WEBVTT 00:00:06.387 --> 00:00:07.971 It's a real pleasure to be here 00:00:07.971 --> 00:00:10.648 and to present the work I've been doing 00:00:10.648 --> 00:00:15.957 over the last five years or so since my PhD. 00:00:15.957 --> 00:00:19.860 Genuinely, I want you to try and understand 00:00:19.860 --> 00:00:20.860 as much as you can 00:00:24.717 --> 00:00:24.967 So it's not the easiest material, 00:00:26.289 --> 00:00:26.741 And especially when you don't have a background in neuroscience. 00:00:32.709 --> 00:00:36.318 It's not always that easy to get a handle on these processes. 00:00:36.318 --> 00:00:41.169 But I'm going to do my absolute best 00:00:41.169 --> 00:00:42.211 to try and help you understand, and 00:00:42.211 --> 00:00:43.714 I'll provide some metaphors to try and 00:00:43.714 --> 00:00:46.387 break things down to make things more accessible. 00:00:46.387 --> 00:00:50.003 Also it would be useful to keep 00:00:50.003 --> 00:00:50.867 some pens out because there will be 00:00:50.867 --> 00:00:52.618 some references, so if you genuinely you do 00:00:52.618 --> 00:00:53.672 want to understand how these drugs 00:00:53.672 --> 00:00:55.459 work in the brain, then it does require 00:00:55.459 --> 00:00:57.785 a bit of work on your parts as well, unfortunately. 00:00:57.785 --> 00:00:58.979 So you'd have to go away and look up 00:00:58.979 --> 00:01:00.289 some of these references and do some 00:01:00.289 --> 00:01:02.367 background reading. 00:01:02.367 --> 00:01:04.470 So I just want to start by saying 00:01:04.470 --> 00:01:06.482 that this work is part of the 00:01:06.482 --> 00:01:10.031 Beckley-Imperial psychedelic research programme, 00:01:10.031 --> 00:01:12.757 which is an initiative between David Kotts 00:01:12.757 --> 00:01:14.753 and Amanda Fielding of the Beckley Foundation. 00:01:14.753 --> 00:01:18.726 Amanda is a key collaborative partner in this work, 00:01:19.699 --> 00:01:21.353 and David Nutts, the principal investigator on it. 00:01:21.353 --> 00:01:24.647 So we'll start with the science. 00:01:24.647 --> 00:01:27.212 We know that psilocybin is an ingredient 00:01:27.212 --> 00:01:29.467 in magic mushrooms. 00:01:29.467 --> 00:01:32.338 Now, psilocybin is the [pro-drug] of psilocin, 00:01:32.338 --> 00:01:35.804 which is remarkably similar in its molecular structure 00:01:35.804 --> 00:01:38.330 to the endogenous neurotransmitter 00:01:38.330 --> 00:01:41.192 which is found throughout the brain, serotonin. 00:01:41.192 --> 00:01:43.899 So it is really quite striking how similar 00:01:43.899 --> 00:01:46.699 it is in its molecular structure. 00:01:46.699 --> 00:01:50.325 Just a subtle change in its structure 00:01:50.325 --> 00:01:53.548 confers such profound effects of consciousness. 99:59:59.999 --> 99:59:59.999 So this already 99:59:59.999 --> 99:59:59.999 is a matter of great intrigue 99:59:59.999 --> 99:59:59.999 about how these drugs work in the brain. 99:59:59.999 --> 99:59:59.999 So what was found in the mid-1980s 99:59:59.999 --> 99:59:59.999 was a strong positive correlation 99:59:59.999 --> 99:59:59.999 between a psychedelic drug's affinity 99:59:59.999 --> 99:59:59.999 for the serotonin 2A receptor, 99:59:59.999 --> 99:59:59.999 a particular subtype of the serotonin receptor, 99:59:59.999 --> 99:59:59.999 and the drug's potency. 99:59:59.999 --> 99:59:59.999 So a good example to help illustrate 99:59:59.999 --> 99:59:59.999 it's principle is, LSD has a very high affinity 99:59:59.999 --> 99:59:59.999 for the serotonin 2A receptor -- 99:59:59.999 --> 99:59:59.999 it's very sticky, and it's also incredibly potent. 99:59:59.999 --> 99:59:59.999 So that helps you understand. 99:59:59.999 --> 99:59:59.999 Also, Franz Vollenweider did an excellent study 99:59:59.999 --> 99:59:59.999 blocking the serotinin 2A receptor 99:59:59.999 --> 99:59:59.999 with ketanserin, a relatively selective 99:59:59.999 --> 99:59:59.999 serotonin 2A receptor blocker, 99:59:59.999 --> 99:59:59.999 and he found that pre-treatment 99:59:59.999 --> 99:59:59.999 with this drug blocked the psychedelic effects 99:59:59.999 --> 99:59:59.999 of psilocybin. So there's good evidence 99:59:59.999 --> 99:59:59.999 that these drugs trigger their effects 99:59:59.999 --> 99:59:59.999 on consciousness by initial effect on 99:59:59.999 --> 99:59:59.999 the serotonin 2A receptor. 99:59:59.999 --> 99:59:59.999 So already we have an important 99:59:59.999 --> 99:59:59.999 fundamental relationship that's been discovered 99:59:59.999 --> 99:59:59.999 between the serotonin system and how these drugs work 99:59:59.999 --> 99:59:59.999 in the brain. 99:59:59.999 --> 99:59:59.999 So where is the serotonin 2A receptor in the brain? 99:59:59.999 --> 99:59:59.999 Well, this is the largest serotonin 2A binding study 99:59:59.999 --> 99:59:59.999 that's been done by a colleague of ours, 99:59:59.999 --> 99:59:59.999 David Erritzoe. 99:59:59.999 --> 99:59:59.999 He used a radioactive tracer, or ligand, 99:59:59.999 --> 99:59:59.999 that sticks to serotonin 2A receptors in the brain. 99:59:59.999 --> 99:59:59.999 And then you can detect the signal 99:59:59.999 --> 99:59:59.999 where the ligand is stuck 99:59:59.999 --> 99:59:59.999 And so doing this, he found that 99:59:59.999 --> 99:59:59.999 the serotonin 2A receptor is 99:59:59.999 --> 99:59:59.999 very much a cortical receptor. 99:59:59.999 --> 99:59:59.999 So the outer layer of the brain, the cortex, 99:59:59.999 --> 99:59:59.999 (it's referred to as kind of like the bark of a tree) 99:59:59.999 --> 99:59:59.999 so this outer layer of the brain, that's where you find 99:59:59.999 --> 99:59:59.999 the serotonin 2A receptor. 99:59:59.999 --> 99:59:59.999 And it's especially prevalent, 99:59:59.999 --> 99:59:59.999 especially densely expressed, 99:59:59.999 --> 99:59:59.999 in high-level cortical regions. 99:59:59.999 --> 99:59:59.999 So these are regions that 99:59:59.999 --> 99:59:59.999 don't have a specific sensory function, like, 99:59:59.999 --> 99:59:59.999 for instance, the visual cortex, which is concerned 99:59:59.999 --> 99:59:59.999 with visual processing. 99:59:59.999 --> 99:59:59.999 The heteromodal regions so they have a more 99:59:59.999 --> 99:59:59.999 kind of divergent, and high-level, function 99:59:59.999 --> 99:59:59.999 and so the serotonin 2A receptor 99:59:59.999 --> 99:59:59.999 is especially densely expressed 99:59:59.999 --> 99:59:59.999 in these high-level cortical regions, 99:59:59.999 --> 99:59:59.999 such as the posterior cingulate cortex. 99:59:59.999 --> 99:59:59.999 You will hear this term referred to again 99:59:59.999 --> 99:59:59.999 throughout my talk 99:59:59.999 --> 99:59:59.999 because it's a key region of the brain, 99:59:59.999 --> 99:59:59.999 a very high-level region of the brain, 99:59:59.999 --> 99:59:59.999 and it seems to be especially implicated in 99:59:59.999 --> 99:59:59.999 the mechanistic action of these drugs, 99:59:59.999 --> 99:59:59.999 how they work in the brain. 99:59:59.999 --> 99:59:59.999 We also know that the serotonin 2A receptor 99:59:59.999 --> 99:59:59.999 is especially densely expressed 99:59:59.999 --> 99:59:59.999 in the particular layer of the cortex. 99:59:59.999 --> 99:59:59.999 So the cortex is organized in a kind of laminar 99:59:59.999 --> 99:59:59.999 way, and there's some large, 99:59:59.999 --> 99:59:59.999 what are referred to as pyramidal neurons 99:59:59.999 --> 99:59:59.999 in layer 5 of the cortex. 99:59:59.999 --> 99:59:59.999 That is... (pause) 99:59:59.999 --> 99:59:59.999 This is layer 5 here. 99:59:59.999 --> 99:59:59.999 So there's some large neurons there, 99:59:59.999 --> 99:59:59.999 and these are the principal output layer 99:59:59.999 --> 99:59:59.999 of the cortex, 99:59:59.999 --> 99:59:59.999 and there's also something else, 99:59:59.999 --> 99:59:59.999 which is especially important about 99:59:59.999 --> 99:59:59.999 this cellular group, 99:59:59.999 --> 99:59:59.999 in terms of how this drug works in the brain. 99:59:59.999 --> 99:59:59.999 So we know the serotonin 2A receptor is very important, 99:59:59.999 --> 99:59:59.999 We know where it is, 99:59:59.999 --> 99:59:59.999 in terms of its spatial distribution in the brain 99:59:59.999 --> 99:59:59.999 and also within the cortex itself, 99:59:59.999 --> 99:59:59.999 within its laminae organization. It's dense in the 99:59:59.999 --> 99:59:59.999 deep pyramidal cells in layer 5. 99:59:59.999 --> 99:59:59.999 We also know that if you stimulate 99:59:59.999 --> 99:59:59.999 the serotonin 2A receptor, 99:59:59.999 --> 99:59:59.999 you have an excitatory effect on the host cells. 99:59:59.999 --> 99:59:59.999 So the cell that expresses the receptor, 99:59:59.999 --> 99:59:59.999 if you stimulate it, then you're gonna make that cell 99:59:59.999 --> 99:59:59.999 more excitable. 99:59:59.999 --> 99:59:59.999 So these are all important principles that we know. 99:59:59.999 --> 99:59:59.999 These are kind of the bedrock findings so far 99:59:59.999 --> 99:59:59.999 about how psychedelics work in the brain. 99:59:59.999 --> 99:59:59.999 But these are all quite low level; 99:59:59.999 --> 99:59:59.999 my brain imaging work has been looking at 99:59:59.999 --> 99:59:59.999 a higher level, 99:59:59.999 --> 99:59:59.999 what's referred to as a macroscopic level. 99:59:59.999 --> 99:59:59.999 So, the level you can look at and see 99:59:59.999 --> 99:59:59.999 on a large scale in terms of 99:59:59.999 --> 99:59:59.999 brain networks, for instance, 99:59:59.999 --> 99:59:59.999 and regional brain activity. 99:59:59.999 --> 99:59:59.999 So let's start with our first study, 99:59:59.999 --> 99:59:59.999 our first fMRI study with psilocybin. 99:59:59.999 --> 99:59:59.999 This used the modality referred to as 99:59:59.999 --> 99:59:59.999 arterial spin labelling, which is 99:59:59.999 --> 99:59:59.999 a method which measures changes 99:59:59.999 --> 99:59:59.999 in blood flow in the brain. 99:59:59.999 --> 99:59:59.999 And generally there's quite a reliable relationship 99:59:59.999 --> 99:59:59.999 between blood flow in the brain and brain activity. 99:59:59.999 --> 99:59:59.999 So if blood flow increases, 99:59:59.999 --> 99:59:59.999 we generally infer 99:59:59.999 --> 99:59:59.999 that brain activity has increased. 99:59:59.999 --> 99:59:59.999 So this study had fifteen healthy volunteers, 99:59:59.999 --> 99:59:59.999 mean age of 34, 99:59:59.999 --> 99:59:59.999 the scans were 18 minutes in duration, 99:59:59.999 --> 99:59:59.999 there was a six-minute baseline, 99:59:59.999 --> 99:59:59.999 and then we looked at changes in blood flow 99:59:59.999 --> 99:59:59.999 after that baseline. 99:59:59.999 --> 99:59:59.999 There were two scans: 99:59:59.999 --> 99:59:59.999 a placebo scan followed by a drug scan. 99:59:59.999 --> 99:59:59.999 And volunteers just lay in the scanner. 99:59:59.999 --> 99:59:59.999 They were presented with a fixation cross: 99:59:59.999 --> 99:59:59.999 just a simple green cross that they looked at 99:59:59.999 --> 99:59:59.999 on a screen, and they just relaxed 99:59:59.999 --> 99:59:59.999 and were instructed really just to let their minds wander. 99:59:59.999 --> 99:59:59.999 And then we looked at how 99:59:59.999 --> 99:59:59.999 the drug affected blood flow 99:59:59.999 --> 99:59:59.999 during these conditions. 99:59:59.999 --> 99:59:59.999 We gave a dose of 2 mg of psilocybin-- 99:59:59.999 --> 99:59:59.999 that compares to about 50 mg when given orally. 99:59:59.999 --> 99:59:59.999 We gave the drug intravenously, 99:59:59.999 --> 99:59:59.999 so 2 mg is equivalent to about 50 mg orally, 99:59:59.999 --> 99:59:59.999 so it's a moderate dose. 99:59:59.999 --> 99:59:59.999 Here's the design. Here's our 6-minute baseline. 99:59:59.999 --> 99:59:59.999 Infusion was given over 60 seconds. 99:59:59.999 --> 99:59:59.999 So it's a relatively rapid infusion. 99:59:59.999 --> 99:59:59.999 And then the onset of the effects is also rapid, 99:59:59.999 --> 99:59:59.999 so when the drug is given intravenously, 99:59:59.999 --> 99:59:59.999 really there is very little delay between 99:59:59.999 --> 99:59:59.999 delivery of the drug and the onset 99:59:59.999 --> 99:59:59.999 of the subjective effects. 99:59:59.999 --> 99:59:59.999 So the subjective effects actually begin, 99:59:59.999 --> 99:59:59.999 really, before the end of the 60-second adminstration, 99:59:59.999 --> 99:59:59.999 so the drug seems to really get in the brain 99:59:59.999 --> 99:59:59.999 very quickly and to change consciousness NOTE Paragraph 99:59:59.999 --> 99:59:59.999 profoundly very quickly. 99:59:59.999 --> 99:59:59.999 So what was the first observation? 99:59:59.999 --> 99:59:59.999 Well, the first thing that we get 99:59:59.999 --> 99:59:59.999 before we analyze the results are people's 99:59:59.999 --> 99:59:59.999 descriptions of their experiences. 99:59:59.999 --> 99:59:59.999 So here's one of them: 99:59:59.999 --> 99:59:59.999 This volunteer said that "there was a definite 99:59:59.999 --> 99:59:59.999 sense of lubrication, 99:59:59.999 --> 99:59:59.999 of freedom, 99:59:59.999 --> 99:59:59.999 of the cogs being loosened and firing off 99:59:59.999 --> 99:59:59.999 in all sorts of unexpected directions." 99:59:59.999 --> 99:59:59.999 Now these subjective reports are really useful 99:59:59.999 --> 99:59:59.999 because they give you a sense of the 99:59:59.999 --> 99:59:59.999 mechanics that are going on in the brain, 99:59:59.999 --> 99:59:59.999 and the changes in the mechanics, 99:59:59.999 --> 99:59:59.999 which confer the subjective effect -- 99:59:59.999 --> 99:59:59.999 what's going on in the brain on a mechanical level 99:59:59.999 --> 99:59:59.999 to produce the profound changes in consciousness. 99:59:59.999 --> 99:59:59.999 This volunteer said, "Everything became 99:59:59.999 --> 99:59:59.999 fragmented; things were all in bits 99:59:59.999 --> 99:59:59.999 and it was very hard to hold it all together 99:59:59.999 --> 99:59:59.999 in a coherent stream." 99:59:59.999 --> 99:59:59.999 So it's like I said, this stuff is really useful 99:59:59.999 --> 99:59:59.999 for understanding what is going on 99:59:59.999 --> 99:59:59.999 on a systems-level in the brain 99:59:59.999 --> 99:59:59.999 to produce these subjective effects. 99:59:59.999 --> 99:59:59.999 Now, the default mode network 99:59:59.999 --> 99:59:59.999 you've heard quite a lot about 99:59:59.999 --> 99:59:59.999 over the last two days. 99:59:59.999 --> 99:59:59.999 It is an incredibly important 99:59:59.999 --> 99:59:59.999 system that's been discovered in the brain. 99:59:59.999 --> 99:59:59.999 And one of its properties is that 99:59:59.999 --> 99:59:59.999 it has very dense connectivity, 99:59:59.999 --> 99:59:59.999 so if you look at the white matter 99:59:59.999 --> 99:59:59.999 tracks in the brain, 99:59:59.999 --> 99:59:59.999 so these are the fibers that connect 99:59:59.999 --> 99:59:59.999 different brain regions, 99:59:59.999 --> 99:59:59.999 then you'll find that there's a very dense 99:59:59.999 --> 99:59:59.999 coming together of connections within 99:59:59.999 --> 99:59:59.999 the default mode notwork. 99:59:59.999 --> 99:59:59.999 So there seems to be 99:59:59.999 --> 99:59:59.999 an incredibly important transit hub, 99:59:59.999 --> 99:59:59.999 a place where different regions 99:59:59.999 --> 99:59:59.999 can connect via, 99:59:59.999 --> 99:59:59.999 and information can be projected from, 99:59:59.999 --> 99:59:59.999 and also a very important integration center. 99:59:59.999 --> 99:59:59.999 So, to integrate brain function, 99:59:59.999 --> 99:59:59.999 information comes together at this common 99:59:59.999 --> 99:59:59.999 convergence zone, and then 99:59:59.999 --> 99:59:59.999 that gives a coherence to cognition, essentially. 99:59:59.999 --> 99:59:59.999 That's how it's understood so far. 99:59:59.999 --> 99:59:59.999 What else about the default mode network? 99:59:59.999 --> 99:59:59.999 So here's a metaphor to help you try and understand 99:59:59.999 --> 99:59:59.999 what people are thinking about its function. 99:59:59.999 --> 99:59:59.999 So a metaphor that could be used to explain 99:59:59.999 --> 99:59:59.999 what it does is a capital city in a country. 99:59:59.999 --> 99:59:59.999 It's a place where people come together, 99:59:59.999 --> 99:59:59.999 things come together, 99:59:59.999 --> 99:59:59.999 business gets done. 99:59:59.999 --> 99:59:59.999 And it's an incredibly important hub, 99:59:59.999 --> 99:59:59.999 and if ever 99:59:59.999 --> 99:59:59.999 God forbid, something were to happen to 99:59:59.999 --> 99:59:59.999 London, then, the country as a whole 99:59:59.999 --> 99:59:59.999 would be seriously effected, 99:59:59.999 --> 99:59:59.999 and not just Britain. 99:59:59.999 --> 99:59:59.999 So it's incredibly important 99:59:59.999 --> 99:59:59.999 integration hub, the default mode network. 99:59:59.999 --> 99:59:59.999 What else do we know about 99:59:59.999 --> 99:59:59.999 the default mode network? 99:59:59.999 --> 99:59:59.999 There's some evidences here. 99:59:59.999 --> 99:59:59.999 The default mode network undergoes 99:59:59.999 --> 99:59:59.999 significant ontogenetic development 99:59:59.999 --> 99:59:59.999 from infancy to adulthood. 99:59:59.999 --> 99:59:59.999 It undergoes maturation as cognition matures. 99:59:59.999 --> 99:59:59.999 It has also undergone significant 99:59:59.999 --> 99:59:59.999 evolutionary expansion 99:59:59.999 --> 99:59:59.999 so these regions have increased 99:59:59.999 --> 99:59:59.999 more than other regions 99:59:59.999 --> 99:59:59.999 from primates to humans. 99:59:59.999 --> 99:59:59.999 It's more metabolically active 99:59:59.999 --> 99:59:59.999 than elsewhere in the brain, 99:59:59.999 --> 99:59:59.999 so the posterior cingulate cortex, 99:59:59.999 --> 99:59:59.999 which is the region which is circled there, 99:59:59.999 --> 99:59:59.999 it actually accounts for 40% more 99:59:59.999 --> 99:59:59.999 blood flow than anywhere else 99:59:59.999 --> 99:59:59.999 in the brain. 99:59:59.999 --> 99:59:59.999 So it is a very metabolically hungry system 99:59:59.999 --> 99:59:59.999 and these regions that are part of it 99:59:59.999 --> 99:59:59.999 are incredibly metabolically hungry. 99:59:59.999 --> 99:59:59.999 It's doing something important. 99:59:59.999 --> 99:59:59.999 Now, a matter of intrigue in neuroscience 99:59:59.999 --> 99:59:59.999 is that people don't have a really good handle 99:59:59.999 --> 99:59:59.999 on what the default mode is 99:59:59.999 --> 99:59:59.999 and what it does, 99:59:59.999 --> 99:59:59.999 but of course, they enjoy speculating, 99:59:59.999 --> 99:59:59.999 and the researcher who really discovered 99:59:59.999 --> 99:59:59.999 the default mode network has referred 99:59:59.999 --> 99:59:59.999 to its very high energy levels 99:59:59.999 --> 99:59:59.999 as being like the brain's dark energy. 99:59:59.999 --> 99:59:59.999 So similar to dark energy in cosmology 99:59:59.999 --> 99:59:59.999 it is something that we know is there 99:59:59.999 --> 99:59:59.999 but we don't really know what it does. 99:59:59.999 --> 99:59:59.999 Really, we make inferences about it, 99:59:59.999 --> 99:59:59.999 based on its relative decrease in activity. 99:59:59.999 --> 99:59:59.999 So when you engage in a task, 99:59:59.999 --> 99:59:59.999 you see a decrease in activity 99:59:59.999 --> 99:59:59.999 in the default mode network, 99:59:59.999 --> 99:59:59.999 whereas otherwise 99:59:59.999 --> 99:59:59.999 it is incredibly active. 99:59:59.999 --> 99:59:59.999 So it's a mater of intrigue. 99:59:59.999 --> 99:59:59.999 What's going on here? 99:59:59.999 --> 99:59:59.999 What's all this energy for, and why 99:59:59.999 --> 99:59:59.999 is it consuming so much? 99:59:59.999 --> 99:59:59.999 We know that the default mode network 99:59:59.999 --> 99:59:59.999 is engaged during self-reflection, 99:59:59.999 --> 99:59:59.999 so that is a very staple finding. 99:59:59.999 --> 99:59:59.999 We also know that during 99:59:59.999 --> 99:59:59.999 complex mental imagery, such as 99:59:59.999 --> 99:59:59.999 spatial navigation or imagination, 99:59:59.999 --> 99:59:59.999 fantasy in one's mind eye, 99:59:59.999 --> 99:59:59.999 you'll also see increased activity 99:59:59.999 --> 99:59:59.999 in the default mode network. 99:59:59.999 --> 99:59:59.999 Mental time travel -- so that's being 99:59:59.999 --> 99:59:59.999 outside of the moment and 99:59:59.999 --> 99:59:59.999 daydreaming about future events 99:59:59.999 --> 99:59:59.999 or past biographical experiences. 99:59:59.999 --> 99:59:59.999 So whenever you come out of the moment 99:59:59.999 --> 99:59:59.999 and you daydream in this way, 99:59:59.999 --> 99:59:59.999 you see increased activity and connectivity 99:59:59.999 --> 99:59:59.999 in the default mode network. 99:59:59.999 --> 99:59:59.999 Also, theory of mind -- which is 99:59:59.999 --> 99:59:59.999 putting someone oneself 99:59:59.999 --> 99:59:59.999 in somebody else's shoes. 99:59:59.999 --> 99:59:59.999 You will also see increased activity 99:59:59.999 --> 99:59:59.999 in the default mode network during that function. 99:59:59.999 --> 99:59:59.999 And metacognition -- which thinking about thinking, 99:59:59.999 --> 99:59:59.999 that's also linked with 99:59:59.999 --> 99:59:59.999 default mode network activity. 99:59:59.999 --> 99:59:59.999 So Raichle, who I said is the guy who 99:59:59.999 --> 99:59:59.999 really discovered this network 99:59:59.999 --> 99:59:59.999 has also referred to it as 99:59:59.999 --> 99:59:59.999 the orchestrator of the self. 99:59:59.999 --> 99:59:59.999 So all these things 99:59:59.999 --> 99:59:59.999 led me to start thinking 99:59:59.999 --> 99:59:59.999 having a background in psychoanalysis 99:59:59.999 --> 99:59:59.999 and being interested in 99:59:59.999 --> 99:59:59.999 especially Freudian metapsychology 99:59:59.999 --> 99:59:59.999 instead of the more mechanistic 99:59:59.999 --> 99:59:59.999 ideas of Freud. There is remarkable overlap 99:59:59.999 --> 99:59:59.999 between his descriptions of the ego 99:59:59.999 --> 99:59:59.999 and the relationship between the ego 99:59:59.999 --> 99:59:59.999 and the unconscious mind, or the id, 99:59:59.999 --> 99:59:59.999 and what we're discovering in 99:59:59.999 --> 99:59:59.999 the default mode network. 99:59:59.999 --> 99:59:59.999 So in this paper, with Carhart-Harris & Friston, 99:59:59.999 --> 99:59:59.999 I submitted the idea that 99:59:59.999 --> 99:59:59.999 the default mode network is essentially 99:59:59.999 --> 99:59:59.999 the neural substrate source of the ego, 99:59:59.999 --> 99:59:59.999 which is an idea to be shot down 99:59:59.999 --> 99:59:59.999 if people find otherwise. 99:59:59.999 --> 99:59:59.999 But that's science. That's how we work. 99:59:59.999 --> 99:59:59.999 So what else is there about 99:59:59.999 --> 99:59:59.999 the default mode network? 99:59:59.999 --> 99:59:59.999 Well, what's it's relationship to depression? 99:59:59.999 --> 99:59:59.999 There's a very interesting relationship 99:59:59.999 --> 99:59:59.999 between default mode network parameters 99:59:59.999 --> 99:59:59.999 and depressive symptomatology. 99:59:59.999 --> 99:59:59.999 So we know that connectivity between 99:59:59.999 --> 99:59:59.999 the medial pre-frontal cortex 99:59:59.999 --> 99:59:59.999 of the default mode network 99:59:59.999 --> 99:59:59.999 and the posterior cingulate cortex 99:59:59.999 --> 99:59:59.999 which are 99:59:59.999 --> 99:59:59.999 (pause) 99:59:59.999 --> 99:59:59.999 the front bits and the back bits. 99:59:59.999 --> 99:59:59.999 So when connectivity between these regions 99:59:59.999 --> 99:59:59.999 is high, 99:59:59.999 --> 99:59:59.999 then scores in patients with depression 99:59:59.999 --> 99:59:59.999 on rumination (so these are scores in rumination. 99:59:59.999 --> 99:59:59.999 They are thinking over problems 99:59:59.999 --> 99:59:59.999 and ruminating on negative things), 99:59:59.999 --> 99:59:59.999 when this is high, connectivity 99:59:59.999 --> 99:59:59.999 betwen these regions is especially 99:59:59.999 --> 99:59:59.999 high. And we think this system, 99:59:59.999 --> 99:59:59.999 this overconnectivity, is really causing people to 99:59:59.999 --> 99:59:59.999 have a kind of stereotype style of thinking. 99:59:59.999 --> 99:59:59.999 So they are stuck in this system, 99:59:59.999 --> 99:59:59.999 they are stuck in their own heads, 99:59:59.999 --> 99:59:59.999 they are stuck on their sense of self. 99:59:59.999 --> 99:59:59.999 They are usually thinking very critically 99:59:59.999 --> 99:59:59.999 about themselves, and going over and over 99:59:59.999 --> 99:59:59.999 about how terrible they are. 99:59:59.999 --> 99:59:59.999 So this is a relationship we seem to be discovering 99:59:59.999 --> 99:59:59.999 about the default mode network 99:59:59.999 --> 99:59:59.999 and depressive symptomatology. 99:59:59.999 --> 99:59:59.999 This provides a useful background 99:59:59.999 --> 99:59:59.999 for what we're finding in terms of how 99:59:59.999 --> 99:59:59.999 psilocybin is affecting 99:59:59.999 --> 99:59:59.999 brain networks and brain systems. 99:59:59.999 --> 99:59:59.999 So in our ASL study, we found 99:59:59.999 --> 99:59:59.999 it was really quite surprising findings for us, 99:59:59.999 --> 99:59:59.999 given descriptions of consciousness 99:59:59.999 --> 99:59:59.999 being expanded by psychedelic drugs. 99:59:59.999 --> 99:59:59.999 We are given some previous work, 99:59:59.999 --> 99:59:59.999 for instance, by Franz Vollenweider, 99:59:59.999 --> 99:59:59.999 we were thinking we were going to be seeing 99:59:59.999 --> 99:59:59.999 increases in brain activity or brain blood flow 99:59:59.999 --> 99:59:59.999 with psilocybin. 99:59:59.999 --> 99:59:59.999 And despite dropping the threshold 99:59:59.999 --> 99:59:59.999 and a number of different things, 99:59:59.999 --> 99:59:59.999 we really didn't see this. 99:59:59.999 --> 99:59:59.999 All we were really seeing was 99:59:59.999 --> 99:59:59.999 the same pattern again and again, 99:59:59.999 --> 99:59:59.999 which was decreased blood flow 99:59:59.999 --> 99:59:59.999 in certain regions of the brain. 99:59:59.999 --> 99:59:59.999 What was intriguing was that 99:59:59.999 --> 99:59:59.999 the decreases that we were seeing were 99:59:59.999 --> 99:59:59.999 in these very same important hub strutures 99:59:59.999 --> 99:59:59.999 of the brain. 99:59:59.999 --> 99:59:59.999 So, for instance, the posterior cingulate cortex, 99:59:59.999 --> 99:59:59.999 this bit at the back, 99:59:59.999 --> 99:59:59.999 the thalamus, 99:59:59.999 --> 99:59:59.999 and the medial pre-frontal cortex -- 99:59:59.999 --> 99:59:59.999 so these very reliably 99:59:59.999 --> 99:59:59.999 were coming up as being 99:59:59.999 --> 99:59:59.999 decreased under psilocybin. 99:59:59.999 --> 99:59:59.999 Here's just showing you again, 99:59:59.999 --> 99:59:59.999 the default mode network is this kind of 99:59:59.999 --> 99:59:59.999 hub, this connectivity hub, in the brain. 99:59:59.999 --> 99:59:59.999 We also found that 99:59:59.999 --> 99:59:59.999 there was a relationship between 99:59:59.999 --> 99:59:59.999 the magnitude of the decrease in blood flow 99:59:59.999 --> 99:59:59.999 and ratings of the intensity of the experience. 99:59:59.999 --> 99:59:59.999 So, the larger the decrease in blood flow, 99:59:59.999 --> 99:59:59.999 particularly in the anterior cingulate cortex, 99:59:59.999 --> 99:59:59.999 the more intense people were describing 99:59:59.999 --> 99:59:59.999 their experiences. 99:59:59.999 --> 99:59:59.999 So whenever you find these relationships 99:59:59.999 --> 99:59:59.999 it kind of reinforces your inferences, really, 99:59:59.999 --> 99:59:59.999 and provides some consolidation 99:59:59.999 --> 99:59:59.999 for what you are finding 99:59:59.999 --> 99:59:59.999 and supports its functional meaning. 99:59:59.999 --> 99:59:59.999 So since our ASL study 99:59:59.999 --> 99:59:59.999 we did a [bold] study. 99:59:59.999 --> 99:59:59.999 This is kind of the classic [signal] 99:59:59.999 --> 99:59:59.999 of functional magnetic resonance imaging (fMRI). 99:59:59.999 --> 99:59:59.999 We really repeated the same protocol: 99:59:59.999 --> 99:59:59.999 15 healthy volunteers, 99:59:59.999 --> 99:59:59.999 infused with a drug over 60 seconds at 2 mg, 99:59:59.999 --> 99:59:59.999 and we found exactly the same thing. 99:59:59.999 --> 99:59:59.999 So this was really nice reinforcement 99:59:59.999 --> 99:59:59.999 for the initial finding that we had found 99:59:59.999 --> 99:59:59.999 with ASL. 99:59:59.999 --> 99:59:59.999 And these regions where there was a common 99:59:59.999 --> 99:59:59.999 overlap between the decreases in blood flow 99:59:59.999 --> 99:59:59.999 with ASL and the decreases in, 99:59:59.999 --> 99:59:59.999 essentially venous oxygenation, 99:59:59.999 --> 99:59:59.999 or oxygenated blood with the BOLD signal 99:59:59.999 --> 99:59:59.999 of fMRI. 99:59:59.999 --> 99:59:59.999 So one of the merits of BOLD fMRI is 99:59:59.999 --> 99:59:59.999 that it allows you to do these 99:59:59.999 --> 99:59:59.999 functional connectivity analyses. 99:59:59.999 --> 99:59:59.999 So just to give you a feel for what that is, 99:59:59.999 --> 99:59:59.999 here is an image which shows 99:59:59.999 --> 99:59:59.999 the default mode network in orange 99:59:59.999 --> 99:59:59.999 and let's concentrate on the default 99:59:59.999 --> 99:59:59.999 mode network for a moment. 99:59:59.999 --> 99:59:59.999 So you can see that there are two regions in it, 99:59:59.999 --> 99:59:59.999 and there is one that has has yellow text, 99:59:59.999 --> 99:59:59.999 the PCC? and then you can see there is this 99:59:59.999 --> 99:59:59.999 time series underneath. 99:59:59.999 --> 99:59:59.999 So the PCC time series is in yellow 99:59:59.999 --> 99:59:59.999 and you can see that it overlaps with NOTE Paragraph 99:59:59.999 --> 99:59:59.999 anothertime series, and that is 99:59:59.999 --> 99:59:59.999 the medial prefontal cortex. 99:59:59.999 --> 99:59:59.999 So it is by looking at correlations between 99:59:59.999 --> 99:59:59.999 fluctuations in the BOLD signal 99:59:59.999 --> 99:59:59.999 that we identify functionally coherent 99:59:59.999 --> 99:59:59.999 brain networks. We know these regions 99:59:59.999 --> 99:59:59.999 work together as a common network 99:59:59.999 --> 99:59:59.999 doing a common function.