Pinkel Lecture Series 2009 – Q&A
Alvaro Pascual-Leone
Berenson-Allen Center for Noninvasive Brain Stimulation
March 20, 2009
QUESTION 1:
First of all, thanks, that was an amazingly interesting talk. And I just had a
question about the craving measure and I guess the craving findings. Were you
surprised in a way that stimulation of the right prefrontal cortex would actually affect
ratings of craving, which I thought, “well, that would be a read-out from the sub-cortical
appetitive areas,” right? I mean, unless craving is being interpreted as “would you do
it?” collectively, kind of, a revealed preference?
Alvaro Pascual-Leone:
Yah, that is a good question. So, we measure it using the visual analog scale, so,
basically, it is just how much desire they felt for whatever item—the smoking or the
alcohol. What we had predicted is, actually, that the craving would be decreasing. We
had predicted the results, but I think it was because we were just simply thinking of the
craving as manifestation of the desire to do this, rather then the elaboration of, what
you were saying, of how to express the desire I have. I think that more sophisticated
measures of craving, obviously, could be done to try to parse out what is really going on.
This was just a very preliminary proof of principle, and, similarly, this is very much
triggered by the movie and immediately measured. So, I think that it would be
interesting to see the craving desire cross situations that expose them to other stimuli
and get a sense of what is really modulated.
QUESTION 2
Your headline story is the right side of the prefrontal cortex; it matters. Your
results suggest that there is something more nuanced going on. Sometimes, it is
different. I’m having a little trouble understanding when the differences matter. Could
you help to explain the apparent difficulty?
Alvaro Pascual-Leone:
Yah, the subtlety is there. We were hoping for slamdunk results, and it didn’t
quite work out that way. So, it is more complex, and, to be honest, you didn’t get it
because I don’t know myself. We look at the tasks. I don’t think it is anything specific of
the tasks that we could identify. We had not predicted, for example, that with the
smoking and with the alcohol, with its bilateral effect, with food only unilateral. You can
hand-wave your way around an explanation, which is what I think we did in the papers,
which is to say that there is something different about craving that may be more
engaging the left side, because some aspects of it are more interpretative of what you
are perceiving, and that’s the issue that we are having their separate from the actual
desire control that is more right-sided, but that is a tested hypothesis, but it is untested
with the results, so I don’t know if that is really the full story.
It’s not only in the application and the translation application that the bilaterally
comes out in those two craving studies, where it could be related to the craving. In one
of the tasks that Shirley did, the [Bar] task, the effects were also bilateral, and so, it
wasn’t only lateral. So, the characteristics of the tasks seem to play a role, and,
presumably, that has to mean that there is specific underlying cognitive processes that
may be more or less lateralized to one side or the other, and I think that we need to try
and disentangle it more. I don’t have a better answer than that. Just perhaps to add one
more other thing. There are some data, proof of principal data from other groups, those
are targeting only the left side—left versus sham—for smoking, for nicotine, and one for
cocaine showing beneficial effects too, so, it may be that, depending exactly on how you
set things up and whether or not you look across the two sides, you might have greater
bilaterality.
QUESTION 3:
Hi, did you find a threshold effect? What is the least amount of stimulation that
you could do and still see the effect?
Alvaro Pascual-Leone:
Yah, I don’t know the answer to that. So, there are two sides to that question
that can be empirically tested. One is you can do a dose-response kind of curve within
subject, and which would be very interesting. It’s not a trivial experiment to do, because
the residuality of effects is from session to session, and, so, if you do the same subject,
you need to wait long enough, otherwise, there will be a build up of the effect of the
second session onto the first. But, it can be solved. So, it could be done. The other way
to do it is bank on the fact that the effects are individually different, so, even though you
stimulate the same parameters, you modulate the amount of cortical activity
differently, and so, Miguel is, in fact, now doing a study currently, running the study
with obesity, using EEG and FMRI during the TMS, to measure not only the effects that it
has behaviorally, but what impact it has genealogically, with the aim of correlating the
ultimate impact on behavior with the physiological impact and see whether there is a
correlation there.
QUESTION 4:
Second one is only slightly frivolous. When you talk about ethics are you also
interested in defining non-invasive?
Alvaro Pascual-Leone:
Oh, you think that this is invasive?
QUESTION 4:
Well, I can imagine that many people could think that that would be invasive,
yes.
Alvaro Pascual-Leone:
So, the term invasive I use simply from the point of view that we are opening the
skin and the skull in targeting the brain, but, obviously, it’s invasive in the sense of
invading into your personal sphere in more behavioral ways.
QUESTION 5:
[unintelligible]
Alvaro Pascual-Leone:
Yah, that’s what I am saying, that in a sense of neurosurgically speaking, it’s noninvasive, even though it clearly is modifying brain activity, we know that, and so, in that
sense, it is doing something to the brain. So, there is that ethical aspect of are those
effects safe in their own right. I think that there is a lot of data over the last twenty
years on non-invasive, in this sense, non-invasive, in general, on brain stimulation to
have sense of what, if any, long term effects might be there, and, if you apply the
stimulation in a therapeutic aim, multiple sessions in a row without [any effects], there
will be lasting impact, but, if you just apply the stimulation one session, short session for
a quote-unquote “agnostic” effect, like in the experiments that I was showing you, there
are no lasting effects. So, in that sense, I feel comfortable with the safety of it, but, of
course, the impact of modifying the behavior of a person may have on that person in a
more global sense, it becomes an interesting question, and I don’t know the answer to.
QUESTION 5:
Alvaro, throughout the talk, you link the ideas of impulsivity and self-interest
together in the sense that a number of your tasks actually, if a person is acting in their
short-term self-interest, they’re also acting impulsively. And, I am wondering to what
degree you think those emotions are actually linked? Whether you have thought about
pursuing experiments that might disassociate those ideas, or, perhaps, manipulating
impulsivity in a way that actually works against this notion of self-interest?
Alvaro Pascual-Leone:
Thank you, that is a great question. Yah, so I…it didn’t come across properly
because I didn’t mean to link them. Some of these tasks actually don’t disentangle them,
and so, because of that, the fast response, impulsive response in that sense, ends up
being also self-interest driven or maps to the self-interest, but that’s not with all the
tasks. So, you can separate some of the tasks, so, for example, the fast response of…it
depends on how to define it in the part, you can say, “I’ll take the money now to have a
little bit,” it’s more self-interest, whereas they keep on pushing, that is more impulsive,
or is it not? So, the speed of response, either one of the two, doesn’t really get modified
by the stimulations, so I don’t think it is the impulsivity per se that is being modified by
the stimulation, but rather how much self-centered motives are weighed by the
individual in performing the task.
In some of the tasks, like the ultimatum game, it turns out that when you are
driven by self-impulses of keeping the money, you also respond faster, and so it looks
like it is impulsive. Daria has gone on to do some tasks, looking at just the fast versus
slow decision-making, where you have to weigh more information, but that the decision
is made, or do so quicker. And there is some literature in the faster, more impulsive, not
dependant of self motives tasks, there is more activity in the prefrontal cortexes as well
in functional imaging, [McClure] and others has shown that. So, in that setting, TMS
didn’t affect the decision—it did affect the response time—but it didn’t affect the
decision. So, I don’t think that this is a bad impulsivity, to answer your question, but of
the content of the decision, but, sometimes, it is not possible to disentangle with these
tasks.
QUESTION 6:
In the ultimatum game, the reward is measured and it is money, but in the real
world, rewards can be complex, intangible, perhaps, like helping a blind person cross a
road. How would you account for that?
Alvaro Pascual-Leone:
Yah, I think that that is a good question. So, in as much as there is a reward that
is translated to a benefit to the individual, I would argue that the same holds true, that
this is not just about money, and, hence, the argument that it applies to behaviors, to
eating what is in front of you, or taking the pleasure related to the smoke or the alcohol
immediately, or whatever. So, in as much as helping somebody cross the street leads to
a benefit recognition, being told how nice you are, whatever, I would argue that that
would be following similar regulatory controls. So, I would say that the right prefrontal
cortex in that setting is still exerting the same control on your drive to do what you think
is the thing that will bring you the reward, in this case, helping somebody cross the
street.
QUESTION 6:
It can also be that people vary in their sense of ethics, so it’s not necessary that
the same result may hold for in their case.
Alvaro Pascual-Leone:
Yah, there is no question that there is huge individual variability in all these
measures and in all these personal characteristics, and I think there are, arguably, I
would say, because the amount of right prefrontal control onto sub-cortical structures
may be different in different people. So, these measures are all within subject, so,
whatever you do, if I activate your right prefrontal cortex more, it seems like you do
differently, which is why I’m saying that it opens a whole ethical debate. I think there is
great value in the fact that some people are different than others and that we are not a
nice homogeneous, everybody’s same amount of, whatever, altruism. So, that’s, in fact,
part of the concern, who defines what is appropriate and how do you hold people to it?
But, it is within subject that I am talking about, modifying the decisions like that.
QUESTION 6:
Thank you.
QUESTION 7:
I wonder, if I were to summarize what you’re saying, if I had to tell someone
what I heard today, I would say you have done these beautiful studies that show
regulating the right or the left prefrontal cortex reduces the tendency to be attracted to
a (?) stimulant but, what is going on there I mean why would that be happening? I
mean, do you have a theory? Is it like are they thinking more about their future and
saying I shouldn’t be doing this now because the future will be bad for me? Why is it
that up-regulating, you know, such a gross [intervention] should be so uniformly
powerful with the same result?
Alvaro Pascual-Leone:
Well, I would turn it around. I would say, I think, we have the same interest in
pursuing the question. The question is, to me is given these results, which are
surprisingly strong to me. There should be, there is now a whole reason to start trying to
disentangle what is really going on. At two levels, I think, both at the biological level,
what is the circuitry that actually accounts for this, what are the areas that when you
modify the right prefrontal are being impacted? [Mark Halco] is now in the lab now
targeting the right prefrontal cortex, or the left, with the TMS and looking at what
activation do we see as opposed to what the bolt changes? and how is that change
results by engaging the subject in a task like this when you apply the stimulation, it turns
out the connectivity, the bolt-induced connectivity is highlighting functional
connectivity, is not just anatomy that matters, but the state of the connectivity matters.
So if you’re engaging in one task that is going to demand the decision from you down
the road using different activities than if the subject is addressed which is not surprising,
but may hopefully allow us to find out what is the target area of that modulation? What
is the neurobiology of it? At the same time in parallel when you’ve modified the activity
in that manner and you decide to go with the different decision, what is driving that
decision? What is the cognitive process that the subjects are quite blind to it, so you tell
them and their arguments are, well I don’t think this is surprising either, yah, they’ll tell
you, “Oh yah, in the ultimatum game, he was a complete jerk, I can’t believe he did that,
offer only two or whatever. “ So, why did you accept it? “It just made sense.” But a
week ago you didn’t accept any of those offers. “I didn’t feel like it then, but it was the
right thing to do now. “ OK. There is no link established even to the stimulation. A few
subjects, when you go through this questioning session at the end they will say well I
presume it must have been whatever you were doing.
But there is no insight
whatsoever. So basically we need to design tasks that will capture the phenomena with
other tasks that presumably try to characterize also what else is going on. We’ve tried to
do some things, so for example we know that the go, no-go is not affective, is not simply
an across-the-board inhibition regulation. That’s not it. It’s more complex than that, at
least for the same amount of stimulation that we’re applying. That’s a good question.
John Trueswell:
If there are no more questions, let’s thank Alvaro again. And if you have other
questions that you want to talk to him one-on-one about, there’s a reception just
outside here.