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The Mental Health Forecast explores cutting-edge developments shaping the future of mental healthcare. Each episode features conversations with researchers and innovators about emerging therapies, technologies, and approaches to emotional wellbeing. From AI-powered therapy tools to advances in neuroscience, we examine how these changes might transform mental health treatment. Join us as we investigate what's on the horizon and discover how tomorrow's solutions could help address today's mental health challenges.
Arjun Nanda (00:01)
Okay, welcome back to the Mental Health Forecast where I interview awesome people building and innovating at the forefront of mental health innovation. I'm your host, Dr. Arjun Nanda. This conversation is with Dr. Noah Phillip, who is a professor of psychiatry and human behavior at Alpert Medical School of Brown University and section chief for psychiatric neuromodulation at the VA Providence and Center for Neurorestoration and Neurotechnology.
We talked about his path into neuromodulation, about transcranial magnetic stimulation or TMS, and a very cool way to mix TMS and virtual reality to treat veterans with PTSD. Enjoy.
Arjun Nanda (00:50)
All right, well, thanks so much for joining me, Dr. Philip. Very excited to have you on the podcast. Wonderful. So, you know, I wanted to bring you on, you know, I reached out to you after looking at one of the papers that you published in JAMA Psychiatry about virtual reality and TDCS and, you know, just taking a look at your profile, you've
Noah S Philip MD (00:56)
Delighted to be here and delighted to be asked.
Arjun Nanda (01:17)
really involved in neuromodulation for many years. And would love to pick your brain on what, first of all, brought you to study neuromodulation and all those years
Noah S Philip MD (01:30)
Yeah, so it's a great question and I really appreciate it. So I've been doing this now for some time and I think much like many of these stories often go, there is a little bit of happenstance and a little bit of luck. So when I was in residency, so transcranial magnetic simulation was a thing that was sort of about to come
So TMS, clinical TMS, really came to the fore really in late 2008, 2009 with its FDA clearance. And then in 2012 is when it really accelerated. That was when the Centers for Medicare and Medicaid updated its coverage to include TMS. And so, you know, I graduated in 09. And so,
I was there to see these things starting to evolve and got to see its early use and early implementation and its early promise. Right after residency, I did a fairly standard, if you will, inpatient psychiatry job for a couple of years and really enjoyed that, but was also struck by how people were not responding to standard treatments.
and really wanted to do better. And one of the things I will say that I was very struck by was the number of individuals who were treated and retreated unsuccessfully, but had a mounting burden of side effects over time from the pharmacology, and also at times from the psychotherapy, depending on what they were doing. And so I was really interested in finding something that would have a more benign side effect profile.
and transcranial magnetic stimulation because it's using energy. It's not, you're not taking pills. There's really an absence of systemic side effects. And so I found, know, as a physician, a physician early in practice, I found that to be really appealing. And that's really the origin of this, of seeing these things going on. There's lots of other intersectional elements in terms of being with and working with individuals with different
expertise and but it all comes back to sort of asking the question, well we want to help our patients. We want to help them feel better, we want to give them some symptom relief, we want to help them get them back to their lives and at the same time do it in a way that really does not cause a lot of
Arjun Nanda (04:04)
Right.
Noah S Philip MD (04:05)
The other thing, and actually maybe if you'll permit me just to add on to it a little bit more, the other thing that I find very appealing is that we're using what we understand about the brain to come up with a new treatment or find a new way to help people. And I do feel that that's sort of, it's a rational sort of precision design that I do find particularly enjoyable.
Arjun Nanda (04:28)
That seems like a common thread. People really getting frustrated with some of the pharmacological treatments that we use in daily practice and frustration that there are better alternatives that we can do if we really apply the science. You mentioned that you've been there for the evolution. I'd be curious to see what sort of evolution you've noticed over throughout your career.
Noah S Philip MD (04:44)
Yep.
Yeah. Yeah. So when transcranial magnetic simulation came out, I mean, guess the first question was, it do anything? And there was a lot of skepticism around that. The early studies of TMS often were in individuals who were medication -free, which was not a standard of care. Most people are not medication -free when they're being treated. The effect sizes were modest.
in the very beginning and there wasn't I would say enormous difference. I mean there were clear differences between active and sham stimulation, so real stimulation and placebo stimulation, but they weren't sort of unbelievably life -shatteringly enormous. And so that generated a lot of I would say early skepticism about this, how this, you know, whether or not it worked or it didn't work. You know, I was always
I mean, I've always been a realist and so I never really expected something to be much, much better. We very rarely see things in psychiatric research where there's enormous, enormous, enormous effect sizes. So I was, but I was simply happy to see that we could get people better without the systemic side effects of the pharmacology. You know, the early treatments in the way that we did TMS, it was actually really neat. in the first study, I was not involved in
But in the early studies, so people were medication free, and then at the end of their trial, actually were added, medications were added in. And what the field saw in sort of in the taper phase of that original study was that people actually continued to get quite a bit better. And so it sort of raised in my mind this really interesting question of, well, maybe if we did this in real life, right, if we did stimulation plus medication, maybe it would really help people. And that's
One of the first studies, and this was with one of my key mentors, Dr. Linda Carpenter, who's at Butler Hospital and also here at Brown University. She was the first author on the first naturalistic study of transcranial magnetic simulation for depression. So the first application of TMS in the real world, and she found that it worked. It provided quite a large degree of symptom reduction for treatment resistant individuals. And I think that
That was when I certainly started to believe it. was once we moved out of the rarefied patient populations, again, get into randomized clinical trials, it was into real world settings where I actually believed the data. And I would say that observation, and even in my own research, I conduct randomized clinical trials of brain stimulation, but I generally don't even believe my own data until I have been following my patients for some time.
my prior participants and then they would be patients because they're not in trial anymore and see how they do. And so then that, you know, seeing how these things kind of work in the real life in real world settings has been something I've gotten to watch over the years. You asked about the evolution of TMS. So the other thing that's been really neat to watch is there's been an evolution in the ways that we do
And so in the early days, it was something called a five centimeter rule to target. So they'd find the motor cortex, we'd go up, if you will, towards the forehead, about five centimeters, that's where the coil would be placed. Then many more things have been added in over time. There were adjustments to that. There was individual scalp -based landmarks. There's been neuro navigation. There's now functional targeting. And seeing all these different things, different...
sort of ideas of how can we use our neuroscience tool again to get people better. It's really exciting. And certainly when I put myself back in the seat of a resident or someone in training and asking, what is all this fancy neuroscience guess? The answer is, gets our patients better. And that's really, really cool to see. And then there've been all sorts of really neat evolutions in the ways that the devices can deliver the stimulation really
decade now. Sort of second generation approaches to transcranial magnetic simulation, so -called theta burst simulation, now accelerated TMS, and this is a, you know, in a short period of time, just an enormous amount of change, and I think it's, I'm really grateful that I can be here for a part of the field where there's just this enormous change in a very short period of time. We should be so lucky in all our careers that we can see just like so much change.
not just in the entirety of our career, but in a very, very short period of time and have it be relevant to getting our patients better.
Arjun Nanda (09:33)
Right. Yeah. It's a, it's a pretty incredible time, in psychiatry. We've been waiting for this for a long time.
Noah S Philip MD (09:39)
Yeah, I would say I have a lot more hope for patients now than I did when I was in training, which is a really nice thing to have. I think it's, and I hope that the trainees of now can share in that. My fear is that, you know, it's part of my reference and that, you know, I was around at a different era not that long ago. But I do hope that our trainees get an idea of the hope that we have now that we did not have previously.
Arjun Nanda (10:06)
Right, right. Do you mind speaking to a little bit about these different forms of TMS or you mentioned the accelerated TMS and theta burst, so.
Noah S Philip MD (10:17)
Yeah,
so let me start with a basic quote unquote vanilla, right? So that's 10 hertz stimulation. So the stimulation is 10 times per second over the left dorsal lateral prefrontal cortex. And then it stimulates for four seconds, and then it's off for 26 seconds, and then on again for a total of 3 ,000 pulses. That's sort of the standard single session and done once per
And an enormous amount of work came into coming up with these numbers, be it the frequency of the use or the inter -train interval, that 26 seconds, right? That was really carefully derived so that it could be done safely and not have a risk of someone having a seizure. so that's sort of where we started. And then there were all sorts of other interesting questions that we could start to ask, like, well, maybe could we do things a little bit more
Could we maintain the safety with a shorter interstimulus interval? So then there was some work done saying that we could bring the intertrain interval down to like 11 seconds. And that actually allowed us to deliver like stimulation in 20 minutes instead of 37 and a half minutes, which actually allows us to treat, you know, if you have a single chair allows you to treat, you know, more than one person per hour, which allows some larger volume, which is great for access.
I would say, you know, the other major milestone that we had was the introduction of theta -burst stimulation. This was something that came up from one of the laboratories over in England. And it really was a pattern designed to mimic intrinsic hippocampal rhythms, of an oscillatory 5 -hertz rhythm, with the hope that stimulation could entrain, enhance, or inhibit.
And the thing about that is it delivers its 50 Hertz, it's a 50 Hertz stimulation done at a 5 Hertz sort of almost carrier frequency, if you will. So it's theta burst, the theta is the 5 Hertz. But regardless of the physiology, regardless of what it's hoping or attempting to do,
What it does allow us to do is deliver an enormous amount of stimulation in a very short period of time. So for example, in three minutes, you can get what seems to now be a dose equivalent of 20 minutes to 37 and half minutes. And that all of sudden allows us to start thinking creatively about its application. And I would say of the things that have
really have the field leapt forward. mean, one is the introduction of TMS in the first place and showing that it works. The second was showing that we could use theta burst stimulation in a clinical way that was at least non -inferior to the other things that we had been doing. And three minutes per stimulation, three minutes per session allows us to do things we wouldn't otherwise do. And so for example, we did a study.
using theta burst stimulation, slightly different protocol actually, nine and a half minute protocol, you know, for post traumatic stress disorder. And aside from showing that it worked and it improved people's lives and things like that, other, it also, it allowed us to do a number of things that actually never made it into the paper. So at the time, you know, we were having a lot of construction at our local hospital here. So there wasn't a lot of parking spots.
And so what we actually did was we didn't give appointments for that study. We told people, if you show up, we'll stimulate you as long as you don't mind waiting maybe 10 or 20 minutes because we had other people coming in. And so it wasn't quite drive -through TMS, but it was pretty close. And because of this technical innovation, because of this ability to deliver large amounts of stimulation in short period of time,
Arjun Nanda (14:06)
Mm.
Noah S Philip MD (14:20)
you know, we could do things that again, increase the access to the stimulation in ways that are not immediately measurable in our randomized clinical trials or in our journal articles. And I would say just to continue the thought for a moment, you know, now if you can do large amounts of STEM in short periods of time, then you have to ask the question, well, why not just do lots and lots and lots of
And that introduces the idea of accelerated TMS, which briefly, sort of speaking, is using large quantities of stimulation in a short period of time with the idea and the hope that we can get people better faster. And there's a lot of questions about, is it better? Is it worse? How long is it going to last? Is that any other? But I think that the mere fact of matter is, we can do the equivalent of several months of stimulation in a week. And that, again, allows us to
dose exposure in a safe way. And as you've heard several times now, right, get people better faster. And that's ultimately what this is about, which is really, really neat.
Arjun Nanda (15:25)
Right. That's incredible. mean, being able to pack that much stimulation in such a amount of time is, would be a blessing. can imagine for a lot of people don't simply have the time or the ability or the downward trajectory of their functioning to be able to get them get back on track.
Noah S Philip MD (15:44)
Yeah. Yeah.
Yeah. I mean, one of the major limitations to getting transcranial magnetic stimulation, there's sort of two. One is if it's in the private sector, it's insurance. has to go through all sorts of levels of appeal and things like that in the United States, which is unfortunate, but that's the state of medicine. And the other thing is that standard TMS is once a day for 30 sessions over six weeks. And, you know, coming into a hospital
clinic to a doctor's office every day over a long period of time, you know, a large number of people in our society just simply cannot do that. They have homemaking responsibilities, they have childcare responsibilities, they have work responsibilities, they have elder care responsibilities, or they have jobs that just don't let people take time
And so that's been a real barrier. And I always used to say to patients when I would give them, sort of do a neuromodulation consultation with them, and I'd say, this is what we can do, and this is what I think is going to work, and this and the other. And then we'll get to the end of this, hey, hey, dog, this sounds great. But I just, can't. I can't come in for this much. It's just not physically possible. You know, I've got to eat. I've got to work. And so to have an option now where I...
can and do, offer admittedly an off -label course of accelerated TMS. But a course of accelerated TMS that is a week, most people can take a week off as long as they have enough lead time to do so, work or with other things. It really is a nice model and it really does change the access question.
Arjun Nanda (17:26)
Right. In the spirit of access, what are the sort of challenges that you see for making interventional psychiatry or for accelerated TMS more accessible to a broader patient population?
Noah S Philip MD (17:44)
Yeah, so it's a great question and I appreciate it. I'm going to keep it just in the range of brain stimulation because I think, so interventional psychiatry is an interesting term and it, so it has started to include more or less everything that's not meds and therapy, but it does include some meds, but not others. And so I'm going to just for the sake of our discussion, keep it just within brain stimulation. I don't want to go too far into the ketamine, ascetabine, et cetera.
or psychedelic space. So with the more accelerated approaches, we have seen the interventions get more intensive, bring higher degrees of technology, and ultimately become significantly more expensive in the individual components. So in the Stanford
neuromod therapy or SAINT, right? So that's 10 times per day with a functional targeting. Functional targeting requires an fMRI scan, requires specialized pre -processing and send it through the cloud or to here or to there. And there's a lot of steps in there
And so my fear, same thing too, even if you're gonna do a you need a device that can do quite a bit more, right? That can cool much more aggressively if you're gonna do five times a day, seven times a day, 10 times a day. And those devices are more expensive. They can be more expensive, not always necessarily. They start out more expensive. And so every time you add more dollars into the delivery of care,
you can start making it more exclusive. And so that is, you know, we're coming to a challenge. shouldn't say coming to a challenge. One of the things it's our duty to think about, you know, as medical providers and ethical researchers is that what can we, is making sure that people, everybody, regardless of income, regardless of skin color, regardless of background, you know, can access the things that we're doing.
I think all of us can be appropriately uncomfortable if only those with large amounts of disposable income are able to access the best new treatments. That's fundamentally problematic. And so there is a tension there right now in the field.
My hope and my expectation is that we use large numbers of different neuroscience tools that are extremely expensive. We use those to sort of figure out what we need to do and then we gradually sort of withdraw all the really expensive elements and that leaves us with something less expensive that we can then do. I'll draw your attention to actually this really lovely small paper from Harold Sackheim who's one of sort of
fathers of ECT and TMS just published in Brain Stimulation, using a very pragmatic accelerated course of TMS. something that you could do with the regular, standard, old, boring devices that you buy on the street. You're not going to buy this on the street, you from a representative. And so I think that's the sort of example of we can come in with enormous amounts of neuroscience -based tools.
and then establish that something works to some degree, kind of figure out kind what the core components are, and then ask ourselves how can we do this more cheaply, how can we do this in a way that is more accessible.
Arjun Nanda (21:23)
All right. Fascinating. Yeah.
Noah S Philip MD (21:24)
This is, by the way, this is not unique to psychiatry, right? I mean, this is the
same conversation you have in surgery or in other interventional procedure -based things where stuff just gets read up expensive, very fast.
Arjun Nanda (21:36)
Right,
right. And then over with time, things become cheaper and more accessible for everybody.
Noah S Philip MD (21:43)
Yeah, yeah, but that doesn't happen like automatically, right? That's sort of, that is on us as researchers to make sure that we are not just pushing the envelope in terms of discovery, but making sure that we're pushing the envelope in terms of accessibility.
Arjun Nanda (22:00)
Right, With regards to virtual reality, I'm superficially familiar with Skip Rizzo's work that he used to do with, or that he does with virtual reality and PTSD and veterans. So I wanted to get, pick your brain a little bit on that, where you're using virtual reality and where you see that going in the future.
Noah S Philip MD (22:21)
Yeah, so this is a great story over about 10 years of our use of virtual reality. we, and again, it comes down to some fundamental ideas, which is how can we help people knowing the things that we know about neuroscience and about the brain. And so we originally, myself and Masha Van Woodfrank,
I've been working with, she's an associate professor here at Brown, and I've been working with her for very, long time. And so she's a behavioral, like experimental biology sort of background, whereas mine's much more clinical. And so I said, all right, so we want to help individuals with PTSD. And she said, all right, and we can do this. And there's a couple of different sort of tools and things, but.
What's the fundamental neuroscience problem that happens when people have post -traumatic stress disorder? And you can think about PTSD as an illness related to memory and sort of disordered memory and disordered fear. So people taking military veterans as an example, you might go overseas, they have to learn that a particular context is dangerous. There are things that can kill them.
and they need to recognize that these elements are dangerous. And that's a highly adaptive learning process and our brains are really good at doing that kind of stuff. The challenge is what they do is when they come home, they come to a different context that is somewhat similar. There are a lot of things that are similar. They have to realize that this somewhat similar thing is no longer dangerous. In that process we call extinction.
And we have to generate new memories knowing that these new things are safe and the process of generating these safety memories helps, if you will, of suppress these others' fear memories or at least sort of fights back against them at a neural level. And individuals with PTSD can't do that. So they still feel like they're in their old context. They're still reacting as if they're in their own context, even though they're somewhere new. And so...
What we were, and that process is, so that extinction process requires the ventromedial prefrontal cortex. That's the part of the brain that has to be working in order for that process to happen. That's the part of the brain that needs to be working when people go through successful exposure therapy for PTSD, cognitive processing therapy for PTSD, and otherwise. And so we asked ourselves, how can we modulate
that part of the brain. And we're going to get back to the virtual reality part in just a sec, but just bear with me on the story. And we couldn't use TMS to hit that part of the brain. TMS can't reach there. It's not yet. And so we had to look for a different thing. And this is transcranial direct current simulation, which is a low level neuromodulatory intervention. That was fine, except the problem is that that low level neuromodulatory intervention doesn't actually make neurons depolarize. And so what we had to do is we had to think of a way to induce a context.
where we knew that people's brains would be actively engaged, depolarizing, in a particular context, and that's where we got to virtual reality. So I said, how can we sort of make a simulated environment that is similar enough that we're trying to enhance that process? And really the only thing that you can kind of come up with is virtual reality, right? How can we put people where they otherwise can't go, shouldn't go? And so that created a lot of excitement between the two of us.
And then we spent the better part of a decade putting together brain stimulation and virtual reality to create sort of a program where we could help people with PTSD.
Arjun Nanda (26:10)
And that's pretty incredible use of both of those technologies together. And with regards to the virtual reality simulation, was this a single simulation that was applied? I imagine a single simulation that was applied for all study participants.
Noah S Philip MD (26:28)
Yeah, so we agonize over this exact question for a while. So this is based on Skip Rizzo's work. And we ultimately decided that we wanted to give everybody the same thing to minimize sort of variability. This is going to be a clinical trial. We're going to be launching. And so actually we chose a driving scenario that was, and this is going to be in military veterans. So we chose a driving scenario that was a common experience across all branches of the military.
all kinds of PTSD, all kinds of not PTSD, but a common experiential phenomenon. And then what we did was a first sort of a pilot study where we actually, we did this where we came up with a protocol, roughly the sort of a driving protocol repeated a few times. And then that experience repeated three times a week for two weeks with some stimulation and sham to see what would
And we showed in a pilot study that when we, mean, everyone's symptoms got a little bit better, even with a virtual reality. Virtual reality exposure is something that can be used as a standalone treatment. But what we found was that people who got real stimulation as opposed to sham got quite a bit, they got better over time. And also their bodies told us that they were getting better. They had less of a sort of a fight or flight reaction during the virtual reality. And that...
pilot work then prompted us to launch a much larger randomized controlled trial, which was the one that was published in JAMA Psychiatry.
Arjun Nanda (28:01)
Right. I can see in the future things being even more personalized for each person, maybe in a more clinical context, less so in a study because it won't be all the same, perhaps a sort of generated world for each patient.
Noah S Philip MD (28:15)
Yeah, I mean, so maybe, and it's an interesting thing to think about, the provocative counterpoint would be that some people probably don't want it to be matching their own individual experience all that much, because that's hard to tolerate. Some degree of distance from the trauma sometimes is appreciated by our patients. So we don't know whether or not a personalized approach would be better.
Or could be worse. We actually had a remarkably small number of people get worse in this study, which is, that's unusual. You always see some folks who get worse without any intervention. We really didn't see that here. I can only speculate why, but my thoughts are that part of it is actually we had a, we put the brain in the context so it could be stimulated in learning and things like that, but we didn't actually sort of put them into their own individual.
Arjun Nanda (28:50)
Hmm. Hmm.
Noah S Philip MD (29:11)
trauma very aggressively. But we don't know. And I think it's a great question. I think people who are going into these kinds of fields right now, this is exactly the sort of question that we need to be asking. So where do we need to bring the precision? What matters? What matters less? And what can we leverage and what can we do?
Arjun Nanda (29:28)
Right, right. The feature is very bright and a lot of questions. I feel like every time something like this comes out, there's more questions that need to be asked, which is a beautiful place.
Noah S Philip MD (29:40)
Yeah. The one thing I want to add, just one of which is not, it's accepted for publication so I can talk about it, is that we actually, we took the, we took these 50 people who went through our study of stimulation plus virtual reality. And actually I followed them in the medical record for the next year. So they're not part of a trial. And what we found was that those people who got the active stimulation compared to the sham, they, they did, they were much better over
So they, and not just better in terms of clinical rating scales, that's actually not what I looked at at all. What we looked at actually was measures of sort of a function of so -called relapse. So the people who were in the active group, actually they went to the emergency room less, they used less like inpatient hospitalizations, they had less suicide attempts. you know, so, and that was in the year after they got their, you know, after they got their intervention. So,
We are definitely moving the needle here. It does give you an idea of how these things could be deployed clinically in future, which is
Arjun Nanda (30:43)
I'd love to ask you a final question, just looking now towards the future. Where do you see the role of neuromodulation in the next five to 10 years and sort of advancements that you're looking
Noah S Philip MD (30:47)
Sure, please.
Yeah. So I think the first thing I want to say, and again, I want to be a little provocative, is that I think we should be using them much earlier in our treatment algorithms. I think we should not be waiting for people to be having failed a zillion meds in order to start doing this kind of stuff. I really think we should be doing this almost at the get -go. Maybe try an SSRI once, but if you have a single SSRI failure, I
go there or even before that. I mean, there are patient populations, both in the young and the old, for whom adding meds is not always a great idea for a lot of reasons. And so I would love to see it moved much earlier in the treatment algorithm. I should say, by the way, TMS is currently cleared for the use of resistant major depression when you failed one antidepressant. But if you actually look at who gets it, that's not reality. Like almost nobody gets it when they've only failed one. It's always like six or seven or 12 different med trials.
So, getting it earlier. And then the other question will be how can we not just get people well, but how can we keep them well once we do so, and can we do better? If you look at the response and remission rates, just talk about TMS for depression, actually even TMS for PTSD or Neuromod for PTSD, the outcomes do look like they keep getting better over time. I think that has to do with the familiarity of the use and different ways of using it.
We also need to make sure, I'd like to imagine a world where we can get someone better with neuromodulation in an acute series or an acute setting, and then use that to boost them over time. Not maintenance treatment, but actually doing it in a way where we understand their trajectory and help keep them well before they deteriorate. I don't think we're too far from that. I don't think we're too
Arjun Nanda (32:48)
It's fascinating stuff. you know, thank you for all of the work that you've been doing, you know, with bringing more research to this topic and really pushing the field forward and ultimately helping patients get better, which is what this is all about. So thank you so much for doing that and for joining this podcast. It's been a real pleasure having you on
Noah S Philip MD (33:12)
That's great. And again, thank you very much for the invitation. I really do, really do appreciate