Good morning, Dr. Harvey.
Good morning, Dr. Maltzberg. How are you doing this morning?
I'm doing good. I'm really excited about today. I think we're talking about how TMS works. Is that correct?
We are. We're going to talk about how TMS works. Yeah. And for those of you who didn't hear, this is kind of a part two thing because the part one, we talked about how TMS doesn't work, right?
um so it's not serotonin it's kind of what we concluded from from part one right
right yeah I think there's kind of this prevailing idea that the brain is a big chemical soup and if you get the right chemicals in the soup then you feel better you know more serotonin good more norepinephrine good and as we discussed in the previous episode um That's just not well supported by science. There's something other than just something more to it or something other than just boosting serotonin, boosting norepinephrine, things like that.
Thank God. The thought of something as complex as depression being decided on by three levers, up serotonin, up norepinephrine, up dopamine, and that explains all of human experience right there.
Right, right. Like I said, the brain is very complicated, so there's probably more than three things.
Most likely, more than three variables to decide.
Yeah, maybe five. I don't know.
Yeah, but I think we just were missing that glutamate. We got that fourth knob, and we're good to go.
That's right. Oh, there we go. Now we're, yeah, we got it all figured out now.
So how, you know, in your opinion, how does it work? You know, what, how did... Yeah, good question. So I think probably the best way to describe it is to kind of walk through the history of how we did this thing. So as far as TMS, you know, TMS
We discovered that we could use transcranial magnetic stimulation to stimulate the brain. And that was in 1985. And even way back then, people were like, wow, what can we do with this? Certainly there's something we can do with this technology to make people better. And a lot of the early thinking and a lot of the early effort was, can we use this to treat people with major depressive disorder?
Mm-hmm.
and they kind of thought through what part of the brain should we stimulate and very early on they kind of settled on the left dorsolateral prefrontal cortex as probably the best candidate target and that's and for those of you listening so that That, if you imagine, like if you put your finger a couple inches above your left eyebrow and then move it to the side a couple inches, it's roughly there.
Okay. So it's kind of in the front, but kind of off to the side and on the left side. So left dorsolateral prefrontal cortex.
In the last episode I mentioned that the purpose of discovering mechanisms is so that us doctors can feel good about sounding smart and so that's why I really believe in the left orsolateral prefrontal cortex because just look how smart we sound saying that,
right? No, that's a lot of syllables, right?
Yeah, yeah. So that's why I think it's more likely to be true because I feel very smart when I use words like I feel very anatomical too. So, you know, I'm liking this theory already.
I do too. I do too. And you know, if you want to sound even more smart, you say the left DLPFC.
Yeah, because you don't time. We don't time to say the full thing.
We're so important and so busy, we have to abbreviate things. And yeah, exactly.
But why did they pick that spot?
Yeah. Well, yeah. So there were a few reasons. Part of it was lesion studies. If you look at patients who have small strokes and see how are they different after that small stroke, one thing that they had discovered is that patients with a stroke at the left dorsolateral prefrontal cortex were more likely to have depression after that stroke. Even if they did not have much functional impairment, even if it was a stroke that wasn't that bad otherwise, they still had a tendency to suffer from depression after their stroke.
So it's as if that part of the brain looked like it had something to do with mood. So that was part of it.
I think lesion data is so cool because essentially my understanding which is very overly simplistic is people get lesions in all different sort of patterns and then there's certain spots that like all over the place that it's a common denominator across So I'm assuming the you know all these people got depressed when there was all these different spots and then when you mapped them all on together there was just one little spot that was common for all of them um
Yeah, yeah, kind of like a Venn diagram and you look at it, where do all those things overlap? Yeah, exactly. Oh, and for our listeners, yeah, a lesion is like an injury or a part of the brain that died because of a stroke. Yeah, yeah, yeah, yeah. So partly it was the lesion studies from strokes and But also just imaging data, you know, imaging from, you know, doing brain scans to look at how much metabolic activity there is in different parts of the brain.
And from some of those studies, it looked like there was decreased activity right there in the dorsolateral prefrontal cortex. And also some scans, some studies seem to show that there's, you know, maybe just decreased gray matter there or maybe like a little bit of Decreased Stuff Or Decreased Not As Much Brain There As There Should Be For People
Who Had Bad Depression So Is The Gist That If You Know We Found The Region That's Underactive Team S Works By Stimulating It And Bringing It Back To Normal And The People Feel Better Is That Is That It
That's basically it, yeah, yeah, and I gotta tell you, that's when I first started giving people TMS in 2013, and people asked me, you know, how does this work? You know, the way I explained it is I said, you know, we think it's because there's this underactive region, and if we stimulate that underactive region, that that makes things better. It turned out that what I was telling people is probably just a half-truth.
I thought it was true at the time, but now that we understand things better, we have better ways of explaining it. But yeah, I think originally that was the thinking. That was the original thing we thought was happening.
So yeah, I guess we understand it better now. Keep going on the story.
Oh, yeah, yeah. So... So now we know, I mean, you know, another thing we know about the dorsolateral prefrontal cortex is that it's, you know, it's not really the mood part of the brain, you know? I mean, it's not, that's not part of the brain we think of as having to do with mood. It's a part of the brain that has to do with, you know, attention and executive functioning and things like that.
And it's not the mood part. So that leaves us wondering, well, why does What is stimulating this part of the brain that's not a mood part? Why would that make your mood better? You know, what up with that? And so one thing we know, and this won't completely answer your question, but it gets us partway there. One thing we know is that, you know, in the brain, stuff is connected to other stuff, right?
So you can stimulate the left dorsolateral prefrontal cortex and And that will secondarily activate other parts of the brain. So, you know, this part of the brain is connected to that part of the brain. And, you know, maybe it's that other part that might be the part that really matters. And for the left dorsal lateral prefrontal cortex, it's connected to a lot of different things. But one part of the brain that might be especially important is the subgenual cingulate cortex.
Mm-hmm.
the subgenual cingulate so that's uh you know the genu is like the knee like the part that kind of bends over so it's it's the part that's uh underneath that that that we think might be what really matters and that's a part of the brain that's deep in there and we can't get to that part with a magnet so we stimulate the dorsal lateral prefrontal cortex which is on the surface and that secondarily activates that other part.
So I think that's part of it. That's part of what's going on.
I'm glad you said stuff is connected to other stuff. Actually, I appreciate that There's a lot of people with nice clothes and shiny teeth that can pitch it in terms of very highfalutin, very intelligent things. But in my opinion, the depth of knowledge really is stuff is connected to other stuff and we stimulate this area and that stuff gets better, question mark. And I really feel like anyone who's, you know, of course, you know, we do know a little bit more, but I do think in terms of like how much, you know, just in terms of the lessons we learned with serotonin, when we try to take it too far and sound like we know more than we do, history usually tells us that we're making a mistake.
And so I'm actually glad to see that, you know, because I think There's some seriousness and stuff is connected to the other stuff and that it's acknowledging that we don't have this stuff perfectly mapped out. There is more to it, sure, but this isn't something we have perfectly down.
Right. Oh, absolutely. Yeah. And there's good people out there who are trying to have a better understanding of it and are making a lot of progress. But yeah, on a fundamental level, it's like, yeah, stuff is connected to other stuff. I mean, you know, all those neuroscience classes we took over the years, I think stuff is connected to other stuff is kind of the takeaway list. It could have been an email, you know?
Yeah. Yeah.
So you mentioned you initially thought it was this area was low, we stimulate it, and then we bring it back to normal in some sense. What is it, I guess, how do you think about it now if you feel like you mentioned that you felt like that was a half-truth and you better understand it now. How do you understand it?
Yeah, so I think there's a couple different stories in parallel that kind of explain our current understanding of how TMS works. So part of it is that there's There's now a lot of evidence that the way TMS works has to do with neuroplasticity. There's another word with a whole bunch of syllables there, but neuroplasticity seems to be how a lot of things work to fix depression. And just kind of to explain the background here, there's a lot of evidence now that problems with neuroplasticity are at the root of a lot of psychiatric problems and also that modifying or boosting or doing something to neuroplasticity is a big part of what makes our treatments work.
So we know that by stimulating with TMS we're Boosting neuroplasticity, at least at the area that we're stimulating and probably also areas that that area is connected to. So part of it, we think, is improving neuroplasticity, strengthening synapses, growing new dendrites, things like that. Kind of like brain fertilizer, sort of.
Yeah. Now, I do... So I'm on LinkedIn, and I see... Neuroplasticity is one of those buzzwords and I hate to argue against you I don't think I'm arguing against you I'm just providing another perspective Neuroplasticity is one of those big buzzwords and it feels like the fact that we had the serotonin hypothesis I'm putting this all in quotes overturned four years ago and then now we're being given a new sexy sleek thing that we can start selling stuff and Neuroplasticity I think is a hot word I remember Seeing it come a lot Come up a lot In like positive psychology And now it's kind of moved Into this thing of like Oh the real good stuff Is working on neuroplasticity And I think To me it has the same It has the same issues As the serotonin hypothesis So one thing I think is Because I You know When you see the slides You think of neuroplasticity As like Brains growing And we're learning And we're getting smarter Neuroplasticity is actually is pretty value neutral.
And a counterpoint is recreational drugs, you know, they don't just quote unquote damage the brain. Recreational drugs have a lot of powerful neuroplasticity. And there's a lot of accelerated learning Neuroplasticity and learning and cognitive connections don't necessarily all mean good things. It doesn't mean that we're learning Spanish and doing wonderful in the world. Neuroplasticity can go in ways that objectively we don't think is that great for people.
So I just bring that up in that I worry, and I'm not saying you did this, I'm saying I see the field on LinkedIn where we've just replaced the serotonin hypothesis with neuroplasticity and now we're selling different stuff.
We're at it again. Science is at it again. Yeah. Oh, yeah. But yeah, yeah, I agree. I mean, yeah, and I think one part of what I totally agree with is, you know, neuroplasticity is a powerful part of how the brain works, you know?
Yeah.
So when things malfunction, there's something about neuroplasticity there. If we have a treatment that works, there's probably something with neuroplasticity going on to make it work. But Neuroplasticity is not magical fairy dust. It's not like sprinkle on neuroplasticity and you make it better. No, it's not. Kind of like serotonin. You boost someone's serotonin. It's not necessarily a good thing. It's not magic fairy dust. Also, I think when neuroplasticity becomes a buzzword, Yeah, I think people might overuse that buzzword to kind of explain everything, and then it loses its meaning.
You know, kind of like the phrase chemical imbalance, you know? Like, what the heck does that even mean, chemical imbalance? You know, it could mean anything in the world.
Yeah.
And I think neuroplasticity is the same. If we start throwing around that phrase too much, then it just becomes neuro babble, you know? Yeah.
And the flip side is I do think it's an important part of our treatments because most of our treatments, we do see increased neuroplasticity as an end result.
Yeah, right. Yeah, yeah. And it's interesting because there's a lot of evidence that antidepressants boost neuroplasticity in some ways. You know, we know TMS boosts neuroplasticity in some ways. ECT boosts neuroplasticity. You know, that's shock therapy. Ketamine and S-ketamine boost neuroplasticity. But also, you know, physical fitness and exercise, they boost neuroplasticity. And we know those things also work for depression or they help, you know. So just kind of like everything that does good things Neuroplasticity
Now, how would you summarize all this? You know, we talked about networks. We talked about, you know, stimulating low areas. How would you kind of summarize, you know, what it is in regards to how TMS works and what it's doing?
Yeah, you know, I have a couple ways of summarizing it. So I think I'll tell you both. But I think, I mean, if it's just a practical thing, if I'm there with a patient and they want to know, you know, how does TMS work? I have my own personal favorite answer for that and everyone here in the audience is welcome to steal my answer. I don't have a copyright on it or anything like that.
So my favorite answer is with TMS we're stimulating a specific part of your brain and there's something about that stimulation that makes people better. And that's it. Boom. Done.
Now You said that, and when you said that early on when we were going to know each other and you were kind of doing a talk, I loved it. I just love that it's not selling anything. It's giving credence to how much we know while still giving an explanation for what's going on. And I really like when teachers are like that. You're not making it more complicated than it needs to be.
It's something that someone can grasp onto to understand it.
you know I like it oh thanks yeah yeah that's kind of what I'm going for you know to be to give an explanation that's maximally honest maximally true and you know to not sprinkle in fake science you know because I think sometimes when you look online you see this the explanations of TMS that are like like you know someone someone who's not a scientist to sprinkle in gobbledygook there you know yeah yeah yeah yeah yeah But, and I think there's, like, if I'm talking to a science person or another physician who kind of wants to know more, then I think that the next part of my answer is to say we don't know, but...
We're pretty sure it has something to do with neuroplasticity. And I also say it has something to do with modulating brain networks. And if they ask, like, which network are you modulating, then I have to admit that I don't know. But it is. It's not just the spot on the brain we're affecting. It's a network of the brain that we're affecting. And I think that's another important Psychiatry or Neuroscience in general is that we have to let go of this idea that this spot on the brain does this, that spot on the brain does that.
It's not spots, it's networks. There's this whole interconnected system within the brain that does complicated things and we have to start doing our best to think of networks instead of spots.
Yeah, we don't want to go back to phrenology and make the same mistakes
Right, right, yeah. I remember when I was a little kid and we visited my aunt and uncle's house, and my uncle was a psychologist, and he had this model of a head on his desk at his house, and it had the phrenology things. It had a map on the head, You know, this part of the brain is for empathy and this part is for love and this part is for anger and I don't know, things like that.
And I mean, I think, I mean, looking back, I think he knew the brain didn't work like that. It's just like a phrenology historical thing, you know. But I think that kind of affected me. Like I was always like, oh, which part of the brain does this and which part of the brain does that?
Which part of the brain sees Leonardo DiCaprio? Yeah.
Right, exactly. Yeah, which part is that? You know, is it the gyrus of DiCaprio? I don't know. Yeah, yeah.
Well, you know, awesome. I really appreciate this. I think this is super helpful. Anything else you want to, you know, wrap up?
I don't think so. I think that's kind of everything we know about the Mecca. It's not everything we know about TMS. It's everything I know and everything you and I know about TMS. How TMS Works but you know in the future we're going to find out more and I'm really excited to come back to this podcast and tell you all more as we find out but anyway yeah so I'm so glad all you could join us I hope you all enjoyed the show and if you didn't enjoy the show you know just remember that in the infinite vastness of the universe it doesn't really matter all right have a good one Dr.
Harvey