My name is David Adam and I have
obsessive-compulsive disorder OCD.
I want to find out more about my condition so
I've come to the University of Cambridge
to find out how so at the top scientists
in the field are studying this disorder
and why, sometimes controversially, this
involves the use of animals.
As our understanding
of specific pathways in
the brain increases, it's our contention
that there are specific pathways that go
slightly wrong in OCD and those brain
areas correspond to the same brain areas
that we studied in experiment animals
and shown the same symptoms of rigidity
and thought using the same tests but the
differences in the experimental animal were
able to understand the mechanisms by
which this rigidity occurs which we
can't in humans because we can't use
interventional techniques to test the
causality of the involvement of that area
in thinking or behaviour.
So that's the theory but what does research
with animals actually look like well it
can be a bit difficult to find out
because institutions like this usually
keep this work pretty secret but
actually Trevor Robbins has arranged for
me to see some of it for myself so we're
going to see research with humans, we're
going to look at brain scanned and we're
going to look at what's probably among
the most controversial work with
marmosets but we're going to start with
a staple of research at animals we're
going to look at studied for OCD
involving the laboratory rat.
So these
rats are part of a study looking at
checking behaviour and we're interested
in the circuits of the brain that
control checking behaviour. We use
surgical techniques to just inactivate
part of their frontal cortex and through
our studies of checking behaviour we can
see that this rat who has this part of
his frontal cortex inactivated shows a
higher level of checking behaviour than
we would normally expect.
Okay so you put
the rat in, to do this experiment
but we thought we'd leave it to do its
thing and look at footage of one that
you filmed earlier. So just describe
what we're looking at. So this is a
picture of the inside of our test box
and you can see on the right hand side
there are two levers. When the rats are
training on this test then we show them
a light above the lever that is the
correct one to press and they learn that
very quickly, they learn to associate
that light with a food reward. Now when
we're looking at their checking behaviour
we take that light away and instead we
give them a lever at the back of the box,
so this lever on left hand side is
a lever that they can press to give them
access to the light above the correct
lever to press. So it puts it on? So they press
one lever to show which lever to
press to get the food. Yes so they can
effectively check on this lever at the
back of the box for information about
where to go next. But then sometimes they
just return back again and again and
keep checking, keep checking to see if
that light is turned on or off. Right. And
and do the rats with the changes in the
brain then do that more? Yes, so the rats
we've just seen with disruption to the
circuits in the brain that we think are
involved in OCD show much higher levels of
checking behaviour than we would expect
and this is an indicator that perhaps
that part of the brain is somehow
controlling checking behaviour. Right and
in this case the checking is it's a
complete waste of their time because if
they were to go to press the lever
they'd get the food. It's a waste of time
it takes them away from the part of the
task that's actually useful for them
which is.. Which is eating because we
think the more time they spend checking
the less time they get to eat. Yes.
But of course rats are quite different to
humans so Angela Roberts Professor of
behavioral neuroscience has offered to
show me what we can learn studying a
closer relative of ours, the marmoset.
So I've just been to see Dawn and we met
her rats but I understand you you are
working with a different animal. Can you
tell me about that?
Yes, so we're working
with a new world monkey called the
common marmoset and we're using the mamoset
because whilst the rodent brain in
some ways is very similar to that of
humans, the primate brain has the much
more closer resemblance to the human brain
and when you're studying these kinds of
complex human behaviours then ultimately
at some point you need to study a brain
that's a lot more similar to human than
a rodents. So even though Dawn told
me then that the mouse brain is similar
enough to a human brain was was that
that not enough information I mean, why
do you need to do it with ...
We've gained a considerable amount of
knowledge from studying the rat brain
but ultimately the, if you compare a rat
brain with the human brain the most
important part of the brain for
information processing is something
called the cortex which sort of over
lies the deeper structures the brain and
that cortex in a rat is probably makes
up about twenty eight percent of a rat
brain. The human brain the cortex makes
up eighty percent or besides the brain
and then in monkeys it's sort of
somewhere around about 60 to 70
depending on the species so there's far
more information processing going in the
cortex going on in the cortex of a
monkey compared to a rodent and given
that highly complex behaviours in humans
are ultimately being controlled by that
information processing going on in
cortex that's why someone on the line
you need to be able to do some of these
studies in monkeys. Now using primates in
science is about as controversial as it
gets you know I've met many even fully
committed scientists who don't think we
should be doing it. So why should we?l
Well, I mean the answer that ultimately comes
in the suffering that you see in
patients with in case of what we're
studying neuropsychiatric disorders.
Sixty percent of patients can't be
successfully treated very effectively
with the current therapies whether
that's cognitive behavioral therapy or
drugs, pharmacotherapies. And we really do
need to generate a much better
understanding of the kinds of brain
circuits that are involved in
controlling these complex behaviours in
order for us to actually generate the
new, new generation of drugs or
therapists and in order to do that we
have to turn to animals and we have to
turn at some level to a primate which
has got the complex brain that you see
in a human. And ultimately it's about
weighing the balance and we all, we all have
to make that decision about what we feel
comfortable about working with but you
having to balance the the studies we're
doing in primates versus the kinds of
suffering that humans are under with
some of these disorders which can be
debilitating and for years they've been
on one drug therapy or another one and
it hasn't worked along with all the side
effects that go with taking drugs and so
ultimately you're weighing up well
should we let this person continue
suffering or should we do careful
controlled restricted studies in animals
that we think are really important and
particularly in primates.
Well why can't
we just do that work with humans so I
have OCD why can't you just look at my
brain and and and try and work out how
those treatments might be developed.
Well we've gleaned lots of information about
looking at your brain and other people's
brains with regard to some of these and
disorders and we get a lot of
information about what areas are brain
are more active or what areas of the brain are
less active compared to someone which
doesn't have that disorder but the
problem with that is ultimately the
informations correlation and what you
don't know is whether those changes that
you're seeing are they actually causal
to some of the symptoms you're
experiencing or are they for sample
compensatory? So is this bit of the brain
that we're seeing is more active is it
actually more active and causing your
problems or actually is it just tried to
compensate not very well for the
problems that you're experiencing and
you can't address that causal question
with a human that's where you have to go
to an animal because then in an animal
if you've got those two changes in
activity we can actually make those
changes in an animal we can over
activate one bit of the brain, we can
under activate another bit and look to
see which one of those potentially
produces a behaviour that's similar to a
behaviour you're experiencing.
So what I want
to show you here is a marmoset
performing a particular tasks that we
have been using which is quite useful
for trying to understand some of the
repetitive behaviours that you see in OCD
sufferers. This particular marmoset that you
can see they're these little metal tubes
just coming out of its head here and
that's because we've implanted what
effectively what they call cannula in a
one-off surgical operation we implant
least annually into the brain of the
momma debts allowing us to target a
particular brain region this is a
special surgical cement that is keep
feed can you lean plate it sounds quite
extreme so the monkey lives with these
two tubes it's Frank does it does it
bother it no they don't it doesn't seem
to bother them at all and their partners
don't seem to mind them takes no notice
of them sometimes some of the partners
will groom it so they'll find them
grooming around the area but and the map
the Marmot Ector who's got the canyon II
sort of sits there enjoying his grooming
from his partner so no they don't think
too bothered by it at all once it's in
place so there's an image of a monkey
with tubes coming into its brain it is
is about as severe as it gets probably
for people and and those are the kind of
images that are used to try and counter
animal research I mean would you do that
sort of thing in a human well yes I mean
when you do some of the surgical
treatments for example Parkinson's
disease and for OCD deep brain
stimulation you know you are having to
insert devices into the brain and
electro is all I know right now and in
order to be able to perform these
treatments so in that sense it's it's
what's being done in patients as well
but of course here we're using it to ask
the experimental questions of when we
temporarily activate a particular part
of the brain what are the effects on
that and the reason that's a really
important question to ask and sort of
bills on the research we've done before
in the past we tended to make permanent
lesions so you'd make you destroy a
small localized region of cell bodies
and look at the effects of that in order
to try and localize where some of these
deficits are coming from but now as the
approach we've sort of developed over
the years is that you can actually
inactivate these areas temporarily so if
I haven't use cannula placed firmly in
the brain you can infuse drugs down them
which we'll just act for the short
period of time that they are around and
in which case it may be to inactivate an
area or to activate an area depending on
what you're trying to mimic that seen in
patients but then once the drugs worn
off 20 minutes half an hour afterwards
45 minutes afterwards then the that part
of the brain goes back to working
normally again
in this task then so what the moment
that they're doing they're being
presented with two colored Stingley on
the screen and they've learned actually
some previous day that this red and
yellow one just rewarded if they respond
to it where's this other blue flower
isn't rewarded if they respond to it and
so as you can see this animal knows that
is in the apparatus happily pressing
away the red and yellow luminous every
time you responded on it there's a
little pussy sounds which comes on
telling introduces available and then
he's licking redtube analogies to get
into reward but the interesting part of
this is that suddenly halfway through
this session we're going to change the
relationship between us communal award
so having been responding to the yellow
and red stimulus for so long getting the
board here we go everything to yell
you've got it wrong so that's kind of
put him off a little bit and he does it
again because it has always been
rewarded and suddenly it isn't so an
animal normally will make few of those
repetitive behaviors to the wrong
stimulus getting it wrong but then he
loved to start thinking oh I better do
something else so then he ends up
touching the other stimulus and you'll
see eventually does start to touch the
other students is just under there but
for us we've got this reward so now we
can start this realizing learning oh
it's other stillness now that's rewarded
what's interesting about this task is
that firstly quite a few years ago now
we showed that a particular part of the
prefrontal cortex the orbitofrontal
cortex which is just above the orbits
hence its name if you inactivate that
bit of the orbitofrontal cortex it
causes animals to be more reflective in
their behavior so it doesn't stop them
learning this discrimination they're
happy to learn that the yellow and red
stainless is awarded but when suddenly
halfway through the task whose
relationship has changed they find it
very difficult to change their behavior
and so them stickier they just carry on
responding to the stimulus that was
rewarded but actually isn't reward
anymore and they no longer getting
reward for it but they take much longer
to switch and this task is quite
interesting because it's been used in
patients with OCD and some patients with
OCD you see very marked changes within
the orbitofrontal cortex the very area
we know
oughtn't to this task of twitching in
this task we see changes in activity in
the area of the brains of patients with
OCD when they're performing this task we
even see it in first degree relatives
and so we're going interested in trying
to understand the circuit involved in
this kind of behavior because it may
give us some insight into ultimately you
know the development of compulsions so
this is one one example of a test that
we've been using because it does seem to
have quite a lot of applicability given
the effects we've been seeing in OCD
patients and also the relationship with
the drugs they're taking in the next
film I find out how this work in rats
and Mama's eps relates to what we know
that further frame and what better way
and to look inside my own brain
you