Variety of announcements, tomorrow, office hours
are shifted because at 4:30, there's
a really interesting lecture over at Clark.
This guy is one of the experts on the whole notion
that there are brain metabolic abnormalities
in sociopathic humans, violent criminals.
He's got the distinction of having the world's only
He has a big old Winnebago with an MRI machine.
And he drives all around the country
from one maximum security prison to another,
trying to look at aspects of frontal cortical dysfunction
in extremely violent individuals.
I have no idea if he's a good lecturer or not,
the material is going to be really interesting.
So that's something that probably should
be caught Friday, again, is not going
to be videotape, but just audiotape
for a number of reasons.
Finally, over next year, I will be doing,
if anyone is interested, some directed readings
with people that are-- that will be essentially
more of an exploration of some of the topics in the course
So if you are interested, do not send me anything whatsoever
until it's the summer.
At that point, CV, transcript, anything I need to know,
but it will be posted on the coursework,
so as to more details about it.
So we pick up with the homestretch here of language.
And what we got to just on the edge of two days ago
is the now begin to look at the genetics of language use.
In general, there's the usual types of techniques
for behavior genetics.
The first is looking for covariance
of certain language abnormalities
in certain families.
And the evidence for that is clear with Williams syndrome,
with the selective language impairment.
Those tend to run in families and they
tend to show classical Mendelian inheritance,
very readily thought of as genetically
Then, going to our usual deal of looking
at adopted individuals, twins, identical twins separated
at birth, that whole armamentarium
of behavioral genetics stuff, what does that show?
There's a fair degree of heritability
of things like vocabulary complexity, ability to spell,
skill at phonology, things of that sort.
In general, the evidence is pretty
poor for a strong genetic load on dyslexias,
on learning disorders of that type.
Of course, the modern version of it
all is to start looking at the actual genes,
the molecular biology of language disorders, of language
First thing that comes up is this gene
that has been at the center of the whole field for years now,
a gene called FOXP2.
And it was originally identified as having a mutation
in a family that had a very specific linguistic problem
running through it, language generation speech.
This family had severe problems with it,
classic looking for a genetic marker,
and eventually narrowing down to the gene
itself, turning out to be this mysterious gene FOXP2, which
turned out to be a transcription factor,
and a mutation in it in this family.
What immediately became clear is this theme
over and over again with language,
in so far as there's a problem in this family,
is it at the cognitive level of what language
is about symbolically or is it just getting your lips
and tongues and articulating and that much more
It initially looked like it was much more
the latter in this family.
It is apparently more of a mixture of both,
just to make things really confusing.
What you see is it is preferentially
expressed in that part of the brain
we heard about the other day, the basal ganglia.
That area that's playing a role in gesturing when you're
speaking, playing a role in facial prosody,
that sort of stuff, motoric stuff, and the fact that it was
found so heavily expressed in there
was part of what got people to think what's fundamentally
wrong with this family is motor aspects of language production.
Again, it's gotten messier since then
because these folks have a variety
of cognitive impairments in the realm of language.
So, of course, immediately, what we need to be asking
is what's FOXP2 doing in other species.
Does it occur in other species?
And it turns out that it is all over the place.
You find FOXP2 in birds and mammals
and all sorts of things, large and small.
It is very, very widespread.
But, importantly, a different version than you
find in humans.
It is immensely conserved, which is
to say you see the same version of FOXP2
ranging from apes to birds, everything in between.
Nothing has changed with that evolutionarily
in a long, long time.
So what does it do?
A handful of studies in animals where the gene has been knocked
out, it has been removed, where you now have
mice that do not have the gene.
And what you see is there is less of vocalization
and simpler vocalization.
And that's back to our whole world
of that subsonic vocalizations that you
can't hear when mice are giggling
and that sort of thing.
Knock out this gene, and there's less vocalizing
and there's less complexity to it.
So we're just doing something or other that looks plausible.
And it's expressed in motoric parts
of the brain preferentially in these other species.
So this super conservative version
of this gene, everybody else has the same version.
And then you look at the human version
and there's a bunch of differences
and they emerged very recently, best estimates
are the last couple of 100,000 years.
Each one of the changes extremely
positively selected for, whatever this gene is about,
once it sort of went on the human path,
it changed real fast under major selective advantageous
And thus, we've got a real different version
from everyone else.
The next interesting thing about it,
in so far as it is a transcription factor, when
you look at the genes that it regulates-- so this is now
taking her step further, our old genetic network deal,
when you look downstream, what genes it regulates,
they tend to be fairly differentiated
from other primates and to have differentiated
as a result of positive selection.
So this is a whole cluster of genes
that evolution was doing some pretty stringent things
on in hominids in the last couple of 100,000 years.
Now, what you do is one of the all-time cool studies, which
was last year, which you take mice
and you knock out their FOXP2 gene.
And now, you stick in the human version.
And, amazingly, what happens is once these animals mature,
they speak just like Mickey Mouse.
People were listening.
What you wind up seeing is-- it's probably
the Disney people probably are working on it,
and that's going to be the end of life
as we know it when they let those ones lose.
What you get when you overexpress-- when you express
the human FOXP2 in a mouse is a mouse
with more vocalizations and more complex ones.
Whoa, that is mighty interesting area of lots and lots of work
these days, trying to figure out what this transcription
factor is about.
But, clearly, just this screaming imprint
of major league selection that has gone on
for the human version and for the genes
that it regulates, fairly recently, it
is no surprise that this gene is central to such
a different unique thing that we're doing.
More evidence for genetic components of the language,
and this one is a very indirect one
with this totally interesting phenomenon that
has been shown in lots and lots of different places
on the globe.
So you get some circumstance where a whole bunch of people
are brought together from different cultures,
with different language groups, and why they're
having to deal with each other.
Classic version is you get, for example, slave populations
brought from different places in West Africa
to some of the Caribbean islands.
You have, on some of the Hawaiian Islands,
early in the last century, people from all over Asia
are brought over to worth the plantations there,
the fields, whatever.
What you have in these cases, there's
a whole bunch of people thrown together who
have languages from every which way
who don't understand each other.
And what always emerges, what has
been extremely well-documented, is some sort
of fragmentary communication system that
is made up of bits and pieces of all the relevant languages,
which everybody can kind of limp through and begin to be
understood with each other.
And what that is wounds up being called is a pidgin language.
Pidgin, very simplistic version that shows virtually nothing
in the way of complex grammar, and it's basically
a vehicle for getting individuals
who almost always, in these cases,
are societally pretty under the foot of powers that
be to deal with each other, to work with each other,
working out this proto proto communication system
with fragments of each language.
That's not surprising.
What is totally cool is what happens next over the next one
to two generations, which is this pidgin thing,
this committee glued together amalgamation
of fragments of different languages
within a generation or two has evolved
into a real language, which is then
known as a creole language.
Creole languages are languages that
are a couple of generations descended from pidgin.
And what you see is it winds up being a real language.
That's fine, that's fine, given that, two days ago, we're
hearing that it was possible for kids
to come up and invent Nicaragua in sign language
within a generation.
So you start with this pidgin thing,
and within a couple of generations,
it turns into a real language, fits the rules,
grammar, all of that.
Here is the thing that is so interesting
about this phenomenon, which is all of the creoles have
the same grammatical structure.
What is that about?
Creoles from all over the planet that
were built upon all sorts of differing
hodgepodge of the original languages in the pidgin, Creole
languages all have a similar grammatical structure.
Easy explanation, easy boring one, which is it's
very simple grammatical structures and this
is a language that's just getting off
its feet in each case.
No, in all these cases it is grammatical structures
that are not necessarily the simplest.
It's not just some baby step languages.
It's languages that all seem to come up
with the same graphical structures there.
And what this has given rise to is the notion
that there is a default grammar built into humans.
Let humans go running with a whole bunch of fragments
in different languages and, not surprisingly, we
were able to turn it into a real communicative system
within a generation or two.
And when pulling language out of thin air,
humans always tend to come up with the same sort
of grammatical structures that are not necessarily
the simplest, argument there being there is an innate,
there is a hard wire, there is an ancient pattern of grammar
that humans use when they come up with a language.
So totally interesting.
What you find, also, with the sign languages,
as they get invented, Nicaraguan sign language,
it went through a first generation
of being pidgin, and soon turned into a signing
equivalent of creole.
And it has some of the same grammatical structures.
Even when humans are defaulting into a new language that's
purely gestural, it shows some of these constraints
that you see with the creole languages.
Other features of this that come through,
apparently, there's like 24 different ways that you
can put together objects, and subjects, and rejects,
the participles, and whatever it is, grammatical structures.
This guy, Joseph Greenberg, linguist,
who was here at Stanford until a few years ago when
he died, apparently, incredible titan in the field,
he did some of this research.
There's 24 possible different ways
languages can do this object subject business,
and all across the earth, all across the 6000 languages
there, you only see 15 of them used.
And the vast majority of grammars on earth
only use four of them.
So the argument there winds up being this
is a pretty nonrandom skew.
Again, we're seeing some kind of prepared learning default
grammars, this very imprecise sense of there's
something genetic floating around here.
So that complementary to the whole world
instead of looking at things like FOXP2
and this mutations, the usual two very different approaches.
That whole pidgin to creole transition
is really, really interesting and it really has this feel
in the undercurrents of it that there is a basic human grammar
that floats around there, a notion
that Chomsky has pushed for a long, long time.
Jumping one box further back, ecological factors
I'm going to touch on that only briefly, but what you've got
is something similar to a theme we heard a couple of weeks ago,
which is possibly not something we heard a couple weeks ago
and we'll instead hear on Friday.
But what you see is diverse ecosystems,
very biodiverse ecosystems.
Rain forest ones, for example, produce
cultures which have a great deal of diversity in them.
What we're going to see on Friday,
the version of that, which I'm now
thinking I did mention before, is that polytheistic cultures
are the things you tend to see coming out of rain forest
settings, that notion that if there's hundreds, if there's
a thousand different types of edible plants in your world,
it doesn't take a great leap to decide there's
a whole lot of different spurred things in the world going
Polytheism, a very similar theme,
great work done a few years ago, a guy named William Sutherland
from the University of Dundee, I think, where what he showed
was looking all over the planet, looking
at the biodiversity in different regions
on the planet, the more ecological diversity,
the more linguistic diversity you would find in that region.
The more different languages, which, of course,
thus translates down into small groups, small numbers
of speakers, this is an interesting phenomenon,
which it's not completely clear to me what to make of that.
But ecosystems that are very diverse
generate an abundance of theistic notions
and at above expected rates and also produces
a whole lot more languages, something on the diversity
What his work then showed is about everything else
I'm going to say in this area, which is just
totally depressing stuff, which is linguistic diversity is
going down the tubes faster than biodiversity.
He shows that the rate of language extinction
proportionately is faster than the rate of extinction
of various species, plants, etc.
In these rain forest ecosystems, totally grim,
What seems to be the case, given where things are heading,
is in the next century, in this century,
90% of Earth's languages will go extinct.
The vast majority of humans on this planet
speak less than 10 different languages
out of the 6,000 existing ones.
How's this for depressing?
There's a couple of hundred different languages that
are Inuit, and Northwest Native American,
and some other population as well.
And currently, only of 5% of those languages
have speakers who are not elderly.
That's real depressing.
Also, and something that strikes me as extraordinary
is, in each one of those cases, somewhere along the way,
there's going to be somebody in old age
who's the last person on earth who understands their language.
There's not a single other person alive
who will be able to talk in their mother tongue with them.
Language is disappearing left and right,
along with, of course, cultural diversity
going down the tubes, the process
of turning the whole world into a lowest
common denominator of McDonald's culture, blah, blah.
Along with that comes a huge, huge loss
of language diversity.
Finally, jumping to our last box,
if we're talking about ecological factors,
thinking about things like genes,
thinking about things like highly, highly
driven positive selection for genes like FOXP2
in humans, of course, we have to talk about the evolutionary end
So evolution of language and humans, general notion
is click languages, which you tend to see in hunter gatherers
in Africa, that that might have been the earliest
forms, the most ancient types of languages on Earth.
And what you also see is hunter gatherers are probably
the most ancient sort of populations of humans that
live in Africa, with waves of agriculturalists coming
from North Africa, the Middle East, at later points,
pastoralists coming from around there as well.
The original populations in Africa were hunter gatherers.
And they have high frequencies of these click languages.
That might be the starting point for human language.
Interestingly, though, you also see click languages
among a lot of aboriginal groups in Australia.
What does that tell you?
Those became separately.
There was a huge gulf of time between leaving
Africa and the first populations winding up in Australia,
For some reason, click languages is a very fundamental way
that people come up with communication systems.
So selection issues often run in with
our social biological notions of language advantages,
it's easy to see what the advantages are
of having a language system.
It is easier to store, to archive, knowledge,
It is easier to coordinate hunts.
It is easier to figure out what we did the last time there
was a famine, figuring out things like that, all of those
facilitated by language.
In the memorable words of Steve Pinker from Harvard,
"Language is how we outsmart plants."
Language allows us to do all sorts of organizational stuff.
Language evolution is all about sequence.
We don't say a words simultaneously.
It's all sequences.
And a number of people have emphasized
that's what the construction of tools are about also.
The whole process of careful logical sequential transitions
of steps almost certainly tool use and language use
is sequential processes emerging in parallel.
Finally, obviously, you see all sorts of room for cooperation
with kin selection, cooperation with reciprocal altruism being
enhanced with communication.
But very importantly, for our game theory world,
what language also allows you to do
is lie, that whole business from two days ago.
In human language, there's that arbitrariness.
There's a dissociation between the message and the messenger.
It's not like dogs that have to put
the lid on their fear pheromones by tucking their tale.
What you have is the capacity to lie.
And, of course, running off from that, a whole world
of evolutionary strategizing.
Pertinent to that, there's a huge, huge disproportionate
share of neurons in the motor system devoted
to facial expressions, and mouth coordination,
and all that kind of world.
A really good thing if you plan to lie
is to be able to have good control
over your facial expressions.
Finally, formal game theory models
showing when you have pairs of individuals playing
against each other, when you introduce,
when you allow the emergence of communication
between two of the players versus not
in the other group, you immediately, no surprise,
have been getting a big advantage.
If you allow them semanticity, to have words
that they can communicate, that is advantageous,
that improves outcome.
Even better is if you allow semanticity and structure,
syntax, grammar, so that they can have
more complex communication.
All of those wind up being things
that facilitate winning in game theory settings.
Finally, interesting parallelism,
back to that biodiversity stuff, which
is, when you look at all those different possible grammatical
structures, the 24 of them, 15 of which
is the total of what appears on Earth,
the rarest of the grammatical structures
are the ones that are closest to extinction.
The rarest not in terms of the number of people
speaking it within a population, but the structures
that have occurred the fewest number of times in cultures
across the planet are the ones that
are in cultures where the languages are
most readily to be a lost, some sort of connection there.
And thus, you've got some sort of
weird grammatical imperialism that
has emerged over the years.
Again, what strikes me as a totally depressing number,
90% of Earth's languages will disappear in the next century.
So now we jump.
We jump to our next topic, which was
our first psychiatric disease.
And to remind you from two days ago,
we're not going to have a depression lecture.
The depression chapter in the zebra's book
will tell all the same stuff in much better, more clear terms,
I say, proving my point.
And what you should do is read it with as much attention
to it as if it has been a lecture subject.
It is an important subject, enough hints.
So check that one out.
What we focus on today though is schizophrenia.
And we're going to take our same old strategy,
starting off with what is the disease look like.
And as you will see, all sorts of surprises in there,
and then what goes on in the brain
just before early development, prenatal, genes, evolution,
the whole deal there.
We know this drill once again.
So starting off, making sense of schizophrenia,
as a bunch of behaviorists, you've
got a challenge right off the bat, which
is lots of people use the word schizophrenic in an every day
sense that has no resemblance whatsoever
to its actual technical use.
Schizophrenic, or schizian-- we all know that one.
We've thought, my God, I am having such a schizi day.
I overslept, I missed my first class, it was terrible.
I totally screwed up, but then I found out
I got this great grade on a midterm,
but then I had this fight with a friend,
but then in the afternoon, and then this crashed,
and, blah, blah.
God, what a schizoid day I'm having.
No resemblance to how the term's actually used.
That's not any sort of real term in psychiatry.
Whatever the schizi days are that we all
experience now and then, schizophrenia
is something else.
On the most technical level, schizophrenia
is a disease of people where, when you start talking to them,
within two or three sentences, you
realize there's something strange with their thinking.
They're not thinking normally.
They're not communicating normally.
On the most fundamental level, that's what the disease is.
Obviously, far more precise than that, schizophrenia,
disease of thought disorder, disease
of inappropriate emotion, disease
of inappropriate attribution of things, and what you'll see
is this is not just some sort of generic craziness in the way
that that word means nothing whatsoever.
There are typical structures to the ways in which things
are not working right in the behavior of schizophrenics,
which we'll hear about in a bit.
Part of what begins to bring that across
is the obvious fact that there's no way
that schizophrenia is just one disease,
because there's all sorts of subtypes.
It is a bunch of heterogeneous diseases.
You have a subtype paranoid schizophrenia,
where what it's all about is thought disorder built
around a sense of persecution.
You have catatonic schizophrenia,
where the person is in a frozen state,
immobile for long periods of time.
You have schizoaffective disorders,
which is kind of a mixture of schizophrenia and depression
It's not just one disease.
So the whole array of behavioral symptoms
we're going to look at now, remember, some of them
are more common in different subtypes than others.
This is just the first broad overpass.
So beginning to make sense of the disease, what
it is, above all else, is a disease
of cognitive abnormalities, of abnormal sequential thought.
And the term that's given for it is loose associations.
All of us can tell a story where we have a pretty good ability
to put it sequentially and have the facts go in a way
where it will make sense to any other listener.
You do not see this in schizophrenics.
Sequential thinking is greatly impaired.
And instead of having logical sequences of information
that they give, things tangent all over the place,
bouncing around all over, where, in retrospect, you
can kind of see how they might have gotten
from A to Z, although most people would have gone
from A to B at that point, the tangential thinking
being another term for it, the loose associations.
So what do you wind up seeing there?
You get schizophrenics, for example,
who get terribly confused in a sentence,
whether when they are hearing about boxers,
they are unable to keep straight within one sentence
to separate out whether they're talking about a dog
or they're talking about an occupation.
Because they slip back and forth between the two.
Confusion between being a caddy, a caddy,
someone who a golf whatever, and a Cadillac, short term
All sorts of ways in which they can't hold on
to the sequential logic.
And, instead, there's just this tangenting,
getting caught up in the loose associations.
You're talking about a boxer, if you were a schizophrenic,
you were talking about a particular boxer,
you follow that sport whatever, and, suddenly,
you are expressing an opinion about how
that person would do in a ring against a St. Bernard.
And you're often talking about dogs
from there, just getting caught by a loose association
between the sound of the word and its multiple meanings,
going off the tracks on that, so the loose associations.
Next, you have a trouble, consistent one,
All of us have a pretty good intuitive sense,
when someone is telling us a story,
is this meant to be literal reporting of events
in a sequential way, is this meant to be a parable,
is this meant to be a somewhat secondhand,
through the grapevine story.
We have a very good sense of how concrete
or how abstract the information that we're getting is.
Schizophrenics are terrible at that.
They have no intuition to get the right level of abstraction.
And schizophrenics always skew in the same direction,
which is to interpret things far more concretely
than is actually the case.
And that's the term that's used in the business, concreteness
of thought, which is having a lot of trouble doing the more
abstract process of seeing things
on a metaphorical level, things of that sort.
So here, here's the standard sort of test
you would give to someone if you think they're schizophrenic.
You give them an association task.
And you say something like, OK, can you
tell me what do these things have
in common, an apple, an orange, and a banana.
And they'll say all of them are multi-syllabic words.
You'll say, OK, well, that's great, that's true.
But anything else they have in common?
All of them have letters that involved closed loops, just
getting caught up in the most concrete possible level
of interpretations of it, not able to step back and do
any sort of abstracting.
You see this in all sorts of other ways.
Therapist role, meet the patient and say something like so
what's on your mind today, and they'll
say my hair in this very literal sort of way.
Or you'll say can I take your picture, holding a camera,
and they'll say, I don't have a picture to give you,
this very literal sense again.
Or things like you would sit down a schizophrenic
with a piece of paper and a pen and say, just
as part of what we're doing here,
can you write a sentence for me, any sentence.
And then you look at what they've
written which is a sentence for me, any sentence.
And then you say, no, no, no, actually, that's
not what I mean.
I mean can you come up with a sentence.
And when you've thought of that sentence, write it.
And they'll write the word it because they can't get out
of the concreteness of saying could you write a sentence, can
you write colon a sentence.
They're caught up in the concrete level of that.
A way that that always pops up, one
of the classic types of tests that's done,
is called proverb tests.
Proverbs, by definition, they are metaphorical.
They are parables, they are abstract.
And we all know intuitively that when
you're talking about birds of a feather flock together,
you're doing something symbolic about the well-known homogamy
of lips with people who they choose to marry
and the similarities.
Yes, birds of a feather flock together,
it's talking about like tend to assort with like.
Give proverbs to schizophrenics and they
can't get out of the most concrete level
of interpretation of it.
So you're sitting down and you say, OK, tell me
what this means.
A rolling stone gathers no moss.
And we all know that that's people are on the move,
don't make an emotional connections,
there is a detachment.
And they're often saying stones, stones rolling down hills,
it's very hard for plants to grow on them.
It's very hard because the surface tends to be smooth.
And then on top of it, if it's rolling,
you've got like this angular motion that move to it.
So it's very hard for moss to grow on stones.
In fact, I don't think I've ever seen that happen.
And I've seen many stones.
And on the most concrete possible level,
incapable of pulling it back to the level of abstraction.
Consistent, consistent feature of this.
Here, friend of mine who's a psychiatrist
came up with what has to be one of the all-time great proverb
tests for figuring out if someone
has the remotest tendency towards schizophrenic
There was a abstract phrase, a proverb,
that was very popular, that was very prevalent in the United
States during World War II.
It was up on posters and all the post offices, places like that.
And it was a way of abstractly telling people be careful
the information you put in letters that you are sending
off to loved ones who are off at war
because it may inadvertently wind up in the wrong hands
and could carry information that could be extremely damaging
to the war effort.
Do people know what it is?
Loose lips sink ships, loose lips sink ships,
wonderfully abstract notion.
Try sitting down a schizophrenic and saying
what does it mean when you say loose lips sink ships.
And, suddenly, there's this imagery
of ships being capsized by big lips coming out
of the water and things of that sort
because it can only be dealt with on the very
More symptomatology, delusions, belief in things that cannot
be, belief in having participated in historical
events that cannot be.
You're sitting there interviewing a schizophrenic
and they suddenly say have you heard
of the Great Wall of China.
And you will say, well, yes, in fact, I have.
And they'll say my idea, my idea.
The generals came to me at night with a map
and I said this is where it goes.
This is probably not what happened.
Delusional thought, inserting yourself,
conversations with people who no longer exist.
Related to that is the paranoia, which,
of course, is most florid in paranoid schizophrenia,
but it is a frequent theme.
What do apples, oranges, and bananas have in common?
They're all wired for sound.
If the fruit is listening to you,
this makes for a rather disquieting life.
And almost certainly, it has something
to do with if the world is making so little sense to you,
it is a world that is very threatening.
Along with that, most famously, perhaps,
with schizophrenia, is you get hallucinations.
Those are the defining features.
Somebody is trying to figure out if somebody in an emergency
room has come in with some sort of schizophrenic type disorder
and hear that the person is hearing voices
and that pretty much nails down the diagnosis.
For reasons that are very poorly understood,
the vast majority of hallucinations are auditory.
However, there's all sorts of notions with that.
And one great theory coming from our own Patrick House, given
two years ago, which is you get auditory hallucinations more
often than visual ones because we're
more accustomed to visual stuff in the world
having fragmented visions or seeing it across two mirrors,
reflections, things of that sort.
We are more vulnerable towards sounds not making sense.
Vast majority of hallucinations in schizophrenia
are auditory hallucinations.
When we see in a little while what the neurochemistry is
of hallucinations, by all logic, what they should be
is just random splatters of noise, and random visual dots,
and all of that.
Instead, they're structured.
They have content.
People hear voices, rather than random sound.
People see very structured hallucinations,
sufficiently so that researchers can even do studies
as to which are the most common voices heard by schizophrenics.
And, no surprise, in Western cultures,
forever and ever, the number one voice on the hit parade
is that of Jesus, the number two voice, Satan, the number three,
typically, whoever is the head of state
in the country at that point.
It's structure to that extent that you can publish papers
about what the hallucinations are like.
There's all sorts of structure underneath.
It is not just disordered thought,
it's loose associations, and tangenting,
and concreteness, and structured hallucinations.
Another feature of the schizophrenic symptoms
is social withdrawal.
And schizophrenia, everybody thinks
of as a disease of abnormal thought,
it is a disease of abnormal social affiliation.
You look at a-- you look at a schizophrenic
in some village in who knows where in the Amazon,
or in Bloomington, Indiana, and this is going to be someone who
is somewhat ostracized and socially disconnected, very
It is not just the disease of disordered thought.
More and more people are realizing
the core with schizophrenia is the disordered thought.
The standard view has always been
to hone in on the most florid feature of the disease.
Schizophrenia is the disease where you hallucinate,
where you hear voices.
And the vast majority of the neuropharmacology research
that's been done out there on the disease
is meant to go and cure the hallucinations.
But far less responsive to any of the drugs
are the tangenting thought, the concreteness,
the loose associations.
More and more people are thinking
that that's really at the core of what the disease is about.
Couple more features of it, which
is the whole world of the social withdrawal.
Apathy, what we're beginning to see
is a dichotomy in the business, positive symptoms
in schizophrenia, paranoia, loose thoughts hallucination,
all of that.
Negative symptoms of schizophrenia,
the absence of social connectedness,
the absence of affect, a very flat expressive style.
Physiologically, you see some damping
of autonomic nervous systems in schizophrenics, so the positive
and the negative symptoms of the disease.
Last a couple of features of it, one is the notion
that, of course, schizophrenia has
something to do with violence.
Everybody knows that there is the scenario lurking out there
that occurs endless number of times which
is you have some psychiatrically unstable individual turning out
to have schizophrenia who winds up doing something
horribly violent, the danger of schizophrenics cracking
and going postal.
And every now and then, something like that happens.
20 years ago, there was a horrifying incident
A student there who was schizophrenic and probably
should not have been there at the point because he was not
well-medicated, something cracked and he
took a bunch of Berkeley students,
women, hostage in a bar at Berkeley,
did all sorts of horrific sexually abusive things there
before he killed himself after killing a few of them.
This is what happens when something like that
occurs with a schizophrenic.
Oh, my God, so we've got all these people
running around where that could be happening any second.
Schizophrenics are far less dangerous
than are normal individuals in society.
The rates of violence are extremely low,
with one exception, which is schizophrenics
being violent and damaging themselves.
Self-injury, a huge feature of schizophrenia,
part of the delusions, part of the thought disorder,
part of the despair, when every now and then your head
clears enough to see what the rest of it is like.
And there are even studies as to which
are the most popular places in the body that are mutilated
Genitals are top on the list, and going down from there.
Horrific thing that happened, also about 20 years ago,
Columbia Medical School, and this
was an individual, a student there,
with a history of a lot of psychiatric instability,
and schizophrenia, and somewhat well-controlled with meds.
And somewhere in the third year when
starting the clinical rotations, the various stressors of it,
the person kind of unravelled.
Probably should not have been there in the first place,
but, nonetheless, had a schizophrenic break
and had withdrawn from med school and was sitting at home.
Part of his paranoia, part of his delusions
were that he was satanically possessed.
And, specifically, the way Satan was driving him to madness
was with obsessive sexual thoughts.
So being a relatively well-trained endocrinologist,
because we know better than him at this point how it works,
he decides how do I make those thoughts go away,
let me get rid of my testosterone.
So he castrated himself.
But at least being well-trained in one domain of endocrinology,
he knew that other fact we've had
in here which is that the adrenal glands also
make a certain degree of testosterone.
And he proceeded to try to adrenalectomize himself.
He sterilized with some alcohol.
He made an incision with anesthetic.
He had a mirror there, angled to be
able to see what he was doing.
And at one point, he hit a blood vessel, which started bleeding.
And he went to the ER at Columbia Presbyterian,
going in there, not saying to his former classmates,
oh, my God, guys, can you help me, look what I've done.
Saying instead, hi, guys, I'm trying to take out my adrenals
and I'm having a problem here with it,
can you give me a hand.
This is very disordered thought.
This is a very elegant version of it
schizophrenic self-injury, schizophrenic suicide,
is anything but clean.
Number one on the list, genitals, number two
for women, female schizophrenics, breasts, number
three, thighs, on it goes.
This brings up another feature of the disease, which
is, back in the 1960s, when all sorts of laudable things
happened along certain cultural lines,
there amid that was one horrifically
damaging idiotic thing that emerged
in psychiatry at the time, which was a minority
view in psychiatry, a lunatic fringe view,
that, basically, schizophrenia is not so bad.
Schizophrenia has all sorts of hidden blessings.
And soon, it had frameworks of things
like schizophrenia is the disease of being
healthy in a crazy world.
Schizophrenia is the disease of having insights into life that
other people can't.
And psychiatrists at the time, one of them,
a man named Ronald Laing, who became famous
for this, for arguing it's not a disease,
we shouldn't be medicating, we shouldn't be hospitalizing,
it's a bunch of blessings.
And it is even continued to this day.
The quote that I put on the top of the handout, Andrew
Wild, who is one of the gurus of sort of complementary medicine,
and you'll see an absolutely ridiculous statement
there along the lines of the hidden blessings
There were movies at that time, King of Hearts
was one, very popular one about somebody having
to hide from the police or who knows what, and the asylum,
and eventually releasing the schizophrenics who
were so much saner than the other people around,
And all you need to do is be schizophrenic or know someone
who is or have a family member and you will see
there are no hidden blessings.
This is not a disease of hidden compensations
and more insight into the world.
This is one of the most horrific ways that biology can go wrong.
And one of the best demonstrations of it
is half of schizophrenics attempt suicide.
And the more often you have periods of remission,
the more likely you are to commit suicide.
What's the significance of that?
The more often you have periods where
you're clear-headed enough to see what your life is
like the rest of the time, the more likely
you are to try to kill yourself.
A disease with no hidden blessings whatsoever.
Other features of it, there's an aging component,
two different forms.
First one is as schizophrenics become older, elderly,
what you see is the positive symptoms tend to disappear.
The hallucinations get damp, the delusions,
the loose associations, and the negative symptomatology
is what comes to the forefront, this world of just flat affect
The other age feature of it we will hear about it
in a bit, which is real defining, which
is schizophrenia is a disease where,
in the vast majority of the sufferers,
it has late adolescence, early adulthood onset.
It is a disease of 18 year olds who
come down with a diagnosis for the first time.
If you make it to age 30 without schizophrenia,
you have virtually no chance of ever having it.
It is a disease of adolescent onset.
And this is going to fit with two
things we'll be talking about.
One is the epidemiological evidence
showing that what schizophrenic attacks-- what
schizophrenic breaks typically are at the very beginning
are in response to major stressors.
These are individuals who have always
been a little bit odd, who, in elementary school,
had imaginary playmates far later than most other kids did,
who had all sorts of periods where they seemed
not to be paying attention and lost in their own thoughts, who
had trouble making friends, but they were OK.
They were sort of hanging on.
And then it was late in high school
when they had the car accident, or the first boyfriend was
so horrible to them, or the parent died,
or whatever the crisis was, and this person who was just
sort of holding on, that's where the dip occurs,
and that's where it crashes.
Schizophrenia as an adolescent onset disease
where stress plays a major precipitating role.
The other piece that we'll see is the fact
that schizophrenia almost certainly is heavily
anchored in the frontal cortex.
Frontal cortex, you remember the frontal cortex.
Frontal cortex, which is not fully mature
until age 25 or so, the last big burst of frontal maturation,
late adolescence or early adulthood,
we'll see there's lots of reasons
to think that schizophrenia is a disease where,
around late adolescence, a fragile, vulnerable
frontal cortex gets kicked once too hard with something
And that's one where the problems emerge.
A couple of other features, demography
in every culture ever looked at on Earth, 1% to 2%
of the population comes down with it,
no gender differences, no social economic status
differences in terms of who becomes a friend.
But once you are, there is the not very surprising
downward socioeconomic spiral, which
is, no surprise, people who are schizophrenic
do not make very good CEOs of large corporations.
These are the street people.
These are the homeless.
The majority of people living on streets in this country
are individuals who are schizophrenic, not alcoholic.
That is the far more common thing that you see.
So a disease of complete collapse into some of the least
cared for sort of strata of society, that is part
of the demographics as well.
So that's what the disease looks like.
And if you're really thinking about these symptoms,
at this point, you should be jumping out
of your chair because of something
really disturbing about this collection of symptoms.
So what is schizophrenia?
It's a disease of thinking abnormally.
This is a disease of thinking differently from everyone else.
This is a disease of thinking, in a way, that everyone
else thinks isn't right.
And, suddenly, we are skating on thin ice of this transitioning
from a world of neuropsychiatric disorders and medicine
into a world of all sorts of hidden agendas of abuse.
And psychiatry has been hand in hand
in bed with all sorts of ideologues over the decades,
over the years, and willing to hand out diagnoses
of schizophrenia to political dissidents,
to people you want to get rid of.
And this is a totally loaded, loaded diagnosis,
when, most fundamentally, this is
a disease of everybody else thinks
you're not thinking normally.
Because, some of the time, that describes
a florid psychiatric disease that destroys your life.
And some of the time, it describes people
who are just a pain in the ass.
And some of the time, it describes
people who are going to transform the world by thinking
How can you possibly approach this disease
in an objective way rather than it having just
shot through with ideology?
And one of the ways in which this can happen,
one of the ways where you get some grounding in it
is to look at what the disease appears like in other cultures,
because you begin to see the commonalities.
And this begins to impress you with the notion
that there is, in fact, a core set of dysfunctions
to the disease.
So let me tell you about the one case
of cross-cultural schizophrenia I have ever been exposed to.
And I was going to bring slides, but I couldn't quite
figure out how to scan them.
So maybe eight years from now, I'll
get together for that technology.
But it has to do with the time I spent in Africa and my nearest
Nearest neighbors there are from a tribe called the Maasai.
These are nomadic pastoralists.
And these are not the folks next door.
This is as different of a culture
as you could find on this planet.
Men, around puberty, boys around puberty
become warriors, spend the next 10 years in their warrior
clans, as we've heard about, pillaging the neighbors,
getting killed in return around age 25.
As elders, they settle down and marry their first wife,
typically a 13 year old.
And, well, as soon as they can, add on more.
This is a culture with, up until recently,
a life expectancy in the 30s.
This is a culture where people believe in all sorts of things
that we would view as being paranormal.
This is a culture in which people celebrate events
by drinking tureens of cow blood.
This is a very different bunch of folks.
Let me tell you about the one schizophrenic
Maasai who I've ever seen.
And this was about 25 years ago.
And I was in my camp, which was a few miles away from this one
village where I knew a lot of folks,
and just sitting there minding my own business.
And I had this one woman in there
who was my-- closest friend or whatever in the village.
And I suddenly see she is running up
the mountain with a bunch of the other women
from the village in this completely agitated state.
They come roaring into my camp, totally flummoxed and just
like completely agitated.
These are people who do not get agitated over things very
These are people who, as a puberty right,
have to go out and kill a lion or don't come back.
So when Maasai are getting all crazed about something,
this is something worth paying attention to.
They're totally crazed and they're saying somebody
in the village has done something very wrong
and I need to come and help them.
It turns out what they wanted me to do was bring my car.
That's the way in which I was going to be helpful.
So they impressed me into doing this.
And we all pile into the car and started
driving down and heading towards the village.
And as we're getting there, I'm beginning
to get some information.
And what I see is them telling me
about a woman in the village who's
done something wildly inappropriate
and they've had it with her.
Now, I had been around that area for about four years,
at that point, knew most of the people in that village.
And this was someone who I had never encountered.
A-ha, socially isolated, living in the back of some hut
at the far corner of the village, a first sort of hint.
So they're describing to me that she has
done something inappropriate.
She has killed a goat.
You don't do that.
You don't do that if you are a woman.
You don't do that if it is not a ceremony.
You don't do it the way she has done it.
She has grabbed somebody's goat and ripped
its throat open with her teeth and was now there with a goat.
And everybody had had it with her.
So we're driving there and I'm listening to this,
and I'm saying, whoa, this sounds like a psychotic break.
This is going to be cool.
This is going to be really interesting.
I wonder what it'll be like to talk to the family
and find out what the symptoms have been.
Or I wonder if she's going to have any insight.
It's going to be fascinating to talk to her about this.
So I get into the village, and this person
I was now planning to have some good heart to hearts with about
their tangential thinking, out comes this huge naked woman
with a goat in her mouth by the throat, covered in goat blood,
and goat urine, and goat shit.
And this woman gives this howling yell, charges
across the village, knocks me over, and attempts
to strangle me.
I'm a normal kind of guy, normal fantasy life.
Never once in the darkest recesses of my mind
did this strike me as something that was appealing.
I'm lying there, she's throttling me.
I'm thinking this is how I'm going to wind up dying.
My poor parents are going to have
to deal with the stigma of this for the rest of their lives,
that this is-- he's done in by someone
with a goat in her mouth, and thinking that.
So, fortunately, everybody else was much more clear-headed
and they pull her off me.
And what they proceed to do is push her into my Jeep.
And they pile on top of her and they say let's go.
So I collect myself and leap in and we head off driving there.
And this woman was floridly out of control of there.
But we're driving somewhere.
Where are we driving?
We're driving to the nearest government clinic, which
was about 25 miles away and consisted
of a wood shack and a nurse there,
a government nurse, who as a result of this three
weeks of training, gave out malarial medication
for anything you came to complain about.
And what they were going to do was
they wanted to get rid of her.
So we go driving and we eventually get to this clinic.
Well, what they proceed to do is push her into the hut
and hammer the door closed.
So I'm sitting there, at this point,
saying, OK, well, we've containment.
So what do we now?
Do we-- do we talk to her?
Does the nurse talk to-- do we go and get the family?
What are you-- so I turned to my friends
there and say so what do we do now.
And they say let's get the hell out of here,
showing an important thing.
Even in a culture as different from ours,
nobody has a whole lot of tolerance for the mentally ill.
Let's get out of here.
So they persuade me to go.
We get into the vehicle and start the long drive back.
After a while, the car's aired out a bit
and everybody's calming down a bit.
And I decide this was wonderful.
What a marvelous opportunity to learn
about some cross-cultural psychiatry or whatever.
So I turned to my friend who's sitting next to me there
and I say so what do you think was wrong with that woman.
And she looks at me as I'm an idiot.
She says she's crazy.
And I said, well, how do you know.
How do you know?
And she said she hears voices.
And I say, ha, you guys hear voices.
Maasai hear voices, they do trance dancing
before they do sort of these around the clock cattle runs.
They hear voices of ghosts, that sort of thing.
I say to her what's the big deal, you hear voices.
And she says, no, no, no, it's different.
Then I say, well, what else was she doing wrong.
And she says she killed a goat.
And I say you guys kill goats.
But, again, this wasn't how it's done.
There is an old longstanding belief among Maasai men
that it is very bad luck to have women observe eating meat,
so they get to go off on their own and eat all the goat meat.
And it's done in a certain ritualized way.
You do not kill a goat if you are a woman,
if you are a naked, yelling banshee
of a woman in the middle of the village with your bare hands
You don't do this.
So I'm sitting there and I'm saying, well,
do you know this-- it's kind of hard for me
to tell the difference here.
And she says, in the sense, idiot,
she hears voices at the wrong time.
And that's the core, ultimately, of the objectivity
that's needed in this disease.
In order to understand what counts as abnormal thought,
you first have the huge challenge
of understanding all the different ways
that normal thought can manifest itself.
And that is a classic problem in training psychiatrists sitting
in some inner city clinic recognizing
that the amount of cultural variety there,
or the different ways in which you can be normal,
is extraordinary and extraordinarily challenging
You are on very thin ice deciding
you know what counts as abnormal thinking
before you have a very wide sense
of what can count as normal.
So now let's take a five minute break.
And all sorts of very accomplished artists
over the years who've turned out to be schizophrenic.
And schizophrenia is not what made their creativity possible,
schizophrenia is what destroyed their careers.
Other question is so what happened to that woman.
And this was shortly before I was coming back to the states.
And it was about nine months later that I went back there.
And some point, when seeing my friend,
saying whatever happened to that woman.
And her response was, oh, she died.
Maasai do not like to stay indoors, she died.
That's all I ever found out, once again,
as different to the culture on Earth as you can imagine.
And they are no more tolerant of the mentally ill than we are.
So now, beginning the neurochemistry of it,
what's going on in the brain, what's
going on with brain chemistry?
And for decades and decades, there
has been one dominant model for schizophrenia, which
is the dopamine hypothesis, the notion that somewhere
in the brain, stay tuned, there is
an excess of dopamine winding up in the synapses.
What's the evidence for it?
First off, you do things like look
at levels of dopamine breakdown products in the bloodstream,
in the urine, in the cerebral spinal fluid,
tending to be elevated in schizophrenics.
Next, what you see is the most important fact
which is all of the classic drugs that
work with schizophrenia block dopamine receptors.
Anti-psychotic drugs, neuroleptics,
Haldol, Thorazine, when, at some exciting moment
in the made for TV movie, where the person has gone mad
in the ER and someone yells for a syringe,
they're yelling for a syringe of something that will
block the dopamine receptors.
If you give schizophrenics dopamine or some drug that
activates dopamine receptors, their symptoms
get worse, which kind of makes you wonder who
approved that kind of study.
That doesn't sound very logical.
You look post-mortem at the brains of schizophrenics
and there's elevated levels of dopamine receptors
in the frontal cortex.
So we have a whole bunch of ways that things can go wrong.
We can have too much dopamine coming out,
for some reason or other.
We can have too many dopamine receptors,
We know another possible way, which is dopamine
is then broken down by this is enzyme.
And if this enzyme isn't working very well,
levels are going to accumulate.
And there's a bit of evidence of abnormalities
of this enzyme in some individuals.
So one additional interesting piece
of evidence for this dopamine hypothesis,
which seemed absolutely clear by now,
you have somebody who's schizophrenic,
you give them a drug that blocks dopamine receptors
and thus decreases the dopaminergic signaling,
and they start getting better.
What's your hypothesis have to be?
I bet you they had too much dopamine.
This is shown in another interesting way.
18 counties over in the brain from where
dopamine's got something to do with this,
dopamine serves another role.
In a motor system related to the basal ganglia, all
of that, involved in fine motor control, a part of the brain
called the substantia nigra.
And if you get a little bit of damage there,
I think I mentioned a couple extras ago,
you get the tremor of old age.
If you get a lot of damage there,
you got yourself Parkinson's disease.
And what occurs in Parkinson's is
90% of the neurons in the substantia nigra die.
And people are even beginning to understand why.
These are dopaminergic neurons.
Parkinson's is a disease of losing all the dopamine
signaling in this part of the brain.
People began to figure this out in the early '60s.
And out of that came one of the first drug treatments
for any neurological disease.
What's the strategy?
These are people who have too little
dopamine in this part of the brain.
Give them replacement dopamine.
Turns out it's hard to get dopamine in the brain,
so you would give people one step earlier
in the biosynthesis a drug called L-DOPA.
L-DOPA, which then gets converted into dopamine,
and this was miraculous.
All sorts of people who were just
paralysed with their Parkinson's, L-DOPE
suddenly liberated them.
There's a movie 15 years ago or so,
called Awakenings with Robin Williams,
which was based on a book by Oliver Sacks,
based on his own work, which had to do
with this rare disease that emerged after World War I,
having something to do with the influenza pandemic, then
a post-encephalitic paralysis, which became
known as stiff man syndrome.
And people who were essentially frozen in place,
and what we now know is it's an autoimmune disorder that
targets something with the dopamine system.
Sacks was a medical resident at the time, was-- at that point,
the L-DOPA stuff was just coming out with Parkinson's.
And Sacks was the one who had the insight
to say I bet the stiff man syndrome is
a case of the most extreme severe Parkinson's that you
could possibly get.
And, thus, he was the first one to try L-DOPA on people
with the syndrome, and thus you had miraculous awakenings,
people moving voluntarily for the first time in decades,
But then, you have a downside.
And the downside that we know sort
of the structure of by now, you've
got a problem with dopamine in the substantia nigra,
lower than normal levels.
Everywhere else in the brain, you've got normal levels.
So you're trying to fix up this depletion,
you give the person L-DOPA.
But you're not spritzing it into their substantia nigra,
you're putting it in their stomach or their bloodstream.
You are raising dopamine levels in the substantia nigra
and things get better, but you're also raising it
everywhere else in the brain.
And what you wind up seeing is if you give a Parkinsonian
patient too much L-DOPA, they become psychotic.
They are indistinguishable from a schizophrenic.
And what was shown in the movie was this character
played by Robert De Niro wound up
having this florid paranoid psychosis from the L-DOPA,
so, oh, that being more evidence,
you give a drug that raises dopamine levels
throughout the brain and somebody
starts acting schizophrenic.
You give somebody a drug that causes very rapid dumping
of dopamine, and they will transiently
What's the drug?
That's what amphetamines do.
And you get somebody coming to an ER who is loose associations
and hallucinating delusions and all of that,
and most clinicians cannot tell whether this was somebody with
an amphetamine psychosis or schizophrenia.
Pump their stomach out.
If they suddenly start making more sense,
it was probably the amphetamines.
So this being more evidence.
Now, you should be thinking what about the flip side.
So you have schizophrenics, where you give them
these neuroleptic drugs to block dopamine receptors
in the frontal cortex, as it turns out.
But you're not injecting it straight in there,
you're putting in the guts.
And, now, you've got too much dopamine here.
You lower its levels, but everywhere else it
gets a little lower than normal-- not dopamine levels,
but dopamine signaling.
And, suddenly, you should generate this prediction
that if you over medicate schizophrenics,
they should start looking as if they have Parkinson's disease.
And that's exactly what you see as well,
a disorder called tardive dyskinesia, kinetics,
body movement dyskinesia, abnormal one.
And these are individuals who look Parkinsonian.
Go into a state hospital, go into the back ward,
and find somebody sitting there who
is tremoring like this all over their body the entire time.
And that's somebody who was going
to have been taking these drugs for 20, 25 years or so.
So, collectively, this winds up telling you
all these different ways of suggesting the problem
is that there is too much dopamine in this disease.
However, just to make life miserable,
there is at least one anti-schizophrenic drug
out there which what it does is it increases dopamine signaling
and people get better.
Bummer, nobody knows what to make of this at this point.
So what's the excess dopamine doing in there?
It's not having anything to do with movement stuff.
That's substantia nigra.
It's not having anything to do with pleasure.
That's dopamine in different parts of the brain.
The best evidence is this is dopamine
functioning in the frontal cortex,
stimulating normal executive function.
And what you've got is a frontal cortex
that is not making a whole lot of sense.
Loose associations, that seems to be
where the dopamine problem is played out.
Next neurotransmitter that's been implicated,
serotonin, look at the chemical structure of serotonin,
and then look at the chemical structure of all
of the major hallucinogens, LSD, mescaline, psilocybin,
they are all structurally almost identical.
And all of those hallucinogens fit into serotonin receptors
and activate them.
What is a hallucination induced by a drug?
You've got some serotonin synapse
where nothing's happening.
The pre-synaptic neuron hasn't had
anything interesting to say in weeks,
it hasn't released any serotonin.
But, now, there's something that kind of looks like serotonin
percolating its way into the synapse, where it could then
bind to the serotonin receptors.
And as far as this neuron thinks,
it just got a message from there.
And it didn't come from there.
This neuron is hearing voices.
And the fact that that's how the hallucinogens work immediately
generated all sorts of hypotheses
that there are abnormalities in serotonin in schizophrenia
as well having something to do with the hallucinations.
Next, the neurotransmitter glutamate
has also been implicated.
What's the evidence there?
When you take a drug that wildly stimulates
one subtype of glutamate receptor,
you begin to look a bit like a schizophrenic.
What's the drug?
PCP, angel dust, phencyclidine.
That stimulates a subtype of glutamate receptors.
And a lot of people have argued this
has enough resemblance to what schizophrenia looks like
that there has to be a glutamate problem going on
in the disease.
Very, very little bits of evidence
for that, the one thing that has been shown in rats
is when you stimulate the brain with PCP,
what you get is an increased levels of receptors
for serotonin in some interesting parts of the brain,
some kind of connection running around there.
So very, very solid implication of dopamine, some serotonin
thrown in there, glutamate, eleventy other
neurotransmitters that people are thinking about,
but these are the main ones.
And, overwhelmingly, the dominant hypothesis
remains the dopamine hypothesis.
What about brain metabolism?
What's going on in the brain, for example,
during a hallucination?
And what you essentially get is wild activation
of everywhere in the brain and you are hallucinating.
You get wild activation, people who are in imaging studies
have taken these drugs voluntarily,
you get wild activation in the cortex,
except for, say, the first couple
layers of the visual cortex, or the first couple of layers
of the auditory cortex.
What's that about?
The cortex is seeing things and hearing things
that did not come in from the outside world, that
never stimulated the primary sensory cortex.
Otherwise, during hallucinations,
you see extremely high levels of metabolism
throughout the brain.
The next interesting thing in that realm,
you give schizophrenics some standard declarative
memory tasks and metabolism in the hippocampus
does not increase as much as in other individuals.
So that brings us to structural features of the disease.
Does the brain-- while hallucinating,
does the brain work somewhat like when dreaming?
Does the brain, in terms of patterns of activation,
look somewhat like during dreaming?
It's not the primary sensory cortex regions that activate.
Frontal cortex is relatively quiet.
And the rest of the brain is going like mad,
and certainly makes sense.
So structural stuff, there's all sorts
of structural abnormalities in the brains of schizophrenics.
How do you learn this though?
Very difficult, because, for the first couple of decades
in the field, it was all post-mortem analysis, which
is you take out the brain of a schizophrenic
and you go and look at it, and you
see if there's anything weird.
So what's the problems with that?
All sorts of things, which is to try
to do post-mortem studies on human brains, different brain
sit for different lengths of time
before they're autopsied and removed.
So that's a huge piece of variability.
Moreover, you can get post-mortem artifacts,
which is to say you're pulling out
the brain and somebody squeezes it too hard
and squishes something in here and it's not
going to look normal afterward, reflecting the handling of it.
And out of that has come this whole world
of neuropsychiatry types were what they
live for are rapid autopsies.
And a whole bunch of medical centers
have rapid autopsy teams connected
with their Alzheimer's folk, connected
with some of the psychiatric diseases,
where their idea is to get in there as fast
as possible with patients who have
or whose family have given permission for that
and get the brain out as fast as you can.
And I remember, a few years ago, I
was down to Duke Medical Center, and they
had one of these rapid autopsy SWAT teams.
And they were bragging about how they were getting brains out
in under 30 minutes from death.
So that solves a whole lot of the post-mortem rotting
away lag time.
So all of those wind up being problems.
More confounds, very often you're
trying to understand the brains of schizophrenics who have died
who are older, who are elderly.
And the confound there is schizophrenics
have horrible diets.
You are seeing perhaps the brain consequences
of malnutrition all those years, rather than seeing
the consequences of the disease itself.
Another problem that you've got is you get someone
who's schizophrenic, and, almost certainly,
what they have been doing for a long time is taking
drugs for their schizophrenia.
And if you see something different in the brain,
maybe it's due to the schizophrenia
or maybe it's due to the effect of the drugs.
And what that has generated is the other thing
that people in this business kill for, which
is unmedicated schizophrenics.
And researchers love these people,
they can't get enough of them.
This is the teenager who is brought
in for the first diagnosis.
And the family is no doubt thinking finally we're
going to get some help.
And all the researcher physician there is thinking
is they want to centrifuge this kid
and do research and find that out,
getting unmedicated schizophrenics.
Finally, a big boon in the field has been brain imaging.
So instead of trying to figure out the normal size of things
after you've taken the brain out,
you could image the brain in situ,
while the person is still alive.
So given all of those methodological constraints,
there's a number of things that have come up.
Here's a cross-section of the brain,
although I'm realizing this is a cross-section of a rat brain.
And it also is a amusing face.
And what you have are these things
that run through the brain called the ventricles.
They are these caverns running through, filled
with cerebral spinal fluid.
What you see in schizophrenia is enlargement of the ventricles.
So the ventricles enlarge.
The skull isn't going anywhere, and, thus,
if the ventricles are getting bigger,
something else has to be getting smaller.
There is contraction compression of the cortex.
So you get cortical compression in schizophrenics.
You get it particularly so in the frontal cortex.
A-ha, that's kind of interesting.
Meanwhile, over in the hippocampus, what you have,
normally, are these very characteristic cell fields,
where-- I just drew them wrong, where
neurons that are called pyramidal neurons that,
shockingly, are pyramidally shaped.
And what they have is they're organized in layers.
And they send all of their projections
off to the next cell layer that happens to be diamond shaped.
And that's how it works.
You look in the brains of schizophrenics post-mortem
and there's fewer hippocampal neurons.
And there's some of them are facing the wrong way.
They've been flipped over.
They're sending projections where they're not supposed to.
This is not going to make for a whole lot of solid sequential
thought if you've got neurons pointing
in the wrong direction.
So that's popped up in the literature.
Then, of course, frontal cortex, where
what's been seen as, in some studies, fewer neurons,
in some studies, fewer glia, in some studies,
fewer of both, what you see is, also, lower levels of a protein
And what reelin has to do is with cortical maturation.
There's lower levels of it in the frontal cortex
All of this begins to fit in this picture of you're
not getting a normal final burst of frontal maturation
late adolescence, early adulthood.
You're seeing a lot of problems there.
You also see a couple of other minor things.
The thalamus tends to be atrophied.
Nobody really knows what's going on.
The sense is hippocampus pointing
in the wrong direction, frontal cortex, that's
getting compressed, because it's got fewer neurons perhaps.
This is not going to make for a normal brain.
So now switching one box back, what about the genetics?
And you'll notice this is one of our first topics
where there's nothing been happening here
in terms of endocrine effects, acute releasers not terribly
pertinent to this field.
So what about genetics?
Going back to all of our classic behavior genetics approaches,
this has been the psychiatric disease
where there was the first evidence
for a genetic component to it.
The twin studies, the Kety adoption studies
that we've heard all about, and what they have suggested
was about 50% heritability for schizophrenia.
And you are all over now what heritability means
and what it doesn't mean.
What you see within families is if you have an individual who
has schizophrenia and they have an identical twin,
the twin has a 50% chance of the disease.
If they have a full sibling, about 25%
chance of a disease, half sibling, about 12%.
Take a random person off the street, 1% to 2%,
so there is a large genetic load.
What you also see is in a higher than expected number
of close relatives of schizophrenics
are mild versions of thought disorder.
And that's going to come in on Friday
in a very interesting way.
What this is saying right off the bat,
it is not saying that all relatives of schizophrenics
have these abnormalities, but they are occurring
at a higher than expected rate.
So that's old classical behavior genetics.
Now, jumping forward a decade's worth of technology,
how about molecular approaches the version of just getting
Not identifying the gene itself, but you remember this approach
by now where you are finding a stretch of DNA.
And inside that stretch is a gene
that is very pertinent to whatever it is,
and the folks with the disease have a different version
than the other folks.
But you don't know what the gene is or where it is.
So using this marker technique, some of the first disease gene
markers came out in the mid '80s, late '80s,
And these were landmark studies.
And everybody was incredibly excited about them.
And these were really, really important.
And there was a problem, which is somebody
would isolate a marker for schizophrenia
in an Amish population.
People love studying the Amish for things like this
because they've got big families,
because they don't have a whole lot of substance abuse,
because they have very healthy lifestyles,
and, most importantly, because men, Amish men who
say they are the father of somebody or other
are probably the father of the somebody or other.
There's not a lot of messing around going on.
And that's kind of helpful.
You're trying to understand genetics.
And if you don't even have the right person pegged
as the father, that's going to make for some messy data.
People love the Amish, people love inbred Icelandic fishing
These are all the folks who get studied.
And in those years, out came some
of the first genetic markers.
And the problem was each of the studies
was getting a different marker.
And nobody was coming up with any replication,
a complete uninformative mess that
was a major disappointment in the field.
So very little happened in terms of the genetic marker approach.
So we had to wait another decade or two, and, now,
our current more modern version, which
is forget a genetic marker, what about actual genes?
Are there are genes that have been implicated
in schizophrenia where there are abnormalities,
where there are variances?
And then it comes from two different flavors,
eight different flavors, our usual deal.
We've already heard about one of these,
which is variance in versions of this gene
coding for this enzyme that degrades dopamine carries
an association with schizophrenia.
Nonetheless, very small effects.
Interesting finding, and this was the last year,
these were three papers back-to-back in science,
from three different groups, all of whom
used a very contemporary technique
for looking for genes, which is a snip analysis.
And it's really interesting, and not in a million years
could I describe it clearly.
But using this very state of the art thing,
they all had huge populations of schizophrenics,
thousands of people in the study, great studies.
And the amazing thing is they all
found genetic abnormalities, and they all found one in common
with a huge effect, which was very, very reassuring,
until you looked at that the gene, which
made no sense at all.
All three of these groups, superb scientists,
reported that, in schizophrenia, you
have a higher than expected rate of abnormalities
in genes of the major histocompatibility complex.
What is that about?
The human equivalent, wait, we're
back at pheromones, and individual signatures,
and the immune system.
What is this about?
Nobody has a clue.
But a remarkable consistency in these three studies,
they all found abnormalities in these major histocompatibility
genes that have to do with cell signatures and immune defenses,
all of that.
And these were big effects in all three studies.
All the studies were done superbly.
People are just beginning to digest that one.
Nobody really has a very clear idea.
Some other genes have popped up as having mutations
or a lot of variants, where one particular variant is more
associated with schizophrenia.
And there's this one gene that's been found and replicated
So does DISC1 do?
Nobody has a clue.
And just showing how pathetic this whole finding is,
what does DISC, D-I-S-C, stand for?
Disrupted in schizophrenia 1.
That sure tells you a lot about what's going on.
Well, what happens in schizophrenia?
You have abnormalities in genes that
are abnormal in schizophrenia.
So you got DISC1, and people trying to figure out it's
got something to do with second messengers.
Nobody really knows.
There's not a whole lot that has been
happening in this field that counts as progress,
People still need to make sense of this finding.
One area, though, that's getting a lot of traction
in the last few years goes back to one of our weird mutations
from our macroevolution type lectures,
that business of different numbers of copies
of a gene, macro mutations on that level,
transposable events, gene duplications, a term we
got back then is copy number variants.
How many copies of particular genes?
And the one thing that seems to be
consistent is all sorts of genes in schizophrenia
are popping up with abnormal numbers of copies of the gene
rather than abnormalities in the gene itself.
So that's really exciting.
What's unexciting is nobody's replicating
which the duplications are.
And most of the genes, nobody has a clue what they do.
People are flailing other than seeing
there's all sorts of different genetic abnormalities
that are popping up.
How can that be?
How could they all be relevant to this disease?
Back one hour, it's not a disease.
It's a whole bunch of heterogeneous ones,
and there's going to be all sorts
of different genetic components to it.
Now our next box, early experience,
and what early experience immediately translates into
is parenting style.
What does schizophrenia have to do with parenting style?
We will see shortly, which is my smooth way
of trying to say that I just jumped a paragraph by accident.
So, of course, of course, where we
begin is looking at the role of early stress
in life, because that's obviously
where you have to begin discussing early experience
It's that whole stress model thing.
We already heard one version of it, the adolescent stressor,
takes the kid who's just barely holding on and dips him
Another version of it that should seem plenty
logical to us by now, prenatal stress.
People who were fetuses during the Dutch Hunger Winter
have a higher than expected rate of schizophrenia.
People who were fetuses during a huge famine
in China, 1959 to 1961, higher incidence of schizophrenia.
Rats, expose them prenatally to lots of glucocorticoids,
and they wind up having elevated dopamine levels
in their frontal cortex.
Have mechanical trauma at birth, birth trauma, brief hypoxia,
any of those things, increased incidence of schizophrenia.
This is very interesting.
Back to our business, remember, identical twins,
they can either share one single placenta
or have two of them, monochorionic or bichorionic.
Monochorionic twins are more likely to share
the trait of schizophrenia than bichorionic identical twins.
Fetal environment, stuff's going on there.
What else with that?
You wind up seeing a lot of suggestions of interactions
between the neurochemistry of stress,
and some of the abnormalities here.
You know how this works.
Somewhere lurking out there is a data set
that's going to wind up looking like this,
bad version of the gene, good version of the gene,
more and more stressful of the developmental environment.
It hasn't been identified yet, but it's
got to be something like that because everything's like that.
So leading us now obviously to discussing parenting style
So where does that come in?
Take the best psychiatrists in the field, the titans,
the grand poobahs in 1950, and they
would know the exact answer, which
is parenting style is the cause of schizophrenia.
Abnormal parenting is the cause of schizophrenia.
And out of this, of course, since in those days,
fathers did no parenting, what you were saying is abnormal
mothering is the cause of schizophrenia.
And the great term that was used there
was schizophrenogenic mothering, mothering style
that generates schizophrenia.
What was schizophrenogenic mothering about?
Well, it depends on whose paper you're reading.
But, in general, what they tended
to have were elements of conflicting emotional messages,
conflicting, a double bind is the phrase
that always ran through it.
The mother gets their son two ties for his birthday,
he puts one of them on.
She says what's the matter, you don't like the other tie
I got you, or, at the more fundamental level,
saying you never say you love me, you never say you love me,
you never say-- I love you.
How can that mean anything to me when I just
forced you to say that?
There's no winning.
And, in that view, what schizophrenia
was about was raising a kid with distorted, contradictory,
fragmented emotional demands from the schizophrenogenic
mother and out comes schizophrenia.
Now, actually, by the early '50s, people in the field
were feeling far more broad in their thinking,
recognizing this might be damaging,
in fact, to women who were the mothers of schizophrenics.
And a much more humane model came in,
which was recognizing the possibility that fathers could
screw kids up in the same way.
What was more broadly called this double bind
theory of schizophrenia, it is caused by parenting.
It is caused by particular parenting style.
And then, in the early '50s, along came the very first drug
for schizophrenia, the neuroleptics,
the dopamine receptor blockers.
And over the course of the next few years,
90% of the hospital beds in this country
for psychiatric patients were emptied out,
the first medication that effectively
And at that point, if one had any sort of capacity
to face reality, all of the proponents
of schizophrenogenic mothering should
have been shocked and stopped in their feet
at that point, saying, my God, what have we done.
It's a biochemical disorder.
It is not a disorder of mothers who are not competent mothers.
And it is fascinating to read in the leading psychiatry
journals from that time, you would get these editorials
from grand old men in the field, where
they would be saying I have spent my whole life researching
this disease, I have spent my life
trying to fight this disease, which is hell, which tragically
I've been trying to do the right thing.
I have been trying to help people.
Look, what I have done instead.
This realization that ran through the community
that parenting style has nothing to do with it.
And it's half a century's worth of mothers
bringing in their late adolescents
for the first diagnosis and being told, unfortunately,
it's this nightmare of a disease.
How could this have happened?
Where does it come from?
You caused it.
You caused it with your mothering style.
Endlessly, during the period where modern biochemistry
sweeps into psychiatry, over and over,
there are cases like this, where the whole field has
to stop and say, my God, what have
we done telling people they caused it
through some parenting style, something of that sort.
It's a biochemical disorder.
So this was a shocking finding at the time
and transformed the field in terms
of schizophrenogenic mothering going down
the sink at that point.
Nonetheless, there is an interesting literature
showing abnormalities or oddities
in the way communication works in the families
And this is a field now that's called communication deviance.
What you see is, on the average, among first order relatives
of schizophrenics, parents, siblings, immediate family,
what you see is, on the average, an odd communicative style.
You see a very fragmented communicating,
a very telescoped terse, broken phrase sort of style.
This has been noted very often.
Again, this is not what is seen in every close relative
of a schizophrenic, but higher than an expected rate.
What you also see is all sorts of realms of, in a sense,
private communication between schizophrenics
and their close families.
And the way this is shown is with things
like-- this was a classic version.
You take schizophrenics and you show them
a bunch of-- no, that's not what you do.
You give them a Rorschach print, one
of those ink symmetrical things that's just
completely chaotic looking.
And they look at it for a while, and then
you put it into a stack of a dozen other ones,
and you mix them up.
And you give them to the parents of the individual.
And the schizophrenic or the healthy control
is now trying to describe to the parents which one they
saw, how to find the correct one in there.
Control healthy individuals sitting
there trying to explain which Rorschach block they saw,
like no accuracy whatsoever.
The schizophrenic starts saying it
looks like a butterfly with a Van Dyke beard
and ears on fire, and the parents pull out
the right one instantly.
It works in the opposite direction
as well, where the parents are the ones trying
to describe the Rorschach test.
It only works within families.
The parents of the schizophrenic are no better at chance
when doing it with someone else's
child of a schizophrenic.
There seems to be this going on.
Logical interpretation, this has nothing
to do with the emergence of schizophrenia.
This is an obvious compensation.
You have a child, you have a sibling who
is this thought disordered, and there's
going to be a whole lot more adventurous communication
in the family to try to compensate for it.
Few other things in terms of early experience, and this
is a whole other domain of the disease,
which is being exposed to all sorts of infectious thingies.
And this is a really interesting provocative literature
There's a far higher than expected chance
rate of schizophrenics whose mothers were exposed
to a number of different viruses in third trimester
Ah, some sort perinatal stressor,
pathogenic challenge to the system.
And when you look at the genomes of schizophrenics,
they have much higher than expected rate of viral DNA
that has been inserted in there, things called retroviruses.
Technical matters don't matter.
The main thing is more evidence of higher exposure
to viral pathogens, an elevated history
of neonatal viral infections.
And then, the cruelest one of all,
which has to do with a protozoan parasite,
not a virus or bacteria, but this protozoa
called Toxoplasma gondii.
And not Gandhi in the Gandhian sense, but probably
because it's even pronounced differently.
How are you pronouncing it these days?
Gondii, because there's two Is at the end,
which the old Mahatma never quite came up with.
But this parasite manages to get more Is in there than he did.
So it's Toxoplasma gondii, as everybody knows.
Toxoplasma is interesting.
It has this interesting life cycle.
It reproduces in the gut of cats.
It comes out in cat feces, feces are eaten by rodents.
Now in rodents, and toxo's evolutionary challenge
has been to figure out how to get
rodents inside cats stomachs.
And toxo does this amazing thing, which
my lab is doing some work on, including Patrick,
and looking at the thing that toxo does
is it makes rats begin to like the smell of cats, and to go up
and check it out.
And soon, you are inside the stomach of the cat
and completing toxo's life cycle.
How it does it is incredibly interesting
and slowly emerging.
So what's going on with toxo in humans,
people who are infected with toxo
have a higher than expected rate of mild neuropsychological
disinhibition, a little bit of problems
with frontal regulation of behavior,
higher than expected rates of serious car accidents,
higher than expected rates for the same degree of depression,
of attempting suicide, a picture of a certain degree
Not big effects, but, nonetheless, it pops up there.
But parallel with that, from day one,
there's also been a literature showing that Toxoplasma
exposure increases the risk of schizophrenia.
Individuals whose mothers were exposed to toxo
during pregnancy or looking at schizophrenics
and looking in their blood and seeing higher
than anticipated levels of antibodies against Toxoplasma,
evidence of this whole world of a connection between cats
and schizophrenia, and all sorts of hints
there, very, very slowly emerging field.
It is a real finding and it is a well-replicated one.
There's some connection there.
So where does these genes having to do with immune function
Maybe this is pertinent to this world
of viral correlates of schizophrenia, parasitic ones.
Finally, what have we got?
This challenge that we're going to have with-- when you read
the depression chapter, all of that,
is how do you put these pieces together.
How do you put together adolescent stress