Parkinson's, depression and the switch that might turn them off - Andres Lozano

[Applause] Uh, one of the things I want to establish right from the start is that, uh, not all neurosurgeons wear cowboy boots. I just wanted you to know that. Uh, so I am indeed a neurosurgeon, and I follow a long tradition of neurosurgery. What I'm going to tell you about today is adjusting the dials in the circuits in the brain; being able to go anywhere in the brain and turning areas of the brain up or down to help our patients.

So, as I said, uh, neurosurgery comes from a long tradition. It's been around for about, uh, 7,000 years. In Mesoamerica, there used to be neurosurgery, and there were these neurosurgeons that used to treat patients. They knew that the brain was involved in neurological and psychiatric disease; they didn't know exactly what they were doing. Not much has changed, by the way. But they thought that if you had a neurologic or psychiatric disease, it must be because you were possessed by an evil spirit.

So, if you are possessed by an evil spirit causing neurologic or psychiatric problems, then the way to treat this is, of course, to make a hole in your skull and let the evil spirit escape. This was the thinking back then. And, uh, these individuals made these holes. Sometimes, um, the patients were a little bit reluctant to go through this because you can tell that, um, the holes were made partially, and then I think, you know, there was some trepidation, and they left very quickly, and it was only a partial hole. We knew these patients survived these procedures, but this was common.

There were some sites where 1% of all the skulls had these holes; you can see that neurologic and psychiatric disease is quite common, and it was also quite common, uh, about 7,000 years ago. Now, in the course of time, we've come to realize that different parts of the brain do different things. There are areas of the brain that are dedicated to controlling your movement, or your vision, or your memory, or your appetite, and so on. When things work well, then the nervous system works well, and everything functions.

But once in a while, things don't go so well, and there's trouble in these circuits. There are some rogue neurons that are misfiring and causing trouble, or sometimes they're underactive and they're not quite working as they should. Now, the manifestation of this depends on where in the brain these neurons are. So when these neurons are in the motor circuit, you get dysfunction in the movement system and you get things like Parkinson's disease. When the malfunction is in a circuit that regulates your mood, you get things like depression. And when it is in a circuit that controls your memory and cognitive function, then you get things like Alzheimer's disease.

So what we've been able to do is pinpoint where these disturbances are in the brain, and we've been able to intervene within these circuits in the brain to either turn them up or turn them down. This is very much like choosing the correct station on the radio dial. Once you choose the right station, whether it be jazz or opera, and in our case whether it be movement or mood, we can put the dial there and then we can use a second button to adjust the volume to turn it up or turn it down.

So what I'm going to tell you about is using the circuitry of the brain to implant electrodes and turning areas of the brain up and down to see if we can help our patients. This is accomplished using this kind of device, and this is called deep brain stimulation. What we're doing is placing these electrodes throughout the brain. Again, we are making holes in the skull about the size of a dime, putting an electrode in, and then this electrode is completely underneath the skin down to a pacemaker in the chest. With a remote control, very much like a television remote control, we can adjust how much electricity we deliver to these areas of the brain; we can turn it up or down, on or off.

Now, about 100,000 patients in the world have received deep brain stimulation, and I'm going to show you some examples of using deep brain stimulation to treat disorders of movement, disorders of mood, and disorders of cognition. So this looks something like this when it's in the brain. You see the electrode going through the skull into the brain and resting there, and we can place this really anywhere in the brain. I tell my friends that no neuron is safe from a neurosurgeon because we can really reach just about anywhere in the brain quite safely.

Now, the first example I'm going to show you is a patient with Parkinson's disease. This lady has Parkinson's disease and she has these electrodes in her brain. I'm going to show you what she's like when the electrodes are turned off and she has her Parkinson symptoms, and then we're going to turn it on. So this looks something like this: turn off now, and you can see that she has tremor on the right side. Can you touch my finger a little better?

We're now going to turn it on... it's on, just turned it on, and this works like that instantly. The difference between shaking in this way and not, the difference between shaking in this way and not, is related to the misbehavior of 25,000 neurons in her subthalamic nucleus. So we now know how to find these troublemakers and tell them, "Gentlemen, that's enough! We want you to stop doing that," and we do that with electricity.

So we use electricity to dictate how they fire, and we try to block their misbehavior using electricity. In this case, we are suppressing the activity of abnormal neurons. We started using this technique in other problems. I'm going to tell you about a fascinating problem that we encountered, a case of dystonia. So dystonia is a disorder affecting children; it's a genetic disorder, and it involves a twisting motion.

These children get progressively more and more twisting until they can't breathe, until they get sore urinary infections, and they die. Back in 1997, I was asked to see this young boy. Perfectly normal, he has this genetic form of dystonia. There are eight children in the family; five of them have dystonia. So here he is. This boy is 9 years old, perfectly normal until the age of six, and then he started twisting his body: first the right foot, then the left foot, then the right arm, then the left arm, then the trunk. By the time he arrived within the course of one or two years of the disease onset, he could no longer walk, he could no longer stand, he was crippled.

Indeed, the natural progression is that this gets worse for them to become progressively twisted, progressively disabled, and many of these children do not survive. He is one of five kids. The only way he could get around was crawling on his belly like this. He did not respond to any drugs. We did not know what to do with this boy; we did not know what our operation should do, where to go in the brain. But on the basis of our results in Parkinson's disease, we reasoned, why don't we try to suppress the same area in the brain that we suppress in Parkinson's disease and see what happens?

So here he was; we operated on him, hoping that he would get better. We did not know. So here he is now, back in Israel where he lives, three months after the procedure, and here he is on the basis of this result. This is now a procedure that's done throughout the world, and there have been hundreds of children that have been helped with this kind of surgery. This boy is now in university, uh, and leads quite a normal life. This has been one of the most satisfying cases that I've ever done in my entire career: to restore movement and walking to this kind of child.

We realized that perhaps we could use this technology not only in circuits that control your movement but also circuits that control other things. The next thing we took on was circuits that control your mood and we decided to take on depression. The reason we took on depression is because it's so prevalent. As you know, there are many treatments for depression with medications, with psychotherapy, even electroconvulsive therapy, but there are millions of people and there are still 10 or 20% of patients with depression that do not respond. It is these patients that we want to help and let's see if we can use this technique to help these patients with depression.

So the first thing we did was compare what's different in the brain of someone with depression and someone who is normal. We did PET scans to look at the blood flow of the brain, and what we noticed is that in patients with depression, compared to normals, areas of the brain are shut down; those are the areas in blue. So here you really have the blues, and the areas in blue are areas that are involved in motivation, drive, and decision-making. Indeed, if you're severely depressed as these patients were, those are impaired; you lack motivation and drive.

The other thing we discovered was an area that was overactive: Area 25, seen there in red. Area 25 is the sadness center of the brain. If I take—make any of you sad, for example, I make you remember the last time you saw your parent before they died or a friend before they died, this area of the brain lights up. It is the sadness center of the brain. Patients with depression have hyperactivity in this area of the brain for sadness; it's on red hot. It's as if the thermostat is set at 100°, and the other areas of the brain involved in driving motivation are shut down.

So we wondered, can we place electrodes in this area of sadness and see if we can turn down the thermostat? Can we turn down the activity? And what will be the consequence of that? So we went ahead and implanted electrodes in patients with depression. This is work done with my colleague Helen Mayberg from Emory, and we placed electrodes in Area 25. In the top scan you see before the operation, Area 25, the sadness area, is red hot and the frontal lobes are shut down and blue. Then, after three months of continuous stimulation, 24 hours a day, or six months of continuous stimulation, we have a complete reversal of this.

We're able to drive down Area 25 to a more normal level and we're able to turn back online the frontal lobes of the brain. Indeed, we're seeing very striking results in these patients with severe depression. So now we are in clinical trials; we are in phase three clinical trials, and this may become a new procedure if it's safe and we find that it's effective to treat patients with severe depression.

I've shown you that we can use deep brain stimulation to treat the motor system in cases of Parkinson's disease and dystonia. I've shown you that we can use it to treat a mood circuit in cases of depression. Can we use deep brain stimulation to make you smarter? Anybody interested in that? Of course, we can!

So what we've decided to do is we're going to try to turbocharge the memory circuits in the brain. We're going to place electrodes within the circuits that regulate your memory and cognitive function to see if we can turn up their activity. Now, we're not going to do this in normal people; we're going to do this in people that have cognitive deficits, and we've chosen to treat patients with Alzheimer's disease who have cognitive and memory deficits. As you know, this is the main symptom of early-onset Alzheimer's disease.

So we've placed electrodes within this circuit in an area of the brain called the fornix, which is a highway in and out of this memory circuit, with the idea of seeing if we can turn on this memory circuit and whether that can, in turn, help these patients with Alzheimer's disease. Now, it turns out that in Alzheimer's disease there's a huge deficit in glucose utilization in the brain. The brain is a bit of a hog when it comes to using glucose; it uses 20% of all your glucose, even though it only weighs 2%. It uses 10 times more glucose than it should based on its weight.

Twenty percent of all the glucose in your body is used by the brain, and as you go from being normal to having cognitive impairment, which is a precursor of Alzheimer's, all the way to Alzheimer's disease, there are areas of the brain that stop using glucose. They shut down; they turn off. Indeed, what we see is that these areas in red around the outside ribbon of the brain are progressively getting more and more blue until they shut down completely. This is analogous to having a power failure in an area of the brain—a power failure.

So the lights are out in parts of the brain in patients with Alzheimer's disease, and the question is: Are the lights out forever, or can we turn the lights back on? Can we get those areas of the brain to use glucose once again? So this is what we did; we implanted electrodes in the fornix of patients with Alzheimer's disease, we turned it on, and we looked at what happens to glucose use in the brain. Indeed, at the top, you'll see before the surgery the areas in blue are the areas that use less glucose than normal; the parietal and temporal lobes. These areas of the brain are shut down; the lights are out in these areas of the brain.

We then put in the DBS electrode and we wait for a month or a year, and the areas in red represent the areas where we increase glucose utilization. Indeed, we are able to get these areas of the brain that were not using glucose to use glucose once again. So the message here is that in Alzheimer's disease, the lights are out, but there is someone home, and we're able to turn the power back on to these areas of the brain. As we do so, we expect that their functions will return.

So this is now in clinical trials; we are going to operate on 50 patients with early Alzheimer's disease to see whether this is safe and effective, whether we can improve their neurologic function. So, the message I want to leave you with today is that indeed there are several circuits in the brain that are malfunctioning across various disease states, whether we're talking about Parkinson's disease, depression, schizophrenia, or Alzheimer's.

We are now learning to understand what the circuits are, what areas of the brain are responsible for the clinical signs and symptoms of those diseases. We can now reach those circuits; we can introduce electrodes within those circuits; we can graduate the activity of those circuits; we can turn them down if they are overactive, if they're causing trouble that has fell throughout the brain, or we can turn them up if they are underperforming. In so doing, we think that we may be able to help the overall function of the brain.

The implications of this, of course, is that we may be able to modify the symptoms of disease. But I haven't told you, but there's also some evidence that we might be able to help the repair of damaged areas of the brain using electricity, and this is something for the future to see if indeed we not only change the activity but also some of the reparative functions of the brain can be harvested.

So I envision that we're going to see a great expansion of indications for this technique. We're going to see electrodes being placed for many disorders in the brain. One of the most exciting things about this is that indeed it involves multidisciplinary work. It involves the work of engineers, imaging scientists, basic scientists, neurologists, psychiatrists, and neurosurgeons. It's really at the interface of these multiple disciplines that there's the excitement, and I think that we will see that indeed we will be able to chase more of these evil spirits out from the brain as time goes on. The consequence of that, of course, will be that we will be able to help many more patients. Thank you very, very much.