FRIDAY, June 25, 2004
Session 6: Neuroscience, Brain, and Behavior V: Deep
G. Rees Cosgrove, M.D., Associate Professor of Surgery
(Neurosurgery), Harvard Medical School, and Attending Neurosurgeon,
Massachusetts General Hospital
CHAIRMAN KASS: Some wag in the room at
the break indicated that we need to develop a new kind of
disorder for the DSM which is called change the question and
quick to metaphysics disorder.
And we have fMRIs ready for all of you
between now and the next meeting.
I don't want to take any time away from the session.
The change in the weather has led some of our colleagues to
have to leave before this session is over, and on their behalf,
I offer their apologies for the necessity of leaving before
It's a great pleasure to welcome Dr. Rees Cosgrove to
the Council. He's Associate Professor of surgery and
neurosurgery at Harvard Medical School and the Associate Visiting
Surgeon at the Mass General Hospital. He kindly interrupted
his vacation to come back and offer us a presentation on the
just newly emerging uses of deep brain stimulation not for
motor disorder, but for disorders of behavior.
And, Dr. Cosgrove, thank you very much. Welcome, and we
look forward to the presentation.
DR. COSGROVE: Dr. Kass, thank you very
much for inviting me.
What I would like to do briefly this morning is give a very
short historical perspective because I think that's paramount
to understanding some of the moral and ethical issues that
are involved with surgery for psychiatric illness; briefly
describe for you the current practice of ablative surgery
for psychiatric illness; then discuss the issues of deep brain
stimulation and some of the very vestigial or rudimentary,
early experience, and it is tiny, of deep brain stimulation
for psychiatric illness, specifically obsessive compulsive
disorder; and then trying to address some of the ethical issues
which Dr. Kass so kindly directed me to consider; and then
leave plenty of time for questions and discussion.
The modern era of psychosurgery was begun by this man, Egas
Moniz, who is a very celebrated and famous Portuguese neurologist
who experimented by injecting alcohol into the frontal lobes
of 20 institutionalized psychiatric patients and thought that
16 of the 20 were favorably improved.
He subsequently went on to devise a more discrete operation
in the frontal lobe through burr holes, and this was such
a major public health problem in those days with the asylums
full of the psychiatrically impaired and mentally ill that
these initial, early experiments in treating psychiatric illness
were very favorably received because, in fact, they did actually
improve behavior, and Dr. Moniz was, in fact, awarded the
Nobel Prize in medicine in 1947 for his work in this area.
And he was the man who coined the term "psychosurgery."
At the same time, the champion of this field in this country
was a psychiatrist-neurologist named Walter Freeman, and he,
in conjunction with Washington, D.C. neurosurgeon James Watts,
performed multiple prefrontal lobotomies, which was disconnecting
the entire frontal lobes with the use of a sort of calibrated
butter knife inserted through holes in the coronal temporal
region and inserted to the midline.
Dr. Freeman himself was an unusual man. There may have
been some psychiatric diagnoses potentially attached to him.
DR. COSGROVE: But his zeal and his sort
of overenthusiastic adoption of this procedure really was
difficult for the neurosurgeon. It's rare that the neurosurgeon
is the responsible character in these teams.
But actually the neurosurgeon showed great responsibility
by actually declining to participate and collaborate with
Dr. Freeman because he thought Dr. Freeman was over extending
the applications and misusing the surgery.
That didn't really stop Dr. Freeman who was a neurologist
remember, who then devised a procedure that he could do himself,
and this was the famous transorbital "icepick" procedure
in which a sharp blade was inserted over the globe, over the
orbit through the very, very thin roof of the orbit into the
underside of the frontal lobes, and he performed thousands
He actually would cross the country in his van, really advertise
his arrival in major metropolitan centers, and actually perform
these at asylums and hospitals throughout this country, and
he'd perform ten or 20 in a morning and then off he'd
So Dr. Freeman was probably in large part responsible for
some of the negative feelings toward psychosurgery of this
sort of closed, nonstereotactic methods that were used.
As you might imagine, these procedures were associated with
some significant mortality and morbidity. It's estimated
that there was about a ten percent major mortality and morbidity.
Nevertheless, these procedures were considered actually useful,
and despite the fact that the National Commission on the use
of Human Subjects and behavior in research experiments in
the mid-1970s said that at least half of the patients whom
were operated upon sustained benefit from these procedures.
The psychosurgery had its grand demise slowly throughout
the '70s for many reasons. I think in large part the
most compelling ones were these moral, social, and philosophical
aspects in which I think we heard a little bit this morning
about operating on the brain to heal the mind.
Issues arose probably in large part because of, again, the
morbidity associated with these gross and very crude techniques.
There was a lot of, I think, people harmed by the early times
of surgery. There were a variety of political stances against
this kind of surgery because of the outrage, and there are
a variety of medical and legal issues.
But probably most compelling was that in the mid-1950s,
the first psychopharmacological agent, chlorpromazine, was
introduced. And so right at this time alternative psychopharmacological
agents became available.
And as we've heard, it's far easier to give a pill
than do an operation to treat illness. then over the next,
you know, 30 years a huge variety of more selective psychopharmological
agents that were very effective in treating schizophrenia,
depression, and even obsessive compulsive disorder arose.
And so for a large variety of reasons, surgical interventions
for psychiatric illness basically declined to just a handful
of cases throughout the world.
And if you want to read a great book to describe all of
the somatic therapies that were used in these times of great
need, read Elliot Valenstein's book. It's a wonderful
document of this history.
Currently, however, surgery is still practiced in rare occasions,
and the only two indications that we typically perform the
surgery for are major depression and obsessive compulsive
disorder, and the surgery is only performed in those patients
who have severe and incapacitating psychiatric illness.
The degree of severity is typically estimated or estimated
with a Beck's Depression Inventory score of greater than
30, and the global assessment and function score of less than
50. These are people who are severely ill and completely
In terms of obsessive compulsive disorder, we typically only
operate on patients who have a YBOCS — that's called
the Yale-Brown Obsessive Compulsive Score — of 25 to
30, and this is an enduring illness. This is chronic illness
usually of many, many years' duration.
In addition, we only perform the surgery on patients who
are being completely refractory to all forms of conventional
therapy. So you must look at this as a salvage operation
or a palliative procedure, and it's only performed on
patients who have actually exhausted all forms of modern psychopharmacology
and pharmacotherapies. Typically this means that in the obsessive
compulsive disorder group that they've had three trials
of modern SSRIs with up to maximum tolerated doses augmented
with either lithium or Wellbutrin or clonazepam, any of those
In addition, one of the major therapies for obsessive compulsive
disorder is behavioral therapy, and they have to have exhausted
all forms of behavioral therapy or at least committed to 20
or 30 hours of behavioral therapy, and they've also had
to fail when appropriate electroconvulsive therapy, which
we know is a very practical and important intervention for
This procedure is undertaken, and I will review for you
our own. We have all patients who are referred to us undergo
evaluation by a psychiatric neurosurgery committee, and this
is a committee that has been in existence for the past 20
years at our institution, and it is composed of six members,
three psychiatrists, the former chief of psychiatry in our
institution and then a specialist in obsessive compulsive
disorder and a specialist in major depression.
There's one neurologist, myself as the neurosurgeon,
and a recording secretary to document all of the information
that passes through our hands. and it is this expert multi-disciplinary
panel that is charged with the selection and implementation
of the interventions. And this panel, primarily the psychiatrist
actually, are responsible for insuring that the accuracy of
the psychiatric diagnosis, the adequacy of drug and pharmacological
therapies, the adequacy of behavioral therapy and ECT.
One of the psychiatrists is assigned as the primary on the
referral and actually does a review of a detailed psychiatric
referral form, and all of the records are reviewed and summarized
for the committee, and then all of these things are discussed
in a committee, and there has to be unanimous approval by
all members of the committee that the patient meets criteria
for surgical intervention, and there's a whole bunch of
other tests, including EEGs, MRIs, PET scans, neuropsychological
And then if they meet these criteria, then they're brought
in person for evaluation by the primary psychiatrist on the
case, the neurologist and the neurosurgeon for final decision
One of the important aspects of modern psychosurgery is
the use of appropriate outcome measurements. What we have
attempted to do and what is occurring now in the past decade
has been implementation of these outcome measurement scales.
These are the same scales and using the same thresholds in
terms of determining successful treatment as are used in pharmacological
So one of the important things is if we're going to
promote any sort of surgical intervention for a psychiatric
illness, we have to use terms and outcome scales that are
recognized by the psychiatric community, and so that we can
show by comparison how they rank with appropriate psychopharmacological
These are very standard and accepted throughout the world.
A Beck's depression inventory or a Hamilton depression
inventory of 50 percent improvement from baseline would be
considered a success in the psychiatrist's eyes.
Obsessive compulsive disorder, which we'll talk about
a little bit more, is much more difficult to treat, and there
are fewer successes. And so in this instance a 35 percent
improvement in their YBOC score is considered a successful
pharmacological intervention or behavioral therapy intervention.
A global assessment of function is sort of a psychosocial
level of functioning and the minimum is a 15 point improvement
in the GAF.
And then also, although a subjective score, this clinical
global improvement scale is a seven point score with one or
two being either very much improved or much improved.
So these are the scales by which modern psychosurgery is
measured, and in terms of our own institution, we actually
put additional — because we're looking at individual
patients and not groups of patients, we actually characterized
our outcomes as a patient who responds to our intervention
as having in the depression scale either a 50 percent improvement
in their Becks and a CGI of very much improved or much improved,
or in the obsessive compulsive patients, a 35 percent improvement
in their YBOCS and very much improved or much improved.
And of course, patients have a continuum of response, and
so we considered partial responders as meeting the numerical
criteria for a pharmacological therapy or either that or being
considered very much improved or much improved by the rater.
And then all other patients were considered nonresponders,
even though there might be some improvement overall, but they
didn't reach significance or threshold.
So if we use these very much more stringent criteria, these
are very much more stringent criteria than was ever used in
the older psychosurgical literature, and I think that's
in large part explained by some of the differences in outcomes.
And one also has to consider that, in fact, in the old psychosurgical
literature none of the SSRIs and current modern pharmacological
therapies were available so that the patient on whom we're
performing this surgery on are much sicker, in general, and
have failed a whole host of selective pharmacological agents.
However, these are two of our own studies. This was the
first prospective study ever done to look at cingulotomy,
which is one of the procedures, ablative procedures, that
is performed for obsessive compulsive disorder, and performed
prospectively using unbiased, unrelated observers, and those
more stringent clinical outcome criteria, and in our group
of those patients who had failed everything else, you see
about a third of the patients became responders and, you know,
17 percent were partial responders for an overall response
rate of about 45 percent.
And we subsequently continued this prospective accrual of
data, and so some of these patients are in here obviously,
but more recently with a larger number of patients, with a
longer follow-up, surprisingly almost identical response rates.
So now neurosurgeons typically would look at a response
rate of 30 to 45 percent as being not particularly encouraging.
If we had a 30 percent response rate or success rate in surgeries
that we do, we wouldn't be doing much surgery anymore.
But I think that psychiatrists, if you take that this is
now a complete salvage rate, these are patients who failed
all of other forms of therapy, and I think that if the psychiatrists
in the group said that they did a drug trial in which a new
agent was added on to everything else that was being done
and they got a 45 percent response rate, that would be a powerful
new drug in the treatment of obsessive compulsive disorder,
to salvage a completely treatment refractory group.
So while these numbers are not fabulous, they are, I think,
Now, that's one particular procedure. That's cingulotomy
in modern times. The other typical procedure performed for
obsessive compulsive disorder is capsulotomy, and in this
instance, this is the gamma knife capsulotomy results from
the Brown Group. Unfortunately it's unpublished results,
but this is a very impressive group with a lot of experience
in dealing with severe and intractable obsessive compulsive
disorder, and they have a similar number of patients with
a similar degree of follow-up, and the gamma knife capsulotomy
is done with radiosurgical lesions in a slightly different
part of the brain, in the anterior capsule of the brain bilaterally.
And what's interesting is using, again, appropriate
criteria for rating outcome, they have 22 out of the 35 patients
responding, so for a 63 percent response rate.
What is very similar in terms of the two kinds of ablative
surgery performed for this condition is that there's no
immediate benefit from intervention. In fact, it goes six
to 12 months before we begin to see improvement, and in fact,
as we follow the patients further and further, in fact, the
success rates go up, and that's true for gamma knife capsulotomy.
That's true for cingulotomy.
So as we follow the patients out further, they improve more,
which is completely in contradiction to the natural history
of obsessive compulsive disorder and argues against any sort
of placebo response.
So if these ablative interventions are so successful, why
would we want to consider deep brain stimulation? Well, there
are a variety of reasons. Deep brain stimulation is now currently
widely applied to the treatment of movement disorders, and
so many groups in the country are very familiar and expert
in the technology.
But the real advantage of deep brain stimulation is that
it's reversible. What is done is that using stereotactic
techniques and the same techniques that are used to make these
small lesions in the brain, instead of making a lesion, we
implant an electrode with multiple contacts, usually four
contacts, into the target zone.
And so because it's reversible and we're not creating
a lesion, any side effects associated with implantation or
stimulation can be dialed down or you can turn the stimulator
off, and the side effects and the benefits are reversible.
So this allows us to explore areas that would not be previously
conceived as possible to place lesions in. The best analogy
is subthalamic nucleus stimulation for Parkinson's disease.
No neurosurgeon with experience would want to place a lesion
in there because the target is so small and the real estate
so expensive surrounding this small, you know, five millimeter
nucleus that any minor error in lesioning could create a devastating
and irreversible neurological deficit.
Now, by placing an electrode into the area, we all do now
with great regularity and with great safety.
So that is a primary advantage of deep brain stimulation.
The other thing, it's adjustable. So one can adjust in
terms of getting therapeutic benefit, and one can adjust in
terms of any negative side effects, and it also is adjustable
potentially over the course of that patient's illness.
So whereas a lesion is succinct and defined and irreversible,
deep brain stimulation is adjustable, which has very specific
We've talked about how it allows placement in otherwise
risky targets in the brain. So, in fact, most targets in
the brain now are potentially accessible by deep brain stimulation.
It's familiar technology to us, all neurosurgeons and
stereotactic and functional neurosurgeons.
And the other important thing — and this is where
I think it creates certain ethical issues for the Council
— is that it reduces psychological barriers to implementation.
There's something about creating a small lesion in the
brain that neurologists, psychiatrists and lay people and
patients have a problem with, although it has been used successfully
over the past 50 years.
But if you talk about stimulating the brain, and the fact
that it's reversible, the barrier to considering this
kind of intervention drops significantly. I can tell you
that that's true both in the Vegas nerve stimulation study
for depression. That's a relatively low risk procedure,
and patients would volunteer. They'd come into the office
with their neck exposed like this and say, "Can I be
part of this trial?" because it's a relatively low
risk, and it's stimulating.
Similarly, when you stimulate the brain, I think a lot of
negative biases naturally are reduced. I'm not necessarily
saying that's a good thing, but it does actually reduce
these barriers to referral and barriers to implementation.
Deep brain stimulation, as we know, is currently accepted
and has FDA approval for all sorts of treatment of movement
disorders, intractable tremor, Parkinson's disease, and
the dystonias, and certainly in pain. It's widely performed
throughout the world for these indications.
It's under investigation for intractable epilepsy, cluster
headaches, and obsessive compulsive disorder, and soon depression.
So these are still experimental. We don't know the results
of these studies yet.
But there is the potential for a wide variety of behavioral
and other psychiatric conditions: anorexia, morbid obesity,
addiction, self-mutilation, violence and aggressivity, and
schizophrenia. All of these, in all of those indications,
ablative surgery has been performed in the past.
But you realize that here's an interesting moral question.
Anorexia nervosa is a life threatening condition. We've
all seen cases of that. Now, the psychiatric or the psychological
situation is that the patient is uncomfortable with their
body image typically. They can look in the mirror and they
can say even though they are thin and what you and I would
say that's a very thin person; they think of themselves
as ugly and fat or their perception of themselves is fat.
If you did an operation that restored their willingness
to eat and consume, because many of these patients in their
worst conditions are actually so malnourished that even minor
physical activity can actually result in pathological fractures.
They die of starvation.
And so here's an interesting question. If you take
that patient, to save the patient's life and you do an
operation to make them consume more calories and eat so that
now we're happy with the image of the patient, but now
they're looking in a mirror and saying, "God, I thought
I was fat then. Now, I'm" — it would be pure
psychological torture for the patient.
So that's an interesting conundrum. Even though you're
doing the best thing that you think for the patient and you
might save the patient's life, that's a horrible position
to put the patient in. Anyway, something to think about.
Now, there have been approximately greater than 25,000 cases
of deep brain stimulation performed worldwide for Parkinson's
disease pain, tremor, dystonia, a variety of things. As of
May of this year, there have only been 23 cases performed
for psychiatric indications. So you're talking about
.001 of the experience. So this is in its absolutely embryonic
And yet so why are we interested in it? We're interested
because of the early results and because of some of the advantages
of deep brain stimulation which I've spoken about. The
first published experience was from Belgium by Nuttin and
they operated and used the anterior capsular target. So instead
of making a lesion placing electrodes into this area, into
the exact same area in which we would perform a capsulotomy.
So we know that capsulotomy empirically has a pretty favorable
track record in refractory OCD patients, but instead of making
a lesion, we say let's stimulate, and in four of his patients,
three of them became responders and meeting criteria of that
same sort of 35 percent improvement in their YBOCS. One patient
was a nonresponder. And this was done using blinded observers
and was done in a very appropriate fashion.
So that was the initial experience that prompted enthusiasm
in this area, and I should say that one of the reasons that
it's important to discuss deep brain simulation is that
there's so much enthusiasm in the area that, in fact,
some of it may need to be reigned in, and the reason I say
that is very year I give a seminar on psychosurgery for neurosurgeons,
and you know, typically I tell people it's not something
that you want to do very much of because, first of all, it's
not paid for. It's all gratis. It's uninsured by
Medicare. So all of the professionals and the hospital institution
gets no money for Medicare patients. It's one of the
eight specific procedures that Medicare and CMS denies.
But whenever I ask a group of neurosurgeons, stereotactic
and functional neurosurgeons who do surgery for Parkinson's
disease, do surgery for epilepsy, do deep brain stimulation,
I ask, you know, "Who's considering doing this this
The hands go up, about 75 percent of them, and that to me
is a scary thought because it's a neurosurgical procedure,
but it's based upon an expert multi-disciplinary group
of psychiatrists and neurologists, and the neurosurgeon actually
in this instance is the technician, skilled technician nevertheless.
But in any case, so this was the original paper. There
have been a couple of anecdotal reports, and this initial
experience has prompted a 15 person/patient investigational
trial in this country, the results of which are not yet available.
One of the things that was learned from this early anterior
capsule experience was that although it's nice for us
to think that deep brain stimulation, you can turn it on and
off and, therefore, you can have a control state to this.
Patients and evaluators, both the patients and the evaluators
know when the DBS is on. So you really cannot blind this.
In fact, the Belgian investigators sent in medical students
to try and figure out if they could accurately predict whether
they could tell whether the stimulator was on or off, and
they were 97 percent accurate in determining whether the thing
was on or off.
So thinking that you can do one of the .- one of the proposed
advantages of deep brain stimulation is that you can do blinded
studies. You can't do blinded studies. Patients and
evaluators know when the stimulators are on or off.
PROF. SANDEL: How does the patient know?
DR. COSGROVE: Perception, feeling, how
they're feeling better.
PROF. SANDEL: No, but independent of
the relief of the symptoms, do they know it's on?
DR. COSGROVE: No, because these thing
are turned off and on with a magnet, and it's simply their
perception of how they're feeling when it's on.
DR. HURLBUT: How does the observer know?
DR. COSGROVE: Well, I think it's
actually how in talking about the patient and looking at their
behavior, looking at their movements, looking at their interaction.
It's a behavioral thing.
The other way, of course, you have a monitor which you check.
This stimulator, the electrode is attached via a subcutaneous
lead to a pulse generator here that's placed just under
the clavicle, just like a heart pacemaker is, and you can
interrogate this through the skin, and you can program and
change the settings all through the skin, just like .-
PROF. SANDEL: With a magnet? How do
you do it?
DR. COSGROVE: It's a little computer
that's telemetry, via telemetry, the same way you do cardiac
pump pacemakers, the same technology.
And the neurologist or the psychiatrist, as we do for patients
with Parkinson's disease, you can select which contacts,
the current, the pulse duration, the frequency, and you do
that all through the little hand held device that is superimposed
over the pulse generator.
PROF. SANDEL: Who holds the clicker?
Like where is that, in the doctor's office?
DR. COSGROVE: The doctor has that, yeah,
The patient can turn the device on or off with a magnet
that they just pass over the device. So they only have the
ability to turn it on or off. The physician is the one who
has the ability to program.
So what's very clear, and this gets to your question,
is that when the DBS is on, patients were more alert, more
spontaneous, less anxious, and less depressed, very clear.
When the stimulator is on, it does not appear to impair
frontal lobe tasks. So neuropsychological tests looking at
frontal lobe tasks, decision making, all of these things.
The improvement in their Yale-Brown obsessive compulsive
score is sustained if DBS is continued, but when the battery
fails or you turn it off, the YBOCS improvement goes back
to where they were preoperatively. And then you turn it back
on again and you can see the sustained improvement again.
PROF. SANDEL: Is it immediately or over
a period of time?
DR. COSGROVE: No, it's over a period
of time. What is immediate is the mood effects, but the obsessive
compulsive traits or disorder symptoms do not improve right
away. They take time.
And the other interesting thing is that it requires high
stimulation parameters, and what happens is what or when.
So it means you go through a lot of batteries, maybe every
one and a half to two to three years you have to replace the
battery. So not inexpensive.
And the other very interesting thing is that the optimal
effect is contact dependent. So we have four contacts in
there, and Paul Cosyns, who is one of the investigators in
Belgium, relates this very wonderful anecdote that one of
the patients who successfully treated has, you know, their
four contacts, and she says, "Well, Dr. Cosyns, when
I'm at home doing my regular things, I'd prefer to
have contact two, but if I'm going out for a party where
I have to be on and, you know, I'm going to do a lot of
socializing, I'd prefer contact four because it makes
me revved up and more articulate and more creative."
So there's an example of contact dependency, and we
have our own patient who is a graphic designer, a very intelligent
woman on whom we performed the surgery for severe Tourettes
disorder and blindness resulting from head tics that cause
retinal detachments, and we did this in order to try and save
her vision. The interesting observation was that clearly
with actually one contact we could make her more creative.
Her employer saw just an improvement in color and layout in
her graphic design at one specific contact, when we were stimulating
a specific contact.
And that raises this very thorny issue of improving performance
with deep brain stimulation, which is not where we're
at obviously, and I don't think it's a place where
we should ever go to, but you can see that different stimulation
through different contacts has different effects.
So one of the things that Dr. Kass asked me to try and address
is are the indications for deep brain stimulation for neurologic
disorders, such as Parkinson's disease or epilepsy; are
they different from psychiatric disorders?
And it's my belief, and it's actually the belief
of all members of our committee that, in fact, trying to differentiate
surgical intervention for Parkinson's disease from psychiatric
disease is artificial. Trying to distinguish those things
I believe that psychiatric illness is a manifestation of
the mind, the disease of the brain and disease of the mind.
So if we choose to perform surgery to help a patient, it should
be done more based upon the assessment of the risks of your
intervention versus the possible benefits that can be supplied,
and then a critical element obviously is the ability of the
patient to give informed consent.
And I think that one of the important things for this committee
to understand is that the patients on whom we're operating,
patients with severe depression, the patients with severe
obsessive compulsive disorder, these are severely ill psychiatrically,
and yet they are in the vast majority, they are completely
aware of their illness and they are completely able to give
And so one has to avoid being paternalistic about our protection
of patients in the sense that if they are aware of the risks
and benefits and if they are able to give informed consent,
then we should allow them the opportunity to explore some
of these novel interventions in the same way that we would
allow them to explore enrollment in a clinical drug trial.
So to me the differentiation between neurologic versus psychiatric
indications is artificial and unnecessary, and I think it
stems in large part from the history of psychosurgery in
the past and some of the hold-over from the early and less
precise interventions, but it's clear that outcomes have
to still be measured using the clinically validated rating
scales that I have told you about.
And is deep brain stimulation different from pharmacological
trials? Many times we're dealing with the same patient
population. Most of our patients who come to surgery have
already failed multiple novel investigational pharmacological
agents, and there clearly is a difference, however, from a
pharmacological add-on agent to a surgical intervention, and
it has to do with the surgical risk.
The risk of deep brain stimulation for intracranial hemorrhage
is probably somewhere between one to two percent. The risk
of neurologic deficit associated with that is not insignificant
in that one or two percent. The risk of malfunction of the
device, infection, abscess, all of those things, disconnection,
a whole bunch of different things, is probably in the five
to ten percent range now. So it's not trivial.
There are also risks of adding on pharmacological agents,
of course. You could get an idiosyncratic reaction and have
a problem, but you know, it's much easier to stop a medication
than to explant a surgical device.
So that's a major difference between deep brain stimulation
and pharmacological trials, but the design of these trials
and the selection of the patients, the follow-up, and the
usage of appropriate outcome rating scales should be similar.
The only difference, I guess, is some of the selection criteria.
I would propose that, in fact, for surgical interventions
patients should be refractory to all appropriate therapies,
whereas one might consider drug trials in patients with mild
depression and you use a different agent or, you know, moderate
depression or moderate OCD. I think surgery should be reserved
for the most refractory and severe cases.
And then the issue arises. You can certainly do placebo
blinded crossover trials with drugs. There's some intimation
that you could do this with deep brain stimulation, but I
think that's fallacious.
I think that, first of all, you can't really do a placebo
surgical procedure, not a good one. You may have discussed
some of these, but certainly there is some micro lesioning
effect of just placing an electrode onto the target.
As I've said before, you can't really blind the
patients nor the observers. You can certainly do crossover
trials with deep brain stimulation because you can turn it
on and off, and I think that that's a real value.
I'll finish up shortly.
One of the important issues and outstanding issues for deep
brain stimulation is that we are not clear what the optimal
targets are. We don't even know what the optimal stimulation
parameters are, and we don't know what the long-term effects
We don't understand how deep brain stimulation works.
We know that in gray matter it typically inhibits gray matter
structures, and in white matter it typically excites white
But any neuroscientist knows that even in gray matter nuclei,
the deep brain nuclei, that yes there's a predominance
of nuclei or neurons, but they're all attached with a
myriad of white matter tracts, and so it's not as simple
as we make it out to be.
It's extremely expensive in terms of time and money.
The hardware, the equipment is expensive, and when you're
utilizing one of these pulse generators every one to two years,
that's a very important annuity to the manufacturer.
Not only that; it's extremely expensive in terms of
time for the treating physicians. Seeing the patients, adjusting
the stimulators, we know this for a fact in the Parkinson's
group. Always trying to get at a little better. There's
no "okay. that's good enough," and accepting
it as such.
And you can imagine in the psychiatric population of always
trying to get that little bit better so that it's endless.
One important issue is to realize that currently, you know,
deep brain stimulation is device based, and there's only
one manufacturer in the world. So Medtronic has a monopoly
on this. Medtronic is the sole financial supplier for the
investigational studies. Most of the people who are involved
in these studies are Medtronic consultants in some way or
another, or if not directly, indirectly receiving a lot of
research support for their activities from Medtronic.
Now, I know many of the people, and they're all upstanding
people who are involved. I know the people involved in the
OCDDBS study, and they're all upstanding and wonderful
people, but one has to be cognizant of this very fact, that
there's no alternative to the supplier.
And one of the other big issues, and it's true for all
psychiatric research, is that there are no good animal models
exist. So we are doing this. We are doing experimentation
on humans. In Parkinson's disease we had great animal
models. We understood some of the basic neurocircuitry, and
we had hypotheses in which we directed our interventions,
and we don't have that in deep brain stimulation for psychiatric
So I'll conclude by saying that deep brain stimulation
for psychiatric illness and indications are currently experimental
and remain so. The preliminary experience appears encouraging
and, therefore, proceeding thoughtfully and cautiously seems
appropriate, but — and this is the big "but"
— we must guard against the indiscriminate and wholesale
experimentation and repeating the mistakes of the past because
this is, I think, an important opportunity to do this right.
We won't get a third chance to do this right.
On a very final personal note, I will say that as a neurosurgeon
— and Ben will back me up on this — as neurosurgeons,
we see an incredible amount of death and disability in our
daily life, in our daily work, from a huge variety of different
illnesses. So we're used to seeing death and disability
And in my near 25 years of doing neurosurgery, never in
my professional experience have I ever witnessed the suffering
that these people have, and it's suffering, constant suffering,
and such disability that affects not only the patient, but
every member of their family and friends around them. It
So that anything that we can do to alleviate or lessen,
reduce these patients' suffering is important work.
CHAIRMAN KASS: Thank you very much.
There are a couple of our colleagues who are going to have
to promptly leave soon, and I'd like to give them the
first shot if they would like to take it, to ask a question.
We're going to excuse them shortly.
Michael Sandel is one.
PROF. SANDEL: This is just a naive factual
question. Is this different from or the same as what we read
about in the popular press about the use of high powered magnetic
treatments for depression?
DR. COSGROVE: No, this is different.
What you're talking about is transcranial magnetic stimulation,
and this is quite different from that. There is a possibility
— it does supposedly the same things internally in the
brain, but noninvasively, but it's not continuous. You
go and receive the transcranial stimulation. It stimulates
the train in certain areas and thereby that's how we think
that the improvement might result from. It's electrical
But it's only done episodically, and once these electrodes
are placed, it's internal and continuous.
PROF. SANDEL: And do you have a view
about the comparison between the two, the promise of the two?
How would you compare them?
DR. COSGROVE: Well, the great promise
of transcranial magnetic stimulation is that it's completely
noninvasive, and I think that the problem is that I think
that without continuous stimulation, I think that it's
less likely to be successful on the long term, but both areas
are investigational, completely investigational.
PROF. SANDEL: Right, and there's
no data really to compare them yet. It's still being
DR. COSGROVE: No, there's no data.
One synergy that might come from this is actually predicting
which patients might respond to deep brain stimulation because
if you can focus your stimulation in a certain area, then
you might be able to predict which patients would respond,
and then you would go to the risk and effort to implant an
electrode if you could select that.
This person seems to be responsive to transcranial magnetic
stimulation. Therefore, why don't we take the next step
and do deep brain stimulation?
CHAIRMAN KASS: Before Michael goes, it
seems to me, just to try to connect this conversation with
the one we have in the previous session, admittedly this is
at a very early stage and there are obstacles to having this
implemented because of the Medicare restriction and the like,
but Dr. Cosgrove listed amongst the potential applications
of these addiction, self-mutilation, violence and aggressivity.
And assuming that one had rather severe instances of those
things that this is not a treatment of first resort, but for
refractory cases, would you be uncomfortable following this
as a mode of treatment? Would this be making us guilty of
some kind of wrongful understanding of the underlying foundations
of a disease if in the retail business you've got a patient
with a severe problem of this sort, and Dr. Cosgrove through
deep brain stimulation can rescue them?
PROF. SANDEL: Well, yes to the first
question and no to the second. Yes, I would be uncomfortable,
but only because I'm squeamish about all of this stuff,
but no to the second question. I wouldn't rule it out
on moral grounds without knowing more about what kind of success
it could achieve. I wouldn't say it's some fundamental
violation of our humanity or of our understanding of moral
responsibility, no. I'm squeamish about it, but that
CHAIRMAN KASS: And squeamish about it
in a way different from being — are you equally squeamish
about doing this for Parkinson's disease?
PROF. SANDEL: Yes, it's just as squeamish
about planting the thing into the brain, but morally, no.
Morally I don't see a difference, provided it —
CHAIRMAN KASS: So the fact that it's
a behavioral disorder as opposed to a motor disorder is no
part of your concern?
PROF. SANDEL: No, for reasons that were
partially developed in the earlier discussion. I don't
see the intervention to deal with behavioral disorders as
crowding out or being inconsistent with other interpretive
or therapeutic ways of treating or of understanding. I don't
see the two kinds of description as incompatible and at odds
with freedom in a way that on a certain picture they would
CHAIRMAN KASS: Questions?
DR. McHUGH: But I would be. I would agree
completely. I would say yes and no in the same ways, but
I would be squeamish for another reason than just invading
the brain, and that's the reason that Dr. Cosgrove brought
up. Whereas in Parkinsonism we do understand the mechanisms
that we're working on in relationship to these things;
we have no clue as to what the mechanism is. Now, I'd
still do it, but I'm squeamish until we begin to discover
whether, for example, doing these brain stimulations are releasing
certain endorphins or exciting the pathways for self-stimulation
and things of that sort and then I would become less squeamish
because I would then know what we're doing.
Because we don't know what we're doing here, even
though we know that it's effective, I would be squeamish,
but I would be accepting of it.
PROF. SANDEL: Well, I would agree with
that. That doesn't reach the philosophical question that
you were asking though. Yeah, I would accept that.
CHAIRMAN KASS: Dan, do you want to comment?
You look like you were.
DR. FOSTER: Well, just one quick question.
You've mentioned over and over again how expensive this
is and so forth. Let's say if it were fundable in some
sense. Would you have a ballpark figure of what, let's
say, the first two years of treatment might be?
DR. COSGROVE: That's a difficult
figure to come up with. The equipment ballpark figure is
in the $15,000 range. That's for the first time. Each
time you put in another IPG it's $8,000.
Hospital cost for the initial implantation is probably in
the $30,000 range, and again, these are Massachusetts rates.
So they're very low.
But then the real hidden cost is all of the time and multiple
visits required for stimulation adjustment and that. It has
got to be over the space of — I can't really give
an accurate number on that because I haven't been involved
in the trial, but it's significant.
DR. ROWLEY: But doesn't that have
to be weighed against the costs? Otherwise, these are not
patients who otherwise you're spending no money on at
all. So it's the differential that you're asking
about that's important.
DR. COSGROVE: Yes, that's absolutely
true, but I guess one has to also remind people that nobody
is ever cured with these operations. I think that's very
important. So that nobody ever gets off medication and nobody
is ever cured, especially in the OCD population. Their function
may be improved and restored more back towards normal, but
in the patients on whom I have operated on and what we have
seen, nobody is ever cured and they remain under treatment,
both pharmacological and behavioral and medical.
DR. ROWLEY: But can they go back to work?
DR. COSGROVE: It's very rare because
they're so severely ill and they've had such disabling
illness for so long. We don't know about that in the
deep brain stimulation because we're talking about a tiny
In my experience with ablative surgery, yes, there are some
people who go back to work. There are some people who are
working still. Those are the minority, but, yes, there are
a percentage that will go back to work.
PROF. SANDEL: Why don't you play
out a little bit the objection that underlay your question
CHAIRMAN KASS: It wasn't so much
an objection. It's partly what interests us here is whether
any kind of initial disquiet that anybody might have about
these kinds of — in fact, Mike asked before: is there
a difference? People would be happy giving drugs for these
things but might be unhappy doing brain surgery. Is that
just because there's surgical risk or is there some kind
of quasi philosophical reason that you don't somehow fix
people by putting your hands on the brain?
And if that's your concern, how do you differentiate
between going to work on Parkinson's disease or removing
a tumor and actually doing this, even if we don't exactly
know what we're doing?
PROF. SANDEL: So we say no, but you may
think yes. So could you say a little bit, or what do you
think? What would you say?
CHAIRMAN KASS: I don't have a firm
opinion. In other words, this is a real question. And, indeed,
the more one sort of talks about this, the harder it is for
me to make the distinctions between. That's partly why
I was leaning on you in the other session. I'm not sure
it's so easy to make a distinction between a behavioral
disorder. The lines are fuzzy.
DR. KRAUTHAMMER: I'm not quite sure
it matters whether we know the mechanism or not. When we
first started using anti-psychotropic drugs, I'm not sure
anybody knew the mechanism, or lithium. I don't know
the entire history, but a lot of these there's an extremely
obscure, but it worked, and if it worked it works.
I'm not sure that's the salient.
I wanted to ask our presenter. Do you feel personally any
differently, a difference between ablative and stimulative
DR. COSGROVE: No, because the scientific
evidence isn't there for deep brain stimulation, you know.
So there are theoretical advantages for deep brain stimulation.
It's an important opportunity to learn more about how
the brain works in these disease states and how it may be
modulated. So I think it's an important moment, but I'm
not necessarily sure at this point that deep brain stimulation
is better than ablative surgery, and we won't know that
until we actually get many more years of experience.
DR. KRAUTHAMMER: If I could just ask
you, you had expressed some concern about the enhanced creativity
by your patient who used electrode number four. Could you
draw you out on that a bit? Assuming you have a stimulative
treatment that helps someone and they do have enhancement
of normal functions by tweaking it on occasion, are you against
the tweaking on principle or how do you feel about it?
DR. COSGROVE: Well, yeah. So now we're
treading on this tricky moral ground. In my opinion our concept
is to restore normal function. In the same way that I would
have an aversion to trying to use deep brain stimulation for
social, political, or, you know, legal issues, I have also
a problem with trying to enhance function artificially because
it seems beyond what is normal for that person.
So I think of these interventions as trying to relieve suffering.
I think we can all agree that that's typically a good
thing and a laudable goal, and then to try and restore function
back to normal for that not beyond because then I think you're
treading on very difficult areas.
DR. KRAUTHAMMER: And just to follow up,
do you think that's scientifically plausible? Aside from
the moral issues of whether you ought to do it or not, do
you think it will be doable in our lifetime?
DR. COSGROVE: Could you improve function?
DR. KRAUTHAMMER: Yes.
DR. COSGROVE: I believe it will be, and
that's why I think it's important to have these discussions
now when it's not an option at this point, but that there's
a firm ethical framework upon which we will judge and make
decisions going forward because I do think we will be able
to improve certain functions in different individuals.
DR. HURLBUT: What kind of functions?
DR. COSGROVE: Well, this is just an example
of creativity that was manifest in a single patient. So if
you could work harder and better and faster and do better
work, then is that something — well, that's what
we try and encourage our kids to do.
DR. HURLBUT: What do you mention?
DR. COSGROVE: Well, one could be, again,
more creative from a scientific perspective. You may have
clarity of thought. You might have better as we've said
artistic endeavors. I mean these are all scary things. You
might be able to analyze a situation more clearly.
Whether that's a specific effect or whether it's
a relief of some underlying problem. For example, on many
of the patients in whom you improve with depression, their
performance on neuropsychological tests often increases, improves
after even appropriate medication or even a surgical intervention,
and it's not because they are any really smarter or better.
It's that their mood is improved, which allows them to
pursue and attend and function at a higher level.
So all of these things are very speculative, and I'm
not typically a speculating type.
CHAIRMAN KASS: Peter, Janet, and Gil.
DR. LAWLER: So in your opinion, to summarize,
right now this is for symptom relief in very extreme cases.
DR. COSGROVE: Correct.
DR. LAWLER: But it could be a lot more
than that, but you're against that.
DR. COSGROVE: Yes, at this point in time.
DR. LAWLER: What if I had been a great
neurosurgeon, but I was suffering from mild depression and
I could save many lives if this option were open to me? What
would be wrong with that?
DR. COSGROVE: Because there are other,
much better alternatives for the treatment pharmacologically,
and Ben probably is a little depressed, and he still saves
a lot of lives.
DR. COSGROVE: We all get a little depressed
when you do neurosurgery for this long.
So I guess it all comes down to — it all comes down
to the risk-benefit analysis, and you know, surgery always
has risks associated with it.
DR. LAWLER: I agree there's no ethical
question if it's symptom relief in genuinely extreme cases,
but what's to keep your colleagues from disagreeing with
you as these procedures become easier and the cost-benefit
analysis starts to shift on you?
DR. COSGROVE: Well, when we have the
evidence to demonstrate that we really understand what the
outcomes are, what the benefits are, and what the risks are,
then, of course, one reassesses the situation, and in the
same evolution in epilepsy surgery it used to only be done
for patients who had failed all anti-convulsive medications.
In the past decade or so, we have evolved into the patients
with medial temporal sclerosis as that's a surgically
curable epilepsy, and we know that about 80 percent of those
people with appropriate operation will be cured.
So we've evolved from only doing it for the intractable
patients that failed medications to saying there is a subset
that really looks good and, you know, we know what the outcomes
are. Therefore, the risk-benefit is good.
Similarly, with Parkinson's disease, we used to only
do it for the end stage. Now we do it for younger patients
because we know what the track record is and we feel that
there is an advantage to doing it when you're younger
to maintain function for longer.
When we get the information about deep brain stimulation
for psychiatric illness that we can hang our hat on and know,
then we might —
DR. LAWLER: Well, now you're scaring
me. Then Leon's question kicks back in, right? This
is a radical stand. I'm for complete eradication of Parkinson's
disease. I know it's controversial, but the same thing
with epilepsy and so forth and so on. But what you're
saying is over time what seems extreme becomes less extreme
because it becomes easier to do.
DR. COSGROVE: No, not because it becomes
easier to do. It's easy to do this now. That's not
the difficult part. I mean, it's easy for any good neurosurgeon
to do this now. That's the dangerous part. It's
easy to do right now.
What we don't have is the knowledge and the experience
with it, and that is what's missing.
DR. LAWLER: So it becomes more easy and
reliable and comprehensible and stuff, right?
DR. COSGROVE: It's much more predictable.
DR. LAWLER: Predictable. That's
the word I'm looking for.
DR. COSGROVE: "Predictable"
is what you're looking for. When we can predict exactly
what the outcomes are going to be, then it makes it easier
to make a decision.
DR. LAWLER: Then the analysis for the
decision is easier.
CHAIRMAN KASS: And now much a technical
point in follow-up, Janet, if I might intrude myself in the
queue. On the one hand, you seem to be saying that it's
much too early to tell, but it's at least conceivable
that once the data were in, that psychosurgery, precise psychosurgery
of the sort we're now talking about and precise stimulation,
might become not a treatment of last resort, but maybe even
for certain kinds of conditions a treatment of first resort.
I mean if the trouble with obsessive compulsive disorder
is that these people who have had it for such a long time
are now hard to restore to work because, as you indicated,
disease is so severe; there has been so much damage as a result.
Then one could make an argument if one knew what one was doing
that you shouldn't allow them to have 20 years of this
disease and that it would be more efficacious to go in there
early, assuming you could —
DR. COSGROVE: Predict outcome.
CHAIRMAN KASS: Predict outcome.
DR. COSGROVE: In that specific patient.
CHAIRMAN KASS: In that specific case.
DR. COSGROVE: So, yes, we have that same
analogy in epilepsy. We prefer to operate now on children
with epilepsy because we know what the natural history is
of that disease.
CHAIRMAN KASS: Right.
DR. COSGROVE: To try and, you know, allow
them to have a 40-year history of epilepsy and then operating
on them when they're 40 seems a waste of time, but we
have intimate knowledge of the natural history. We have intimate
knowledge of what the expected outcome will be from an intervention,
and we can make it even individual specific because of our
characterization, our knowledge of the disease, our understanding
of the pathophysiologic mechanism.
So while we can draw an analogy to that, I think that, you
know, I would not consider it as a first line of resort ever
because there are pharmacological and behavioral therapies
that are really the mainstay of treatment.
And as I've told you before, this surgery, ablative
surgery or this surgery, does not cure these patients. It
improves sometimes just their response to behavioral therapy
or their response to the medicines. So it would not be considered
in the same way we talk about surgical cures. It's a
CHAIRMAN KASS: Janet.
DR. ROWLEY: Well, actually the question
I had has been in part answered by these conversations. I
was reminded of my colleagues in oncology who started out
with new drug therapies on the patients who have failed everything,
partly to get experience with a particular drug or treatment,
the dose, the scheduling, and all of the rest of it, and for
those that appear to be efficacious, and then moving on to
using them in earlier patients.
And so this conversation has said that, in fact, that might
be a possible scenario as you gain more experience both with
the type of patient that could respond to the treatment as
well as all of the down sides of this treatment so that you're
more comfortable going earlier in the patient's disease.
What I take away from this conversation in the last few
minutes is that, in fact, this would be an appropriate, reasonable
way to move, but you do indicate that surgery is not the first
line for virtually any patient, but that there may be a subset
of patients in whom some kind of surgical or deep brain stimulation
intervention would be appropriate much earlier in the disease
than you presently feel comfortable with, but you need more
experience to determine that at that point.
CHAIRMAN KASS: That's true.
PROF. MEILAENDER: Just a question. When
you were discussing the surgical procedures and the percentages
of people who are responders and partial responders and so
forth, you said that the improvement is greater over time.
It's not immediate. Why is that?
DR. COSGROVE: That's one of the enduring
questions, isn't it? It speaks to our relative lack of
understanding of the neurobiological basis of these illnesses.
PROF. MEILAENDER: Could I just sharpen
it? Is it certain — does it raise questions about whether
the basis is entirely neurobiological?
DR. COSGROVE: No, not in my mind. I
believe, you know, in the same way that it takes time for
an antidepressant medication, you know, you have to have it
in the patient for two to four weeks at appropriate levels
before you begin to see any change in the neurochemistry and,
you know, before you begin to see change in symptoms. The
making a lesion or stimulating the brain is sort of an internal
neural modulation of some sort, and it's probably because,
you know, it's not a specific nucleus that drives all
of these things; that it's some rebalancing act that is
We don't understand why it takes that long and why we
tend to see improvement over time, and you know, even some
of the speculative mechanisms that we've used to explain
some of these things are just wrong. You know, we find out
20 years down the road that, well, it seemed like a good explanation
for it, and it seemed to fit our empiric observations, but
it was just totally wrong.
So I don't believe in speculation. I have too much
work to do to spend time speculating, and I am a fairly strong
believer in empiricism if it's valid, but nobody really
understands why it takes time. I think it has to do with
interfering with circuitry that allows the brain to remodel.
CHAIRMAN KASS: Ben Carson.
DR. CARSON: Yeah, Rees. That was a very,
very informative talk. I think it's going to give us
a lot of food for thought.
One of the things that I think people need to understand
is that neurosurgeons tend to be extraordinarily conservative
people, and you can see from Dr. Cosgrove's presentation
that he fits into that category.
I have no doubt that as time goes on and as people become
more and more familiar with the techniques and as more less
invasive types of techniques become available, that the degree
of conservatism will slacken and that the number of applications
will begin to expand, and this will become a significant issue.
You look at things like intervention at the level of the
hypothalamus. You know, if you ablate the ventral medial
hypothalamic nuclei, all satiety goes away. A rat will eat
until, you know, it explodes.
The same thing would happen to a person. You stimulate
the lateral hypothalamic nuclei, they're not going to
want to eat. Now, don't believe for one moment that somebody
isn't going to try to exploit that, you know, when we
come to all of this dieting and ways of getting people to
be looking, you know, the way they think they should be.
All of these things are going to happen because we can do
it. We have the ability to do it.
Like Clinton said, "I did it because I could."
You know, it's going to happen, and we're going to
need to deal with it.
CHAIRMAN KASS: Could I follow that?
Because the measuredness and sobriety of the presentation
I very much appreciate. In fact, that's one of the reasons
why you were recommended to us, and you didn't disappoint.
But you indicated that, on the one hand, there is a kind
of unfortunate restraint based upon the past history which
prevents these procedures from being reimbursed under Medicare,
right? This is by name specified as a no-no, and that now
stands in the way of actually people doing these procedures
as much as they would be indicated to actually help the people
who were in desperate straits.
On the other hand, you say that whenever you get the neurosurgeons
together, you ask them, "How many of you guys are ready
to do deep brain stimulation for psychiatric indications?"
and all of the hands go up, which means that there is an enthusiasm
for doing this already, even in the absence of the kind of
knowledge that we have, and if that financial constraint,
if the reimbursement constraint were removed and you have
also this kind of monopoly, you know, of the device driven
and monopolistic character of the equipment, should we not
be concerned that there is something ready to take off here
in a few years?
I mean, or is this just science fiction and that we should
rely on the good, conservative sense of the Carsons and the
DR. COSGROVE: No, you shouldn't because
neurosurgeons actually — I'm not sure I agree with
Ben entirely that they are a conservative group. Neurosurgeons
often operate first and ask the questions later, and in this
regard neurosurgeons are not well equipped to assess the accuracy
of diagnosis, the adequacy of treatment. I mean all of those
They are equipped to do the surgery, but sometimes it's
frightening to me how even ill equipped some of the people
are that undertake the surgery, where I get phone calls about,
well, you know, "I'd like to do a cingulotomy for
such-and-such," you know, and they're calling about
the coordinates, about how you do this.
And I have repeated, you know, experiences this way, and
then at the end, after I'm thinking, well, are you sure
you want to do this or are you sure you have support of your
institution, because of the lay people's impressions and,
you know, all of the trouble you can get yourself into.
And then, you know, at the end of the conversation where
I've described everything and sort of put up all of the
warning signals and then at the end, you know, the neurosurgeon
says, "Well, are you supposed to do that on both sides?"
DR. COSGROVE: And I think, "Oh,
my God," you know. So I'm not so sure that we're
all going to be responsible practitioners. You see, I'm
very sensitized to the irresponsible practitioners of the
past, and I do believe that this surgery, whether you use
ablation or deep brain stimulation, is an important intervention.
Currently it's an intervention of last resort, and it
is a good palliative procedure.
I do not think we will have another opportunity to do this.
So if we do not do this right and carefully and, you know,
properly, I don't think it will come back.
DR. ROWLEY: Can I just ask you a question?
Is there a role for the IRB here? I mean, you would think
that somebody couldn't just go and do an operation willy-nilly
particularly in what is an experimental operation.
So where are the institutional safeguards?
DR. COSGROVE: So one of the things, as
I said, if we're going to move forward with this, it should
only be performed by expert, experienced, multi-disciplinary
groups, number one, with all of the people that I've proposed.
Two, it has to have institutional review or board approval
for the institution. And so, you know, it has to because
it is an investigational, any intervention.
One good thing to say is that the company, Medtronic, which
creates all of this equipment, is actually very responsible
in its behavior. It is not out there trying to get people
to do these procedures.
In fact, they, you know, don't want these done outside
of the context of a trial because they are also concerned
about misuse and abuse, and again, if it's not done properly,
well, their bottom line will suffer, and that's why they're
interested in it.
But you know, we as practitioners and as leaders of society,
we have to concern ourselves with not their bottom line, but
the society's best interest and then the individual patient's
best interest within that society.
CHAIRMAN KASS: Bill. We're coming
to the end of this session.
DR. HURLBUT: One very quick little question.
When you proceed from the costs, the practical and the aesthetic
constraints on this, wouldn't this really be better than
pharmacologic treatment? It's more targeted. It's
more specific. You're actually addressing a local problem
instead of the global, systemic delivery of a drug.
And secondary to that question is are these techniques eventually
going to be very valuable in explorations as well? I mean,
you wouldn't explore in a well patient, but we'll
learn a lot from patients on this.
Can you combine this with local drug delivery through these
same devices and can you do a micro electrode analysis of
what's going on in the local area while you do it?
DR. COSGROVE: Those are fabulous questions.
Yes, it is conceivable that this would be more locally specific
than a medication taken systemically, although, again, it
reveals our basic lack of understanding of the neurobiological
basis of these illnesses, but we do know there's a lot
of evidence that implicates the frontal orbital cortex, the
ventral striatum, the anterior cingulate. All of these areas
that we've targeted in the past and that we're stimulating
now have broad ramifications primarily in the frontal lobes,
and cortical thalamic connections and striatal connections.
So, yes, it is possible that you could get a better, more
selective, therapeutic effect with deep brain stimulation.
It's possible. No evidence to suggest that that's
so at this point in time.
Can you learn a lot about human behavior with these? Yes,
by implication you can stimulate different contacts, and can
you by stimulating alter behavior and, therefore implicate
those areas? Yes. You have to remember though that just
because you're stimulating in one little area doesn't
mean you're not stimulating afferents and efferents that
are going to far reaching neural systems.
And so, you know, it's not as simple as, well, if we
push this button, if we stimulate here, that that is the seat
of that function.
What was the other one? Oh, could you inject through the
catheter stimulator? Yes, it's quite possible. I mean,
we do those kinds of experiments and injections in Parkinson's
patients in whom we're studying. We have an opportunity
to study neural function at the target zone because we are
there. We actually use micro electrode recordings to fine
tune our targeting. While we're doing that, it's
a fabulous opportunity to study human neurophysiology, and
we actually undertake those experiments.
And when you're dealing with psychiatric and behavioral
issues, you know, you can train a monkey to move a joy stick
and you can time and you can analyze the motor systems much
more easily, and we know much more about motor systems because
we have monkeys that can do that. We can train them, and
we can train animals to do certain things.
But you can't train a non-human primate to make moral
decisions about a — well, it's much harder to train
them about reward and negative consequences and various things,
whereas a human gets it like that.
So the ability to explore human brain function that is unique
to human beings, yes, it does provide an opportunity. I will
say it's not easy to do that, you know, in an operating
room with a patient. You only have a short period of time
and the set-up and the rig and all of the requirements to
do that well is difficult. You can certainly do it poorly
and come up with all sorts of speculative reasons why this
works, but, yes, in my mind it's a unique opportunity
to understand brain function both on a macro level and a micro
CHAIRMAN KASS: I'm going to wind
up. Indulge me one last question because you've sat through
the somewhat chaotic discussion in the last session, but could
I bring you to comment?
If it were the case that neural imaging were able to give
some fairly clear correlations now, without understanding
causation, to identify populations of patients who have difficulty
controlling rage, and that borders on violence and aggresivity
that you spoke about earlier, do you see a possible future
that these things might not be controllable pharmacologically?
Is there a possibility that brain stimulation or ablation
might be able to lend a hand here?
I know this is not what you get paid to do. I mean, you
get paid to deal with the people in the retail business, but
as you were listening to that conversation, did it sound to
you like something that might sooner or later come your way
as a result of what brain imaging is going to disclose?
DR. COSGROVE: So can I give it a little
preamble about braining imaging and neuropsychiatric illness?
CHAIRMAN KASS: Please.
DR. COSGROVE: So it's already there.
Helen Mayberg has shown that with PET studies you can predict
almost with 100 percent accuracy which patients are going
to respond to Prozac, one of the first SSRIs, by a demonstration
in the anterior, most rostral cingulate gyrus of metabolic
changes there. If a patient has those changes, then you know
that they're going to respond to the Prozac. If they
don't have the changes, they're not going to respond
to the Prozac.
So there are already several other examples of the same
thing. So functional neuroimaging can predict outcome to
drugs. We have only pilot data both in our depressed patients
and in our OCD patients. We would love to be able to predict
which of our patients are going to be responders because if
we can get all of those nonresponders out of our pool, then
all of a sudden our statistics look great and everybody would
say it's a great operation, right?
We do the same thing in epilepsy, of course. We do PET
scans to try and ascertain, you know, the PET scan showing
temporal hypometabolism predict outcome. It's a much
better predictor of outcome.
We have done this work in about a dozen patients in both
populations, trying to correlate preoperative PET scans with
outcome from surgery, and the remarkable thing is that in
both the OCD population and the depressed population, there's
one area that predicts outcome, and it's linearally correlated
with improvement. In the OCD population it happens to be
posterior cingulate, well behind where we do our lesion.
That's the only area. It has broad connections in that
area to some of the areas that we're talking about, and
in the OCD population it happens to be the right thalamus
and the right orbital frontal cortex.
So these predict and, again, in a linear fashion. So if
this holds true, and we're trying to substantiate that
with larger numbers, and this might be just an epiphenomenon.
You can never be sure, but it makes sense with our a priori
knowledge of what systems are involved. If this holds true,
then we have a much better predictor of response to our intervention.
Now, getting back to your more thorny question of if, you
know, somebody was presented to me with aggressive behavior
and you know we had a predictor of response based upon neuroimaging,
well, it would have to be a convincing predictor of response.
Then you would have to correlate that with your response
to outcome or your outcome in response to the treatment, and
then it would also still have to satisfy in my mind the two
preeminent criteria that the patient understands the risks
and benefits as we know them, and so, you know, assuming you
have great data on that, and that they wish to pursue this
and they're able to give their own informed consent, not
that the institutional advisor in the penitentiary, you know,
says this guys is bad and you should do it because then I
think that you're revisiting the issues that were addressed
in the '60s of mind control, violence in the brain, all
of those thorny issues which did nothing to help the discussion
and debate on the subject matter at hand.
CHAIRMAN KASS: Thank you very much, and
thank you really for a wonderful presentation —
DR. COSGROVE: Thank you.
CHAIRMAN KASS: — and very thoughtful
stuff for discussion.