 Can we learn something about the circuits in the brain that mediate depression? And you have to go back and forth between animals and brains. So this is a PET scan. And what this scan shows you is the areas of activity in the helpless animal against the control and the non-helpless animal against the control. And I want you to look right here and right there. You see, there's a bright spot that just doesn't exist there, and there's a spot for low activity that doesn't exist right there. And those are the key findings that we found in these two animal strains. And what this did is it sent us to a structure called the lateral habanula. This is a teeny structure that I didn't know existed. I had to look it up when we found it. And I thought, my god, what is this structure doing? Turns out that the input to this structure includes the hypothalamic tract. That's the area that does this cortisol stuff. So that has an input into the habanula. The prefrontal cortex has a direct input into the habanula. That's the area where we do the cognitive thinking. And the limbic system through the hippocampus amygdala up through the basal nucleus of the striaterminalis comes right in here. And that's the system that's responsible for anxiety and fear. So all of those inputs come in here. And what this system does is it talks to all of those amines. This is dopamine. This is serotonin. This is norepinephrine. And it controls them. And so we thought, my goodness, if it's overactive on our rats and it controls all these guys, what's going on? Well, what's going on? Don't look at all this data for a minute. Just listen for one second. What's going on is that another group at the NIH was working on this structure quite independently of us with nothing to do with pathology. Hikasaka's lab was doing this. And what they found, I've taken these slides out because I have to work fast, isn't this tough, is that this little structure, the lateral habanula, controls our thinking about things and feeling disappointment. It's a circuit of disappointment. When we don't get a reward when we should, if you don't applause, I'm going to have my habanula fire and I'll be disappointed. If you applaud and I know it was a lousy talk, my habanula will shut off and I'll feel rewarded. So it's a circuit of disappointment. And that makes sense to just what we found. And we said, if this is really the place that's controlling all those amines, maybe if we shut it off because our animals are too active, maybe we could cure depression. So we took some slices with Bowley and Robert Malano here at Cold Spring Harbor and we looked and we put high-frequency stimulation and shut them off. So we showed we could shut this structure off with a certain kind of input. My postdoc, Martin, looked where you put electrodes to shut it off in animals and showed only if you hit the output of the lateral habanula did you reverse helplessness. So that made us think maybe this is a place where something called deep brain stimulation might work in depression if we're right. And so we did a case of deep brain stimulation in Germany two years ago and we're setting up now to do a larger study at Mount Sinai in the city. And here's the history of this case. This was a woman with a 25-year history of depression who was suicidal and psychotic in that she really had ideas that weren't related to reality and she really wanted to kill herself. And I had just left Germany a couple years before but I knew this patient and they called me in 2008 and said look we don't know what to do anymore because we can get her better with ECT but we can't get her better with anything else and it only lasts four or five days and if you keep giving a person ECT you cause cognitive problems, you can't do that. What can we do? Can we do deep brain stimulation of the habanula? And I swallowed and I said well we have this evidence that maybe it will work, let's see. So we went through all of the ethics panels in Germany and we got a very good neurosurgeon and we did it. And this woman remitted to a ham D that's better than mine. I mean she is really normal. When I went back to Germany to see her after the first stop, after the only operation she was doing fine and her husband told me this is the woman I knew before she ever got sick and you can't do better than that. At least as a physician I've gotten that very few times that people are that good. And then three times over the last two years because they miscalculated, you have to keep the stimulation going in this circuit. They miscalculated the battery life. The batteries went dead. All three times neither her doctor nor her knew it and all three times within 24 hours she was totally psychotically depressed and when the battery was put back she was well again. So we are hopeful that this is a clue to the circuit of depression. That's the kind of thing we're doing here. We now want to find the drugs that will help us cure depression because we're not gonna put electrodes in everybody's brain. That's just incomprehensible and you don't want to do invasive work. So we tried to use non-invasive ways of doing this. We first measured the lateral abenule using something called arterial spin labeling in NMR and we measured to see whether it was turned on or off in depression and we showed it was turned on in depression, turned off when people got better. We then used MRS, Magnetic Resonance Spectroscopy to try and see what was changed in the brain and I'm not going to go into the details tonight but there was a change in something called the GABA glutamate ratio. Both of these are neurotransmitters and the way that change took place made us think that maybe it wasn't the nerve cells, it was glial cells. These are cells that are thought to be a glue that kind of sits between the nerve cells and it turned out that we've gotten some hints that maybe they're at fault. Now what could they be doing if they're at fault? Well, our hint was, I should have another slide, I guess I took it out, I'm sorry, but the synapse consists of a pre-synaptic bulb and a post-synaptic membrane density and all around it are these glial cells and one of the main synaptic transmitters is glutamate and when glutamate is released, it has to be removed quickly to make the nerve cells work just right and the main thing removing it is a pump located in these astrocytes, these astroglia. We think maybe that pump is screwed up. Now what we know is in depression in the prefrontal cortex and this is a lot of work from other people, these synapses are disturbed and knocked down. In my rat model, if I look at synapses in the prefrontal cortex in my poor helpless animals that are genetically helpless, we find 40% less synapses. We also find 40% less of the transmitter, I mean of the transporter that removes these things from the glial cells. So our thought is maybe this is the source of pathology. One of the treatments that people are looking at and Hussaini was very involved in this in treating depression because our current drugs take weeks is ketamine and ketamine works rather quickly in a matter of a day or two and sometimes in hours and it unfortunately will probably be never a drug that we can use because in higher doses it's psychomimetic and it's a party drug and it's an abusable drug but it does cure depression in a controlled situation in people who are treatment resistant and what does it do? What it does is it turns on a whole series of pathways called the mTOR pathway which remake these synapses. It makes new synapses. So we think our idea that their synapses are gone because of too much glutamate fits with the way this works and so our hope is here it shows that in the frontal and the infralimbic cortex which is exactly the piece of cortex we think is important and another group, Helen Mayberg's group uses this as a target for deep brain stimulation exactly there is where our rats have a decrease in the number of synapses. So our best guess is that in the prefrontal cortex you've got disturbed synaptic physiology because of too much glutamate and the glutamate uptake may be abnormal and that if we can find ways to normalize it we would probably reduce the overactivity in the venula which we've clearly shown is overactivity because of too much glutamatergic input and we would probably get it to stop sending these constant disappointment signals. So how am I doing for time, Sydney? Four minutes, oh we're gonna have time for questions. I've rushed because of you. So the summary is that actually depression first of all is a very, very serious disease that encompasses nearly a fifth of the population. We at the moment don't have really effective treatments for it and that it probably involves many, many systems in the brain and has many, many causes but clearly it's partially induced by environmental stressors and you notice this in a period of recession you can see that the proportion of the population with depression actually goes up and so it's a condition that's probably fairly complex but we think we may now understand the final common anatomical pathway that mediates it and it runs through this little structure called the lateral venula which becomes a major locus of controlling the rest of the brain and it controls these neuromodulators. These amines are really neuromodulators. They go back and touch almost all portions of the brain and modulate the activity. Dopamine is the drug that modulates reward activity and everything we know about addiction suggests that the dopinergic system is the system that is driving addiction. If you take cocaine you really increase dopamine stimulation and noradrenaline obviously modulates our level of anxiety. Serotonin modulates almost everything. So our hunch is that this circuit controls those things and if we can normalize that circuit maybe we will find a treatment that's really effective and I'll just stop there. You've rushed me so much, Sydney. So we wanna talk about how bad these illnesses are what we need to try and do about them and what I'm going to do is talk a little bit about depression, bipolar disorder and when I'm going to end the presentation talk about a major what we're calling public-private partnership that's being initiated to try and bring universities, NIH and companies together to try and understand these illnesses better and to come up with better treatments. This wasn't planned but indirectly Fritz Hand referred to this. So this is the study that the World Health Organization conducted called the Global Burden of Disease Study and they wanted to ask the question which illnesses affect in humanity every illness, cardiovascular, respiratory, infectious disease, et cetera which ones cause the most disability and what this slide shows is that in the US and Canada in what some people consider the highly productive years, 15 to 44, severe mental illnesses are by far the leading causes of disability worldwide and as you heard from Dr. Hen, depression's a big part of that and it's estimated unless we come up with much better treatments depression may be the number one cause of disability. Now why would that be? I mean that sounds odd to people. You know mood disorders or mental illness are the most disabling. I think there's many reasons for it. One is that they're surprisingly common. You heard about 16 to 18% for depression, bipolar disorder, schizophrenia, probably more than 1% each. So these are illnesses that are actually very common. Probably the biggest factor is that they hit people when they're young. So by and large it's people in their late adolescence, early 20s, when they first get these illnesses and these illnesses are lifelong. So that's why many of us call these the chronic diseases of the young because they hit people when they're young and they stay forever. And that's why they contribute to so much disability. In the United States today we think we spend about a hundred billion dollars every year on what we call direct costs which is cost of treatment, hospitalization, et cetera. And it's estimated that there's an additional 200 billion dollars lost in terms of productivity, people not being able to work, et cetera. These are very disabling illnesses but unfortunately they can also be fatal illnesses. So today we think there's approximately 36,000 suicides a year in the US which is twice as many deaths as we get from homicide. And there's only three forms of cancer which have a higher annual death rate than the death rate from suicide. So this is...