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It's a real pleasure to be here

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and to present the work I've been doing

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over the last five years or so since my PhD.

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Genuinely, I want you to try and understand

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as much as you can

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So it's not the easiest material,

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And especially when you don't have a background in neuroscience.

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It's not always that easy to get a handle on these processes.

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But I'm going to do my absolute best

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to try and help you understand, and

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I'll provide some metaphors to try and

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break things down to make things more accessible.

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Also it would be useful to keep

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some pens out because there will be

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some references, so if you genuinely you do

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want to understand how these drugs

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work in the brain, then it does require

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a bit of work on your parts as well, unfortunately.

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So you'd have to go away and look up

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some of these references and do some

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background reading.

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So I just want to start by saying

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that this work is part of the

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Beckley-Imperial psychedelic research programme,

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which is an initiative between David Kotts

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and Amanda Fielding of the Beckley Foundation.

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Amanda is a key collaborative partner in this work,

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and David Nutts, the principal investigator on it.

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So we'll start with the science.

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We know that psilocybin is an ingredient

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in magic mushrooms.

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Now, psilocybin is the [pro-drug] of psilocin,

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which is remarkably similar in its molecular structure

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to the endogenous neurotransmitter

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which is found throughout the brain, serotonin.

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So it is really quite striking how similar

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it is in its molecular structure.

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Just a subtle change in its structure

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confers such profound effects of consciousness.

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So this already

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is a matter of great intrigue

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about how these drugs work in the brain.

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So what was found in the mid-1980s

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was a strong positive correlation

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between a psychedelic drug's affinity

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for the serotonin 2A receptor,

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a particular subtype of the serotonin receptor,

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and the drug's potency.

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So a good example to help illustrate

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it's principle is, LSD has a very high affinity

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for the serotonin 2A receptor --

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it's very sticky, and it's also incredibly potent.

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So that helps you understand.

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Also, Franz Vollenweider did an excellent study

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blocking the serotinin 2A receptor

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with ketanserin, a relatively selective

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serotonin 2A receptor blocker,

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and he found that pre-treatment

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with this drug blocked the psychedelic effects

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of psilocybin. So there's good evidence

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that these drugs trigger their effects

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on consciousness by initial effect on

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the serotonin 2A receptor.

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So already we have an important

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fundamental relationship that's been discovered

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between the serotonin system and how these drugs work

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in the brain.

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So where is the serotonin 2A receptor in the brain?

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Well, this is the largest serotonin 2A binding study

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that's been done by a colleague of ours,

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David Erritzoe.

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He used a radioactive tracer, or ligand,

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that sticks to serotonin 2A receptors in the brain.

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And then you can detect the signal

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where the ligand is stuck

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And so doing this, he found that

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the serotonin 2A receptor is

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very much a cortical receptor.

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So the outer layer of the brain, the cortex,

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(it's referred to as kind of like the bark of a tree)

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so this outer layer of the brain, that's where you find

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the serotonin 2A receptor.

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And it's especially prevalent,

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especially densely expressed,

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in high-level cortical regions.

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So these are regions that

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don't have a specific sensory function, like,

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for instance, the visual cortex, which is concerned

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with visual processing.

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The heteromodal regions so they have a more

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kind of divergent, and high-level, function

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and so the serotonin 2A receptor

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is especially densely expressed

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in these high-level cortical regions,

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such as the posterior cingulate cortex.

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You will hear this term referred to again

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throughout my talk

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because it's a key region of the brain,

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a very high-level region of the brain,

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and it seems to be especially implicated in

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the mechanistic action of these drugs,

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how they work in the brain.

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We also know that the serotonin 2A receptor

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is especially densely expressed

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in the particular layer of the cortex.

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So the cortex is organized in a kind of laminar

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way, and there's some large,

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what are referred to as pyramidal neurons

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in layer 5 of the cortex.

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That is... (pause)

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This is layer 5 here.

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So there's some large neurons there,

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and these are the principal output layer

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of the cortex,

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and there's also something else,

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which is especially important about

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this cellular group,

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in terms of how this drug works in the brain.

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So we know the serotonin 2A receptor is very important,

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We know where it is,

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in terms of its spatial distribution in the brain

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and also within the cortex itself,

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within its laminae organization. It's dense in the

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deep pyramidal cells in layer 5.

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We also know that if you stimulate

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the serotonin 2A receptor,

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you have an excitatory effect on the host cells.

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So the cell that expresses the receptor,

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if you stimulate it, then you're gonna make that cell

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more excitable.

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So these are all important principles that we know.

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These are kind of the bedrock findings so far

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about how psychedelics work in the brain.

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But these are all quite low level;

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my brain imaging work has been looking at

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a higher level,

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what's referred to as a macroscopic level.

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So, the level you can look at and see

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on a large scale in terms of

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brain networks, for instance,

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and regional brain activity.

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So let's start with our first study,

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our first fMRI study with psilocybin.

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This used the modality referred to as

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arterial spin labelling, which is

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a method which measures changes

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in blood flow in the brain.

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And generally there's quite a reliable relationship

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between blood flow in the brain and brain activity.

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So if blood flow increases,

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we generally infer

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that brain activity has increased.

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So this study had fifteen healthy volunteers,

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mean age of 34,

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the scans were 18 minutes in duration,

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there was a six-minute baseline,

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and then we looked at changes in blood flow

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after that baseline.

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There were two scans:

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a placebo scan followed by a drug scan.

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And volunteers just lay in the scanner.

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They were presented with a fixation cross:

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just a simple green cross that they looked at

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on a screen, and they just relaxed

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and were instructed really just to let their minds wander.

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And then we looked at how

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the drug affected blood flow

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during these conditions.

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We gave a dose of 2 mg of psilocybin--

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that compares to about 50 mg when given orally.

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We gave the drug intravenously,

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so 2 mg is equivalent to about 50 mg orally,

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so it's a moderate dose.

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Here's the design. Here's our 6-minute baseline.

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Infusion was given over 60 seconds.

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So it's a relatively rapid infusion.

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And then the onset of the effects is also rapid,

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so when the drug is given intravenously,

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really there is very little delay between

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delivery of the drug and the onset

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of the subjective effects.

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So the subjective effects actually begin,

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really, before the end of the 60-second adminstration,

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so the drug seems to really get in the brain

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very quickly and to change consciousness

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profoundly very quickly.

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So what was the first observation?

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Well, the first thing that we get

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before we analyze the results are people's

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descriptions of their experiences.

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So here's one of them:

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This volunteer said that "there was a definite

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sense of lubrication,

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of freedom,

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of the cogs being loosened and firing off

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in all sorts of unexpected directions."

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Now these subjective reports are really useful

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because they give you a sense of the

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mechanics that are going on in the brain,

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and the changes in the mechanics,

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which confer the subjective effect --

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what's going on in the brain on a mechanical level

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to produce the profound changes in consciousness.

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This volunteer said, "Everything became

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fragmented; things were all in bits

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and it was very hard to hold it all together

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in a coherent stream."

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So it's like I said, this stuff is really useful

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for understanding what is going on

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on a systems-level in the brain

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to produce these subjective effects.

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Now, the default mode network

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you've heard quite a lot about

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over the last two days.

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It is an incredibly important

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system that's been discovered in the brain.

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And one of its properties is that

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it has very dense connectivity,

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so if you look at the white matter

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tracks in the brain,

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so these are the fibers that connect

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different brain regions,

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then you'll find that there's a very dense

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coming together of connections within

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the default mode notwork.

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So there seems to be

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an incredibly important transit hub,

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a place where different regions

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can connect via,

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and information can be projected from,

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and also a very important integration center.

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So, to integrate brain function,

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information comes together at this common

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convergence zone, and then

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that gives a coherence to cognition, essentially.

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That's how it's understood so far.

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What else about the default mode network?

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So here's a metaphor to help you try and understand

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what people are thinking about its function.

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So a metaphor that could be used to explain

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what it does is a capital city in a country.

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It's a place where people come together,

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things come together,

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business gets done.

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And it's an incredibly important hub,

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and if ever

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God forbid, something were to happen to

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London, then, the country as a whole

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would be seriously effected,

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and not just Britain.

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So it's incredibly important

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integration hub, the default mode network.

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What else do we know about

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the default mode network?

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There's some evidences here.

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The default mode network undergoes

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significant ontogenetic development

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from infancy to adulthood.

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It undergoes maturation as cognition matures.

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It has also undergone significant

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evolutionary expansion

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so these regions have increased

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more than other regions

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from primates to humans.

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It's more metabolically active

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than elsewhere in the brain,

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so the posterior cingulate cortex,

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which is the region which is circled there,

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it actually accounts for 40% more

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blood flow than anywhere else

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in the brain.

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So it is a very metabolically hungry system

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and these regions that are part of it

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are incredibly metabolically hungry.

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It's doing something important.

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Now, a matter of intrigue in neuroscience

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is that people don't have a really good handle

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on what the default mode is

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and what it does,

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but of course, they enjoy speculating,

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and the researcher who really discovered

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the default mode network has referred

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to its very high energy levels

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as being like the brain's dark energy.

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So similar to dark energy in cosmology

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it is something that we know is there

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but we don't really know what it does.

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Really, we make inferences about it,

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based on its relative decrease in activity.

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So when you engage in a task,

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you see a decrease in activity

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in the default mode network,

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whereas otherwise

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it is incredibly active.

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So it's a mater of intrigue.

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What's going on here?

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What's all this energy for, and why

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is it consuming so much?

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We know that the default mode network

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is engaged during self-reflection,

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so that is a very staple finding.

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We also know that during

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complex mental imagery, such as

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spatial navigation or imagination,

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fantasy in one's mind eye,

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you'll also see increased activity

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in the default mode network.

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Mental time travel -- so that's being

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outside of the moment and

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daydreaming about future events

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or past biographical experiences.

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So whenever you come out of the moment

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and you daydream in this way,

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you see increased activity and connectivity

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in the default mode network.

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Also, theory of mind -- which is

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putting someone oneself

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in somebody else's shoes.

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You will also see increased activity

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in the default mode network during that function.

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And metacognition -- which thinking about thinking,

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that's also linked with

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default mode network activity.

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So Raichle, who I said is the guy who

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really discovered this network

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has also referred to it as

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the orchestrator of the self.

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So all these things

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led me to start thinking

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having a background in psychoanalysis

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and being interested in

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especially Freudian metapsychology

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instead of the more mechanistic

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ideas of Freud. There is remarkable overlap

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between his descriptions of the ego

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and the relationship between the ego

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and the unconscious mind, or the id,

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and what we're discovering in

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the default mode network.

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So in this paper, with Carhart-Harris & Friston,

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I submitted the idea that

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the default mode network is essentially

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the neural substrate source of the ego,

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which is an idea to be shot down

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if people find otherwise.

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But that's science. That's how we work.

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So what else is there about

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the default mode network?

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Well, what's it's relationship to depression?

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There's a very interesting relationship

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between default mode network parameters

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and depressive symptomatology.

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So we know that connectivity between

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the medial pre-frontal cortex

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of the default mode network

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and the posterior cingulate cortex

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which are

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(pause)

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the front bits and the back bits.

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So when connectivity between these regions

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is high,

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then scores in patients with depression

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on rumination (so these are scores in rumination.

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They are thinking over problems

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and ruminating on negative things),

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when this is high, connectivity

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betwen these regions is especially

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high. And we think this system,

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this overconnectivity, is really causing people to

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have a kind of stereotype style of thinking.

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So they are stuck in this system,

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they are stuck in their own heads,

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they are stuck on their sense of self.

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They are usually thinking very critically

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about themselves, and going over and over

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about how terrible they are.

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So this is a relationship we seem to be discovering

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about the default mode network

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and depressive symptomatology.

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This provides a useful background

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for what we're finding in terms of how

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psilocybin is affecting

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brain networks and brain systems.

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So in our ASL study, we found

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it was really quite surprising findings for us,

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given descriptions of consciousness

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being expanded by psychedelic drugs.

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We are given some previous work,

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for instance, by Franz Vollenweider,

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we were thinking we were going to be seeing

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increases in brain activity or brain blood flow

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with psilocybin.

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And despite dropping the threshold

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and a number of different things,

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we really didn't see this.

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All we were really seeing was

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the same pattern again and again,

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which was decreased blood flow

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in certain regions of the brain.

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What was intriguing was that

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the decreases that we were seeing were

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in these very same important hub strutures

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of the brain.

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So, for instance, the posterior cingulate cortex,

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this bit at the back,

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the thalamus,

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and the medial pre-frontal cortex --

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so these very reliably

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were coming up as being

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decreased under psilocybin.

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Here's just showing you again,

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the default mode network is this kind of

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hub, this connectivity hub, in the brain.

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We also found that

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there was a relationship between

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the magnitude of the decrease in blood flow

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and ratings of the intensity of the experience.

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So, the larger the decrease in blood flow,

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particularly in the anterior cingulate cortex,

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the more intense people were describing

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their experiences.

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So whenever you find these relationships

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it kind of reinforces your inferences, really,

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and provides some consolidation

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for what you are finding

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and supports its functional meaning.

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So since our ASL study

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we did a [bold] study.

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This is kind of the classic [signal]

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of functional magnetic resonance imaging (fMRI).

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We really repeated the same protocol:

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15 healthy volunteers,

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infused with a drug over 60 seconds at 2 mg,

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and we found exactly the same thing.

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So this was really nice reinforcement

436
99:59:59,999 --> 99:59:59,999
for the initial finding that we had found

437
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with ASL.

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And these regions where there was a common

439
99:59:59,999 --> 99:59:59,999
overlap between the decreases in blood flow

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with ASL and the decreases in,

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essentially venous oxygenation,

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or oxygenated blood with the BOLD signal

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of fMRI.

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So one of the merits of BOLD fMRI is

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that it allows you to do these

446
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functional connectivity analyses.

447
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So just to give you a feel for what that is,

448
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here is an image which shows

449
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the default mode network in orange

450
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and let's concentrate on the default

451
99:59:59,999 --> 99:59:59,999
mode network for a moment.

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So you can see that there are two regions in it,

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and there is one that has has yellow text,

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the PCC? and then you can see there is this

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time series underneath.

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So the PCC time series is in yellow

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and you can see that it overlaps with

458
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anothertime series, and that is

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the medial prefontal cortex.

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So it is by looking at correlations between

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fluctuations in the BOLD signal

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that we identify functionally coherent

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brain networks. We know these regions

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work together as a common network

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doing a common function.