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