0:00:06.387,0:00:07.971
It's a real pleasure to be here

0:00:07.971,0:00:10.648
and to present the work I've been doing

0:00:10.648,0:00:15.957
over the last five years or so since my PhD.

0:00:15.957,0:00:19.860
Genuinely, I want you to try and understand

0:00:19.860,0:00:20.860
as much as you can

0:00:24.717,0:00:24.967
So it's not the easiest material,

0:00:26.289,0:00:26.741
And especially when you don't have a background in neuroscience.

0:00:32.709,0:00:36.318
It's not always that easy to get a handle on these processes.

0:00:36.318,0:00:41.169
But I'm going to do my absolute best

0:00:41.169,0:00:42.211
to try and help you understand, and

0:00:42.211,0:00:43.714
I'll provide some metaphors to try and

0:00:43.714,0:00:46.387
break things down to make things more accessible.

0:00:46.387,0:00:50.003
Also it would be useful to keep

0:00:50.003,0:00:50.867
some pens out because there will be

0:00:50.867,0:00:52.618
some references, so if you genuinely you do

0:00:52.618,0:00:53.672
want to understand how these drugs

0:00:53.672,0:00:55.459
work in the brain, then it does require

0:00:55.459,0:00:57.785
a bit of work on your parts as well, unfortunately.

0:00:57.785,0:00:58.979
So you'd have to go away and look up

0:00:58.979,0:01:00.289
some of these references and do some

0:01:00.289,0:01:02.367
background reading.

0:01:02.367,0:01:04.470
So I just want to start by saying

0:01:04.470,0:01:06.482
that this work is part of the

0:01:06.482,0:01:10.031
Beckley-Imperial psychedelic research programme,

0:01:10.031,0:01:12.757
which is an initiative between David Kotts

0:01:12.757,0:01:14.753
and Amanda Fielding of the Beckley Foundation.

0:01:14.753,0:01:18.726
Amanda is a key collaborative partner in this work,

0:01:19.699,0:01:21.353
and David Nutts, the principal investigator on it.

0:01:21.353,0:01:24.647
So we'll start with the science.

0:01:24.647,0:01:27.212
We know that psilocybin is an ingredient

0:01:27.212,0:01:29.467
in magic mushrooms.

0:01:29.467,0:01:32.338
Now, psilocybin is the [pro-drug] of psilocin,

0:01:32.338,0:01:35.804
which is remarkably similar in its molecular structure

0:01:35.804,0:01:38.330
to the endogenous neurotransmitter

0:01:38.330,0:01:41.192
which is found throughout the brain, serotonin.

0:01:41.192,0:01:43.899
So it is really quite striking how similar

0:01:43.899,0:01:46.699
it is in its molecular structure.

0:01:46.699,0:01:50.325
Just a subtle change in its structure

0:01:50.325,0:01:53.548
confers such profound effects of consciousness.

9:59:59.000,9:59:59.000
So this already

9:59:59.000,9:59:59.000
is a matter of great intrigue

9:59:59.000,9:59:59.000
about how these drugs work in the brain.

9:59:59.000,9:59:59.000
So what was found in the mid-1980s

9:59:59.000,9:59:59.000
was a strong positive correlation

9:59:59.000,9:59:59.000
between a psychedelic drug's affinity

9:59:59.000,9:59:59.000
for the serotonin 2A receptor,

9:59:59.000,9:59:59.000
a particular subtype of the serotonin receptor,

9:59:59.000,9:59:59.000
and the drug's potency.

9:59:59.000,9:59:59.000
So a good example to help illustrate

9:59:59.000,9:59:59.000
it's principle is, LSD has a very high affinity

9:59:59.000,9:59:59.000
for the serotonin 2A receptor --

9:59:59.000,9:59:59.000
it's very sticky, and it's also incredibly potent.

9:59:59.000,9:59:59.000
So that helps you understand.

9:59:59.000,9:59:59.000
Also, Franz Vollenweider did an excellent study

9:59:59.000,9:59:59.000
blocking the serotinin 2A receptor

9:59:59.000,9:59:59.000
with ketanserin, a relatively selective

9:59:59.000,9:59:59.000
serotonin 2A receptor blocker,

9:59:59.000,9:59:59.000
and he found that pre-treatment

9:59:59.000,9:59:59.000
with this drug blocked the psychedelic effects

9:59:59.000,9:59:59.000
of psilocybin. So there's good evidence

9:59:59.000,9:59:59.000
that these drugs trigger their effects

9:59:59.000,9:59:59.000
on consciousness by initial effect on

9:59:59.000,9:59:59.000
the serotonin 2A receptor.

9:59:59.000,9:59:59.000
So already we have an important

9:59:59.000,9:59:59.000
fundamental relationship that's been discovered

9:59:59.000,9:59:59.000
between the serotonin system and how these drugs work

9:59:59.000,9:59:59.000
in the brain.

9:59:59.000,9:59:59.000
So where is the serotonin 2A receptor in the brain?

9:59:59.000,9:59:59.000
Well, this is the largest serotonin 2A binding study

9:59:59.000,9:59:59.000
that's been done by a colleague of ours,

9:59:59.000,9:59:59.000
David Erritzoe.

9:59:59.000,9:59:59.000
He used a radioactive tracer, or ligand,

9:59:59.000,9:59:59.000
that sticks to serotonin 2A receptors in the brain.

9:59:59.000,9:59:59.000
And then you can detect the signal

9:59:59.000,9:59:59.000
where the ligand is stuck

9:59:59.000,9:59:59.000
And so doing this, he found that

9:59:59.000,9:59:59.000
the serotonin 2A receptor is

9:59:59.000,9:59:59.000
very much a cortical receptor.

9:59:59.000,9:59:59.000
So the outer layer of the brain, the cortex,

9:59:59.000,9:59:59.000
(it's referred to as kind of like the bark of a tree)

9:59:59.000,9:59:59.000
so this outer layer of the brain, that's where you find

9:59:59.000,9:59:59.000
the serotonin 2A receptor.

9:59:59.000,9:59:59.000
And it's especially prevalent,

9:59:59.000,9:59:59.000
especially densely expressed,

9:59:59.000,9:59:59.000
in high-level cortical regions.

9:59:59.000,9:59:59.000
So these are regions that

9:59:59.000,9:59:59.000
don't have a specific sensory function, like,

9:59:59.000,9:59:59.000
for instance, the visual cortex, which is concerned

9:59:59.000,9:59:59.000
with visual processing.

9:59:59.000,9:59:59.000
The heteromodal regions so they have a more

9:59:59.000,9:59:59.000
kind of divergent, and high-level, function

9:59:59.000,9:59:59.000
and so the serotonin 2A receptor

9:59:59.000,9:59:59.000
is especially densely expressed

9:59:59.000,9:59:59.000
in these high-level cortical regions,

9:59:59.000,9:59:59.000
such as the posterior cingulate cortex.

9:59:59.000,9:59:59.000
You will hear this term referred to again

9:59:59.000,9:59:59.000
throughout my talk

9:59:59.000,9:59:59.000
because it's a key region of the brain,

9:59:59.000,9:59:59.000
a very high-level region of the brain,

9:59:59.000,9:59:59.000
and it seems to be especially implicated in

9:59:59.000,9:59:59.000
the mechanistic action of these drugs,

9:59:59.000,9:59:59.000
how they work in the brain.

9:59:59.000,9:59:59.000
We also know that the serotonin 2A receptor

9:59:59.000,9:59:59.000
is especially densely expressed

9:59:59.000,9:59:59.000
in the particular layer of the cortex.

9:59:59.000,9:59:59.000
So the cortex is organized in a kind of laminar

9:59:59.000,9:59:59.000
way, and there's some large,

9:59:59.000,9:59:59.000
what are referred to as pyramidal neurons

9:59:59.000,9:59:59.000
in layer 5 of the cortex.

9:59:59.000,9:59:59.000
That is... (pause)

9:59:59.000,9:59:59.000
This is layer 5 here.

9:59:59.000,9:59:59.000
So there's some large neurons there,

9:59:59.000,9:59:59.000
and these are the principal output layer

9:59:59.000,9:59:59.000
of the cortex,

9:59:59.000,9:59:59.000
and there's also something else,

9:59:59.000,9:59:59.000
which is especially important about

9:59:59.000,9:59:59.000
this cellular group,

9:59:59.000,9:59:59.000
in terms of how this drug works in the brain.

9:59:59.000,9:59:59.000
So we know the serotonin 2A receptor is very important,

9:59:59.000,9:59:59.000
We know where it is,

9:59:59.000,9:59:59.000
in terms of its spatial distribution in the brain

9:59:59.000,9:59:59.000
and also within the cortex itself,

9:59:59.000,9:59:59.000
within its laminae organization. It's dense in the

9:59:59.000,9:59:59.000
deep pyramidal cells in layer 5.

9:59:59.000,9:59:59.000
We also know that if you stimulate

9:59:59.000,9:59:59.000
the serotonin 2A receptor,

9:59:59.000,9:59:59.000
you have an excitatory effect on the host cells.

9:59:59.000,9:59:59.000
So the cell that expresses the receptor,

9:59:59.000,9:59:59.000
if you stimulate it, then you're gonna make that cell

9:59:59.000,9:59:59.000
more excitable.

9:59:59.000,9:59:59.000
So these are all important principles that we know.

9:59:59.000,9:59:59.000
These are kind of the bedrock findings so far

9:59:59.000,9:59:59.000
about how psychedelics work in the brain.

9:59:59.000,9:59:59.000
But these are all quite low level;

9:59:59.000,9:59:59.000
my brain imaging work has been looking at

9:59:59.000,9:59:59.000
a higher level,

9:59:59.000,9:59:59.000
what's referred to as a macroscopic level.

9:59:59.000,9:59:59.000
So, the level you can look at and see

9:59:59.000,9:59:59.000
on a large scale in terms of

9:59:59.000,9:59:59.000
brain networks, for instance,

9:59:59.000,9:59:59.000
and regional brain activity.

9:59:59.000,9:59:59.000
So let's start with our first study,

9:59:59.000,9:59:59.000
our first fMRI study with psilocybin.

9:59:59.000,9:59:59.000
This used the modality referred to as

9:59:59.000,9:59:59.000
arterial spin labelling, which is

9:59:59.000,9:59:59.000
a method which measures changes

9:59:59.000,9:59:59.000
in blood flow in the brain.

9:59:59.000,9:59:59.000
And generally there's quite a reliable relationship

9:59:59.000,9:59:59.000
between blood flow in the brain and brain activity.

9:59:59.000,9:59:59.000
So if blood flow increases,

9:59:59.000,9:59:59.000
we generally infer

9:59:59.000,9:59:59.000
that brain activity has increased.

9:59:59.000,9:59:59.000
So this study had fifteen healthy volunteers,

9:59:59.000,9:59:59.000
mean age of 34,

9:59:59.000,9:59:59.000
the scans were 18 minutes in duration,

9:59:59.000,9:59:59.000
there was a six-minute baseline,

9:59:59.000,9:59:59.000
and then we looked at changes in blood flow

9:59:59.000,9:59:59.000
after that baseline.

9:59:59.000,9:59:59.000
There were two scans:

9:59:59.000,9:59:59.000
a placebo scan followed by a drug scan.

9:59:59.000,9:59:59.000
And volunteers just lay in the scanner.

9:59:59.000,9:59:59.000
They were presented with a fixation cross:

9:59:59.000,9:59:59.000
just a simple green cross that they looked at

9:59:59.000,9:59:59.000
on a screen, and they just relaxed

9:59:59.000,9:59:59.000
and were instructed really just to let their minds wander.

9:59:59.000,9:59:59.000
And then we looked at how

9:59:59.000,9:59:59.000
the drug affected blood flow

9:59:59.000,9:59:59.000
during these conditions.

9:59:59.000,9:59:59.000
We gave a dose of 2 mg of psilocybin--

9:59:59.000,9:59:59.000
that compares to about 50 mg when given orally.

9:59:59.000,9:59:59.000
We gave the drug intravenously,

9:59:59.000,9:59:59.000
so 2 mg is equivalent to about 50 mg orally,

9:59:59.000,9:59:59.000
so it's a moderate dose.

9:59:59.000,9:59:59.000
Here's the design. Here's our 6-minute baseline.

9:59:59.000,9:59:59.000
Infusion was given over 60 seconds.

9:59:59.000,9:59:59.000
So it's a relatively rapid infusion.

9:59:59.000,9:59:59.000
And then the onset of the effects is also rapid,

9:59:59.000,9:59:59.000
so when the drug is given intravenously,

9:59:59.000,9:59:59.000
really there is very little delay between

9:59:59.000,9:59:59.000
delivery of the drug and the onset

9:59:59.000,9:59:59.000
of the subjective effects.

9:59:59.000,9:59:59.000
So the subjective effects actually begin,

9:59:59.000,9:59:59.000
really, before the end of the 60-second adminstration,

9:59:59.000,9:59:59.000
so the drug seems to really get in the brain

9:59:59.000,9:59:59.000
very quickly and to change consciousness

9:59:59.000,9:59:59.000
profoundly very quickly.

9:59:59.000,9:59:59.000
So what was the first observation?

9:59:59.000,9:59:59.000
Well, the first thing that we get

9:59:59.000,9:59:59.000
before we analyze the results are people's

9:59:59.000,9:59:59.000
descriptions of their experiences.

9:59:59.000,9:59:59.000
So here's one of them:

9:59:59.000,9:59:59.000
This volunteer said that "there was a definite

9:59:59.000,9:59:59.000
sense of lubrication,

9:59:59.000,9:59:59.000
of freedom,

9:59:59.000,9:59:59.000
of the cogs being loosened and firing off

9:59:59.000,9:59:59.000
in all sorts of unexpected directions."

9:59:59.000,9:59:59.000
Now these subjective reports are really useful

9:59:59.000,9:59:59.000
because they give you a sense of the

9:59:59.000,9:59:59.000
mechanics that are going on in the brain,

9:59:59.000,9:59:59.000
and the changes in the mechanics,

9:59:59.000,9:59:59.000
which confer the subjective effect --

9:59:59.000,9:59:59.000
what's going on in the brain on a mechanical level

9:59:59.000,9:59:59.000
to produce the profound changes in consciousness.

9:59:59.000,9:59:59.000
This volunteer said, "Everything became

9:59:59.000,9:59:59.000
fragmented; things were all in bits

9:59:59.000,9:59:59.000
and it was very hard to hold it all together

9:59:59.000,9:59:59.000
in a coherent stream."

9:59:59.000,9:59:59.000
So it's like I said, this stuff is really useful

9:59:59.000,9:59:59.000
for understanding what is going on

9:59:59.000,9:59:59.000
on a systems-level in the brain

9:59:59.000,9:59:59.000
to produce these subjective effects.

9:59:59.000,9:59:59.000
Now, the default mode network

9:59:59.000,9:59:59.000
you've heard quite a lot about

9:59:59.000,9:59:59.000
over the last two days.

9:59:59.000,9:59:59.000
It is an incredibly important

9:59:59.000,9:59:59.000
system that's been discovered in the brain.

9:59:59.000,9:59:59.000
And one of its properties is that

9:59:59.000,9:59:59.000
it has very dense connectivity,

9:59:59.000,9:59:59.000
so if you look at the white matter

9:59:59.000,9:59:59.000
tracks in the brain,

9:59:59.000,9:59:59.000
so these are the fibers that connect

9:59:59.000,9:59:59.000
different brain regions,

9:59:59.000,9:59:59.000
then you'll find that there's a very dense

9:59:59.000,9:59:59.000
coming together of connections within

9:59:59.000,9:59:59.000
the default mode notwork.

9:59:59.000,9:59:59.000
So there seems to be

9:59:59.000,9:59:59.000
an incredibly important transit hub,

9:59:59.000,9:59:59.000
a place where different regions

9:59:59.000,9:59:59.000
can connect via,

9:59:59.000,9:59:59.000
and information can be projected from,

9:59:59.000,9:59:59.000
and also a very important integration center.

9:59:59.000,9:59:59.000
So, to integrate brain function,

9:59:59.000,9:59:59.000
information comes together at this common

9:59:59.000,9:59:59.000
convergence zone, and then

9:59:59.000,9:59:59.000
that gives a coherence to cognition, essentially.

9:59:59.000,9:59:59.000
That's how it's understood so far.

9:59:59.000,9:59:59.000
What else about the default mode network?

9:59:59.000,9:59:59.000
So here's a metaphor to help you try and understand

9:59:59.000,9:59:59.000
what people are thinking about its function.

9:59:59.000,9:59:59.000
So a metaphor that could be used to explain

9:59:59.000,9:59:59.000
what it does is a capital city in a country.

9:59:59.000,9:59:59.000
It's a place where people come together,

9:59:59.000,9:59:59.000
things come together,

9:59:59.000,9:59:59.000
business gets done.

9:59:59.000,9:59:59.000
And it's an incredibly important hub,

9:59:59.000,9:59:59.000
and if ever

9:59:59.000,9:59:59.000
God forbid, something were to happen to

9:59:59.000,9:59:59.000
London, then, the country as a whole

9:59:59.000,9:59:59.000
would be seriously effected,

9:59:59.000,9:59:59.000
and not just Britain.

9:59:59.000,9:59:59.000
So it's incredibly important

9:59:59.000,9:59:59.000
integration hub, the default mode network.

9:59:59.000,9:59:59.000
What else do we know about

9:59:59.000,9:59:59.000
the default mode network?

9:59:59.000,9:59:59.000
There's some evidences here.

9:59:59.000,9:59:59.000
The default mode network undergoes

9:59:59.000,9:59:59.000
significant ontogenetic development

9:59:59.000,9:59:59.000
from infancy to adulthood.

9:59:59.000,9:59:59.000
It undergoes maturation as cognition matures.

9:59:59.000,9:59:59.000
It has also undergone significant

9:59:59.000,9:59:59.000
evolutionary expansion

9:59:59.000,9:59:59.000
so these regions have increased

9:59:59.000,9:59:59.000
more than other regions

9:59:59.000,9:59:59.000
from primates to humans.

9:59:59.000,9:59:59.000
It's more metabolically active

9:59:59.000,9:59:59.000
than elsewhere in the brain,

9:59:59.000,9:59:59.000
so the posterior cingulate cortex,

9:59:59.000,9:59:59.000
which is the region which is circled there,

9:59:59.000,9:59:59.000
it actually accounts for 40% more

9:59:59.000,9:59:59.000
blood flow than anywhere else

9:59:59.000,9:59:59.000
in the brain.

9:59:59.000,9:59:59.000
So it is a very metabolically hungry system

9:59:59.000,9:59:59.000
and these regions that are part of it

9:59:59.000,9:59:59.000
are incredibly metabolically hungry.

9:59:59.000,9:59:59.000
It's doing something important.

9:59:59.000,9:59:59.000
Now, a matter of intrigue in neuroscience

9:59:59.000,9:59:59.000
is that people don't have a really good handle

9:59:59.000,9:59:59.000
on what the default mode is

9:59:59.000,9:59:59.000
and what it does,

9:59:59.000,9:59:59.000
but of course, they enjoy speculating,

9:59:59.000,9:59:59.000
and the researcher who really discovered

9:59:59.000,9:59:59.000
the default mode network has referred

9:59:59.000,9:59:59.000
to its very high energy levels

9:59:59.000,9:59:59.000
as being like the brain's dark energy.

9:59:59.000,9:59:59.000
So similar to dark energy in cosmology

9:59:59.000,9:59:59.000
it is something that we know is there

9:59:59.000,9:59:59.000
but we don't really know what it does.

9:59:59.000,9:59:59.000
Really, we make inferences about it,

9:59:59.000,9:59:59.000
based on its relative decrease in activity.

9:59:59.000,9:59:59.000
So when you engage in a task,

9:59:59.000,9:59:59.000
you see a decrease in activity

9:59:59.000,9:59:59.000
in the default mode network,

9:59:59.000,9:59:59.000
whereas otherwise

9:59:59.000,9:59:59.000
it is incredibly active.

9:59:59.000,9:59:59.000
So it's a mater of intrigue.

9:59:59.000,9:59:59.000
What's going on here?

9:59:59.000,9:59:59.000
What's all this energy for, and why

9:59:59.000,9:59:59.000
is it consuming so much?

9:59:59.000,9:59:59.000
We know that the default mode network

9:59:59.000,9:59:59.000
is engaged during self-reflection,

9:59:59.000,9:59:59.000
so that is a very staple finding.

9:59:59.000,9:59:59.000
We also know that during

9:59:59.000,9:59:59.000
complex mental imagery, such as

9:59:59.000,9:59:59.000
spatial navigation or imagination,

9:59:59.000,9:59:59.000
fantasy in one's mind eye,

9:59:59.000,9:59:59.000
you'll also see increased activity

9:59:59.000,9:59:59.000
in the default mode network.

9:59:59.000,9:59:59.000
Mental time travel -- so that's being

9:59:59.000,9:59:59.000
outside of the moment and

9:59:59.000,9:59:59.000
daydreaming about future events

9:59:59.000,9:59:59.000
or past biographical experiences.

9:59:59.000,9:59:59.000
So whenever you come out of the moment

9:59:59.000,9:59:59.000
and you daydream in this way,

9:59:59.000,9:59:59.000
you see increased activity and connectivity

9:59:59.000,9:59:59.000
in the default mode network.

9:59:59.000,9:59:59.000
Also, theory of mind -- which is

9:59:59.000,9:59:59.000
putting someone oneself

9:59:59.000,9:59:59.000
in somebody else's shoes.

9:59:59.000,9:59:59.000
You will also see increased activity

9:59:59.000,9:59:59.000
in the default mode network during that function.

9:59:59.000,9:59:59.000
And metacognition -- which thinking about thinking,

9:59:59.000,9:59:59.000
that's also linked with

9:59:59.000,9:59:59.000
default mode network activity.

9:59:59.000,9:59:59.000
So Raichle, who I said is the guy who

9:59:59.000,9:59:59.000
really discovered this network

9:59:59.000,9:59:59.000
has also referred to it as

9:59:59.000,9:59:59.000
the orchestrator of the self.

9:59:59.000,9:59:59.000
So all these things

9:59:59.000,9:59:59.000
led me to start thinking

9:59:59.000,9:59:59.000
having a background in psychoanalysis

9:59:59.000,9:59:59.000
and being interested in

9:59:59.000,9:59:59.000
especially Freudian metapsychology

9:59:59.000,9:59:59.000
instead of the more mechanistic

9:59:59.000,9:59:59.000
ideas of Freud. There is remarkable overlap

9:59:59.000,9:59:59.000
between his descriptions of the ego

9:59:59.000,9:59:59.000
and the relationship between the ego

9:59:59.000,9:59:59.000
and the unconscious mind, or the id,

9:59:59.000,9:59:59.000
and what we're discovering in

9:59:59.000,9:59:59.000
the default mode network.

9:59:59.000,9:59:59.000
So in this paper, with Carhart-Harris & Friston,

9:59:59.000,9:59:59.000
I submitted the idea that

9:59:59.000,9:59:59.000
the default mode network is essentially

9:59:59.000,9:59:59.000
the neural substrate source of the ego,

9:59:59.000,9:59:59.000
which is an idea to be shot down

9:59:59.000,9:59:59.000
if people find otherwise.

9:59:59.000,9:59:59.000
But that's science. That's how we work.

9:59:59.000,9:59:59.000
So what else is there about

9:59:59.000,9:59:59.000
the default mode network?

9:59:59.000,9:59:59.000
Well, what's it's relationship to depression?

9:59:59.000,9:59:59.000
There's a very interesting relationship

9:59:59.000,9:59:59.000
between default mode network parameters

9:59:59.000,9:59:59.000
and depressive symptomatology.

9:59:59.000,9:59:59.000
So we know that connectivity between

9:59:59.000,9:59:59.000
the medial pre-frontal cortex

9:59:59.000,9:59:59.000
of the default mode network

9:59:59.000,9:59:59.000
and the posterior cingulate cortex

9:59:59.000,9:59:59.000
which are

9:59:59.000,9:59:59.000
(pause)

9:59:59.000,9:59:59.000
the front bits and the back bits.

9:59:59.000,9:59:59.000
So when connectivity between these regions

9:59:59.000,9:59:59.000
is high,

9:59:59.000,9:59:59.000
then scores in patients with depression

9:59:59.000,9:59:59.000
on rumination (so these are scores in rumination.

9:59:59.000,9:59:59.000
They are thinking over problems

9:59:59.000,9:59:59.000
and ruminating on negative things),

9:59:59.000,9:59:59.000
when this is high, connectivity

9:59:59.000,9:59:59.000
betwen these regions is especially

9:59:59.000,9:59:59.000
high. And we think this system,

9:59:59.000,9:59:59.000
this overconnectivity, is really causing people to

9:59:59.000,9:59:59.000
have a kind of stereotype style of thinking.

9:59:59.000,9:59:59.000
So they are stuck in this system,

9:59:59.000,9:59:59.000
they are stuck in their own heads,

9:59:59.000,9:59:59.000
they are stuck on their sense of self.

9:59:59.000,9:59:59.000
They are usually thinking very critically

9:59:59.000,9:59:59.000
about themselves, and going over and over

9:59:59.000,9:59:59.000
about how terrible they are.

9:59:59.000,9:59:59.000
So this is a relationship we seem to be discovering

9:59:59.000,9:59:59.000
about the default mode network

9:59:59.000,9:59:59.000
and depressive symptomatology.

9:59:59.000,9:59:59.000
This provides a useful background

9:59:59.000,9:59:59.000
for what we're finding in terms of how

9:59:59.000,9:59:59.000
psilocybin is affecting

9:59:59.000,9:59:59.000
brain networks and brain systems.

9:59:59.000,9:59:59.000
So in our ASL study, we found

9:59:59.000,9:59:59.000
it was really quite surprising findings for us,

9:59:59.000,9:59:59.000
given descriptions of consciousness

9:59:59.000,9:59:59.000
being expanded by psychedelic drugs.

9:59:59.000,9:59:59.000
We are given some previous work,

9:59:59.000,9:59:59.000
for instance, by Franz Vollenweider,

9:59:59.000,9:59:59.000
we were thinking we were going to be seeing

9:59:59.000,9:59:59.000
increases in brain activity or brain blood flow

9:59:59.000,9:59:59.000
with psilocybin.

9:59:59.000,9:59:59.000
And despite dropping the threshold

9:59:59.000,9:59:59.000
and a number of different things,

9:59:59.000,9:59:59.000
we really didn't see this.

9:59:59.000,9:59:59.000
All we were really seeing was

9:59:59.000,9:59:59.000
the same pattern again and again,

9:59:59.000,9:59:59.000
which was decreased blood flow

9:59:59.000,9:59:59.000
in certain regions of the brain.

9:59:59.000,9:59:59.000
What was intriguing was that

9:59:59.000,9:59:59.000
the decreases that we were seeing were

9:59:59.000,9:59:59.000
in these very same important hub strutures

9:59:59.000,9:59:59.000
of the brain.

9:59:59.000,9:59:59.000
So, for instance, the posterior cingulate cortex,

9:59:59.000,9:59:59.000
this bit at the back,

9:59:59.000,9:59:59.000
the thalamus,

9:59:59.000,9:59:59.000
and the medial pre-frontal cortex --

9:59:59.000,9:59:59.000
so these very reliably

9:59:59.000,9:59:59.000
were coming up as being

9:59:59.000,9:59:59.000
decreased under psilocybin.

9:59:59.000,9:59:59.000
Here's just showing you again,

9:59:59.000,9:59:59.000
the default mode network is this kind of

9:59:59.000,9:59:59.000
hub, this connectivity hub, in the brain.

9:59:59.000,9:59:59.000
We also found that

9:59:59.000,9:59:59.000
there was a relationship between

9:59:59.000,9:59:59.000
the magnitude of the decrease in blood flow

9:59:59.000,9:59:59.000
and ratings of the intensity of the experience.

9:59:59.000,9:59:59.000
So, the larger the decrease in blood flow,

9:59:59.000,9:59:59.000
particularly in the anterior cingulate cortex,

9:59:59.000,9:59:59.000
the more intense people were describing

9:59:59.000,9:59:59.000
their experiences.

9:59:59.000,9:59:59.000
So whenever you find these relationships

9:59:59.000,9:59:59.000
it kind of reinforces your inferences, really,

9:59:59.000,9:59:59.000
and provides some consolidation

9:59:59.000,9:59:59.000
for what you are finding

9:59:59.000,9:59:59.000
and supports its functional meaning.

9:59:59.000,9:59:59.000
So since our ASL study

9:59:59.000,9:59:59.000
we did a [bold] study.

9:59:59.000,9:59:59.000
This is kind of the classic [signal]

9:59:59.000,9:59:59.000
of functional magnetic resonance imaging (fMRI).

9:59:59.000,9:59:59.000
We really repeated the same protocol:

9:59:59.000,9:59:59.000
15 healthy volunteers,

9:59:59.000,9:59:59.000
infused with a drug over 60 seconds at 2 mg,

9:59:59.000,9:59:59.000
and we found exactly the same thing.

9:59:59.000,9:59:59.000
So this was really nice reinforcement

9:59:59.000,9:59:59.000
for the initial finding that we had found

9:59:59.000,9:59:59.000
with ASL.

9:59:59.000,9:59:59.000
And these regions where there was a common

9:59:59.000,9:59:59.000
overlap between the decreases in blood flow

9:59:59.000,9:59:59.000
with ASL and the decreases in,

9:59:59.000,9:59:59.000
essentially venous oxygenation,

9:59:59.000,9:59:59.000
or oxygenated blood with the BOLD signal

9:59:59.000,9:59:59.000
of fMRI.

9:59:59.000,9:59:59.000
So one of the merits of BOLD fMRI is

9:59:59.000,9:59:59.000
that it allows you to do these

9:59:59.000,9:59:59.000
functional connectivity analyses.

9:59:59.000,9:59:59.000
So just to give you a feel for what that is,

9:59:59.000,9:59:59.000
here is an image which shows

9:59:59.000,9:59:59.000
the default mode network in orange

9:59:59.000,9:59:59.000
and let's concentrate on the default

9:59:59.000,9:59:59.000
mode network for a moment.

9:59:59.000,9:59:59.000
So you can see that there are two regions in it,

9:59:59.000,9:59:59.000
and there is one that has has yellow text,

9:59:59.000,9:59:59.000
the PCC? and then you can see there is this

9:59:59.000,9:59:59.000
time series underneath.

9:59:59.000,9:59:59.000
So the PCC time series is in yellow

9:59:59.000,9:59:59.000
and you can see that it overlaps with

9:59:59.000,9:59:59.000
anothertime series, and that is

9:59:59.000,9:59:59.000
the medial prefontal cortex.

9:59:59.000,9:59:59.000
So it is by looking at correlations between

9:59:59.000,9:59:59.000
fluctuations in the BOLD signal

9:59:59.000,9:59:59.000
that we identify functionally coherent

9:59:59.000,9:59:59.000
brain networks. We know these regions

9:59:59.000,9:59:59.000
work together as a common network

9:59:59.000,9:59:59.000
doing a common function.