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Thursday, October 17, 2002

Session 3: Remembering and Forgetting: Physiological and Pharmacological Aspects

James L. McGaugh, Ph.D., Director, Center for the Neurobiology of Learning and Memory, University of California-Irvine

CHAIRMAN KASS:  Let me just remind Council members that we are in the midst of a three month inquiry into various uses of biomedical technology, present and projected, for purposes that go beyond the treatment of individuals with known diseases and disorders or that have uses that could go beyond those purposes, and we are doing so because we were, by executive order, encouraged to undertake some fundamental inquiry into the human and ethical significance of developments in biomedical technology and to contribute to the public understanding of these questions.

And that meant at least that we have the opportunity, but also the liberty to step back from some hot button topics and to try to take a look at the field as a whole and to discover whether there are certain kinds of questions that cut across the uses of this or that technology.

And as I suggested in the memo that was circulated to you before, the prospect of these kinds of uses of biomedical technology really do raise for us some of the weightiest questions in bioethics, as we saw this morning, already touching on not just the means that are to be used, but also the ends that we wish to pursue and touching very often on certain fundamental features of human life.

We've been looking at technologies that affect the body, whether in terms of muscle enhancement or blood doping for athletics.  We will be talking in December about research on aging and the human life span, and we have been looking now — this will be the second of three sessions in which we will be looking at technologies that offer the possibility of influencing certain features of the human psyche, mood and affect the last time; next time, attention and conduct and the discussions of Ritalin and the use of stimulants; and this time things that affect memory and cognition.

And we are very, very fortunate to have with us today two of the leading researchers in the field of human memory.  Dr. James McGaugh, since the 1950s, has been a pioneer in the neurobiology of learning and memory.  He's Professor in the Departments of Neurology and Behavioral Science, Psychiatry, Pharmacology, the School of Social Sciences, and the Director of the Center for Neurobiology of Learning and Memory at the University of California at Irvine.

And we have PROF. Daniel Schacter, who has written very widely and for a broad, nonspecialist audience wonderful books on the psychology of memory.  He's the William R. Keenan PROF. and Chair of the Department of Psychology at Harvard.

We're delighted to have both of you with us, and by prior arrangement Dr. McGaugh will go first.  We'll then take our break after about an hour and a half, and then we'll have PROF. Schacter's presentation.

But the conversation can flow with all of you present.  Please, Dr. McGaugh, thank you for being with us.

DR. MCGAUGH:  Well, thank you very much for inviting me.  It's nice to come here and speak about a topic that I have been interested in for over four decades and which serves as my current interest, deep current interest, at the present time.

I'm going to talk about memory, and I think we can all agree that memory is a good thing to have.  You'll hear later on this afternoon that it comes in different forms and provides different advantages and different disadvantages.

But I'm going to focus on only one aspect of it, and that is the experimental or other treatments that will make long lasting memories longer lasting and stronger, and the general assumption underlying this, which certainly can be questioned, is that if it's good for us to have memories that enable us to get along during the day, to remember where we parked our car, to remember our motor skills, and so on, then maybe it's a good idea to have a little bit more of that.  That's an underlying assumption that's been made.  I'm even going to question that assumption.

Now, there are several reasons for investigating memory enhancement which I'll start with later.  I'll talk about memory blocking and start with memory enhancement.

First is just the basic research on brain memory, and that's what drives my research.  I use drugs and other treatments to enhance memory in order to understand how the brain ordinarily works when memories are made.  That's the purpose of it.

If we take drugs, in particular, if we know something about the mechanism of actions of drugs, let's suppose we give a drug which is a GABA receptor antagonist, and we find that this drug does something to memory in a very precise way.  Then we can conclude that GABA receptors located in some places of the brain are very important in the making of the memory process.

Beyond that, if we focus on those places in the brain, we can learn much more about not only the receptors of a particular kind, but a receptor in a particular location.

And out of this is unraveling little by little more and more understanding of the key neurochemical systems and the key anatomical systems that are involved in making and preserving memory.  So that's a fundamental line of inquiry that drives this research, where memory enhancement is a way of inducing the brain to behave in a different way so that you can learn something about it.

Another more obvious reason is the question for finding treatments for memory disorders, such as Alzheimer's disease.  I probably shouldn't say "such as Alzheimer's disease" because the research is almost restricted to that.

There isn't any research on the drug effects for the mentally retarded or it's just minuscule research.  There isn't any research for drug effects on people who have brain damage that prevent them from learning and remembering.  That's a nascent field.  It really doesn't exist.

The focus has been on progressive disorders of learning and memory and cognition that are progressive, such as Alzheimer's disease, because as you know, the incidence is estimated to be at least 25 percent, if not 30 percent, in people over the age of 85.

So we're all looking at something that can happen to us.  So it drives our attention.

Now, there are other interests of the pharmaceutical companies and the biotech companies that overlap, but differ somewhat from the two categories that I've given you, and one is looking for treatments for a new disease, which is age related memory decline.

Now, that's a new disease because drugs can be found to treat it.  It was new to me that it was a disease.  I thought normal aging was normal aging, and we have known for at least a couple of decades that there is, on average, a slow decline over the decades starting at the age of 30 in cognitive processing on memory tasks, in particular, memory tasks that use speed as a criterion.

For example, if you ever watch "Jeopardy," you don't see many 80 year old people on "Jeopardy" because of speed of response is such a high priority, but those of us who are over 50 or well over 50 know that we curse the television because we know, but we can't respond as quickly as the folks that are there.

I'm also concerned about that because while there is age related memory decline, without question, on average there are plenty of people who show absolutely no age related memory decline, and there are others who show rapid age related memory decline.

And underlying all of that, by the way, is a countervailing influence which is an increase in knowledge and wisdom and ability to deal with the environment, which readily compensates for the speed driven responses.  But that is a new target for drug development.

Another target for drug development which sometimes is said explicitly, but most of the time it's implicitly, is just drug improvement for everybody else, and why not?  And why not?

If you look at the health stores or even your drugstores or your supermarkets, you can find dozens, if not hundreds, of bottles and packages on the shelf which are entitled something like "memory boosters" or "brain busters" or something of that kind, and they're not on the shelves because people want to fill up the shelves and make them look pretty.  They're on the shelves because they're being sold.

Ginkgo biloba, which is now the latest study shows has no effect at all in age related memory decline, still sells, makes millions and millions of euros in Germany and, I suppose, somewhat less than that here, but nonetheless, I get more questions about ginkgo biloba than anything else appearing on my E-mail screen.

But that's a target you can see.  That is, as soon as you see there is a market, you can see that there's a target for it, and so there is a slippery slide from disorders of memory to the new disease of age related memory decline, which is in normals, to just having a drug to improve memory in normal subjects.

Now, I have done a nonscientific sample of this by just asking lots of people I know.  I've asked if there were a drug that was safe and effective and would improve your memory for such things as where I parked my car yesterday or, you know, things of that kind.  I have yet to find anyone who said, "No, I wouldn't be interested in it."

And I would have thought that most people would say, "No, you'd have to convince me to take it."  But even people whose judgment I trust and have trusted and maybe no longer trust have said, yes, they would take it.

And then I had another question.  I said, "Well, let's ask how eager you are.  Would you do it if it was free?  How about a penny a day?  How about ten dollars a day?  How about a hundred dollars a day?"

Well, they drop off, of course.  Now, the drop-off doesn't occur for family members of people who have memory disorders.  The drop-off is not really quite so steep because they will do anything to try to keep their family members more cognitively competent for a longer period of time.

But what this nonscientific study tells me is that this is almost a frivolous kind of thing for most people.  Yes, if we're there, and, yes, if it were cheap, and if it would give me a slight edge, yes, I would do it. 

And don't misunderstand.  The pharmaceutical companies and biotech companies are listening to that by looking at the sales of ginkgo biloba and other ones.

ow, there are other reasons you have to come that are implicit, unstated.  One of them is memory enhancement in children, that is, school children, just regular school children.  I'm not talking about children with disorders. 

I was driving to a concert with a neighbor, and our families went, and she said, "Oh, Jim, I'd like to have a drug for my daughter to make her more competitive in school.  Could you give me the name of one?"

It wasn't "do you know anything about it," "are there any things that are safe and effective."  It was "can you give me the name of one," and the model that she had in mind was Ritalin because some of her children friends take Ritalin.  So there must be something else that her child could take so that she wouldn't have to study very hard, you know, just to make up the difference.

But I think that that's coming down the road, and it's something I think appropriate for this group because that's part of the slippery slope.  If there is a drug which is safe and effective and not too expensive for enhancing memory in normal adults, why not normal children?  After all, they're going to school, and what's more important than education of the young?  And what would be more important then than to give them a little chemical edge in getting a better education if it didn't do damage, and so on?

So I see that that's there.

Now, we also have genetic manipulation, which I'll talk about perhaps a little bit more later down the line.  Many of you, I'm sure, saw the cover of Time magazine and read the article after the report of a genetic manipulation which increased the number of a certain kind of receptors, glutamate receptors in the brain, and the mice that had that genetic manipulation, those mice were better at a couple of memory tasks than were other mice.

And so all of a sudden Time magazine began talking about designer babies, I think, which would fit in with your topic of discussion this morning.  If you think selecting for sex is a problem, think about selecting for learning or selecting for intelligence using genetic manipulation, gene transfer or knockouts or something of that kind.  I think that is an incredible morass.

Now, as we consider these latter, however, in children and even for adults, there's an important confusion to clear up that was not cleared up by Time magazine, on the contrary, and that is the distinction between intelligence and memory.

All these things do — all of these things do, including all of the drugs that I work with, is make animals and humans remember a little better information that they have been presented.  That's all they do.

Now, intelligence is quite another matter, whether you think of it conceptually or whether you think of it the way it's tested in an intelligence test.  Memory is a very small component and memory tests are small components of intelligence tests.  They have to do with reasoning.  They have to do with judgment.  They have to do with all kind of things, and there's no evidence that inserting a gene or taking a gene away from a mouse imparts it with greater ability to make better judgment, better reasoning or anything of that kind.

So I think that these experiments, however interesting, do not lead to the conclusions that were jumped on by Time magazine, that all of a sudden we can do genetic engineering, and we have to be worried about intelligence.

If that is something of concern, then I think those people who are interested in it have to be better educated about what it is that memory is and what can be expected from such manipulations.

And finally on this, there's a huge caveat.  I'm now going to question the assumption that I made at the very beginning, that if memory is good, then more is better.

Well, more is not better.  At the extreme more is worse.  There are two famous cases, one a fictional case of "Funes de Memorias" by Borges, a short story in which Funes was capable of memorizing everything that was presented to him, and he remembered everything that he encountered such that towards the end of it he said, "Sir, my mind is like a garbage heap.  It's all there."

And over 100 years ago the famous psychologist William James, in whose hall Dr. Schacter lives, said that to remember everything is as valuable as to remember nothing because it's all there and needs to be sorted out.

Now, there's also the case written in Luria's book, The Mind of a Mnemonist, which you can get at your local Border's bookstore, a subject that he studied for many, many years.  This was a subject who could memorize very well.  He memorized by using synesthesia, by mixing the senses which enabled him to remember better, and he could remember very detailed information for 15 years, very precise knowledge of what numbers were given to him in what order over a 15 year period of time.  He had a very unhappy life and ended up a failure.

I also had a subject.  Up popped on my E-mail one day as the Director of the center, "I have a memory problem.  Would you talk with me?"

And I sent back, "This is not a memory disorders clinic.  I can direct you to one."

"No, I have a kind of a problem you might be interested in.  Would you at least talk with me?"

And this was a young woman who claimed that she had such a powerful memory that it interfered with her daily life, and could I at least listen to her and direct her to someone who might help her, and I had trouble at first understanding what she meant by that.

So I got out the two books that were published at the millennia about all of the things that happened in the last hundred years and just randomly opened pages, and I couldn't stump her.  I just randomly opened pages, and several times she said, "Well, you have the date wrong."

And I said, "No, no, it's written right here.  It's a date line out of a newspaper."

"No, no.  That's the date in which they wrote it.  The date of the occurrence was three days before that," and so on.

And I said, "Well, how did you do in college?"

She was a C student in college, barely made it through, and I said, "Well, why couldn't you put this extraordinary capacity of being able to remember to good use?"

She said she never could because it's disorganizing.  "I'd begin to do something and somebody would say, 'Well, it's Thursday,' and I'd begin to go backwards, Thursday last week, the week before, the month before, the month — five years before, and it's just like going through a Rollodex, flip, flip, flip, flip, flip, flip, like that," and she was distracted from what she was to do because she had such a powerful memory.

Now, lest you think I'm making this up, we also have her diaries, which she kept over all these years, and with the help of an assistant, we are able to check information that she said that she has by going through her diaries, and we have yet failed to find any error or any mistake.

Here's a failed person in life who has an extraordinarily strong memory for events that occurred in her life.  She's unable to use that, and the only way she used it productively was she worked for a while with a very well known trial attorney, and she was the assistant standing there or sitting there so that when some claim was made about something happening on a certain day and it rained that day and so on, this trial attorney could turn to her and say, "Did it rain on that day?"  And she could say yes or no without having to go to the records and see.  That's all that she was good for.

So a little, maybe a little is good, but I don't think any of us would want to have the memory of Mr. S, Mr. Luria's patient, or Funes, the Memorias, the fictional character, or the subject that I've worked with.

Now, let me turn a little bit to the research on drug enhancement of memory, which is my special interest.  This was all started in 1917 by a study by Karl Lashley, a very famous neuropsychologist, in which he gave a drug, strychnine sulfate, which many of you know to be a rat poison, to rats each day shortly before they were trained on a simple, little maze, and he found that they learned the maze faster.

Now, this was of interest to me many years ago because we thought we knew something about the mechanisms of strychnine.  So in the mid-'50s, with a colleague I replicated and extended this study and found that, yes, strychnine did what Lashley said it did.

But we couldn't draw the conclusions that we'd like to draw, which has to do with the drug making memory stronger, because we're confronted immediately with what we know is a classic learning performance problem.  The animals learn better.  The drug influenced the learning, but did it influence the learning because the animals could smell better, because they were more attentive, because they were more reluctant to enter alleys and so they were more selective?  All kinds of performance factors.

Now, if one is only interested in having human performance better, then one doesn't care about this distinction.  That is, if you just want to get humans to perform better, you don't care whether they remember better, whether they're more attentive, or whether they're more highly motivated or whatever.

But if you're interested in mechanism, it's very important.   So I introduced the procedure of injecting drugs not before learning, but immediately after learning, and the reason I did that is because it had already been established or already been suggested that when you make a new memory, there's a period of consolidation in which the formation of the memory is susceptible to influence.

This was first seen with electroconvulsive shock so that humans and animals that are given electroconvulsive shock treatments remember less well those things that happened just before the treatment, and this and other things led to the view that memories consolidate over time.

Now, if that's the case, I said it should be possible to give a drug after the animals are trained and find the same effect, and, lo and behold, I did.

Now, that led me and many others down a path of using this post training drug injection procedure to find out which drugs would enhance memory, which would not, where they acted in the brain, and what mechanisms they used in acting in the brain to produce these effects.

And I won't bore you with all of the details.  Suffice to say that we know that there are several brain regions that are very important, and for those of you who are interested in neuroanatomy, they include primarily the basolateral amygdala. They include the hippocampus, the entorhinal cortex, and the medial part of the prefrontal cortex, in particular, but there are some other regions as well.

We can enhance memory in laboratory animals by microinfusing microquantities of the same drugs that we would inject peripherally into specific regions of the brain and get exactly the same results or we can put antagonists of those drugs directly into those brain regions and completely block the memory enhancing effects induced by peripheral drug injections.  So this is a way of learning about the anatomy of memory, the pharmacology of memory, and the neuromodulatory systems that are involved in memory.

Now, interestingly many of these drugs converge on promoting the release of noradrenalin, norepinephrine or acting on the receptors that adrenalin and noradrenalin use because if we use blockers of those compounds or of those neuromodulatory influences, we can prevent the memory enhancing effects.

Now, we asked then a number of years ago why is it that we have a brain that's organized in such a way as to be labile to influences that happen after learning.  Why is it your and my brain is made that way?

Because I can skip ahead and say some of the same drugs have been studied in humans.  Amphetamine, for example, given post training to humans will enhance memory just as it does in laboratory animals.  Well, why are our organs organized this way?

We came up with the idea that this might be part of the selection process that enables us to keep things that are important to us and not clog up our brain like Mr. S in Funes, the Memorias with things that don't happen.  It's a way of allowing a period of time for selection.

So you have an experience, and a decision has to be made.  Is this memory to be kept or not?

Well, we ask what is it that ordinarily would act in the body that does the same things that drugs do?  Well, what happens when you get excited?  You release stress hormones to yourself.  We all do that. 

When you are aroused, when you are insulted, when you're frightened, you release adrenalin into the blood stream from the middle part of the adrenal gland, and you release cortisol from the outer part of the adrenal gland.  They go into the blood stream.  Both of these stress hormones are released.

So we ask the question then:  do the stress hormones do the same things as the drugs?  And the short answer is, yes, they do exactly the same thing, and they work exactly in the same places in the brain, and they use the same mechanisms that I describe for the other drugs that work on GABA systems and noradrenurgic systems, and so on.

So here's a built in system that does the job, and our conclusion is that what happens with this release is that a correlation is then created between the significance of an event and the subsequent remembrance of the event, and I'll come back to that a little bit later.

Finally, there's a caveat in all of this research, which is very important to think about whether it's drug manipulation or whether it's genetic manipulation, and that is if there is simply a tradeoff between a drug and additional training.  We have found nothing that a drug can do that additional training won't do.

So it's not as though the drugs turn the animals into super animals.  It just means that they get there a little faster.  That is, it gives them a little edge in how they get to that point.  That's very important to think about because if you're thinking about outcome, then there's lots of ways to get that outcome.  You don't have to give a drug to get the outcome.

If you have a child that's not learning well, you don't need to give it a drug.  Give it more training to get to the same outcome.  Now, if you want to use a drug as an aid to get to that outcome, then that's a decision that you have to make, but it's not going to get you someplace that you otherwise wouldn't get.

For example, Mr. S could do all of these marvelous feats of memorizing.  Well, we know perfectly ordinary people who have been trained to memorize a telephone book.  You can do that.  I mean if you want to spend your time learning a telephone book, you can do that.  I wouldn't particularly advise that unless you had some special reason for doing so.

All right.  Let me turn now more specifically for a moment to the effects of drugs used in the treatment of memory disorders, and here we have a sad story. 

Despite many millions and millions and millions of dollars that have been spent by pharmaceutical companies and biotech companies, and despite a lot of academic research, we only have one class of drugs that is useful in treating Alzheimer's disease.  It's all the same class.  They're all acetylcholinesterase inhibitors, which means that they inhibit the enzyme that destroys acetylcholine when it's released.  If you inhibit that enzyme, then this neurotransmitter, neuromodulator is around at the synapse for a longer period of time.

And the drug such as Tacrine, Aricept, Exelon, and so on, they're all "me, too" drugs.  They're all acetylcholinesterase inhibitors, and the further development is to try to get rid of the gastric distress, all of the cholinergic side effects that one would not want to have, and they are more or less effective in doing that, but they are not horrendously effective drugs.

As a matter of fact, they're modestly effective.  The underlying problem is that Alzheimer's disease is a progressive disease.  Subjects are going to get worse and worse and worse no matter what you do, and all you can do is squeeze a little bit more effectiveness out of a patient for some period of time.  It is no cure.

And — and this is a tough one — no new or novel drugs have been produced.  So there isn't any drug out there which is a novel drug, which has been found to be effective, and there have been a lot of them that were this close to being effective and didn't make it all the way through for one reason or another.

There are lots of them that have been developed by pharmaceutical companies that are very effective in animal models, and then they drop out along the way because of side effects.  I'll just give you one odd ball side effect.  There was a company that I was consulting with that had a very powerful memory enhancing drug in laboratory animals, which means they could learn much faster, not ever better, but much faster, and it was yanked out because in Phase 1 it caused nosebleeds in humans.  So it was kicked out because of that, and others have liver damage and they have other things.

They just haven't made it through for whatever variety of reasons.  And I was wrong because a dozen or so years ago because so much money was being put into it, I bet that we'd have three or four by this time working on different classes, that are different classes of drugs working on different systems, but they don't exist.

What's really needed when you look at it carefully in disorders such as Alzheimer's disease is not the palliative types of drugs we're talking about that squeeze a little bit more out of a deteriorating brain, but we need drugs that will or some treatments which will prevent the disorder from occurring in the first place or restoring cellular function through some other means if that's possible to do so.

And there is an awful lot of effort going on at the present time, and now I switched my bet, and my bet is that these are going to pay off.  Let's say, in the next ten to 15 years we'll have some treatments which might — particularly because so much more is known about the etiology of Alzheimer's disease that it's a good bet that something will happen in that area.

All right.  Now, let me say a few words about blocking memory formation.  Can we block the formation of memory?  The answer is, yes, we can do that.

I already mentioned that electroconvulsive shock will do that.  That's been known since 1949 approximately, and it's known both for humans and animals that if you give such a treatment, there will be a selective forgetting of things that have just been learned.

But there are also a lot of drugs that are in common use  that are antagonists of memory that impair or block memory, and I'll mention some of them.  Anti-cholinergic drugs will do that, drugs like atropine and scopolamine will prevent memory formation.   There's not much danger of that happening because these drugs are not used in high doses ordinarily, and they're not anything that's subject to abuse, by the way.  These drugs have  such unpleasant side effects that you wouldn't find many people abusing them.

But there are others that are abused.  Benzodiazepines are memory impairing drugs, drugs like Valium, Halcyon, clonazopam.   All of these drugs induce anterograde amnesia, in both humans and in animals, if these drugs are taken in high doses.  Performance can be reasonably normal without registering the information acquired while under the drug.  This is anterograde amnesia.

And these drugs certainly will weaken the formation of memory, and in some cases they will have very powerful effects, and these are drugs that are commonly taken by many of us.  They were anti-anxiety drugs originally, but  we apparently have lots of anxiety because they are sold in vast amounts throughout the world, much vaster, I think, than the extent of anxiety.

So benzodiazepines are there, and interestingly they work in the same place in the brain that I talked about.  They induced their amnesia by acting specifically in the basolateral amygdala.  So there's something about that region of the brain that's integrating an awful lot of neuromodulatory influences coming in, including those for the benzodiazepines.

In the last category are the beta blockers, which are commonly used for the treatment of heart disease, and I'll say a little bit more about those.

This work came out of the work in my laboratory with laboratory animals in which we found that a common effect of many drugs that enhance memory had to do with the activation of the noradrenergic system within the brain and then this particular region of the brain and some other regions as well.

So it looked as though with that information and the information that we had from the stress hormones that it might be that ordinary emotionally aroused memory, the memory of emotionally arousing experiences might involve the systems in humans.

So Larry Cahill, a colleague of mine in the laboratory, set out to do this.  We did the following study, which is now well known in the literature.

He told human subjects a story about a boy, and it had two versions.  One is an emotionally arousing story, and the other is a boring story.  And then he measured the memory in a surprise memory test three weeks later, and the subjects selectively remembered better the information presented to them during the exciting part of the story.

So let me run through it for you.  A boy and a mother leave home and they cross the street and there's a slide.  There are 12 slide that are shown.  Cross the street.  They see a damaged — I'm giving you the boring story — they see a damaged automobile.  They visit father who works in the hospital.  They're having disaster prepared in the demonstration that day.

They see people with make-up on to make them look like they've been injured.  The mother makes a telephone call and goes to the bus and goes home, and that's the story.

And you can divide it into three parts.  Early stages, leaving home, in the hospital, and then the denouement at the end.

On the surprise memory test three weeks later, the subjects remembered all three parts equally well.

Now, other subjects, exactly like those, were told a different story, same 12 slides, and the test is on what's in the slide.  Told the same story.

The boy and a mother leave home.  They cross the street.  The boy is hit by the car.  He's seriously injured.  They rush him to the hospital.

Surgeons work frantically to save his life and reattach his severed legs.  A distraught mother makes a telephone call, goes to the bus and goes home.

So here it is.  Same pictures, and then the surprise memory test is:  tell us what you saw in the picture.  Don't tell us about the story.  What was in the pictures?

And there is a significant increase in the information remembered in the pictures in this subjects that had the exciting story told.

So then Larry and I did the same experiment, except we gave the subjects a beta blocker, Propranolol or Endurol, in clinically used dose, in a clinically used dose, and told them the story, and then tested them three weeks later, and those subjects were — their memory was just like that of subjects that had received the boring story.

So here's a blocking of emotionally influenced memory by Propranolol.  Now, this turns out to be important, we think because it has some implications for the etiology of post traumatic stress disorder, and as you may know, about 25 percent of the Vietnam veterans had or have post traumatic stress disorder, and any time there is  crisis, traumatic event, there can be a significant amount of this disorder, which in many cases will never go away.

In some cases it will go away in a few months, and what Roger Pitman did was to get hold of human subjects that had been traumatized in an accident or in some way and put them on beta blockers as quickly as possible afterwards and maintained them on for several weeks and then looked to see symptoms of PTSD several months down the line.

And a first study that was just published showed that there is a significant decrease in the expression of PTSD several months down the line, and subjects were put on the beta blockers.

Well, what is the logic of this?  After all, the exciting event is over. 

The logic is based on the evidence from studies of post traumatic patients, that the events will flash into the mind after  they're over the next day and the day afterward, and you consider each one of these as a rehearsal.

So every time they relive the experience of being mugged or being raped or being almost killed in a car or whatever, every time that comes up again, there's the same emotional reaction again.  It's like a rehearsal with the autonomic concomitance of this, and the effect of the propranolol is to allow this inadvertent rehearsal, but without the stress hormone consequences of that, which would lead to a strengthening of the memory.

There's another study in press that shows the same results.  So there now will soon be two studies showing the effects on PTSD.  Whether this will hold up in the long run we don't know.  This is very early in this research.

Now, let me bring up very quickly some issues.  You asked me to, some issues that might be worth discussing, and one is the blocking memory.  I'll start with that because that's where we just finished discussing, and there is some concern that it might be a bad thing to reduce the strength of memory for people who have had a traumatic event for lots of reasons.

Maybe we need to remember trauma in order to deal with life or maybe we need to remember the trauma in order to testify in court, and so on. 

So one could make an argument that it is certainly a judgment to be made as to whether if this really does work, as it appears to, but we're not sure at this point; if it really does work, then one would have to make a judgment.  Is it better to reduce the probability of development of PTSD and forego a strong memory, or is it better to save strong memories, complete with the suffering, and forego the opportunity to decrease the suffering?

That's a judgment call that each individual would have to make if what I have told you turns out to be validated and substantiated.

Here's another one that's of deep concern to me, and this is, by the way — we've had several conferences on this topic, including one at the Ciba Foundation in London a few years ago, and so we've discussed these issues many times in small conferences.

This one concerns me.  Arresting neurodegeneration, I said that there were likely to be such drugs.  I'm worried about that because I could anticipate a situation in which Alzheimer's disease was identified, let's say, because a person is becoming demented.  Now there's a drug which will prevent any further deterioration, and now you have an arrested dementia, which means that people will be in this arrested state for a longer period of time.

It is not necessarily the case that you would want to stop deterioration if the deterioration is far along.  Once, again, that would be a judgment call.

The next one I touched on, drugs for children.  If we go down that slippery slope from Alzheimer's disease to age related declines in memory to drugs for normal people who would like to have an edge, well, children can be normal people who would like to have the edge.  They would be on that slope, and so the question would, in the subjunctive, or will, if things have a certain way, come up; should drugs be given to children as an ancillary treatment for learning?  Why?  Which children?  Is this going to be another economic divide?  The rich kids get the pill in the lunch box and the poor kids don't, if it's readily available.

I mean, I can certainly foresee that happening.  I can't predict that it would happen, but I can foresee that happening.  And is this yet another cost that we're going to have to bear in society in treating the walking well?

We already spent a lot of money on treating the walking well.  Here's yet another example of it.

And finally, the worst one of this is the designer baby and what I call the Time magazine issue.  Time magazine, based on this study that was published in a very reputable journal took unfortunately a word that was used in the paper, both in the abstract and in the introduction of the paper, "intelligence."

That PET study did not study intelligence.  That study asked does a mouse freeze when you put it in a place where it had received a shock.  Does a mouse swim more rapidly to a platform where it could escape from cold water?

The genetic manipulation produced mice that both of those did better than their controls.  That's what they did.

Now, there's nothing in there that 100 other people haven't already done with drugs.  Those are the same studies that have been done literally hundreds of times with drugs, enhancing memory of this kind.  So there's nothing conceptually new.

What's new is the permanence of it and the use of molecular genetics to produce it, which leads people to think, and Time magazine certainly thought that and the author of the paper implicitly suggested that by using the word "intelligence" rather than "memory" or "performance," that it might be possible with right consultation of the right people to have designer babies in which you insert particular genes which are guaranteed to make them learn better.

Well, there's no guarantee, but my guess is that we would have, if they worked, we'd have more Mr. Ses and more Mr. Funes de Memoriases and not necessarily more thoughtful, intelligent human beings that will help to make this place a better world.

Thank you.

CHAIRMAN KASS:  Thank you very much.

We should just open the floor for discussion.  Mike Gazzaniga, please.

DR. GAZZANIGA::  Thanks, Jim.  That's terrific.

It might be helpful though for us to have you distinguish between memory as sort of a unitary event and memory as you and I know it to be, which is this complex system of information and coding, retrieval and all of the rest.

The reason I say that is that one of the benchmark observations in the clinical and neuropsychology  is that the memory quotient score correlates perfectly with the IQ score.  And so when we have these enhancing devices that allow for, quote, increased memory, probably what we mean by that is increased sort of lexical entries or something.  It isn't enhancing the entire memory system that allows the intelligent encoding and retrieval of all that information for use.

And if that pill came along there might well be an impact, it would seem to me, on these matters.  What do you think?

DR. MCGAUGH:  Well, starting way back when I first began working on the drug enhancement, I tried to ask the question are there limits to the kind of information that, let's say, post training drug injections will influence.  And the answer so far is no.  That is, I found memory enhancement with post training administration of a variety of drugs in every task that I could think of that would tap different kinds of information that the animals were acquiring.

So it appeared to be general over a very broad range.  Now, we're going to hear more about different forms of memory in the human this afternoon, but as far as different kinds of things that animals are capable of being taught, I haven't found any constraint on that, nor has anyone else.

Now, with respect to the memory and the IQ, however, wouldn't you agree that if the memory test was a perfect predictor, then you wouldn't need the IQ test, and the IQ test covers things besides just the memory subtest, correct?

DR. GAZZANIGA::  Oh, yes, yes.  The fact is though that if you take a look of somebody with an IQ of 100 versus an IQ of 125, the memory subtest goes right up with it.

DR. MCGAUGH:  Sure, sure, and it would have to because that's the way it was built.

DR. GAZZANIGA::  Well, no, in separate, totally different, independent memory tests, too.  But anyway, you know my point.

But one final point.  Beta blockers and Baghdad.  So let's say you're going to send troops into harm's way.  Is in some sense modern neuropharmacology suggesting in order to prevent post traumatic syndrome you ought to give them a beta blocker before they go in for their dirty work?

DR. MCGAUGH:  Well, first let's assume that what has been found will be replicated.  Let's make that case.  I don't want to make that too strongly because this is an early stage in the human application.

      But once again, that's your tradeoff question, isn't it.  Let's suppose they really were to prevent or to attenuate the development of post traumatic stress syndrome, and actually the number from Vietnam, I think was 29 percent of the veterans of the Vietnam War had post traumatic stress syndrome, from which many never recovered, and then they filled up the veterans hospitals.  That's just a fact of life.

Would it be worth using pharmacology to prevent that from happening, if it didn't do anything which would harm the person?  That's the judgment to be made.  Somebody would have to make that.

DR. GAZZANIGA::  That's right.

DR. MCGAUGH:  Now, stimulants have been given to soldiers for years to make them implicitly, and I think explicitly in some cases, to make them better soldiers.  Nicotine is a memory enhancing compound in laboratory animals.  Post training injections of nicotine enhance memory.  It just does.  It's been known for many years.

One doesn't do those studies in humans because of the taint from the tobacco industry so that one just wouldn't do that research.  You don't want to be tagged as somebody who's going to increase tobacco sales, but my guess is it's probably is memory enhancing in humans as well, and caffeine as well.

Soldiers are routinely given cigarettes, and that came in with their K rations.  Amphetamines were used by the Germans, given all the time to their soldiers.

So the use of pharmacological enhancement of human performance is not new to the military.  So the question is if you think that they're going to survive and they have a quarter percent, a 25 percent chance of being debilitated even if they win, would you want to do something to prevent that from happening?  That's a judgment that would have to be made.

CHAIRMAN KASS:  Gil and then Dan.

PROF. MEILAENDER:  I don't know I even know enough to know how to ask my questions here, but I have two sorts of questions.  One is — and this is really a naive layman's question — but in some of the things you talked about with respect to — actually it was particularly with respect to sort of blocking memory formation, which it seemed to involve controlling various kinds of emotional responses that one might have in various ways.

In what sense is that — in what sense were you doing something that specifically touches memory when you do that?

I mean, I don't know.  As I say, this may just be too naive, but is it really memory that one's dealing with at that point?  That's my one question.

Let me just ask my other and you can do what you want with both of them.

Is it conceivable just in terms of the mechanisms one's working on that one could go to work on Alzheimer's, on trying to find ways to stop that kind of degeneration, that would not also be applicable to, you know, possible memory enhancement in school children, say, or something like that?  Are these separable categories?

So those are my two questions.

DR. MCGAUGH:  Well, those are both very good questions, but I do think they are completely separable from my perspective.  Let me take the first one.

The answer is no.  We're not only affecting memory.  The question is are we affecting memory, and the answer to that is yes.  We can show that it's not due to some other side effect of it.

We are affecting memory, but we're also affecting — I mean, after all, these beta blockers are going to affect the action of the heart.  I mean, that's what — think of all the things that adrenalin are required for.  They're required for releasing glucose from the liver and so on.

So that when we give a beta blocker, lots of systems are going to be affected.  The body is going to be changed in lots of different ways, but we've been able to sort out with our experiments the question is it specifically, no matter what else it's doing, is it working on memory, and the answer is, yes, it's working on memory while it's doing all of these other things.

Does that answer that part of it?

All right.  The second one is that I think that they're really quite different questions.  Let's take the Alzheimer's disease, and let's assume for the moment that the cause of it is the anatomical sequelae that lead to these plaques and tangles in the brain.  Let's just assume that for a moment, and that's still a little contentious in the field.

The kinds of drugs that one would use for that would be the ones that would interfere with the cellular processes that lead to that kind of neuronal damage, and they may have no other effects.  They may have no other effects at all.  They just may prevent that sequelae from taking place.

Whereas the drugs that are currently given for Alzheimer's disease, the acetylcholinesterase inhibitors, make better use of a declining brain system that uses acetylcholine as part of its communication mechanism, makes better use of that, but it doesn't do anything that we know of to stop the degenerative process.

So the degeneration is continuing, and it's sort of like trying to squeeze a little bit more lemon juice out of the lemon juice that's been squeezed.  You can always find a little bit more.

It's like the economists who say that we are never going to run out of oil, and their reason is because there will always be some oil.  Now, we'll never run out of coal because there will always be some coal.

Well, there will always be some acetylcholine.  Can you make it work better with a declining brain?

But the drugs that are used to make the acetylcholine work better or whatever neurotransmitter may do nothing at all to deal with the underlying cause of the disease, whatever that may be.

So I see them as going in different mechanisms.  To put it in another way, I don't think that there's any danger that normal human beings will run out and buy Exelon or Cylert or one of the other Alzheimer's disease to try to make them a better sales manager.  That's not going to happen, and those drugs are not going to be given to children.  I mean, nobody in their even quasi right mind would think of doing that, nor if there were drugs that would prevent neurodegeneration would a normal person take them unless they thought they were at risk for the degeneration, which brings up another question.

If we were able to make those predictions, would there be drugs to deal with that?


DR. FOSTER:  Just a comment and then my question.

Of course, the Alzheimer syndrome or disease is sad, but the sadness and pity is not so much for the patient, who doesn't remember anything, but for the caregivers. The caregivers are continually stressed and presumably releasing epinephrine and norepinephrine all the time. Maybe that is what keeps them going. It is not a bad disease for the patient when fully developed because memory is gone, but one wants to prevent it if at all possible.

Now, you just made a statement which I was going to follow up.  You said that even if you knew that there was a drug that was going to be preventive, let's say, of the Alzheimer's dementia, as an example, would I take it or would you take it, and the answer might be if that were solely an effect of the drug that you would not.  You don't have a family history of Alzheimer and so forth.

But one of the things that there's an increasing interest in in medicine, I believe, is where a drug which is used for one reason has powerful effects in others.  For example, probably the cheapest and safest chemopreventive drug that you can take with the rare exception that you're going to bleed is an aspirin.  It's going to cut colon cancer 50 percent, probably going to diminish, slow down Alzheimer dementia.  You know, it's got a variety of things that are additional.

Now, one of the drugs, and I'd be interested in your comments, that's been very much of interest lately in terms of chemoprevention of the Alzheimer dementia are the statins, the drugs that are used to lower blood cholesterol. I mean, at least in terms of retrospective studies, if you've ever taken them, you may be as much as 70 percent in large populations.  The veterans population study is the one I know best.

It also is very helpful, it turns out in odd ways of preventing osteopenia in women, bone loss, and of course, the people who really work on cholesterol, we have two guys that are Nobel Laureates for cholesterol at our place.  They believe that, you  know, to take a target of a cholesterol of 100, let's say, even if you've got diabetes and so forth.  The NIH says 130 LDL, the bad cholesterol.

They clearly show a linear progression back to the 60s and so forth.  In other words, if your LDL is 100, that's great, but if it's 60, it's better if you want to prevent atherosclerosis and so forth.

So the question would be:  would you have the same anxiety about a single prevention for something like dementia if at the same time you could handle — and this is before they get a disease.  So you're in prevention and not treatment.  Would that change your thought about the approach to this fairly common problem?

I guess I don't know whether I'm saying this very well, but if you get several effects from a drug that's relatively cheap and seems to be — and I don't want to confirm that it's really stopped.   It's not due to the cholesterol.  That's clear.  It's not due to the cholesterol even though E4 — I mean apolipoprotein, E4, E4 is one of the genetic risks for early Alzheimer's and so forth, and that also gives you lipid disease, as well.

But if you could do that, would you have the same concern about it?

DR. MCGAUGH:  Well, let me shift diseases to Huntington's.

DR. FOSTER:  Okay.

DR. MCGAUGH:  There it's clear.  If there was neuroprotection for Huntington's disease or for multiplesclerosis, I don't think there would be any question at all because they're well understood or pretty well understood.

DR. FOSTER:  Sure.

DR. MCGAUGH:  But at the present time, in the case of Alzheimer's disease, it's etiology is not well understood even though we know that there are genetic predictors of it, and so it's not clear what one should do.

You know, take ten times the amount of Vitamin E and take more aspirin and all the rest, statins, whatever.  If I had three of the genetic markers for Alzheimer's disease, I probably would look for all of the above in order to keep that from happening, just as I would if I were destined to have Huntington's disease do everything I could to find out how I could be neuroprotected.

Now, let's think about it more broadly, about the general public where they're not going to have genetic information about this.  Already people are taking Vitamin E.  People are taking aspirin, I mean, much more than they used to.  So there are people who are trying to be neuroprotective just to cover the odds.

Now, let's suppose it costs $100 a day to be neuroprotected.  What do you think would happen to the Vitamin E sales and the aspirin sales and so on?  They'd go down to the floor because people would say getting that new car today is more important than what happens to me when I'm 70 years old or 80 or whatever.

So there are huge economic consequences that have to be factored into this, just as there are economic factors for dealing with AIDS, for example, or the cost of the medication influences how well it's point to be accepted and used in different countries and so on.

So the same thing would apply in the United States.  The cost of these things, even if you knew their effectiveness, would have a big influence.

DR. FOSTER:   I was just really trying to get to the issue that sometimes there are surfaces, and we've heard a little bit of it today, that if you do anything to alter the natural development of nature, that is to say if you — I'm not talking about acute disease or, you know, a kid who gets zapped by a sniper or something like that — but if you alter it, that that is both — it should not be done.  The playing God syndrome.

And I just want to be sure that your worry about the issue of the side effects and so forth of dementia did not imply in some sense that if scientific investigation could give us prevention against some of these major things and at a reasonable cost, which also has to be taken that you — I just wanted to be sure I understood your philosophy about that, and you've just answered it, but I wanted to bring that to the floor.

DR. MCGAUGH:  And I think in the case of neuroprotection that that's likely to happen.  I mean, that's the greatest effort that's being made at the present time on finding neuroprotection, even some thinking that it might be possible to make the cells behave better and behave the way they're supposed to after they have started to degenerate.

So not only protection, but recovery are two targets that are being actively pursued at the present time.

What I was trying to say though is that this is quite apart from the other reasons for having drug enhancement of memory, quite separate.

Thank you.

CHAIRMAN KASS:  Could I clarify?  I was in the queue.  I've also got Janet and Paul.

I would like to clarify just the bottom line on what is currently available or likely to be available in terms of interventions both for enhancement and for blockage.

I think I heard you say that notwithstanding the huge amount of effort, we have nothing really available with respect to the already existing degenerations of Alzheimer's disease. 

Nevertheless we do have in animal models various kinds of things that can enhance memory at least as testified, the performance of certain kinds of tests, but that the attempt to use these things in human beings have run afoul because of side effects in most cases.

Let me add one additional fact that you alluded to at the beginning, but stayed away from.  As I understand it, the main interest in the biotech companies or the others who are pursuing this is less Alzheimer's disease, but much more the memory enhancement —


CHAIRMAN KASS:  — of — I can't find the keys.

DR. MCGAUGH:  That's where the market is.

CHAIRMAN KASS:  That's where the market is and enhanced probably further by the market of the people who want their kids to do better on the SATs or as you have it.

With respect to those things, is there likely to be something — if you leave aside the treatment of the degenerations, but talk about possible things that would be coming in the area of the potentiation of more or less normal memory or this new age related; is this 20 years, 30 years or —

DR. MCGAUGH:  Well, we always think it's right around the corner because so much money is being spent doing exactly that.

I did send in a tape [to the Council Staff] of a BBC program that is about ten years old.  It's available from somebody here, and in it I was interviewed, and I said that my belief was that the real target of this drug development was not for the memory impaired, but it was for the normal because that's where the market is, but nobody will say that.

I'll be damned if they didn't find the Director of Marketing of a major pharmaceutical company that they put right after my statement who said, "Yeah, that's what we're going after.  That's where the market is."

I mean, he just said what I said that nobody would say in public.  I mean just opening.

Well, their compound failed.  They put a lot of money into a compound, and it just didn't work.

Now, let me back up here and say there are things that work, but they have no interest because there's no money in them.  Paul Gold has shown that glucose enhances memory, not only in normal people, but in elderly people and in Alzheimer's patients.  You get a little improvement with glucose, but there's no money to be made in that.

Amphetamine is a very potent memory enhancing drug, as I mentioned, both in humans and in animals, and it works even when injected in humans or given to humans after they've learned something.  It strengthens consolidation.

But there's no money to be made in amphetamine, and besides that, it's a nasty drug, and people get dependent on it and they get addicted to amphetamines.

So there are things right now that people could take that will enhance memory, but pharmaceutical companies are not very interested.

Now, one major company, Abbott Laboratories, certainly knew about nicotine.  So they decided to modify the nicotine molecule and, once again, the count was millions of dollars to make a drug that is like nicotine, but for which they could get a patent, and it didn't work all the way through Phase 3.  So that was a big loss of financial investment.

Now, nicotine probably works, but it's also addicting.  So there are these side things, the things that might do something for memory that we know of or that companies have tried to develop.  All have some kind of a restriction.  They just — there's no free memory enhancement that isn't going to do something else.

It's sort of like looking for a nonaddicting opiate.  You remember in the early part of this — well, right at the turn of the last century when heroin was introduced by Bayer.  It was called Heroin because it was heroic.  That's why they called it that, as the nonaddicting opiate for children, and it was in children's cough medicine for probably 20 years.

And after the discovery of the opiate receptor, there was a huge increase in looking for nonaddicting opiates.  If we could only take that drug which is analgesic and modify it, you know, pull off a methyl group here, add another group over there; we'll find an opiate that is nonaddicting.

Well, the less analgesic it is, the less addicting it is.  So memory enhancing compounds, let's say, our own memory enhancing compounds are adrenalin and cortisol, and they do all kinds of things.  I mean, you wouldn't want to give adrenalin to a heart patient, for example, but we know that if we give adrenalin to a rat or a mouse, we can make it learn a lot faster or if we give a drug that will activate those receptors it will happen.

But there are always going to be these side effects, and I don't see them disappearing, but that's what the pharmaceutical companies are looking for.  They're looking for the pure memory enhancing drug that doesn't do these other nasty things.

And is that around the corner?  Maybe it will be in the paper tomorrow.  I don't know.

CHAIRMAN KASS:  On the parallel side now on the memory blocking, the same answer?

DR. MCGAUGH:  Well, that can be done right now.  I don't think —

CHAIRMAN KASS:  But also with drugs that have systemic effects, right?


CHAIRMAN KASS:  I mean blockers are also not innocent —

DR. MCGAUGH:  You pay for it, but let's put the emphasis.  You want to reduce the anxiety, and so you take a benzodiazepine.  Well, the sufferance there is that you are also likely to induce anterograde amnesia.  It was discovered after it was approved for anxiolytic effect.

So now you take, let's say, benzodiazepine to produce anterograde amnesia.  The payoff is you're going to be less anxious.  I mean, you don't have to remember.


DR. MCGAUGH:  I mean, the way this — many of you here probably know that it was discovered by psychiatrists and psychologists after the benzodiazepines were introduced.  People would come back after having been on a trip, and they were very anxious about going, and they would come back in the report, "I don't remember what happened on this trip," and so that's what stimulated the research on it.

And then it was discovered in animal models as well as in humans it's a very strong anterograde amnesia, which of course is dose dependent.  So that you can certainly take a benzodiazepine and get an anxiolytic effect without having severe anterograde amnesia, but you can also take a high dose, and you think you're okay, and then have anterograde amnesia.

CHAIRMAN KASS:  Thank you.

I have Janet and then Paul.

DR. ROWLEY:  Well, I want to follow up.  My question is in a sense related to what you just said because many, many individuals are taking beta blockers, particularly older individuals, and the question then is — and I don't even know what doses are generally used for beta blockers, but what is the relationship of the dose that would be used clinically and that which causes retrograde amnesia?

DR. MCGAUGH:  The clinically used doses, let's say, propranolol, 20 milligrams, is not going to induce any retrograde amnesia.  What it does in a study so far is simply prevent the added memory that is induced by emotional arousal.  So we have not found in human subjects any memory impairment in these doses, but we have found complete blockage of the effect of this emotional arousal on subsequent memory. So in that sense I don't think there's any danger.

This, by the way, independently in the same year, an experiment was done in a very different way by Rob Jenson and his colleagues in southern Illinois, but in place of emotional arousal what they — these were now with elderly people who are on beta blockers or on other drugs for controlling heart disease, and they taught them standard psychological verbal material.

And then after that they had them squeeze what's called the hand dynamometer in which you squeeze it, and you can see how much pressure is induced by squeezing it, and this is well known to release catecholamines, including adrenalin.  You do this.

And they found that the memory, squeezing this thing, enhanced memory in the elderly subjects who were on other drugs for treatment of heart disease, but did not enhance memory in subjects who were taking beta blockers.

In normal subjects now, Larry Cahill has used another technique which is standard procedure in cardiology studies, and that is just thrusting one's hand into a bucket of ice water.  I know that doesn't sound very sophisticated, but it will certainly get the heart going, and it releases adrenalin massively right at that time, and Larry Cahill has now found that memory for ordinary verbal material is significantly enhanced.  Subjects learn something and put their hand in this tub of ice water.

So it doesn't have to be an emotionally arousing response, but we think in our nature that's probably what ordinarily controls it because we don't go around putting our hands in buckets of ice water to release catacholamines.  We get catacholamines release when people say, "You're dumb, you're ugly, you're stupid.  You did a good job.  You won the lottery.  You got a Nobel Prize.  You're going to be executed.  Things like that tend to get epinephrine or adrenalin released.


DR. MCHUGH:  Well, we could talk all afternoon after that wonderful talk, Dr. McGaugh.  I had two comments and then one question.

The first comment was in your deep wisdom you reinforced what my father told me when I first went off and recognized that there were a lot of people in schools that were smarter than I was.  He said, "Don't worry.  You can out work them."

DR. MCGAUGH:  That's right.

DR. MCHUGH:  And it's the truth.  You're backing that up.

DR. MCGAUGH:  That's a missed point.  My neighbor, who wanted the drug for her child, I don't think had asked the child to work a little harder.  I think she was just saying she's not doing well.  Let's make up for that..

DR. MCHUGH:  That's right.  That was my father's idea.  Just work harder.  You can do it.

DR. MCGAUGH:  Well, he was right.

DR. MCHUGH:  He was right in many things.

The other thing was, of course, in relationship to treatments for the conditions, the deteriorating conditions like Huntington's disease or Alzheimer's disease and the like, which are devastating when they occur and which have their beginnings before, if we understood not just the risk factors, but the mechanisms, it probably would be that everybody who had those mechanisms in play would probably take the treatments even no matter what they cost.

The real problem now is not for Huntington's, but something like Alzheimer's disease.  We only know that there are risk factors that are tied to it.

DR. MCGAUGH:  Think of all the people who are taking Vitamin E and aspirin at the present time.

DR. MCHUGH:  Oh, I'm well aware of that.  Aren't you?

DR. MCGAUGH:  So that there is at least among people who pay attention to these things — we try to reduce our risk.  I mean, if we knew more about it, we could do more selective things to reduce that risk.

DR. MCHUGH:  That's right.  So the mechanisms would help us to know more things.

DR. MCGAUGH:  Absolutely.

DR. MCHUGH:  I had one real question I wanted because it was very interesting what you were saying about the effects of beta blockers on consolidation of memory.  But as you know, lots of people use beta blockers who are performers, particularly artistic performers.

DR. MCGAUGH:  Absolutely.

DR. MCHUGH:  Stringed instrument players and the like, and they discovered in their performance that they can do much better if their hands aren't trembling and the like.

And I wondered about you making the point that beta blockers inhibit consolidation.  Do they have any effect on retrieval, on memory retrieval, which would both affect the piano player who was following the Schuman approach of doing it by memory, but also might affect us otherwise negatively?

DR. MCGAUGH:  I had a whole section on that that I didn't include because of lack of time, but may I just say something about that?

First of all, it is the case that beta blockers are the drug of choice for stage fright, speech fright, and also for controlling trembling and things of that kind.

But in the case of the violin player who is up there performing, that is so over rehearsed that the memory is not going to be affected for that.  That's on automatic drive at that point.  So that's not an issue.

But these same hormones that I told you enhance memory consolidation on other circumstances, on other conditions, will impair the retrieval of memory, and we have studied that fairly carefully using cortisol in the human or corticosterone in the rat, and the experiments are as follows, and we try to make them as parallel as we could for the two.

The subjects learned something on one day to some criterion, and then the next day they are tested on it, and then we check to make sure it's not interfering with their performance or anything of that kind.

And it turns out that a glucocorticoid, a cortisol, has an impairing effect for about one hour after it is either released or after it is injected, and we know that it is the cortisol because if we give a drug that blocks the release of cortisol, then there is no memory impairing effect of the treatment or  in a rats it can be a shock, an electric shock to its feet.

And this is an effect that lasts for about an hour, an impaired retrieval selectively induced by that.  So we think that all of the things that we have learned from our undergraduates over the year about how they knew the information very well and they just panicked on a test and couldn't remember it.  We now think that at least some of that may have been honest, that there was an over excitement and there was a temporary depression of selectivity of memory retrieval lasting for about an hour, and this we found both in rats and in human subjects.

And we are now doing experiments at the moment to find out the involvement of beta receptors, beta adrenergic receptors in that mechanism.  We had experiments in place right now doing that.  So I can't answer the question.

But in everything else I said it had to do with getting information in and getting it stored.  It all had to do with making a memory, and now we're shifting it.  That's why I left it out of my main talk here.  We're shifting to something else and saying are there things that affect our ability to utilize information that we have, and stress hormones do affect that.

DR. FOSTER:  Just one quick question.  Does epi/norepi also do the same thing, that one hour impairment of retrieval?

DR. MCGAUGH:  No, we haven't examined that yet.

DR. FOSTER:  Because oftentimes they're almost always up together.


DR. FOSTER:  And you know that cortisol has a permissive effect on that.

DR. MCGAUGH:  And we're looking specifically once again in the basolateral nucleus of the amygdala because that was critical for our consolidation effect, and I can say our first experiments indicate that activation of beta adrenergic receptors within this same region of the brain plays a role in this memory retrieval effect that I just described.

But that's not published.  That's the only thing I've told you that's not published yet.

CHAIRMAN KASS:  Frank Fukuyama.

PROF. FUKUYAMA: Are you born with a certain natural memory capacity?

And when you talk about memory enhancement, you're talking about the ability to move information in and out of that fixed capacity or can the capacity itself be affected by environmental factors?

DR. MCGAUGH:  You're probably going to hear a lot of that, something about that from  Dan Schacter, but let me just touch it briefly. 

The answer is no because there are lots of ways in which as we go through life we improve our memory capacities.  Let's say in areas that are your hobbies or things that you deal with an awful lot, you just get better and better because you have more information that's related to other information, and it's not stored as an isolated packet, but it becomes integrated.

So that I have two hobbies.  I play jazz clarinet and saxophone, and I do woodworking.  So I have lots of things that are very easy for me to learn because they are related to that, but if somebody starts talking to me about their hobby which is something I don't know anything about, I would have trouble remembering it just because I don't have the contextual connections formed to do that.

Now, also, if you take very specific domains, memory can be trained.  So that if you want to be able to memorize digits, let's say for some reason you have a zip code which is 2,000 numbers long.  You could do that.  You could do that.  And you would be better then for a while in memorizing of digits.  So that this specific domain can actually be improved. 

So you're not born with a capacity.  What we're born with is without any extra effort to get seven digits plus or minus one, and that's one reason we had seven digit telephone numbers and the area code was kept separate, because you can remember seven digits at least long enough to write them down.

That's probably the native thing that most people have, but  you can have a digit span of 15 if you'd like to have it for some reason.  You can get special training to do that.

CHAIRMAN KASS:  Bill and then —

DR. MCGAUGH:  And, Dan, I hope that you'll elaborate on that because that's more in your domain.

Excuse me.


DR. HURLBUT:  I want to ask you about something you touched on briefly, the engagement of possible memory enhancing agents in education.  If you say that, as you more or less said or at least implied strongly, that memories related to life significant issues because the body itself produces through at least the adrenal gland, and probably in many other ways, agents that modulate memory retention.  It then implies from that that if you enhance one component of that system artificially that you might be disrupting the psychophysical unity of your identity or your normal life processes.

In other words, you'd be forcing on your system memory of things that your other normal process wasn't encoding.

DR. MCGAUGH:  Absolutely.

DR. HURLBUT:  So in other words, we have a therapeutic model of memory enhancement where we think there's a deficit.  That makes sense, and just as it's easier to fix a broken link in a chain than it is to strengthen the whole chain, we can comprehend how that might work where there was a problem.

But would you really improve life overall is a large question I hear going on in the background of what you said.  In fact, you started at the beginning in saying if memory enhancement were a simple good, then evolution probably would have done it.  Didn't you say something like that?

strong>DR. MCGAUGH:  Somebody.

DR. HURLBUT:  Okay.  Here's my question.  The work that Mike Merzenich is doing with enhancing Ó- going back to basic neural processing, things like dyslexia and reworking very fundamental things in the way a person takes information where they have a learning deficit or, for that matter, any strategy of approaching life tasks.

He suggests that maybe you could combine what he's doing now with computers with drug enhancement to reinforce or make more powerful that basic neural revision.  You're familiar with —


DR. HURLBUT:  Do you think this is something that is coming?  Is it realistic?  Would it be profoundly disruptive?

And what do you see as the ethical questions associated with that?

DR. MCGAUGH:  Well, I hope it's not coming because I think that the ramifications are really very broad.

The reason I hope it's not coming is because you picked a particular case, but I could pick many others.   Let's just say the school teacher who is teaching the number facts to the children, and number facts are not very exciting, but you need to know how to multiply at least 12 times 12 and how to do the division, and that's not any different than dealing with dyslexics.  You're trying to correct here a disorder.

The disorder is that they don't know the number facts, and they have to know them or that they have to know the grammar.  And so why not a little chemical aid to do that?

So if you start with something as narrow as that and say:  folks, this is a very special case.  We're going to do this for the dyslexics under this condition because we think we can give a drug to enhance this particular thing.  All right?  Then we'll expand it.  What about English literature?  You  know, how about the sonnet?  You know, memorization of the sonnet is due tomorrow, or how about language?  I have to learn German, as I did in graduate school in four months in order to pass the exam.  Wouldn't that have been nice?

Well, we did have amphetamine in those days.  So that was helpful.  Amphetamine and caffeine, as you know, were not — amphetamine was not controlled when I was a graduate student, and it was commonly taken.  Would keep you awake, but probably helped a little bit.

No, I think that you've given a very special case, but it's easy to make an argument for a large number of cases.  I don't know how you would constrain it after that.  I mean, that just happens to be his interest in what he's doing, but other people are interested in other things, and they say, "Fine.  What we need is a little pharmacological help."

And now remember the basic thing I said is that whether it's hormones, our own pharmacological agents or the ones that we manipulate, we have never been able to do anything that we can't do by just more training, never.

Now, in the case of Alzheimer's patient, that isn't the case.  With some subjects, particularly with Exelon, which appears to be a little bit better than some of the others, they can get them to do some things that they couldn't otherwise do.  So there's some help for a degenerating brain to make it work a little better so that it can finally do something that it couldn't do.  That data on that are weak, but that's another case.

So I guess what I was trying to do is present things here, which were tailor made for this group, and so in this context I would say this is not immune from my criticism.  It falls into, let's say, my concern.  It falls into my bag of concerns because it is a very short step from there to giving the drug to my neighbor to give her child because she's not going to tall the child to work harder, but it's just a little bit easier to do.

It's sort of like taking a valium when you're anxious rather than to use the anxiety to help cope with the problem.

DR. HURLBUT:  I hear a strong preference, if not prejudice, for the natural in what you're saying because one could argue, well, so what if it enhances one thing even at the expense of the other.

DR. MCGAUGH:  No.  I'm neutral.  I'm bringing it to your attention.  I'm neutral on this.

What I was trying to say is that I don't think that that special case solves the problem for us.  If that works, then I don't see any reason not to do it for any learning condition.

I do favor the natural circumstance.  I think I would go back and say how can you become a better teacher to use the naturally occurring devices that children have rather than to use some ancillary treatment, which we know we're probably going to have to do for the deteriorating brain, but that kid has all of the machinery.  The machinery is there.  How can you make that machinery work better would be the first approach that I think should be taken.

DR. HURLBUT:  Well, you've convinced me that I should be scaring my students more.  A little more adrenalin would help them learn better, but really —

DR. MCGAUGH:  Let me — let me — I don't think you're entirely wrong in the statement that you just made.  It's nice to be nice to people, but I just had to write something about my earlier experiences recently, and the two teachers that I singled out as having the biggest impact on my life were two of the sternest teachers that I had.

I mean it just didn't dawn on me that until I've thought about it pretty systematically.  These were not touchy-feely people.  These were the most demanding teachers I ever had in my life.  One of them was my band and orchestra instructor whose aim was to embarrass you in front of everybody else.

And so we knew that at any moment during rehearsal he would stop it and point at somebody and say, "Play the next 16 bars.  Stand up and play the next 16 bars."  At any moment.  Now, that kept our attention.  It really did.

So if you want to get learning to take place and have an impact, I don't think that roughness is necessarily bad.  I mean, it's better if they could do it in a nice way and say, "Gee, Jim, would you do the next 16 bars?  We'd sure love to hear you do it in a nice way for the group." 

You know, that would be helpful, but that's not the way it was.

CHAIRMAN KASS:  Rebecca and then we'll take a break.

PROF. DRESSER:  This is in line with some of the other comments.  I think at one point you said there is no memory enhancing free lunch or something like that.  I mean, the tone of your presentation seems to me to be a good corrective to the media, kind of public image about a lot of these prospects, which is there are always going to be costs, financial costs, adverse effect costs, as well as your great problem of what if we could arrest neurodegeneration in the early stages of Alzheimer's disease.  Would that be a good thing or not?

I mean that's a very complicated question socially.  So thank you for the really, I think, balanced point of view and perspective.

DR. MCGAUGH:  Well, let me comment on that.  I do memory enhancement as a living, and that's what I do for a living.  So that's what my research is all about.  So I wouldn't want you to let me get out of here saying that I have dissed memory enhancement.

But I think there is a role for it, and I think it has been excessively over-hyped by pharmaceutical companies, biotech companies, and by the press because it requires the kind of thoughtful thinking that you people as a group have as your mission in order to evaluate these things and find out what is the proper place.

I think that there may well be — just as I believe some children need Ritalin, all hyperactive children do not need Ritalin.  All right?  I think there may be some children who need memory enhancing drugs because they can't do it.  They don't have the machinery to do it in the same way that the deeply disturbed hyperactive child does not have the machinery which enables normal behavior.

So some children's brains will need this, but once again, I come back to the slippery slope.  Which ones do and which ones don't and under what conditions  and so on?  And that's a tough one.  That's a tough one.

CHAIRMAN KASS:  Let's take a break.  the conversation will continue.  Let's take 15 minutes.

(Whereupon, the foregoing matter went off the record at 3:24 p.m. and went back on the record at 3:44 p.m.)

  - The President's Council on Bioethics -  
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