It's a real pleasure to be here
and to present the work I've been doing
over the last five years or so since my PhD.
Genuinely, I want you to try and understand
as much as you can
So it's not the easiest material,
And especially when you don't have a background in neuroscience.
It's not always that easy to get a handle on these processes.
But I'm going to do my absolute best
to try and help you understand, and
I'll provide some metaphors to try and
break things down to make things more accessible.
Also it would be useful to keep
some pens out because there will be
some references, so if you genuinely you do
want to understand how these drugs
work in the brain, then it does require
a bit of work on your parts as well, unfortunately.
So you'd have to go away and look up
some of these references and do some
background reading.
So I just want to start by saying
that this work is part of the
Beckley-Imperial psychedelic research programme,
which is an initiative between David Kotts
and Amanda Fielding of the Beckley Foundation.
Amanda is a key collaborative partner in this work,
and David Nutts, the principal investigator on it.
So we'll start with the science.
We know that psilocybin is an ingredient
in magic mushrooms.
Now, psilocybin is the [pro-drug] of psilocin,
which is remarkably similar in its molecular structure
to the endogenous neurotransmitter
which is found throughout the brain, serotonin.
So it is really quite striking how similar
it is in its molecular structure.
Just a subtle change in its structure
confers such profound effects of consciousness.
So this already
is a matter of great intrigue
about how these drugs work in the brain.
So what was found in the mid-1980s
was a strong positive correlation
between a psychedelic drug's affinity
for the serotonin 2A receptor,
a particular subtype of the serotonin receptor,
and the drug's potency.
So a good example to help illustrate
it's principle is, LSD has a very high affinity
for the serotonin 2A receptor --
it's very sticky, and it's also incredibly potent.
So that helps you understand.
Also, Franz Vollenweider did an excellent study
blocking the serotinin 2A receptor
with ketanserin, a relatively selective
serotonin 2A receptor blocker,
and he found that pre-treatment
with this drug blocked the psychedelic effects
of psilocybin. So there's good evidence
that these drugs trigger their effects
on consciousness by initial effect on
the serotonin 2A receptor.
So already we have an important
fundamental relationship that's been discovered
between the serotonin system and how these drugs work
in the brain.
So where is the serotonin 2A receptor in the brain?
Well, this is the largest serotonin 2A binding study
that's been done by a colleague of ours,
David Erritzoe.
He used a radioactive tracer, or ligand,
that sticks to serotonin 2A receptors in the brain.
And then you can detect the signal
where the ligand is stuck
And so doing this, he found that
the serotonin 2A receptor is
very much a cortical receptor.
So the outer layer of the brain, the cortex,
(it's referred to as kind of like the bark of a tree)
so this outer layer of the brain, that's where you find
the serotonin 2A receptor.
And it's especially prevalent,
especially densely expressed,
in high-level cortical regions.
So these are regions that
don't have a specific sensory function, like,
for instance, the visual cortex, which is concerned
with visual processing.
The heteromodal regions so they have a more
kind of divergent, and high-level, function
and so the serotonin 2A receptor
is especially densely expressed
in these high-level cortical regions,
such as the posterior cingulate cortex.
You will hear this term referred to again
throughout my talk
because it's a key region of the brain,
a very high-level region of the brain,
and it seems to be especially implicated in
the mechanistic action of these drugs,
how they work in the brain.
We also know that the serotonin 2A receptor
is especially densely expressed
in the particular layer of the cortex.
So the cortex is organized in a kind of laminar
way, and there's some large,
what are referred to as pyramidal neurons
in layer 5 of the cortex.
That is... (pause)
This is layer 5 here.
So there's some large neurons there,
and these are the principal output layer
of the cortex,
and there's also something else,
which is especially important about
this cellular group,
in terms of how this drug works in the brain.
So we know the serotonin 2A receptor is very important,
We know where it is,
in terms of its spatial distribution in the brain
and also within the cortex itself,
within its laminae organization. It's dense in the
deep pyramidal cells in layer 5.
We also know that if you stimulate
the serotonin 2A receptor,
you have an excitatory effect on the host cells.
So the cell that expresses the receptor,
if you stimulate it, then you're gonna make that cell
more excitable.
So these are all important principles that we know.
These are kind of the bedrock findings so far
about how psychedelics work in the brain.
But these are all quite low level;
my brain imaging work has been looking at
a higher level,
what's referred to as a macroscopic level.
So, the level you can look at and see
on a large scale in terms of
brain networks, for instance,
and regional brain activity.
So let's start with our first study,
our first fMRI study with psilocybin.
This used the modality referred to as
arterial spin labelling, which is
a method which measures changes
in blood flow in the brain.
And generally there's quite a reliable relationship
between blood flow in the brain and brain activity.
So if blood flow increases,
we generally infer
that brain activity has increased.
So this study had fifteen healthy volunteers,
mean age of 34,
the scans were 18 minutes in duration,
there was a six-minute baseline,
and then we looked at changes in blood flow
after that baseline.
There were two scans:
a placebo scan followed by a drug scan.
And volunteers just lay in the scanner.
They were presented with a fixation cross:
just a simple green cross that they looked at
on a screen, and they just relaxed
and were instructed really just to let their minds wander.
And then we looked at how
the drug affected blood flow
during these conditions.
We gave a dose of 2 mg of psilocybin--
that compares to about 50 mg when given orally.
We gave the drug intravenously,
so 2 mg is equivalent to about 50 mg orally,
so it's a moderate dose.
Here's the design. Here's our 6-minute baseline.
Infusion was given over 60 seconds.
So it's a relatively rapid infusion.
And then the onset of the effects is also rapid,
so when the drug is given intravenously,
really there is very little delay between
delivery of the drug and the onset
of the subjective effects.
So the subjective effects actually begin,
really, before the end of the 60-second adminstration,
so the drug seems to really get in the brain
very quickly and to change consciousness
profoundly very quickly.
So what was the first observation?
Well, the first thing that we get
before we analyze the results are people's
descriptions of their experiences.
So here's one of them:
This volunteer said that "there was a definite
sense of lubrication,
of freedom,
of the cogs being loosened and firing off
in all sorts of unexpected directions."
Now these subjective reports are really useful
because they give you a sense of the
mechanics that are going on in the brain,
and the changes in the mechanics,
which confer the subjective effect --
what's going on in the brain on a mechanical level
to produce the profound changes in consciousness.
This volunteer said, "Everything became
fragmented; things were all in bits
and it was very hard to hold it all together
in a coherent stream."
So it's like I said, this stuff is really useful
for understanding what is going on
on a systems-level in the brain
to produce these subjective effects.
Now, the default mode network
you've heard quite a lot about
over the last two days.
It is an incredibly important
system that's been discovered in the brain.
And one of its properties is that
it has very dense connectivity,
so if you look at the white matter
tracks in the brain,
so these are the fibers that connect
different brain regions,
then you'll find that there's a very dense
coming together of connections within
the default mode notwork.
So there seems to be
an incredibly important transit hub,
a place where different regions
can connect via,
and information can be projected from,
and also a very important integration center.
So, to integrate brain function,
information comes together at this common
convergence zone, and then
that gives a coherence to cognition, essentially.
That's how it's understood so far.
What else about the default mode network?
So here's a metaphor to help you try and understand
what people are thinking about its function.
So a metaphor that could be used to explain
what it does is a capital city in a country.
It's a place where people come together,
things come together,
business gets done.
And it's an incredibly important hub,
and if ever
God forbid, something were to happen to
London, then, the country as a whole
would be seriously effected,
and not just Britain.
So it's incredibly important
integration hub, the default mode network.
What else do we know about
the default mode network?
There's some evidences here.
The default mode network undergoes
significant ontogenetic development
from infancy to adulthood.
It undergoes maturation as cognition matures.
It has also undergone significant
evolutionary expansion
so these regions have increased
more than other regions
from primates to humans.
It's more metabolically active
than elsewhere in the brain,
so the posterior cingulate cortex,
which is the region which is circled there,
it actually accounts for 40% more
blood flow than anywhere else
in the brain.
So it is a very metabolically hungry system
and these regions that are part of it
are incredibly metabolically hungry.
It's doing something important.
Now, a matter of intrigue in neuroscience
is that people don't have a really good handle
on what the default mode is
and what it does,
but of course, they enjoy speculating,
and the researcher who really discovered
the default mode network has referred
to its very high energy levels
as being like the brain's dark energy.
So similar to dark energy in cosmology
it is something that we know is there
but we don't really know what it does.
Really, we make inferences about it,
based on its relative decrease in activity.
So when you engage in a task,
you see a decrease in activity
in the default mode network,
whereas otherwise
it is incredibly active.
So it's a mater of intrigue.
What's going on here?
What's all this energy for, and why
is it consuming so much?
We know that the default mode network
is engaged during self-reflection,
so that is a very staple finding.
We also know that during
complex mental imagery, such as
spatial navigation or imagination,
fantasy in one's mind eye,
you'll also see increased activity
in the default mode network.
Mental time travel -- so that's being
outside of the moment and
daydreaming about future events
or past biographical experiences.
So whenever you come out of the moment
and you daydream in this way,
you see increased activity and connectivity
in the default mode network.
Also, theory of mind -- which is
putting someone oneself
in somebody else's shoes.
You will also see increased activity
in the default mode network during that function.
And metacognition -- which thinking about thinking,
that's also linked with
default mode network activity.
So Raichle, who I said is the guy who
really discovered this network
has also referred to it as
the orchestrator of the self.
So all these things
led me to start thinking
having a background in psychoanalysis
and being interested in
especially Freudian metapsychology
instead of the more mechanistic
ideas of Freud. There is remarkable overlap
between his descriptions of the ego
and the relationship between the ego
and the unconscious mind, or the id,
and what we're discovering in
the default mode network.
So in this paper, with Carhart-Harris & Friston,
I submitted the idea that
the default mode network is essentially
the neural substrate source of the ego,
which is an idea to be shot down
if people find otherwise.
But that's science. That's how we work.
So what else is there about
the default mode network?
Well, what's it's relationship to depression?
There's a very interesting relationship
between default mode network parameters
and depressive symptomatology.
So we know that connectivity between
the medial pre-frontal cortex
of the default mode network
and the posterior cingulate cortex
which are
(pause)
the front bits and the back bits.
So when connectivity between these regions
is high,
then scores in patients with depression
on rumination (so these are scores in rumination.
They are thinking over problems
and ruminating on negative things),
when this is high, connectivity
betwen these regions is especially
high. And we think this system,
this overconnectivity, is really causing people to
have a kind of stereotype style of thinking.
So they are stuck in this system,
they are stuck in their own heads,
they are stuck on their sense of self.
They are usually thinking very critically
about themselves, and going over and over
about how terrible they are.
So this is a relationship we seem to be discovering
about the default mode network
and depressive symptomatology.
This provides a useful background
for what we're finding in terms of how
psilocybin is affecting
brain networks and brain systems.
So in our ASL study, we found
it was really quite surprising findings for us,
given descriptions of consciousness
being expanded by psychedelic drugs.
We are given some previous work,
for instance, by Franz Vollenweider,
we were thinking we were going to be seeing
increases in brain activity or brain blood flow
with psilocybin.
And despite dropping the threshold
and a number of different things,
we really didn't see this.
All we were really seeing was
the same pattern again and again,
which was decreased blood flow
in certain regions of the brain.
What was intriguing was that
the decreases that we were seeing were
in these very same important hub strutures
of the brain.
So, for instance, the posterior cingulate cortex,
this bit at the back,
the thalamus,
and the medial pre-frontal cortex --
so these very reliably
were coming up as being
decreased under psilocybin.
Here's just showing you again,
the default mode network is this kind of
hub, this connectivity hub, in the brain.
We also found that
there was a relationship between
the magnitude of the decrease in blood flow
and ratings of the intensity of the experience.
So, the larger the decrease in blood flow,
particularly in the anterior cingulate cortex,
the more intense people were describing
their experiences.
So whenever you find these relationships
it kind of reinforces your inferences, really,
and provides some consolidation
for what you are finding
and supports its functional meaning.
So since our ASL study
we did a [bold] study.
This is kind of the classic [signal]
of functional magnetic resonance imaging (fMRI).
We really repeated the same protocol:
15 healthy volunteers,
infused with a drug over 60 seconds at 2 mg,
and we found exactly the same thing.
So this was really nice reinforcement
for the initial finding that we had found
with ASL.
And these regions where there was a common
overlap between the decreases in blood flow
with ASL and the decreases in,
essentially venous oxygenation,
or oxygenated blood with the BOLD signal
of fMRI.
So one of the merits of BOLD fMRI is
that it allows you to do these
functional connectivity analyses.
So just to give you a feel for what that is,
here is an image which shows
the default mode network in orange
and let's concentrate on the default
mode network for a moment.
So you can see that there are two regions in it,
and there is one that has has yellow text,
the PCC? and then you can see there is this
time series underneath.
So the PCC time series is in yellow
and you can see that it overlaps with
anothertime series, and that is
the medial prefontal cortex.
So it is by looking at correlations between
fluctuations in the BOLD signal
that we identify functionally coherent
brain networks. We know these regions
work together as a common network
doing a common function.