University Place  Jack Nitschke Anticipation, Uncertainty and Anxiety  June 12, 2013 UP886   cc >> Welcome, everybody, to Wednesday Nite at the Lab. I'm Tom Zinnen. I work here at the UW-Madison Biotechnology Center. I also work for UW Extension Cooperative Extension. On behalf of those folks and our other co-organizers, Wisconsin Public Television, the Wisconsin Alumni Association and UW-Madison Science Alliance. Thanks for coming to Wednesday Nite at the Lab. We do this every Wednesday night, 50 times a year. Tonight, it's my pleasure to introduce to you Dr. Jack Nitschke from both the Department of Psychiatry and the Department of Psychology. He's going to be talking about three of my favorite subjects, anticipation, uncertainty, and anxiety. He's a neuroscientist, clinic psychologist, and he's an associate professor of psychiatry and psychology here at UW-Madison. 

His research centers on the neuroscience of human emotion, anxiety and depression, with a primary emphasis on anxiety disorders. His studies use clinical and non-clinical samples, and employs an array of MRI methods alongside the measurement of behavior, genetics, and peripheral psychophysiology. He and his colleagues in his lab have developed a laboratory based model of anxiety that targets anticipatory and uncertainty processes preceding a range of emotional stimuli. Other prominent research interests include the power of expectancy and positive emotion. I hope he realizes what it means to have the name Nitschke in Wisconsin. He was born in Germany, grew up in Oklahoma City. He does not wear number 66 that I know of. [laughter] Please join me in welcoming Jack to Wednesday Nite at the Lab. [applause]  >> It was indeed wonderful to move to Madison 15 years ago, to Wisconsin, because for the first time in my life, I could say my last name and people wouldn't ask me how to spell it. [laughter] Let me tell you, when people tried to spell it in Oklahoma, boy did it get brutalized. 

So what I'm going to be talking to you about today is some of the work that we've been doing on anxiety. Let me just provide a little bit of context first. Most of you probably either have experienced extreme or severe anxiety yourself at some point in your life, or you know somebody who has. It's an endemic problem here in the United States, and really, throughout the world. There are a number of different anxiety disorders. We'll talk about those in a few minutes. But basically, these disorders cause untold suffering and really, exact a very high societal burden. Lessons from the brain have already taught us some really important lessons about anxiety and the disorders of anxiety, as well as they're beginning to inform treatment. I'll spend some time talking about that. Indeed, today's talk is intended to share with you some of the work that we've been doing in this area. 

So, here's a little outline of where I'd like to take you today. What I'll say at the outset is actually, fasten your seatbelts, because I'm going to cover a significant amount of territory. I'm going to fill up this whole slide with what we're going to talk about. We're going to start with this question, and often, I'll put it to audiences. I think for this particular setting, I will provide some of the answers that I often hear, but I encourage you to think about that first question. You can start doing that already. What is anxiety? Anticipation, controllability, uncertainty. Those are some constricts I'll talk about, and then how the brain is mediating our experiences of those types of processes. There's a range of MRI approaches that we use in our lab. It includes functional MRI, or fMRI. 

There, we can use that to look at the activation of specific brain regions. The second bullet point up there is another fMRI technique that's called functional conductivity. This is where you're looking at how two different brain regions are essentially talking to one another, if you will. Then from there, we walk down to structural conductivity. We use a different type of MRI technology, it's called the fusion tensor imaging, to look at what we call the white matter tracts in the brain. This is, if you harken back to days of neuro-anatomy, these are the axons of neurons, and those have myelin on them. That's white. Lots and lots of those put together show up when you do a diffusion tensor imaging scan. We can look at whether different groups have more or less conductivity between different brain regions. Then finally, I'll just talk a little bit about some very recent work that we've done, looking at what's called brain morphometry. 

Here, we're not looking at the function of the brain, but again looking at structure, and we're talking about the size or shape of specific brain areas. From there, I'm going to go to a very new model of anxiety, one that's really been about 10-12 years in the making, and has been importantly informed by some of the work that we've been doing over the past couple of years. Also then, I'll talk about our latest research, which is a really exciting treatment program that we've developed for veterans from Iraq and Afghanistan, people that are coming back over these past ten years. Finally, I'll close with where we're going, the future of anxiety and its disorders. So here we go. What's anxiety? Again, take a moment just to think about what anxiety is for you. For some of you, what may come up is work. Others of you, it may be a panic type of feeling. For others of you, it might be just kind of a general jitteriness, nervousness. For some, you may think about it in a more, and also general terms, just like a lot of negative affect, kind of concerned about the future. 

So just look at those ideas I just put forward just now, and how different they are. Panic. Worry. Yet, when we talk about both, we kind of talk about both of those as being anxiety. This is a really important question to address in starting to research this, because we have to know what it is that we're researching. If you're going to go and investigate a panic attack, and what that looks like in the brain. You're going to come up with something very different than going and studying somebody's worry processes, as they're concerned about maybe a test or some important family event that's occurring next week. If you're going to try to study both of those things, you're going to get a very different picture in the brain. And if you're going to call both of those anxiety, then we've got a lot of problems, because those are very different phenomenon. So it's very important to be very explicit about what it is that we're referring to when we're talking about anxiety. 

Indeed, anxiety in our textbook of mental illness, this is now about ready to be updated after 15 years. Actually, it's really been 20 years since the DSM-IV originally came out. We've finally come out with a new textbook. Unfortunately, it's not a great improvement over what we already had. But essentially, the way these two books, called the DSM-IV and now the DSM-V, which just came out last month, the way they divide things up, is they list out six primary anxiety disorders. There's social anxiety disorder, and you can think about, that's just a fear about social circumstances and being humiliated. There's specific phobia. That's fear of like a snake phobia, a spider phobia, blood injection phobia. There's post-traumatic stress disorder, which involves an exposure to a really horrific event, such as being at war, but other common ones are being in a very serious motor vehicle accident. And what's all too common in our country, rape and sexual abuse is often a traumatic event that serves as a trigger and leads to some really serious post-traumatic stress disorder symptoms. 

Obsessive compulsive disorder. Again, quite a different form of anxiety. Here, we're talking about obsessions about, oftentimes worry, cleanliness, but it could be about a range of different things. That often is accompanied by different types of compulsions, these types of repeated behaviors that people need to do in order to bring their anxiety levels down, such as washing one's hands 400 or 500 times in a day. Panic disorder, I already mentioned a little bit about having panic attacks. But that's not all panic disorder is about. A lot of panic disorder is about being worried about having future panic attacks, and indeed it's that that's most debilitating. Generalized anxiety disorder is a disorder that is characterized by extreme excessive worry. So, before I walk on into how we're looking at this, let me just say these anxiety disorders exist here in Madison. They exist in big cities. 

They exist in rural areas. I know that this talk is broadcast throughout the state. These are just as much real issues up in the north part of our state as they are here, and throughout our country, and throughout our world. All these anxiety disorders. I think part of what I'll be talking about today is post-traumatic stress disorder in these veterans that are coming back. That is affecting our state very importantly. A lot of these individuals who are coming back are suffering extremely. A lot of them are up in the northern part of the state, just as we also have a number down here in the southern part of our state. It's really important that we educate our entire state about anxiety, about what we know about it, as well as about how to go about treating it. Because the great thing about these anxiety disorders, if there is to be some silver lining here, it is that these disorders in general are very treatable. 

However, sometimes one medication or one psychotherapy approach won't work, but oftentimes another one will if somebody stays at it. Here's how we've gone about researching anxiety disorders, is just to present people in the scanner, either a PET scanner or an MRI scanner, with things that provoke their symptoms. They're called symptom provocation paradigms. We use social stimuli for the social anxiety disorder. We use snake stimuli for people who have snake phobia. We use traumatic stimuli, reading out a script that describes somebody's traumatic event while people lie in the scanner and we're measuring their brain activity. Over the past ten years, more and more studies have been looking at just generic emotional stimulus, so how people respond to emotional faces, how people respond to what's called here as IAPS slides. These are International Affective Pictures System. It's a set of pictures that have been developed, rated and normed that show very aversive types of images, neutral images, as well as positive images. I'll be sharing a few of those because we've used them in our research as well. 

The question there is does this get at the heart of anxiety and what's debilitating about anxiety. Just understanding how people or snake phobics respond to snakes, is that what's important? Or is there something more to it? Let's go back to the definition of anxiety. Anxiety is maybe panic, maybe worry. Is this getting at some of that, some of those types of processes? I would say it doesn't. What's very important is to really think carefully about what is it that makes anxiety so debilitating for so many people, that makes it hard for some patients even to come into the clinic, and indeed, I have had patients, so part of what I do, a small part of my job is as a clinical psychologist. I see patients every Tuesday and Thursday and have half-day clinic days where I'm seeing patients. I have, over the years, had patients that have come and seen me, but things have been so hard, oftentimes it's hard for them just to get out of their home, because their symptoms are severe enough. A big focus has been on this. This comes from what's called fear conditioning literature. It's where people are making maladaptive associations between fear responses in a given situation and then specific stimulating situations that are not inherently dangerous. 

So for example, individuals coming back from war, just somebody slamming a door really loud, so a really abrupt, loud noise is going to trigger symptoms for them, because it's going to remind them of a mortar blast. That door slamming, which is going to happen when you have, you know, a four year old and a six year old living in your house, as is the case with a lot of these individuals coming back, is a totally innocuous occurrence. It's just a door slamming in the house. Having this part of it, what we try to do in therapy is help patients develop new associations between those stimuli and situations that are inherently safe, and safety. Building up some new associations, and then strengthening them through practice. That's the very essence of one of the forms of treatment that has been most effective in treating most of the anxiety disorders, and that is exposure based psychotherapy. However, there's aspects of this, this has not led us to really come to a complete answer of what's going on with anxiety. And a piece that's often not appreciated fully that I have focused on is that the anticipation of bad things that might happen in the future is absolutely essential to all the anxiety disorders. For generalized anxiety disorder, it's really obvious, because that's all about being worried about a number of different domains in one's life: one's job, one's health, one's family members. Social anxiety disorder is also really involved. 

It's a lot of time spent being worried about being in situations that are going to lead to somebody feeling really socially humiliated. That becomes so extreme, that anticipation of it becomes so problematic and anxiety provoking for somebody that you know, eventually, they just can't get to the wedding of close friend that they need to, or can't get to a class, or a course that they need to be attending, because the social anxiety is so great. As I alluded to at the outset of this talk, panic disorder, some people level at me and say, well, there's a disorder that doesn't involve anticipation. That's all about fear in the present moment, having a panic attack. Indeed, panic attacks, when you have them, are fear in the present moment. But that's not what's debilitating about panic disorder. What's debilitating about panic disorder, what keeps people from leaving their homes is the anticipation about the possibility that they might have a panic attack later in the day or in a certain situation at the store when they go there, at a family gathering, and so then they don't go there. That gets extreme enough and you've got somebody who's not leaving their home. So here, we can target such anticipatory processes to directly diminish the anxiety, using cognitive strategies that also require practice. So you're seeing a theme here that's essential for actually all of psychotherapy, and that is that it requires practice. 

Because what you're doing is you're really laying down some new neuro connections that need that kind of reinforcement. Here is some of the key structures, just to make sure that we're all on the same page as to anxiety disorders. What's shown up here in "A" is looking up at the bottom of the brain, if you will, and up on the top here is the front of the brain. This is the bottom area. The front of the brain is right behind the eyes. This is called the orbitofrontal cortex. Right on the inside, some people call that region the ventromedial prefrontal cortex. This area is very important for emotion processing, as well as important for emotion processing, as well as important for emotion regulation, telling other areas of the brain that are really activated by anxiety, hey, you can down regulate, you can chill out some. Right here in "B", is an area called the dorsolateral prefrontal cortex. This is looking at the brain from the left side. 

This is up in the front of the brain. This is an area that's really involved in a lot of different types of cognitive functions, but also really importantly involved in different aspects of emotion. Here in "C", these are very important areas. This is essentially a slice of the brain that's right here, right in front of the ear, going this vertical direction. And what it highlights here first is the insula, which is a really interesting part of the cortex. You say cortex, why is cortex so far in there? Usually, we think about cortex as being all on the outside of the brain here, right? But this is on the inside. If you look, if you could see into this yellow that I've used to mark, it's actually gray there. That's gray matter. That's cell bodies, cortical cell bodies. What's happening there, is it's essentially serving to connect this frontal lobe here, which ends right there, with the temporal lobe right down here, which ends there. 

That's the cortical region that connects the two. It is really important for different types of emotion processing, emotion function. It's important, the primary taste cortex is actually in there. There's been recent work really suggesting this may be essential for awareness and consciousness. Right below that in the same image is areas of the medial temporal lobe that are called amygdala, very important for anxiety. Most people have probably heard of the amygdala. Right next to that, below it, and then extending quite a ways back from it is the hippocampus. Most people think about that as the memory center of the brain. It is indeed very importantly involved in memory functions, but it's also really important in laying down the context that a person is, you know, experiencing different things, so that is very importantly involved in emotion, as well. Finally, another vertical slice of the brain, but this time doing what's called a midsaggital slice, right through the middle of the brain here, what's shown in white here right in the middle, you probably have heard of is the corpus callosum. 

These are the tracts that connect our right and left hemispheres, which aren't connected throughout the brain, but most of the connections are right through that corpus callosum. Then, right in front of that is what's called the anterior cingulate cortex, another area that's very important in a variety of emotional cognitive functions, as well as emotion regulation. So there's kind of a number of the brain areas. What we do in our work is really probe this network in anticipatory processing, as well in anxiety disorder. This is what we have done. Over the past 12 years, we've been developing this model of anxiety that we can use with fMRI. It is a model that is looking at anticipation. We call it an emotional anticipation paradigm, and it's very straightforward. When a subject comes in for our studies, I give them a straight-up instruction. Whenever you see the minus sign, it's always going to be followed, after a short duration, by an aversive picture. 

Whenever you see a circle, it will be followed, after a short duration, by a neutral picture. This is just a set of four trials. There's no tricks to it. That's what people got initially. Over time, we've done some various modifications to the paradigm, but this is what we looked at first. I'll present some of the first data that we looked at to just try to understand what's going on in non-anxious individuals, in terms of different brain areas that are being activated by the anticipation of aversion. At the time that we ran the study, it was unknown, whether some areas of the brain that were specific to anticipatory function or not. Because at that time, we knew a lot of the areas of the brain that were involved to responding to different types of aversion, such as fearful stimuli. Those are the amygdala and the insula. But we didn't know anything about what happens when somebody is spending time anticipating, and that is indeed what people who are anxious are doing. 

It is also good, let me say it is normative to actually anticipate certain bad things happening a lot of times, because that helps you to prepare for them, right? So that's what we are looking at. This is just a picture of our GE MRI scanner. It's more powerful than the scanner than you typically have been in, if you've been in a scanner for clinical reasons in a hospital. It's twice as powerful. This just shows what a person looks like right before they're going into the scanner. Right here is what's called a head coil. Right here are some goggles that are mounted. They're distended above a person's eyes, just by a centimeter above their eyelashes, so we're really filling their whole visual field. These also shows just how we can use taste. This is for a taste study that we did a number of years ago. 

These are five different tastes that all centralize on a single tube and then drop this substance into a person's mouth, so there's some really cool things we can look at and do studies of olfaction, as well, so smell. Here's the basic paradigm. You might just look at that, so I just want to show you that picture, that kind of gory image a few minutes ago. It was nice and small. But this, what you want to think about is this is your entire visual field, because that's the way it is when you're in the scanner, so this is a huge minus sign. Nothing particularly bad about that. But then after a short duration, this is little dog is all of a sudden pretty menacing. It's right up in your face showing you some teeth, okay, and it gets a reaction in folks. A circle always is followed by a chair. Then a minus sign. 

Those of you who have just had some dinner, or don't particularly like gory images, you can look down on this one, but I feel like it's important to show these gory images, because we use them a lot. The reason that we use them is because they are very universally, with the exception of med students, very universally viewed as being quite aversive, where as a lot of the other stimuli, like the dog, doesn't really have quite as big of a hit for people. You might say well, why are you being so mean to your subjects, you give them all this aversive stuff. There's a specific reason why I'm doing that. That is because that image is nowhere near as bad as actually a single panic attack. That image and what's going on in these paradigms is nothing compared to the anxiety and suffering that I see in the patients that come into the clinic. So what I'm trying to do is, you know, develop a proxy for anticipating really bad things. So this is just the final slide. Then, what we found in this particular study, and I went in saying, okay, I'm going to have a really good paper that's going to say here's the area of the brain that's really involved in the anticipation of aversion. We looked and we looked, and we kind of saw something here, but there really wasn't anything that was really specific to anticipating aversion, anticipating bad pictures. 

Instead what we saw is that, here's some of the brain regions, and those of you who can see, some of you are pretty quick and can figure out what these regions are. Those of you who need a little help, I'll bring in some titles for you. But what we saw was the very brain regions that activated in response to aversion also were activating in response to the minus sign. Amygdala, hippocampus, cingulate, prefrontal areas, insula. All the brain regions that had been highlighted in the work prior to me doing this study, in symptom provocation and response to really bad things, they were all showing up here in response to the minus sign. So here it is. It's all these brain areas that I just showed you in the previous slide when I was introducing some of the key areas. They're all engaged, so we don't have just one area that's involved in responding to fearful or aversive stimuli. So the work that we did essentially showed that the anticipation of aversion recruits the same brain areas as exposure to aversion. There are similar effects across a variety of different stimuli and modalities. 

I've replicated the findings I just showed you there in a number of different papers that are highlighted here, a number of different samples. We've done it with video clips. We've done it with taste. And we've done it now with pain, from thermal pain or electrical stimulation or shock. Then one thing, part of what I want to do in this talk is not just throw a bunch of data at you on what we find. I want to share with you what it is that we know about anxiety. I also want to give you a sense for what it's like to be in the lab. I mean, that's what this is all about, Wednesday Nite at the Lab, is what it's like to be in the lab, and how you go about studying these things, and what are the important things to be thinking about. I talked to you at the outset about thinking carefully about what the construct of interest is, anxiety in our case, in this case. Here, another really important aspect of neuroimaging research, which was totally ignored ten years ago, and still is ignored by some groups to some degree, is to get past just showing a pretty picture. 

Just, oh, wow, I've got this nice, beautiful activation, those pictures I've just showed you. It's like, oh, neat, you know, you can get that in. But what are all these areas doing? Are they all doing the same thing? Is one involved in one thing more than the other? That's what we've done in the subsequent studies, is found out what area is involved in emotional memory. What area is involved in regulatory processes. What area is involved in negative affect and threat-related vigilance. It's indeed not all the areas. Different areas are doing different things. Rather than me going into each of the brain areas here, mostly this slide is here just to illustrate that point. Then we go to what I'm very interested in. That is, are there anomalies, are there irregularities in the circuitry in anxiety disorders. 

Anticipation about negative outcomes is essential to the debilitating consequences seen in anxiety disorders. How does this manifest in the brain? The disorder we started out with was the one that was the most obvious to be looking at anticipatory processes, because it's defined by anticipatory processes. The hallmark feature of generalized anxiety disorder is excessive, uncontrollable worry about possible adverse events in the future. This excess results in significant distress and really impairs people's day to day functioning. There have been a number of different theories put out there about psychological mechanisms involved in GAD. There's the work I've done with anticipation, suggesting anticipating bad things that might happen in the future is key to understanding all the anxiety disorders and why they can be debilitating. I'm not the first one to come out with that. I'm the first one to do that with brain imaging work, but David Barlow is an important anxiety researcher that has highlighted that in his own work. Regulatory processes, to the extent that emotion regulation processes are happening, so as things are coming online, maybe the emotion expression and generation is perfectly normal, but what wrong with people with anxiety disorders is they're not regulating that step in some way. So, there's theories about that. 

Finally, it's important to just acknowledge the avoidance theory of generalized anxiety disorder and of worry, which suggests that what -- argued, which is that by worrying people, although not necessarily trying to do this, what they're doing is actually avoiding more negative emotions by getting caught up in the cognitions of worry. Again, this is just a slide to just say, so in this first study we had a small group of participants, 14 generalized anxiety disorder patients, 12 controls. Again, the idea here is just to give you an idea of what this kind of research looks like. Here, we were looking for what we call a squeaky clean patient group, because a lot of people who have generalized anxiety disorder also have social anxiety disorder, also have major depressive disorder and depression. We were really looking for, in this first study, people that just had GAD, pure and simple. What we found is that of all of the different brain areas that I showed you before, and contrary to some of the predictions I had, which I thought the insula was going to really be the place that was going to show the difference in our patients, the one area that showed the difference was in the amygdala, and it's in the bilateral amygdala. The difference is really interesting. Because what's shown here in the red bars is the response to the minus sign for the patients and then for the controls here. This is just for the right amygdala and the left amygdala. That's all this is. 

You'll notice, yeah, there's a lot more activity in the patients to the minus sign than there is in control. But what's shown in blue is the circles. Look what you see there. You're seeing the same pattern in this area of the amygdala, where the blue is showing more activity in the patients than in control. If you've ever known somebody who has suffered from generalized anxiety disorder, you would say to this, well, yeah, of course, because that's just they way these folks are. They're just kind of, you just start talking about the future, or acknowledge the future, and these folks are revved up. Essentially, what we're finding here is the amygdala is firing once I put up anything that's saying, hey, something's about to happen in the future, even if I told them that what's about to happen in the future is innocuous, it's not going to be a bad image at all. Maybe there's some, yeah, but maybe this time I will get the bad image. We don't know exactly what's going on. But that's what our data is showing in the amygdala. 

In addition, in this particular study, we were able to administer some medication for an eight-week period that followed, that is the standard medication and is provided by Wyeth, a pharmaceutical industry. So what we were able to do, is to use the pre-treatment, so before they started getting treatment, we looked at the brain activity to see whether we could predict treatment response. There's some people that respond to meds, and there's others that don't. What we found is that the more anticipatory activity that you had in the anterior cingulate cortex, in this region, the better was your response to Effexor after an eight-week trial of Effexor. These people up here had big changes in their symptoms, and huge symptom reduction, whereas these people down here did not. We see this for two different measures of anxiety. So that is suggesting, here we've got the ACC. What exactly is this area doing? So the idea here is that it's involved in regulation, and it may be somehow linked up with resilience. If you have a certain amount of, you know, baseline activity going on here, even though you're struggling with anxiety, you may be one of the people that's going to respond better to treatments. That's what we think is going on. 

We took the next step here to really look at this circuitry that's involved in this regulation, this ventromedial prefrontal cortex, as well as the anterior cingulate cortex, looking at how it might be involved in emotion regulation and perceived control. So top down, we know from other work that it's involved in the modulation of amygdala and other areas. There's direct connections between those regions, and I'll show you some data supporting that in a few minutes. Again, this may be really important for the construct of resilience, as well as for helping us to predict who's going to respond better to which treatments. In the study, what we did was built on some work that has shown that perceived controllability is core feature of resilience, and also what we know so well is that part of why anticipation of bad things happening in the future is such a problem for people with anxiety disorders is because there's no controllability. We can't, general speaking, control what's going to happen in the future. This lack of controllability has also been found to be very important for depression and has led to what's talked about is this next point, the helplessness theory of depression. Essentially, this is an animal model that was developed by Marty Seligman and held up by others, that has shown, that's elucidated some of the neurobiological mechanisms that are involved when an animal does not have control over avoiding some sort of really aversive circumstances. What they found is the VM, ventromedial prefrontal cortex, activity inhibits normative stress responses in the amygdala and other areas. This becomes a key region to take a look at. 

That's why we designed the study, to test whether the vmPFC is also critical for controllability in humans. What we did, was we used a clever design where we brought in 20 snake phobics into the lab. They were otherwise healthy, didn't have to meet criteria for any other anxiety disorders or for depression. But what we know with them is they really fear snake images. What we did is on half of the trials, we put up an anticipatory cue that indicated that they could avert a video presentation of a snake if they responded quickly enough to the target. For the other half of the trials, the cue indicated that the response time to the target, so they still were asked to respond as quick as they could to the target, but that it had no impact on whether or not the video would be presented. That's the uncontrolled situation. Hang with me on this for just a second, because that might look a little bit busy. But what I'm doing here, is rather than walking you through a set of trials horizontally as I did before, we're now just doing it vertically at this oblique angle. So what we have here at the start of the trial is, and you can't see it very well with this light, is up here is an "S", and it's in blue. 

The S signifies, this is a possibility you're going to see a snake. The blue signifies, this is a possible controllable trial. If you press the button fast enough here, you can avoid seeing this image. So that's what happens, come down here, the S, and boom, here comes the square. You press the button as quickly as possible while you're in the scanner. If you're quick enough, you get to go down this route and you just see, you know, a fixation cross until the next trial. If you're not quick enough, then boom, you're over here, you view a three-second video of a snake. Remember, this looks pretty harmless here, but when you have that filling up your whole visual field, that's pretty horrific for somebody who's got snake phobia. Then what you're doing right after that, is you're providing some ratings of how aversive or fearful that stimulus was there, and that's the end of the trial. On the other hand, if you're in an uncontrollable condition, that's indicated by yellow. 

People are instructed about that at the outset. Again, it's an S, suggesting it's a snake, or indicated it's a snake trial. Here comes the red square. You still press very quickly, but this time, it doesn't matter. You may get this on some trials and you won't on others. Then here is the snake that you're looking at. There we go. So, it's not just a static image of a snake. It's a snake that's moving for three seconds. There are some that are up like this, doing this kind of thing. 

So it's freaky, even for people that don't have snake phobia, when you're actually in the scanner. Then for our control stimulus, we used a fish. Initially, I thought about using and I proposed in the grant that we got to fund this project, to use a turtle, because I'm like, oh, another reptile. But you know, turtles, they don't do a whole lot in three seconds. [laughter] So we had to move over to fish, which had a kind of similar type of motion, right? So that's what our fish stimulus was. Then, but remember, what we're looking at is not just responses to those. We're looking specifically in this ventromedial area of the cortex, to see if when things are controllable, when you're looking at a controllable snake versus an uncontrollable snake, whether it's a controllable snake versus a controllable fish, whether this area is going to be activated. What we find is indeed an area very up front of the ventromedial prefrontal cortex is showing more activation when people are seeing the blue S. That's all that this is a response to, prior to seeing the snake. They know they have some control, and they're ready to go. 

Then what we also looked at is, well, okay, that's good to see that activation. That's what we want. But does that really involved, in any way, with the amygdala? Here's where you have to go beyond functional activation, which is what I talked at the outset, and we're now talking about functional conductivity. So what we do, is special types of methods where you can look at the connections between the activation of different areas across the whole brain, with that ventromedial prefrontal area. We call it our seed region. Then we see what else in the brain is correlated with it. And lo and behold, you have both amygdala that are highly correlated with it, and also directly above that, another really interesting area that we've been paying more attention to lately, the BNST. At any rate, this amygdala is what's the focus here. Then what we're seeing here is that there's much greater conductivity with that amygdala during the controllable snake than there is during the controllable fish for both the right and the left amygdala. Let me just kind of sum up where we've been so far, and make sure that I've got everybody here with me. 

So, GAD patients, these are generalized anxiety disorder, showed greater amygdala activity than healthy controls in anticipation of both aversive and neutral pictures, which is consistent with hypervigilance in GAD. Among GAD patients, pretreatment, ACC activation in anticipation in both aversive and neutral stimuli predicts treatment response to venlafaxine or Effexor, eight weeks later. Then, the controllability data. When you give a person some control over bad things that might happen, their bringing the vmPFC online to be involved in the top-down regulation of the amygdala and other areas that respond to stress. So, is elevated anticipatory amygdala activity in GAD due to a top-down regulatory deficit, or is it just that the amygdala is just activating so strongly, even though you have good regulation coming from the prefrontal cortex, it's just so strong that regulation just can't keep up with it. There's a number of ways that we can look at this. The way that we have focused on is now using a different technology, is just to look at the white matter, the structural connections between that ventromedial prefrontal area and the amygdala. So what we know is that, as I mentioned before, these areas are importantly involved in the top-down regulation of the amygdala, as well as, and also serves other regulatory functions. The incinate fasciculus is the what matter tract that connects these two area, and I'll show you that in just a moment. In this particular study, we have a much larger, and some people had no other disorders, but a number of people also had social anxiety disorder and major depression, and that's what's illustrated here. 

Then our controls, they had no family history of mental illness, and they don't have any mental illness themselves, either. So what we were looking at here is to test the hypothesis that GAD patients would exhibit reduced structural conductivity between these ventro regions of prefrontal cortex and the amygdala, as indexed by new tractography methods for DTI. Tractography methods just means analyses that are used to really elucidate how strong connections are between two areas. So this is what we are looking at. We're now at the front of the brain. I'll walk through this probably twice. But what you can see illustrated here is the uncinate fasciculus. Right here is where the amygdala is. So now we're in the back of the brain, seeing where the amygdala would be. Then it connects. 

These are all axons bound together, many millions of axons bound together in big white matter fiber bundles. I'll show you again, just so you really can get a good sense of it. Here we are at the front of the brain. This is the ventromedial prefrontal cortex, where a lot of these axons terminate. Then on the backside, they terminate in the amygdala, using that kind of a shape. What we found in this study is that the GAD folks indeed showed less conductivity in this uncinate fasciculus tract than did the controls. That's shown for both the left uncinate fasciculus, as well as for the right. It's shown across all the participants that we had, as well as it was shown just in looking at the 21 subjects that had no other co-morbidities. We know that it isn't just, it's not social anxiety disorder or major depression that's leading to some of these differences. But again, we want to say, well, that's nice we've got that, but does that have any significance for functional relationships. 

So what we did was actually look at whether there's any association of that tract to what should be negative conductivity between the ventral prefrontal cortex and the amygdala. What this shows is there indeed was an association, both in the controls, as well as in the GAD subjects with people that have more structural conductivity between, or in these regions, are showing a greater negative functional connection between those regions, indicating the more ventomedial prefrontal cortex activity you have, the less amygdala activity you have. [inaudible] >> ...the scale, the difference between .32 and .30, is that a magnitude? Is there some way to describe that difference? >> The question, just so everybody can hear, is there a way to describe the difference along the scale, so the magnitude of the difference, say here on the X-axis, between .32 and .34. Essentially, I'd have to get a little bit more into exactly what's being measured. It's called fractional anisotrophy. But what it's just showing is there's probably not-- If somebody has .34, and somebody else has .32, it's not like one person has a lot of dysfunction and the other person doesn't. I mean, this is, you know, the levels that you're seeing is really along a bell curve. However, once you start talking about something at .38, and somebody down here at .30, you're talking about, you know, some pretty dramatic difference in the amount of white matter that these individuals have. [inaudible] Yes. The question was, is it distributed normally, and yes is the answer. 

This image has now taken uncinate fasciculus outside and saying, in these patients, do we see any group differences in functional conductivity between these areas. This is similar to the approach that we used in the controllability study, looking at the ventromedial prefrontal cortex being associated with the amygdala. Here, what we see is that the GAD patients show less, reduced ACC-amygdala negative coupling, compared to the control. So the controls are showing this pattern of more ventromedial prefrontal cortex and less amygdala, which is what you're expecting to see. The controls, if anything, are showing equivalent levels of activation of both. So again, here is just some summary there. GAD patients have reduced white matter conductivity between the ventromedial prefrontal cortex and the amygdala. This structural conductivity in the uncinate fasciculus is associated with functional conductivity between the ACC and the amygdala, and that's what we're really interested in. This white matter abnormality, so what does this mean? This white matter abnormality may lead to poorer top-down regulation of the amygdala, resulting in the elevated anticipatory activity that's observed in generalized anxiety disorder. That was the first study that I showed you with patients. 

Indeed, this compromised top-down modulation of the amygdala may correspond to emotion regulation deficits in generalized anxiety disorder. Now I'm going to show you just a snippet to show you we are doing some work on this level, as well, because in the same group of patients, we actually just went in and said, hey, what's going on in the gray matter? Are there any differences anywhere in the brain? In particular, are there any differences in the amygdala or in this ventromedial prefrontal cortex area. We don't see anything anywhere, except for, so nowhere in the brain except for bilaterally, a little bit more on the lateral side, so toward the outside of the brain. Again, but ventral surface of the brain that is the orbitofrontal cortex, where there is reduced volume in this area amongst people with GAD. So, part of my title was "uncertainty." And some of you may be saying, well, what happened to uncertainty in this whole thing. Well, here's the uncertainty. Let's just now take a look, again, at anxiety. Because what I've talked about is anxiety and the anticipation of bad things happening as being, you know, the problematic component of it. But really, what's central to the anticipation of bad things happening is the fact that one, it's uncontrollable, but two, is that we don't know what's going to happen. The future is inherently uncertain. 

So, if we could know what the future was, if we had that crystal ball, even though we might be concerned, or not like something that's going to happen in the future, our anxiety levels are going to go way down. The bottom line, too, is the vast majority of what patients worry about and probably a lot of us who aren't patients worry about, never comes to pass. So if you're honest with yourself about what you worry about, and then whether or not that actually ends up happening, you know, oftentimes, it doesn't end up happening. So you're basically putting a lot of energy into, you know, something that never comes to pass. If we had that certainty, we wouldn't have that problem. This uncertainty is absolutely critical for anxiety. So, one of the first ways we started to look at that was just to look at, was to include-- Here I just have an "X" instead of a minus sign. It's the same type of anticipation paradigm I showed you before, an X before aversive, an O before neutral pictures. But now we add a question mark to the game. That is, when they see a question mark, I told them it's either going to be followed by aversive or neutral pictures, as you can see two example trials here, one with aversive and one with a neutral. 

Then here what we see that's very interesting is that the responses in the amygdala and in the insula are much larger to aversive pictures, the same aversive pictures I showed you before, are much larger to aversive pictures if it follows a question mark as compared to if it follows the X. So that whole thing that I just said, you know, if it's uncertain, it's really ramping up our brains and our responses to aversive things that are coming to pass. So, here just very briefly, insula and amygdala activation to aversive pictures were larger after an uncertain cue than a certain cue. Important for this is that ACC activity, that same area I've been talking about throughout this talk, its amount of activation to the cue, to the question mark and to the X is predicting how much of a difference there is to the pictures that follow that cue to the aversive pictures. So we're able to kind of spell out the trajectory of time. This ACC is getting activated first and sending an important message to the insula and the amygdala, telling it the level of modulation that should occur, and then the insula and amygdala are doing their things. So let me return to this question. I just laid out a bunch of stuff about what's going on in the brain with anxiety. So what is anxiety? I'm now going to define it much more explicitly. It's an emotional state that's characterized by anticipatory, affective, cognitive, and behavioral changes in response to uncertainty about potential future threat. 

Let me just say that one more time. It's an emotional state that's characterized by anticipatory, affective, cognitive, and behavioral changes in response to uncertainty about bad things potentially happening in the future. This is the basis of the new model that we've developed. It's called UAMA, Uncertainty and Anticipation Model of Anxiety. It's actually, I think, going to be out later this week in Nature Reviews Neuroscience. If not, it's coming out within the next couple of weeks, we've been told. The model essentially posits the following, that an essential feature of all anxiety disorders is this aberrant and excessive anticipatory responding under conditions of threat uncertainty, in other words, extreme worry. This model identifies five processes that are involved in adaptive responses to threat uncertainty that function maladaptively in anxiety. Inflated estimates, heightened estimates of the cost and probability of threatening events. What that means is there are inflated estimates that whatever is about to happen, it's much more likely to happen than it actually is, and it's ending much worse than it actually will be. 

Hypervigilance and increased attention to threat. That's a key aspect of the various anxiety disorders, particularly pronounced in post traumatic stress disorder. There's deficient learning about safety. So, people learning that certain symbols that they've come to think might be dangerous, really aren't dangerous and that may be really difficult for people with anxiety to just learn online as they're walking through life. Then there's behavioral and cognitive avoidance, avoiding things that are related to your anxiety that lead to triggers of some of the symptoms that you might have. Finally, there's heightened reactivity to threat uncertainty. Here is just a figure from that. I'm not going to go into all the details, but just to lay it out a little bit. Process number one, the brain regions involved are here. Here's process two. 

Here's process three, process four, process five. Then here in the middle is the proposed role of the interior midcingulate cortex. This is an area that's a little bit further back from the cingulate cortex right on top of the corpus callosum, that maybe is serving very important functions in terms of modulating some of the other circuitry that serves these five different functions. Here are just how these different psychological processes, again, A, B, C, D, E, are just processes one thorough five, are working together, and how they all relate to these elevated threat expectations. This is this anticipation that bad things might happen and it's going to be bad. Finally, what I'd like to do is just talk about some research that we've been doing over this past year that's really exciting to me, and also has become very deeply meaningful for me in ways that my other research has not. It's been working with veterans that are coming back from Afghanistan and Iraq. This started with me thinking, oh, wow, this is a convenient sample for me to take my work into yet another anxiety disorder. It's become so much more than that, as I've realized and come to have an appreciation of what it is that these individuals have sacrificed, ways in which they have been trained that actually are encouraging PTSD symptoms, but also make them very good fighters, and just the degree of suffering that's occurring as they're coming back with what they've been trained to do, and then walking back into their home lives and facing the difficulties there. What we have done is developed two intervention programs. 

One is called Sudarshan Kriya Yoga, SKY program, which is a breathing-based meditation program that incorporates basic yoga movements. Then a second program that we're comparing it to is a mindfulness program that's gotten a lot of attention here in the community and throughout the country, and now the world, as a mindfulness-based meditation practice. This particular branch also incorporates some basic Tae Kwon Do movements. What people do, is they come in, we scan them during a paradigm I'm going to show you in just a second. Then they participate in a seven-day intervention program. It's a short treatment program, but it's intensive. It's three hours per day for seven days. Then we are measuring their brain activity right after they get done with the program. The format of both of the intervention programs is as I just said, three hours per day for seven consecutive days. They're group-based programs. 

There's a wait-list control group, so these are randomized to either one of those treatment options or to the control wait-list group. The veterans are offered participation in subsequent intervention waves. We run this in intervention waves. Then there's a non-PTSD control group. These are veterans without PTSD who do not get the intervention. Here's the paradigm I'm just going to walk you through this. This is what people are doing. It doesn't involve pictures. But when they see the blue, they're told that's safe. That little red mark means that the trial is going to end, and they'll just get a little beep of noise, which hopefully you'll hear. 

[beep] So they know that's predictable and there's no uncertainty. It's like, boom, I'm going to get that then. So we run a safe trial. Now, it's unpredictable. They don't know when they're going to get this little beep, but it's not, you know, the little sound is not going to bother anybody. Again, this is our safe trial. That hand could just go, or it could stop, you don't know where it is. [beep] That's our measure of predictability. Now we have the yellow trials. The yellow trials means there's a possibility of an electrical stimulation that they receive on their wrist. 

So now, the guy knows when they're going to get that here. [beep] And boom, that's what happens. It doesn't occur on every single trial. It occurs on a third of the trials. But here, it's unpredictable. So they're like, uh-oh, when's this thing coming? [beep] You know, it's a very different process that's going on for somebody. What we found, these data are actively being analyzed. Dan Grupe in my laboratory, he's an advanced graduate student. This is his dissertation. He has been instrumental in this work, as well as in the development of our model. 

It's a model that we've written, developed together. So in our early findings that were just recently presented, what we're seeing here is that this is a main effect of that threat condition. So this is just as we would expect to see, certain brain regions showing more activity. We see that, you know, in the insula really big. We see that in the anterior cingulate and the cingulate cortex, the mid-cingulate cortex. Then we're seeing some greater activation in this ventral area, to safety. That area of the brain is again, signaling, hey, we don't need to be involved here, is activating very appropriately across all of our veterans that are coming back. Here's some group differences that are going on. This is veterans compared to veterans with and without PTSD. We're seeing this group difference that is driven by the unpredictable trials. 

Some of these legends are not totally intuitive for people outside of my lab. But at any rate, here are the predictable trials, so these are predictable threat and predictable safe. What you're seeing is that there's not a huge difference between the two groups in terms of what's going on between the two things here. It's over here in unpredictable where things start to change. The PTSD group kind of looks like they're still doing predictable. There's not much differentiation. But the controls, people that don't have PTSD, they're showing this really large difference here. Really, what they're doing is showing a response to the safe trial that's much, much larger than to the threat trial here. So these are data that just, you know, that's just hopefully an enticing tidbit of the directions that we're going here. These data are actively being processed, because he is going to be defending his dissertation at the end of the summer, Dan Grupe. 

So, just in terms of conclusions. Anticipatory dysfunction in the face of uncertainty is essential feature of anxiety disorders. It has a role in pathophysiology. It may have promise as a prognostic tool. What's that, a prognostic tool? That's where you can use pretreatment brain activity to predict a person's response to a treatment. Then it has potential as a therapeutic target. So we could have treatments that are targeting anticipation and uncertainty, and potential that they'd reduce anxiety and suffering. You could do this with psychotherapy, but you could also do this with different types of biological means, by going in and targeting brain regions that we know show differences in anticipatory processing. Then regulatory dysfunction, this is emotion regulation and modulation I've been talking about. It's also, we know, going to be important in anxiety disorders. 

It's again, going to have a role in the development and the expression of the disease, as well as going to have potential as a therapeutic target. As I said, teaching effective regulation skills for overcoming the excessive anticipatory responding to uncertainty. In other words, skills for reducing worry. Future directions in our lab and in the field. This is what's on the horizon, is really to start to develop variables and different types of groupings that show promises for a different way of classifying the anxiety disorders. It may lead to a different way of conceptualizing how we think about anxiety that might help us to treat and to reach more people more effectively. There's a lot of classifier approach, cluster analysis. These are different types of statistical methods that have been developed that we can use to do this. We may have an idea, those of you who know this term, DSM-IV, DSM-V, it's kind of the bible or the descriptive manual of mental illness. That may look very different when we come out with DSM-VI, if we can utilize these types of approaches. 

And very important to me is just the identification of variables that show promise for guiding treatment decisions. This is already happening with various forms of cancer. This is definitely on the horizon for different types of mental illness, as well. You would use pretreatment MRI, DTI data as a prognostic tool to predict treatment outcome. Then finally, anxiety disorders can not be reduced-- So here are some take-home messages. If you're not going to remember much from here, this is what I'd like you to take from here. Anxiety disorders cannot be reduced to abnormalities in a single brain region or system. Understanding anxiety disorders and how to best treat them will come through research across multiple domains. I didn't talk about genes here, but we're doing some genetic work. A lot of that's going on in this building, as well. 

We're relating that to some brain data we have, and there is structural and functional conductivity, peripheral psychophysiology, heart rate, skin conductiveness, behavior, a whole range of different factors that are going to be important to understand as we move forward in our understanding and treatment of anxiety disorders. We also want to appreciate the complexity of the brain and anxiety disorders. It's not a simple one-to-one correspondence. There's likely a number of different brain regions that are involved that are serving a variety of functions that are importantly involved in anxiety. The question is, are we on the right track in our current conceptualization and labeling of anxiety disorders. Finally, as relates to this last study that I spoke about, it's of paramount importance the realization of how much the men and women serving in the OEF/OIF/OND Iraq and Afghanistan conflicts, dating back to 2001 have sacrificed and are now suffering, and certainly other conflicts have done or had the same type of sacrifice. But this is what we're really seeing right now. We have currently today, from these conflicts, we have more people dying at home by their own hand, than we have dying over there. That's a tragedy that we need to be rectifying. The mission of our research now is really to push us forward as much as possible in reaching these veterans with effective treatments. 

Finally, I just want to say that this work is in no way near possible for me to be doing on my own. There's a huge number of people who have contributed in a variety of different ways. I've highlighted the individuals, in orange, that have played particularly important roles in this work, and then also some of the funding agencies that have helped this expensive research to be conducted. So with that, thank you very much for your attention. [applause]