In this episode, we talk to Dr. Nolan Williams about repetitive transcranial magnetic stimulation (rTMS) for depression and finding treatment options for people who want or need to be treated quickly.
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Dr. Williams is an Assistant Professor within the Department of Psychiatry and Behavioral Sciences and the Director of the Stanford Brain Stimulation Lab. Dr. Williams has a broad background in clinical neuroscience and is triple board-certified in general neurology, general psychiatry, as well as behavioral neurology & neuropsychiatry. In addition, he has specific training and clinical expertise in the development of brain stimulation methodologies under Mark George, MD. Themes of his work include (a) examining the use of spaced learning theory in the application of neurostimulation techniques, (b) development and mechanistic understanding of rapid-acting antidepressants, and (c) identifying objective biomarkers that predict neuromodulation responses in treatment-resistant neuropsychiatric conditions. He has published papers in high impact peer-reviewed journals including Brain, American Journal of Psychiatry, and the Proceedings of the National Academy of Science. Results from his studies have gained widespread attention in journals such as Science and New England Journal of Medicine Journal Watch as well as in the popular press and have been featured in various news sources including Time, Smithsonian, and Newsweek. Dr. Williams received two NARSAD Young Investigator Awards in 2016 and 2018 along with the 2019 Gerald R. Klerman Award. Dr. Williams received the National Institute of Mental Health Biobehavioral Research Award for Innovative New Scientists in 2020.
Social Media Handle: NolanRyWilliams
Publications: https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2021.20101429
Memorable Moments:
4:17 I've been very focused on specifically trying to help develop rapid acting interventions with you know, with a lot of a lot of work in the, in the kind of emergence emerging psychedelic space with some, you know, with with drugs like Ibogaine and ketamine being explored in the lab. And that's, that's part of it. And those studies are definitely important in trying to understand the mechanism of those drugs and trying to understand what we can use those drugs for. Where we've been very focused is using and kind of engineering a rapid acting form of for repetitive transcranial magnetic stimulation.
5:47 So we've been very focused on trying to develop rTMS and kind of re-engineer rTMS into an approach that allows for us to treat people over a very short period of time.
7:25 The idea there is this is a way of treating rapidly by rearranging the stimulation in space, and time and dose.
13:25 The highest risk of completed suicide is in the period right after psychiatric hospital discharge. [That's] rate of the whole lifetime. So we were very interested in that particular population, because we wanted to be able to treat people in these high emergency settings.
22:42 To me, the problem of really getting TMS in particular out there has been an educational problem.
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Allison Walsh: Hello and welcome to the dear mind, do you matter podcast? My name is Allison Walsh. I'm a longtime mental health advocate and vice president at Advanced Recovery Systems. On each episode I will be joined by my colleague and clinical expert, Dr. Angela Phillips. This show along with our mental health and wellness app, Nobu are just some of the ways we're working to provide you with actionable tips and tools to take really good care of yourself each and every day. So sit back, relax and grab your favorite note taking device, it's time to fill your mind with things that matter.
Angela: Dr. Nolan Williams is an assistant professor within the Department of Psychiatry and Behavioral Sciences and the director of the Stanford brain stimulation lab. Dr. Williams has a broad background in clinical neuroscience and is triple board certified in general neurology, General Psychiatry, as well as behavioral neurology and neuro psychiatry. In addition, he has specific training and clinical expertise in the development of brain stimulation methodologies under Mark George MD. The themes of his work include examining the use of space learning theory and the application of neuro stimulation techniques, development and mechanistic understanding of rapid acting antidepressants, and identifying objective biomarkers that predict neuromodulation responses and treatment resistant neuro psychiatric conditions. He has published papers and high impact peer reviewed journals including brain, the American Journal of Psychiatry, and the Proceedings of the National Academy of Science. Results from his studies have gained widespread attention in journals such as science and New England Journal of Medicine, journal watch as well as the popular press and have been featured in various news sources including time Smithsonian and Newsweek. Dr. Williams received two NARSAD Young Investigator awards in 2016 and 2018. Along with the 2019 Gerald R. clairement award, Dr. Williams received the National Institute of Mental Health bio Behavioral Research Award for innovative new scientists in 2020. And I have had the great opportunity of working with Dr. Williams at Stanford. He was such a great mentor to me. I am so excited to have him on the podcast today. Welcome, Dr. Williams.
Allison: All right. Well, Nolan, thank you so much for being on the show today. Would you mind introducing yourself to our audience?
Dr. Nolan: Yeah, absolutely. Normally, so I'm assistant professor of psychiatry at Stanford University, and the director of the brain stimulation Lab at Stanford. And yeah, basically, somebody who's very interested in and developing new biological treatments for neuropsychiatric conditions.
Angela: Well, Nolan, you know, I'm super excited that you're here, because you and I have had the chance to work together. And it's was such a joy for me to work with you and be able to do so much within your lab at Stanford. So, again, just super stoked, you took some time to talk to us today. And I'm really excited also, because I know that a lot of our listeners just may not be aware of a lot of the work that you do that the type of treatment that you offer. And this was really the first opportunity, I've really had to bite my tongue over the last 20, some episodes to not talk about it. And to be able to wait for you to be here as our expert, to talk a little bit more about the types of treatment that you really specialize in. And of course, what we work together on what they're used to treat and the kind of results that you've seen. And so to kind of tease that apart a little bit, can you really just talk first about the types of treatment that you you work within, in the field of psychiatry and kind of where that intersects with what you're doing on a daily basis.
Dr. Nolan: Absolutely. So thanks, Angela. And Angela is one of my favorite postdocs through the years and really appreciated her approach to things and, and we had a great time working together for a couple of years at Stanford. So yeah, so I you know, I've been very focused on specifically on trying to help develop rapid acting interventions with you know, with a lot of a lot of work in the, in the kind of emergence emerging psychedelic space with some, you know, with with drugs like Ibogaine and ketamine being explored in the lab. And that's, that's part of it. And those studies are definitely important in trying to understand the mechanism of those drugs and trying to understand what we can use those drugs for. where we've been, you know, very focused is using and kind of engineering a rapid acting form of for repetitive transcranial magnetic stimulation and so our TMS is an approach that has been around for some time. The TMS device itself has been around since the mid 80s. Our TMS is a treatment has been around since the mid 90s is an experimental tool, and FDA approved in 2008. But it doesn't work rapidly, it takes, you know, weeks and weeks to work almost two months to work. And so it's not really a treatment for, for folks that want to be treated quickly, all the way out to, you know, psychiatric emergencies. So we've been very focused on trying to develop our TMS and kind of re engineer our TMS into an approach that allows for us to treat people over a very short period of time. And so the idea there is that you can stimulate in the old way of doing it kind of once a day, using kind of inefficient forms of our TMS. And, you know, get people well, but it's an incredibly inefficient process. Or you can utilize stimulation approaches that are much more in line with the, with the mammalian biology with the way our brains kind of signal. And we can do that in very short periods of time. And that's just by rearranging the stimulation pulses in time, right? And so instead of giving, you know, 90,000, rTMS pulses over six weeks, can you rearrange those pulses in time, so that you can give that over five, five days, and that's really the idea behind what we called, initially called St, or Stanford accelerated intelligent neuromodulation therapy, you know, that it was a good damn name, you know, kind of similar to the football team, I got some feedback, that, that maybe, maybe not the greatest name, so we kind of abbreviated s&t to, to kind of deal with some of that. So you'll see it referred to in the in, you know, in papers, and in the late presses, both st and s and t. But, you know, the idea there is, is this is a way of treating rapidly by rearranging the stimulation in, in space, and time and dose. So the dose, the I'm sorry, the time bit already talked about using signals from the mammalian brain could playing the back in the space bit is this idea that, that not everybody's brain is the same and rTMS was, was kind of historically applied in the same skill spot and everybody, but if that same skill spot wasn't in the same position is the, the brain spot that we were trying to stimulate? For everybody. So you, you can control for one or the other, you can go in the same skill spot, you can go in the same brain spot, but you can't go on the same skull and brain spot for everybody. And so the old studies, they utilize the same spot on the skull, you know, so based off of tape measure measurements, we didn't say, Okay, we're gonna, we're not gonna go to the same spot in the skull, we're gonna go to the same spot in the brain. And then we're going to stimulate that same brain circuitry in the brain circuitry that we focused on, is based off of, you know, what I will explain as kind of an over simplified idea, it's certainly more complex than this, but just for, for folks kind of getting into this, you know, there's two main brain areas that we think about, with with this targeting approach, one of them is, is thought to be down in depression, one of them is thought to be kind of up in depression, you know, down meaning low activity, meaning high activity. And the area that has kind of low activity is an area called the left dorsolateral prefrontal cortex. Interestingly, if you have somebody who's who's going through psychotherapy, and it's effective, that left dorsolateral prefrontal cortex engages in the psychotherapeutic process, right, just to kind of tie it to other things. That effective psychotherapy kind of engages that system. The other area called the sub genuinely anterior cingulate is an area that comes online is really active in depression. And when depression is better, that area goes down. And so we found a way to target the TMS coil. So it would get into the part of the left dorsolateral prefrontal cortex that most effectively shut down that that hyper active area and then we figured out a way to give you know a six week course of it or my database every single day. So we were able to compress seven and a half months of our TMS into five days with, you know, with this stimulation approach and effectively treat people and in a few days, and that's, that's the big thing that that Angela worked with me on, I was very lucky to have her as part of that. And in a big focus the lab kind of in the past and going forward trying to really get that done.
Angela: Yeah, and for context there too. And I know Allison and others, you know, when when I first sort of, was exposed to TMS, I was working in a clinic. And as Nolan mentioned, it's like, we're treating people for four months at a time and seeing great improvement by the end of that time period. But I'm sitting here thinking, you know, as a, as a therapist and clinician that's working with someone, you know, some people responding at different rates, but just, there's got to be a way to get this done more quickly, and more effectively. And why is it working in this person and not this person. And so the more I connected with Nolan and others at the lab, it was very clear that, you know, there was a really strong connection there with what he was trying to do. And that's really what kind of what brought me to be able to work with him in the lab. And so I think just it's so fascinating to see. And it's been so great to see how far that's come. And so Nolan, you mentioned, depression, and you know, what, what you're essentially treating there, can you describe, you know, what the sort of ideal candidate for this type of treatment is? And kind of the, the results that you've seen?
Dr. Nolan: Yeah, absolutely. So, you know, we were struck with this problem within psychiatry, where as you as you kind of, you know, escalate acuity. Normally, in the rest of medicine, you escalate the number of tests and treatments, right. So if I'm having chest pain, and I go into the primary care, doctor's office, maybe they have an aspirin, they can give me or whatever, but they're not gonna be able to do much more than that you go into the emergency room, there are more tests and treatments, you go into the ICU having a heart attack, there are more tests and treatments. In psychiatry, as we escalate acuity, we there are no tests, as far as biological tests and the treatments. While there is kind of enhanced psychotherapy within an inpatient stays there, there is no kind of an you know, there's no increase in the number of biological treatments, on average, in an inpatient stay. Now, some people come back at that statement, say, Well, what about AECT. But if you, if you look at AECT, only 10% of us psychiatric hospitals have it. So on average, if you're going to the psych hospital, you're in a psych hospital that doesn't have it, you don't, you don't have access to all these other entities that may be able to give you UCT. So if you're an outpatient, and you're in 90%, of the US psychiatric hospitals, you you actually lose access to EC t. So an average people have less access to EC T on an inpatient Ward than they do walking around, not on the inpatient ward. And, you know, there's no rTMS, there's no, there's no, no real other rapid acting drugs or anything like that are consistently in those settings. And so you know, and that's coupled with the statistic that the highest risk of completed suicide is in the period, right after psychiatric hospital discharge rate of the whole lifetime. So we were very interested in that particular population, because we wanted to be able to treat people in these high emergency settings. You know, the reality is, we've tried this in the high emergency settings, we've tried it in, in more of an ambulatory kind of clinic setting. And it worked quite well in both of those settings. And we're really looking for people that are, you know, treatment resistant depression. So folks who have failed at least one oral antidepressant medication for depression, you know, and what, you know, in some circumstances, folks, maybe had a suicide attempt, and they only tried one med sort of thing, and they're quite severe. You know, that makes a lot of sense for somebody like that, you know, where folks have tried more medications and their outpatient, they're not in that emergency setting. And so it's that whole range, but basically folks who are trying to get out of that depressive episode and get kind of get back to their lives. It's important. You know, I've seen people who've gotten our TMS and then I'm sure you have to Angela, you've gotten our TMS and they started it in the clinic and they're, they're about to lose their job. And they end up losing their job and week one or two of the TMS course and then they remit it week six, you know, and if they would have, if they could have done the TMS faster, maybe they didn't lose their job, you know, and so it's that that crew of folks too, and so, you know, we're just trying to we're trying to put a rapid acting approach out there. that can really work for folks. And then really, you know, really try to have another option for people.
Allison: ARS University is the perfect go to resource for anyone looking to learn more about mental health, addiction and other related topics, the on demand library offers a wealth of engaging and informative content that can help you gain a deeper understanding of these complex subjects. With ARS University, you'll have everything you need to empower yourself with knowledge and support to learn more, go to www dot Ars university.com. Think it's so important that there are other options, right? As you've already mentioned, some things are gonna work for some people, others are not. But I know this one in particular, this treatment has to be done in person. Right. And so how is this impacted during COVID? What did you see?
Dr. Nolan: Yeah, I mean, so all of its in the, in the realm of studies still. And, you know, Stanford, to their credit, has both been very careful, but also kind of came up with a way of dealing with COVID, that once they came up with it, then they haven't really deviated from the plan. So they were able to put together like a fully, you know, very careful, you know, plan and then and then and then there hasn't really been much in the way of bumps on that plan, which is that folks are you know, all the treaters are wearing full garb full, you know, 90 fives and gay in gowns and all that stuff on the treater end, and then all the patients have masks. And, you know, that's really, that's really been helpful, that's really allowed for us to keep treating people in studies through the whole COVID. You know, times and you know, we're, obviously, at least, you know, knock on wood, it seems like we're in a lull now, and things are going well, but we still keep those same safety parameters up. And we're trying to keep the ball rolling to get these trials done as fast as we can. So, you know, we can have as much evidence out there as we can to get this FDA approved and paid for and all that good stuff.
Angela: Yeah, and just kind of prior to hop in on the pod here today, you had already mentioned, you know, so much of what you're continuing to do, being sort of still still online, still following a lot of safety protocol, things like that. But one thing I'm curious about, in your opinion, is like, where do you see technology kind of fitting in with psychiatry and mental health? As we move forward? I know, obviously, COVID kind of pushed that in different directions. But has that changed? In your mind? Or? Yeah, just where do you see that going?
Dr. Nolan: You're saying like technology generally, and how it interfaces? Yeah. So the, you know, you may have heard me say this before, but you know, I see psychiatry in kind of three epochs, or three eras, right? You got the first era, which is kind of that Freudian era of like, traditional psychoanalytic, you know, psychotherapy, right. And, in psychiatry, one point out, right, and so in psychiatry, 1.0 You could have eight, eight patients, you're seeing them every day. And, you know, and, you know, you can have a patient's total. And so the problem with with psychiatry, 1.0 is it's absolutely not scalable, unless 1/8 of the world's population wants to be a mental health professionals, right, that would be that would be what would need to happen to scale psychiatry. 1.0 and, you know, maybe, maybe that would be a good thing, I don't know, but it's certainly not going to happen, you know, we'd have 1/8 of the world's population, you know, being mental health professionals. And so, I don't, I don't believe that, you know, that that particular flavor of things would not just be scalable, it's kind of historical at this point, psychiatry, 2.0 which I'd argue we're in the tail end of is traditional oral antidepressants, like the ones that you take every day like Prozac. And the psychiatrist sees the person for 30 minutes, every month, right? And so if you're talking about an eight hour day 30 Managing see 16 patients a day, times 20 You're talking about 320 patients in your roster that you could see that you could be their doctor if you do pyramid management sorts of things. Also, not that not particularly that scalable, right, which is why you know, as you guys know, a lot of the medication prescriptions for folks with with you know, mild to moderate depression anxiety of coming from primary care doctors, you know, we're there's just like so many more of those guys to be able to do it. So it's not scalable for for In the, in the general sense of having an actual mental health professional, involved psychiatry 3.0, which I would argue is the kind of era, the circuit, you know, and the era of technology in the era of like, you know, how do we how do we really kind of scale this? You know, I went to Japan and visited a TMS center in Japan, one time was the largest TMS center in the world. It's 70 chairs, 35 techs, five psychologists, to psychiatrists, to psychiatrists would, you know, one would be there the other you know, it was really one psychiatrist at a time. And you're talking about treating seven zero people at the same time, right? And with with a lot of the like, the mental health apps and that sort of thing. It's the same, you know, or better sort of scale. Right. David Spiegel, is a Stanford has developed this hypnosis app, right? How many? How many people can David Spiegel kind of, in some sense treat and I think that's, that's going to be where technology really gets us there and really can actually fulfill the needs that that folks have, you know, given the large prevalence of mental illness, you know, in the population, we're never going to be able to, in my view, we're never going to be able to kind of solve it with psychiatry, 1.0, psychiatry, 2.0 sorts of solutions, just because of the scaling. That'll be the those things are kind of reserved at this point, for folks that have more resources in psychiatry, 3.0, you know, has the potential, you know, with all these technologies to really scale it. And that's why I think it's going to happen, you know, is because we're going to actually be able to treat everybody that needs treatment.
Angela: Yeah, and what, what an exciting time, and just position to be in as someone who's a huge part of that. And also, I will say in a slight pivot is, you know, the other half of the TMS power couple, which is you. So, you know, I was gonna bring this up. So, I'm just curious, though, you know, as one of our last questions to you, what's it like to have a partner in the same field that's growing like this? And you're both really heavily involved? What's that like, for you, Nolan?
Dr. Nolan: Oh, it's great. I'm super proud of her. I mean, I think that, you know, what we do is, is important and, you know, trying to try to kind of get new therapeutic approaches, but a bigger part of the problem, I think, and really, the, to me the problem of really getting TMS in particular, out, there has been an educational problem, right? This idea that, that you've really got to be able to not only just educate the people that you think you're educating, like the students and residents and fellows and all that, but actually also doing the work of educating folks who are in senior positions, and obviously, with a whole lot of political navigation in doing so to really be compelling to say, look, like, I know that you've grown up in psychiatry, 1.0 and psychiatry, 2.0. And that you're very, you know, you're very comfortable, and even maybe attached to those ideas, you know, but, but that doesn't mean that, that this these things are mutually exclusive. Right. Like, I mean, you know, and I was said this earlier, I was careful to say, this is the area of the circuit, we know, drugs affect the circuit, we know, we know, you know, therapy affects brain circuitry. And so the idea that, that you can believe all of that and believe that, that focal neuromodulation can affect brain circuits and improve mental illness, which is, you know, is kind of a is not, you know, the same lens of looking at the problem in many ways in in somebody as talented as Christian to be able to get in there and in work that and really get that done at the local level with Stanford, but also in her kind of national engagements to do that, you know, is great, and I'm super, you know, I'm super happy every day, you know, to have a partner that's, that's, you know, on that mission. And so it's been, it's been awesome.
Allison: Well, it sounds like it's been amazing, and there's probably so much amazing work to come that you guys are going to tackle together and continue to be pioneers in this space. And we're just really glad to spend some time with you today. But we'd love to ask every guest that comes on our show, at this point in your life. What matters to you most right now.
Dr. Nolan: Yeah, it's a great question. I mean, I think that I'm in I'll be 40 in June. And you know, that's that's obviously you know, made had some had some effect on my thinking about things is I was talking to you about earlier. I have A two year old, also having affected my thinking, and I've really, you know, I've, I've been, I've spent a lot of time from my early 30s, until now really pushing the envelope hard and burning the candle at both ends, just trying to get, you know, get this, get the lab bill and get these technologies out there. And I've been, you know, I've been kind of transitioning into, into being, you know, what I would say is like a mid career mentor vibe of thinking about thinking about really, you know, and I've always had that focus, but really, really even more thing, focusing on growing folks. And, and also focusing on on the family thing, and I think, really trying to, you know, balance have have more of this kind of hybridized work life balance than I that I may have had the last few years. And so that's been a big focus of mine, but you know, also important to kind of get, get this technology fully out there. And luckily, we've been able to have success with a startup spinning out of Stanford with some of the folks that I've worked with, over the years, taking leadership roles in, you know, within that startup and, and being able to, you know, to kind of push the push the envelope further. And so trying to try to support that, and ways that I can and, and be there for that too. So I can kind of see, see all the all the kind of kids of mine in different ways kind of grow, right. And so that's, that's the width, I've seen it.
Angela: That's amazing. And yeah, I've appreciated kind of being around in the background during a lot of the transition, too. And it's been, it's actually been really nice to see, as I've been able to work with you Nolan in the past, and just kind of that that shift to and when you feel that coming from a mentor and that sort of balance that you do speak to, I think like, we know that that's important. But when we're in those positions where, you know, obviously the position that you've been, it's really nice to see that emulated and people that you look towards. So that's just something I know that's made a huge impact on me. So thank you for that. Yeah. And so Nolan, thank you so much for joining us today. Really appreciate you taking the time, can you share with our listeners, how they can find you follow you or just reach out?
Dr. Nolan: Yeah, absolutely. Thank you. Yeah. So I have a Twitter account that I've kind of been stumbling through use effectively, you know, so it's my first name, Nolan Ry Williams. So the first two letters of my middle name and why that was I don't even remember when I started his Twitter account. But it is what it is. So at Nolan, Ry Williams, and then the brain stimulation Lab website is bsl.stanford.edu. And that's going to have all of our ongoing studies. And in the kind of interface portal if folks are interested in in kind of touching base with with the lab if you're interested in finding out about treatments for yourself or for loved ones, and also has a lot of the lay lay media press on on some of the papers that have come out and the papers themselves. So if folks are wanting to look into this a little bit more, that would be a good, good source. Yeah. Awesome.
Allison: Excellent. Well, thank you so much for being on the show today. We really appreciate you spending some time with us.
Dr. Nolan: Yeah. Thanks for having me.
Angela: Thanks, Nolan. Thank you so much for listening to today's episode. If you're not already subscribed, we hope you join us regularly and please leave us a five star review wherever you get your podcasts. We hope that this podcast is beneficial to you and your wellness journey. Dear mind you matter is brought to you by Nobu, a new mental health and wellness app. You can download it today using the link in our show notes will talk to you next time and until then remember, you and your mind matter