Good morning, Dr. Malesburg.
Good morning. How's it going?
It's all right. I was surprised today to find out that the schedule for this, which is off of our usual day, was actually three hours earlier than I expected. This is my punishment for being a West Coast man.
Well, you made it. We're happy to have you here.
I don't know about that. Who do we have today as a guest?
Well, yeah, today I'm excited to introduce Dr. Owen Muir, probably the person on the most forefront of psychiatric advancements, huge ambassador for TMS, probably the person working hardest to transform the future of mental health care, focusing on interventional brain medicine. With his wife, Dr. McMillan, he is the founder of Fermata Health in Brooklyn, shows a little bit of his musical background. There he offers a range of cutting-edge treatments that we're going to be talking about today, hopefully, including advanced TMS protocols, non-invasive vagus nerve stimulator, prism neurofeedback, external trigeminal nerve stimulation, and Spravato.
He works with a bunch of different companies involved in AI, medical devices, screening tools, and biomarkers. uh compared to the rest of the field it really feels like he's like five to ten years in the future beyond his clinical work he also writes an awesome blog called frontier psychiatrists where he shares humorous insights and updates on the latest
in the field all right sounds like it's gonna be a banger this is the psychopharm podcast let's jump in
this podcast i want it to be as if someone had no clue what tms was they could still walk away and feel like they had an idea um so i kind of just want to start with you know foundational questions so to get started for someone who's never heard of tms what is it how does it work what does it look like can we start even
earlier like how does the brain talk to itself and then tms will make more sense
question mark perfect absolutely would love to hear that okay so
Arthur Sackler, the kind of scion of the Sackler family, was a psychiatrist. In fact, most of the Sacklers, and you've heard of Purdue Pharma, et cetera, who did bad things when it comes to the opiate crisis. That was mostly his sons, Richard, David, et cetera. But they were all psychiatrists. And Arthur is the person who created, at least according to me, modern drug advertising. He actually worked his way through medical school as a copywriter for a medical advertising firm, a company he would later go on to buy.
But he wanted to change the field too. And one of the ways he wanted to change the field is he wanted to have a language that doctors could talk about mental health problems and that would be appealing to doctors. He was a good psychiatrist for psychiatrists. He knew what we wanted.
Advertising for psychiatrists, that's very interesting.
Well, I mean, it was, and for other doctors as well. It used to be, you know, prior to the creation of the FDA, which is in the 60s, Drug companies would make a drug, they'd send it to doctors, and the doctors would just have to figure out how to use it. I would say, here's Adderall, figure it out.
Wow.
Tell us what this does for your patients. There was no indication for use. There was no regulation around marketing of drugs or other treatments. It was physicians being very trusted, and perhaps too much so, to do what they thought was best for their patients. And in order to get a drug to the world, you had to convince a doctor there was a reason to use it. So the story that drug companies decided to tell, mostly thanks to Arthur Sackler's influence, was that there are chemical imbalances in the brain, which is a story that makes a ton of sense if you're selling a chemical.
Yeah, very controversial these days. But of course, you know, we all need little ways of organizing how we believe things. A good one at the time, I would say.
I mean, the four humors work.
Yeah, that's right. And, you know, there's still some basis there. I mean, I kind of believe in that. But that's a different podcast.
So these explanatory models have power. And all models are wrong, but some are useful. The real story, at least as I understand it in the brain, is that chemicals are a last mile problem. And they're solving for only the littlest bit of communication between neurons. And so most of the communication between the neurons in the brain actually happens within those neurons. There are these very long axons.
You have a cell body, which is basically a calculator, adding up fire and don't fire signals coming in from other neurons, creating some math around that using voltage, and then if they get to a threshold, they fire. A neuron firing means an electrical signal is conducted down a very relatively long path, And then at the very end of that, what we call an axon, there's an axon terminal, and it will release neurotransmitter that floats chemically across a very, very tiny, tiny, tiny gap and binds to the other side.
And so although it's true, you can put chemicals in the blood that will get into the brain to some degree and influence that transmission from neuron to neuron, most of the actual, like, distance is over the wires that are axons. Mm-hmm. And so transcranial magnetic stimulation, or TMS, takes advantage of the interaction between magnetism and electricity and changing magnetic fields from physics to when you took it studying for the MCAT, or at least I did, changing magnetic fields at a right angle to an electrical wire, which the axons in your brain functionally are, can create an electrical current.
And so TMS, transcranial, okay, going across the cranium into the brain, harmlessly. Magnetic, using magnetism. Stimulation is basically an external pacemaker for your feelings. And so our brain talks to itself by using rhythms. If you've ever heard a polyrhythm, three against four, if you're a musician, that's actually how the brain works. It's using these patterns of rhythms to get in sync with itself. And it's actually a really elegant system.
If you think of a band, they're not like handing each other notes about going to the next chord in four, three, two, one. We even have to count it down to get it right. When you see two people dancing, they like didn't have an elaborate plan beforehand on when they were going to step to the left, to the left, to the left. They did it with rhythms.
And they did it with synchronizing those rhythms by kind of firing in sync or at least in relation to the rhythms in the other part of the brain. And so TMS uses changing magnetic fields to induce current in a rhythm. And that rhythm helps sync up the brain with itself. Does that work for you?
I love your explanation there. It's probably the most poetic and elegant one I've heard of TMS. And I like it a lot. If you don't mind, I'm going to steal that.
Please, all day long.
For my use in the future. I thought I'd just add to it, you know, for those of you out there listening who don't have too much personal familiarity with TMS, I can recall in training, one of the ways to make sure you've oriented the machine, I don't know if this is still how it's done, but back then, to orient the machine to the right part of the brain, we'd have it fire so that it would trigger your trigger finger.
So make your hand twitch directly. Is that right, Dr. Mary? They still do that?
A hundred percent. Yeah. We use the stimulating the motor cortex and it's like hitting a reflex hammer on your brain.
Right. Yes. So, you know, it's quite mechanical. And, you know, I do like the explanation and the treatment, which, you know, is a lot, I hope that sounds less scary. I think it is less scary for many patients. But to me, you can get a little creative and say it supports that we're beings of rhythm and light.
And I mean, keep in mind, changing magnetic fields is what light is, right? This is literal energy healing.
That's right.
So, I mean, the backstory, like turning an idea, you can make a brain neuron fire into a treatment required a tremendous amount of work from scientists. So, you know, this was invented in the 1980s in the UK, but turning it into a treatment for neuropsychiatric illness was done at MUSC through the relentless work of Dr. Mark George. And so he took early work on this, what it could do in the motor cortex, which is cool because we can see it, right?
You fire it on the motor cortex. It makes your thumb move or your foot move or wherever it is, depending where you put it. But wait, could that be a treatment for another problem? And so Mark George said, sure, let's move it forward to the left front of the brain where prior research had suggested it could be helpful in modulating mood. And, you know, a decade of science later, we have a treatment for major depressive disorder, now also obsessive compulsive disorder, now also smoking cessation all approved or cleared by the FDA, some de novo approval, some clearance.
And this morning I published an article on a meta-analysis or a review of a meta-analysis on its use in anorexia nervosa, where it seems to be quite promising, bipolar disorder, etc. This is a way to change the brain, but it helps to remember that there's a brain to be changed. And all the things that it's doing are jacking into basic things the brain can already do. So if you wonder what therapy is, it's neuromodulation using your eyes and ears.
And when the person talks to you and smiles or frowns or says something important, your brain is also its own stimulator in creating those same patterns in your brain that can re-sync it with itself. Literally everything that we interact with in our world is neuromodulating our brains, and we're doing the same to others. We're creating patterns in the minds of those in our lives. And so when we say, I felt so in sync on that date, it was literally true.
Nice. Now, you know, I'm a novice with TMS. I've heard also some psychiatrists describe or theorize serotonin-based pathways or mechanisms downstream to the modulation aspect. Do you put stock in that yourself? Is that a remnant of the chemical imbalance in your transmitter simplification of the brain? What do you think?
I think we got really sold hard on serotonin. I'll give you my best. I mean, like, look, it matters, right? Like those neurons can't connect to each other without that synaptic cleft. But these are remarkably complex systems evolving for hundreds of millions of years. And I do think there was a serotonin receptor, a gene duplication event about 300 million years ago in the Cambrian explosion, right around the time we got jawed bony fish.
And I do think that event in evolution was one of the events that let our ancestors evolve so rapidly. Because essentially, I suspect, and this is mostly work from Adam Safran at Hopkins, but that gene duplication event kind of overclocked our ability to regulate our sensory system and and and so later in post-production we'll be adjusting the gain on this recording right and that matters a lot and it matters so much that if it's too quiet we can't hear it and if it's too loud it won't make any sense if it's too compressed there won't be any amplitudes the ability to modulate amplitude of the same information can profoundly change our experience of it.
And that's what that gene duplication event did, at least from my understanding, to our sensory system. And that let cool stuff happen. Like, have you seen fish swimming in a school? Yeah. How do they do that? That's amazing.
It turns out- Right. As if they're single cells in a large organism.
Yeah.
Yeah, right. And so what happened, and I think the serotonin system was crucial in the evolution of this, is we built the ability to synchronize with each other by building models of other organisms in our environment, in our own brains.
Mm-hmm.
And so our ability to synchronize with each other, which started when we were fish, persists to this day. And it's worth remembering we're kind of running on fish hardware. Now,
I hate to hijack any structured structure that we have, but there's something that always stuck out to me about TMS. And I've always wondered, to what degree can we attribute the treatment response? I really don't believe this anymore, but this is something I thought of before. You have a tech sitting with you. The patient, that is, for quite a long period of time, several times a week, I believe, still.
Couldn't that be part of the treatment? Have we done studies to remove that aspect?
Yes. Yeah, actually. So there are a couple, actually. So great question. You're asking, like, does paying more attention to someone, is that the treatment effect? Is that why they got it? And there's a reason we have placebo controlled trials, right? Because it turns out paying attention to somebody is powerful healing because we can synchronize with each other. Hmm. So there are a couple of studies that do this.
So I'll give you the data that convinced me at least. So first off, you'd want to compare whether the placebo effect of someone handing you a pill in a drug study was more or less powerful than sitting with someone during a TMS treatment. And it turns out we've done that. There's a really nice paper that looked at just the placebo groups in TMS treatment and other instrumentation trials.
Overwhelmingly, it was TMS and drug trials. So we just looked at fake pill versus sham stimulation. And we saw which was a more potent placebo. And it turns out sham drug has an effect size of 3%. And sham TMS has an effect size of 72. Wow. So just being handed a placebo pill is a more potent placebo than sham TMS, at least in those different populations.
I would not have expected that.
Very interesting. Also, we've got a robot now. So there is a thing called the cobot that is a robotic TMS machine arm. So there's no one sitting with you whatsoever. And it turns out TMS still works when a robot does it.
Okay.
Yeah.
Very good.
So it's actually less powerful than you'd think. And I think part of that has to do with the populations. Most TMS studies are looking at treatment resistant depression, AKA it's a more refractory population who are less likely to respond to placebo. Yeah. But like, heaven forbid, a nice person makes it go better.
Yeah.
Now the opposite is true for a second. The opposite is true in OCD or close to it. It's nice if they're nice, but it's more important if they're provoking the obsession or compulsion that the person turning on that OCD circuit. And so we instruct our technicians to provide stimulation to the person that turns on their OCD so that when the pulse hits, it's creating more recruitment and more neurons per pulse.
So we get a better response. Yeah.
Can you talk about what a typical TMS treatment looks like for a patient? What's the spiel that you guys give in the intro room for explaining what it's going to look like?
And so again, when we say TMS, we'll remember that it's like saying medicine, right? There are a bunch of different medicines. And so for transcranial magnetic stimulation or TMS, we have about 7 trillion parameters, like where we put it, what pattern of stimulation. But kind of broadly, you're going to come into an office or in the future, it's going to come near home. You're going to have a motor threshold measured, generally, at least in the beginning, and we're going to map your brain.
So we're going to move the coil, which is either a paddle or a helmet or some other orientation of thing. We're going to move it around in your head to find the spot where it makes your thumb move or your foot or whatever we're targeting. And then we're going to elicit a response, and once we've found exactly the right place, which is the most robust response, we've mapped the motor cortex.
And then we will reduce the dose, and usually we'll do, you know, 3 out of 6 is the minimum response, and we'll decrease the power. So your thumb will move 6 times out of 6. four times out of six, and then three times out of six, and then at a certain power, it'll be less than half the time. We call that the motor threshold, the minimum dosage to make your thumb move at half of the pulses we deliver.
And that's the energy we're going to use. We then move the coil to the treatment position. Now this can vary depending on the indication or the protocol, but historically we used a tape measure, which I don't know is the absolute best way to do it. And in fact, Dr. Robin Cash has answered that question, I think, meaningfully by comparing this. You know, in depression, we have this in the left front of the brain, which is the first place we started doing this.
There is a functional connectivity target we could use called the anti-correlated region with the subgenual cingulate, which that gets pretty brain sciency. But essentially, it's just the right spot to turn on the off switch for your depression. And what Dr. Cash did to validate that was he said, okay, well, what happens if you stimulated someplace that either was or wasn't that spot? How close to that spot matters?
And so he used a bunch of clinical trial data where we had the targeting from a brain scan, but we used a tape measure target to deliver the treatment. And so some of the targets were right on that subgenual spot. or the anti-subgenual spot, and others were not. And essentially, the amount it mattered was about 30%. And so getting to just the right spot for depression matters, it turns out there are other depression circuits as well.
I would argue Sean Siddiqui has done a tremendous amount to advance this particular part of the science at Harvard. And Dr. Siddiqui's work has looked at this brain imaging where we're looking at kind of a movie of how the brain talks to itself in real time to generate a target. And then we stimulate that target um specifically many tms centers will just use a tape measure some will use a coil in a helmet that's so broad it's basically the whole the brain part of the brain in the front like you put your entire like hand on the top of your forehead and it's like that much area like 75 cubic centimeters of your brain all at once and so we're engaging large areas of these brain networks exciting area you know i gotta
say my favorite area the frontier Frontier psychiatrists. Frontier psychiatry.
That's me.
Yeah, exactly. Risk-benefit, I like it. It seems like most of the adverse effect may be simply cost and time as opposed to some of the things that people are a little more excited about these days. Comparatively, maybe psychedelics. I'm a little worried about those, but we'll see about it for another time.
So, I mean, if you want to say that for another time, we can. I actually wrote the entire April issue of the American Journal of Therapeutics on psychedelic medicine. Like nine articles on LSD, Ibogaine, MDMA, DMT, ayahuasca, blah, blah, blah.
It's a great...
It's a great little write-up for primary care doctors. We tried to make it really readable. But yeah, the adverse effect profile is important to understand. And to the best of our knowledge, we have seizure as a severe adverse effect extremely rarely. It's about 100 times less likely than from any given drug, and it would happen in your office. So literally, Prozac does give people seizures at a rate 100 times that of TMS.
But since TMS is happening in your office... Well, we see it and so we know it's our fault. Um, there are, there are other extremely rare adverse effects like, uh, ringing in the ears or tinnitus, which we have to walk out, watch out for. Um, there is, we've seen recently and haven't published this yet, but, uh, discoordination that's time limited. So like missing the button when you're texting somebody and that lasted for about a month in somebody.
And, and, you know, the person is a health professional and a very reliable reporter. Um, And so we were really curious about that. And so at least on a few occasions that's happened. But we're changing brain networks. Another side effect, and this is strange to say, is improve cognition.
And that's not good for anyone.
Well, I'm, I'm a little shocked that TMS hasn't been used for essentially brain doping for athletes because like there's no trace of it. Like they do all sorts of stuff in competitive sports to get even a tiny edge. And I, I strongly suspect this would do it, but it just hasn't caught on yet.
Oh, God.
I mean, I'm not the right guy for that. I treat disorders, but I'm happy. I'm sure somebody will do it for, performance improvement. It's just not the time I have in my day.
Now, on the topic of adverse effects, is there anything in the data to suggest any worsening or cycling for bipolar disorders? I haven't seen it in my clinical population of people who have been sent for treatment with TMS, but from you, what do you think? Anything that we're seeing?
So bipolar disorder is a really important illness for anyone to understand who's either a psychiatrist or at least interested in the field because it tests a lot of our assumptions and forces us to think. And the short version is we don't have reliable signal from any of our clinical trials that says the TMS causes mania.
Great.
We literally don't. That having been said, people with bipolar disorder get mania sometimes.
Mm-hmm.
And maybe that happens in your chair, and maybe your chair and stimulation did it, or maybe it didn't. But when we're randomizing people, we don't see that. And some of that may be the people who can consent to a randomized control trial are different from the people who are in clinical practice. We're not doing as many studies on the treatment of acute mania as I would like.
And so we don't know the answer, but we don't have a conclusive. Yes, it does it. And we don't have a conclusive. No, it doesn't.
Right. Right. Do you exclude them, people in mania or people diagnosed with bipolar disorder in your clinical practice? I believe some people do that. No.
I will often choose a different target. And again, working with Dr. Siddiqui, I have the ability to select anti-mania targets if I need to, but I tend to be a bit more cautious. And so the best advice I can give to anyone using even just kind of traditional left left of front of the brain, left DLPFC treatment for bipolar disorder is when the person's better stop. In depression, in depression, we tend to keep going to get a more durable effect.
But we take the foot off the gas in bipolar disorder treatment more often.
Sorry, I want to change the conversation a little bit. I think a lot of our listeners are going to have no picture of what TMS looks like. So can you describe what the patient experience is of TMS? Are they just putting magnets on their head? Is it uncomfortable? And then how often are they coming in to do the treatment? Yeah.
So the second part is a longer answer. The first part's easier. Any given TMS treatment, there's going to be a machine There's a device and that device is gonna go on your head. What it looks like is either a helmet or a paddle or something, right? It's a stimulator and there are different designs there. I wouldn't worry too much about that. It's going to feel like, first off, a little bit of a ball peen hammer tapping on your baseball helmet.
So if you imagine putting on a baseball helmet and then someone whacking it with a hammer lightly, that's what it's gonna feel like when we're doing that mapping of the motor cortex. The stimulation itself depends on your motor threshold. So we measure the dosage to give you. And generally we increase it gradually for tolerability because in the beginning, if we just started at full power, it might hurt.
And so we start where it's annoying, but not frankly painful. And your brain edits out the pain experience as the treatment goes on. Traditionally, we did 36 treatments. We did one a day. That's an intersession interval of 24 hours. And my argument is that's not the best intersession interval. And it should probably be something shorter, like, for example, 30 minutes or 50 minutes or something. And so in my career, I focused on accelerating the treatment.
So doing 5, 10, 20 treatments in a day. Yesterday, I literally did 40 as part of a clinical trial in one day. And it appears to be that we can do that both safely and effectively. And thanks to the work of Jonathan Downer, Nolan Williams, David Carey, and to a limited degree myself, we've seen that stacking those treatments has a beneficial effect in terms of both getting it over with, which matters for people, especially people who are working.
Oh, yeah.
um, fitting it into your life and getting a better response. And so people are remitting with accelerated TMS, having no signs or symptoms of disease, uh, when they got no response to once daily TMS, many places still do it once a day. I don't think that's the future because I think most people would like to get it over with. So when you're coming in, And it feels like an angry woodpecker banging on your baseball helmet.
And it's not fun. I don't have to worry about anyone abusing it because it's so fun. But it's anywhere between, you know, 160 seconds and 45 minutes. That's the range of time a treatment will take.
So for patients, how often are they coming in? Like, let's say, you know, I'm starting on a Monday. What should be my expectations for how often I'm coming in, how long the treatment is, and when will I start to feel better?
So if you're coming into my office, you're going to get it all over within a day or five days or something like that on average. In most places, you're going to get it over within 36 days.
It's a barrier for a lot of people, unfortunately.
Yeah. And I never thought, A, I don't think it works as well. And the data supports that assumption. And I think you have a greater chance of remission if you use this accelerated approach. But insurance doesn't pay for it yet.
It's a shame.
It's both a shame and a call to action, everybody. Mm-hmm. But part of this has to do with what we call a medically unlikely edit that CMS pushes out that got changed last year, thanks to Dr. McMillan, who full disclosure is my wife, who works with the American Medical Association and CMS on working on making these code sets make more sense for clinical practice. But now you can do two a day under Medicare and most payers as opposed to just one a day.
And anyone who wants to do that, I'd recommend space it out by 50 minutes or so and keep looking at the data to see what is going to make the most sense over time. But you can't do them like back to back and not lose something.
And you guys talk about how the spacing makes a difference. Did you use like Anki cards in med school or was that after your, probably was after your time?
Oh, no, we used those, yeah.
Yeah, it seems like it's using the similar principle in terms of there are certain intervals that most cement learning.
It's exactly the same. It's space learning theory that's behind the Anki cards and space learning theory that's behind the TMS treatment intervals, yes.
So, yeah, what have you seen with regards to the different spacing and how effective it's been?
So, again, this is the kind of thing where Jonathan Downer is the scientist from Toronto who we have the most to kind of thank for this. So there was a series of really carefully done trials. And they did one where they said, okay, we're going to use this intermittent theta burst pattern, which in his 3D trial was less non-inferior to 45-minute high-frequency treatment. So it's 600 pulses in three minutes, just as good as 45 minutes of 10 hertz.
Okay, and now what happens? Well, what if happens if you put 600 and 600 right next to each other, so 1,200, versus doing 600 space out by an hour, 600? Same number of pulses, but different spacing. Which is better? And what Dr. Downer discovered was that 600 space, 600, better. Wow, that's cool. Okay, so what should the best time interval be? And he just completed and published, or at least in preprint, the 1D trial for one day.
And you're doing 20 treatments with pre-treatment with a drug called D-cycloserine, which is a pro-plastinogen agent, like making your brain more able to change, along with Vyvanse, both of which work. Uh, and you put those things together in the morning and you give someone 20 treatments spaced out by 30 minutes, 90% of people are under remission after that treatment.
Interesting. So you're trying to make the brain as plastic as possible.
That was the approach in that study. Yeah. Without any, any drugs at all, the, the, the saint trial and, and, uh, other, other papers on that topic on accelerated TMS, uh, use 10 stimulations in a day and did it over five days in a row. And we're getting remission in 79% of people at the end of a month. Um, 60, 60% are in remission. Their depression is over at the end of day five.
And like, Wait, what? My depression can just be over? Uh-huh. Yeah, that is actually the most likely outcome. It's incredible. There's nothing not incredible. I joke that people choose medical specialties based on the bodily fluid they don't mind, so surgeons don't mind blood, urologists don't mind pee, and psychiatrists don't mind tears. But I'm really a smile junkie. I'm just really patient. And I love seeing people smile.
That's one of the things that really does it for me. And TMS does that pretty reliably, and I don't have to wait that long. So I guess I'm that patient.
So those are the promises. What do you see as the barriers to getting this out to be a little bit more broadly available, more of a common treatment?
I mean, the thing I say all the time is payment model, payment model, payment model. So... If it were paid for tomorrow, I think there would be businesses getting this to every patient everywhere the day after that. If Medicare just said, yep, we're paying for it. I think there's a business model there. I think when there isn't a guaranteed payer from the government that sets the standards for the other commercial payers in the
, it's really hard to get this to scale. I think there's also just a marketing push that, you know, similar to our friend Arthur Sackler, he understood you got to market. And people have to know depression can be over. And psychiatrists have to stop thinking of themselves as psychopharmacologists. What a scam that was.
Yeah.
And think of ourselves as physicians who are healing illness using a variety of tools, some of which are biological interventions and some are psychosocial. And so I say, I also hate the term prescriber. I mean, I am prescribing TMS, but it's not what I do. I care for patients using my medical judgment. And sometimes that involves prescribing a treatment. But it would be like denigrating neurosurgeons because they didn't prescribe a drug.
Yeah.
No, they're going to solve a problem. There may be a drug involved, but probably it's going to be, you know, going to the organ of interest and cutting out the bad part.
Now, are there any conditions that we generally consider psychiatric that you think that TMS is definitely ineffective for or unlikely to be effective for? Just in your own opinion, you know, we haven't done the research, maybe.
Yeah, so... I mean, I get surprised all the time. So like a year ago, I would have had schizophrenia. But now we have multiple trials demonstrating reduction in auditory hallucinations with TMS to the temporal parietal junction, which is a part of the brain in the auditory cortex. So I was wrong about that. Wow. Last week, I would have said eating disorders. And this morning, I published on a meta-analysis in my newsletter, The Frontier Psychiatrist, on the efficacy of TMS broadly in eating disorders.
So I keep getting surprised. I think I'm dubious that we're going to have a durable version of TMS for ADHD.
Mm-hmm.
that haven't been said, a lot of this is based around like, well, what if there was, you know, you have an espresso machine in your house and what if you had your brain espresso machine right next to it? Would that change what we think TMS could do? If we could make it so cheap, so easy, so accessible that everyone could have it every morning, would it be a different world?
And that might be the case.
Yeah. How about personality?
Ooh. Yeah. So we have a really remarkable study by Dr. Nolan Williams called the SHIFT trial.
Mm-hmm.
which is a little bit of a head job, but I mean, it is stimulating your head. So he used functional connectivity to change a, like depression's a state, right? You're depressed or you're not depressed. We all accept that states can be changed. That's the purpose of the field of psychiatry is to change your bad state to a good one. But what about traits? What about, you know, personality is a trait, but there are others.
And so the trait he used in this study was hypnotizability. Oh, wow. Right. It's got the stability in the brain. It doesn't change at the level of handedness. Like, can you change from left-handed to right-handed? Yes. How often does that happen? Pretty rarely.
Mm-hmm.
And hypnotizability is similar. And so he found a functional connectivity target for people with fibromyalgia and thus pain and changed their hypnotizability to be able to alleviate their pain. And a single fMRI-guided TMS stimulation changed the hypnotizability of people in that study. So we were able to change a trait that's very stable using a brain stimulation approach. Okay, so what else? Look, Right? Like that's weird.
That is pretty interesting.
It's weird, weird, but possible. And I think TMS isn't the only stimulator we've got. We have transcranial focused ultrasound coming online. Companies like Sanmai are bringing that technology to the fore. And that's essentially a non-invasive stimulator. modality that has the depth of deep, you know, surgery going into the brain very deeply to reach those deep brain structures and change how they're functioning or firing in a way that's durable.
And, you know, TFUS is tremendously exciting. We have EEG neurofeedback like the gray matter self prism system, which is FDA cleared for the treatment of post traumatic stress disorder and has effect sizes three months after the treatment of 03, which is the equivalent of a drug that made you about two and a half inches taller if it was a drug for height. So, like, that's the brain as its own stimulator.
You're literally playing a video game with an EEG lead on your head, right? And when you do it right, when you think in the right way, the people in the video game sit down, and that 15 sessions later means you're vastly less traumatized than you were at the beginning. Like, okay, so the brain's its own stimulator. We can use external stimulators. We can use, you know, trigeminal nerve stimulation, like the Monarch ETNS device.
We can use, right? There are a bunch of ways to get into the brain in terms of changing how it functions using kind of those ancient systems that we have for, you know, whiskers, right? on rodents, all that, all that hardware in the brain or those circuits are still there that let us make use of our whiskers to navigate our environment. And that's in, you know, cranial nerve division one, division two, division three of cranial nerve five, all that wiring that hooks into those networks of the brain is still there.
And so we can stimulate those nerves in order to modulate those brain networks. And we can do that directly with TMS, we can do it a little bit indirectly with trigeminal nerve stimulation, even more indirectly with EEG neurofeedback. But all of these approaches are doing the same thing, letting the brain heal itself. Ta-da.
Yeah. And I'm super excited to go into what you see as the future. But before we do that, I do want to get a better feel for where TMS is now and for people who want to refer to TMS. Yeah. So can you talk about what is a typical patient experience? Like what does the patient usually say during the treatment, after the treatment? Are they, you know, like I have an idea of, you know, when I start a medication, how the patient reflects back on what treatment looks like.
I've seen what people who take psychedelics, how they reflect back on their experience. So someone, what's like your average TMS patient? What are they, what's their experience during the treatment? And how do they usually reflect back on the treatment and their depression?
So there's, I mean, more likely than not, the experience is a profound change. And that level of profound change is really hard to explain and meaningfully consent for in advance. So, for example, I warn people getting accelerated TMS that we've seen people get a divorce after this treatment. Wow. Now, it turns out a lot of people who are depressed and have been depressed for a long time will get married to someone.
And that relationship makes a ton of sense when they're super depressed.
Do we consider that a side effect? Yeah. 24% of patients.
We see that. It's rare, but it happens. And I've never had to worry, I've never had to worry when I prescribed Prozac, that getting 50% less miserable, which is the outcome by which oral medications and depression are measured, 50% reduction in symptoms is considered successful. Whereas remission is the most likely outcome with the TMS treatments I use, which is not all of them, but still, it's vastly more likely to be the case than in a medication.
So in treatment resistant Depression, we have multiple randomized controlled trials this very year in 2024. Of this, one of which was even a cost effectiveness study, but the next drug you take after the first has about a 5% chance of ending your depression. If you use TMS, it's greater than 25% or higher, depending on the kind of TMS. Even underdosed once daily TMS for only 20 sessions, still orders of magnitude literally more effective than the next medication.
So what I tell people is the most likely thing that's going to happen is your depression will be over. And by the way, that's not trivial. Like it may be a big deal and you may have stuff to do in your life. Like now that you can work again, you may want a new job.
Mm hmm.
Now that you, it may change the dynamics of your relationship. If you've had a person who's never known you, right? Brain injuries do this too. You get a brain injury and many people will get a divorce thereafter because there are changes. And this is like, you know, a brain injury in reverse, right? You are taking away a brain dysfunction in a way that may change the dynamics of your relationship.
So I do warn people that it may be a big deal and they should not make any abrupt changes in their life all of a sudden. Let it settle in. Some people will say, look, yeah, no, it wasn't a big deal at all. I mean, I did get a new job and, you know, left my partner who wasn't right for me and started a new company, but nothing really changed.
Right. And so unlike psychedelic treatments where there's this experience that you have that's really profound, like the experience of TMS is like really not profound. Like you're sitting there and there's like a woodpecker banging on your head from a magnetic coil and it's like boring and annoying and then it's over. But oh my gosh, I feel so much different now. And so the experience for a patient, I hope is one where they're going to get tremendous relief, but then they've got a whole life to live.
And I think preparing people as best we can matters. Following closely thereafter is important. And there's a really important role for psychotherapy, I think, in making sense of our world with this new set of facts that people find themselves living with.
Right.
Does that answer your question satisfactorily, Greg?
Yeah, definitely. And I think what you're pointing to is I think a lot of people when they're depressed might think that being depressed means everything's going great. And what you're saying is when you're not depressed, it actually opens up different experiences than you expect. It's not that you're not depressed so your relationships are great or you're not depressed so you love the work that's not right for you.
It's you're not depressed and then, oh, I actually can change my work. It's not I'm not depressed and I love it. It's very interesting. And it's kind of what I would expect if you were to treat depression. It's not this, oh, I feel great and everything's going great. It's, oh, I've got some things I need to change.
It's quite interesting, too, because it's a reversal, I think, of how we have to approach things often with psychotherapy and medication where we say you need to make these changes concurrently with the treatment. But with this, the speed and action is so rapid. It's this new sequence.
And like changing your life is hard. Yeah. But it's been quite humbling for me to like cure an illness and still have real problems in people's lives. And I think it behooves us to remember that like life is really challenging and we're there to help our patients make the best of it. And we should not be too cocky about like, yeah, I cured your disease. My job is done.
Everything's fine now for me. I don't know about you. You really hate your job now and you can't tolerate it anymore. Oh, well, shucks. You know, these are questions of informed consent. When you look at the literature on psychedelic medicines, there's a paper that came out on veterans who were treated with Ibogaine and 5-MeO-DMT, and they rated the experience as the most profound in their life in half of cases.
And I think, like, there's an informed consent process that has to happen if you're about to have the most profound experience of your life. Yeah. So that's my like, this could be a big deal in a way you might not be prepared for. And people just kind of look at me blankly when they're depressed, because like, how could you imagine that if you've been depressed for 20 years?
And yet they generally thank me at the end of like, thanks for the heads up, because it was as weird as you said. And I'm happy I checked in with my therapist.
Mm hmm. And, you know, I'm reminded of, you just mentioned, like, making big changes. AA has a similar principle for firmware that you're not supposed to make any big changes for the first year of sobriety. And I wonder if that's a similar principle acting there in that, I don't know, with that newfound freedom.
Keep in mind, AA was built by someone after an LSD trip. Yeah.
Yeah. And also, just free associating here, it reminds me of office space when you have that enlightenment moment that you hate your job. And yeah, the changes are not what you expect.
Yeah. The ability to be glibly assured that we're doing only good for our patients is not there. Look, surgery has risks.
Mm-hmm.
Like major risks. It could be life-changing. It could be life-saving. But like surviving cancer, even if everything goes perfectly, changes your perspective. Surviving depression changes your perspective. And importantly, for patients to know, none of these changes are permanent. And so TMS both causes no permanent changes in brain function that we're aware of. and causes no permanent change in brain function that we're aware of. So it's likely that if your underlying depression is recurrent, you're gonna need the treatment again.
And retreatment is, again, necessary and highly likely to be successful, like greater than, I don't actually have the real numbers, but like 90% plus of people are gonna respond to a second course of treatment if they need it. The durability is on the order of a year And that's in some work I've done, actually. About 50% of people have a durable response to a year. Some people less, some people more, depending on what's their underlying biology.
But you're going to need more of this in the future. And FYI, the second you start feeling bad, you should come back for more.
Now, I'm curious, are there characteristics of patients that you hear and you feel like there's going to be... Now I'm going to go off research, going off your fan theories or what you've just observed in the clinic that you haven't seen backed up by data. Um, certain things, certain types of depression or symptoms that you feel like you've, you know, the patient's going to have a good response or certain things that you go like, I don't know if this, you know, this might not be as effective.
Are there certain things that you hear and you feel like it's going to be, it's going to work and it's not or, or vice versa?
This is where I like, again, research is really helpful to me. Sorry.
Yeah. Yeah. I mean, that's great.
Every time I think that I end up being like, I think our hopelessness as clinicians is a reflection of what the person's going through. Getting back to that, we are exquisitely connected and in sync with each other. When you feel hopeless and like something's not going to work, that tells you something about what's going on for the patient. their hopelessness becomes our hopelessness. Like the, the, the article by Thomas May and the ailment from 1957 did an amazing job of this.
The best kind of patient is the one who gets well with a treatment that interests his or her doctor. The patients that are difficult are the ones who, despite long devoted care, get worse. And it shouldn't be surprising when, um, human suffering elicits in ardent care providers something of the same gamut of feeling. So be careful when you see a lot of suffering. Patients who I think it's really not going to go well, dependent personality disorder.
If they have a tremendous need in their personality life that they've built, the way they interact with the world to be taken care of, this might threaten their need to be taken care of and they may have a reason for it to not work. We have remission in OCD on the order of 31%, but full remission is less likely than it is in depression. When there are heavily involved family members who have a vested interest in the sick role of the patient, I am unlikely to see it, at least in my mind, work.
That having been said, You know, we looked at borderline personality disorder. We looked at narcissistic personality disorder in multiple studies now, and they don't predict non-response to TMS treatment. Very interesting. So... I don't know. There are other factors that make it, you know, somewhat less likely that it will be helpful. So benzodiazepines co-administered, and it's hard to get people off of Ativan or Klonopapacillus annex every day, but they predict a slightly lower rate of response.
Not enough to say we shouldn't do it, but just like we should be cautious about it. Cannabis may lead to lower rates of response, and this shouldn't surprise us because cannabis is an anti-epileptic, or at least CBD is. And if you want to keep drinking, well, your life is probably going to still have alcohol use disorder if we're not using an alcohol use disorder target, which, by the way, exists now.
Thanks, Colleen Hanlon and other researchers. This is not a panacea, and the targets are meaningfully different. um, in, in different people. And so, you know, one of the fun things is getting to see we had, there was a paper published earlier this year by Dr. Siddiqui looking at his lesion derived PTSD circuit. And, uh, and we described both how that was developed. We looked at a bunch of people in Vietnam who got, you know, shrapnel to the head.
Some of them got injuries that seemed to protect from PTSD and others still got PTSD and they all got hit in the heads. They all had trauma. And then we use that, what we assume to be a circuit mapped out by those lesions, what we call a lesion-derived map. And we chose a stimulation target in someone with PTSD who hadn't gotten shrapnel over the head. And lo and behold, it was an effective treatment.
One of the things we're finding is that that left frontal target, that left DLPFC's anti-subgenual target, which we call the dysphoric network, that seems to be specifically and specially anti-suicidal. And so, you know, a person who gets a treatment for their PTSD and it gets better and later gets suicidal, it may be that you go after that anti-suicidality target. I just had this happen last week with a young woman, all of 12 who had had her obsessions get a heck of a lot better but became suicidal.
We treated that left frontal target and her suicidality remitted in the course of a week.
So it's just such fascinating stuff. I can really see that as the database of treatment effects and targets gets more robust, gets more broad for TMS, that it will potentially, and I think likely influence the whole field's way of conceptualizing certain conditions, states, continua of interest as biological, psychological, or even systems. You know, what you said about Some patients being very dependent or with certain family members, it makes you wonder, to what degree are we underappreciating that certain pathology is because of the system of the brain being in a system of personhood within a certain family or something else?
Fish swim in schools.
Yeah. I'm right. Do you guys know David Burns, the CBT guy? Yeah. His big, he wrote Feeling Good and Feeling Great. And the big, for all the patients he noticed, he wasn't responding. But the difference between the two books, he added the resistance part. And his first question before kind of going into the CBT is like, what is your anxiety doing for you? What is your depression doing for you?
And the point being is that when you live with these things for a long time, there's resistance to improvement because, you know, maybe the depression or anxiety is what allows you to live happily in your family. Maybe it's what allows you to serve a relationship, serve as a part of your relationship because you're the one being taken care of. You know, like our symptoms aren't. you know just bad things that we need to get rid of sometimes they serve a function and poking at that resistance first before getting better can make a big difference.
I think a takeaway is, look, if you think a treatment isn't going to work, a lot of that has to do with the person feeling hopeless if you're the doctor. And if you're the person, like, is it worth giving a try? Like, I think, yeah, probably. Because again, you know, the data says it's likely to work. And if it doesn't work, the risk is low. And so, you know, as long as your symptoms aren't saving your life in some regard, which, I mean, they might be.
It's worth at least considering trying something that could do something useful. And the good news, again, TMS, no permanent changes in brain functioning. So if you don't like feeling better, just wait. And I'm confident that over enough time, it's likely to get you back to that state you found comfortable. I miss the comfort of being sad if you're Kurt Cobain. He wasn't wrong.
Thank you for listening. We'll see you next time.