 A key human capacity is our ability to experience emotions and to talk about them to express them a subjectivity. As a psychiatrist, this is one of the core capacities that I rely on every single day. In fact, the very definitions we use for psychiatric disorders are based on the subjective. So my job then to try to heal people and help ameliorate their distress, people with emotional disorders like depression or anxiety, is to try to understand and help them understand their emotions and work with that. The problem has been, however, as I'll show you in a minute, that psychiatry is at a standstill. Our ability to do anything about that, the suffering that we recognize, is very limited. So I'm going to invite you in the next little bit to rethink psychiatry with me, but hold on to that thread of subjectivity because we'll need that later. This story is going to start almost 30 years ago in 1987. So before we start the story, let me give you context. 1987 was an interesting year. Stock market crash. Black Monday happened. Madonna started reaching the peak of her career and we saw movies like Fatal Attraction. In fact, it was actually a very good year for Michael Douglas. He had another movie that echoed events of the day. But another very interesting thing happened in 1987 in the biomedical space. EZT was introduced. It was the first drug approved for HIV, as well as Prozac. Prozac's not the first drug for depression, but it was the first in a new series or new class of drugs called SSRIs or Selective Serotonin Reuptake Inhibitors. So where are we now in these two conditions? Well, HIV can actually be managed successfully and people live pretty normal lives now. Depression, it's a different story. Morbidity and the mortality associated with any mental illness, depression just being one example, has not changed over all of these decades. So let's start to think about why and what that means. Well, the first of which is what does it mean that it doesn't change? What are the effects of depression, anxiety, schizophrenia, bipolar, what have you, not changing? This graph shows, this is from the World Economic Forum. It goes by 2030, a mere 15 years from now. The economic toll the non-communicable diseases are going to take. And as you can see, here we have cancer, cardiovascular disease, all things we think a lot about, diabetes. The cost is dwarfed by the cost associated with mental illness. And this bar right here, COPD, that's due in large part to smoking and pollution. If you decrease those, the bar goes way down. So mental illness overwhelms in terms of economic impact and personal impact, any other chronic disease, and yet we've not moved the bar. How do we diagnose mental illness? I mentioned any psychiatric disorder is defined by subjective report of that person. And we define it based on a checklist. And not just any checklist, a checklist you can meet any number of ways. So depression, you have to have five out of nine criteria. Post-traumatic stress disorder can be diagnosed in 600,000 different ways, all with that same disorder. That to me doesn't sound like biology, that's very descriptive and distant. So what if we start using biology, let's say brain imaging scans that we would be doing a lot of in the lab, to try to ask questions about the brain basis of mental illness. Well we did that recently, we found something very interesting. There are 300 plus psychiatric disorders in the Diagnostic Manual in the United States. And then we said, well maybe simply having a psychiatric disorder is in being distressed, not being able to understand and experience your emotion, not being able to deal with, put labels, words to your emotion, not being able to regulate your emotions, as well as all the other things that come with psychiatric disorders. Maybe they take a toll on the brain that underlies or belies this diagnostic criteria that might suggest different disorders, but in fact there may be at least a common thread, not necessarily the only thread, and that's what we found. What I'm showing you here is a brain section with little blobs on it that show where across all psychiatric disorders there is decrease in gray matter or brain tissue. I'll come back to what this means in a second. Then we said, you know, maybe that's just one way to kind of look at the data, let's look at how people engage their brains in tasks and do the exact same thing, all psychiatric disorders, and you might think I'm actually showing you the same picture, it's not, slightly different, but it tells the same story, which is when you start looking at the brain you get very surprising answers. In this case, it's three regions here and three regions there that are the same three regions that are abnormal across all psychiatric disorders, and guess what, they're not three random regions, they actually form a circuit, an interconnected circuit that we understand quite well. So maybe one way to think about and solve the problems of mental illness is by understanding the brain as circuits that do human things like understand and regulate emotions. The brain is made of many circuits. This isn't a picture here of wires interconnecting different parts of the brain in different colors. What you see here is brain activity unfolding over those circuits, and however you want to look at these things, well, it's sort of a map, right? You can start thinking about where in the brain you might go and where it might be connected to, but what kind of tool would you want to use to start to address questions related to circuits? Let me introduce you to one called transcranial magnetic stimulation or TMS. It is an electromagnet placed outside the head that noninvasively turns on or off little bits of brain underneath. Our brain is an excitable organ, and so we're using an electromagnet to talk to an excitable organ. There are wires there that I just showed you. And so you take a TMS coil like this, you stimulate a part of the brain that's interconnected to some other parts of the brain, and you can see activity evolve in the brain. And I'll show you examples in a second over time. So it's a way of interrogating circuits. It's also a way of manipulating circuits. So this image that I've shown you here is not just a pretty cool-looking brain that you might want to put on a wall just as a piece of art. These are different networks in the brain that you can see in every single person, and they're very much the same or at least highly similar between people. So looking at this, that's a nice picture, but what does it tell us? Fortunately with brain imaging, it's a story that we tell when we take pictures. When you start to intervene with circuits, you get what I call the causal connectome. You get information about cause and effect in brain circuits. So for example, you stimulate one part of the brain and you see activity evolve in yellow here over time. Stimulate another part of the brain and this goes on. We're going to stimulate all these regions at the same time and look at the patterns. These patterns as a loop playing is 120 millisecond, a fraction of a second in brain time that's playing out when I stimulate a bit of the brain. What should become readily apparent to you in looking at this is the patterns aren't all the same. The pattern depends on where you stimulate. So if you want to reach one part of the brain or another, you want to know where to go. So now we have a map, we have tools to start to manipulate this, and you can start thinking like this is great. We can now think of modulating these circuits. The trick is finding the right circuit to modulate to get you the effects you want. So I'm going to argue that this is not pie in the sky, this is actually happening right now. And I'll give you an example in a second. The brain then is a bunch of circuits. Our job on the one hand is to build tools and know how to use them to manipulate those circuits better but then appreciate the brains are really complicated interconnected place and so we have to really start to untangle this even as we build tools that allow us to go much deeper and more precisely in the brain than we ever could before. The reason I'm saying it's not pie in the sky is I'm going to give you a very concrete example coming into the lab right now that speaks to this issue of understanding, labeling and regulating your emotion. The amygdala, this is a monkey brain. The amygdala is a region deep in the brain that cannot currently be reached by TMS. But it's a region that's very important for a lot of our emotional experiences whether they be fear, happy, sad, all these sorts of emotions that are critical to psychiatric disorders. And so we looked at this study in monkeys and notice that there's this little area labeled L12 this colored area that actually sends projections down to the monkey amygdala. This area has never been stimulated in humans before and we don't know what it does. So we said let's use our TMS tools while we do brain imaging turn on this area which you can see on somebody's head right there. So we stimulate and then see what happens. Well, it turns out when you stimulate this region in healthy people you inhibit or turn down activity in the amygdala and that's what you can see in the cool colors up there is the amygdala turning down. We then took patients in this case with post-traumatic stress disorder who are unable to regulate their emotions did the same thing and nothing happened. So we identified a causal pathway to the amygdala that's never been targeted before that's abnormal in these patients and then when you disrupt this pathway in healthy people guess what happens? They're unable to label and put words on emotions. So it starts to give us a completely new perspective on how to use the circuit approach to interact with the subjective component. So what does psychiatry look like in the future? Well, psychiatry I don't think is going to be one thing. It's going to look something like this. We interact with patients and we do maybe psychotherapy or maybe we talk to them we engage that subjective sense. So now we're taking that thread and we're going to try to weave it back into this tapestry. We then engage brain circuitry in a targeted way now much more intelligently understanding how their brain circuitry underlies these subjective experiences. And you know what? Let's just throw something else in. Let's throw medication in. Maybe that medication is targeted towards making the brain changes that we're inducing by stimulating last longer. It's a very different psychiatry than what we have now. This is psychiatry meeting the patient, honoring their subjective experience, leveraging tools to understand their brain and modulate their brain at the same time so it's no longer stuck hopefully in the way that it's been stuck before and hopefully be better for all of us going forward. Thank you very much.