WPT University Place Wednesday Nite at the Lab  Michael Koenigs, "How the Brain Makes Up the Mind"  November 10, 2010 UP 518     cc >> Tom Zinnen: 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, and on behalf of our partners, the Wisconsin Public Television folks and the Wisconsin Alumni Association and especially tonight with the Wisconsin Veterans Museum, welcome to Wednesday Nite at the Lab. We do this every Wednesday night, 50 times a year. Tonight, I'm delighted to be able to introduce to you Michael Koenigs. He's an assistant professor in the Department of Psychiatry here at the UW Madison School of Medicine and Public Health. He was born and raised in Fond du Lac, Wisconsin. And he went to school at the University of Wisconsin-Madison. And he graduated in 2002, but he looks like he graduated about last year. 

[LAUGHTER] Sorry about that. And after he graduated from here he went to graduate school at the University of Iowa and got his PhD in neuroscience and then he went on to a post-doc at the National Institutes of Health just north of Washington, DC, in Bethesda. Part of his work was studying Vietnam veterans with brain injuries suffered during combat. About two years ago he was hired here and is currently studying brain damaged patients at the UW Hospital, as well as in prison inmates, especially psychopaths, through the Wisconsin Department of Corrections. I specifically asked Michael if he could talk tonight because it is the day before Veterans Day, and I think it's really appropriate. Two years ago we had an historian of science talk about the role of science in World War I, and so, on these days, especially since my dad and my grandpa were both veterans, I always like to have something special for Veterans Day. Tonight's that night. Please join me in welcoming Michael Koenigs to Wednesday Nite at the Lab. [APPLAUSE]  >> Michael Koenigs: Thank you very much for having me. I'm really pleased to be able to do this. 

We're going to get to talking about veterans in a little bit but a lot of ground to cover before that. The topic how the brain makes up the mind, there's really, I guess, two ways to take this. So one is how the brain composes the mind, so how we have a mind at all. Then the other thing is how the brain contributes to decision making by the mind. So we'll explore both of those themes in this talk. So the story about how the brain makes up the mind really starts over 200 years ago in Vermont. And it starts with a railroad crew who was trying to lay tracks through a rocky mountainous region. And so as you can imagine if you're trying to lay tracks in a mountain it doesn't really work. Railroad tracks have to lay relatively flat. So if you want to have a train go through a mountainous region, you have to find a way to flatten the land. 

And how this was done in the 1800s was with dynamite. More specifically how it was done is you would break a hole into the rocks, fill it with gun powder, then you would fill the hole or you'd feed a wick, then fill the hole with sand, light the wick, get the hell out of there and boom, flatten the land. Well the tool that you would use to pack this sand down into the hole is something called a tamping iron or a tamping rod. A tamping rod looks like this. So this is in relation to a human head. And this is what you would call foreshadowing. [LAUGHTER] So Phineas Gage was a foreman of this railroad crew. And so one day it was his job to do the tamping. And so he has this rod, it's about three feet long and about an inch thick, and he thrusts it into this rock expecting there to be sand in there. The sand was missing. 

He lit a spark. The dynamite blew and shot the rod through his face and out the top of his head. So you could say what a gruesome way to die, what does this have to do with decision making in the brain. But in fact he didn't die. And this is the write up from the Ludlow, Vermont, Union for the next day. And so you can see at the end of this little write up is says "The most singular circumstance connected with this melancholy affair is that he was alive at 2:00 this afternoon and in full possession of his reason and free from pain." So this shot through his head presumably damaged some part of his brain but whatever part of the brain that was damaged seems not to be important for your ability to walk, or talk, or think. However, this patient was followed up for a number of years later by his neurologist who is named John Harlow, and the very literal title of this report was "Passage of an Iron Bar Through the Head." [LAUGHTER] And here's an excerpt from that report. So what he describes here is a very marked change in personality. So Phineas became profane, disrespectful, irresponsible, traits that were not characteristic of his former self. And the changes were so striking indeed that his acquaintances remarked that his mind was radically changed and that he was no longer Gage, he was no longer the same person. 

Phineas' skull was been preserved, and I think it's in a museum actually at Harvard. So you can see the holes where the rod went in and out. And based on those holes some colleagues of mine at the University of Iowa did some calculations, and they figured out what part of the brain was likely damaged by this rod passing through the head. And so that's what's shown in these slices there at the bottom. So you're looking at the brain in a plane like this. What they call an axial plane. And you can see in the top left slice there the eye is at the top. So that would be the front of the head and the bottom of the head. And you can see the white circle is where the rod went through. So you can see it's really going through the front of his head, front of his brain, really above and between the eyes. 

So in this area here. All right, fast forward a couple of years to another individual who I had a pleasure meeting and spending a fair amount of time with myself. This is a neurological patient that goes by the initials EVR, and in some senses he's a modern Phineas Gage. Here's the brain of this patient. So what you're looking at there on the left is a midline view of the left hemisphere. So the back is to the left and the front is to the right. Then the other upper right portion there you're looking at the right hemisphere, midline view. And on the bottom you're looking at the brain from the bottom. And so what you can see there is that very conspicuous area of black in the brain. So that's missing brain tissue. 

The reason that tissue is missing is this patient had a tumor that grew in that area of the brain that had to be surgically removed. And when the tumor was removed that part of the brain was removed as well. So like Phineas Gage, this patient survived and is still living to this day. He's lived for at least 30 years since he's had this tumor removed. And also like Phineas Gage, he had some striking changes in his personality. So before he had this tumor, he was the chief accountant at a small firm, supervised a number of employees, regularly secured promotions for good performance at work. He was married and a good father. Had to two very well-adjusted children and a stable marriage. Well-respected by his peers and co-workers and family. By all accounts just a smart guy who had his life together and was doing very well. 

So after this area of brain damage, or what we call a brain lesion, he quickly became bankrupt, made a lot of very speculative ill-informed financial decisions, very risky. He was divorced from his wife of a number of years, remarried a woman of questionable reputation, was very quickly re-divorced from her. During this process, became estranged from his family and friends. And there were two very striking changes in his emotional makeup. So one was that he didn't exhibit any kind of guilt or empathy for anything that was going on. And the other was he had very poorly modulated anger. So he was very quick to be frustrated, would get very upset, loud and aggressive, but very quickly forget about it and act like nothing happened. Very interesting thing about this is we gave him a number of IQ tests since his brain injury and he still scores very highly. So I think the highest he's ever scored on a conventional IQ test is about 140. Which is more than two standard deviations above the normal mean, and I would venture to guess higher than most of us, if not all of us, in here. 

So what this patient, what Phineas Gage and this patient really indicate to us is it takes a lot more than an IQ score to navigate your life effectively. So what this indicates is there's something fundamentally important about this area of the brain. So I'm going to call this area of the brain ventral medial prefrontal cortex. Ventral means belly so it's the lower part of your brain. Medial means middle. Prefrontal is in the front. So ventral medial prefrontal cortex. I promise I'm not going to use a lot of words like this but just bear with this one. So anyway, the point is that this area of the brain is really responsible for something fundamental about how we interact with each other, how we make decisions for ourselves. So the question that's been motivating my research or a good portion of my research is how this area of the brain influences decision making. 

And so one way to test that is to collect a number of patients who have damage to this area of the brain. And so these are all individuals, again you're looking at the midline views of their brain, the left hemisphere on the left and the right hemisphere on the right. And the area red shows what it damaged. So these were either patients that had tumors surgically removed from their brains, aneurysm ruptures that had involved a hemorrhage and a loss of some brain tissue, things like that. A stroke, things of that nature. And so you can see all six of these individuals had damage that included this ventral medial sector. >> Are these images taken by some kind of scanning? >> Yes, these are done originally in either an MRI or a CT. This isn't the image you get from the MRI or CT, this is more of a cartoon that we make just to illustrate clearly the lesion. And so what we do, I guess this is a good question, so what we want to do is be able to directly compare these areas of damage in sort of the same virtual brain space. If that makes sense. 

So this is how we do that with analysis that we call lesion overlap map. And so what this lesion shows, or what this map shows is the degree of overlapping lesions in those six patients that I showed you. So the hotter colors, the reds, indicate the greater degree of overlap. So where you see the deep red is where all six of those patients had damage. And so the deep red area that stands out is, again, this area in right above and between the eyes. This area I've been calling the ventral medial prefrontal cortex. So we have these six patients that all have damage in this area, and so if they all share some common decision making impairment we could, I think, reasonably infer that that impairment is due to damage of this area, and thus the damage to this area is critical for whatever function is impaired. And so to describe some of the research I've been doing, the question I was thinking about is what kind of decisions rely on emotion? So what we saw in these patients is they have these certain very diminished emotions and other emotions they have a hard time controlling, how might that affect their decision making? So one domain of decision making that probably relies on emotional input to some degree is moral judgment, morality. Now throughout history a lot of very deep thinkers have weighed in on what is the basis of human morality. And you'll see there's very little consensus on what that is. 

This debate really crystallized around one question in the 1700s, and there were sort of two sides of the question. One was posed by Immanuel Kant. He firmly believed that morality was a product about reason. So he was this worshipper of reason. He would say all our knowledge begins with the senses, proceeds then to the understanding and ends with reason. There's nothing higher than reason. So in his view if we could just rationally think about the outcomes and the considerations that would be sufficient to determine what is the morally right thing to do. David Hume had a very different idea. So he says the rules of morality are not the conclusion of reason, reason is and ought to be the slave of the passion. So in this view, our moral judgments are determined by a more intuitive or affective instinct and that we use reason maybe just to rationalize or justify what we feel is the right or wrong thing to do. 

So which one of these viewpoints is right? In order to test this question, we again turn to philosophy. And philosophers have developed this thought experiment they call the trolley paradox. The trolley paradox works like this. So imagine you're this guy with the blue pants and the red shirt right there. You're standing next to a train track. Now you notice there's a trolley barreling down this track. If you don't do anything, the trolley and going to take the track to the left and kill that unsuspecting workman. I'm sorry, if you do nothing, the trolley is going to go to the right and kill those five unsuspecting workman. But you realize you're standing next the switch in a track, and if you pull this switch, the trolley will switch tracks and kill the one workman instead of the five. So let's take a poll in here, who thinks it's the morally right thing to do to pull this switch so the train will switch tracks and kill the one person instead of the five? So virtually everybody in here thinks that's the morally right thing to do and why is that? Who said yes? >> Greatest good for the greatest number. 

>> Greatest good for the greatest number. It's a math problem. Easy. So now consider this slightly more ridiculous hypothetical situation. So again you're standing near this train track. If you do nothing this trolley is going to come down and kill these five unsuspecting workmen again. You happen to standing on a foot bridge over this train track, and you happen to be standing next to a large stranger on this foot bridge. [LAUGHTER] And you realize if you push this stranger to his death, he'll stop the trolley and these five people will be saved. So who here would push an innocent stranger to his death to save those five workmen? Right. So who said before it's a math problem? [LAUGHTER] So how is the equation different here? So someone who said no to this, why would you say no to this? >> You'll get caught. 

>> You'll get caught. So let's say you won't get caught. >> Difference in physical proximity, like dropping a bomb or killing somebody with a knife. People would drop the bomb and kill 10,000 people probably easier than killing them by knife. Physical proximity of pushing them off. >> Here you have the opportunity of stopping without killing anybody except yourself. So you're given the option of sacrificing yourself. >> Well let's say you weren't big enough to stop the train. So that's the whole thing. [LAUGHTER] So what philosophers suppose is what this gentleman here suggested is there's something about this physically intimate thing of hurting somebody that we're just hard wired to be averse to. 

And this makes sense. If you think about it evolutionarily, we evolved during a time where if you wanted to hurt somebody you had to do it essentially with your hands. Well now, of course, that's not the world we live in. We can hurt people a number of ways. Dropping bombs, pushing buttons, all sorts of very impersonal things. So the idea is that these are not equivalent because this foot bridge scenario, this fat man scenario, involves an emotionally aversive personal harm. And that's sufficient to change the moral judgments of effectively all of you in here. And so another way to think about these choices is that one is utilitarian. So this is, even in this foot bridge scenario, this is just a math problem. So you calculate the greatest outcome for the greatest number of people and that's your answer. 

That's the morally right thing to do. By contrast, any decision other than that would be non-utilitarian, that other things matter. So this just doesn't feel right, I would feel guilty, this is not the way to treat people, something like that. And so the hypothesis here is that if you have a patient that has lost this capacity, this sort of interpersonal connection with other people, a lack of empathy, a lack of guilt like we've seen in these ventral medial patients, then we might expect their moral judgments to be abnormally utilitarian. So the way we tested this was to have people evaluate a number of scenarios that share this common feature of the choice to sacrifice one to save a greater number of others. And so they sat in front of a computer screen and read these scenarios like this.  And then they gave their response. They simply said yes I would do this, yes I would smother the baby, yes I would push a stranger or no I would not. And so here's the data from that study. On the Y axis, on the vertical there, this is the percentage of utilitarian response. 

So utilitarian response is this is just a math problem, yes I'd push a stranger. So we studied three groups of individuals. First, we studied neurologically healthy adults. And we found that for the most part they were unwilling to push a stranger. We also studied a group of brain injured patients whose damage did not include this ventral medial sector of the brain. And they, like the neurologically healthy individuals, were not likely to push a stranger. And if we look at these ventral medial patients who we know to have deficits in guilt and empathy and emotion, we see they're more than twice as likely to push a stranger. So David Hume, I suspect, to be very satisfied with that result. So another domain of decision making where emotion probably plays a role is in financial or economic decision making. So any of you who have any amount of money in the stock market know that economists are very poor at predicting human economic behavior. 

And the reason for this probably is that their assumptions, all their models are based on the underlying assumption that humans are rational economic actors. And what that means to economists is that in any situation where they have a choice they will always choose to maximize their financial gain or minimize their financial loss. But with a little introspection we see that that's not true, that's not how we operate. We care about other things. We care about being treated fairly. We care about our reputations, things like that. We can get angry and do something spiteful. So these are all very natural human reactions that feed into our economic decision making. And so as you know, economic decision making in the real world is very complex and it would be hard to do an experiment in natural circumstances, but there are ways to distill down to some very essential features of economic decision making that make it amenable to laboratory experimentation. So one way to do this is with something called the ultimatum game. 

And rather than explain it, I guess, through these diagrams, I'll just ask if someone will play with me. So could I have a volunteer to play? All right, we're going to play the ultimatum game and this is how it works. You don't know anything about me, and I don't know anything about you. We're never going to see each other again in our lives. We have one chance to make this financial interaction and here are the rules: I make the first move, I'm going to propose that we split a sum of $10. Your only choice is to accept my proposal, in which case I get to keep what I proposed to keep for myself, and you get to keep what I offered to you, or you can reject my proposal, in which case we both get zero. So I say out of those $10, I'm going to propose an even split. I'm going to propose that I get $5 and you get $5. What would you say? >> Sure. >> You would say sure, and you walk away with the $5. 

So that's done. Who else will play with me? Will anyone else play this game with me? I need one volunteer. [LAUGHTER] Okay, so now we have the same rules. So out of this $10 I'm proposing that I get $9.75 and you can have a quarter. Would you accept that offer or reject that offer? >> I reject it. >> Why would you turn down a free quarter? [LAUGHTER] >> I want $9.75.  [LAUGHTER] >> Right, he's spiteful. He's angry. [LAUGHTER] So this is the laboratory model for there's more that matters to people than just maximizing money in certain kinds of interactions. And so if you recall, one feature of these patients is that they have very poorly modulated frustration. 

They have a very hard time being able to calm down and act in their own best interests in the long-term. And so the hypothesis is that these patients might be hyper-irrational in this game. And so this is how it worked. We had this sort of computerized interaction like I just demonstrated. So this guy makes you an offer. Here's what it is. It's a split of $10. And then you decide whether you accept it or reject it. And say you reject it, you see the outcome that you don't get the money. And I should add this was played for real money. 

So there's a real motivation to do this in a meaningful way. So let's look at the data. So the Y axis here, the vertical, is the percentage of offers that were accepted. And on the X axis or the horizontal you see different offer amounts. So the $5 offer is an even split. So you get $5, I get $5. And then all the way down to the $1 offer which is the most unfair. So this is the proposer saying I get $10, you only get $1. So first this is the data from neurologically healthy adults. And as you can see there as you'd expect for the fair offers they generally accept those. 

But as you get more and more unfair they're more and more likely to say the hell with you, I reject it, I'll take nothing rather than be treated like this. If you look at patients that have brain damage that does not include this ventral medial sector you see a very similar pattern of behavior. These ventral medial patients you can see the fair offers make sense to them too. Sure I'll take that. But when you're being treated unfairly you can see they're increasingly likely to reject more of the offer. So it's hyper-irrational. >> Did you do the experiment and what would you expect if it was $500 or $5,000 or $5 million? >> Could you repeat the question, please. >> Yeah, so the question was what if you did this with a more significant amount of money? $500, $5,000, $5 million? To be honest if the NIH would give me that amount of grant money... [LAUGHTER] I would be happy to do that. So economists have thought about this. 

And so one way they could do that is they went to very poor countries where a dollar is like a thousand dollars. And they found that it changes the pattern a little bit. So people are willing to put up with more of an insult, but the basic pattern still holds that the more unfair it gets, the more likely they are to reject it. And so this was, I think, done in, I don't know, maybe India or something. But people were rejecting like a month's salary just because of this perceived slight, this perceived unfairness. So another domain of decision making where emotion probably matters or it might matter is in brand preference. So one point to make about preference for commercially available goods, advertising is wildly successful. I don't, I guess, well I do have some data on that, but let's just take that as a premise. And from there ask why is advertising so successful? So this is an example, for those of you who don't know, Obsession is a perfume or a cologne. And so if you just saw this and you didn't know what Obsession was, what do you think they're selling there? [LAUGHTER] Maybe upholstery cleaner or something like that. 

[LAUGHTER] So anyway, this ad gives virtually no information about any redeeming qualities of the product whatsoever. And I think you can say that for a lot of kinds of ads. They're just designed to make you laugh or to make you lust for something or, again, that's why you see so many monkeys and babies, I guess, on TV. Or something like this, this exhilarating adventure. I think it's safe to say or fair so say that a lot of most commercial advertising is really trying to elicit some kind of emotional connection to the product. They're not just filling you with product attributes that will help you make an informed decision. They're doing quite the opposite. And so I was very interested in testing whether these patients that seem to lose a certain amount of emotional connectedness are less likely to be influenced by commercial advertising. So again, it's sort of tricky, how do you do in this a lab? Well, Pepsi actually offered a good suggestion for this. So some of you might remember in the 1980s there was an ad campaign by Pepsi that was called the Pepsi Challenge. 

And it was essentially just a blind taste test between Coke and Pepsi. And of course in the commercials Pepsi always won. But it turns out that that's true. If you do blind taste tests, Pepsi is more often preferred than Coke. But Coke wildly outsells Pepsi in the marketplace. So they call this the Pepsi paradox. You heard about the trolley paradox, this is the Pepsi paradox. So Coke and Pepsi are both effectively pedaling brown carbonated sugar water. So if you're going to choose one over the other, it must be because one tastes a little better than the other, but what the Pepsi paradox shows is that's probably not true. So the hypothesis of the study is very simply that these ventral medial patients wouldn't have this paradox. 

So their brand preference wouldn't be corrupted by the commercial advertising. It would be based on their actual taste preference. And this was a very simple experiment. So it started with a blind taste test. So you just had these two Styrofoam cups. One had Coke, one had Pepsi. Try one, try the other and point to which cup you prefer. So here's the data from that. The Y axis is the percentage that were preferred and the three subject groups, again, on the bottom. So neurologically healthy individuals prefer Pepsi to Coke. 

Patients with brain damage that did not include ventral medial prefrontal cortex prefer Pepsi to Coke. And ventral medial prefrontal cortex damaged patients prefer Pepsi to Coke. So here's your scientific proof that Pepsi tastes better than Coke. [LAUGHTER] And it tastes better than Coke irrespective of whether or not you have brain damage. [LAUGHTER] So that's not the interesting thing. So that's what the Pepsi commercials told us. I guess we can take their word for that. [INAUDIBLE] No I haven't applied to Coke for any grant money. So here's the more interesting manipulation. So now instead of having just two unlabeled cups, we're going to insert some brand information into this choice and see if that is sufficient to change preference. 

So here they're drinking two cups. One is labeled with the Coke brand label. They really don't know what they're drinking, one or the other. And we also tried this with the Pepsi brand label, and we switched the positions of the brand label. And then here's the data from that. So now you can see that neurologically healthy people, they prefer the labeled Coke to the labeled Pepsi. The non-ventral medial lesion patients they prefer the labeled Coke to the labeled Pepsi. These ventral medial patients, they still like the Pepsi. [LAUGHTER] So if we go back and forth. So here's the blind taste test data. 

So what you can see is that the presence of the Coke brand label is sufficient to flip the preference of these individuals. So there you go. Just a quick summary of these studies. So what this suggests is that this area of the brain is critical to decisions that involve emotional input. So that's all well and good. Those are sort of cute and fun studies to do, but I think a more important question is we think we understand that this area of the brain plays an important role in terms of emotional input in decision making, does this also play an important role in disorders involving emotional related decision making? And so one disorder that's characterized by difficulties with emotion is post traumatic stress disorder. And this is work that I did with combat veterans. And so just a quick summary if you're not familiar with post traumatic stress disorder. It's an anxiety disorder that develops after you've been exposed to some horrific life threatening event. There are three kinds of symptoms. 

One is you're re-experiencing the horrific event, nightmares, flashbacks, that kind of thing. You avoid reminders of the event. You feel emotionally numb and detached and you just have a hard time calming down. You don't sleep well at night, you're very vigilant, you startle easily, those kind of things. So the way we studied this is with a large group of Vietnam veterans. So this is work I did while I was at the National Institutes of Health out in Washington, DC. So the United States government has followed a group of Vietnam veterans since the war. And so these were veterans that suffered a penetrating head injury during combat. So penetrating head injury means bullets or shrapnel that went through their skull, damaged their brain but they survived. These guys have had, they're all men, they've had extensive evaluations since that time. 

And one thing in particular they were evaluated for was psychiatric disorders, including post traumatic stress disorder. So the hypothesis is that if this area of the brain that seems to be important in the experience of certain kinds of emotion, if this area of the brain is critical for post traumatic stress disorder than those veterans that had damage in that area of the brain would be less likely to develop post traumatic stress disorder. So this is another one of those lesion overlap maps. This is a different sample of patients. These are, as I mentioned, combat veterans with penetrating head injury. It's set up sort of the same where the hotter colors indicate a greater degree of overlap. So there were 40 veterans with ventral medial damage out of the group of 200 with brain damage. So the you see that the greatest overlap was in sort of the anterior or the very front part of that ventral medial sector of prefrontal cortex. So here's the data. The Y axis is the percentage of those veterans that were diagnosed with post traumatic stress disorder at any point since their injury. 

So here first is a group of comparison veterans that served a similar tour in Vietnam but did not have any amount of head injury. And you can see the rate of post traumatic stress disorder was very high. Almost half of those men developed PTSD at some point. The veterans with brain injury that did not include ventral medial prefrontal cortex, similarly high. It's not significantly different. The ventral medial patients, the veterans with ventral medial damage rather, much less. So less than half the prevalence. So this suggests that this area of brain is critical in the development of this disorder. And to give you a little flavor about how damage to this area of the brain affects emotion and social behavior I have a couple video clips here of a veteran who has extensive ventral medial damage. So this is a CT scan of the guy you're just about to see an interview with. 

And you can see, I guess the picture in the middle is maybe the easiest to see. So that's a slice like this in the brain. The front of the brain is at the top. And so you can see this ventral area of his prefrontal cortex is almost completely wiped out. And so here in this first clip, if I can pull it up, he's going to be describing a situation where his unit came under attack in the middle of the night, and through some mistakes that he made, he ended up hurting a lot of people. And what I should add is that most veterans are very reluctant to talk about anything like this. And when they do, they do so with great gravity, and it's a very sort of emotional and wrenching thing for them. So have that sort of picture in mind when you listen to this. And unfortunately, I'm not getting...  >> It was way off to the right. 

>> Was it? There it is. Thank you.  [INAUDIBLE]  [INAUDIBLE]  >> So I don't know if you got that, but when he got to the punch line of the story where he had essentially killed this village full of innocent people, he even made a little chuckle, like it's an honest mistake. So this next clip is the same guy, and this is just to give you a flavor that his deficits in feeling certain kinds of emotion and understanding, certain kinds of behavior, is not just restricted to guilt over combat related things. So subsequent to that attack he had suffered this major brain damage that you see in the slide there. And his prognosis was very bad. He spent some time in a hospital in Germany, I believe, recovering for a number of months. And then was shipped back to the United States at Walter Reed Hospital, and so his parents this whole time are hearing your son had this terrible injury, we don't know if he's going to make it. So you can imagine this was a very wrenching thing for them. So here he is describing when his father came to see him at Walter Reed Hospital for the first time. 

So you can imagine this is a very, very tender and emotional moment. And so here he's going to describe his perception of that.  [INAUDIBLE] >> He looked right at me and said-- [INAUDIBLE] He came back and said he didn't even know who I was. [INAUDIBLE] I had a bandages on my head, -- my nose, and IVs, and all that. Like I said, I lost 65 pounds. [INAUDIBLE] But he didn't know who I was. [INAUDIBLE] I remembered having a feeling, was he a homosexual? >> Ah, I mean-- So you can see how sort of far off he is in his social perceptions. He mistook his father's very intimate and tender kiss for a homosexual advance. Okay, moving on. Depression. 

Depression shares a lot of common features with post traumatic stress disorder. In fact, people with post traumatic stress disorder are very likely to have depression as well. So we wanted to, following this same line of reasoning, we wanted to find out whether damage to this area of the brain would also confer a type of resistance to depression like it did for post traumatic stress disorder. So on the Y axis here, this is again a study with the Vietnam vets. The BDI is just the Beck Depression Inventory. This is just a self-report and measure of depression severity. So higher numbers indicate more severe depression. So the neurologically healthy veterans had a score there. The non-ventral medial lesions had a score there. And then the veterans with ventral medial lesions had a much lower self-reported depression severity. 

So we also wanted to know if this was true for neurological patients. So people that had relatively normal lives and normal experiences. So not these horrific combat ordeals. But following things like a stroke or a tumor or an aneurysm is the severity of depression different in those with ventral medial lesions. So again this is the same measure, the Beck Depression Inventory. Non-ventral medial lesions were there. Ventral medial lesions, again, much lower. Interesting thing about these data. So this is the Beck depression scale, individual item data. And so on the X axis or the horizontal, these are all the items on the Beck Depression Inventory. 

And so these are the common symptoms of depression. So things like feeling sad, crying, feeling guilty, changes in appetite, feeling tired, those kind of things. And the dots indicate the self-reported levels for each of the different patient groups. And what I want to draw your attention to is the ventral medial patients are that dark diamond there. There are a number of symptoms of depression for which these patients endorse almost none of. So they're at zero or very close to zero. The interesting thing about these symptoms is that they're all related to these thoughts about yourself. So if you look at suicidal thoughts, I feel sad, I feel worthless, I don't like myself, I've lost interest, I'm critical of myself. If you look at the symptoms where they're mostly normal, these are a very different kind of symptoms. So these are symptoms like I don't have an appetite, I have a change in my sleeping pattern, I feel tired. 

So these are what's called the cognitive and effective symptoms of depression. These are what's called the somatic symptoms of depression. So it seems like what ventral medial prefrontal cortex is particularly important for are these thoughts related to emotions. There was a very interesting patient that we came across in this one in looking for these patients that had ventral medial lesions and looking at their depression scores, a very interesting case. This was a 30-year-old woman who had severe depression for almost her entire adult life. It was so bad she attempted suicide with a gunshot to her head. So she shot herself like this at the temple and the gunshot blast destroyed, wiped out her entire ventral frontal cortex, so including her ventral medial prefrontal cortex. That's what's circled in red there the missing area of brain damage. So remarkably she survived and her psychiatrist remarked that following this suicide attempt she had no sign of depression whatsoever. Her boyfriend remarked no distress, worry or anger. 

So what I mean by the title of this slide is that coupled with the other data these data suggest that if you could somehow turn down the activity of this area of the brain you might be on the way to improving the symptoms of depression. And by the way, I also did a literature search for something similar to this and I found this: a 33-year-old man, similar story, severe depression his adult life. He put a cross bow underneath his head and shot is up sort of very similar to Phineas Gage. And you can see in the x-ray there in the top, that's the arrowhead lodged in the top of his skull. And if you look in the bottom right you can see an MRI reconstruction there of the area that's damaged. And again this is this ventral medial sector right above and between the eyes. He survived this suicide attempt and afterwards, these are the words of his physician, indifferent and inappropriately cheerful. And so this may conjure up for some of you, this memory, this really black eye in the history of psychiatric medicine, this era of prefrontal lobotomy. So prefrontal lobotomy was a procedure where they tried to remove part of your prefrontal cortex with the goal of making the patients more tranquil, docile. There's a lot that was horrible about this, which we can talk about at some length in the Q&A if you're interested in, but what I want at that point out is that at probably the worst and most prevalent period of this procedure it was done with literally it started with an ice pick that they went through the orbit of the eye and tapped with a hammer up into the brain and sort of moved it around like this. 

And that was supposed to cure certain kinds of mental illness. Now what I want to point out about this if you think about it, so with the ice pick going through the orbit into the eye, it's going right through the ventral medial sector prefrontal cortex. Now, unfortunately, I mean it's unfortunate that this ever happened, but on top of that misfortune, an unfortunate thing is there was never any good records kept for these patients, so whether it worked or not. So there's anecdotal reports that in some cases it did work. So it improved the mood of some patients or made them get along a little easier. And it could have worked through inflicting damage to this ventral medial prefrontal cortex. So the science of this was very poor. And in fact they probably did more damage than they ever needed to. So this is, just to put this in perspective, some pictures of a lobotomized brain. On the left this is an MRI so you can see those gaping wounds in the frontal cortex. 

And then that's a brain postmortem where you can see the prefrontal cortex is basically eviscerated on both sides. So obviously this is a very crude thing, and I'm not recommending anything like this. And, again, this is just an anecdote to underscore that point. So Rosemary Kennedy, for some of you who are probably aware, she was the older sister of President Kennedy and Robert Kennedy. She was mildly retarded as a child. By all accounts very petulant and difficult to deal with adolescent and just happened to be a difficult and petulant adolescent at the time where this prefrontal lobotomy was gaining great favor. And so at the request of her parents, she was given this procedure and afterwards was never able to live independently and essentially incapacitated. [INAUDIBLE]  >> That was transorbital. >> It was transorbital? >> Yeah. So what happened is, so you can imagine when the ice pick goes in it's a little movement here but at the tip of the ice pick it's carving out a big section. 

>> Did they know enough back then in the era that that part of the brain was going to do what it's supposed to do. >> Well, I mean they knew about Phineas Gage. They knew about certain kinds of strokes and tumors, and they knew that those patients tended to be more docile or not really care. So they had some limited information. We know a lot more now and we have a lot more sophisticated tools if we want to potentially try for turn off an area of the brain. And so what I'm going to describe just really briefly is some work that's been going on really at the cutting-edge of the management of very difficult cases of depression. So it's something called deep brain simulation. And how it works is you implant electrodes. So very thin wired electrode. You can feed down in the brain. 

You can see the black marks there. Those indicate the pathway of the electrodes. And you can feed it down to that ventral medial sector of the brain. And if you turn this simulator on, it essentially injects electrical noise into the brain and disrupts the signaling. So effectively renders it dysfunctional. And so this has been tried as a very drastic and last resort treatment for people with very severe depression that's not responded to any other kind of treatments. And interestingly, it seems to work or at least the initial data is promising. And the red line shows the depression scores of people that have had this treatment. So this is a small number of people but you can see on the far left is when they just started the treatment, and so you can see there was a very fast and sustained decrease in the depression symptoms. So this is again I said very preliminary data but it gives some hope that we're on the right track. 

If we're trying to help treat these diseases a little better, these mental disorders, this might be an appropriate therapeutic target. Yes? >> Have they found any collateral damage? >> That's a great question. So as I told you, I just spent the last half an hour telling you how damage to this area can really impair decision making and overall how you're getting along in life. So the short answer to your question is yes, but if you look at where they were coming from it's still an improvement. So it's not like they're getting to a point where they're going to get along perfectly in their life, but they're getting to a point where they're probably not suicidal or something like that. So it's better than it was. >> Is that the modern correspondent to electroshock therapy? >> No, so electroshock therapy, what they call ECT, is very different. And in fact it's still done in psychiatry departments today. So ECT essentially is very much more crude. It's not really anatomically specific. 

So you put these giant electrodes and you deliver this massive amount of electricity and it sends the brain into sort of this epileptic convulsive state. And it's not clear really why it works but it does seem to work. And so they keep using it and there don't seem to be any major, major side effects. >> But it's supposed to scramble or interfere with the processes in that same part of the brain? >> Well ECT is sort of like a whole brain wide thing. That's like a sledgehammer approach where this is more of a scalpel. >> Your charts were very dramatic. At the same time they weren't 100%. In other words, there were always cases that didn't follow the general trend, which must mean, at the very least, that some other part of the brain rallied to protect that reaction. >> Yes, you're absolutely right. And this is a great... 

>> The question, repeat it. >> I'm sorry. So the question was essentially that you see these dramatic group differences but it's not that everyone in the particular group is behaving the exact same way or the function is completely wiped out. There's some residual function so that other areas of the brain may be compensating. The point is very well taken and it's exactly right. So all of these data can show is that, not that this is the only area of the brain that's involved, but that this is one of the areas of the brain that is important. >> And then I have a different kind of question. Which goes in the other direction. If you grow up in a very supportive, nurturing family where you're treated with kindness and caring so that the individual grows up and develops a sense of compassion and empathy, doesn't that influence the structure of the brain? >> Sure, yeah, absolutely. Let me try to answer that question in the context of this next study I'm going to talk about. 

Let me revisit that point about experience. And so we're going to talk about psychopathy and some work I've done on this. Who knows who this is? Ted Bundy, right. And so this is probably one of the most famous psychopaths, and he's sort of the kind of thing you have in mind when you hear the term psychopath. I only bring him up to illustrate that not all psychopaths are like this. So in the media there's sort of this sensationalization of psychopaths as always these blood-lusting mass murderers. They certainly can be that way. They're not always that way. Psychopathy is defined as a constellation of antisocial, affective and behavioral traits. And so here's the score board or the scoring measure for psychopathy. 

So it's a list of 20 items. This is something called a Hare Psychopathy Checklist. It's the gold standard instrument so diagnosing psychopathy. And the individual is scored on a score of zero, one or two for each one of these items. So the highest score you can get is 40, and you're called a psychopath if your score is greater than 30. So this amounts to less than 1% of the general adult population but about a quarter of the male adult male prison population. So this is a significant issue in terms of the legal system and how the dollars flow in our society, like out of our government into these prisons. So the question that I'm going to address very briefly here in the last few minutes is whether psychopathy can arise from a single causal mechanism. So what I mean by that is that two different kinds of people could end up as a psychopath. So a psychopath is just you have these very extreme antisocial behaviors. 

On one hand you may be a psychopath in what we'll call a primary psychopath is that you just have some innate social and emotional deficit. You don't feel anxious about stuff, you don't have any sort of interpersonal connectedness and as a result of that you can end up doing these horrible things to people. And so you might suspect that this could be associated with a neurobiological defect, some innate neurological biological dysfunction. On the other hand, you may become a psychopath and have this pattern of antisocial behavior because of environmental factors. So this is what you're asking about. And so a secondary psychopath is conceived of some type of acquired disturbance. So you can have grown up in an abusive household, gotten involved in drugs at a very young age or a gang or something that led to this antisocial lifestyle that is reflected by this high score on this psychopathy scale. So these people you can imagine are not just low anxious cold blooded people. They might be emotionally very volatile. They might be very aggressive. 

And for those people, that might be a mixed bag. You might not expect any consistent neurological biological defect. So the question I want to explore or one thing I think we can gain experimental traction on is whether in this primary case, this low anxiety type of psychopath, whether there's a consistent neurobiological defect. And so one thing I'll point out about these individuals, these individuals could come from any kind of a family. So this is sort of what you're related to. So matter how caring and wonderful mom and dad are, if you just have innate lack of sensitivity for other people's emotions, you could end up doing these antisocial crimes. Now, if you're very intelligent, you could end up the CEO of a company, or a general. [LAUGHTER] And I don't just mean to sound just like a joke. There's no doubt that a lot of these CEOs are psychopaths. It's the only way, you can imagine in some ways it's adaptive. 

You're able to make very tough decisions just based on the utilitarian calculations. So anyway, if there is some type of consistent neurobiological defect that gives rise to primary subtype of psychopath, I think this ventral medial area that we've been talking about would be one of the prime suspects. And in fact, if you look at the Hare, this PCLR checklist, and you consider which of these traits apply to these ventral medial patients, well a lot of them do. And some of them do to a T. So I've highlighted those here that virtually all of these patients we've tested have some degree of these changes. So much so, and I don't want to act like I'm the first person that ever thought of this, a couple neurologists in the 1970s even started calling patients like this with frontal lobe damage pseudo psychopaths. So very much resembling a psychopath. So by way of a hypothesis we might expect that these primary, low anxious psychopaths would resemble these ventral medial patients in certain tests of  social and emotional decision making. So a lot of the things I just described. So in collaboration with a psychologist that works at UW and does forensic work in prisons, we've been testing prisoners, we've been evaluating for psychopathy and seeing how they perform on these tests. 

So you remember this ultimatum game, this one shot deal of splitting an offer. You recall the data there that the ventral medial patients were much more likely to reject the unfair offers. So let's look at the inmate data. So again the scale is the same. And here I'm just showing the unfair offers because that's the most interesting for our purposes. As I said, not all prisoners are psychopaths. Most of them, in fact, aren't. So this is a group of non-psychopathic inmates who are matched for age and education, those kinds of things. These are the secondary psychopaths. So these are the guys who score high on the PCLR. 

They're definitely psychopaths but they're high anxious. They don't have this trait of being cold blooded in a sense. And here's the primary psychopaths. So you can see this pattern is very much reminiscent of the ventral medial patients. We did another economic decision making game called the dictator game. This is somewhat like the ultimatum game but there's only one step and it's that I have a chance to split $10 with you and I'm just going to tell you how it is. You're going to get this and I get this and that's it. Now, most people, presumably they feel some amount of empathy for the person, they feel guilty if they just gave them nothing. Most people would give something. And in fact a lot of people will split it evenly even though it's not to their financial benefit. 

So if you look at first the neurological patients, these are neurologically healthy individuals, give a good chunk of that $10 just out of the goodness of their heart. Non-ventral medial lesions, a little less but not significantly different. The ventral medial lesions almost nothing. So we presume this is because they don't feel the guilt or whatever it is, some type of pro-social emotion. Now let's look at the prisoner data. Non-psychopathic prisoners are giving almost half. These high anxious psychopaths, the secondary flavor, are giving almost half. Primary psychopaths, this low anxious flavor, very much less. So again the primary psychopaths and the ventral medial patients behaving rather similarly. Let's go to the moral judgment data. 

You remember the trolley paradox. So just to remind you, the ventral medial patients were very much more likely to be utilitarian, to say yeah, push the stranger, this is just a math problem. If we look at the prisoner data, there's the non-psychopaths, the secondary psychopaths. And again these low anxious primary psychopaths are more likely to resemble the ventral medial patients in their decision making response. So just to summarize those studies, these laboratory games, for one thing, discriminate these two types of psychopaths, and moreover the low anxious primary psychopaths are much more like the ventral medial patients. And so what this hints at is that ventral medial dysfunction may be a cause of psychopathy. Now admittedly this is a very speculative theory and there's not direct evidence for that. And I was very glad to be humbled by The Onion who made a point of emphasizing this. So this says in their parody, so this is a parody of the study that we did. "Psychopaths Behave Like Stroke Victims." So we said that psychopaths and stroke victims play these games similarly. 

And I thought Jenny Blumberg, the systems analyst, had a very insightful comment. She said, "I've seen enough Law & Order and House to tell you my own personal bullshit theory on this." So at some level it is still a theory, but one of the last points I want to make is that this is not just an academic question. And so I think this could have very real implications for how psychopaths are treated in the criminal justice system. And so by analogy, if you'll indulge me in this somewhat far reach of analogy, Parkinson's disease, we know what goes wrong in the brain to cause that. So in a normal healthy brain on the top there are these dopaminergic dark cells in the midbrain. That's called the substantia nigra. So you can see that's a healthy brain. And in Parkinson's patients that's gone, and we know that their motor problems are a result of that loss of brain cells. And so if you had Muhammad Ali and Michael J. Fox over to your house for dinner and they, because of the tremor in their hands, spilled some wine on your carpet you'd probably give them a break because you know that they can't control that. This is just a result of their dysfunctional nervous system. 

Likewise, let's say you were friends with Ronald Reagan before he passed. So on the left, the brain, that's a healthy brain. You can see very robust and full amount of tissue there. Advanced Alzheimer's on the right you can see is very much atrophied, and of course that gives rise to the memory loss and other symptoms you see in depression. And so if you were friends with Ronald Reagan and he forgot your birthday, you'd probably give him a break. You wouldn't treat Ronald Reagan the same way you would if your son or daughter forgot your birthday, for example. Well, what about psychopaths? So we're very early on in this research but what if we could define some consistent neurobiological defect in these individuals that we knew just made them less able to interact with people in a socially appropriate way or essentially rob them of their moral compass. Would we hold them accountable for their actions? And so, as I mentioned, this is not just hypothetical, it's not just academic. So this is evidence presented in a kidnapping trial a few years ago, and unfortunately this kind of stuff works on juries because there's a scientist in there saying look, you can see it in the scan. His brain is not working the same way. 

How can we hold him accountable to the same degree as we would someone with a normally functioning brain? Now, if we push this far enough we're going to be arguing whether free will is an illusion. But just suffice to say in the future I think this will be a very important area of research. So just by way of general summary, I think the studies I've shown indicate that this area of the brain, the ventral medial prefrontal cortex, is critical for emotion, social behavior and decision making. It also indicates that it plays a critical role in disorders of emotion, things like depression, post traumatic stress disorder and psychopathy. And lastly, I'll just say that the study of brain lesion patients is a unique and important source of data revealing brain behavior relationships. So with that, I'll take any questions. [APPLAUSE]