24. Schizophrenia


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 put
these pieces together. How do you put together
adolescent stress with prenatal viruses
with enlarged ventricles, with funny genetic
abnormalities here? There isn’t a very
good integrated model at this point to how to
put the pieces together. The field has not
gotten that far. So we’re talking about genetic
abnormalities, blah, blah, all of that. And thus, you
know, our final box has to be the evolution
of schizophrenia. Where did schizophrenia
evolve from? First question you would ask
is, well, do you see something like schizophrenia
in other species. And you don’t. You look at complex
primates and you see things that look
like depression, you see reactive depression,
you see melancholia, you see, in some cases,
depression so severe as to prove fatal. You don’t see animals
having to loose associations with proverbs, and concrete
thought, and delusions, and hallucinations. Animals that start
acting schizophrenic get eaten that evening. So there’s not a
whole lot of insight from the zoological world. There’s not any animal
precedents for schizophrenia. So how about in humans? How did schizophrenia evolve? We are now back to one
of our first lectures. Why did giraffes
have long necks? Because it’s a good
thing that allows them to pass on more
copies of their genes, because it’s an adaptive trait. By the rules of Darwin,
schizophrenia is maladaptive. Schizophrenics have a
lower reproductive rate than their unaffected siblings. By the math, that
is thus a trait that should be being
selected against. Yet, schizophrenia persists at
this 1% to 2% in every culture out there. Historical records
indicate things that convincingly sound
like schizophrenia have been there forever. And, thus, one has to bring up
the question that always lurks in a scenario like this, which
is are there circumstances where schizophrenia is
in fact adaptive, where it is advantageous,
where it increases one’s reproductive success. The only domain where
that has had any evidence at all in the literature
is schizophrenics appear to have a lower incidence
of certain types of cancers, in particular, lung and
throat, esophageal cancers. And that’s after controlling
for smoking rates, all of that. Not a big effect, but
that causes people to mumble something
about maybe schizophrenia was selected for its anti-cancer
properties in the disease, and balanced
selection, all of that. However, there is another
possible adaptive thing that’s lurking around
in there, something which causes some
of these traits to not only no longer
be maladaptive, but to be wildly useful
in certain contexts of human society. And what you’ll see is it’s
not full-blown schizophrenia, it’s the milder
versions that you see in some of the relatives. And thus, just to give you
a sense of where things are heading, we’ll talk about
that on Friday in the lecture on– For more, please visit
us at Stanford.edu.

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