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Practice English Speaking&Listening with: 24. Schizophrenia

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Stanford University.

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

portable MRI.

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

here.

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

influenced disorders.

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

in general.

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

mechanical level.

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

conditions.

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

and language.

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

on there.

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

there.

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,

depressing picture.

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

of things.

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,

convergent evolution.

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,

information.

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

disorders.

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

for that.

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,

with abstraction.

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

concreteness.

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

concrete level.

What else?

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.

What else?

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

much alone.

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

at Berkeley.

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

in schizophrenics.

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

of schizophrenia.

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 heartwarming.

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

and withdrawal.

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

or other.

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

differently.

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

neighbors.

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

readily.

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

and teeth.

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

at times.

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,

enhanced sensitivity.

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,

totally amazing.

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

appear schizophrenic.

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.

Yeah?

Does the brain-- while hallucinating,

does the brain work somewhat like when dreaming?

Good question.

Does the brain, in terms of patterns of activation,

look somewhat like during dreaming?

Yeah.

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

called reelin.

And what reelin has to do is with cortical maturation.

There's lower levels of it in the frontal cortex

of schizophrenics.

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.

What else?

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

genetic markers?

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,

for schizophrenia.

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

villages.

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

called DISC1.

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.

Let's party.

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,

really frustrating.

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

in schizophrenia.

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

way down.

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

and schizophrenia.

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

treated schizophrenia.

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

destroys lives.

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

of schizophrenics.

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

floating around.

There's a far higher than expected chance

rate of schizophrenics whose mothers were exposed

to a number of different viruses in third trimester

of pregnancy.

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.

Gondii.

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

of impulsivity.

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

come in?

Maybe this is pertinent to this world

of viral correlates of schizophrenia, parasitic ones.

Nobody knows.

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