we do know that there is a little bit of neurogenesis that happens in certain brain regions and more than we previously thought. And that's a part of plasticity. It's a part of what the brain does. And we also know that there's, new ⁓ even within the same neurons, you can have new dendritic branchings. And then of course, within a branch, can, we frequently see spines that are spontaneously, you know, emerging and then coming, you know, absolving back into the dendrite. And when they get active, when they get activity, essentially if they don't sense, they call it, they're called filopodia as they come out. And if they, if there's not a presynaptic signal, they'll just come back in ⁓ and they'll, ⁓ you know, it essentially just kind of flatten out again. And I can think of these sort of like, leaves of a tree, but they'll just basically go back into the branch and they'll no longer be there. And so they have to have some sort of signal and that's where the synaptic plasticity comes in. you know, all of these forms of plasticity are an essential part of, ⁓ you know, what we do as humans and it's part of our learning and ⁓ synaptic plasticity is, it's, you know, we're doing it all the time. Like anything, anytime we're ⁓ taking something into some sort of longer term more than just an immediate working memory and even that, it's involving synaptic plasticity. This ⁓ form of plasticity is really the basis of learning and memory. It's how it works at the cellular level. So ⁓ within that, there's many things that are necessary. You have a whole bunch of proteins, dozens of proteins actually that are required for synaptic plasticity to occur. It's a very intricate process. But there's only a couple of things that are sufficient for it to occur, such that if you increase the activity of that thing, it increases the plasticity. One of those key elements is the NMDA receptor. And it's sort of this key rate limiting ⁓ gatekeeping step. And it's has a co-incident detection. So you have to have two things at once for it to be opened. And to me, kind of signifies the importance of not activating it erroneously or unintentionally or inadvertently. Like it's something that we don't want to just have happen without tight control. Those things are you have to have glutamate bind it. And then you also have glutamate that binds ampereceptors Ampereceptors let sodium in, sodium depolarizes the membrane, the depolarization of the membrane removes the magnesium plug, which sits in the NMD receptor. And so that's where you have both things involved. And then as the NMD receptor opens, you have a rush of calcium that floods into the dendritic spine. And the calcium ⁓ switches at low levels. It activates phosphatases, that's what it preferentially activates, and phosphatases actually lead to removal of amperoceptors. But at high levels, it changes the ⁓ confirmation of the enzymes and leads to ⁓ kinase activation, and kinase adds the phosphate groups, and ⁓ that drives amperoceptors into the synapse. so this is the postsynaptic side. There's also presynaptic. mechanisms that lead to increased or decreased neurotransmitter release. And then there's also plasticity that can occur within ⁓ the, we would call intrinsic ⁓ neuronal plasticity where it's changing actually the channels within the neuron itself and not to mention plasticity of non-neuronal cells. So there is different levels, but this is sort of the classic type of LTP and LTD that we know we have the most information about these and have a lot of ⁓ sense about how these correlate with learning and memory processes. So with TMS, we have a decent amount of evidence that it works in this way. There's still ⁓ some pieces that I would like to see completed to really kind of nail that down, but a pretty good idea that that's how how it works and one of the things that would translate from that is if we, know, just like we saw two decades ago in animal studies, if you activate or increase NMDA receptor activity, you would get, you know, improved learning and memory, you get higher LTP, more LTP. ⁓ If that's the case and if that's how TMS works, then we should be able to get better responses from our TMS by activating the receptor. And so ⁓ that's one of the things that we have done in motor physiology studies. ⁓ then ⁓ we did see that plasticity was increased by adding an NMDA receptor agonist. ⁓

Dr. Adrian Preda (29:10) Yeah. So that's my next big question. What is it that we can do to make TMS better? Right. So, but before we get to that, you know, is it then fair to say based on this mechanism of action that's very complex, but you so nicely described that TMS, contrary to maybe popular opinion, isn't zapping the brain. It's in fact teaching new patterns to the neural networks through synaptic plasticity. in a way to think about TMS is that we are looking at learning at a cellular level, isn't it?

Dr. Joshua Brown (29:45) Yes. Right. Yeah. Yeah. I think that, yeah, I think that that's, that's well put. And that's, and that's usually the way I describe it to patients is that we're, changing the strength of, ⁓ of neuronal connections in the brain that are important for, for normal health.

Dr. Adrian Preda (30:00) And then, know, going back to what you started to talk about, right, this very complex interplay and dynamic between the NMDA and ⁓ the Ampari receptors, actually that maybe creates opportunities for improving ⁓ on TMS efficacy. this brings me actually to my next question, right? What is it that we can do that we can then move TMS from being effective? Because it is, right? To making it maximally effective.

Dr. Joshua Brown (30:29) Yeah, it's a great question and kind of the, at the center, I would say of my own research and what a number of us in the field are working on. So ⁓ as I had kind of mentioned, alluded to, and thanks for ⁓ doing a kind of a recap and leading into this question. ⁓ You know, we had that, we wondered if TMS works through LTP. We thought that, ⁓ you know, Increasing an MDL receptor activity might be the best way to test this because it's the most specific way to test. There's a lot of things that we could block that would block the response, but ⁓ much more specific is to see if we could increase it in this way. So we saw an increase in ⁓ motor evoked potential plasticity. We look at it before, we do a TMS protocol with decyclocyrene on board and then versus placebo. And then we look at it after and Compared to placebo, we saw a higher increase in plasticity ⁓ after the TMS protocol with T-cycloserine than just with TMS and placebo. ⁓ so this was, I would say, ⁓ this was like the first idea that we could enhance TMS in this way. And then ⁓ my ⁓ colleague, Alex McGurr at the University of Calgary, he was the first to test this clinically and did the first clinical trial. published in 2022, showed a very strong effect. Response and remission rates were two to three times as high as they were with just TMS alone or TMS with placebo. And he replicated that with an open label. He also replicated it in OCD. So, you know, this suggests with, you know, my studies previously were with healthy human subjects. And then we have depressed subjects and OCD subjects. And in all of these, we see this increase. ⁓ And ⁓ he has some some new data that's not quite published yet, but in something that we don't see TMS benefits in just TMS by itself, fibromyalgia. ⁓ He tested it there to see if it would make a difference and it did not. ⁓ you know, it's I kind of we both sort of see that as an important negative control. ⁓ So it's not just this magic thing that you can throw at whatever like it's it's only when it's working in that way that that it's actually going to enhance. And I think that it's important. that we kind of see those, ⁓ know, those kind of understand what the limitations are of what something is, because, you know, there's nothing in existence, you know, even with some of the psychedelic kind of things that we are hearing good news about, you know, there's always limitations to what something can do.

Dr. Adrian Preda (33:12) On the d-cycloserian side, please correct me if my understanding is ⁓ not entirely accurate. So d-cycloserian ⁓ is actually a partial NMDA ⁓ agonist and coupling it with TMS. You can understand that as a way of priming the TMS effect on the synapse, meaning that improves the efficacy of TMS at the synaptic level, because we are coupling the action of the and MDA and paraceptives. Is that kind of a way to understand it?

Dr. Joshua Brown (33:47) Yeah, what it specifically does is decyclocerine binds the glycine ⁓ receptor binding site on the NMDA receptor subunit so that when you have that coincident detection that I talked about, this is, it doesn't, the decyclocerine doesn't open the NMDA receptor. You still have to have the normal synaptic event. That's where TMS comes in. You know, TMS, as I described, hits the axon, it causes this neurotransmitter release and when that's in sufficient quantity, that's going to... ⁓ activate AMPA, depolarize, open NMDA, and so forth. ⁓ D-cycloserine helps hold that open, the NMD receptor open, allowing more calcium to flood in, and that tilts the scale towards ⁓ activating kinases, which lead to AMPA receptor insertion. And so that's ⁓ what we see happening. We're, of course, in humans, not measuring directly LTP-like responses, but a colleague in Germany, in ⁓ Freiburg, They, Stefan Westring, they looked at ⁓ not TMS, but just de-cycloserian added to ⁓ traditional LTP-like protocols. And they found that in weaker LTP protocols, which we think TMS acts like, ⁓ that enhances that as well. And so, you know, that's consistent across.

Dr. Adrian Preda (35:02) So a way to make TMS more effective is through this mechanistic enhancement, boosting synaptic plasticity, right? Now you are also talking in your article about ⁓ an alternative way of improving efficacy, which I would describe maybe acceleration, increasing the treatment density, right? What about that option?

Dr. Joshua Brown (35:25) So yeah, earlier when we were talking about how TMS is done, people can drive in, they get a treatment, three to 20 minutes, then they drive home or drive back to work or whatever. ⁓ That's the traditional way, the conventional way of doing TMS. It's once daily. ⁓ It was started that way for historical reasons, ⁓ a lot of safety concerns early on before we knew really, come to find out we weren't even getting close, not even touching sort of what the upper limits are. We still don't quite know. what the upper limits are of safety of like, what is too much. ⁓ But ⁓ Nolan Williams, ⁓ who I don't know if you've heard, he actually died last month. ⁓ He ⁓ came up with this thinking of like pushing things further on that curve, like how much TMS can we give in a short period of time? And that led to the very well known Saint Protocol. ⁓ It stands for the Stanford Accelerated Intelligent Neuromodulation Therapy. And ⁓ this is 10 sessions in a day, every hour, and for five days. so this really showed that ⁓ we could deliver one, we could deliver a lot more stimulation safely than we previously had been doing. ⁓ The other that it showed us is When we give a lot of stimulation, so that's 50 sessions in one week. ⁓ and the responses they had were really strong responses. ⁓ you know, if you look in the publication, at one week and four weeks out, it's like 70 % response, 50 % remission. ⁓ that's pretty much right on pace of what it would be if you were to do 50 sessions spread out over 10 weeks, you know, once per day. ⁓ and so we kind of get this idea that we can. push this system quite a bit more than we are, whether it's daily or whether it's at once. we can either get there quickly or we can get there slowly. ⁓ There may occasionally be reasons to do either one, but in either way we see this movement in this direction. then some, you know, we actually had ⁓ to kind of get even more accelerated. There's this idea of combining decyclocerine with TMS with accelerated TMS and potentially pushing this even further. so we actually, ⁓ you know, kind of a, ⁓ well, I don't know if it's funny, but a story ⁓ is ⁓ we had started doing this one day. We wanted to test, you know, about the mechanism of Saint. And we also wanted to see if we could push this further. Something that we're ⁓ submitting ⁓ any day. ⁓ So it's not actually published yet, but we did a one day. one day of the same five days in the same kind of protocol. We added decycloserine or placebo and we started seeing some patients a year and a half ago or so. And then around that time ⁓ after we had maybe seen 10 or so go through and there was some reasonable responses. Like people were actually seeming to get a little bit better, a little bit more than I had expected. We were looking at biomarkers and things, but also clinical response. And then Jonathan Downer, ⁓ You know, we had conversed at the clinical TMS Society meeting and he was thinking also about adding D-cycloserine along with Vyvanse as another agent to enhance plasticity with 20 sessions in one day, although shorter sessions of 600 pulses of intermittent theta-verse instead of 1800. ⁓ So kind of in parallel where, you know, he starts doing that, we finish up our experiment and we saw no difference. between placebo and decyclocerin with our protocol when we ⁓ completed our study of 30 people. At the same time, Jonathan treated 30, a low 30 number ⁓ of patients in the clinic with this protocol and saw a really robust response, like 80, 90 % remission, like ⁓ out to like three months. So this really robust response. In the meantime, we weren't seeing a difference between them and a modest response. And, ⁓ you know, there's a lot to unpack there, but one of the things that is, ⁓ on the forefront of my mind is the protocol. So we use the 1800 pulses. think that that produces probably a, ⁓ you know, based on some motor evoke potential, ⁓ work that's been done before maybe a more robust plasticity. ⁓ if you induce. Well, actually the, the article that I had mentioned before from Stefan Vestring, when they added decyclocerine to, I mentioned the weak LTP protocol, they get an enhancement. Well, if they add it to a strong LTP protocol, there's an occlusion, like they don't get additional benefit from that. I suspect with our study that that's what we were seeing was, ⁓ that there was no, that's why we didn't see an enhancement from the decyclocerine. So we're, we're now testing a, ⁓ protocol more similar to what Jonathan had done. And yeah, that's. You know, there's an enormous amount of enthusiasm right now about that single day protocol. And, you know, we're testing that as well in another controlled trial, but ⁓ there's a number of people that I've heard, you know, that are doing this and seeing good results. ⁓ You know, I think that without any ⁓ controlled studies yet, it's not something that I would go out and recommend to people. You know, I think we need to know a little bit more first. But there are situations that we encounter in medicine where we don't have any other choices. And so we have to go with something that is relatively unproven. And I think that that's the scenario that Jonathan describes. that's what I think he advocates. that's kind of the only scenario I'd say that I would be comfortable myself ⁓ doing at this point.

Dr. Adrian Preda (41:30) It's very interesting and exciting. ⁓

Dr. Joshua Brown (41:33) So it's a fascinating future, yeah.

Dr. Adrian Preda (41:35) It is, it is. And these are very interesting developments that will closely follow. Which brings me to, there is so much that's happening. So it brings me to my next question, looking ahead, five to 10 years, what do expect is going to happen? What changes?

Dr. Joshua Brown (41:52) Yeah, that's an exciting question right now. I really think there's a number of different aspects that we talk about that I think in five years it's going to look a lot different. And maybe it ends up being 10 years for a lot of the stuff to come into fruition. I actually feel like sometimes I compare ⁓ TMS to like an automobile. I feel like from my perspective, we're sort of in that early phase of the automobile before things really kind of turned a corner, before they really started to manipulate the engines and we started to get into these, you know, the cars in the 50s and 60s and that kind of a thing. ⁓ I think that we're sort of in that transition phase where like it won't be too long before we're in a new generation of TMS. I think that that includes different indications. I mentioned, you know, some of the things that have a good amount of evidence now and I think that we'll likely get there. think that both in neurology and psychiatry, we'll see quite a bit and that'll bring more neurologists into the field as well. I think that we'll see a variety of different protocols, ⁓ including these very highly accelerated protocols. ⁓ Right now, insurance companies are just barely starting to cover ⁓ Saint or Saint-like protocols where it's accelerated until like one week. ⁓ As insurance companies start to cover that more, we start to see more naturalistic data and outcomes. We start to see more ⁓ experimentation with that and other indications. And so I think that this starts to quickly spread. We're also getting an idea of how to target differently ⁓ through things like lesion network mapping and basically being able to take lesions mapped onto the human connectome and then identify targets. ⁓ That's worked by Sean Sediki and ⁓ and Mike Fox and his group. you know, there's ⁓ a lot of different directions, the mechanisms that we're starting to better understand and how to implement those using D-cycloserine as one agent and one receptor out of a number that could have a significant impact. So there's a lot more to explore in that regard. ⁓ D-cycloserine with this recent attention is getting a lot like it's been hard to acquire for everyone. that's I think that's going to change pretty quickly. so, you know, it's a, funny story is when, ⁓ we first saw our results that we could enhance motor plasticity with Decyclo-Serine, ⁓ a mentor of mine, Greg Salem, ⁓ he, you know, was, ⁓ on the manuscript and we were kind of talking about the data and he's like, who knows, maybe we'll end up giving Decyclo-Serine to everyone getting TMS. And at the time it was such a funny ludicrous thought, cause like no one had any idea, like no one had ever heard of Decyclo-Serine and you know, it's now so many people in the field have, heard of it. And, ⁓ you know, he may end up proving prophetic in that regard, because it really does seem to enhance if TMS works on something, it seems to, to be able to enhance that effect. ⁓ so I think that we'll see improvements in that. think that we'll see optimizations of, ⁓ parameters that the, you know, with, have a number of different parameters we have to select to create a protocol for TMS. So I think we'll see that, as well. ⁓ Yeah, so I see a lot of movement in the next five years especially and you know, I think even in the next 10 years and then you know, maybe we'll kind of kind of reach a new plateau again before ⁓ before we hit the you know, the version electric car version or something like that, you know the ⁓ the new or modern application so

Dr. Adrian Preda (45:32) Josh, final takeaways, one core message.

Dr. Joshua Brown (45:37) One core message, you think that part of that would depend on the audience. ⁓ I think my core message probably comes down to what you asked about earlier, you know, for folks that are ⁓ out of residency for a while, they haven't had a chance to be trained in this area. I think Seeking out and learning and understanding. That's I think that's part of what drew all of us to medicine is in a you know, that's why we didn't You know do something that required less education that could have been more direct and easier is like we like to learn we like to understand and so and so doing that and searching out the evidence for TMS ⁓ and for for anything ⁓ You know, I think that that's something that will help all of us become the best clinicians that we can and I think that we have ⁓ I think that we have a, we get more joy, I think, out of what we do when we ⁓ search and seek after knowledge like that. ⁓ And, you know, maybe I'll add one more kind of core message, ⁓ and that's kind of in the spirit of Nolan ⁓ and his recent passing is that, you know, all of us are trying our best, we're working really hard, we're doing all these things, and I think it's really critical that we Also make sure that we're taking time to do those things that make life the most meaningful, the most enjoyable, slowing down and identifying those things that are most important to us to kind of keep us grounded. ⁓ it's very easy to kind of sort of drift from those core things that ground us. And so I would say, ⁓ I gave you two things, one more career oriented and one more life oriented. So that would be my core message.

Dr. Adrian Preda (47:31) great core message. And I think throughout all of this, ⁓ the other core message that you emphasized is that TMS is not a niche therapy, right? It is a really a foundational treatment option. And we are only at the beginning of what it can do. ⁓ And probably for the clinicians out there and for other people who might be listening to this podcast, it sounds like we have Really, the evidence is in that could lead to a recommendation to start a conversation about TMS early, let our patients know that TMS is not zapping intrusive, something that's going to have negative consequences, but it is actually well tolerated evidence-based option. Really not a resort. It should be considered much earlier in our treatment.

Dr. Joshua Brown (48:28) Yeah, absolutely. Yeah. No, think you ⁓ gave me a great core message. You did it for me, ⁓ which is it really shouldn't be a last resort. mean, my perspective on this is I think it's reasonable to start. Sometimes people ask like, should we just start with TMS? I'm like, well, if you live by a TMS center or something, then maybe, or if you can kind of get accelerated TMS, but with ⁓ medications, it's just so easy. Reasonable to go home, you know, we know that you know a good number of people will remit from depression as just one example of disorders With the first two medications and then if they don't after two medications, you know, you know three months in or ⁓ four months in whatever then yeah that good then I think it's time to turn to TMS because it's it's like why why wait until you've exhausted all the opportunities to go to something that's safe and most effective you know, there's no reason to kind of put someone through that and, and with the safety factor, there's no, you know, there's no downside to doing that earlier. So I do think it's reasonable to start with medications, one or two, and then, you know, and then if they're not getting better than I would go to TMS, that would be my, my overall take home.

Dr. Adrian Preda (49:39) Josh, thank you for this insightful discussion and also for your leadership in advancing the science of neuromodulation. And to our listeners, you can read the full special report in the latest issue of Psychiatric News. We have posted the link below. Please subscribe, rate, review, and share this episode. Josh, thank you so much. Appreciate you being on the podcast.

Dr. Joshua Brown (49:48) hydrants, glitter. It's my pleasure. Thank you so much for having me.

Dr. Adrian Preda (50:07) It's my pleasure. I'm Dr. Adrian Breda. Thank you for listening. We'll see you again next month. Until then, stay informed, stay compassionate, and take care.

Dr. Joshua Brown (50:18) you