Pinkel Lecture Series 2009 - Lecture
Alvaro Pascual-Leone
Berenson-Allen Center for Noninvasive Brain Stimulation
March 20, 2009
Alvaro Pascual-Leone:
Thank you very much, John, and all of you, and the Pinkel family. It is a pleasure
to be here. I hope that what I was planning on telling you will be interesting to you. I am
a neurologist from training and so I tend to approach cognitive neuroscience with the
ultimate aim of translating it to patient populations, and I think that one talent that we
have as a cognitive neuroscience community is actually to try to do that and to try to
explore ways by which we can really meaningfully illuminate clinical interventions that
oftentimes lag behind the insights that we have from cognitive neuroscience and that
could benefit from greater cognitive neuroscience guidance, but, oftentimes, the leap to
the clinic fails to be done. So, what I would like to do is start with the problem of the
neurobiology in cognitive neuroscience of decision-making and try to make the
argument that some of what we are learning can be meaningfully translated to patient
populations around the topics of drug abuse and obesity. The idea of how to deal with
the fact that we as humans are really bad at making up our mind and making the right
decision is by no means unique of neurobiology. It’s broadly in the popular press now,
but it dates back as far back as people have started thinking about these issues.
Arguably, one of the first influential positions on what these decision-making
challenges is like goes back to Plato, who in Phaedrus describes the chariot allegory: two
horses drive us basically in opposite ways—one full of energy and impulse and,
oftentimes, making a rush to one direction and another one more thoughtful and calm
and making less impulsive decisions—and the challenge is how to control those two
forces so that the chariot ultimately moves forward rather than break in pieces. I don’t
know about you, but I struggle with that. My sixteen year-old struggles with it even
more, and my eleven year-old hasn’t realized yet what many struggles lie ahead. So, the
question is what does that ultimately mean? Have we learned something about this?
And, of course, many, many disciplines have addressed this, but even social
neuroscience now in the conceptualization of dual process models, characterizing a
reflexive versus a reflective system, come remarkably close to what resonates in Plato
and with different terminologies—a reflexive system that has automatic processes, it’s
fast operating, it’s slow in learning, it’s phylogenetically older, it’s linked to brain
structures that are largely sub-cortal in [way] and very closely linked to emotional and
immediate reward processing, versus a reflective system, or a C-system, that is more
controlled processes, slow-operating, it’s faster to learn, therefore, also more plastic,
phylogenetically newer linked cortal areas, presumably, particularly engaged in
situations of uncertainty, and, perhaps, this is the one horse and the other horse of
Plato with new novel characterization.
Now, if you think about it from maybe more anthropological (I am by no means a
evolutionary neuroscientist of any sort), but, from a more humanistic point of view,
arguably, contrary to the horse allegory, humans are rather unique in that we are able
to really control uncertain circumstances (seems to anyway, one of the horses) to the
point of going against what would be self-benefit. Altruism, ultimately, is the true
selfless giving of one’s self to others for no secondary motives. In that sense that
humans are able to do that (well, few are) we become, in some sense, true evolutionary
outliers, seems like, that we are driven not by the one horse and the reflexive system
motives, but rather are able to control them to a very high degree. So, what does it all
mean in terms of brain function, and how can we try to disentangle that? More
importantly, perhaps, as a neurologist, if all that is identifiable could we go in and
actually modify the amount of control that one system can exert onto the other?
Because if we could, aside from illuminating the mechanisms that are at work, that
might have meaningful applications to control my sixteen year-old daughter and all the
ethics that come with it, but, in addition to that, perhaps to control and help aging
populations that have significant problems in that sort of [bias]. Obviously as you start
thinking about the possibility of modifying behavior, human behavior, in the decision-
making to that degree, it becomes a real ethical issue that you open up as well. I am not
going to spend much time in addressing it, but there are substantial issues to discuss as
to what constitutes normal behavior, what is appropriate or not appropriate to do, both
from an experimental point of view and, ultimately, from an application point of view.
So, what do we know about all this? So, I think that the way we started thinking
about it is that, if it is possible to control one form of decision-making—call it impulsive
or reflexive for the time being—an overlay on that control that takes into consideration
social norms and is more reflective, less impulsive, and fast-learning than, perhaps, the
capacity that we’re tapping on, is that of an ability to inhibit more sub-cortical
responses. And, of course, there is a whole [like sense] of literature; this is just one
summary paper of one aspect of the literature that has argued that there are such crossmodality inhibitory capacities of specific parts of the nervous system, particularly,
prefrontal cortex, lateral prefrontal cortex, and, perhaps, particularly, the right lateral
prefrontal cortex, across tasks, both in animals, in macaques, and in humans that
require a stop-signal or a no-go signal or a task-switching where activities in those areas
impose a control that allows for that switch for that no-go to take place. Might it be that
such a capacity of this neural substrate is applied not only for specific tasks but across
decision-demanding domains? So, in order to address and explore this question, we
paired up with Aaron [Sawyer] and Daria Knoch (did their work) and explored the
ultimatum game.
The ultimatum game is a neuroeconomics game that some of you may be
familiar with. It’s a rather simple game. Two people are brought in and they are going to
play with each other. One will be the proposer, the other one the responder. The
proposer is given twenty dollars or twenty Swiss Francs and told he or she can offer, or
propose, a way to split it. Anything goes. You can say, “I’ll keep twenty and give her
nothing,” or you can say, “I’ll split it ten-ten,” or “I’m generous, I’ll give her sixteen and
keep four,” or whatever. There are no restrictions. The responder on the other hand can
listen to the proposal and can accept it, in which case they’ll both walk out of the room
with whatever was agreed upon, or can reject it, in which case, neither one will get
anything. That’s the game. It’s very simple. So, I’ll give you twenty and you propose. And
most people at the beginning will say twelve-eight; humans are not that generous, we
generally don’t split ten-ten. We generally try to get some advantage of it, it seems like.
Most of them, in the case of the responder, when they are offered eight and had twelve
against them, and so realize it is not quite even, still think “well, better eight than
nothing, I’ll take it,” and, so, most people with twelve-eight will accept, even though
they will walk out of there thinking, “I’m better off than with nothing, but the guy is not
that nice.” However, if the offer is sixteen-four then it gets interesting. How low are you
willing to go to walk out of here with something when you came in with nothing, in the
face of what you perceive to be unfair? That’s the quirks behind the ultimatum game.
So, basically, you have to balance your self-interest—I want to take off
something—against fairness, equity, and reciprocity principles. So, how do we each
balance this? Obviously, each one of us will balance it somewhat differently. But as it
turns out, from behavioral tasks it is known, that people will reject low offers even if
what is at stake is as high as three months their own income, which is quite puzzling. So,
maybe in these economic times, it may not be quite as much, but in Switzerland this is
what you get. The rejection rates when the offers are below twenty-five percent will be
about eighty percent, so most people will reject it—will reject it even though they’re
doing something that will harm them.
And so, neuroeconomists have spoken about altruistic punishment. We are as
human beings willing to punish another for [what] we believe to be morally wrong even
if we are harming ourselves in the process. Sam [Fay] and Jonathan [Cohen] did a study
some years ago looking at the brain activity in the responders and asking what brain
activity is seen when people go and reject the offer. And what they found was
essentially two main areas: the amygdala, the anterior cingulate, and the dorsolateral
prefrontal cortex on the other hand, so certain sub-cortical structures of the quoteunquote “reflexive system” and the dorsolateral prefrontal cortex of the reflective
system. And they argue that the dorsolateral prefrontal cortex, which they found more
strongly activated when the subjects were facing unfair offers, as compared when they
were facing fair offers, was there to implement the altruistic punishment. So they say
the prefrontal cortex is involved in the control of the emotional impulse to reject the
unfair offers. What happens to us is that we get an unfair offer and our blood boils, and
if you are a Spaniard particularly, and you say, “no way,” and yet, then, your prefrontal
cortex, if you are lucky, will kick in and control you a little bit, give you a little bit of time,
then you will still reject it. So, it’s the cognitive control of the emotional impulse that
drives you to the [un]fairness goal. That’s how they interpret it.
But, of course, they say a different interpretation is possible, and the different
interpretation is that, in fact, the prefrontal cortex is there to inhibit the selfish impulse.
So, that, rather than the first thing that comes being, “no way, that’s unfair,” the first
thing that comes is, “hey, I get four bucks.” And then you go, “wait, that’s unfair, he’s
taking sixteen.” And so, the question is what is the first impulse? Is the first impulse to
take, even if it’s unfair, because at least you have something, or is the first impulse to
reject because it’s unfair? If the first impulse is the selfish one, then what we need is the
capacity to inhibit the selfish impulse under certain circumstances, in a sense, to enable
what might be more morally appropriate behavior. So, that’s the question that we were
going after. And, of course, consistent with the idea of the right prefrontal cortex
implementing some sort of inhibitory control, we hypothesize that this is what goes on,
that, as humans, not very different from rats, and certainly not very different from any
other animal, the first impulse is to preserve yourself. If you have food at your disposal
you’ll reach out for it, if you have four bucks and you had nothing, you’ll reach out for it,
and then, as a second elaboration, the cognitive control may kick in. So, how did we go
about doing that? Well, if you disrupt the dorsolateral prefrontal cortex in the task, and
if Sam [Fay] and Jonathan are correct, then the prediction would be that the disruption
will essentially reduce the acceptance of unfair offers, the acceptance rate of unfair
offers, because that is the consequence of controlling your rejection impulse. Whereas,
if the lateral prefrontal cortex is actually suppressing the selfish impulses, then its
disruption will lead to exactly the opposite; it will lead to faster acceptance of more
offers, because you basically are not able to reject it anymore.
So, we went about functional MRI, identifying the same areas that Sam [Fay] had
identified, then using TMS to target the areas. For the sake of those of you that are not
familiar with TMS, that stands for Trans-cranial Magnetic Stimulation. This is Tony
Barker who developed the system as we currently use it. In a box like this there’s a band
of capacitors. They store an energy of a few thousand amperes and, using an electronic
switch, they can be discharged in a matter of milliseconds into a stimulating coil. The
shape of the stimulating coil, the geometry of it, determines the geometry of the
magnetic field that is generated, and that, in turn, determines the focality of the current
that you deliver. If you use an eight-shaped coil like this, and it is appropriately sized and
small enough, then you can target an area of about the tip of a little finger, zero point
five by zero by five centimeters or so. When you do that and target the motor cortex
(we’ll hopefully hear a click), the current passes (there, you heard it), and if you look at
his hand, his hand twitched. So, targeting the motor cortex, that current depolarizes the
neurons and leads to descending volley contra-lateral that activates the muscles and
induces movement. You hopefully see that he is not grimacing in enormous pain; it is
well tolerated. And if you are doing it right, it is safe. You do need to follow appropriate
guidelines. We want to know exactly where we are on the brain not where we are
holding the coil by the subject’s head.
And so, what we do is, we track the position of the subject’s head and the coil
with these cameras that are projecting infrared and reflecting it on these little balls. And
we digitize the coil and the head, register the subject’s own MRI, and, as you are moving
the coil around, it tells you where you’re targeting on the subject’s own brain MRI. You
can go around it the other way around and define the region of interest in the MRI, and
then, when you are in that region and only then, will it trigger the stimulation. So, you
can take the functional MRI of the subject and say, “this is my region of interest, now I’ll
move the coil around, when I’m there, it will trigger the stimulation.” We’ve done
modeling and I don’t want to bore you with too many physics details, but to give you a
little bit of the sense of the issues that are involved (there are a number of technical
issues involved), there is a very strong current that you deliver, but you deliver it in a
very rapid changing field so that you go from zero to two point five Tesla of magnetic
field in a matter of about fifteen milliseconds. And so, that very rapid rate of change
determines and induces a current field that is sufficient to depolarize neurons. It’s not
the magnetic field that does it; it’s the induced current that does it. The magnetic field is
basically just breaching the skin, the skull, and allowing you to get into the brain
essentially with very little attenuation, so non-invasively. Depending on the exact tissue
characteristics, as Anthony [Watner] has shown in lab, the current distribution is
different, and so you need to take into consideration the [Salcack] pattern of each
individual, presence of pathology or not, to be sure that you are really targeting the spot
you are targeting, but you can actually model that and be certain that you target the
appropriate spot. If you do that then there’s things that we have learned as to what
happens when you apply trains of stimulation. I’ve shown you what happens when you
give one single stimulus, you depolarize the neurons; if it’s in the motor cortex, the hand
twitches. If you apply the stimulation repetitively over any one area, depending on your
frequency and pattern of stimulation, you leave the cortical area modified. So, you can
apply train of stimulations, say targeting this area, apply it at low frequency, one
stimulus per second for sixteen hundred stimuli, and then, after you’ve stimulated, the
area is rendered depressed in its level of activity, whereas, if you applied in burst of
twenty hertz, the area is rendered hyperactive, facilitated after you’ve stimulated. If you
look at the effects carefully, like Tony Valero has done, you can see that the effects are
not limited to the targeted region, but actually spread from the targeted region across
neural networks based on the connectivity between the targeted region and a given
area.
So, here, for example, we’re targeting the visual parietal cortex that has a lot of
connections to the splenial visual area, and those are excitatory, so you suppress the
visual parietal cortex, you withdraw the excitation at a distance, and, therefore, there is
a knock-on, trans-synaptic suppression of the visual splenial cortex, whereas
neighboring areas that don’t have connections show no impact. So, it is a tool to noninvasively modify activity in a given targeted area, either up or down depending on your
stimulation parameters, and, through that targeted area, affect the network, depending
on the connectivity. In fact, the distant effect is very telecoupled with the strength of
the connections that exist. Now, if you (let me skip through), if you want to know what
the connectivity is in any given human individual (this was CAT experiments), you can
combine TMS with functional imaging, target a given area with the TMS coil inside the
MRI scanner, as done here by [Amir Emidian and John Campodrone], and look at the
bold, [vogue] responses to TMS itself, so, you can see here that if you target the visual
cortex, you can activate the visual cortex, you can trans-synaptically activate sub-cortical
areas (LGN), and you can activate, tie a visual path, dorsal and mental stream, because
of this trans-synaptical effects. And, of course, that way you can either study the
connectivity or modify it by applying repetitive stimulations to one or multiple areas.
So, let’s go back to the ultimatum game. We’ve identified from the functional
imaging study an area in the prefrontal cortex, the same one that is [on the head]
shown. We can now use the TMS to guide the stimulation to that area and suppress the
activity in that region. So, what happens if you do that versus target the left side? Now, I
didn’t point out, but in some face cases, and, in fact, ours, there was activation in both
prefrontal cortexes. It’s slightly more on the right than the left, but is bilateral. So, we
targeted the left versus the right versus sham stimulation. And you can see that the
acceptance rate significantly increases when you suppress the right prefrontal cortex.
Not only does the acceptance rate significantly increase, but subjects respond and
accept significantly faster when you suppress the right prefrontal cortex. In other words,
you tell them, “sixteen-four,” and they go, “yes, I’ll take it!” That’s contradictory to the
prediction that this is controlling your emotional response because of the unfairness. Is
that sufficient to be sure? Well, we wanted to take it a step further, and, so, in the case
of a human proposer, you’re faced with self-interest, on the one hand, for yourself to
keep whatever you have, and you have to balance that against the fairness and
reciprocity principles related to this other fellow that just came into the lab with you
and is doing something that you think is not right. Because, it turns out when playing
with this proposer, you just accept it, but you still thought that this was an incredibly
unfair thing that the person was doing.
So, what happens if you get the same exact offers but via computer and you are
told these are random? So, that was the second behavioral control that we had.
Obviously, you’re sifting through, the motives will be the same, you still want to keep
the money, but reciprocity really makes no sense, because, although I have to say I
often feel like throwing my computer across the room, I know it makes no sense. And
fairness and equity, arguably, are also not very important motives, because they don’t
carry the day in this case. This is a random generation. So, in that case, the prediction
would be that the right prefrontal cortex suppression may have a very different impact,
because you are not balancing the two principles, and, indeed, the acceptance rate
when you modify the right prefrontal cortex with the TMS versus the left or sham is
significantly different. So, when playing with the computer, there is no reciprocity and
fairness as opposed to balance against your selfish, if you want to think of it that way.
It’s, sort of, impulse intake, and, there, the right prefrontal cortex doesn’t kick in;
essentially, it doesn’t come online.
So, what have we learned from this? The implication from this is that, indeed,
the right prefrontal cortex is apparently modifying your tendency, your controlling
tendency, to impulsively accept what, at least in this task, will lead to a benefit to you—
the selfish impulse to take the money. Most of the times, though, these tasks are not
played one-on-one; they’re played in a whole group. They’re all interacting with each
other, and, in that setting of social context, the behavioral signature of this task has
been generally figured out. And that is important because, it turns out, that it matters
who exactly you play; it matters what you think about the other person, it matters
whether you think that the other person is your boss, not your boss, dresses nicely,
doesn’t dress nicely, the gender and all this kind of stuff. So, TMS, to modify activity in
any given are (for that matter, functional limiting) to capture the activity, it’s difficult to
do in a group with those interactions, but there is another technique of non-invasive
brain stimulation that can be used in that setting. So, with Daria, we tried to play the
ultimatum game, modifying right versus left prefrontal cortex activity on some of the
subjects and, in others, applying sham using trans-cranial direct current stimulation.
So, trans-cranial direct current stimulation goes back, not just to Faraday in the
1800s, but to Galvani and Aldini centuries before. It’s essentially faradizing the cortex.
You apply a very small, one to two milliamp current, through an anode and a cathode.
You apply it either continuously for some period of time or you put it on and then, after
a period of a few seconds, you switch it off. Subjects feel this ramping up of current as
an itching in the skin and then they feel nothing else. They feel no difference if you
apply anodal stimulation or cathodal stimulation. Most of the current stays in the skin,
but enough goes through. There is current in the cortex sufficient to, not depolarize the
neurons (it doesn’t cause a twitch, you don’t see anything), but it changes the firing
range of these neurons. In fact, it appears to change the membrane potential of the
neurons, and so, when another input comes in, if you’ve applied anodal stimulation,
there is an increasing firing, if you’ve applied a cathodal stimulation, there is a
suppression. So, it’s a pure neural modulatory intervention, and the subjects don’t feel
anything; they are truly blunted, and so you can, therefore, play it in this context of
applying to different subjects in different ways and seeing how they perform while their
prefrontal cortex is modified in its activity.
So, Daria had subjects play under either sham or cathodal TDCS conditions, and
what she found was that subjects significantly accepted more offers when the cathodal
stimulation was in place, remember, suppressing right prefrontal cortex, than sham.
This is four versus sixteen, the same condition as before. The fairness judgment didn’t
change; subjects, just like with the TMS, still thought, “this is unfair,” but just took it
when the right prefrontal cortex was suppressed in its activity. And that was for each
subject when exposed to cathodal stimulation. So, even though the likelihood that each
one of us accepts or rejects is variable, any one of us appears to be susceptible to
accepting more when our right prefrontal cortex is suppressed. So, from these
ultimatum game experiments, we feel that we’ve learned a few things. First, it’s possible
to modify the response to this high, complex decision-making processes without altering
the fairness judgment that is involved. Suppressing the right prefrontal cortex increases
the acceptance, and, so, it is consistent with the hypothesis that the right frontal cortex
or the dorsolateral prefrontal cortex suppresses self-centered impulses.
Now, is this as true for the ultimatum game or can it be demonstrated in other
tasks? Of course, depending on the task conditions, there is a greater or lesser demand
on impulsive, fast decisions, and, so, arguably, it may have to do with the characteristics
of the task. How much the dorsolateral prefrontal cortex comes into play rather than
the judgment per se? So, we tried to explore this issue with a different task, the Rogers
risk task. In this case, subjects are presented with six boxes. The six boxes have different
colors, two possible different colors. Each color is associated with a given reward
amount that is given to the subjects and explicitly shown to the subjects. And the task is
to find the winning token under any one of these boxes, but the probability being
identical that the winning token is in any one of these boxes. You are just supposed to
give the color. So, in this case, if you say “green,” you have five, six likelihood of being
right, but if you are right you will only get twenty bucks. If on the other hand you say
“pink,” you’re much less likely to be right, but if you are right, you’ll get eighty. So,
subjects know how much risk they are taking, how much reward they can expect from it,
and they can take it in consideration when making their decision. So, the level of this
can be calculated, the balance of the reward is explicitly told. It’s not really a life
situation, most of the time we don’t have that, and we’ll get back into that in a second,
but you can then target their same right prefrontal or left prefrontal as a control area,
and then have the subjects play for some period of time, and see how modifying activity
in the prefrontal cortex changes the performance. What you get is that, when you have
suppressed the right prefrontal cortex, subjects make significantly less points than they
did with the left or the sham condition. Because of that, they actually end up making
significantly less money. The reason is because they make significantly less low-risk
choices. They end up risking more, presumably driven by the probability of the reward
being significantly higher. So, they see eighty with pink; it’s a much higher risk, chance,
but higher potential reward opportunity, and they go with that, even though, because of
the way that the task is designed, if you do that, you end up losing. You get less points.
So, suppression of the right prefrontal cortex essentially leads to increased risktaking behavior in this task, and, because of the design of the task, that is not a good
thing. If the task is balanced the other way around, which we have done, then it still
leads to impulsive behavior. It still leads to the high-risk behavior being the predominant
with suppression of the right prefrontal cortex, but, in that setting, subjects win. So, it’s
not about their winning or losing, it’s about the apparent inability to control the
tendency to go with the immediate reward and the high risk when they are confronted
with the absence of, or in the face of, suppression of the right prefrontal cortex. So
that’s nice, but, of course, from the neurological point of view, it would be nicer to do it
the other way around. It would be nicer to decrease risk-taking behavior rather than to
increase risk-seeking behavior. Can we modify activity in the right prefrontal cortex,
increasing it rather than decreasing it, and modify behavior in the opposite direction?
So, Shirley Fecteau has been doing these studies—same task—she’s done it with
TMS and with TDCS, these are the results of the TDCS. So, instead of targeting the right
prefrontal cortex with the cathode to suppress the activity, she’s applying the anodal
stimulation, which will increase the activity. And what happens then is that when the
right prefrontal cortex is increasing its activity, subjects make significantly more low-risk
choices. And, again, they do that even if you modify the task and make this be a losing
proposition. So, it’s not about the outcome; it’s about the way that they go about doing
the task. In this particular case, this particular task, the points earned increase, you
make more money with the lower-risk choices, but you can play it the other way
around, and people will still go with the low-risk choices. So, increasing activity in the
right lateral prefrontal cortex decreases risk-taking behavior. So, again, in the risk task, it
appears that the lateral prefrontal cortex on the right side is suppressing impulsive selfcentered behaviors. But, again, as I mentioned before briefly, this is a situation that is a
bit artificial because you know the balance of your risk and, most of the time, we don’t
in real life. So, what happens if you do a task where you cannot judge the risk? At least,
you cannot be sure of it. The Balloon Analog Task allows you to do that.
This is a task in which the subject sits in front of a computer screen. There is a
button and there is a balloon. And you’re told to push the button, and, every time you
push, the balloon will pump up, and with every pump, you’ll collect some twenty-five
cents, or something like that. At any point you can stop and whatever you’ve collected
you will move into permanent storage, but, if you keep going and the balloon bursts,
you will lose everything. [Co-edit]. You should know that each balloon has a different
bursting point. They are completely unpredictable. You just need to decide whether
you’re willing to take the risk. Now, this is a much more ecologically valid thing, because
most of the time in real life we don’t know what the risk of the situation really is until it
is too late. And this is exactly what happens here, but there are some senses that people
develop, and, much like in real life, they believe they actually can gauge how much they
can keep going. They really can’t, but they do pretty good. Overall, they pump a number
of times, decide to move it into permanent storage, or not, and, if they don’t, they keep
pumping again, they will lose it. So, what happens if you modify activity in the right or
left prefrontal cortex in this setting? So, in this case, it’s not so lateralized. In fact, the
effect is there whether you increase the right, increase the left, or vice versa, it doesn’t
really matter; it’s about the balance between left and right that appears to be critical.
But, the net result is that the number of pumps is significantly less when you
create an imbalance between the frontal lobes, in the level of activity, by increasing the
left and decreasing the right or vice versa. Doesn’t matter which direction you modulate
it. So, if you apply a nodal situation to the left and cathodal to the right, or a nodal
situation to the right and cathodal to the left, in any case, subjects become more risk
averse, as it were, and end up pumping less number of times the balloon and,
ultimately, making less money. So, this is the total money earned; it’s significantly less.
So, even though they see that they are making less money and they just played the
game a number of times before, they still err on the side of making less choices when
the stimulation is going on in a particular way. So, the idea is that whether you know the
risk or don’t know the risk, whether you can calculate the probability or not, the desire
to go with the immediate reward, perhaps the selfish desire, the self-centered behavior,
is regulated and controlled, or can be regulated and controlled, by the lateral prefrontal
cortex. In some people it is more so, in others it is less so, but, if that is the case, then
modifying activity in the right prefrontal cortex can allow us to either exert less or more
control over this self-centered behaviors, perhaps, enhancing reflective control over
reflexive mechanisms.
Presumably, this is particularly critical in situations where there is an ambiguity
conflict, so, decisions, or choice-behaviors, where there are both cultural and
moral/social conventions that are opposite to the self-motivated, self-centered
behaviors, like the ultimatum game. In that situation, the regulation of the balance
between those two, similar to what Plato was talking about, becomes really critical. The
argument is that these small experiments that I was showing you reveal a critical role of
the right prefrontal cortex in that setting. So, what happens if you have a condition that
leads to right dorsolateral prefrontal cortex failure? We have a trauma, frontal
dementia, mood disorder, and so forth, where there is evidence that the right prefrontal
cortex is dysfunctional, where the presumption would be that you would have
impulsive, self-centered behaviors with disregard to social norm and conventions and
with disregard to other expectations. If that were the case, then, there is a translational
opportunity there. You could use the same type of modulation that I’ve shown you in
normal subjects to target the lateral prefrontal cortex and increase the control the id
exerts onto sub-cortical areas that, presumably, drives self-centered behaviors.
So, we have tried to model this and proof of principle this with addictive
behaviors and eating disorders. Just want to show you some of those results quickly to
give you a sense of what the findings look like. So, Philipe Fregni did a study in smokers,
initially with acute-provoked nicotine craving and then with, just, spontaneous smoking
behavior, tracking their smoking and the acute-provoked nicotine craving, presented a
little movie clip of someone smoking and then applied TDCS, the same way that I’ve
described, to increase the right dorsolateral prefrontal cortex activity, or left as a
control, or sham, and then had the subjects judge again the amount of craving that they
experience to the same movies. What he found, is that, over time, from the base line to
after the TDCS, in follow-up, there was with the right dorsolateral prefrontal cortex
stimulation, but also with the left, a significant small effect, but a significant effect, in
decreasing the craving that actually sustained over time. So, not only the right, as we
have predicted, but in fact also to the left, increasing activity in right or left dorsolateral
prefrontal cortex in each individual subject led to a sustained demonstrable decrease in
the craving that was induced by the cue. [Paulo] Poggio has looked at the same type of
design for alcohol craving and found essentially the same results, that with the left or
the right dorsolateral prefrontal cortex stimulation, increasing activity in either one
leads to a significant reduction in the craving compared to sham. John [Compadrone]
has looked at it in cocaine addicts, in six cocaine addicts, and found with TMS rather
than with TDCS, that the left, in this case, does have the effect, but that the right
significantly decreases craving and, in fact, sustains the suppression of the craving for
five weeks on average after just five sessions of stimulation. I find the results in obesity
particularly interesting, so I want to spend a little more time with that. The argument
that Miguel Alonso has put forth is that eating behavior, of course, is critically linked to
homeostatic control and reward gratification, but that in humans, in addition, there is a
whole cognitive aspect of eating that we often don’t take in consideration in dealing
with eating behavior in obesity and that relates to cultural, social messages that we
send with food. If you are from Spain and you come to my house, and I put something in
front of you to eat, if I don’t, I’m committing a sin, but if I do, and you don’t eat it, you
are committing a sin.
And so, therefore, there is a whole elaborate behavior involved with this, which
we as humans are able not only to use to our advantage, depending on the situation,
but also make it trump all homeostatic control and work gratification principles. The
point of killing ourselves by not eating on the basis of, motivated by, political
principles—something that seems to go at the very core against nature. If the right
prefrontal cortex in all these experiments is playing a role in controlling self-centered
behavior, this is the ultimate control mechanism potentially of self-centered behaviors,
where you have even a capacity to suppress self-preservation.
In fact, what Miguel has recently done is look at how is food items processed by
the brain when you present them in an fMRI context. He had subjects look at a fixation
point then presents non-edible or edible items, some are quote-unquote “healthy,”
others obesogenic, and they can be presented for a very brief period of time, sixteen
milliseconds, or for longer periods of time, two hundred milliseconds, followed by a
mask. In a separate session, subsequently to the functional limiting that I want to show
you, Miguel has made sure that the subjects, when presented for the sixteen
milliseconds, truly don’t see the objects. In fact, don’t have a clue that there are any
items presented. (This is shown here.) They are completely random as to whether or not
they know what was a picture presented here. The task for the subject is simply to
respond to whether these squares, presented subsequently, whether the filled one was
on the left or on the right. But what we are interested in, is what is the brain activity
related to these items, specifically, to the contrast between these two food items? If
you look at brain activity related to the subliminal processing of obesogenic versus nonobesogenic food items, what you get is activity in the right dorsolateral prefrontal
cortex. And if you define that region of interest and look at what is correlated with it,
you find that any number of risk factors detract personality characteristics that would
lead to obesogenicity: eating breakfast away, emotional eating responses, low energy
expenditure, family history of obesity, a number of items that are well-recognized in
behavioral studies to be predictors of personality, predictors of obesogenity, show a
correlation, an inverse correlation, with the amount of activity in the right prefrontal
cortex. So, in other words, the less activity the subject shows, the more risk factors they
have for obesogenic behavior.
So, if that is the case, what happens when you take any one of us and modify
activity in the right prefrontal cortex, just like we were doing, but what happens, is as
Philipe and Miguel have done together, that if you do the TDCS, you can basically (just
cut to the chase), you can basically show that subjects, when the right prefrontal cortex
is increasing its activity by exposure to the anode, but not the other way around, when
the left is increased, you get a reduction in food craving when exposed to stimuli of food
craving. You can also show that in a spontaneous [unintelligible] of eating, when they go
into a buffet and eat as much as they want, they actually eat significantly less. And this is
always at the same time, always with the same amount of food during the day. These
subjects were admitted to the general clinical research center, we know exactly that
they have been eating the same amount of calories. And, finally, which is very
interesting too, when you look at the eye movements that the subjects make when
exposed to these pictures, they have to explore and answer a given question, to an
unrelated question too, turns out, that when they have been exposed, or are being
exposed, to the right anode-stimulation enhancing activity in the right prefrontal cortex,
they show significantly less time fixating, looking at the food items than at other items.
So, the idea is that the lateral prefrontal cortex appears across tasks, perhaps, to
exert repressive control and to self-center behaviors, might be thought of as a switch
between reflexive and reflective modes of operation. And it appears that that insight
lends itself to translational applications, where we can take those insights and apply
them to patient populations that have dysfunctions in the right prefrontal cortex or
behavioral dysfunctions related to a lack of control of impulsive behaviors, in such a way
that we might offer them a helpful, therapeutic intervention. On the other hand, in
broader context, it appears that we’re able to influence and control behavior in humans
with this brain stimulation techniques, and, of course, having myself significant trouble
controlling how much I eat, the temptation is large to wake up in the morning and do
some stimulation before I walk out the door. Jokes aside, it would seem that the
temptation to define in some arbitrary way what are desirable behaviors to modify and
how to guide decisions, it’s…all these techniques appear to be quite powerful in their
ability to modify decisions—they’re non-invasive, they’re relatively simple—and so, as I
was saying at the beginning, an ethical debate would seem to be important to open up.
Just want to finish up acknowledging again all the people that have actually done all the
work and hope that you have lots of questions. Thank you very much.