Parkinsons depression and the switch that might turn them off Andres Lozano

one of the things that one established

right from the start is that not all

neurosurgeons wear cowboy boots I just

wanted you to know that so I am indeed a

neurosurgeon and I follow a long

tradition of neurosurgery and 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

neurosurgery comes from a long tradition

it’s been around for about 7,000 years

in Mesoamerica there used to be

neurosurgery and there were you these

neurosurgeons I used to treat patients

and they were trying to they knew that

the brain was involved in neurological

and psychiatric disease they didn’t know

exactly what they were doing not much

was changed by the way but they were

they they thought that if you had a

neurologic or psychiatric disease it

must be because you are 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 so this is a thinking back then

and these individuals made these holes

sometimes the patients were a little bit

reluctant to go through this because you

can tell that the holes are made

partially and then I think you know

there was some trepidation and they left

very quickly and it was only a partial

hole so and we knew these they survived

these procedures but this was common and

there were some sites where 1% of all

the skulls AB these holes and so you can

see that neurologic and psychiatric

disease is quite common and it was also

quite common about 7,000 years ago now

in the course of time we come to realize

that different parts of the brain do

different things so their areas of the

brain that are dedicated to controlling

your movement or your vision or your

memory or your appetite and so on and

when things work well then the nervous

system works well and everything

conscience but once in a while things

don’t go so well and there’s trouble in

these circuits and there are some rogue

neurons that are misfiring and causing

trouble or sometimes they’re in

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 to

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 so 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

then our case would 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 and this is

accomplished using this kind of device

and this is called deep brain

stimulation so what we’re doing is

placing these electrodes throughout the

brain these are 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 and 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 a hundred thousand 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 let’s look 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 rain' quite safely now

now the first example I’m going to show

you is a patient with Parkinson’s

disease and this lady has Parkinson’s

disease and she has these electrodes in

her brain and I’m gonna show you what

she’s like when the electrodes are

turned off and she has her Parkinson’s

symptoms and then we’re gonna turn it on

so this looks something like this now

and you can see that she has tremor

we’re now going to turn it on it’s on

just turn it on

and this works like that instantly and

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 define these troublemakers and

tell them gentlemen that’s enough we

want you to stop doing that and we do

that with electricity so use electricity

to dictate how they fire and we try to

block their misbehavior using

electricity so in this case we are

suppressing the activity I have normal

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 is a disorder affecting

children it’s a genetic disorder and

involves a twisting motion and these

children get progressively more and more

twisting until they can’t breathe that

till they get sores urinary infections

then they die so 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 nine years old perfectly

normal until the age six and then he

started twisting his body first the

right foot from the left foot and the

right arm from the left arm then the

trunk and then by the time he arrived

within the course of one or two years

the disease onset he could no longer

walk he could no longer stand he was

crippled and indeed the natural

progression is this gets worse is for

them to become progressively twisted

progressively disabled and many of these

children do not survive so 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 operation to 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

let’s 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

procedure that’s done throughout the

world and there’d been hundreds of

children that have been helped with this

kind of surgery this voice now in the

university 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 we realize that perhaps

we could use this technology not only in

circuits that control your movement but

also circuits that control other things

and the next thing we took on was

circuits that control your mood and we

decided to take on depression and the

reason we took on depression is because

it’s so prevalent and as you know there

are many treatments for depression with

medications or 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 and 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 we compared

what’s different in the brain of someone

with depression and someone who is

normal and what we did was 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 and those are

the areas in blue so here you really

have the blues and the areas in blue our

areas that are involved in motivation

and drive and decision-making and 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 and

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 and so

patients with depression have

hyperactivity the area of the brain for

sadness is on red hot it’s the

thermostat is set at a hundred degrees

and the other is 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 May bird

from Emory and we placed electrodes in

area 25 and on the top scan you see

before the operation area 25 the sadness

areas red hot and the frontal lobes are

shut down and blue and then after three

months of continuous stimulation 24

hours a day or six months of continued

simulation we have a complete reversal

of this we’re able to drive down area 25

down to a more normal level and were

able to turn back on line the frontal

lobes of the brain and indeed we’re

seeing very striking results in these

patients with severe depression so now

we are in clinical trials in our phase 3

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 in 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’t write so what we

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 gonna 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 symptoms of

early onset Alzheimer’s disease so we’ve

placed electrodes within the circuit in

an area of the brain called the fornix

which is a highway in and out of this

memory circuit with the idea to see 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 year even

though it only weighs 2% it uses ten

times more glucose than it should based

on its weight 20% of all glucose in your

body is used by the brain and as you go

from being normal to having mild

cognitive impairment which is a

precursor of Alzheimer’s all the way to

Alzheimer’s disease then there are areas

of the brain that’s stopped using

glucose they shut down they turn off and

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 cut down completely

this is analogous to having a power

failure in an area of the brain a

regional 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

and indeed at the top you’ll see before

the surgery the areas in blue are the

areas that use less glucose than normal

predominantly 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 electrodes

that we wait for a month or a year and

the areas in red represent the air is

where we increase glucose utilization

and indeed we are able to get these

errors 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 and 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 Alzheimer’s we are now

learning to understand what are the

circuits what are the areas of the brain

that 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

the circuits we can turn them down if

they are overactive if they’re causing

trouble trouble that is fell throughout

the brain or we can turn them up if they

are underperforming and 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 can

might be able to help the repair of

damaged areas of brain using electricity

and this is something for the future to

see if indeed we’d not only change the

activity but also some of the reparative

functions the brain can be harvested so

I envisage that we’re going to see a

great expansion of indications of this

technique we’re going to see electrons

being placed for many disorders on the

brain one of the most exciting things

about this is that indeed it involves

multidisciplinary work it involves the

work of engineers of imaging scientists

of basic scientists of neurologists

psychiatrists neurosurgeons and

certainly 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 and the consequence of that of

course will be that we will be able to

help many more patients thank you very

much